GLOBAL HEALTH CASE STUDY ANALYSIS

GLOBAL HEALTH CASE STUDY ANALYSIS

GOAL: To analyze a model case study published in “Case Studies for Global Health: Building Relationships, Sharing Knowledge.”
CASE STUDY ANALYSIS OVERVIEW:
The Bill & Melinda Gates Foundation, the World Health Organization, Global Health Progress (GHP), International AIDS Vaccine Initiative (IAVI) and the Association of University Technology Managers (AUTM) published a set of thirty-three (33) multi-sector case studies to identify ways in which key stakeholders are addressing global health concerns. These case studies briefly describe existing or planned collaborative relationships, projects and transactions with the aim of sharing lessons learned with the wider global health community. They cover the spectrum of global health work including research, development, delivery, and financing mechanisms. ASSIGNMENT INSTRUCTIONS To complete this case study analysis, do the following:
1
ACCESS…
…the “Case Studies for Global Health,” posted as a .PDF file under the Assignment 14 tab on Blackboard.
2
READ…
…through the table of contents on page 7 of the .PDF document.
3
SELECT…
…a case study from the booklet to analyze. You may choose a case study based on a health topic of interest to you, or based on an area of the world of interest to you. Read your chosen case study thoroughly.
4
WRITE…
…a 4-5-page paper about your case study (1000-1250) words, providing a critical analysis of the case study based on what you have learned in class. You should make comparisons between information learned in class & issues discussed in the case study, drawing conclusions about the majors lessons learned from the case study. Your paper should:
• …have a well-written introduction and conclusion which clearly identifies which case study you selected.
• …use specific examples, be thorough, be clear, and provide plenty of detail.
• …frequently make reference to terminology introduced in the weekly course lectures.
• …NOT be a repetition of what is written in the case study. I have read them already; you do not need to tell me what they are about. You do need to tell me how they are related to what you learned in class, and to global health in general.
• The grading rubric on the next page will be used to evaluate this assignment.
5
SUBMIT…
…your completed paper via Blackboard before 11:59 pm on the due date listed in the course schedule found in this syllabus. DO NOT send this paper as an attachment.
• Make certain that this assignment complies with the Requirements for the Submission of Written Work listed in this syllabus.
GRADING RUBRIC FOR CASE STUDY ANALYSIS
PBHL 3110
Qualities & Criteria
Poor (0-76)
Good (77-89)
Excellent (90-100)
Organization of Assignment
(15% of grade)
• Presentation and structuring of the text as indicated in the assignment instructions
• Organization and coherence of ideas, including introduction/concluding paragraphs, when indicated
• Clarity of sentences and paragraphs
• Length (1000-1250 words)
Follows poorly the requirements related to presentation of the text. The assignment is badly organized, lacks clarity and/or does not present ideas in a coherent way. Unacceptable length.
Follows, for the most part, all the requirements related to presentation of the text. Some requirements are not followed. The assignment is for the most part well organized, clear and presents ideas in a coherent way. Acceptable length.
Closely follows all the requirements related to presentation of the text. The assignment is well organized, clear and presents ideas in a coherent way. Acceptable length. Content/Information in Assignment (60% of grade) • All elements of the assignment instructions are addressed • Writing is based on careful reading and analysis of the information presented in the case study. • Inclusion of sufficient relevant, specific, and thorough examples from course lecture notes, readings, films, and/or supplemental material to illustrate mastery of the course content as it relates to the chosen case study The assignment addresses poorly the issues/questions referred in the assignment instructions. The provided information is not necessary or not sufficient to discuss these issues. Responses to questions do not include sufficient, &/or relevant &/or specific, &/or thorough examples to support the thesis/opinion. The assignment for the most part addresses with an in depth analysis most of the issues/questions referred in the assignment instructions. The provided information is, for the most part, necessary and sufficient to discuss these issues. Responses to questions for the most part include sufficient, &/or relevant &/or specific, &/or thorough examples to support the thesis/opinion. The assignment addresses with an in depth analysis all the issues/questions referred in the assignment instructions. The provided information is necessary and sufficient to discuss these issues. Responses to questions include numerous relevant &/or specific, &/or thorough examples to support the thesis/opinion.
Quality of Writing
(25% of grade)
• No errors and spelling, grammar and use of English
The assignment is not well written, and contains many spelling errors, and/or grammar errors and/or use of English errors.
The assignment is well written for the most part, without spelling, grammar or use of English errors.
The assignment is well written from start to finish, without spelling, grammar or use of English errors. Overriding criteria: • 0riginality and authenticity. If the assignment is identified as not being original, and/or not done by the student, the instructor has the right to grade the assignment as an F. • Requirements for the Submission of Written Work: Additional points will be deducted for not following the instructions listed in the syllabus.

Case Studies for Global Health
Building relationships. Sharing knowledge.
®
www.casestudiesforglobalhealth.org
Alliance for Case Studies for Global Health
Case Studies for Global Health
Building relationships. Sharing knowledge.
Case Studies for Global Health
Case Studies for Global Health: Building relationships. Sharing knowledge.
ISBN #0-9778444-8-X
Copyright ©2009 by the Alliance for Case Studies for Global Health
The logos of the Bill & Melinda Gates Foundation, International AIDS Vaccine Institute (IAVI), Association of University Technology
Managers (AUTM), Global Health Progress and TDR are the trademark of the respective organizations.
All rights reserved. This material may be quoted or reproduced without charge for noncommercial purposes only; please acknowledge
source. This publication does not imply endorsement by the Alliance for Case Studies for Global Health of any product or service, nor any
organization, corporation or institution.
Case Studies for Global Health is available in electronic format and limited print copies are available. You may download a copy of the book
or individual case studies at: www.casestudiesforglobalhealth.org.
All other inquiries:
Managing Editor
Alliance for Case Studies for Global Health
111 Deer Lake Road, Suite 100
Deerfield, IL 60015 USA
Web site: www.casestudiesforglobalhealth.org E-mail: info@casestudiesforglobalhealth.org
Printed in the USA on FSC-certified paper.
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(As of October 2009)
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This publication is an initiative of the Alliance for Case Studies
for Global Health, a collaboration of the Association of University
Technology Managers (AUTM), the Bill & Melinda Gates
Foundation, Global Health Progress, the International AIDS
Vaccine Initiative (IAVI) and Tropical Disease Research (TDR).
The alliance members conceived of this multisector case study
initiative in December 2007. Over the following nine months,
representatives from each organization shaped our vision of the
scope and nature of this publication. We rested on the following
objectives for the case studies:
• They would be solicited from a wide range of stakeholders
within global health (e.g., private funders, multilateral
organizations, academia, pharmaceutical and biotech companies,
product development partnerships, and governments) and
reflect current transactions and relationships.
• They would illustrate how people, organizations, companies
and governments have worked together to try to solve a
global health challenge. The wide range of potential topics
would include the complexity of intellectual property,
length and stage of product development, costs and nature
of manufacturing, purchasers and markets, financing
mechanisms, regulatory issues, capacity building, delivery
mechanisms, and adoption hurdles.
• They would provide information on current practices and
lessons learned in the course of conducting business and
structuring partnerships.
We reached out to many universities, organizations, companies
and governments to identify potential case studies. To capture as
many diverse stories as possible, we published a call for case studies
in various newsletters, journals and on Web sites during the fall
of 2008, which generated considerable interest and a significant
number of submissions.
In February 2009, we established a selection committee made
up of representatives from the five Alliance members, along with
a representative of BIO Ventures for Global Health and several
global health experts from Africa and India. The members of
the committee selected a total of 32 case studies based on their
adherence to the core themes, framework and objectives of the
initiative.
During the following months, the case studies were developed
and written with the help of many individuals and organizations,
including those involved in each partnership; this book would not
have been possible without them taking the time to share their
experiences, challenges and successes.
The result is the set of stories contained in this publication, which
represent a wide range of stakeholders, activities and approaches.
We would like to acknowledge the following organizations and
individuals for their many hours of hard work and dedication.
Methods and Acknowledgement
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Association of University Technology Managers (AUTM) –
Vicki Loise, Executive Director; Jon Soderstrom, Ph.D.,
Immediate Past President: AUTM is a global network of
more than 3,500 technology transfer professionals who work
in academic, research, government, legal and commercial
settings. AUTM is dedicated to promoting and supporting
technology transfer through education, advocacy, networking and
communication.
Bill & Melinda Gates Foundation – Erik Iverson, Associate
General Counsel, Global Health Program; Jennifer Haberman,
Paralegal, Global Health Program: Guided by the belief that
every life has equal value, the Bill & Melinda Gates Foundation
works to help all people lead healthy, productive lives. In
developing countries, it focuses on improving people’s health
and giving them the chance to lift themselves out of hunger and
extreme poverty. In the United States, it seeks to ensure that all
people — especially those with the fewest resources — have access
to the opportunities they need to succeed in school and life.
Global Health Progress – Paul Antony, M.D., M.P.H., Executive
Director (GHP) and Chief Medical Officer, Pharmaceutical
Research and Manufacturers of America (PhRMA); Mark
Grayson, Deputy Vice President, Communications &
Public Affairs (PhRMA); Stephen Sobhani, Senior Director,
International Alliance Development (PhRMA); Margaret
Wu, Senior Associate (APCO Worldwide): The Global Health
Progress initiative brings together research-based biopharmaceutical
companies and global health leaders to improve health in the
developing world. The initiative provides a platform for researchbased
biopharmaceutical companies, governments, public health
leaders, universities, foundations, and other stakeholders to share
experiences and best practices and to forge new partnerships.
International AIDS Vaccine Initiative (IAVI) – Labeeb
Abboud, Senior Vice President & General Counsel: IAVI is an
international not-for-profit organization whose mission is to ensure
the development of safe, effective, accessible prophylactic AIDS
vaccines for use throughout the world. IAVI is headquartered in the
United States, with regional offices in Amsterdam, Delhi, Nairobi
and Johannesburg, and operates in 25 countries. IAVI works in
partnership with governments, civil society, academic institutions
and industry in its research and development, advocacy and policy
activities.
Special Programme for Research and Training in Tropical
Diseases (TDR) – Solomon Nwaka, Leader, Drug Discovery
for Infectious Tropical Diseases and Innovation for Product
Development in Developing Countries: TDR is an independent
global program of scientific collaboration that helps coordinate,
support and influence global efforts to combat a portfolio of major
diseases of the poor and disadvantaged. TDR is administered by
the World Health Organization, and co-sponsored by the United
Nations Children’s Fund, the United Nations Development
Programme, the World Bank and the World Health Organization.
MANAGING EDITOR
Jill Hronek, The Sherwood Group, Inc.
GRAPHIC DESIGN
Shirley Soda Opasinski, The Sherwood Group, Inc.
AUTHORS
Pam Baker
David Gilden
Unmesh Kher
Ashley Mastandrea
John Otrompke, J.D.
David Perilstein
Contributing Individuals and Organizations
Uche Amizago
Priya Mehta
Carl Montague
Samlee Plianbangchang
Wendy Taylor
BIO Ventures for Global Health (BVGH)
Organizations Within the
Alliance for Case Studies for Global Health
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Methods and Acknowledgements……………………………. 5
Organizations Within the Alliance for
Case Studies for Global Health……………………………….. 6
Foreword…………………………………………………………………….. 9
Access
A Marriage of Divergent Interests: Partnerships in the
Making of the World’s First Advance Market Commitment……. 10
Vaccine Vial Monitors:
Small Labels With an Immense Impact……………………………….. 16
Growing Network Extends HIV Treatment to
Children in Developing Countries……………………………………… 22
Saving Uzbek Hearts:
A Program for Best Practices in Controlling Hyperlipidemia…… 30
MAP’s Globetrotting Travel Pack Program
Meets a Universal Need…………………………………………………….. 36
Global Interagency Efforts Stem
Counterfeit Drugs in Greater Mekong Asia………………………….. 42
Discovery/Development
Breaking Down the Barriers to Sharing Knowledge……………….. 50
HIV Vaccine Trial Centers Forge Research Network in
Developing Countries………………………………………………………. 56
Making New Medical Innovations Available in Developing
Countries First, Where They’re Needed Most……………………….. 64
Product Development Partnership Aims to Develop
First Vaccine Against Malaria Parasite………………………………….. 70
Historic Confluence Promotes Malaria Breakthroughs…………… 76
TB Alliance Partnership Charts Course for
Future Neglected Disease Treatments………………………………….. 82
Dengue Fever Partnership Changes the Rules for
Vaccine Development……………………………………………………….. 88
Global Access License Between University and
Biotech Benefits Developed and Developing World……………….. 94
New Broad-Spectrum Vaccine Protects Against Most
Pneumococcal Disease………………………………………………………100
A Glaucoma Treatment Option With Global Promise……………106
The Africa Biofortified Sorghum Project Consortium:
Food Safety and Fighting Malnutrition in Africa…………………..110
Intervention/Prevention
Lesotho Apparel Industry Unites to Fight AIDS……………………116
Nevirapine Single-Dose Packs Improve Protection from
Mother-to-Child HIV Transmission……………………………………124
NATNETS Succeeds in Controlling Malaria in Tanzania With
Effective Public, Private and Nonprofit Partners……………………130
Nontraditional Global Health Partners Team up to Fight
Malaria in Uganda……………………………………………………………138
Public and Private Partnership Helps to Set the Standard of
Care for Multi-Drug Resistant Tuberculosis…………………………144
Integrating Neglected Tropical Disease Control:
Comparing the Experience in Rwanda and Burundi………………150
Integrating Neglected Tropical Disease Control:
Common Themes in Niger and Zanzibar…………………………….158
Human Hookworm Vaccine Initiative Designs Rapid
Deployment Strategy for Developing World…………………………164
Faster, Better, Cheaper: New Vaccine Promises to
Control Japanese Encephalitis……………………………………………170
Multi-pronged Attack on Cervical Cancer Detection
Seeks to Speed Detection and Treatment in
Resource-Constrained Countries………………………………………..176
Systems Strengthening
Links for Life Integrates Programming for Food Security,
Nutrition and HIV/AIDS…………………………………………………182
The Malawi Project: Global Assistance Initiative to
Combat HIV/AIDS…………………………………………………………188
Standardizing Solutions to Change the Face of
Laboratory Services in Tanzania………………………………………….194
Bringing Modern Medical Science to Mali…………………………..200
Freedom of Breath, Foundation of Life:
China’s Neonatal Resuscitation Program……………………………..206
Table of Contents
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“If you want to go fast, go alone.
If you want to go far, go together.”
(African proverb)
In recent decades there has been monumental progress in
addressing the challenges of global health. More public and private
money than ever is targeting the diseases of the poor. New drugs,
vaccines and other tools are in development or in the field. Systems
for delivering health care are improving. In 1960, 20 million
children under age five needlessly died from preventable diseases.
Today, that number is less than nine million. Much more needs to
be done, of course. But without a doubt, nothing can be achieved
without the partnerships and collaborations that are crucial to
enacting meaningful and lasting change.
The stories presented in the Case Studies for Global Health provide
an inside look at the ways in which partners have addressed the
complex challenges of developing and delivering effective health
care for the developing world. They illustrate the ways various
stakeholders — private funders, world health agencies, academics,
pharmaceutical and biotechnology companies, public-private
partnerships, and governments — have come together for a
common purpose. As these relationships are formed and disbanded,
programs initiated and completed, and information gathered and
assimilated, we can all benefit from the lessons learned.
We hope this publication will serve as a guide to the broad range of
stakeholders who have voiced an interest in understanding how to
efficiently build and manage technologies and partnerships. These
case studies focus on the underlying relationships and transactions
that drive each project. They assess the people and organizations
required, how and when these relationships were formed, the
respective roles of the participants, the hurdles in bringing them
together, and the time and other resources required to make the
project happen. Some are success stories. Some are not. Most are
works in progress. But in every case, these are frank and honest
assessments of what was learned along the way.
The case studies are divided into four categories — access to
medicines and health services, discovery and development of new
drugs and vaccines, health intervention and prevention programs,
and health systems strengthening and capacity building. You will
read examples of how partnerships and collaborations accelerate
efforts to fight well-known diseases such as HIV, tuberculosis and
malaria, as well as lesser-known diseases such as dengue fever,
hookworm and Japanese encephalitis. The examples provide lessons
in how organizations can work together to build networks and
capacity, localize training of medical personnel and foster novel
research approaches.
In the process of collecting concrete examples of how global health
problems can be addressed, some common themes emerged.
For example, the success of a program can often be linked to
traits such as early engagement of partners and policy-makers,
open and frequent stakeholder communication and community
empowerment. Yet most of the case studies do not fit neatly into
one of the four categories. Each case begins by citing the lessons
learned to underscore the fact that every situation presents its own
set of challenges and that there is no single approach that will
ensure success. As you read through these stories, you will see that
the parties involved learned through trial and error and built upon
previous successes and failures.
We would like to recognize the impressive efforts that have
previously addressed the demand for case studies, including the
Center for Global Development’s Case Studies in Global Health:
Millions Saved, AUTM’s Better World Report, BIO Ventures for
Global Health’s Global Health Innovators: A Collection of Case
Studies and others. Our hope is that this publication complements
these efforts by presenting the stories from a slightly different angle.
We came together to achieve a common goal, which we feel is
critically important to shaping the way we and our contemporaries
construct programs to address global health issues in the future.
Our collective effort created a publication that is broader in scope
and more comprehensive and insightful than any of us could have
produced on our own.
Most important, however, is the remarkable and critically
important work of the governments, organizations, companies and
individuals highlighted in this publication. The outcomes of their
work, and their desire to collaborate and form partnerships, provide
valuable lessons and insight. We hope our readers will discover
useful approaches and tools for addressing the challenges of global
health — and some inspiration along the way.
Foreword
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A Marriage of Divergent Interests:
Partnership in the Making of the
World’s First Advance Market
Commitment
Lessons Learned:
• The heart of an Advance Market Commitment is that it is
a multi-sector effort to build financing mechanisms as an
incentive to facilitate vaccine development.
• Technical, financial and scientific issues associated with the
AMC require the coordination of a wide range of subject
matter experts.
• Being flexible and willing to revise your approach when new
facts emerge or conditions change is critical.
• Being proactive is essential. Provide opportunities for
continuous communication among all partners and
stakeholders, identify those who can provide constructive
suggestions and ensure they’re heard by the policy-makers.
• Pricing is likely to be a key driver. Be reasonably certain
that parties have consensus on timing and mechanisms for
determining pricing.
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Vaccination remains the most cost-effective intervention
available to modern medicine. It has arguably done
more to improve public health than any measure except
the provision of clean drinking water. Yet some two
million children die each year from diseases for which
vaccines already exist, and millions more lose their lives
to infections against which vaccines could be developed,
but never have been.
There are many reasons for this neglect. One is that the design
and development of vaccines is, in some crucial ways, as much an
industrial art as it is a science. Only a handful of companies have
the know-how required to shepherd a candidate vaccine from its
design stages through clinical assessment and regulatory review
and onto the market. Further, because vaccines are biologics, their
production is a relatively complicated and expensive affair. A single
industrial-scale vaccine plant can cost several hundred million
dollars to build, and its construction must often start three to
four years before the vaccine has even won regulatory approval. It
can, further, take a decade or more before the sizable investments
made in developing and manufacturing vaccines generate the first
trickle of revenue. Given such high risks and steep upfront costs,
manufacturers have long lacked any incentive to invest in vaccines
tailored to meet the needs of developing countries, where few
people could afford them.
This market failure was the focus of a report Italy’s Minister of
Economy and Finance Giulio Tremonti presented to his G7
counterparts on Dec. 2, 2005, in London. The Tremonti report
identified six diseases for which vaccines ought to be developed
and described how a financing mechanism known as the advance
market commitment (AMC) might be used to enable their
development. The AMC, a brainchild of researchers at the Center
for Global Development, Washington D.C., creates an incentive
for manufacturers to invest in vaccines for developing countries by
guaranteeing them, for a defined period, a high price per dose for
vaccines that meet specified criteria. That price, subsidized by donors
supporting the AMC, alleviates some of the risk manufacturers must
take as they expand production capacity. In exchange for this subsidy,
the manufacturers agree to sell the vaccine at or below a preset lower
price (known as the “tail price”) after the donor funds that provided
the initial subsidy have run out.
Enrolled midwife Belita M. Ngoma weighs and
vaccinates baby with mother at Maternal Child
Health unit in Kapiri Mposhi, Zambia.
Photo by Indrias Getachew
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Health worker Elisee Sansa records information
about women and their children at the Barumbu
mother and child center in Kinshasa, Democratic
Republic of the Congo.
Photo by Olivier Asselin
The G7 ministers endorsed the Tremonti report and convened an
expert committee to decide which of six developing world diseases
identified in the report ought to be the focus of a pilot vaccine
AMC. Separate working groups were appointed to build a feasible
technical, institutional and financial framework for the pilot AMC.
The ministers also set in motion a widely inclusive consultation
process to help inform its ultimate structure and vet it with all
stakeholders. The World Bank, which had shepherded the idea
through international summits and conferences since its arrival on
the world stage, led these activities in conjunction with the GAVI
Alliance. The latter has been chosen as the institution that would
house the AMC secretariat and will contribute a vast portion of
the funds for the purchase of vaccines. (See Table I for a list of the
major partners.)
On Feb. 9, 2007, an AMC for a vaccine against pneumococcal
disease — which kills 1.6 million people every year, mainly in
developing countries — was launched with $1.5 billion in funding
from Italy, the United Kingdom, Canada, Russia, Norway and
the Bill & Melinda Gates Foundation. Aside from testing the
practicality of the AMC concept, this pilot is expected to save more
than seven million lives by 2030 and to do so at a cost of $33 per
disability-adjusted life year, a third the accepted benchmark for
health interventions in developing countries.
To qualify for the AMC, a candidate vaccine must target serotypes
1, 5 and 14 of Streptococcus pneumoniae, which are highly prevalent
in Africa and Asia. It must also cover strains responsible for 60
percent or more of serious pneumococcal disease, last at least 24
months on the shelf and be devised for easy delivery via the existing
health systems of developing countries. Companies that meet
these criteria will be able to claim an initial price of $7 per dose of
their vaccine and a tail price of up to $3.50, which represents a 95
percent discount on the price currently charged in industrialized
countries for a similar existing vaccine. Their share of the AMC
funds will be tied directly to the total number of doses they commit
to deliver. (See sidebar.)
Over the past couple of years, the World Bank and GAVI Alliance
have coordinated working groups and held a dizzying array of
consultations with donor nations, developing countries, United
Nations agencies, nongovernmental organizations (NGOs) and
industry to shape the pilot AMC. These meetings helped establish
everything from how the pneumococcal vaccine would be priced
and paid for to the specific requirements it must meet to qualify
for AMC support. This case study examines some of the issues
that arose during the development of this pilot AMC — which
became officially operational in mid-June 2009 — and seeks to
identify lessons that might be learned from the manner in which
they were addressed.
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The Consultations
The tension between human need and corporate profit that
gave birth to the idea of the AMC permeated every aspect of
its subsequent development. It ran like a live wire through the
meetings between government representatives and industry
leaders that took place after G7 summit at Gleneagles, Scotland,
where the idea of the AMC was initially fielded. And it animated
the consultations GAVI and the World Bank team held with
NGOs and industry. Given the controversy associated with any
use of public funds to subsidize drug companies, it was clear
that fundamental decisions about the AMC’s ultimate structure
would have to be arrived at through a transparent process that was
demonstrably independent of political and industrial influence.
The appointment of an independent consultant to draw up the
general structure of the pilot AMC was a good idea, says Susan
McAdams, director of multilateral and innovative financing at the
World Bank, who was involved in the AMC from its earliest days.
It did not, however, protect the pilot program from criticism. Some
NGOs wanted more access to information about things such as
the cost of making vaccines, which are closely held secrets of the
industry. Others wanted the AMC to somehow modify prevailing
intellectual property law. Certain organizations saw no reason
to give pharmaceutical companies public funds to do what they
believed the companies ought to be doing anyway. As far as this
camp was concerned, the very premise of the AMC was flawed.
“Those who are ideologically opposed to market-based solutions
will never accept that anything like the AMC is a good idea,” says
Tania Cernuschi, senior AMC manager at GAVI. “What we tried
to do was to engage those NGOs that had made positive criticisms
and proposals.”
The AMC secretariat took care to brief such critics and see to it
that their concerns were at least heard by the expert committees
charged with writing the details of the AMC. Médecins Sans
Frontières’ (MSF), for instance, had serious concerns about how
the AMC subsidy was structured. In its original form, the AMC
would have permitted a single company to lay claim to the entire
AMC purse. (That risk had not escaped the attention of critics in
academia either.) So GAVI got MSF in touch with the Economic
Expert Group (EEG), which had been appointed after the launch
of the AMC to sort through pricing and design issues. MSF’s
concerns were incorporated into the report ultimately submitted
by the EEG. Subsequently, rules governing how many vaccines a
company can commit to supply under the AMC were modified in
a way that make it impossible for any single firm to monopolize the
entire $1.5 billion fund.
This didn’t exactly make MSF a champion of the AMC; it still
had a list of fundamental criticisms of the scheme. But the
organization was pleased that its concerns had been heard. “It
was very important to engage the MSF,” says Cernuschi. “You
have to be proactive, provide constant briefings to partners.” Such
interactions, she notes, help identify those who are interested
in seeing a proposal succeed and have something of value to
contribute to the problem.
Expert Advice
If transparency mattered in the stakeholder consultations, it was
perhaps even more important to the credibility of the expert
working groups and advisory committees. “Development aid,
even a scientifically driven process like the AMC, is fundamentally
political,” observes David Fleming, who worked on the disease
expert committee that first recommended the pneumococcal
vaccine for the pilot and went on to chair the EEG and co-chair
the implementation working group that penned the details of
the AMC. He points out that a number of interest groups —
advocates for malaria, TB, HIV — were competing intensely to
have their vaccine of choice selected. Any of them might have been
legitimately picked for the pilot
The way the decision to target pneumococcal disease was reached,
Fleming says, illustrates a key strength of the processes by which
the AMC was designed. The group convened for this purpose
comprised experts in everything from epidemiology to the legal
and economic aspects of vaccine manufacturing. Two-thirds of
them came from developing countries. Their deliberations were
conducted in a highly transparent manner. “If it had been some
How the Pilot
Advance Market Commitment Works
• Manufacturers sign legally binding commitments to
supply a certain quantity of vaccines for 10 years at a
price no higher than $3.50 per dose. The vaccine must
meet the target product profile requirements of the AMC.
• In exchange, the manufacturers receive an additional
payment that averages $3.50 per dose for roughly 20
percent of the doses they supply.
• The subsidy gives manufacturers the incentive to invest in
building manufacturing capacity dedicated to supplying
the vaccine of interest to developing countries.
• The AMC price includes a copay, which is paid
for by participating developing countries and GAVI.
• By ensuring the availability and accessibility of
pneumococcal vaccines, the AMC could save 900,000
lives by 2015, and 7.7 million lives by 2030.
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donor group making the decision in a political atmosphere,” says
Fleming, “it would potentially have gone the same way. But then
it would have been subjected to the criticism that political, rather
than public health or scientific issues, were driving the decision.”
That, he says, would almost certainly have bogged down the
process, which was complicated enough as it was. The decision to
delegate scientific, technical and operational decision-making to
groups of independent experts, he believes, did a great deal to nip
accusations of political bias in the bud.
But not everything went smoothly in the advisory process. The
initial, high-level frame of how the AMC was to be constructed
was, for instance, developed in advance of the EEG being
convened. The group was basically told to “figure out the details,”
says Fleming. “But when we sat down to figure out those details,
we realized that some of the fundamental premises underlying the
project’s initial design were not going to work for the AMC.” As
designed, the AMC would allow the first company to market with
a vaccine to claim the higher AMC price for its product, and to do
so until the money ran out.
The whole point of the AMC, however, was that companies
should be incented by the top-off provided by donor funds to
build dedicated manufacturing capacity for the developing world.
But the economic analysis conducted by the EEG revealed that,
if you allowed the first company to make a vaccine to collect the
full subsidy, it would in fact have no incentive to build dedicated
manufacturing capacity. It wouldn’t need to take on the risk of
building a large amount of dedicated capacity for the developing
world. “So it turned out that the original, fundamental concept of
how the reimbursement in the AMC was going to work actually
was not going to work,” says Fleming.
Trouble was, though, that the original frame for the AMC is what
had been sold politically to the donors. Changing the structure
now, the EEG was aware, could provoke protest. After some tough
discussions within the group, says Fleming, the EEG decided that
the AMC would nevertheless have to be modified to remove that
potentially crippling risk. Though many of the experts in the group
had been involved in devising the original scheme, Fleming notes,
they did not balk at revising their initial plan. “In my government
experience,” says Fleming, who was once deputy director at the
U.S. Centers for Disease Control and Prevention, “it’s unusual that
there’s that degree of flexibility built into a process — so that you
can learn and evolve as you go.”
Not everyone agrees that this was necessarily an asset. The EEG,
says McAdams, was charged with basically working out the details
of the AMC: how recipient countries would pay their share
(through the existing GAVI mechanism for vaccine co-payments),
how the subsidy would be paid out and, most critically, what the
tail price would be. “Instead of tackling the issues that had been
laid out for them — filling in the critical blanks — the group
basically went back to the drawing board and wanted to redesign
the AMC,” says McAdams. “This was two-and-a-half years in. It
was well-intended, and it did add concretely in some ways to the
overall structure. But I don’t think it was actually necessary or that
it added materially. There are others who would disagree with that,
but it did cause an eight- or nine-month delay.”
This could have been prevented with the establishment of solid
deadlines for all major steps of the process, says McAdams. Such
deadlines are critically important, she believes, to prevent a sense of
drift from taking hold in a project with as many moving parts as the
AMC. “What really mattered about it going off the rails was not
so much the substance of the AMC, which I think was moderately
improved, but that the timing and the deadlines and, most
importantly, the level of working attention went down the scale.”
Institution Role
GAVI Alliance Houses the AMC secretariat providing programmatic and administrative support to the initiative. It
has overseen the development of the pilot AMC and will contribute substantially to the long-term
funding for vaccine procurement.
World Bank Has overseen the development of the AMC pilot. Its board voted in April 2009 to put the $1.5 billion
subsidy for the AMC on the balance sheet of its subsidiary International Bank for Reconstruction and
Development.
World Health Organization Set the technical criteria for the selected vaccine and will prequalify (for safety and quality) products
bought through the AMC.
UNICEF Will be the primary procurer and distributor of vaccines
Governments of Italy, the United Kingdom,
Russia, Canada and Norway, and the Bill &
Melinda Gates Foundation
Donated the $1.5 billion in funds for the AMC
Table I
Major Partners
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A Fair Price
The groups working through the details of the pilot AMC had
no shortage of information on their hands to guide them through
their decision-making. But the one critical piece of knowledge they
lacked, and had known all along they would lack, was the actual
cost of manufacturing a vaccine. To the enduring irritation of many
NGOs, the vaccine industry has long been jealously protective
of this information. Meanwhile, outside analysts have doggedly
sought to expose it.
The AMC designers stumbled into the middle of that game, says
McAdams. They hired, over the course of the design process, three
different consulting firms and a Nobel laureate economist to help
them tease out the facts. Determining the costs of manufacturing
mattered not just for the appeasement of several NGOs that
suspected vaccine manufacturers would be overpaid by the AMC
subsidy. It was also important for the retention of suppliers. Some
sense of the cost of manufacturing is critical to setting the tail
price of the vaccine at a credible level. “From a rational public
policy perspective, and understanding what the externalities are
about this,” says McAdams, “you should really be more worried
about underpaying than overpaying. But [the AMC] is funded
by sovereign donors, and they worry a whole lot more about
overpaying than they do about underpaying.”
In setting the price, the AMC’s analysts did their research and
crunched the numbers until they were reasonably confident
that they had found a point that would
incentivize suppliers, yet be affordable
to procurers. But they can’t be certain
that they’re not overpaying — not
without having the facts about the cost
of manufacturing in hand. “Industry,”
as Fleming notes, “has every reason from
a business perspective not to share that
information.” This is likely to leave any
AMC of the future guessing the right
price as well. “Some sort of process that
allows for the cost of the goods to be taken
into account in a way that conceals that
information from both competitors and
the public is what needs to be developed,”
says Fleming.
That isn’t likely to happen any time soon.
But could the AMC concept be scaled
up to address other market failures —
say those associated with technology
for climate change? McAdams says the
questions to ask before that one are: what
precisely is the market failure and is an
AMC the right way to address it. Beyond that, the vaccine AMC
isn’t necessarily the best way to tackle all infectious diseases either.
“At the World Bank, we do not believe that an AMC will work for
diseases like HIV/AIDS,” she says. “It’s so far out that you’d have to
create a huge incentive without knowing if it will ever work out.”
The AMC mechanism may well work to entice vaccine-makers
into the business, says McAdams. “But the pricing is going to be
tough.”
By Unmesh Kher
A health worker fills a vaccination card at
the Masuba health center in the town of
Makeni, Sierra Leone.
Photo by Olivier Asselin
This chart illustrates the AMC concept. Cofinancing levels will be in
line with the applicable GAVI cofinancing policy.
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Lessons Learned:
• Be thoughtful about making or demanding technical
or manufacturing changes to a product to avoid
making it impossible for the supplier to provide.
• Widespread support of an initiative like vaccine vial
monitors can facilitate changes in global policy that
allow more flexibility in the way that vaccines are
used, resulting in further cost savings.
• A cost increase, even though minimal, can become
a large obstacle to ensuring supply as procurers are
often extremely price sensitive.
Vaccine Vial Monitors:
Small Labels With an
Immense Impact
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Lab workers in the Bandung Bio Farma
facility in Indonesia examine vials that have
vaccine vial monitor technology incorporated
into their labels.
Photo by Umit Kartoglu
Vaccines can be rendered useless by just a few degrees
difference in temperature or by temperature changes
over a prolonged amount of time, thus, making
transporting these delicate solutions difficult. “All
vaccines are sensitive to heat and some to freezing,”
explains Umit Kartoglu, technical officer and scientist at
the World Health Organization.
“The vaccines leave the production site in temperature-controlled
trucks, are flown as cargo to the country’s capital for storage, then
transported deeper into the country, stored again, and finally
delivered to the location where they will be administered. Storage
facilities often have sporadic electricity or no electricity at all,”
explains Kartoglu. “Transport might be between islands or on dirt
roads across rivers and swamps. Health workers carry the vaccine
using trucks, motorbikes, boats, canoes, bicycles and, in many
cases, on foot. With all these steps, the journey might take a year,
with the most challenging leg at the very end where the vaccinator
struggles to reach populations dispersed by difficult geography,
famine or war. The vaccine is at constant risk of damage.”
In the past, there was no way for health care providers in these tiny,
rural villages to determine if the vials were unspoiled. Do they risk
using costly but now worthless vaccines on patients and leave them
vulnerable to the disease in the end? Or, do they toss expensive and
perfectly good vaccine as a safeguard any time there is doubt of the
vaccine’s viability? Neither alternative is acceptable where disease
might advance quickly and resources to prevent or treat the illness
are far too few.
A tiny sticker is now available that can warn health care providers
if the vaccine has been exposed to heat and, therefore, spoiled.
The label is small enough to fit on the vial label, the top of the vial
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On the National Immunization Day for polio, two health
care workers in Boboye village in Niger administer an oral
vaccine to an infant being cradled in the arms of a woman.
Photo by Umit Kartoglu
cap or on the neck of the ampoule. A simple color change on this
sticker indicates the viability of the vial’s content with respect to
heat exposure.
“Although developed as a heat-exposure indicator, vaccine vial
monitors, often referred to as VVMs, also contribute significantly
to the reduction of vaccine freezing,” says Kartoglu. “VVMs allow
health workers to see the heat stability of vaccines and accept the
fact that freezing is a greater danger than mild heat exposure.”
VVMs are a simple but effective system adapted from a similar
labeling scheme used to guard refrigerated food during transport.
The adaptation was an uncomplicated idea but a difficult reality.
To date, only a single provider, Temptime, has perfected the
technology to work on vaccines.
The tribulations did not end once the technology was mastered,
however. It took more than two decades to turn this idea into a
common practice in developing countries where adding even a
penny’s worth of difference to the price of vaccines was a burden
they hesitated to bear. The price of the vial monitors was small, but
still it was a price increase and, thus, a burden to overcome.
If it were not for the prolonged and consistent push by
organizations like the World Health Organization (WHO), PATH,
the United States Agency for International Development (USAID),
the Global Alliance for Vaccines and Immunization (GAVI),
United Nations Children’s Fund (UNICEF), and the Centers
for Disease Control and Prevention among others, the tiny label
would have become stuck to a pricing hurdle. By adding the simple
procurement specification requiring the VVMs, low-resource
countries, where vaccines are the most at risk, now benefit from its
simple but urgent warning.
Today, most vaccine suppliers comply with the UNICEF labeling
requirement even though some organizations, such as the Pan
American Health Organization (PAHO) still do not require it.
PATH estimates that VVMs will enable workers to effectively
manage vaccine supplies and replace more than 230 million doses
of inactive vaccine and deliver 1.4 billion more doses in remote
settings. UNICEF and WHO have estimated that the use of VVMs
could save the global health community $5 million per year if
it’s applied only to basic vaccines, and far upward of that figure if
applied more broadly.
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The Road to Certain Knowledge
Today’s VVMs appear elementary in terms of design. A square of
heat-sensitive material rests in the center of the circle-shaped label;
it changes color after heat exposure. If the square becomes the same
color as the outer circle, then the vaccine must be discarded because
it is no longer effective. If the inner square is darker than the outer
circle, the vaccine is long past the discard point. The color change is
a continuous process and, thus, continues to indicate how quickly
the vaccine should be used or even if it should be used at all. The
combined effects of time and temperature cause the inner square of
the vaccine vial monitor to darken gradually and irreversibly.
The simplicity of the label belies the difficulty in its development.
The adaptation from existing cold chain (or temperature-controlled
supply chain) labeling technologies used for refrigerated foods
proved far more challenging than anticipated. Even Temptime,
the sole producer of VVMs for vaccines today, abandoned earlier
developmental attempts. PATH interceded and made a compelling
humanitarian case for the product, and Temptime renewed its
efforts until the product eventually was developed. To date, no
other producer has been able to achieve the same success, although
several are still trying.
PATH first tried to develop the technology on its own. The
initial concept for a heat exposure indicator for vaccine vial use
is attributable by all accounts to WHO officials in 1979. PATH
responded by developing first generation prototypes for measles
vaccine using a chemical licensed from Allied Corp. While this
approach worked well with measles vaccine, it soon became
apparent that it had limitations as the chemical was not responsive
enough to work with the more heat-sensitive oral polio vaccine.
The early work was funded by non-USAID sources, but USAID
— through the HealthTech program — eventually became the
most important financial supporter of VVM development and
advancement. In the early 1990s, PATH/HealthTech worked
with the Temptime Corp., then known as Lifelines Technology, to
successfully modify its proprietary heat indicator technology for use
with all vaccines of varying heat sensitivities. The resulting products
became generically known as vaccine vial monitors. The Temptime
brand is HEATmarker™, and it became commercially available in
1996.
Design field trials were conducted from 1990 to 1992 in
Bangladesh, Bolivia, Cameroon, Indonesia, Kenya, Sierra Leone,
Thailand and the United States. An additional detailed study on
the impact of VVMs on measles vaccine discard rates due to heat
exposure was conducted in Zimbabwe with the aid of the Ministry
of Health. At the same time, WHO and PATH representatives
met with eight U.N. vaccine suppliers to explore the feasibility of
integrating the labels with their products. Prototypes were then sent
to vaccine suppliers for integration feedback. In 1993, Lifelines,
now Temptime, developed the means to print VVMs directly
onto vial labels, reducing manufacturer resistance to purchasing
additional labeling equipment for a separate VVM label. PATH has
assisted vaccine producers with VVM implementation throughout
the program.
High on the list of acceptance problems early on was the fact that
VVM is a paradigm-shifting technology available only from a
single supplier, Temptime. The UNICEF Supply Division was not
comfortable with the single-source issue, the subsequent deviation
from procurement of commodity products and the added burden
that the requirement placed on relationships with suppliers. PATH
and WHO have continuously sought to develop other suppliers
to address this issue. Technical assistance was provided to Albert
Browne (U.K.), 3M (U.S.), Rexam/Bowater (U.K.), CCL Label
(U.S.), and Sensitech (U.S.) but none have been successful in
developing a price-competitive product that reaches performance
requirements established by the U.N. agencies. PATH also assisted
Temptime with obtaining low-cost loans to ensure production
levels could meet global need.
Lab worker in the Bio Farma facility in Bandung,
Indonesia, monitors the application of labels with
incorporated vaccine vial monitor technology.
Photo by Umit Kartoglu
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Two vaccination campaign workers give an
injection to an indigenous inhabitant of a
rural area in Peru.
Photo by Carib Nelson, provided by PATH
The principal patents owned by Temptime have expired, but since
Temptime is able to meet global need easily enough and retains
extensive knowledge and experience in manufacturing the
VVMs. Technology transfer to other companies is not currently
being pursued.
Strong support from several prominent agencies was necessary to
continue to move the availability of VVMs forward. WHO was on
board from the start. WHO staff members brought the need for
this type of technology to PATH’s attention, and PATH responded
by identifying and testing appropriate solutions. PATH and WHO
worked collaboratively on every aspect of VVM development and
advancement.
UNICEF was kept apprised of the technology by WHO
throughout the development process. Once the VVM technology
was appropriately validated, WHO and UNICEF published a joint
policy statement encouraging the inclusion of VVMs on vaccines.
Eventually this policy translated into incorporation of VVMs into
vaccine specifications for vaccines purchased by UNICEF.
WHO and the United Nations issued a joint statement in 1999
recommending VVM use on all vaccines, and the labels have since
become a standard feature of all vaccines purchased through U.N.
agencies. GAVI endorsement was a natural next step and was a
straightforward process given the previous endorsement by WHO
and UNICEF. In 2002, the GAVI board also stipulated that, from
the beginning of 2004, all vaccines purchased through the vaccine
fund must include VVMs. In the intervening years, PATH worked
with Temptime, WHO and other collaborators to test, evaluate and
advance the product.
A new advantage to using VVMs is beginning to surface. “VVM
shapes the future of cold chain today, a future in which dependency
on the cold chain is removed,” says Kartoglu. “Today, VVM is
seen as a catalyst for much-needed changes in strategies of vaccine
distribution via the cold chain. VVM allows immunization programs
to exploit the stability of each vaccine to the greatest possible extent,
minimize distribution costs and increase flexibility in the handling of
vaccines in the field, thus helping to make operations more effective.”
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The Struggle for Consistent VVM Use
Even with the advances in VVM technology and the spread of
advantages the technology seems to present, consistent use of the
product has been difficult to ensure.
While VVMs are increasingly supplied on vaccines purchased
for the international market through UNICEF, they are not yet
available on many of the vaccines produced in developing countries
for domestic markets, the exceptions being India, Indonesia and
Pakistan.
Vaccine procurement for developing and emerging countries is
becoming increasingly decentralized, meaning that a variety of
purchasers must include VVMs in their tender specifications to
ensure consistent availability to immunization programs. In 2007,
WHO and UNICEF released a policy statement encouraging
member states, donors and nongovernmental organizations
procuring vaccines to include VVMs in their specifications.
Continued work to strengthen procurement at the country level, e.g.,
through interagency coordinating committees, will be necessary to
ensure vaccine quality and availability of vaccines with VVMs.
Although PAHO supported a number of field trials with early
VVM prototypes, it has never required VVMs on products
purchased through the PAHO revolving fund, citing lack of cold
chain difficulties in its region and unwillingness of consumers
or purchasers to pay the slight price increases for products with
VVMs. Vaccine suppliers complained that they had to supply
vaccine with VVMs for
UNICEF and without for
PAHO, but eventually most
complied with the UNICEF
requirement.
One repeated difficulty has
been the inability of the
UNICEF supply system to
consistently send the same
brands of vaccines to countries
or to notify WHO with regard
to which countries would
receive vaccines with VVMs.
WHO was, therefore, unable to
target early training efforts to
countries that would definitely
receive the VVMs. For many
years, countries received
supplies of vaccines both with
and without VVMs and, therefore, could not rely on VVM use as
a routine management tool. This situation is improving as more
vaccine suppliers have integrated VVMs into their products.
Immense Impact
Despite these difficulties and challenges, the overall impact of
VVMs has been considered a global success. Future vaccine storage
and transport will likely rely even more heavily on VVMs as the
existing cold chains become constrained by the introduction of
many new vaccines. VVMs could enable the removal of some
heat-stable vaccines to higher temperature storage areas to make
room for more heat-sensitive vaccines in refrigerators. The labels
also have a proven history of enabling outreach to difficult areas
and can continue in this role with new vaccines, such as conjugate
meningococcal A vaccine.
The Optimize project is a joint WHO/PATH project focused on
developing the strategies for the future of immunization logistics.
Project Optimize is working to further improve the availability
and utilization of the VVM as a vaccine management tool within
countries.
By Pam Baker
Immunization session in Uganda
Photo provided by PATH
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Lessons Learned:
• Close cooperation between local governments
and foreign organizations is essential for
successfully delivering medical services in resourceconstrained
settings.
• Private and public donations of time, money and
products — including those from pharmaceutical
companies — are a critical component of launching
and maintaining a global health effort.
• Training local health care personnel to meet
international standards in specialized care is key to
ensuring sustainability of the health program.
• The success of pediatric HIV programs leads to
added challenges in sustaining long-term treatment
as the patients mature.
Growing Network Extends
HIV Treatment to Children in
Developing Countries
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Mark Kline, M.D., and a group of physicians and
nurses examine children in the outpatient clinic
in Constanta, Romania, in 1997.
Photo by Smiley N. Pool
In the late 1990s, the new effective HIV regimens
remained largely unavailable in resource-poor
countries. Global AIDS deaths among children under
15 amounted to almost 300,000 in 1999, and the
number of newborns acquiring HIV in the same year
exceeded 400,000. High-income countries contributed
a miniscule amount to those figures because of their
ability to administer antiretroviral therapy (ART).
Mark Kline, in 1995, was savoring his success in treating HIV at
Houston’s Texas Children’s Hospital. Kline, a professor of pediatrics
at Baylor College of Medicine, was pulled out of his complacency
by a group of visiting Romanian doctors. While Kline talked to
them about pediatric HIV care at the Children’s Hospital, his
guests described the unique HIV problem in Romania. Some
10,000 neglected Romanian children raised in orphanages had
contracted HIV due to hospitals’ use of blood microtransfusions
to “fortify” their health. Not only was this practice medically
unfounded, but the transfused blood was unscreened and the
reused syringes unsterilized.
These children received little treatment, and the Romanian doctors
were desperate. Kline returned the Romanians’ visit in February
1996. “I thought I had seen it all before,” Kline says now,
“but I was not prepared for this. There were hundreds of stunted,
wasted children with horrible open lesions. The kids had been
warehoused in the AIDS ward and left to die. After two weeks in
Romania, I thought, ‘My conscience can’t allow me to walk away.’ I
developed the outline for an international pediatric program on the
plane home.”
Kline started with a small amount of seed money but gradually
built a public-private partnership that includes pharmaceutical
company foundations, the United States and other governments,
and international donors. The Baylor International Pediatric AIDS
Initiative (BIPAI) now extends from Romania to nine countries
in Africa (see map). As of 2009, it treats 30,000 patients. In
developing this extensive network, BIPAI created an operational
and financial model for bringing HIV care to resource-poor areas,
something long considered impossible.
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In the Beginning: Constanta, Romania
Kline’s initial visit centered on the Black Sea port city of Constanta.
He was the guest of one of the local pediatricians, Rodica Matusa.
The city was the focal point of Romania’s epidemic. At that point
about 600 Constanta children had died of AIDS and another 600
were known to be HIV-positive. “We began a small program to
examine the children and catalog their problems,” Kline recalls.
“We treated their tuberculosis and diarrhea, gave nutritional
supplements and started training medical personnel. We saw a
modest improvement in health.”
Clearly more was needed. Matusa convinced her institution, the
Constanta Municipal Hospital (since renamed the Infectious
Diseases Hospital Constanta), to donate a nearby abandoned
orphanage. Kline was able to secure initial renovation funding
from a Houston-based religious order, the Sisters of Charity of
the Incarnate Word. In addition, Abbott, the makers of HIV test
kits and the popular HIV protease inhibitor Kaletra®, commenced
its Step Forward program in 2000. Step Forward (managed by
the Abbott Fund, the company’s philanthropic arm) focused on
orphaned and vulnerable children affected by the HIV epidemic.
Its first grant went to create the Romanian-American Children’s
Center in Constanta, which opened in April 2001 with a
Baylor and Romanian staff providing comprehensive medical
and psychosocial services. For specialized HIV care, the center
partnered with the government’s Infectious Diseases Hospital,
whose providers Baylor helped train.
Summarizing Abbott’s early interest in the Romania-Baylor Project,
Abbott Fund Vice-President Jeff Richardson says, “We heard from
several people about Baylor’s outstanding reputation in pediatric
AIDS. Kline was one of our consultants when developing the Step
Forward program. We were impressed not only with his proposed
care and treatment model in Romania, but also with his promise
that Baylor would replicate this model in Africa.”
A steady source of antiretroviral drugs became available at the
center in November 2001 when Abbott provided the Constanta
patients with a lifetime no-cost supply of Kaletra. Kline was able
to secure a stable supply of supporting nucleoside analogs through
a Bristol-Myers Squibb donation. Later on, a grant from the
Global Fund for AIDS, Malaria and TB allowed the Romanian
government to become a reliable ART supplier. (At publication
time, however, recession-induced budget cuts have created a looming
shortfall in ART availability.)
Abbott also entered into an open-ended commitment to fund the
clinic’s operating costs. With the clinic’s sustainability and access to
drugs assured, annual mortality among the Constanta patients on
ART progressively declined from 13 percent to 1 percent.
Aging patient population: The increased survival meant that the
center was faced with a raft of new psychosocial issues. Ana-Maria
Schweitzer is a Romanian psychologist who started working with
the Baylor team in 1999 when all of the clients were under 18 years
of age. She has since become the center’s director, and now almost
all of the clients are young adults. Schweitzer says, “Before, the
priority was to ensure survival. Now the daily needs are covered,
including uninterrupted drug supply. The new priorities include
informed decisions on pregnancy or becoming parents. Out of our
original population, we now have 50 couples with children up to
four years old.” The center provides its own obstetrics-gynecology
and family planning specialists and social workers to provide care
and counseling on the full range of family planning options plus
preventing mother-to-child HIV transmission (PMTCT). So far,
there have been no detected HIV transmissions to newborns.
A related issue is safe sex — counseling both the HIV-positive
patients and their partners on preventing transmission, of which
there have been suspected cases. Transmission as well as disease
risk would decrease if everyone adhered scrupulously to their ART
dosing schedules, but Schweitzer terms adherence “an everyday
Sites of BIPAI’s Clinical Centers of Excellence with opening
dates (UC = under construction as of August 2009). Note that
treatment programs generally began in local public hospitals
with which the centers became associated upon opening.
Modified from: World Outline Map (no date). St. Catharines, Ontario:
Brock University Map Library. (Accessed Aug. 15, 2009).
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struggle” for adolescents. The center’s adherence support efforts
include focus groups, counseling and home visits.
The biggest new challenge is helping HIV-positive young adults
to become productive members of society. Says Schweitzer, “There
was a lack of education: Nobody expected these kids to live, so
many didn’t go to school. Those who did faced considerable stigma.
So we help find jobs by acting as a buffer between our patients,
job trainers and employers. We have special connections with
employers that we have educated on HIV.”
Collaboration with government and international donors: The
Constanta Center has been fortunate that the Infectious Diseases
Hospital continues to partner with it as part of the national AIDS
program. The increasingly capable hospital staff is in charge of
ART treatment for the center’s clientele as well as for the rest of the
local HIV population. This center, meanwhile, transformed itself in
December 2007 into the Romanian Clinical Center of Excellence.
It now welcomes all of Constanta’s 840 persons with HIV, adults as
well as children.
As the center’s primary donor, the Abbott Fund regularly consults
about the center’s accomplishments and further needs. It supported
the expansion of social services while the government oversees HIV
treatment. This pattern of tight cooperation with the local medical
establishment and with funders became basic to BIPAI’s expansion
to African locales.
Thinking Large: Botswana
U.S. pharmaceutical company Bristol-Myers Squibb (BMS)
commenced its $150 million Secure the Future program in 1999
through the company foundation, just as the Constanta center was
taking shape. Secure the Future was focused on southern Africa
from the start. The BMS Foundation had worked previously with
Mark Kline on the Romania clinic, to which it gave small cash
contributions and drugs, and on training Mexican pediatricians.
When launching Secure the Future, it immediately invited him to
put together a new project based on the Romanian experience.
Collaboration with government and international donors: Far
to the south of Constanta lies Gaborone, the capital of Botswana.
Botswana has benefited from remarkable economic growth rates
Baylor International Pediatric AIDS Corps (PAC)
physician, Kebba Jobarteh, M.D., exams a child at
the Baylor College of Medicine Abbott Fund
Children’s Centre of Excellence in Malawi.
Photo by Smiley N. Pool
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since independence and now has a per capita gross domestic
product slightly higher than Romania’s. But with a quarter of its
adult population HIV-positive, Botswana has a far higher HIV
rate. Botswana’s government was also very supportive of bringing
HIV treatment to its citizens. Its president, Festus Mogae, became
personally involved in expanding treatment availability. A place like
Botswana would naturally command Mark Kline’s interest.
Arguably, the government’s biggest contribution to BIPAI was
Gabriel Anabwani, the chair of pediatrics at Gaborone’s health care
centerpiece, Princess Marina Hospital. Looking back, Anabwani
says, “We were so frustrated to helplessly watch children die in
our hands when the treatments were out there.” He met Kline at a
September 1999 BMS Foundation meeting. Kline visited Princess
Marina Hospital, and the two put together a program of exchanges,
training Botswana doctors in HIV treatment and U.S. doctors in
opportunistic infections.
When Anabwani came to Houston for a month, he was impressed
by how healthy the pediatric HIV patients were. They were living
the lives of normal children. He wanted to show that African
children could have a similar experience if ART were available.
Secure the Future funded the initial Botswana-Baylor effort in this
regard, which effectively became a 200-child pilot ART program.
The research team worked out of a small trailer behind Princess
Marina Hospital.
As the Botswana government prepared to introduce ART
throughout the country, Kline and Anabwani floated the idea of
a separate pediatric HIV clinic. With the president’s blessing, the
Ministry of Health signed a memorandum of agreement to work
with the project’s treatment, training and research activities. The
agreement committed the government to providing antiretroviral
drugs as well as land for the clinic on the Princess Marina grounds.
Kline convinced the president of Bristol-Myers Squibb, Kenneth
Weg, to have Secure the Future grant $6 million for the center’s
construction and first five years of operation. Additional funding
came from the U.S. National Institutes of Health and Centers for
Disease Control and Prevention.
“BMS agreed reluctantly,” Anabwani recalls. “Nobody treated HIV
then; they only did prevention. Mark and I agreed that if the center
failed, it would be fatal to attempts to treat children in Africa. We
had a huge responsibility.”
PAC Drs. Kebba Jobarthe, Adrian
Hazbun and John Midturi, discussing a
patient while doing rounds at Kamuzu
Hospital in Lilongwe, Malawi.
Photo by Smiley N. Pool
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Fortunately, the Botswana-Baylor Children’s Clinical Center
of Excellence was a great success from the time it commenced
operations in June 2003. BMS Foundation President John
Damonti says, “It is the most beautiful building at the hospital.
There was fear going in that parents would not bring their children
to an HIV facility given the disease’s stigma. But they had 1,400
children on ART in the first year and 6,000 patients in the first two
years. The center showed that the model works not just for training
but also for catalyzing treatment and care.” Most critically, annual
mortality among the patients fell from 4.7 percent in 2003 to 0.3
percent three years later.
Addressing the shortage of skilled personnel: Training other
doctors is an essential part of the center’s program. “We have
become a very valuable partner of the Ministry of Health,” says
Anabwani. We provide all the training in HIV care for the whole
country. We also sit on the health ministry’s key children’s health
committee.” An international training program sends center
doctors to other African countries for two weeks to one month.
Aging patient population: In 2009, the center had about 2,100
pediatric patients plus 260 families in its family care center.
Botswana’s PMTCT program has proved highly effective, with
transmission reduced to levels comparable to those in developed
countries. As in Romania, the pediatric patient population is aging
rapidly. “In three to five years, the majority will be adolescents,”
Anabwani estimates. “We are advocating with the government,
NGOs [nongovernmental organizations] and funders to sensitize
them to teens’ needs.” In Botswana, too, ensuring adherence
to dosing schedules is a big issue. Safe sex is another looming
problem. One advantage over Romania is that patients’ family
structures are largely intact — and struggling with HIV together.
Orphans are usually under the care of surviving family members.
A major effort has been made to establish teen clubs and an annual
vacation camp. Adolescents also are given more frequent clinic
appointments with doctors specifically interested in adolescent
care. “Our efforts need more development to be effective,” notes
Anabwani. One of the remaining hurdles is transferring maturing
patients to adult care. There are plans to ease the transition by
bringing adult doctors to the pediatric clinic for extended periods.
New Frontiers
The BMS Foundation was so pleased with the Botswana experience
that it moved to fund construction of six other clinics. The
second Clinical Center of Excellence was located 300 miles (500
km) farther south, in Lesotho’s capital, Maseru. Lesotho has a
population similar in size to Botswana, and its HIV prevalence is
about the same, too. But Lesotho is considerably smaller in size and
its economy much poorer.
Collaboration with government and international donors: The
Children’s Clinical Center of Excellence in Lesotho commenced
operations in December 2005 under a Memorandum of Agreement
with the Lesotho government. There was only one pediatrician
in all of Lesotho before the Center of Excellence opened. BIPAI
brought in 10 doctors from the United States to provide sufficient
pediatric care capacity. The government is paying for ART drugs
and operating expenses with a grant from the Global Fund.
UNICEF and private donors also underwrite various aspects of
the operation. As of 2009, the center had 2,300 active patients,
half receiving ART. Some 600 of the patients were adult family
members of the pediatric patients.
To alleviate Lesotho’s shortage of HIV care facilities, the Center
of Excellence is constructing 10 satellite clinics outside Maseru
to serve children and their families. The Lesotho government is
providing the land and supporting the operating costs. Here too,
the BMS Foundation is paying for construction while BIPAI will
supply the staff.
Mark Kline, M.D., examines a patient at
the Baylor College of Medicine Bristol-
Myers Squibb Children’s Center of
Excellence in Lesotho.
Photo by Smiley N. Pool
28 Case Studies for Global Health
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Further expansion: The BIPAI network continues to expand
elsewhere. It opened a Center of Excellence in Swaziland in
February 2006 and in Malawi in November of the same year. In
October 2008, BIPAI opened a center in Kampala, Uganda, the
culmination of a hospital-based program that began in 2002. The
Uganda center cares for 4,000 pediatric patients with 7,000 more
receiving treatment at affiliated clinics in Kampala and around the
country. As of 2009, Centers of Excellence were under construction
in Burkina Faso, Kenya and two Tanzanian locations. Swaziland’s
center is building two satellite facilities, which are also planned
for Tanzania.
The BMS Foundation paid for constructing all but two of these
sites, with international donors underwriting operational costs
(principally the U.S. President’s Emergency Plan for AIDS Relief
and the Global Fund). The Abbott Fund supplied the funds for
building the Malawi center and largely supports its continued
operation. It is also financing construction of one of the
Tanzania clinics.
Addressing the shortage of skilled personnel: A shortage of
doctors has proved to be a universal problem. “We found that
it was easier to build centers than to staff them,” says Damonti.
BIPAI announced in 2005 that it was organizing the Pediatric
AIDS Corps, which Damonti’s BMS Foundation agreed to fund
for five years. The program supports 50 or 60 doctors from the
United States each year at the BIPAI clinics and at remote sites.
The doctors participate in the centers’ care and training efforts
for 12 to 36 months each. The Pediatric AIDS Corps is considered
an interim measure until more African doctors are qualified in
HIV care.
Keeping it all Together
In August 2006, BIPAI reported that it had less than 10,000 active
patients; it reported an active caseload of more than 39,000 in
October 2009. Kline has visions of eventually caring for 100,000
children with HIV — half the infected pediatric population in the
countries with BIPAI clinics. The challenge will be to serve such a
large patient body in a sustainable, well-organized fashion.
Nurses at the clinic in Uganda take the vital signs of
children in the outpatient clinic prior to the construction
of the Baylor College of Medicine Bristol-Myers Squibb
Children’s Centre of Excellence there.
Photo by Smiley N. Pool
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A major effort to ensure continuity is BIPAI’s Children’s Clinical
Centers of Excellence Network. Supported entirely by the Abbott
Fund, this network meets several times a year, bringing together a
large proportion of the far-flung clinic staff. It plays a critical role
in integrating their activities. In addition, Abbott and BMS see the
meetings as another means to informally coordinate their activities
with the network and each other — beyond these donors’ frequent
site visits and personal communications.
The network also provides Abbott- and NIH-funded fellowships
for study at the Baylor College of Medicine. The fellowships
supplement the centers’ many in-country educational courses, and
they are an effort to establish native leadership to oversee continued
HIV care.
Yet troubles loom on the horizon. For example, the Pediatric AIDS
Corps at present fills in the doctor gap, but the $22 million BMS
grant that supports it ends in 2011. Either another funder will
have to step in, or BIPAI will have to rely on the local doctors it
has trained at that point. And where will the funds come for hiring
more African doctors, whose expertise is also needed by nearby
health care institutions?
One of BIPAI’s major strengths has been its strong cooperation
with the national governments where it has operations. “We
consider ourselves an extension of the national government HIV
programs,” says Kline. “Our centers are kind of hybrids — they’re
international but they have one foot in the Ministry of Health.”
Kline believes that active government cooperation is critical. The
governments cut through the ever-present red tape so that the
centers can operate freely. They also support a substantial part of
the centers’ operating expenses in several locations. If motivated,
they might help pick up the tab at other locations that lose grant
money.
It would, therefore, be a bad idea to hire doctors away from existing
institutions. BIPAI has agreed to avoid that in every country
in which it operates. It refrains from economic competition by
paying at the local scale. But the centers of excellence offer other
advantages.
Richardson notes, “Baylor is providing well-operated facilities that
are attracting doctors back to their native countries or inducing
local medical school students to stay. I hear from doctors and
nurses that they want the tools to get the job done, and that this
is at least as important as salary.” BIPAI endeavors to meet the
demand for a quality professional environment through its training
programs, lab facilities and computer technology.
In any case, Kline foresees a period of consolidation. No new
clinics are under consideration. He says, “Our primary thrust will
be to realize the centers’ full potential through extending pediatric
and family care, professional development, satellite facilities and
electronic health records. We are not growing the number of
centers but concentrating on delivering the highest quality care and
supporting the local health system.”
By David Gilden
Baylor International Pediatric AIDS Corps physician,
Kara DuBray, M.D., at the Queen Elizabeth II
Hospital examines a patient in Lesotho.
Photo by Smiley N. Pool
www.casestudiesforglobalhealth.org
Lessons Learned:
• Design your health program in response to a
locally identified need.
• An influential in-country champion will be an
asset to your program.
• A chronic disease program must have a strong
monitoring component.
• Make sure you are cognizant of the resource
constraints of participating organizations.
• Build capacity to ensure your program’s
sustainability.
Saving Uzbek Hearts:
A Program for Best Practices in
Controlling Hyperlipidemia
30 Case Studies for Global Health
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Case Studies for Global Health 31
(As of October 2009)
www.casestudiesforglobalhealth.org To say cardiovascular disease is a problem in Uzbekistan
would be something of an understatement. It is, in fact,
epidemic. According to the World Health Organization
(WHO), more than 56 percent of all deaths in the
former Soviet central Asian republic are caused by this
silent yet efficient killer. Many of them are premature,
the likely consequence of multiple risk factors, such as
heredity, tobacco use, physical inactivity, and untreated
hypertension and high blood cholesterol. It has long
been clear to many Uzbek physicians that preventive
interventions are urgently needed to diffuse what is
clearly a ballooning health care crisis.
In 2006, Alexander Shek, the chief cardiologist at the Republic
Cardiology Center in Tashkent, met with AmeriCares and Soglom
Avlod Uchun Foundation, two organizations that were working
closely with the hospital on a variety of projects. AmeriCares
is a U.S.-based humanitarian aid organization that specializes
in medical commodity assistance, and Soglom is an Uzbek
nongovernmental organization focused on health care. He asked
if AmeriCares could help him address the widespread problem of
hyperlipidemia (high cholesterol) in Uzbekistan as part of its aid
efforts in the country. In particular, Shek wondered whether it
could regularly donate the cholesterol-lowering drugs known as
statins to cardiology centers to help physicians treat hyperlipidemic
patients.
A series of conversations about program design and
implementation culminated in June 2007 with the launch of
the Central Asian Cardiovascular Disease Initiative (CACDI).
To help fulfill the request for hyperlipidemia treatments for
A nurse records disbursement of simvastatin
at the Cardiology Center in Navoi.
Photo by Jim O’Brien
32 Case Studies for Global Health
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indigent patients, AmeriCares reached out to Merck & Co. and
Merck/Schering-Plough Pharmaceuticals, which agreed to donate
the drugs, Zocor, Vytorin and Zetia. “Our program had three
primary goals,” says Ella Gudwin, director of global partnership
development at AmeriCares. “One was the treatment of patients
who lacked the means to pay for treatment. Another was to develop
the expertise among physicians in the treatment and monitoring of
cardiovascular diseases. And the third point of emphasis was patient
and family education.”
The fulfillment of the last two objectives, it was hoped, would give
CACDI an impact that reached beyond its small scale. Owing to
the cost and spotty availability of statins in Uzbekistan, relatively
few physicians had developed a working knowledge in the use
of pharmaceutical agents for hyperlipidemia treatment. That,
however, was slated to change. Three major cholesterol control
drugs — Merck’s Zocor (simvastatin) and Mevacor (lovastatin),
and Bristol-Myers Squibb’s Pravachol (pravastatin) — went off
patent in 2006, and their prices had begun to drop. In 2007 the
WHO put simvastatin on its Model List of Essential Medicines,
which many ministries of health use as a guiding document for
filling national formularies.
Setting Up
CACDI is built around statin therapies, which are regarded as
generally safe and effective medicines. Patients in the program
are treated with simvastatin, ezetimibe — a drug that lowers
cholesterol by a different mechanism of action than do the
statins — or a combination of the two. Roughly 420 patients are
enrolled in the initiative at any given time. They are treated by
heart specialists at one of seven medical centers across Uzbekistan,
though most visit the Republic Cardiology Centre in Tashkent.
Enrollment is not randomized. Indeed, it has been engineered
to bias the outcome positively. To be selected for the program,
hyperlipidemic patients must be of sufficiently modest means to
find treatment financially challenging. But, just as importantly,
they must demonstrate that they and their spouses or other family
members are committed to their participation. This is because the
program requires lifestyle and diet changes in which family are
likely to play a leading role (women, for instance, cook the meals in
most traditional Uzbek households).
A nurse takes blood pressure and pulse
during patient visit.
Photo by Jim O’Brien
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As a component of program monitoring, physicians must
report total cholesterol levels. “We wanted the total cholesterol
measurement to be used as reliable proxy for therapeutic responses
to the antilipidemic therapy,” Gudwin explains. In line with best
practices, physicians also take measurements of the LDL cholesterol
(“bad” cholesterol) HDL cholesterol (“good” cholesterol) and
triglyceride levels of patients. But these measures are only used
by the physicians to monitor patients and inform them of their
progress. They are not reported to the pharmaceutical donors.
Patient monitoring for safety is important to each of the donors,
Merck & Co. and Merck/Schering-Plough Pharmaceuticals,
which together have provided more than $8.7 million worth
of medicines since mid-2007. AmeriCares manages the overall
program and the supply of donated drugs, whose importation
and distribution are handled within Uzbekistan by Soglom. The
Republic Cardiology Center oversees the operational details of
the initiative and reports patient stories and overall progress back
to AmeriCares. The program also enjoys strong support from the
Ministry of Health, which covers the cost of critically important
laboratory tests for patient safety and monitoring. “The Ministry
of Health’s contribution of resources, in terms of funding testing,
creates more equality in the partnership,” says Gudwin. “But,
more importantly, it creates a stronger trajectory with regard
to the long-term sustainability of the best practices we’re trying
to encourage through this program.” Beyond that, says Terry
Conroy, the pharmacist in AmeriCares’ medical unit, the ministry’s
endorsement of the program has added to its credibility. “They
have validated the program,” she says, “especially for the patients.”
Outcomes and Adjustments
Though small as such programs go, CACDI seems to be having an
impact. Between June 2007 and December 2008 it reached 642
patients, making them aware of their blood lipid levels, the need
to keep cholesterol under control and the lifestyle changes essential
to that end. Further, the 177 patients who had participated in
the program for at least 12 months as of August 2008 saw their
total serum cholesterol levels decline by an average of about 20
percent. The cardiologists treating them, meanwhile, have been
trained to be focal points for the dispersal of best practices in statin
pharmacotherapy for the management of hyperlipidemia.
Since one of CACDI’s aims is to create centers of excellence in
treating cardiovascular diseases across the country — thereby
amplifying the program’s effect — it has stressed physician
education. Before its official launch, the Republic Cardiology
Center, a teaching hospital, hosted a training session for specialists
from several regional cardiology centers that were interested in
participating. The training was primarily intended to update
the cardiologists on current best practices for the treatment of
heart disease. At least 45 physicians have so far benefited from
the training and the opportunity to improve their qualifications,
maintain high standards in patient care and follow-up, and to
mitigate cardiovascular complications, such as heart attack and
stroke, in their patients.
After the program started, some practices of care had to be
modified, within medically acceptable limits, for the sake of
affordability. Laboratory tests, especially, posed a problem.
Two types of tests are essential: those used to help monitor the
effectiveness of treatment and those used to identify potential
serious adverse events. One of the tests — the creatine kinase (CK)
assay, originally recommended as a way to monitor patients for the
muscle damage occasionally associated with statin use — proved
too expensive. Indeed, one hospital dropped out of the program
because it could not afford the test. So the program designers
chose not to require repeated CK screening. Instead, Conroy says,
physicians seek to detect such problems early via clinical assessment
of muscle pain. (Only those who report muscle pain during
examinations need to be further tested.) If they wish to do the CK
test, of course, they can, and several do establish a baseline CK
reading for patients against which to compare future assays. They
are just not required to report these measurements to participate in
the initiative.
Reviewing patient records at the Republic
Cardiology Center.
Photo by Jim O’Brien
34 Case Studies for Global Health
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All physicians in the program do, however, take baseline readings
of total cholesterol level and liver function, which is a means of
tracking effectiveness and drug toxicity. Patients are given these
tests at intervals, beginning at six to 12 weeks, and then at six
months and 12 months after starting drug therapy. They are
thereafter tested twice a year. The tests are not just important for
monitoring the effectiveness of the treatments, says Conroy. They
also demonstrate that the physicians are keeping an eye on their
patients’ safety and making fact-based decisions about their therapy.
Most importantly, the cholesterol test results can have a powerfully
positive influence on patients. The measurements are often the
only tangible signal of progress they get for their efforts. “Patients
don’t feel their cholesterol level,” says Conroy, “so the disease can
progress silently. This test gives it a microphone.” Watching their
blood cholesterol levels slide down the chart is, Conroy notes,
a powerful motivator. It helps to keep patients on the diet and
exercise regimen prescribed by their physicians.
The small scope and simplicity of the program, both in terms of
the testing and the enrollment, are also a plus, Gudwin and Conroy
say. These aspects, they say, enhance the continuity of treatment
and monitoring of patients. They do not necessarily limit the
impact of the program either, they explain. Their hope is that
participating institutions, dispersed as they are across the country,
will act like foci from which the knowledge transferred by the
program will radiate throughout the medical community.
Sustaining the Effort
From the donor’s perspective, says Christine Funk, associate manager
of Merck’s Global Health Partnerships, it is reassuring to work with
an organization that has tight oversight and management procedures.
AmeriCares, she says, has strong mechanisms in place to ensure that
the drugs they send to recipient countries go where they’re meant to
and are not diverted into the gray market. Similarly, its management
at the pharmacy level is exemplary, says Funk. This eases donor
concerns about expired products remaining on shelves. “We
Checking the stock of Merck-donated medicines at
the Jizzak Cardiac Center.
Photo by Jim O’Brien
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require partners to tell us if anything goes wrong,” says Funk, “and
AmeriCares hasn’t had to yet.”
Though Funk gives CACDI high marks, she does wonder how
long a program of this sort should continue. Prices for generic
statins have dropped by as much as 50 percent from the time they
were initially introduced to global markets. “Generic simvastatin is
available in Uzbekistan,” notes Funk. “It’s on the WHO Essential
Medicines List, and the price is trending downward, though it
is still expensive for poor people. But we, as donors, don’t want
a forever and ever, open-ended commitment because, then, how
do you get stability and sustainability within the country itself?
Eventually, you want the health system to supply these needs for
its patients. So [the question is] with the trend going in a positive
direction — how much longer do we maintain the
donation program?”
The ministry’s support for the program is, in this context,
particularly encouraging. It did, after all, underwrite the laboratory
tests required by the program protocols. It recognizes that
cardiovascular disease is a serious problem in Uzbekistan. And if
AmeriCares has accomplished even half of what it hoped to do, a
cadre of cardiologists is now well-prepared and primed to spread
the word about best practices in the management of hyperlipidemia
in Uzbekistan.
By Unmesh Kher
A patient prepares to have his blood drawn
for routine lab tests.
Photo by Jim O’Brien
36 Case Studies for Global Health
(As of October 2009)
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Lessons Learned:
• Branding opportunities are an effective way
to attract pharmaceutical manufacturers and
other suppliers.
• Pharmaceutical partners use just-in-time
manufacturing to supply medicines with usable
expiration dates.
• An established measurement and screening
program is critical to quantifying a program’s
health benefits and determining future needs
and areas for improvement.
MAP’s Globetrotting
Travel Pack Program
Meets a Universal Need
Case Studies for Global Health 37
(As of October 2009)
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When San Diego-based emergency room physician
Paul Dohrenwend, M.D., went to Haiti earlier this
year, he went on a special mission of a dual nature.
Dohrenwend went to provide voluntary medical relief to
a Haitian orphanage. He also visited a Haitian child he is
considering adopting.
Dohrenwend carried a special tool to assist him on his mission:
the Travel Pack, a prepacked assortment of medicines and medical
supplies assembled and provided by Medical Assistance Programs
(MAP) International.
“Boy, did that thing take a journey,” says Dohrenwend, an
emergency room doctor at Kaiser Permanente San Diego Medical
Center. “First, we hand-carried it to Haiti. Then we tried putting
it on top of a jeep, which we had to drive over a potholed road.
But we realized it was going to fall off, so we put it and about nine
people in an Isuzu trooper.”
Medicines to Many Distant Cities
Haiti is not the only place served by MAP International’s Travel Pack,
which has become a staple of medical relief missions. Dohrenwend
himself has brought them to Baja Mexico as well as Haiti.
The Travel Pack is a prepacked assortment of medicines designed
to help treat illnesses and injuries common in developing countries.
Each Travel Pack includes two boxes comprised of up to 700
treatments of antibiotics, anthelmintics, analgesics, topical steroids,
rehydration salts, vitamins and other general medical supplies
worth an average wholesale value of $14,000. Physicians contribute
a $450 tax-deductible handling fee that helps MAP International
recover some of the costs associated with the program. Since MAP
began the Travel Pack program in 1993, the organization has
shipped approximately 750 tons of medicine in Travel Packs to 115
countries, providing up to 17 million treatments. MAP estimates
that it will provide 2,400 Travel Packs for medical teams traveling
overseas in 2009.
The Travel Pack was born as a result of growing requests from
short-term medical mission teams for medicines and supplies. The
Travel Pack met the need for those teams and allowed MAP to
minimize costs by using volunteers to prepack the products. The
first 12 months of the program saw 442 packs shipped, and steady
growth continued over the next several years, peaking at more
than 3,000 shipped during fiscal year 2008. To support the heavy
growth in 2008, volunteers contributed more than 2,300 hours of
service in the prepack program.
Volunteers with Amazon Promise use medicines provided
by MAP International at a clinic in Peru’s Amazon Jungle.
Photo provided by MAP International
38 Case Studies for Global Health
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MAP volunteers typically put together 200 Travel Packs at a time,
running the packs through an assembly line as they fill them with
medicines and supplies. “It’s really an amazing process,” says Jodi
Allison, senior representative for philanthropic services at MAP.
“Volunteers pack medicines in a very tight, predetermined fashion
so that no space within the boxes is wasted. This reduces the size of
the boxes needed and, thus, reduces environmental impact, which
is another one of MAP’s goals.”
Each box measures 17 by 14 by 11 inches and weighs between
20 and 30 pounds. The exact assortment of medicines varies
depending on supply. After the assembly process is completed,
MAP ships the Travel Pack directly to the medical professional who
will be traveling overseas.
In creating the Travel Pack program, MAP has partnered
with about a dozen pharmaceutical companies. Of these,
GlaxoSmithKline, Merck, Schering-Plough and Wyeth all have
dedicated donation programs to consistently supply MAP’s needs.
Larry Morris, manager of MAP’s Short-Term Medical Mission
Program, says such pharmaceutical companies help make the Travel
Pack program possible and keep each pack’s contents consistent.
The incentive for each company is slightly different, but all of them
benefit from getting their products into the hands of the people
who need them most, often in the most remote places in the world.
The many physicians who are served by the Travel Pack program
gain a greater awareness not only of the products produced by
the company but also of the philanthropic spirit of the company
that participates. The company gains an efficient outlet to refer
physicians when they ask for products to be used on short-term
medical mission trips.
“MAP realizes that branding is important to our pharmaceutical
partners,” he said. “We also know that the packs would not
be possible without their generous donations. In order to help
participating physicians recognize the key role our partners play in
the provision of the packs, MAP adds our major partners’ logos to
each pack.”
Morris also noted that MAP’s Short-Term Medical Mission
Program, which includes both Travel Packs and custom orders,
complements MAP’s Long-Term Health Development Program,
which provides bulk shipments of medicines and medical supplies
to partner organizations operating health care facilities overseas.
Anatomy of a Travel Pack
While Travel Packs may not be as uniquely tailored as MAP’s
custom order program (see sidebar), they contain sufficient supplies
to help with some of the common and important needs in the
developing world.
“The Travel Packs contain medicines for treating infections,
allergies, asthma and other illnesses,” Dohrenwend says. “The
boxes come packed with just about everything you could want for
just about everything you would treat. A lot of the diseases these
children face can be treated with antibiotics, so the antibiotics
that come in these packs are a major help to us. Also, many of
these people, children included, are only eating rice and beans,
so the vitamins are very helpful. And the oral rehydration salts
are instrumental because many patients are suffering from
dehydration.”
Dohrenwend also said that many of the medical needs of his
Haitian patients are similar to those of his patients in Mexico,
where he and other volunteers treat as many as 300 people a day.
Dohrenwend makes the 30-minute drive to the clinic across the
border about once every six weeks. The clinic, which lacks labs and
equipment such X-ray machines, is located in a barrio comprised
primarily of cardboard homes that stretch for about 15 miles along
the Tijuana River.
Volunteers with Amazon Promise use boats
to bring much-needed MAP International
medicines to villages in the Amazon jungle.
Photo provided by MAP International
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“We see a lot of asthma and pneumonia, in part because they burn
their garbage right next to the river,” Dohrenwend says. “Our
patients also typically suffer from malnutrition and frequent fevers.”
The commitments of the four major pharmaceutical contributors
have helped MAP maintain the program with a reliable supply
of essential medicines. For instance, Merck & Co., Inc., has
committed to supplying the program with three medicines in 2009
(Noroxin®, Pepcid®, and Singulair®). In order to get companies to
participate, MAP identifies the appropriate products from the items
manufactured by the company. MAP then develops a proposal
highlighting the products they need, how many of each item will
be included in each pack and how many packs they plan to ship
each year. When the company agrees to support the program, MAP
works with them on a shipping schedule that will allow appropriate
expiration dating for each pack shipped. It will often require the
companies to ship product two to three times per year.
Christine Funk, Merck’s associate manager for global public policy
and corporate responsibility says, said there have only been one or
two instances when Merck could not provide the entire assortment
of medicines MAP requested for the Travel Packs.
Hurdles and Challenges
In addition to determining how to maintain a consistent supply
of diverse treatments, MAP must also ensure the medicines have
appropriate expiration dates.
“For both short- and long-term programs, it is important that
MAP acquire and distribute medicines with acceptable expiration
dates,” says MAP’s Morris. “For our bulk medicines, which we ship
in 20-foot containers, we generally require a shelf life of at least
12 months. For short-term medical teams, a shorter shelf life of
six months is acceptable because the medicines are generally used
much sooner.”
While just-in-time manufacturing has eased the situation, MAP
employees say that expiration dates are still an issue. Scott Ruschak,
senior manager of MAP’s medicines program, says that 15 years ago
the average expiration date for donated medicines was two years; that
number is now less than one year. “That really limits what we can do
when we ship something on the ocean, because the shipping process
itself may take two months,” he says. “It means we have to look
harder for medicines with a longer shelf life.”
According to Dohrenwend, the demand for medicines on these
short-term missions sometimes outstrips the supply available within
one Travel Pack.
“We voluntarily supplement these packs,” Dohrenwend says. “For
instance, we may go to Costco to buy the industrial-size Ibuprofin.
And the Travel Packs contain Tylenol, but sometimes we need more
because it is the medication we distribute most for fevers and pain.
In addition, vitamins are very beneficial to people who are usually
on a diet of rice and beans. So, more vitamins would be helpful.”
Dohrenwend also suggests that MAP or other nongovernmental
organizations investigate how to use short-term medical teams to
help with vaccine-preventable diseases. It would be very simple to
save a number of young lives, he says.
Quantifying the Unfathomable
MAP measures the value of its Travel Pack based on the wholesale
value (determined by Red Book) of the products included in each
pack. The value of a Travel Pack differs since it is determined by a
rotating supply of medicines and medical supplies based on what
MAP receives for donation. The average value is $14,000.
MAP worked with a licensed pharmacist who calculated that
volunteer physicians have provided up to 700 medical treatments
using the contents of a single MAP Travel Pack. This number was
determined by examining the contents of an average pack and the
treatments included in each.
Photo provided by MAP International
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Another difficulty MAP has encountered involves measuring
the larger impact of the Travel Pack program on communities
that medical teams serve. While the organization has a successful
screening program and may know which three bottles of Singulair
or Noroxin went to Peru and with whom, due to the remote areas
in which treatment takes place, MAP is not always able to capture
outcomes.
“Medical teams are more concerned with providing compassionate
care to those who have lined up outside their makeshift clinics,”
says MAP’s Ruschak. “Having the teams, which visit these
communities on a short-term basis, quantify their impact is a
challenge. For many communities, there are few, if no other
alternatives.”
Ruschak and other MAP staff members perform regular field
assessments to speak with key hospital staff and other officials to
learn about a region’s medical needs. However, Ruschak says it is
impossible to visit all of the more than 115 countries MAP serves.
Morris says MAP’s long-term program was better equipped to
assess impact and numbers of patients treated. “Our clinic and
hospital supply program is better positioned to document how
many patients receive the benefit of MAP-supplied medicines,” he
says. “With the short-term mission program like the Travel Pack,
we prefer to speak in terms of the number of treatments we are able
to provide.”
Dohrenwend says that counting treatments is an easy way to
quantify the benefits of the program. “If each pack contains 700
medical treatments, each dose saves or improves a person’s life,
so each pack contributes to 700 lives, I would say. Take even
something as simple as an oral rehydration solution. If a kid has
diarrhea, you save his life with it,” Dohrenwend says.
Others, such as MAP’s Ruschak, draw conclusions from data
gathered by other organizations, such as UNICEF. UNICEF
reports that in Haiti, which is one of the top two destinations for
Travel Pack users, pneumonia causes 20 percent of deaths among
children under age five.
Still, MAP and its physician clients experience difficulties in
applying supply-chain science as best as possible in a human world,
Dohrenwend admits. “For example, one of the biggest killers in
Africa is cholera. How people respond to cholera is pretty random;
perfectly healthy people die quickly, while sick people might make
it through. There’s no way of quantifying who will make it through
in a situation like that,” he says.
Morris says the issue is difficult. “How can we know when
something could be done better or what can be improved?” he asks,
noting that MAP’s thorough qualification process is one source
of data. “This is a phenomenon that is taking place in short-term
missions as a whole in this country. There are about two million
individuals participating in short-term missions, including medical
missions, in the United States each year.”
However, Morris also says that MAP is in the process of increasing
its data-gathering faculties. “We just completed a survey process
that will hopefully address this very issue,” he says. The survey
allows physicians to assess and grade the contents of the Travel
Packs, give feedback as to what is and is not essential, and
recommend additional medicines to include. MAP provides the
survey to medical providers after they return from Travel Pack trips.
By John Otrompke, J.D.
Photo provided by MAP International
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While the Travel Pack may be one unique product MAP has
developed since it expanded from long-term medical relief,
the organization also offers health care providers a number
of other products as well. Here is a summary.
Custom Order Program
The Travel Pack is actually one of two integrated
components within MAP’s Short-Term Medical Mission
Program. The Custom Order option allows the mission
teams to supplement their mission pharmacy needs with
medicines and supplies on an a la carte basis, outside of
what is available within the Travel Pack.
“The Travel Pack has its limitations regarding emergency
disaster response,” says MAP’s Larry Morris. “When a
disaster hits, the kind of medical needs that exist can be very
different from one disaster to another depending on what
kind of disaster has struck. We respond to relief situations
uniquely, however, so that the Travel Pack is not a square
peg we’re trying to fit in a round hole.
“For example, when Cyclone Nargis hit Myanmar last year,
as part of our own relief efforts, we sent several Travel Packs.
We have them on the shelf so they’re ready to go. But when
the storms went through Haiti last year, we responded by
partnering with medical teams and quickly supplied them
with customized medical packs.”
Future growth within the Short-Term Medical Mission
Program could include other specialty prepacks, such as
pre/post natal vitamin packs, as well as expanding the
inventory selection with the custom order option.
The Johnson & Johnson Medical Mission Pack
Among other manufacturers, Johnson & Johnson Family of
Companies has two unique products with MAP. One, called
the Johnson & Johnson Medical Mission Pack, includes
the company’s Tylenol products and other over-the-counter
medicines. In addition, the Johnson & Johnson Medical
Mission Pack Plus includes over-the-counter medications as
well as antibiotics and other prescription products.
ETHICON Products
Johnson & Johnson subsidiary Ethicon also supplies
products to MAP, but they aren’t medicines. They’re sutures.
In fact, Ethicon provides about 182 types of sutures from
which physicians may choose. Morris said physicians use
the products for operations ranging from hernia surgeries to
repairing children’s cleft palates. For this service, providers
contribute to MAP a tax-deductible $35 service fee.
Other MAP Programs Provide Greater Flexibility and
Unique Branding Opportunities for Suppliers
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Lessons Learned:
• Submit an early request for clearance in each
country and follow up with constant communications
to prevent delays in formal country clearances and in
completing financial transactions.
• Starting on the first day of the project, invoke a sense
of ownership among all parties to ensure unfettered
collaboration.
• Reevaluate technical requirements and make sure
people on the ground are well-trained and have
enough equipment to do their jobs effectively.
• Check the collaborative chain for weak links.
It isn’t enough for agencies, governments and
law enforcement to agree to work together.
The technology and mechanisms for cooperation
must also be in place.
Global Interagency Efforts
Stem Counterfeit Drugs in
Greater Mekong Asia
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Drug-resistant strains of a variety of potentially fatal
diseases are appearing globally at an alarming rate.
Can the lessons learned in eradicating poor-quality
medicines that helped create particularly virulent and
drug-resistant malaria strains in the Greater Mekong be
used to prevent the rise of new strains in other diseases?
In the Southeast Asia/Western Pacific area, an estimated 10 to 35
percent of medicines are improperly made or illegally produced
and sold. The area’s high burden of malaria and elevated resistance
rates to treatment are, in many cases, directly attributable to the
proliferation of poor-quality medicines. Substandard medicines allow
the malaria parasite to survive and then develop resistance to existing
treatments. Beyond the loss of life suffered immediately though
the distribution of subpar medicines, a breeding ground for highly
virulent and resistant strains develops, from which untreatable disease
can eventually spread to kill thousands in many nations.
Finding and eradicating poor-quality drugs in the five-country
region — Cambodia, Thailand, Lao People’s Democratic Republic
(Lao PDR), Vietnam and Yunnan Province in China — has proven
an exhausting exercise. Medicines are sold across all five countries
in public (hospitals, health clinics and posts), private (hospitals,
clinics and pharmacies) and informal (illegal outlets) sectors
making drug collection, sampling and enforcement particularly
challenging.
In an effort to combat the problem throughout the region and
across its many borders, the United States Pharmacopeia Drug
Quality and Information Program (USP DQI) has closely
collaborated with the United States Agency for International
Development (USAID)/Regional Development Mission for Asia
(RDM-A); the USAID/Cambodia Mission; and the Ministries
of Health of Cambodia, Thailand, Lao PDR, Vietnam and
Yunnan Province (China). Together these organizations battle the
Sokpheap Cambodia Pharmacy
Photo by Chris Raymond
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devastating effects of counterfeit and substandard medicines readily
available in the Mekong region.
At the requests of USAID/RDM-A, USAID/Cambodia Mission
and the ministries of health throughout the region, USP DQI
developed a framework to support the governments in their quest
to improve the quality assurance and quality control (QA/QC) of
their medicines and create a comprehensive, sustainable program
to build technical capacity. The process required cooperation
and integral collaboration between each country’s ministry of
health (MOH), medicines regulatory authority (MRA), national
medicines quality control laboratory (NMQCL) national priority
disease control programs, surveillance site staff and, in some
instances, community health care workers. USP DQI secured
commitment from each through the drafting and signing of
memorandums of understanding from the beginning in 2003 until
2007. Currently, the organizations use contract agreements that
outline what USP DQI will provide and what the MRA and MOH
of the respective country will carry out each fiscal year.
Through close partnerships with country MRAs, NMQCLs
and national disease control programs for malaria, tuberculosis and
HIV/AIDS, USP DQI develops yearly work plans of proposed
activities. The USAID missions make decisions on which agreedupon
activities to fund and in what amount; USP DQI oversees
implementation of all activities according to an accepted
time line, making regular field visits to provide guidance and
monitor progress.
Counterfeit drugs are defined as those that are deliberately
mislabeled to obscure source and product identity. Some of these
are perfect mirrors of the drugs they copy; many more are not.
Substandard drugs are defined as legally branded or labeled but
the quality falls below international standards on quality, purity,
strength or packaging. Most commonly, substandard medicines
have one or more of the following qualities:
• lack an active ingredient but inactive ingredients are harmless,
• found to have poisonous or harmful ingredients,
• manufactured in poor conditions or smuggled past authorities,
• obtained registration in country because the medicines
regulatory agency was weak and could not properly evaluate
the application.
• have been improperly stored and/or transported resulting in a
tainting or reduction in strength of the active ingredient.
Since 2003 the Mekong region monitoring program has grown
from 17 to 39 sites and has broadened to include antimalarial,
antiretroviral and antituberculosis medicines, as well as oseltamivir
Trainees practice visual examination in Vietnam.
Photo by Chris Raymond
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(for treatment of avian influenza) and some commonly used
antibiotics. Through information gleaned from the USP DQI
monitoring program, countries have fined sellers of counterfeit
medicines, closed pharmacies, confiscated products and issued
regulatory warnings and notices to alert health professionals and
the public.
From Assistance to Arrests
In 2003 USAID asked USP DQI to provide technical assistance
to the ministries of health of these five Southeast Asian countries.
In response, USP DQI developed a framework to support the
governments in improving the (QA/QC) of their medicines. The
USP DQI also helped each government create a comprehensive,
sustainable program to build technical capacity.
USP DQI began by assessing the existing systems of each
country, including drug registration, quality-control laboratories,
procurement, storage and distribution, and post-marketing
surveillance efforts. It then collected data from the field on specific
antimalarial drugs to determine the quality of medicines in the
marketplace, present findings of gaps or weaknesses and design
individualized plans for improvement based on each country’s
priorities. After assessments were completed, USP DQI launched
the Antimalarial Medicines Quality Monitoring Program in
the Mekong subregion. The newly designed protocol leveraged
established sentinel sites.
In Cambodia, Lao PDR, Thailand and Vietnam, USP DQI works
closely with each country’s ministry of health; relevant government
agencies, primarily the MRAs; various institutions; and national
disease control programs for malaria, HIV/AIDS and tuberculosis;
national medicines quality-control laboratories; World Health
Organization; and INTERPOL. In Cambodia, Laos and Vietnam,
USP DQI supported the creation of interministerial committees
consisting of MOH, ministry of finance/customs, ministry of
interior/police, ministry of trade and prosecutors to collectively
work against counterfeit drugs and illegal outlets.
The USAID/RDM-A and the USAID/Cambodia Mission
have funded all related medicine quality-monitoring activities
in Cambodia, Vietnam, Lao PDR and Thailand since the
program began in 2003. Work in Yunnan Province of China was
discontinued in 2005 due to political sensitivities between the
U.S. and Chinese governments upon discovery of fake artesunate
samples found there.
Since monitoring began in 2003, more than 4,700 samples
have been collected and tested. USP DQI has supported and
encouraged collaboration among the ministries of health, other
country ministries and enforcement-related agencies to act on
negative results.
In one example, USP DQI contributed to Operation Jupiter, an
international enforcement action, by supplying sentinel site data
of medicines that were collected and tested as part of the Mekong
Region Medicines Quality Monitoring program. INTERPOL
and WHO coordinated the various partner efforts. Evidence
from chemical, mineralogical, biological and packaging analysis
suggested that at least some of the counterfeit artesunate was
manufactured in southeast China. This evidence prompted the
Chinese government to act quickly against the criminal traders
with multiple arrests and the seizure of approximately $2.7 million
worth of antimalarial products.
In another example: INTERPOL seized more than $6.65 million
of counterfeit medicines, some of which were for treatment of
malaria, HIV/AIDS, tuberculosis and other common infections in
Southeast Asia in 2008 and made 27 arrests, disrupting the region’s
fake drug trade for the second time in three years. The five-month
investigation, Operation Storm, involved almost 200 raids across
Cambodia, China, Laos, Myanmar, Singapore, Thailand and
Vietnam. Under Operation Storm, police seized more than 16
million pills, including fake antibiotics for pneumonia and childrelated
illnesses. The USP DQI program exposed the counterfeit
antibiotics and, working with country governments, provided the
pertinent information to INTERPOL to initiate investigations.
USP DQI focal point in Vietnam is
collecting samples at retail outlets.
Photo by Chris Raymond
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As a result of these and other measurable actions, the QA/QC
protocol that evolved has served as a model for activities in an
additional 21 resource-limited countries. This protocol was first
introduced into the Mekong region in 2003 and was presented
in 2004-2005 to USAID missions in other countries and regions
and to other donors to attract funding and support. The process,
framework and methodology used in the Mekong region has
since been transferred — with some adjustments to fit any given
country’s specific situation — to other countries in Africa and Latin
America.
From Design to Results
Results from the program are encouraging. Data collected in 2004
revealed the wide availability of poor-quality medicines. Most
notably, up to 44 percent of samples of artesunate, an antimalarial
drug, contained no active ingredient. In 2008, this figure dropped
below 20 percent. Of the 358 antimalarial samples collected and
tested, only 40 (11.2 percent) samples failed quality testing. Results
provided incentive for medicines regulatory authorities to expand
the USP DQI monitoring program.
USP DQI has designed country-specific sampling protocols
plus supplied necessary laboratory equipment and reference
standards for testing and trained almost 2,500 individuals to
date. Additionally, it has facilitated numerous local and regional
meetings to benefit communications among principals. The
country governments that have requested USP DQI assistance
state that their motivations are to improve health conditions in
their nations, reduce the prevalence of counterfeit and substandard
medicines, and restore public confidence in their ability to ensure
safe, effective medicines in the marketplace.
Since sophisticated laboratory facilities are rarely available in
the field, USP DQI teaches simple, practical methods for early
detection of substandard and counterfeit drugs. To reach rural areas
where the disease burden is generally higher, USP DQI supplies
surveillance sites with portable laboratories, known as Minilabs,
designed by the Global Pharma Health Fund. The Minilabs
contain the necessary equipment, reagents and secondary reference
standards to test medicines for presence and content of the active
ingredient and its ability to disintegrate properly.
Local analysts, usually pharmacists and community health workers
from ministries of health, are trained to perform basic tests: visual
inspection, disintegration and thin layer chromatography, for
example. In addition to basic tests, USP DQI has also designed a
protocol and training program in sampling techniques.
The 37 active sentinel sites in the Mekong region were selected in
close collaboration with each country MOH based upon its specific
national priorities. Some sites were chosen due to substantiated
or anecdotal evidence on the prevalence of counterfeit medicines,
especially at the border areas, which are prone to illegal activity.
Other sites were targeted due to the high burden of malaria or
elevated resistance rates to malaria treatment, which can indicate
the presence of poor-quality medicines.
But this is not to say that the project has proceeded unimpeded
by obstacles. Implementing medicines quality monitoring at
the country level has been slow at times, primarily in the initial
stages, according to USP DQI officials. Collaborating with four
separate country governments greatly magnified normally “simple”
challenges, such as processing equipment and supplies through
time-consuming formal country clearances, completing financial
transactions, and making arrangements to the satisfaction of all
parties. Differences in country quality assurance/control systems
and language barriers — which could become confusing in the
translation of sampling and testing protocols, for one thing —
added another layer of delays.
Despite careful planning, a few unwanted surprises appeared
along the way. For example, technical issues surrounding sampling
procedures and testing developed in areas USP DQI had not
anticipated. Some rural area sites had difficulty collecting the
required quantity of samples for testing and verification, and some
countries lacked adequate equipment at the national laboratory
to carry out verification testing. From field visits, it also became
apparent that some of the trainees needed further reinforcement
of basic sample collection and testing skills. To overcome these
challenges, USP DQI amended the sampling protocol; reduced the
number of units per sample to be collected; provided necessary lab
equipment, reference materials, reference substances and reagents;
Christopher Raymond demonstrates Minilab to
INTERPOL inspectors.
Photo by Chris Raymond
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trained sample collectors on analytical methods; and conducted
refresher training for field staff.
Forming a Multi-Dimensional Partnership
The relationships between many of the agencies have cemented over
time and through many projects. The United States Pharmacopeia
is a 185-year-old, not-for-profit public health organization whose
mission is to improve the health of people around the world through
public standards and related programs that help ensure the quality,
safety and benefit of medicines and foods. The USP DQI program,
a cooperative agreement between USP and the U.S. Agency for
International Development, focuses on advancing the health care of
people in resource-limited countries.
USP DQI has maintained a longstanding relationship with
USAID regional and country missions and takes an active role
in the agency’s annual process of scheduling and budgeting
activities through approved work plans. The work plan process is
a collaborative effort in which all partners participate to determine
priority activities. Separate work plans are proposed to each
participating USAID mission and then reviewed collectively in
a regional partners’ meeting to eliminate duplicative efforts and
to coordinate activities. The process is similar with any other
agency funding USP DQI projects, such as the World Health
Organization.
USP DQI determines in which countries activities will take
place and where technical assistance is most needed. The USAID
missions make decisions on which agreed-upon activities to fund
and in what amount; USP DQI oversees implementation of all
activities according to an accepted time line, making regular field
visits to provide guidance and monitor progress.
USP DQI’s medicines quality monitoring project in the Mekong
region is funded primarily by the USAID/RDM-A and USAID/
Cambodia Mission. Supplementary funding on topical aspects, for
instance, testing the quality of medicines for avian influenza, may
be provided by USAID/Global Health Bureau, Office of Health,
Infectious Diseases and Nutrition.
Despite the effectiveness of this extraordinary web of collaborators,
relationships can and do remain delicate and occasionally lack
Family in clinic in Stung Treng Province, Cambodia.
Photo by Chris Raymond
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A Cambodia Undersecretary of State speaks
with an unlicensed drug seller.
Photo by Chris Raymond
conformity. Although all five countries experience many of the
same problems, common goals and the willingness to work for
common good are often lacking. Some key partners lack the
financial resources for collaborative activities or the motivation
to cooperate.
To bring the principals together and build alliance, USP DQI
helped key partners find common ground and the trust to
share data through numerous face-to-face meetings. USP DQI
initiated discussions to obtain their support and encouraged
their involvement as an integral part of the USP DQI project
management team. This approach has created a sense of ownership
in the program among the partners and resulted in demonstrated
efforts of mutual cooperation.
Sharing information among relevant agencies within a country and
between countries has been slow and ineffective, particularly among
national law enforcement agencies and among medicines regional
authorities, report USP staff. Consequently, when counterfeit
or substandard samples are discovered in the field, weak or
nonexistent information-sharing systems can further delay action.
Some of the factors that contribute to the problem stem from
underdeveloped human resources, fewer technology resources and
poor or restrictive regulatory procedures. In many cases, the main
problem is there are no effective mechanisms for collaboration in
place. USP DQI had to make the case for collaboration and then
help build the bridges needed for the collaboration before the
primary work could begin.
The Future
USP DQI’s future plans involve making medicine quality
monitoring sustainable within each country’s own governmental
construct. To that end, the plan calls for the MOH, MRA and
NMQCL to gradually pick up the costs of sampling collection,
testing and necessary reagents, reference standards, supplies and
travel plus payroll costs for associated staff time. USP DQI and
USAID hopes that these programs will become self-sustaining in
the foreseeable future.
Meanwhile, USP DQI will be working with the ministries of health
and other stakeholders to explore possibilities for leveraging other
sources of funding such as from The Global Fund to Fight Aids,
Tuberculosis and Malaria, and WHO. DQI could help the country
develop a proposal to The Global Fund, for example, together with
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WHO and the ministries of health, to include key aspects of QA/
QC of medicines. These efforts work toward eventual government
sustainability and, thus, gradually phase out activities that donors
will fund.
Beyond these measures, USP DQI’s future plans call for project
expansion in both scope and reach:
Supporting regional or south-south collaboration and
capacity building: Regional support can play an important role
in strengthening national capacity and ensuring its sustainability.
In this context, the USP DQI program plans to build sustainable
capacity, where appropriate, by establishing regional centers of
excellence that can serve as a technical resource in quality assurance
of medicines for less-developed countries in Latin America, Africa,
Southeast Asia or any other applicable region.
Participating in international initiatives to combat substandard
and counterfeit medicines: USP DQI provides technical
assistance in the form of training, facilitation of communication
and reporting field sampling and testing data to INTERPOL. A
primary objective of this collaboration is to assist in providing
evidence for enforcement actions taken by INTERPOL, customs
and police resulting from data generated from medicine quality
monitoring programs. These actions are designed to disrupt the
international trafficking of illegal, counterfeit and unregistered
drug products in countries where USP DQI has a presence.
Increasing community outreach to raise awareness about
counterfeit and substandard medicines: In collaboration with
nongovernmental organizations (NGOs) that provide communitybased
services and other local players, such as pharmacists, USP
DQI will attempt to raise public awareness through community
outreach. Often, the first person patients seek for medicines and
medical advice is a community pharmacist; in some countries, there
is a lack of enforcement or an inability to disseminate information
on poor-quality medicines. In such cases, it is necessary to reach the
public through alternative routes.
USP DQI’s plans include working with a broad spectrum of
global partners and expanding collaborations with international
organizations and country partners. Some of the organizations
include: WHO, USAID, the Bill & Melinda Gates Foundation,
The Global Fund, INTERPOL, MeTA Alliance, and many local
nongovernmental organizations, among others.
By Pam Baker
Members of the President’s Malaria Initiative team were accompanied by Dr. Souly
Phanouvong of USP DQI on visits to two cross-border provinces — Chanthaburi,
Thailand, and Pailin, Cambodia (shown) — both high malaria-resistance emergence
areas where USP DQI has medicines quality monitoring activities.
Photo by Souly Phanouvong
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Lessons Learned:
• Innovative collaborations that include flexible
research teams from different institutions help to
provide new insights into the vaccine puzzle.
• Collaborations require open communications
between members and strong scientific leadership.
• Special agreements that allow sharing of
intellectual property rights are an essential
foundation.
• Strong administrative and financial support enable
the collaboration’s researchers to focus on going
beyond the mainstream.
Breaking Down the
Barriers to Sharing Knowledge
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Participation in the AIDS Vaccine Consortia (AVC) requires
adherence to a master agreement that provides a blueprint
for the AVC research program and the set intellectual
property procedures.
Photo by Chris Hondros/Getty Images
Developing an HIV vaccine has proved a very difficult
project. The International AIDS Vaccine Initiative
(IAVI) has, in response, created a model scientific
collaboration to search for breakthroughs. The IAVI
AIDS Vaccine Consortia started with a consortium to
create a vaccine that would elicit neutralizing antibodies.
It has since added two more. The consortia act as
virtual laboratories consisting of geographically distant
researchers who readily share their findings across
institutional boundaries. A major startup issue was
developing an intellectual property master agreement
that dovetails with the policies of the researchers’
institutions. The agreement grants IAVI an option to
license program inventions while giving all participating
organizations a share of any future licensing revenues.
IAVI provides secure financing and covers most of the
administrative work, thus freeing scientists to focus on
their research to an unusual degree.
HIV presents a formidable challenge for vaccine developers.
To block the virus’ invasion, immune responses have to target
constantly shifting viral proteins. In terms of viral diversity, “If flu
is my fist, then HIV is the size of this room,” says Seth Berkley,
president of IAVI. In addition, the HIV envelope is wrapped in a
mantle of captured human cell membrane material. This mantle
protects viral particles from immune recognition and attack.
Finally, there is no adequate animal model for HIV infection.
IAVI was founded in 1996 to promote development of a globally
affordable and accessible HIV vaccine. It supports HIV vaccine
research by partnering with academic, corporate and government
institutions. Since 2001, it has also developed its own research
facilities.
HIV has proved too complex for the individual investigators trying
to develop novel solutions in his or her separate institutions. IAVI
emphasizes the use of “industrial-style project management” to
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Illustration of neutralizing antibodies attaching to HIV
Credit: Samuel Velasco/5W Infographics
prioritize the most promising vaccine strategies and quickly form
ad hoc teams to investigate them.
To facilitate this interorganizational collaborative approach, IAVI
has created a system known as the AIDS Vaccine Consortia (AVC).
By 2009, the AVC network combined the efforts of researchers at
21 organizations across the globe.
Creation of the Neutralizing Antibody Consortium
Traditional vaccines teach the body to produce antibodies against
the virus in question. Antibodies are Y-shaped proteins tailored to
attach themselves to specific viral proteins. Neutralizing antibodies
can block the virus from entering cells and reproducing. HIV
researchers in recent years have largely focused instead on “cellmediated
immunity.” This part of the body’s immune defense
involves white blood cells that eliminate cells already infected by
viruses. But vaccines based on cell-mediated immunity, such as the
one Merck had to abandon, have had disappointing results so far.
The generated immune responses have been too weak, nor could
they compensate for the shape-shifting propensity of HIV proteins
even if they had been stronger.
At the beginning of this decade, Wayne Koff, IAVI’s senior vice
president for research and development, decided to take another
look at antibody research. Papers published in 1999 and 2000
showed that administering antibodies completely protected
uninfected macaques. Koff says that when IAVI surveyed the
ongoing research, “We found many investigator-initiated small
grants and no industrial-style, mission-oriented programs.”
In line with Koff ’s critique, IAVI established the Neutralizing
Antibody Consortium (NAC) in 2002. The initial consortium
included researchers from four institutions: The Scripps Research
Institute (La Jolla, Calif.), the University of Pennsylvania School
of Medicine (Philadelphia), Weill Medical College of Cornell
University (New York City) and the Dana-Farber Cancer Institute
(Boston). In addition, the NIH’s National Institute of Allergy and
Infectious Diseases (NIAID) agreed to support the consortium
through its Vaccine Research Center.
IAVI fully funded the consortium startup with its own resources.
It has continued to do so over the years, allowing NAC members
to spend more time in the lab and less in the office writing
grant proposals. Robert Doms, the initial NAC researcher at the
University of Pennsylvania, says that he was delighted with the
financial freedom the consortium provided. “IAVI has allowed me
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to concentrate on more risky research,” he says. In contrast, “The
NIH tends to put its outside grants into further developed, less
speculative projects.”
The NAC became a virtual research center. It provides a means
for the scientists to share their thoughts and observations across
institutions. “In forming the NAC, groups agreed to several basic
principles,” says Koff. “These included early sharing of data, candor
around the table and shared intellectual property. We wanted
to ensure that all members would benefit from the consortium’s
success and that the developing world would have access to a
vaccine.”
The NAC has since grown to 15 member institutions, including
organizations in the U.S., Europe and Asia. It has established
four priorities based on the research gaps members noticed. These
are: understanding antibodies’ molecular activity, elucidating the
interaction between HIV proteins and antibodies at the atomic
level, developing technology to assist in vaccine design, and
screening HIV protein sequences for use in a vaccine. The order of
these priorities shifts from year to year as research proceeds.
Two New Consortia
Building on the NAC model, IAVI has added two new consortia in
recent years. Members of each consortium include different subsets
of the NAC membership plus several new organizations.
In 2006, IAVI established the Vector Consortium (VEC), which
now has eight institutional members including IAVI. Like the
NAC, the VEC covers a neglected aspect of HIV vaccine research.
In the interests of safety, HIV vaccines under development
generally utilize genetically engineered viruses (viral vectors) that
do not cause major disease in humans. These viruses are altered
to carry HIV proteins and to be nonreplicating. Their ability to
provoke a protective immune response has turned out to be rather
weak. The VEC’s purpose is to investigate replicating viral vectors.
“We are looking at most stimulating kinds of vectors, the live
vector ones and work on how we would create a useful vaccine,”
says Koff.
If replicating viral vectors pose some danger of causing disease, an
attenuated HIV vaccine causes even more shivers. Such a vaccine
might turn out to be not so attenuated in some people, resulting
in HIV disease. This problem occurs with the live polio vaccine.
Yet the only vaccine that has proved protective in a monkey model
is an attenuated virus. (That vaccine was fully protective only
against the same strain of virus as was in the vaccine. It also caused
immune deficiency in some monkeys.) IAVI initiated its Live
Attenuated Consortium in 2007 to study the immune response to
this type of vaccine. The consortium hopes to learn what the key
elements are that make the attenuated virus vaccines protective.
Researchers could then apply the lessons learned when designing
safer candidate vaccines.
A New Regime for Intellectual Property
Intellectual property (IP) rights are critical to IAVI’s goal of
ensuring that an HIV vaccine reaches developing countries at
a reasonable price. Achieving this goal required considerable
ingenuity when drawing up the consortia’s master agreement.
IAVI and the other founding institutions constructed a durable
IP arrangement that grants IAVI the option to license any AVC
inventions including enabling background technology. Revenues
resulting from development of these inventions will be shared
within each consortium according to an agreed-upon formula.
“It took two years of negotiations to hammer out the IP details
before executing the master agreement,” Lita Nelsen, director
of the Technology Transfer Office at the Massachusetts Institute
of Technology, advised the nascent NAC. The agreement went
through 10 or 12 preliminary drafts. Nelsen says, “Traditionally,
universities collaborate but recognize that they have competing
interests: what’s mine is mine and what’s yours is yours. But here,
the researchers just wanted to end a world scourge. Good will can
accomplish a lot.” The consortium concept offered a number of
financial and organizational benefits, so the researchers pushed to
make it work.
IAVI receives an exclusive licensing option for any discoveries
in return for funding the research. If IAVI decides to exercise its
option, it pays the patent application fee and gets the rights in the
area of HIV vaccines. The inventing institution receives the largest
share of any royalties that result, and IAVI receives a smaller share.
The remaining royalties are split among the other consortium
members. “The agreement keeps people at the table, sharing their
ideas. If anyone makes an invention, well, they likely would not
have gotten there without the team brainstorming,” says Koff.
The issue becomes more complicated if multiple institutions
contributed concretely to a particular invention. If that is the case,
all the contributing organizations share in the major inventor’s
portion of the revenues. IAVI’s patent counsel is available to help
resolve patent issues.
All new consortia members have to make a commitment to the
AVC research program and the set IP procedure. As agreed by the
founding members, participation requires accepting the master
agreement on a take-it-or-leave-it basis. A separate Cooperative
Research and Development Agreement (CRADA) governs the
research contributions of the NIH, NIAID’s Vaccine Research
Center. The CRADA states the U.S. government’s standard
technology transfer and licensing terms. In 2007, IAVI signed
another supplementary agreement with the Indian government’s
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Department of Biotechnology (DBT). This agreement allows the
Neutralizing Antibody Consortium to work with two Department
of Biotechnology-funded institutes. It also envisions using Indian
manufacturers to produce reagents for vaccine design.
One alteration to the consortia’s master agreement took place
in 2007, when the VEC received a major grant directly from
an outside source, the Bill & Melinda Gates Foundation’s
Collaboration for AIDS Vaccine Discovery (CAVD). The Gates
Foundation requires prompt dissemination of CAVD-funded
findings and materials to the broader scientific community so as
to speed HIV vaccine research. It also requires that any vaccine
arising from CAVD research be accessible to people in developing
countries. Since the Gates Foundation requirements are consistent
with IAVI’s standard policies, they did not greatly alter the sense of
the AVC’s master agreement.
Organizational Structure
IAVI ultimately incorporated the three consortia into a single
organizational structure, the AVC. A management committee
composed of senior IAVI scientific executives oversees AVC
operations. This committee reviews the work of the participating
research centers and sets organizational priorities to improve
integration and efficiency. It also helps revise the research agenda
for each consortium, whose work plan is supervised by each
consortium’s individual scientific director (or a consortium
executive committee in the case of the NAC).
These scientific directors are critical to the operation of each
consortium. They supervise the science program and consult with
consortium members on a daily basis. They also conduct frequent
work meetings as well as a larger AVC science update meeting.
Researcher recruitment is another task within the scientific
directors’ responsibility. The directors put together a coherent
group to achieve the consortium’s goals, adding new members to
fill any gaps that appear. They are, therefore, in charge of building
the critical team spirit for the collaborative effort.
Koff, who is also the AVC executive director, says that, overall,
“The idea is to relieve the researchers of the grunt work and free
them to do the science.” IAVI’s Business Development Department
has developed agreements with contractors to do the standard
evaluations to expedite data management. The business team also
draws up material transfer and licensing agreements needed for
research materials such as antibodies, reagents and delivery systems
for animal testing. Finally, it manages the licensing of IP coming
from the AVC.
Each consortium has an IAVI-hired project manager, too. These
project managers work with the researchers to obtain needed
testing and materials outside the consortium. They also complete a
lot of the standard paperwork and reports.
Extending the Collaboration
IAVI’s Clinical Protocol G Program is a major ongoing NACrelated
project that illustrates how the collaborations within the
AVC are branching out. This study is screening antibody samples
from 1,200 people with HIV spread across Africa, Thailand and
the United States. So far, two new potent broadly neutralizing
antibodies have been discovered.
The AIDS Vaccine Consortia model is designed to
relieve researchers of nonscientific, business activities
in order to free them to do scientific research.
Photo by Julianna Thomas Photography
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Beyond the NAC, Protocol G involves participation by an
international network of Clinical Research Centers organized
by IAVI as well as outside research institutions. Neutralizing
antibodies uncovered by IAVI and its collaborators will aid vaccine
design work at the NAC and elsewhere. In the meantime, the work
on Protocol G has further honed the capabilities of the Clinical
Research Center’s network during a dry spell in actual vaccine
trials.
In a move to expand the NAC’s work, in September 2008 IAVI
and The Scripps Research Institute announced the establishment
of the IAVI Neutralizing Antibody Center, in La Jolla, Calif.
Scripps and IAVI scientists will work together at this laboratory
center, and IAVI has committed $30 million in funding over a
five-year period. The new facility will complement the capabilities
of IAVI’s other two research laboratories, the AIDS Vaccine Design
and Development Laboratory (Brooklyn, N.Y.) and the Human
Immunology Laboratory (London).
Researchers at these labs have become members of the AVC so
that there is a tight connection between the IAVI facilities and the
geographically disparate consortia. University of Pennsylvania’s
Doms says, “IAVI is moving to a model in which real centers are
embedded in virtual centers. This model will bring an appropriate
organizational scale to a difficult problem.” The synergy from
bringing the new and old AVC components together in this
novel multilayer organization can engender shifts in researchers’
perspectives. New approaches to the HIV vaccine puzzle may
result. That, at least, is the hope in this period when the way
forward is still unclear.
By David Gilden
Illustration of viral vectors into which
HIV gene(s) have been inserted
Credit: Samuel Velasco/5W Infographics
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Lessons Learned:
• With strong in-country leadership, sufficient staff
training and infrastructure investment, it is possible to
establish HIV research centers in developing countries
capable of conducting HIV vaccine trials meeting
international standards.
• There are a number of epidemiologic and immunologic
studies that will contribute to the science of HIV
vaccine development and can be conducted at the HIV
vaccine trial centers.
• The vaccine trial centers can conduct studies of other
vaccines or other prevention technologies; this flexibility
is important as medical research evolves.
HIV Vaccine Trial Centers
Forge Research Network in
Developing Countries
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Pontiano Kaleebu, assistant director of research at the
Uganda Virus Research Institute, and colleagues are at the
forefront of the AIDS vaccine research program in Uganda.
Photo by Vanessa Vick
An HIV vaccine promises to be the magic bullet that
ends the AIDS epidemic. Even a partially effective
vaccine could gradually diminish HIV’s impact.
According to the latest estimates by the International
AIDS Vaccine Initiative (IAVI), new infections would
decrease by a quarter if a 50-percent effective vaccine
reached just 30 percent of the global at-risk population.
But any level of vaccine protection has proved elusive
despite 25 years of effort.
The long wait has only increased the sense of urgency. This decade
has produced a number of vaccine candidates, and IAVI has
emerged as a major player in the race for realizing an HIV vaccine
accessible to all who need it. By 2000, IAVI was already cultivating
connections with academic and corporate researchers to accelerate
a pipeline of potential vaccines making their way to human trials.
To ensure that such products work, vaccine candidates must
undergo human testing in Africa and Asia, where the bulk of new
infections occur. Regional factors may require adjustments in the
vaccine’s composition. Different HIV subtypes are prevalent, and
local differences in immune response may exist due to genetic and
environmental factors.
IAVI, for this reason, has developed clinical research collaborations
in eastern and southern Africa and in India. Working with local
researchers, the organization has helped strengthen clinical research
facilities’ physical and human resources so that when a promising
vaccine candidate is ready, there will be a trial network prepared to
test it.
At first, IAVI staff thought that a vaccine could be rapidly pushed
to fruition. Pat Fast, M.D., Ph.D., IAVI’s chief medical officer
recalls, “I started working with IAVI in 2001. We had one person
in Kenya. I was told to prepare for efficacy trials in three years.
We couldn’t just go to a CRO [contract research organization].”
Efficacy trials involve thousands of trial participants distributed
over a number of locales. IAVI decided to build on the existing
resources to rapidly ramp up local trial capabilities. As it turned
out, none of the available vaccine candidates performed well
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enough in early trials to justify moving them into the more
advanced efficacy studies. The network IAVI established
nonetheless has proved valuable in gathering the data needed to
more efficiently develop and test future vaccine candidates. It has
also enabled local investigators to study additional HIV prevention
measures. Their research outlook has broadened to include other
diseases, as well.
Upgrading Existing Capacity
When IAVI started considering bringing HIV vaccine trials to
developing countries, capacity was limited for both conducting
clinical trials and performing sophisticated laboratory testing.
IAVI’s vision encompassed long-term capacity building; it wanted
to create integrated trial centers able to do their own lab work and
data collection. The goal was to establish a network prepared to
do early, small clinical trials at first and then graduate to larger
efficacy studies.
In 2001, IAVI sent a survey to about 50 facilities, asking about
trial capabilities and local HIV epidemiology. Site visits followed.
According to Fast, “The most important thing we were looking
for was African leadership. Next was high HIV rate — you have
to go where the risk is — and after that came the willingness of
the researchers, community and government to work with us.”
Infrastructure and staff training were lower on the list because these
were “fixable.”
IAVI ultimately agreed to partner with researchers at 11
institutions, which became designated as Clinical Research
Centers (CRCs). These centers involved partnerships with local
research organizations in six countries: Uganda, Rwanda, Zambia,
Kenya, South Africa and India. All the CRC facilities except some
South African locations needed extensive renovations or new
construction. A clinical trial unit has to collect a broad array of
health data to check on safety as well as efficacy. It looks something
like a modern doctor’s office, with a waiting room, exam and
counseling rooms, HIV testing facility and bathrooms to collect
urine samples. Labs to analyze biological specimens are required
to diagnose HIV infection and evaluate vaccine safety. These labs
need a standardized set of equipment and external quality assurance
systems to assure that results from different trial units
are comparable.
This huge organizational effort entailed shipping elaborate, hightech
equipment from distant manufacturers while at the same
time working with local contractors. Regulations and construction
practices were a little different in each country.
Lab staff throughout the clinical research network are trained in
good clinical practices — international standards against which all
clinical trials are conducted.
Photo by Jean Marc Giboux/Getty Images
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To successfully conduct multi-site trials, the CRCs have to adopt
a uniform set of operating procedures. Leslie Nielsen, IAVI’s
country director for Uganda, notes, “The Uganda CRC staff
conduct research in Uganda according to the highest international
standards. But the doctors and nurses here treat patients under very
difficult conditions and have a heavy workload. In a clinical trial,
you need rigorous recording of adverse events and the other data.”
New medical personnel need education in internationally accepted
good clinical practice. Lab staff requires training in good clinical
laboratory practices. This training is coordinated by IAVI’s Human
Immunology Laboratory in London and at the University of the
Witwatersrand’s Contract Laboratory Services in Johannesburg.
Quality assurance testing ensures continued consistency of lab
assays across the network.
An intensive education effort also takes place within the
communities that provide trial volunteers. Communities need
to understand how a vaccine trial operates in addition to basic
information on HIV transmission and disease. This information
can be conveyed through community meetings and educational
outreach materials. To provide informed consent, the actual trial
volunteers require much more specific counseling on the details of
the study and the risks and benefits they incur, if any. There are also
a number of study benefits, as participants receive HIV prevention
counseling and testing. When needed, they also receive care and/or
referrals for HIV, sexually transmitted diseases, reproductive health
issues and basic medical issues. All these efforts, of course, involve
training staff in counseling and advocacy skills.
Local personnel directly manage community programs, and they
have taken over the scientific activities, as well. IAVI maintains
a trial monitor staff to ensure that proper trial procedures are
followed. Megan McBride, IAVI’s senior director for clinical
operations, says, “There’s still a lot of communications between
IAVI headquarters and the CRCs, with frequent visits. But the
centers are now performing at a high level, so they don’t need so
much supervision or training anymore.”
Vaccine Preparatory Studies
With the vaccine pipeline constricted, the CRCs have moved into
vaccine preparatory studies. The studies involve tracking HIV
incidence in large cohorts so as to identify high-risk populations
for future vaccine efficacy trials. Another study evaluates the
immunologic and virologic responses in volunteers recently
infected with HIV. There are also studies evaluating persons
showing possible resistance to HIV: either because they are able
to control virus levels over time without antiretroviral medication
or appear to be high-risk “exposed but uninfected” persons. These
immunologic/virologic studies are useful in determining protective
immune responses that an HIV vaccine should trigger or mimic.
The study tracking HIV incidence has had to adapt to an evolving
HIV epidemic. Observed HIV incidence has been lower than
expected in certain groups, possibly related to extensive counseling
and testing programs. The CRCs have enhanced their flexibility
by broadening the high-risk populations they recruit. Aside from
commercial sex workers, the centers follow discordant couples (in
which one partner is HIV-infected and the other is not) and men
who have sex with men.
Stigma remains strong against HIV infection and the risk activities
associated with it. The CRCs have had to create a safe, nonjudgmental
atmosphere in which study volunteers from each risk
group can feel comfortable. Doing this involves staff with special
sensitivity training and the creation of protected meeting places.
“The objective is to conduct effective HIV prevention research in
an environment of confidentiality and sensitivity to the needs and
safety of the study volunteers,” says Pauli Amornkul, M.D., IAVI’s
regional medical director, formerly based in Kenya.
The protection of study volunteers’ confidentiality,
health, welfare and human rights are central to
HIV-prevention research conducted in IAVI’s
network of clinical research facilities.
Photo by Vanessa Vick
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A completed, published study measured standard clinical
laboratory values in healthy Africans (see E. Karita et al. PLOS
One 2009, 4(2):e4401). It analyzed the test results from 2,100
volunteers throughout the trial network to create local standard
reference ranges for blood values and organ function. By United
States and European standards, a third of these volunteers would
have been ineligible for vaccine trials although their test results
were within the normal range for Africans.
Individual Research Centers
Kenya: The first CRC collaboration was in Kenya. It expanded to
centers in Uganda, Rwanda and Zambia before adding branches in
South Africa and India.
The studies in Kenya take place at three locations. Two are in
Nairobi and associated with the Kenya AIDS Vaccine Initiative
based at the University of Nairobi. One installation is at the
medical school, in Kenyatta National Hospital. The second is in the
impoverished west Nairobi district Kangemi. It originally made use
of converted shipping containers; these have been partially replaced
by new construction. Another CRC, on the northern Kenyan coast,
is run by the Kenya Medical Research Institute, which, like the
University of Nairobi, is a government institution.
The principal investigator in Nairobi, Professor Omu Anzala,
Ph.D., recalls the steps that led to his role in initiating the CRC
network: “I was doing my postdoctoral work at the University
of Oxford’s Institute of Molecular Medicine. My lab was
already constructing an HIV vaccine, and IAVI was looking to
sponsor trials. We made a proposal to IAVI, and I was given the
responsibility to set up trials for the vaccine in Kenya.”
The vaccine in question involved “naked” HIV DNA plus a
booster immunization with MVA, a weakened form of the small
pox vaccine virus. Researchers genetically modified the MVA
booster to produce HIV proteins. IAVI’s original plan was to move
this candidate vaccine into advanced human trials after preliminary
testing. However, the responses to the MVA and other early
vaccines did not appear sufficiently protective, and scientists started
working on alternate vaccine designs.
Aside from the stigma attached to groups with high HIV risk,
Kangemi and other crowded, poverty-stricken Nairobi districts
with high HIV rates have their own stigma arising from a history
of violence and lawlessness. Anzala says that the challenging
environment has not disrupted his studies. “We started slowly,”
he says. “We worked with community groups and educated the
community. The community respects us. We have been there eight
years, and we don’t have any problems.” The Kangemi facility is
also a neighborhood health care resource. It works with a nearby
city clinic to ensure that study volunteers receive proper health
care, including HIV treatment if they need it.
Rwanda-Zambia: The idea of studying discordant couples comes
from Susan Allen, M.D., an Emory University (Atlanta) professor
who directs the Rwanda Zambia HIV Research Group. This group’s
three CRCs (Lusaka, Zambian copper belt, Kigali) joined the IAVI
network in 2003 and 2004. Allen went to Rwanda in 1986. She
ran an HIV prevention and research program there until the 1994
genocide. Allen’s group then moved to Zambia, returning later to
Rwanda. She became interested in discordant couples during the first
Rwanda period, when women in her HIV prevention projects asked
her to involve their husbands in counseling.
IAVI fosters partnerships with local clinical
research centers to build scientific capacity in
countries heavily affected by the AIDS pandemic.
Photo by Vanessa Vick
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Allen’s latest studies indicate that 80 percent of new HIV
transmissions take place within such couples (see K. Dunkle et al.
Lancet 2008, 371:2183-91). For that reason she has become a prime
advocate of couples counseling, a practice that has become a normal
procedure in IAVI trials. Allen says, “I would have a problem with
any study that didn’t include partner counseling. We know the
impact. It can increase condom use to 80 percent of sexual acts and
reduce heterosexual transmission by at least two-thirds.”
The Rwanda-Zambia group identified more than 4,200 discordant
couples between July 2003 and December 2005. This population
forms a substantial base for the heterosexual transmission study
cohort, which IAVI began funding in 2004. The study was
following about 1,240 HIV-negative members of cohabiting
discordant couples as of April 2009. Researchers check these
volunteers’ HIV status monthly or quarterly. The cohort feeds into
the CRC study of recent HIV infection. The Rwanda-Zambia
group is also engaged in vaginal microbicide trials, which can also
advance the study of HIV prevention within discordant couples.
Uganda: Uganda contains three CRCs: one established in
partnership with the Uganda Virus Research Institute (UVRI)
directly and two with UVRI and the U.K.’s Medical Research
Council (MRC). UVRI is a long-established research organization
dating back to 1936. In 2002, Pontiano Kaleebu, M.D., Ph.D.,
a highly trained scientist educated in Uganda and the United
Kingdom, emerged as the point person for founding a CRC. He
became its principal investigator and is now assistant director of
research at UVRI as well as head of basic sciences at the MRC/
UVRI partnership.
Kaleebu had participated in an earlier Ugandan HIV vaccine trial
funded by the U.S. National Institutes of Health (NIH) and was
looking for ways to continue HIV vaccine research. Leslie Nielsen,
who became the IAVI country director for Uganda, had also been
part of the NIH trial’s Uganda investigative team. In addition,
Jill Gilmour, Ph.D., the head of IAVI’s Human Immunology
Laboratory in London, had worked in Uganda and was familiar
with UVRI. She was able to coach the local lab team in meeting
international standards. Nielsen comments, “The university here
is excellent. The doctors and nurses are well educated and quite
prepared to adopt new methods.”
Although the initial team was relatively easy to assemble, physical
infrastructure was lacking. UVRI is a branch of the Uganda
Ministry of Health, which has preferred to concentrate its scarce
funding on treatment rather than research. The CRC started with
a vacant piece of UVRI land that was previously a medical waste
dump. IAVI had to build from the ground up. It constructed
completely new offices, clinic and lab.
The center worked on an early trial of the same Oxford vaccine
candidate studied in Kenya as well as a preliminary trial of another
type of vaccine utilizing a bioengineered nonpathogenic virus.
The CRC network meanwhile expanded to include two Uganda
facilities operated by the MRC (one at nearby Entebbe Hospital
and the other in Masaka on Lake Victoria). They conduct the
CRC vaccine preparatory studies, such as the large HIV incidence
cohort. Borrowing the idea from the Rwanda Zambia group,
they are now recruiting discordant couples in an effort to find
a population with high HIV incidence. Lake Victoria fishing
communities are a new high-risk population being recruited.
Anatoli Kamali, M.D., principal investigator at the Masaka CRC
facility, observes that the inability to move on to advanced vaccine
trials has been frustrating, but “keeping up momentum has been
easier than expected. We should not get distracted from our goal.”
Kamali suggests broadening the CRC collaboration to include
pharmaceutical companies that are developing HIV vaccines.
“That way, we will be among the first to test them,” he says.
The UVRI laboratory has received funding from the Bill &
Melinda Gates Foundation’s Collaboration for AIDS Vaccine
Development and is now concentrating on basic science. One
study that Kaleebu has organized tests a new gene expression assay
(“microarray analysis”) as a way of predicting vaccine response.
The Benefits of International Collaboration
The UVRI CRC’s ability to conduct new basic science studies
on its own is one example of the benefits emerging from the
collaboration. IAVI helped the CRC researchers in the beginning,
but now those researchers are the sources of ideas for new vaccine
designs while keeping the trial organization ready for the time
when efficacy trials are again opportune. As Anzala in Nairobi put
it, “Even if there is no vaccine trial, we can study the mysteries of
HIV, and that, in turn, will help in developing vaccines. We also
want to put the infrastructure to good use by diversifying. We
can test TB and malaria vaccines. Everyone has heard this is an
excellent unit that can do more.”
The CRCs have also blazed the political and regulatory pathways
needed to move future trials ahead quickly. It took Anzala’s group
18 months to get approval for its first vaccine trial. The Nairobi
CRC then worked with the Ministry of Health to streamline the
process. The two organizations sponsored a national stakeholders’
meeting in 2004 that established guidelines for vaccine research.
The meeting also led to an accelerated system for approving new
trials. Now a national vaccine protocol review committee submits
recommendations to the two ministry of health regulatory boards
that oversee pharmaceutical research.
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The Ugandans, too, work to impart a sense of urgency to the
country’s political structure. UVRI initially took advantage of its
high standing in the Ministry of Health to secure government
support for the CRC. IAVI CEO Seth Berkley ultimately met with
Uganda President Yoweri Museveni, and the two wrote a letter to
the Group of Eight (G8) appealing for more HIV vaccine funding.
UVRI continues to give health officials and members of parliament
regular updates on HIV prevention technology. The meetings allow
the officials to comment on the research agenda. Their comments
can result in adjustments to the way research is conducted. These
interchanges preserve the government’s commitment to Uganda’s
leading role in vaccine research. In Kenya and elsewhere, this
commitment smoothes over bureaucratic barriers. It also results
in various kinds of material assistance, such as providing space for
study centers or medical care to study participants.
Government support is not to be assumed, and its absence can
prove disastrous. When Allen started in Rwanda in the 1980s,
the government forbade her from publishing results. It feared that
publicizing the nation’s HIV problem would drive away investors
and tourists. Then the government-promulgated 1994 genocide
resulted in the deaths of half the Rwanda project’s research staff
plus the disappearance of hundreds of the cohort members. The
new government in Rwanda, however, has been very supportive
of HIV vaccine and other prevention research. Despite that
support the CRCs in several countries face challenges recruiting
men who have sex with men into cohorts due to stigma against
homosexuality.
Work on the community level helps to protect against the
capriciousness of national politics. As described, considerable
time is spent on public education so that residents understand
and cooperate with the studies taking place in their locales. Also,
each Clinical Research Center has a community advisory board,
established with IAVI’s guidance. Some have gender advisory
boards or work with peer leader networks.
These types of local organization have broader effects: They
combat HIV stigma and homophobia by providing a sense of
empowerment. As the community boards and networks gain
experience, they seek to advise government officials on policy
matters. In this way, there emerges a grassroots constituency
for scientifically sound, ethical HIV vaccine research. This
constituency’s existence ultimately will engender greater
appreciation of medical research and health care in general.
By David Gilden
Advancing vaccine design by investigating
the intricacies of HIV is critical to
accelerating AIDS vaccine progress.
Photo by Vanessa Vick
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Making New Medical Innovations
Available in Developing Countries
First, Where They’re Needed Most
Lessons Learned:
• Product development partnerships (PDPs)
have a growing role in addressing scientific and
technical challenges.
• Negotiate licenses with private industry to allow
resource-constrained countries widespread access to
new, approved prevention technologies and use in
future combination therapies.
• When possible, conduct clinical trials in developing
countries that have higher disease burden.
• Make use of regulatory mechanisms in developed
countries that offer advisory opinions on medical
products for global public health application.
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An IPM employee works on a ring press at the
Clinical Trial Material Facility in Pennsylvania, where
materials for IPM’s clinical trials are manufactured.
Photo by Andrew Loxley, Felt Photography
While cutting-edge medical innovations may ordinarily
be applied in wealthy nations before they trickle down,
if ever, to poorer countries, the opposite to this rule may
occur if one product development partnership (PDP),
the International Partnership for Microbicides (IPM),
succeeds in developing safe and effective products for
prevention of HIV/AIDS.
IPM, a nonprofit whose donors include the Bill & Melinda Gates
Foundation, 12 governments in North America and Europe, and
several international organizations, hopes to create microbicides
— products to be used vaginally by women — that will help to
prevent the transmission of HIV. These products are based on
a number of experimental and approved therapeutic drugs that
have been charitably licensed to IPM by private industry. Several
pharmaceutical companies have made active compounds available
beginning in 2004 with Johnson & Johnson’s license to IPM for
dapivirine, and with one of the latest being Pfizer, which licensed
its approved AIDS therapeutic maraviroc to IPM early in 2008.
IPM has not yet gotten a microbicide approved, but human clinical
trials of dapivirine are under way, with trials of a product containing
maraviroc scheduled to begin next year.
Why a Microbicide?
Part of the motivation in developing microbicides is to create
a method of AIDS prevention that women can initiate, unlike
condom use, over which men have the most control. “Women in
these settings have so little control over their own reproductive
health, that this represents one of the best options to them,”
says Joseph Romano, Ph.D., executive director of research and
development at IPM.
To date, IPM’s commercial partners have agreed to royalty-free
licenses of their technology for distribution only in developing
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The fundamental purpose of microbicides and the clinical trials
process is keeping women healthy and safe. Here, a study nurse
demonstrates a screening exam at the International Centre for
Reproductive Health in Mombasa, Kenya.
Photo by Geoff Oliver Bugbee
countries, where women carry a higher portion of the burden of HIV
than in resource-constrained countries, according to IPM.
If one or more active compounds are successful in preventing
transmission, IPM is exploring a variety of product formats to fit a
woman’s convenience. “Our goal is to have multiple dosage forms.
IPM is actively investigating the development of various kinds of
vaginal rings designed for sustained release over 28 days, as well as
gels, tablets and films designed for once-a-day use,” Romano says.
Why a Product Development Partnership?
Although from a legal standpoint IPM is a partnership only in name,
it is one of a class of organizations known as “product development
partnerships” (PDPs) featuring public-private cooperation to
overcome thorny medical issues. These PDPs are intended to bring
together the resources and expertise of nonprofit global health
organizations with the proprietary drugs and technology developed
by for-profit pharmaceutical companies.
“‘Partnership’ is part of the name of the organization and an
important aspect of how the organization operates, but in form it’s
a not-for-profit corporation,” says Paul Model, J.D., attorney for
IPM, who helped negotiate its licenses. Established in 2002, IPM
is funded by foundations, international organizations and national
governments, including Canada, Ireland, the Netherlands, the
United Kingdom and the United States among others.
“The notion is that in a larger sense the nonprofit sector and forprofit
sector are becoming partners in the development of drugs
for neglected diseases or drugs that would not get developed for
commercial reasons,” Model says, adding that other PDPs are
working on malaria, tuberculosis and a variety of tropical diseases.
“By their very nature, PDPs are self-selecting for addressing some of
the world’s most difficult technical problems,” says Mark Mitchnick,
M.D., an IPM consultant who was chief science officer for the
company during its formative years. “As an example, there have been
very few commercial efforts to develop a microbicide. Nobody starts
a PDP to look at cardiovascular disease, because ample resources are
being devoted to address that problem. A microbicide would be a
first-in-class drug, because there never has been a product (other than
condoms) to prevent HIV, such as a microbicide. These become very
daunting ventures scientifically,” he says.
While Pfizer is one of IPM’s most recent industry partners, it was
Johnson & Johnson subsidiary Tibotec that enabled IPM to begin
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its development program, by stepping forward and licensing its
experimental drug dapivirine in 2004. “The drug has been evaluated
in multiple clinical trials for safety and pharmacokinetics in a gel
and vaginal rings, in Phase I studies,” says Romano, adding that
the formulations have been tested in more than 200 people. The
microbicide formulations are expected to go into expanded human
trials in the United States and Africa in 2009 and 2010, and Phase
III trials are scheduled for 2011.
Why do pharmaceutical companies license their drugs to IPM? In
some cases, both senior management and product development
scientists within the pharmaceutical company itself realize the
potential for their drug to make a significant difference in the lives of
people in resource-poor settings. While development of products for
these uses may not be consistent with a pharmaceutical company’s
economic model, many pharmaceutical executives and scientists
are nonetheless concerned to make these products available to
populations in need. They will take the initiative to identify potential
nonprofit licensing partners with the capacity to take a product
through to licensure.
In other cases where PDPs approach industry for their drugs, the
potential for improving a company’s public image is an important
incentive. Charitable licenses between pharmaceutical companies and
PDPs can garner significant positive public attention for both parties.
In addition, pharmaceutical executives understand that microbicides
are very different products from the therapeutic agents sold in the
developed world, so there is less reason to worry about the potential
negative impact that a charitably licensed product might have on the
profitable markets in which the pharmaceutical companies operate.
Another potential drug is tenofovir, an approved AIDS treatment
therapy made available by Gilead, which also has a very good human
safety database, according to Romano. In addition to these two drugs,
and maraviroc, which was U.S. Food and Drug Administration
approved about a year-and-a-half ago, other drugs have been licensed
by Bristol-Myers Squibb and Merck, all of them experimental.
A threshold level of trust is essential in establishing relationships
with industry partners. “Getting Tibotec to allow IPM to
work with its compound in a relatively unrestricted way was
enormously important,” Model says. “The Tibotec license originally
contemplated a fairly formal structure of governance that included
the establishment of a committee that would meet regularly and
compose a set of rules for the conduct of the development effort.
This formal governance structure has become less important as
the development project has progressed. Once the two sides got to
know each other pretty well, less formal communication turned out
to work well from the perspective of both sides,” he explains. (See
sidebar on negotiating PDP licenses.)
Pearls and Pitfalls in
Negotiating PDP Licenses
IPM attorney Paul Model says the organization has made
strides in learning how to negotiate beneficial license
agreements with the pharmaceutical industry. “IPM now
has something a lot closer to a standard form than it did
in the beginning,” Model says.
A beneficial aspect of the license agreements that IPM
has sought in negotiations is getting an identical list of
countries in which IPM could distribute an approved
microbicide. “Stapled to the back of each license is the
same list of about 100 countries. This means that IPM
will not be in a situation where it can use one licensed
compound in a particular country, but cannot use
another compound in the same country,” he explains.
The license agreements permit IPM to combine active
pharmaceutical ingredients in case it is a combination
product that ultimately proves most effective as a
microbicide. “As a matter of fact, the license for one of
the compounds contemplates that it will only be used as
part of a combination product. IPM and others in the
field believe that the likelihood of ultimate development
of a combination product is high.”
Another aspect of the license agreements that requires
considerable attention is the balancing of the industry
partner’s concerns about the appropriate use and
development of an active compound with IPM’s needs
for the freedom to innovate. “In the maraviroc license,
for example, the tension is really between IPM’s desire
to innovate and Pfizer’s desire to maintain control over
maraviroc,” says Model.
One way this tension was resolved was through
negotiations over access to the compound and
arrangements for supply. IPM is a virtual development
organization that uses a lot of contractors. The maraviroc
license includes rules and procedures about access
to maraviroc for partners and contractors providing
development services to IPM. These rules and procedures
include standard terms for allocation of intellectual
property rights among IPM, Pfizer and third-party
contractors, as well as procedures for review of the
contractors themselves. IPM and Pfizer also negotiated
detailed terms for supply and manufacture of the active
compound.
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The more recent license of maraviroc by Pfizer was remarkable
because the license was granted in the context of the FDA approval
obtained by Pfizer for marketing maraviroc as a treatment for HIV
infection. The results of IPM’s preclinical and clinical studies of
maraviroc, as well as IPM’s efforts to obtain regulatory approval,
could potentially have an impact on the status of maraviroc as a
therapeutic, a matter in which Pfizer has made a very substantial
investment. A crucial factor in the collaboration was building Pfizer’s
confidence in IPM’s ability to undertake drug development in a
professional manner and in IPM’s understanding of Pfizer’s needs
and drug development generally.
“It was about a year before IPM signed the license agreement that
Pfizer began providing IPM with small batches of the drug for a
shorter period of time under a material transfer agreement,” Model
says. “This allowed important formulation work to get under way
before the agreement was actually formalized, thus speeding the
overall product development process.”
In Case of Success
The challenges in making a microbicide effective for the prevention
of HIV include not only the development of a safe and effective
product, but also making access to that product in resource-poor
countries a reality after the product has been developed. IPM has
already put some thought into access issues.
In part, some of the preparation associated with access has already
gone into IPM’s clinical trials strategy. “Women in the U.S. and
elsewhere are typically tested in Phase I and II studies. However,
Phase III efficacy studies have to be done in areas where the HIV
levels are high enough that if we introduce interventions like
microbicides, we can see reductions in the number of infections.
Infection rates are not high enough in the developed world for
efficient clinical research purposes,” Romano explains.
The ultimate question as to clinical trials comes down to what
country will regulate an approved microbicide. “Our goal is to have
approval with an agency like the FDA or Europe’s regulatory body,
the [European Medicines Agency] EMEA. One of our interesting
options would be to apply under Article 58 of the EMEA. This
would involve engaging in a process by which the EMEA doesn’t per
se approve a product, but scrutinizes it from the same level it would
from an approval perspective, and then offers its opinion to other
regulatory bodies, particularly in the developing world. This was
designed to benefit public health in the developing world,” he adds.
Pricing the ultimate product is another matter. “IPM itself will
never make a profit off of this, but the issue is that a microbicide
would still cost something to make, and there would still have to be
funding coming from some source,” Model says. Cost considerations
are an important issue in negotiating license agreements with
pharmaceutical companies. These agreements give IPM the right to
manufacture and distribute microbicides in developing countries so
that the costs of the product will be kept as low as possible.
“We’d like to make an inexpensive gel, in which the most expensive
component is the applicator itself. The gel and the drug inside the
gel would cost in the pennies range to manufacture,” Romano
says. “In vaginal rings, we know you would only need 12 rings
per year for a woman to be protected since the product would be
used monthly, and if that’s cheaper than it costs to manufacture 30
individual daily doses of a gel product, that would be great. On the
other hand, vaginal films would be very inexpensive to manufacture
and don’t necessarily require an applicator,” he adds. In addition,
the film, which fully dissolves, has the advantage of being less of an
environmental burden.
A priority for studies is that people living in the
community fully understand the research activities
conducted there. This community mobilizer works
with Projet Ubuzima — an International Partnership
for Microbicides sponsored research center in Kigali,
Rwanda — to educate community members about
clinical trials.
Photo by Geoff Oliver Bugbee
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Another major challenge contemplated by IPM is how the
microbicide would be manufactured. While the biggest cost IPM
is thinking about in the foreseeable future is that of doing clinical
trials to demonstrate that a product works, the focus may change
dramatically in the event of a success.
“At the moment IPM is producing product on a small scale, in
order to conduct Phase I and II trials, at a manufacturing facility
in Bethlehem, Pennsylvania,” Model says. “If IPM succeeds, the
scale of manufacturing will go up by orders of magnitude. At the
moment IPM is performing trials in tens or hundreds of women.
If you assume that 10 million women in Africa would be receiving
a successful ring product for monthly use, 120 million rings a year
would need to be manufactured,” Model explains.
“IPM has already thought extensively about local manufacturing in
South Africa, for example. Governments in the developing world
may be very interested in promoting this product,” he adds. IPM’s
plans for manufacturing for clinical trials and initial product launch
include solicitations of interest from manufacturers in Europe, Asia
and Africa. Fortunately, compared to costs for manufacturing of
vaccines, investments in microbicide manufacturing scale-up are
relatively low and will likely be borne by IPM’s new and existing
donors.
Potential Earnings
While IPM’s license agreements don’t permit the PDP to sell any
approved microbicide in developed countries, it is an open question
as to whether a successful product would find a ready market in
countries like the United States and in Europe.
“IPM’s mission is focused on less developed countries. Whether a
pharmaceutical company partner is going to be able to market an
IPM microbicide product in the industrialized world will partly
depend on what other patents or intellectual property might be
involved. For example, suppose that IPM develops a combination
product that has two compounds in it. Let’s say the product includes
Pfizer’s compound and Tibotec’s compound. Pfizer can’t just go out
and sell that product in the United States and Europe, because they’d
have to get the right to the Tibotec compound first,” Model explains.
In general, pharmaceutical companies have agreed to defer these
negotiations until a product has been shown to be safe and effective.
Since almost all of the microbicide development costs are borne by
the PDP (and its donors), and the size of the market in the developed
world is unclear, there is little financial risk to a pharmaceutical
company in postponing these discussions.
In either case, if a successful microbicide were marketed in developed
countries, earnings could result. “If, for example, Pfizer marketed
an IPM microbicide under the arrangements called for in the
maraviroc license, IPM would be entitled to a royalty. It could be
appropriate to try to recover some of the investment made by IPM’s
donors, although earning a royalty is not a priority for IPM and
should not get in the way of the core mission of making safe and
effective microbicides available to women in developing countries,”
Model says.
By John Otrompke, J.D.
During the site development process, clinics, laboratories,
pharmacies and offices all take shape where there were none
before. Here, a lab technician works at the Kilimanjaro
Christian Medical Centre in Moshi, Tanzania, an International
Partnership for Microbicides-supported research center.
Photo by Geoff Oliver Bugbee
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Lessons Learned:
• Maintaining close collaboration and ongoing
communication among project partners is critical.
• Robust systems (financial, management, etc.)
are needed to enable the conduct of complex clinical
trials across multiple centers.
• Ongoing support for capacity-building at study
centers, including helping to ensure capacity for crisis
communications planning and media relations at
trial sites is of primary importance.
• Flexibility — being able to respond effectively and
adapt to unanticipated developments or findings —
is essential during the ever-changing testing phase.
Product Development Partnership
Aims to Develop First Vaccine
Against Malaria Parasite
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Photo by Shutterstock® Images
Malaria kills close to a million people every year and
sickens many millions more. Most of the casualties of
this disease are young children under the age of five living
in sub-Saharan Africa. In an effort to stem deaths from
malaria, the PATH Malaria Vaccine Initiative (MVI) has
collaborated with GlaxoSmithKline Biologicals (GSK
Bio) to evaluate the RTS,S malaria vaccine candidate.
This is thought to be the first full vaccine development
collaboration between a product development
partnership (PDP) and a large pharmaceutical partner.
However, that is not the only “first” designation with
which the project is likely to be labeled.
“If we are successful with RTS,S, not only will it be the first
vaccine against malaria, but the first against a human parasite,”
says Christian Loucq, M.D., director of MVI, a program of the
nonprofit organization PATH.
RTS,S is the first malaria vaccine candidate to ever reach large-scale
Phase III clinical testing, typically the most critical of the last steps
before licensure. This Phase III study is designed to confirm and
more precisely, determine the efficacy as well as confirm the safety
of the vaccine.
Developing the first-ever vaccine against a human parasite has
proven challenging. “The development of RTS,S has taken longer
than that of an average vaccine, which is about 10-15 years, but
RTS,S will be the first vaccine against a human parasite,” explains
Joe Cohen, Ph.D., the co-inventor and one of the original patent
holders for RTS,S, who is also vice president of R&D for Vaccines
for Emerging Diseases and HIV at GSK Bio. “This groundbreaking
scientific achievement cannot be overstated, because it required
scientific breakthroughs, particularly in the fields of genetic
engineering and immunology and even a new clinical testing
infrastructure.”
RTS,S was created in 1987 by GSK Bio, the vaccine division of
GSK, in close collaboration with the Walter Reed Army Institute
of Research. In 2001, with support from the Bill & Melinda
Gates Foundation, PATH and GSK entered into an agreement to
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develop the vaccine for infants and young children in the sub-
Saharan Africa region. Today, clinical development of RTS,S is
led by the Clinical Trials Partnership Committee, a consortium
of leading African research institutions, MVI and GSK Bio. The
Gates Foundation continues to fund the vaccine candidate’s clinical
development through grants to the PATH program.
“This project demonstrates the importance of collaborations and
partnerships,” says W. Ripley Ballou, M.D., deputy director for
Vaccines, Infectious Diseases Development, Global Health at the
Gates Foundation. “Since the vaccine has never been commercially
attractive, it required government labs to take an interest and then
for a multitude of partners to bring specific skill sets to bear or it
simply wouldn’t have happened.”
The RTS,S vaccine is a recombinant protein that couples part of
the P. falciparum circumsporozoite (CS) protein with the hepatitis
B surface antigen in a proprietary GSK adjuvant system. As a result
of its design, the vaccine protects the human liver against both the
malaria parasite and hepatitis B, a severe form of hepatitis that can
lead to liver disease, liver cancer and death.
Development of a Groundbreaking Partnership
Clinical evaluation of RTS,S began in 1992 in adults in the United
States and Belgium and was followed by a trial in more than 2,000
children in southern Mozambique in 2003. In total, seven Phase
II pediatric trials were conducted in Africa. Findings of the 2003
trial showed RTS,S to be effective for a minimum of 18 months
in reducing clinical malaria by 35 percent and severe malaria by
49 percent. Data from a more recent study showed a 65 percent
reduction in first malaria infection (or 65 percent protection against
risk of infection) in infants over a six-month follow-up period.
“The RTS,S vaccine candidate had demonstrated proof of concept,
thereby warranting further clinical development, at a time when
no other candidates had advanced as far,” says Loucq. “Over the
next several years, RTS,S continued to demonstrate that it was safe
and sufficiently efficacious to warrant moving to the next stage of
development — now including the start of a large-scale, Phase III
trial in sub-Saharan Africa.”
Throughout the history of the partnership, Ballou and Cohen have
been key figures in the vaccine’s development. Their paths crossed
many times, first as collaborators and then as colleagues.
As a key member and eventually leader of the U.S. Army’s
malaria vaccine research team at Walter Reed, Ballou oversaw the
development and testing of more than a dozen vaccine candidates
that led, in collaboration with scientists at GlaxoSmithKline, to
the creation of RTS,S. Before Ballou retired from the U.S. Army in
1999, he was instrumental in the creation of the Malaria Vaccine
Initiative at PATH and wrote elements of the original funding
proposal. Ballou’s career path included five years at GSK Bio in
Belgium, working on the vaccine, and finally in April 2008, he
joined the Bill & Melinda Gates Foundation.
Cohen left academic research in 1984 to join the vaccines division
of GlaxoSmithKline (then SmithKline-RIT). Three years later,
Cohen took over the reins of the company’s Malaria Vaccine
Program. Scientists at GSK and Walter Reed had been working
on a vaccine based on the circumsporozoite protein, but the initial
effort had not resulted in a stable, immunogenic and efficacious
vaccine.
The years spent working on RTS,S have been grueling and often
unkind. “You have to be prepared for the failures as well as the
successes,” says Ballou. “The first six years of the efforts toward
developing RTS,S were a series of bitter disappointments and
discouraging news. Indeed, a lot of people did walk away but,
overall the RTS,S project has been blessed with leaders undaunted
by failure.”
Steps in Malaria Vaccine Development
Research and preclinical development: Identify relevant
antigens and create vaccine concept, preclinical evaluation,
develop vaccine manufacturing process.
Phase I clinical trials: Preliminary evaluation of the safety
profile and immune response in malaria-naïve and malariaexposed
populations.
Phase II clinical trials: Monitor safety and potential side
effects, measure immune response, evaluate efficacy against
infection and clinical disease, and determine optimum dosage
and schedule.
Phase III clinical trials: Continue to monitor safety and
potential side effects, and evaluate efficacy on a large scale.
Submission to regulatory authorities: Submit vaccine
application to regulatory authorities for approval to market
(i.e., licensure).
Introduction: Make vaccine available for use.
Phase IV trials: Conduct post-marketing safety monitoring;
answer outstanding research questions.
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Cohen and his team thought they could stabilize the vaccine and
increase its immunogenicity by fusing the CS protein to a form of
the recombinant technology found in GSK’s successful hepatitis
B vaccine. When the team added GSK’s proprietary Adjuvant
Systems, the immune response was even better. Cohen and his
colleagues have since spent more than two decades perfecting and
building upon this fundamental insight.
Structuring the Partnership
The first agreement between GSK and PATH was finalized in
January 2001. This collaboration has involved three iterative, major
milestone-driven agreements between the two organizations:
• Initial clinical development agreement: Project initiation
through Phase II proof of concept (2001-2004)
• Collaboration agreement: Phase II and Phase III development
programs, including establishment of supply and pricing terms
(2005-2009)
• Amendment of 2005 collaborative agreement (2009-2014)
Each phase of the collaboration has taken approximately a year
to negotiate. Ongoing maintenance of the partnership requires a
significant investment of time from both partners.
The two partners bring a range of capacities required for a
vaccine development project. However, one organization will
typically bring a greater depth in the areas where it leads. In
this partnership, GSK Bio leads on applied R&D (recombinant
protein and adjuvant systems technologies); clinical protocol
development; clinical trial operations; regulatory affairs; and
process development, scale-up, and large-scale manufacturing.
MVI leads on African trial-site relations, contracts, and capacity
building; crisis communications planning and media training for
study center investigators; planning for decisions on vaccine use
in African countries; and management and oversight structure for
the project.
To ensure steady and productive progress, the project has three
formal management and oversight structures:
• MVI-GSK Bio Steering Committee contractually defined as
the decision-making body for the partnership
• Commercialization, Policy and Advocacy Working Group,
a Forum for joint discussion of issues around translating
the vaccine into an intervention delivering public health
impact. This body is chartered by and reports to the Steering
Committee.
• Clinical Trials Partnership Committee (CTPC), which
includes GSK Bio, MVI and investigators who address
protocol and other issues related to the Phase III trial and
ancillary studies.
The establishment of the CTPC reflects the importance of the
African study centers involved in the Phase III trial, each chosen for
its track record of world-class clinical research, strong community
relations and commitment to meeting the highest international
ethical and regulatory standards. Relationships with the study
centers are also governed by contractual agreements, with a separate
agreement among MVI, GSK and each study center. The CTPC is
now represented on the RTS,S Steering Committee, which initially
only included GSK Bio and MVI.
“The Clinical Trials Partnership Committee (CTPC) is up and
running, has effective governance structures (including one or more
working groups) that meet regularly, is a route for information
sharing and has successfully facilitated some decision-making,”
says Loucq.
Partnering to Conduct the Phase III trial
Based on the successful trials to date, GSK, MVI and leading
African research institutions are continuing clinical trials in infants
and young children, the most vulnerable groups and those who
would benefit most from an effective malaria vaccine.
A large-scale Phase III multi-center efficacy trial in both infants and
in young children was launched in May 2009. This Phase III study
is designed to further and more precisely determine the efficacy
and confirm the safety of the vaccine in the target population. The
RTS,S Phase III trial will be conducted in 11 sites in seven African
countries, namely Burkina Faso, Gabon, Ghana, Kenya, Malawi,
Mozambique and Tanzania, pending required local and national
approvals. This trial, which will enroll up to 16,000 infants and
children, is expected to become the largest malaria vaccine trial to
date. If all goes as expected, the RTS,S vaccine candidate could be
submitted to regulatory authorities as early as 2011.
The Phase III protocol was developed with input from all the
partners in the trial (all members of the CTPC) and from
regulatory authorities such as the European Medicines Agency and
the World Health Organization (WHO). Each study-country has
undertaken independent reviews to ensure the trial meets national
safety, ethical and legal standards for medical research. In addition,
there is an independent data and safety monitoring board for the
full trial and a local safety monitor will be deployed at each site.
The RTS,S project has built trial capacity throughout Africa that
will greatly aid the testing of other vaccines and the distribution
of RTS,S, once licensed. This capacity building extends beyond
physical infrastructure (such as buildings and equipment)
and training directly relevant to the conduct of the trial, to
strengthening the skills and abilities of study centers in the
financial, management and communications arenas.
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Examples of capacity building include collective activities, such
as bringing together two personnel from each site (typically, the
site principal investigator and the administrator) for a three-day
financial management training facilitated by MVI, as well as oneon-
one endeavors, where MVI identifies a training need during a
site monitoring visit and follows up with a capacity-building visit
tailored to address the specific areas of need. Whenever possible,
best practices are shared across sites to take advantage of local
expertise. On the communications front, MVI has worked closely
with trial sites to ensure their readiness to address potential crisis
situations and provided training on how to work more effectively
with local and international media.
“The key to the collaboration’s success thus far has been, on the one
hand, the care with which the study centers were chosen and, on
the other, having a common goal: clinical development of RTS,S
to the highest ethical and professional standards,” says Loucq.
“Regular communications, a spirit of mutual respect and regular
face-to-face meetings have helped strengthen relationships and
made working together easier, even if it is sometimes challenging.”
It is important to remember both the roles of the partnering
organizations and of the individuals that power them. “This project
is highly dependent on people; the tremendous effort put forth by
each and every participant comes more from the heart than from
any hope of fame,” says Ballou. “There’s a lot of work left to be
done and many of the people involved have dedicated their lives to
seeing it through.”
Paving the Way for Access and Future Vaccines
In addition to their work on clinical development of RTS,S, MVI
and GSK began collaborating in 2005 to foresee and address
potential bottlenecks in the pathway to introduction, another
example of the partnership’s efforts to accelerate the development
process. To this end, the partners worked to reach a shared vision
for RTS,S implementation in order to align subsequent activities:
To ensure that robust evidence and financial resources are
available to all countries in sub-Saharan Africa, allowing each
to take a decision if they want to adopt, defer or not adopt RTS,S
into their [expanded program on immunization] EPI and/
or wider health systems, within one to three years of legal and
physical availability.
Among the activities born of this approach is one led by MVI,
in collaboration with GSK, WHO and other partners, to map
the pathway for a first malaria vaccine through policy, financing,
regulatory and procurement bodies into developing countries.
Another critical activity was the partners’ work with WHO to
determine the optimal formation, presentation and packaging
characteristics so that RTS,S would be able to integrate as smoothly
as possible into African health systems. And finally, WHO and
MVI began assisting countries to put in place the processes and
mechanisms required to facilitate early decision-making around
vaccine use (or non-use). This latter effort reflects a recognition
that the first malaria vaccine may yet fail, but that early planning is
necessary to ensure that if RTS,S is successful, it won’t be left sitting
on the shelf, unused.
“Malaria vaccines have little or no potential in the developed world
market: There are no wealthy buyers,” notes Loucq. “We have to
help ensure that everything that can be done is done to support
countries in making and implementing their own decisions around
vaccine use.”
And while the work of the partnership extends well into 2014,
MVI already has a next-generation vaccine in its sights, according
to MVI’s leadership.
“We all hope that RTS,S will succeed in the Phase III trial,
paving the way for full introduction as early as 2014. At the same
time, we hope to build on the success of RTS,S, finding ways to
reinforce the mechanism by which RTS,S works,” explains Loucq.
“We are already working on next-generation vaccines, including
combination vaccines and other approaches, toward developing a
vaccine with greater than 80 percent efficacy by 2025.”
Indeed, new vaccine development is enhanced by the lessons
learned from the RTS,S development process. “There is no clear
line from one vaccine’s development to another, but rather a
mutually reinforcing process whereby the development of one
informs another and vice versa,” says Cohen. “This is particularly
evident with RTS,S, which has directly benefited from earlier GSK
experience and innovations, such as the hepatitis B vaccine and
Adjuvant Systems.”
Further, an all important trials capacity is now in place that will
greatly aid the testing of other vaccines and the distribution of
RTS,S, once licensed. A network of clinicians and scientists is now
in place as a result of putting these RTS,S trials, including the
Phase III trial.
By Pam Baker
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Lessons Learned:
• Partnerships between organizations with different
but complementary capabilities and strengths are
essential to meeting the challenges of an evolving
parasitic disease. Independent players cannot
make the same progress working alone.
• The long-term effort requires both the initial
commitment of time, money or resources from
management, as well as the motivation and
coordination of staff working at all levels.
• Creative financing as well as incentives for those
involved can help accelerate efforts by making
it financially feasible to invest large amounts of
money and resources into the effort.
Historic Confluence Promotes
Malaria Breakthroughs
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Malaria is an ancient red blood cell-encroaching parasite
that has seen species come and go. There are specific
malaria protozoa for lizards, birds, rodents and, finally,
higher primates. The most widespread and virulent
form of human malaria, Plasmodium falciparum, is
100,000 years old. But malaria as a human scourge
did not take off until the advent of agriculture, about
10,000 years ago. From that point on, the spread was
supported by the expansion of conditions favorable to
the mosquitoes that carry the plasmodium parasites. In
some parts of Africa, residents are exposed to malaria
through mosquito bites nearly every day. Malaria kills
about one million Africans a year, mostly children and
pregnant women. The disease is also prevalent in large
parts of Asia and Latin America (see map).
The United States and European countries succeeded in eradicating
malaria after World War II. These were the easy places, where cool
temperatures for large parts of the year limit replication by both the
mosquitoes and the parasites they harbor. With the end of DDTbased
mosquito control efforts in the late 1960s, the stage was
set for resurgence in tropical countries. Countries that previously
eradicated the disease, including the United States, are at risk for
a return. The mosquito carriers are still present in those countries,
and there is a small but steady stream of infected travelers bringing
the disease home.
Lacking assiduous mosquito control, the only line of defense
against malaria is treatment, and the parasite is notoriously
prone to develop drug resistance. Inadequate treatment has led
to widespread resistance to current malaria treatments. The
only exception is the new combination therapies that include
artemisinin compounds derived from a type of wormwood.
These relatively expensive regimens too are susceptible to parasite
resistance, however. Citing recent reports, Tim Wells, chief scientist
for the Medicines for Malaria Venture concludes, “Artemisinin, like
all drugs, will eventually engender resistance.”
Malaria (see photo) has proved capable of evolving to escape
whatever humans throw at it, whether through the immune system
or through chemistry. With 5,300 genes, plasmodia are much
more complex targets than a virus like HIV. What is more, their
12-step lifecycle includes a variety of distinct physical forms that
grow in human liver and red blood cells as well as in mosquitoes.
Fortunately, human bioscience is also evolving, and modern
biotechnology brings to the battle highly sophisticated tools for
picking apart the parasite and finding its weaknesses. The question
is whether these tools can deliver affordable medicines accessible
by the nearly three billion people inhabiting malaria-infested
regions. Even more fortunately, some of the major biotech players
are establishing novel cooperative partnerships, based on noroyalty
intellectual property agreements that promise to alter the
economics of future malaria treatments.
Malaria’s expanding global reach
Photo by Shutterstock® Images
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One major instance is the cooperative agreement between the
Medicines for Malaria Venture (MMV), headquartered in Geneva,
and two American biotechnology research leaders based in
Cambridge, Mass., Genzyme Corp. and the Broad Institute. These
three bring together a combination of advanced genetic and drug
screening techniques, high motivation and global contacts to speed
drug development. Their goal is to establish an endless pipeline of
malaria drugs — one new clinical candidate every five years — and
stay ahead of the parasite’s capacity for evolution.
Origin of the Partnership
In the beginning there was Professor Dyann Wirth, who chairs
the Department of Immunology and Infectious Diseases at
Harvard University’s School of Public Health. Wirth’s specialty
is drug resistance in protozoan parasites such as the malariacausing
plasmodia. She employed genetic sequencing and gene
modification to identify the cellular mechanisms inducing drug
resistance. In 2002, other researchers reported that they had
sequenced the entire P. falciparum genome. As a followup, Wirth
and colleagues in 2006 published an analysis of the worldwide
diversity in that genome. They paid special attention given to
mutations associated with drug resistance.
The malaria genome diversity project took place at the newly
founded Broad (rhymes with road) Institute, a collaboration
between Harvard and the Massachusetts Institute of Technology
(MIT). In the words of Roger Wiegand, associate director of
Broad’s Infectious Disease Initiative, one important purpose of
the new institute is to “foster local collaborations within Boston’s
biotech community. Before, MIT, Harvard and all the companies
were acting as independent players. There was no integration.”
Wirth was one of the Infectious Disease Initiative’s co-directors.
During the period when the malaria genome work was coming
out, Henri Termeer, Genzyme’s chairman and chief executive
officer, was searching for ways in which he could harness his
company’s resources to find solutions for ignored diseases in the
developing world. This goal in 2006 took the form of Genzyme’s
Humanitarian Assistance for Neglected Disease (HAND) program.
The Broad-Genzyme connection was a natural one. “We started
talking in 2005,” recalls Genzyme Senior Vice President James
Geraghty. “Dyann Wirth said her lab at Broad was doing
breakthrough work. They were looking for an industrial partner
to develop new drugs based on the targets genetic sequencing was
identifying. As we talked, we realized we had the technology they
needed.”
Genzyme had the ability to turn drug concepts into drug
candidates, but it did not have the clinical expertise to test the
candidates in humans. For that, the new partnership turned to
the Medicines for Malaria Venture (MMV), which bills itself
as “philanthropic venture capital.” It was founded in 1999 and
specializes in public-private partnerships for drug development.
MMV, among other strategies, creates “miniportfolios” with
pharmaceutical companies that involve developing antimalaria
compounds from the earliest lab experiments. MMV developed a
miniportfolio with Genzyme and Broad Institute that became the
largest of three such arrangements. MMV also has partnerships
with other research sites around the world. This network enables
it to organize clinical trials to bring drugs to market. In return
for MMV’s drug development work, Genzyme and the other
miniportfolio companies have granted the organization royalty-free
licenses for distributing any approved drugs in malaria-endemic
countries. Government and nonprofit malaria programs will receive
these drugs at cost.
Fitting the Pieces Together
MMV’s Wells observes, “The collaboration is a tribute to Jim
Geraghty’s and Dyann Wirth’s vision. Always in a successful
partnership, there have to be people at the top committed to
changing global health. Then you need people below who are
motivated to make it happen.” The talks between MMV, Genzyme
and Broad mapped out a collaboration that takes advantage of each
partner’s special capabilities.
The Broad Institute, with its push-the-envelope technology, is
central to the partnership. Broad researchers are actively examining
variations in plasmodium and human genes associated with
differences in disease severity. This research can yield new treatment
Red blood cell infection by the malaria
parasite P. falciparum
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strategies, such as inhibitors for the plasmodium version of
dihydroorotate dehydrogenase (DHODH), a critical cell enzyme.
Apart from target discovery, the Broad Institute’s Infectious Disease
Initiative also has a drug discovery component. The rise of drug
screening assays that test hundreds of compounds simultaneously
has greatly accelerated drug development. Broad uses two types
of assays. One checks for malaria parasite killing capacity — it
basically consists of red blood cells and parasites in an array of
384 small wells. Another assay tests for inhibition of specific
molecular targets identified through genetic analysis. The first type
of assay identified a lead family of potent compounds whose exact
mechanism of action has yet to be defined. The second advanced
lead compound arose through the second method, by testing
inhibitors of plasmodium DHODH.
Aside from that antimalaria compounds that Broad has
independently spotted, Genzyme brings a library of 300,000
compounds for the institute’s scientists to test. “Plasmodium is not
particularly protected against drugs. We find about four promising
agents per thousand compounds screened,” reports MMV’s Wells.
Genzyme’s more important contribution is after those compounds
are detected. The company’s scientists first work to optimize the
compounds’ structures. They also test for cell toxicity. This is a
point at which many agents are rejected. They have to be selective
malaria killers; they can’t kill the human cells too. If they pass
this hurdle, Genzyme then tests the compounds in animals. First
come the tests for stability — a drug will not be much good if the
body eliminates it rapidly. Next are tests for effectiveness in animal
models of malaria. Genzyme hopes to be able to have a compound
ready for early human testing in 2011.
MMV also brings money to the table. The organization spent $54
million dollars in 2008 on malaria research, of which $3.8 million
went to the Genzyme/Broad miniportfolio. After Genzyme does its
preclinical work and readies a drug candidate for human testing,
MMV’s clinical trial network will go into action. If the trials are
successful, MMV will escort the drug through regulatory approval
and find manufacturers and distributors for it. Genzyme and Broad
may or may not be involved in this later phase. MMV usually
grants the rights to the relatively small, private, for-profit market to
a corporate partner when developing new drugs. The company in
exchange pays part of the human trial costs. The Broad/Genzyme/
MMV collaboration has not yet had to face this issue.
Organizational Hurdles
Jeffrey Klinger, Genzyme’s vice president for the HAND project,
says that he was skeptical when he first heard about the malaria
project. “We’re just a medium-sized company making a modest
investment. How could we make an impact?” asks Klinger. “We
had to enable each group to accomplish things it couldn’t get done
by itself. We overcame personality and cultural issues to create a
very efficient cross-disciplinary team.”
One of the issues involved differences in organization. Genzyme
followed an industrial team approach. Klinger notes that while
there are 40 or 50 Genzyme staff involved in the malaria research,
their total work is the equivalent of only nine or 10 full-time
employees. People come and go, contributing their skills as
required. The process builds a dynamic synergy. “This flow requires
just the right amount and flavor of project management,” says
Klinger. “You have to be flexible, but still steer the ship. A colleague
of mine, Carol Sherako, does exactly what a project manager is
supposed to do.”
Broad Institute follows a somewhat different model, bringing
together a collection of individual lead researchers with labs at
Harvard and MIT as well as its own in-house scientists. Roger
Wiegand recalls that he “flipped the priorities a bit” when he joined
Broad because his history was in drug development rather than
basic science. Since he asserted his influence, “Broad has hired
more drug development people, with an emphasis on things the
pharmaceutical companies aren’t doing” — one of these being
malaria drug screening.
A major stumbling block at the beginning was the intellectual
property rights issue. Although Genzyme had made clear at the
beginning that it would assign rights to a nonprofit organization
like MMV, the university lawyers were still interested in protecting
their institutions’ interests. “We had to keep telling people that
there was no pot of gold at the end of the malaria rainbow,” recalls
Wiegand. Agreement was reached when Harvard and MIT agreed
to follow Genzyme’s lead. They too gave MMV royalty-free licenses
allowing the organization to supervise drug development.
Wiegand concludes, “In the end we obtained a completely
transparent exchange of information. You can’t tell who is from
where at the meetings.” The collaboration’s management team now
meets on a daily basis with larger whole project meetings occurring
biweekly.
As drugs start to advance, those meetings are expanding to include
chemists, toxicologists and other specialists. The collaboration itself
is expanding. To further identify and refine drug candidates, it
has worked with contract research partners in India, as well as the
International Centre for Genetic Engineering and Biotechnology
laboratory in New Delhi. Chem Partners in Shanghai synthesizes
many of the prototype compounds that have emerged. Exchanges
with these entities take place weekly.
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Overseeing this process is MMV’s yearly review of its projects,
conducted by the organization’s advisory board. “We got grilled,”
Wiegand reported after the July 2009 annual conclave and
before the board issued its findings. “They asked a lot of probing
questions and wanted a few things tweaked. But mostly things
seemed OK.”
Enlightened Self-Interest
One question that stands out in this collaboration is why Genzyme,
a biotech success story with $5 billion in annual revenues, is
interested in malaria. Klinger responds, “We couldn’t do what we
are doing without the new funding organizations, the advances
in biomedical knowledge and the commercial sector’s change in
attitude. Before, the companies were not interested in malaria
drugs because there was no money in it. Now many are showing
enlightened self-interest.”
Klinger argues that there is a real desire among pharmaceutical
company personnel to make a positive contribution to neglected
epidemics like malaria. “It is very attractive to people,” he says.
“When I tell people about this everyone wants to sign on.”
Challenging work using the most advanced scientific methods,
along with having a personal impact on improving the world —
who can resist?
But there is also the self-interest side to his company’s efforts. All
poor nations have a middle class able to buy advanced medications.
In countries like China or India, that population is very large.
Genzyme’s Geraghty says, “Our goal is to be a partner and improve
countries’ health. We have our own products to market [in
developing countries], although those products are very expensive
and for a small group. We need to gain the cooperation of national
governments, and malaria is very important to them.”
A certain confluence of interests sparked Genzyme’s involvement.
The company is not alone in this. A number of larger, more
established pharmaceutical companies are also working with MMV.
These include GlaxoSmithKline, Novartis and sanofi-aventis. But,
observes Wells, “Genzyme is a smaller organization, and the vision
has permeated further there.”
By David Gilden
Upending Malaria Economics
The private, for-profit market also buys malaria drugs, at
a price substantially higher than the nonprofit sector pays.
Novartis charges developing countries’ public programs
80 cents for an adult course of Coartem®, its artemisinin
combination therapy. These countries’ commercial wholesalers
pay about $4 per treatment. In the United States, the Coartem
wholesale price is $70.
Even with these price differentials, the private market has not
proved large enough to support commercial development of
new malaria drugs. Neither have U.S. and European orphan
drug laws. These laws extend market exclusivity and provide
tax credits for drugs that treat rare diseases, which in rich
nations includes malaria. To open up the drug pipeline, the
U.S. Congress in 2007 approved a windfall for developers
of drugs to fight malaria and 15 other tropical diseases.
Companies that see such drugs through to approval by the
U.S. Food and Drug Administration (FDA) will receive a
“priority review voucher” for some future drug. The voucher
ensures accelerated review of a new drug, frequently leading
to six months or more of extra time on the market. This
difference could be worth several hundred million dollars in
additional profits from a blockbuster drug.
The availability of this bonus is constrained by other U.S. laws
regulating drug marketing rights. If the company owning the
voucher does not have a new drug appropriate for the voucher,
it can sell the voucher to a drug producer that does.
Novartis was the first company to receive a priority review
voucher when the FDA approved Coartem in April 2009. A
Novartis executive told The New York Times that the voucher
was “a gift from heaven.”
Though its exact value is still a matter of speculation, the
added income from the voucher promises to transform tropical
medicine into a modestly profitable venture. That income can
go to support more malaria drugs — or it can go to enrich
corporate coffers.
MMV estimates that the vouchers are worth $80 to $150
million. It reckons that this sum is enough to pay for advanced
human trials. When MMV trades private sector marketing
rights to corporate partners in exchange for financial support
of these trials, it now includes consideration of the vouchers.
Its contracts divvy up their eventual value in relation to each
partner’s investment.
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Lessons Learned:
• All parties must have trust in each other and
commitment to a common goal.
• With international partners, the project
requires effective communications and
regulatory strategies.
• Proactive market research can identify
challenges that will inform product development
and distribution.
TB Alliance Partnership
Charts Course for Future
Neglected Disease Treatments
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A TB patient is evaluated by a nurse at the
Brooklyn Chest Hospital in Ysterplaat,
Cape Town, South Africa.
Photo by Eric Miller
A global clinical development program, developed
and managed by the Global Alliance for TB Drug
Development (TB Alliance) and Bayer HealthCare,
is evaluating the commonly prescribed antibiotic
moxifloxacin for use in a new, first-line tuberculosis
(TB) treatment. If successful, the clinical trial program
will deliver what may be the first new TB drug approved
in more than 40 years — one that saves lives because
it will be part of an affordable, shorter TB regimen
that is widely accessible and adoptable by economically
disadvantaged countries and health care systems in the
developing world.
Of no less importance, though, are the lessons learned in
overcoming the challenges leading up to this historic partnership,
as well as those encountered during this TB drug registration
program, which is one of the first to be conducted according
to modern regulatory standards. The TB Alliance and Bayer
partnership, along with various supporting public and academic
organization relationships, represents a potential win-win situation
between a not-for-profit organization and a profit-oriented
pharmaceutical company that has an existing commercially
available drug that has been successful in the global market.
The partnership is ahead of its time with innovative strategies that
can benefit the field of TB drug development and accelerate the
progress of new treatments for neglected diseases.
New Drug for TB Desperately Needed
Tuberculosis usually attacks the lungs but can also affect the central
nervous, lymphatic, circulatory, genitourinary and gastrointestinal
systems, as well as bones, joints and even skin. It is responsible
for killing nearly 1.8 million people worldwide every year. The
World Health Organization (WHO) estimates that one-third of the
world’s population is infected with Mycobacterium tuberculosis, the
organism that causes TB, resulting each year in nine million new
cases of active TB. China and India alone account for 35 percent of
all estimated new TB cases each year. An estimated one billion will
be newly infected between 2000 and 2020; 200 million will fall ill
and 35 million will die. Making the problem even worse, multidrug-
resistant tuberculosis (MDR-TB) is an emerging infectious
disease threat classified as a category C priority pathogen by the
National Institutes of Health.
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Today, therapy for drug-sensitive TB is based on a four-drug
regimen to prevent the development of drug resistance. That
regimen consists of isoniazid, rifampin, pyrazinamide and
ethambutol. Discovered 40 or more years ago, each of these drugs
must be administered for six to nine months, often under the
direct observation of a health care provider. A shorter TB treatment
could improve patient adherence to treatment, lower the rates of
treatment failure and relapse, and ultimately reduce the emergence
of drug-resistant strains that are more deadly, as well as more costly
and burdensome to treat.
Developed and marketed since 1999 by Bayer HealthCare, a unit
of Leverkusen, Germany-based Bayer, moxifloxacin has been
shown in animal studies to be effective against the organism that
causes TB. Preclinical studies commissioned by the TB Alliance
in 2002-03 and conducted by investigators at The Johns Hopkins
University have found, for example, that substituting moxifloxacin
for isoniazid in a mouse model system decreased the amount of
time needed to eradicate TB infection by two months.
A moxifloxacin-containing regimen has the potential to reduce TB
treatment time from six or more months to four.
Finding Common Ground
It is uncommon for major drug companies to provide best-selling
patented drugs for use against diseases of the poor. Many fear the
loss of brand equity in serving poor countries due to possible gray
market sales, overuse and misuse, and the possible loss of sales
in their primary target markets — wealthy residents of North
America, Europe and Japan.
With this challenge as a backdrop, the TB Alliance had to develop
a flexible and adaptable strategy at the onset to make the case for
moxifloxacin as an affordable TB treatment with a company like
Bayer. How does a not-for-profit organization establish a win-win
situation for a profit-oriented pharmaceutical company that has
an existing commercially available drug that is successful in the
global market?
“It seems pretty clear that to manage this and other challenges
that arise throughout a project of this magnitude, you first must
establish a foundation of trust, mutual respect and commitment
to the project for all the parties involved,” says Dr. Mel Spigelman,
president and chief executive officer of the TB Alliance, a not-forprofit,
product development partnership. “In early negotiations it
was integral for each organization to take time to understand the
needs and potential reservations of the other as well as to the end
user; this process takes time and may be incremental. Today, our
organizations work well together and listen to each other because
the knowledge, judgment and expertise of each organization were
clearly communicated in the negotiating process.”
The TB Alliance and Bayer agreement to develop moxifloxacin for
TB brings together some of the world’s leading institutions that
already had some knowledge of the drugs’ potential and had an
interest in doing independent research. These institutions include
the U.S. Centers for Disease Control and Prevention’s TB Trials
Consortium, The Johns Hopkins University Center for Tuberculosis
Research, the Centre of Medical Microbiology of the Royal Free &
University College Medical School at University College London,
and the British Medical Research Council Clinical Trials Unit.
Under this historical agreement, the collaborative effort is clearly
defined:
• Bayer provides drug development know-how, supplies
moxifloxacin (and matching placebo) and will serve as the
regulatory sponsor for any U.S. and global registrations.
• University College London serves as the sponsor for the Phase
III TB trial, called REMoxTB, and is the home institution
of this trial’s chief investigator who provides therapeutic area
clinical and laboratory expertise.
A researcher at Tiervlei Trial Center in Bellville,
Cape Town, South Africa, one of the facilities where
the TB Alliance and its partners are evaluating
moxifloxacin in tuberculosis patients.
Photo by Eric Miller
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• The British Medical Research Council provides clinical
trial expertise, particularly as it relates to studies conducted
in Africa, and develops and manages the REMoxTB trial
database.
• The TB Alliance serves as the lead coordinator of the
moxifloxacin clinical development program and hires and
oversees contract research organizations to carry out a
number of key functions, including packaging, stability
testing, releasing and distributing good manufacturing
practice-compliant study drug and ensuring good clinical
practice-compliance at study sites through site monitoring
and auditing. It also ensures compatibility of the clinical and
safety databases of the different trials, and coordinates final
combined data analysis and writing of the integrated clinical
study report. The TB Alliance is also addressing the issue of
global clinical trial capacity by the TB Alliance clinical trial
site assessment project. Sites selected to participate in the
REMoxTB study receive training from the TB Alliance and its
partners in conducting registration standard TB drug trials.
• Centers for Disease Control and Prevention’s TB Trials
Consortium sponsored two global Phase II trials that evaluated
moxifloxacin in nearly 800 combined subjects.
• The Johns Hopkins University Center performed much of
the research throughout the development of moxifloxacin,
including acting as sponsor for a Phase II trial conducted
in Brazil.
“The success of this project depends on a combination of
experienced, knowledgeable veterans who obviously know what
they are doing and can think out of the box,” says Spigelman.
“This leads to trust and confidence, which are the key underlying
elements whether there is a profit or not.”
Public-Private Partnership Breaking New Ground
It was important for both organizations to mutually commit
to the goals of the partnership, as well as to acknowledge and
respect concerns specific to each organization’s business model.
Once an understanding was cemented, the parties quickly aligned
under an agreement that established the most significant clinical
development program for the treatment of active TB since the
late 1960s.
“This clinical trial program is unique in its dimension for TB
development,” says Dr. Martin Springsklee, vice president of
global medical affairs for Bayer HealthCare. “It is the first of its
kind in TB — to evaluate an existing compound for a new use for
neglected disease and gain regulatory approval.”
With partners and sites on five continents, the members
of the partnership recognized the project requires effective,
communication-based industry and regulatory standards, an
especially daunting challenge given the different languages and
cultures represented across the vast geographical scope of the
clinical trial sites. The partners tackled this issue by forming an
array of working groups, operational as well as strategic oversight
committees, and developing a local network of contacts that
identify and reach key decision-makers and appropriate individuals
in each location.
Few clinical trial sites have the capacity and experience to conduct
large-scale pivotal registration trials of TB drug candidates, a long
standing roadblock to TB drug development. To help remedy this
situation for the future and identify potential sites suitable for
moxifloxacin pivotal registration trials, the TB Alliance initiated
a clinical trial site assessment project to evaluate potential sites.
Presently, 93 sites have been assessed, and a number of these sites
have been selected for participation in the ongoing Phase III
REMoxTB trial. These assessments are available publicly, via a
database, and are an important contribution to the scientific and
clinical infrastructure needed to support current and future clinical
TB research.
As no drugs for TB have been registered according to modern
regulatory standards, little regulatory guidance exists to facilitate
the approval of new TB regimens by global regulatory and
standard-setting authorities. Working together with industry and
advocacy partners, the TB Alliance initiated a dialogue with the
U.S. Food and Drug Administration, European Medicines Agency,
Pill burden often poses an obstacle to a
patient’s ability to complete treatment.
Photo by Atul Loke
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the WHO and a number of high burden countries, through its
Open Forum series, to address key issues in the critical path to TB
drug registration. Bilateral discussions specific to moxifloxacin are
also under way with regulatory agencies.
“The standards that will stem from these activities will be
influential because there are no completed registration programs
for TB drugs in the modern regulatory environment,” says Dr. Ann
Ginsberg, head of clinical development at the TB Alliance. “We’re
charting new territory; it’s a learning curve for everyone because the
moxifloxacin study is designed to simultaneously establish pivotal
data while building capacity.”
In preparing for the launch of a moxifloxacin-containing regimen,
initial market access research identified that universal adoption will
be a much more difficult and protracted process than originally
envisioned due to a lack of established global- and country-level
processes for adopting and implementing new TB regimens.
To solve this problem, the TB Alliance initiated a “Country
Introduction Study” to understand the issues a country might face
when adopting, introducing and making available a new
TB regimen, once a new TB drug is recommended by global
technical agencies. The results will help establish a regulatory
strategy for moxifloxacin registration and identify countries that
might be engaged to actively introduce a moxifloxacin-based TB
treatment regimen.
The TB Alliance and Bayer also have developed an adaptable
forecast model to estimate future demand for moxifloxacin for TB
treatment and prepare for manufacturing if the drug is registered
and adopted for first-line therapy of TB.
“This program is much broader than just about developing
moxifloxacin as a potential TB treatment,” says Bayer’s Springsklee.
“It will also pave the way for building clinical trial capacity and
expertise in TB endemic countries.”
Progress Being Made
Moxifloxacin is in clinical trials to evaluate its potential for
treatment-shortening for TB. The Bayer-TB Alliance clinical
development program includes three completed Phase II trials and
an ongoing pivotal REMoxTB trial. Upon completion, these trials
will have enrolled more than 3,000 TB patients. These completed
Phase II trials were at sites in Africa, Europe and the Americas,
including 10 in the United States. Two drug regimens are being
evaluated: the first substitutes moxifloxacin for ethambutol, and the
second substitutes moxifloxacin for isoniazid in the standard fourdrug
treatment regimen. REMoxTB will determine whether these
new, four-month regimens are not inferior to standard six-month
therapy in terms of failure and relapse, as well as safety.
REMoxTB patient enrollment began in January 2008. A total of
20 to 30 sites, including ones in Asia, Africa and Latin America,
are being recruited into the study to reach enrollment targets.
Assembling this network of sites has spurred an assessment of
the readiness and capabilities of TB clinical trial sites worldwide;
a total of 195 sites contacted, and 93 sites in 42 countries have
been assessed as of August 2009. Thirty-four REMoxTB protocolspecific
assessments have been conducted in addition to these
baseline assessments in 19 countries. Assessments related to
A tuberculosis patient at the Brooklyn Chest Hospital
in Woodstock, Cape Town, South Africa, is given a
dose of the standard four-drug TB regimen, which
he must take regularly for six months under the
observation of medical staff.
Photo by Eric Miller
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capacity to support MDR-TB trials have also been conducted in
eight countries as part of the overall site assessment project.
Public health experts await the registration of a shorter
moxifloxacin-based TB regimen and the subsequent expansion of
the underlying knowledge base, capacities and standards necessary
to accelerate clinical testing, registration and introduction of
additional new regimens. Ultimately, a new regimen will lessen the
burden of TB for patients and health systems alike and save lives.
“It is interesting. When you shed past dogmas and look objectively
at what we’ve collectively been doing for almost the past decade,
it makes all the sense in the world,” says Spigelman of the TB
Alliance. “Doing something novel takes time for people to accept.”
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Lessons Learned:
• Moving critical processes, such as research,
development and distribution, into resourcepoor
countries with high disease burden can
help alleviate the slow trickle down of treatment
discoveries from richer countries.
• Breaking a large initiative down into
individual tasks helps plan proper time and
resource allocations.
• Having key partners with strengths in
regulatory negotiation or other crucial areas
ensures the right people are working on the right
things and keeps a project moving forward.
Dengue Fever Partnership
Changes the Rules for
Vaccine Development
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Dengue fever is an increasing problem worldwide.
The dengue fever virus is spread by the Aedes aegypti
mosquito, which is highly adapted to urban conditions.
A vaccine will be key to controlling the disease. The
Pediatric Dengue Vaccine Initiative (PDVI) partnered
with Brazil’s state-owned Instituto Butantan to rapidly
develop a promising vaccine candidate. Butantan,
which supplies Brazil with most of its vaccines, is also
receiving advice from PDVI contractee Global Solution
for Infectious Diseases. The trio aim to develop the
vaccine in the next few years and bring it to market at a
low price. After approval, PDVI will continue to assist
with planning for mass distribution. The development
route taken by this vaccine represents a new model.
Previously, large pharmaceutical companies introduced
vaccines in rich countries first. It took years for the
vaccine to appear in resource-poor countries. With the
dengue fever vaccine, both research and distribution will
take place in a developing country with a strong interest
in moving quickly against the disease.
The Dengue Fever Epidemic
Dengue fever is on the upswing in most tropical areas of the world,
particularly south Asia and Latin America. The epidemic spread
of the disease has made dengue vaccine research a pressing matter.
Donald Francis, vaccine pioneer and executive director of Global
Solutions for Infectious Diseases (GSID), thinks that the novel
international collaboration behind dengue vaccine development
represents a new paradigm. “There is a major evolution going on,”
he says. “Vaccine development is moving from the industrial world
and its enormous investments to the developing world where the
diseases occur. The NIH [U.S. National Institutes of Health] used
to license vaccines to rich country companies and then years later
the vaccines would get to developing countries. Now the NIH
is going directly to the developing countries. Both for-profit and
nonprofit government entities are playing a role. They used to be
“me too” operations making established vaccines. These groups are
getting more interested in development.”
Isaías Raw (pronounced “rao”) is director of the Instituto Butantan
as well as president of its research branch, the Fondação Butantan.
Butantan is owned by the state of São Paulo, where dengue fever
is “out of control,” says Raw. “Every summer [January through
Dengue virus
Source: http://www.flickr.com/photos/ajc1/1437910835/sizes/o/
Creative Commons license
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March] is worse than the last.” Brazil as a whole recorded 560,000
cases in 2007, with 158 deaths. In the first 35 weeks of 2008 —
the latest period for which data are available — there were already
735,000 cases and 212 deaths. Aside from São Paolo state, Rio de
Janeiro state and parts of the north are heavily affected.
Brazilian-International Partnership
Profiting from the NIH’s recent tilt toward developing-country
vaccine producers, Instituto Butantan has obtained a license to a
promising dengue fever vaccine from the agency. Efforts to create
HIV or malaria vaccines involve northern agencies and companies
collaborating to develop the candidate vaccines and then work with
developing country researchers to conduct human testing. The
location of vaccine manufacture has not yet come up in these cases
but will most likely include developing-country producers that
receive no-royalty licenses. The dengue fever vaccine collaboration
gives the local partner much more authority. It yields project
direction to Brazil’s Instituto Butantan as soon as the vaccine comes
out of the NIH laboratories. This public Brazilian agency is the
country’s main vaccine manufacturer. It will organize the human
trials for the dengue vaccine, steer it through regulatory approval
and bring it to market.
This is the first time that Butantan has attempted to develop
a new vaccine from early human safety trials on. To provide
technical support for this ambitious effort, Butantan called on the
Pediatric Dengue Vaccine Initiative. PDVI is based in Seoul, South
Korea. It is a branch of the International Vaccine Institute, which
was established in 1987 under the aegis of the United Nations
Development Programme.
According to Richard Mahoney, PDVI’s director, vaccine access,
“We started in 2003, and became a coalescing force.” PDVI,
among other things, organized regular meetings to bring experts
together. These meetings provided a venue for real sharing of
information and setting of standards. The Bill & Melinda Gates
Foundation in 2003 granted PDVI $55 million to support its
activities, including establishing vaccine trial sites in Asia and
South America. PDVI thus became a leader in creating the global
dengue vaccine effort along with such agencies as the World Health
Organization.
Butantan, with PDVI’s assistance, hopes to implement an
ambitious plan for rapidly moving from safety studies to largescale
efficacy trials and mass rollout. PDVI has, in turn, brought
in GSID as management and training consultants. “GSID has
experience in scaling up vaccine trials. It sits down with Butantan
and talks about technical requirements and then comes back and
does an audit,” says Harold Margolis, PDVI’s director.
Butantan is able to move a vaccine from the development stage
to distribution. Mahoney has great respect for its capabilities.
He comments, “Brazil has made dengue a high priority, and
we have made Butantan a high priority among developing
country manufacturers for developing the vaccine.” Butantan is
a government-owned, nonprofit entity but works like a private
company. It is able to pump its revenue back into its facilities so as
to maintain an efficient, high-quality operation.
PDVI Facilitates Vaccine Development
Developing a dengue vaccine should be a straightforward affair,
but there are two serious obstacles. Dengue virus has four
strains, designated dengue 1-4. The people at highest risk of
life-threatening dengue hemorrhagic syndrome are those who
were previously infected with one strain and are later infected by
another. The solution to this problem is to create a vaccine that
triggers long-term high antibody levels to each strain. Butantan’s
NIH-licensed vaccine generally showed signs of provoking strong
A Global, Urban Epidemic
Dengue, sometimes referred to as “breakbone fever,”
notoriously involves severe flu-like symptoms, an
extensive, hypersensitive rash and excruciating joint
and muscle pain. There are currently about 36 million
symptomatic cases per year worldwide. Asymptomatic
cases amount to three times that figure. Conversely
about six percent of the clinical dengue fever cases
— 2.1 million — contract life-threatening dengue
hemorrhagic syndrome. Supportive treatment greatly
reduces mortality, which amounts to about 20,000
yearly. Children are especially affected by dengue fever’s
severe consequences.
Even the asymptomatic cases are important because
they help spread dengue via the disease’s mosquito
vectors, mainly Aedes aegypti. “You can’t really control
the mosquito,” says Brazilian vaccine pioneer Isaías
Raw. “It lives in very small bodies of stagnant water. In
cities, it lives in so many vases, tanks and potholes. It’s
very difficult now with the huge urban migration that
we’ve seen. Mosquito control was done many years ago,
but today it is not a good solution. We used to dust
every place with DDT. It’s a stable compound, but it
destroys birds and bees and hurts the forest. Today, we
need a vaccine.”
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immunity in preliminary U.S. trials. Francis praises the NIH
approach. He says, “Rather than the old-fashioned live-virus
culture approach to create attenuated strains here they directly
manipulate the genes and then clone the virus. It’s incredible.”
There is, however, a further issue. The immune response to each
strain in the combined vaccine interferes somewhat with the response
to the other strains. Multiple dosing promises to provide long-term
immunity despite this interference. The optimum vaccine dose and
schedule has to be worked out in carefully designed human trials.
Here, PDVI has played a critical role in advising on appropriate trial
design and the required lab capabilities.
PDVI has also worked with Butantan to assess potential trial
sites, in the process evaluating local epidemiological information
and research infrastructure. The initiative also did an elaborate
computer analysis of the entire vaccine project, breaking it down
into more than 320 individual tasks, including trials, building
manufacturing capacity and regulatory approval. These analyses
allow Butantan to navigate new territory for their institution,
indicating the resources and time that would have to be allocated.
PDVI has been instrumental in clarifying the vaccine’s regulatory
pathway with government officials at Brazil’s National Health
Surveillance Agency — the equivalent of the U.S. Food and Drug
Administration. Mahoney says, “One of the most important things
we do is to bring detailed technical knowledge to discussions with
the regulatory agency. We then help Butantan provide scientifically
accurate and relevant information in its applications for clinical
trials and, eventually, for marketing approval.”
Raw adds, “PDVI has a first-rate team of experts to analyze
the results and plan the next step. Having PDVI shows outside
recognition and gives the project more credibility.” That credibility
is vital when seeking support from the state or from private
funders.
After Approval
Vaccine approval is, of course, only one step on the way to vaccine
access. Vaccines in the past have been introduced first in rich
countries and then very slowly made their way to developing ones.
This process could take years. Recent vaccines, such as those for
pneumococcal bacteria and human papillomavirus, have come
to market at unprecedentedly high prices, making their use in
resource-limited settings still more problematic. But there will not
be much need for the dengue fever vaccine in areas able to support
high prices. The vaccine will go straight to poor countries with
small health budgets and poor distribution systems.
Yet there is no doubt that the vaccine will be highly advantageous
in these nations: A 2004 Southeast Asia cost-effectiveness study
found that a 95 percent effective dengue vaccine with a public
sector price of 50 cents would be very cost effective. It is not clear
if a price of 50 cents per dose can be achieved but PDVI’s free
support work will help reach that target. Then too, the Instituto
Butantan is state-owned. Part of its mission is to keep prices down.
When explaining PDVI’s strategy, Mahoney says, “Butantan will be
a low-cost manufacturer that just covers its costs. One of the little
secrets of the vaccine business is that the major cost is in R&D,
whereas production costs are low. Sometimes the cost of packaging
is more than cost of making the vaccine.” PDVI is working with
Butantan on an analysis of actual costs to establish a rational basis
for the vaccine’s price.
Mahoney has long experience in reducing vaccine expense.
As secretary of the International Task Force on Hepatitis B
Immunization, he was one of the key personalities in bringing
down developing nation prices for the hepatitis B vaccine. In
1986 the worldwide price for this vaccine was about $100 for the
required three doses, and the U.S. private sector cost is still nearly
$70 for children (more than $150 for adults). It is now available in
resource-restricted settings for less than 90 cents for three doses, or
under 30 cents per dose. (The older childhood vaccines typically
cost less than 10 cents in less developed countries versus a U.S.
public sector price of $10 to $20 per dose.)
Butantan intends to sell its dengue vaccine in other Latin American
countries once it has obtained regulatory approval and has
sufficient manufacturing capacity. Making the vaccine is just the
first step toward mass immunization, which necessitates a multiphase
introduction effort. Health care workers require training on
the appropriate population and schedule for the vaccine. Health
Aedes aegypti mosquito
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organizations need to conduct a community education effort to
ensure public interest. Supply chain logistics have to be worked out
in detail — is there enough cold storage space, for example?
Contemplating the post-approval phase of dengue vaccine
development, Margolis says, “Nearly everyone in low- and middleincome
countries receives vaccines through public programs. PDVI
will work to get in place funding mechanisms through GAVI
[Global Alliance for Vaccines and Immunization] and local country
governments. We also will advise on technical implementation and
help to conduct demonstration projects.”
A New Paradigm in Vaccine Development
PDVI is moving forward on several other fronts. In India, it
is advising vaccine makers on developing the NIH vaccine. In
Thailand, PDVI’s epidemiologic studies have helped French
vaccine developer Sanofi Pasteur with its large-scale dengue vaccine
efficacy trial. The Sanofi Pasteur dengue vaccine is the first to reach
this advanced testing stage. If all goes well, the world will see several
competing dengue vaccines by the middle of the next decade. The
promise of multiple sourcing leaves PDVI hopeful. Mahoney and
Margolis contend that competition among producers is a potent
means of keeping prices down while keeping supply up.
In January 2009, the Instituto Butantan announced an agreement
to develop a leishmaniasis vaccine with the Seattle-based Infectious
Disease Research Institute. Although the vaccine will target the
leishmania reservoir in dogs, the agreement in many respects
parallels the Butantan-PDVI agreement for dengue fever. In both
cases, Butantan, with the assistance of an international nonprofit
partner, will adopt a vaccine concept and develop it into a
marketed product.
Butantan is growing into an autonomous vaccine developer that
can produce vaccines for diseases of local concern. It will be able to
license vaccines for such diseases as malaria, tuberculosis and HIV
when the National Institute of Allergy and Infectious Diseases and
other research organizations find promising candidates. Butantan
will then be in a position to ensure that these vaccines become
accessible to the public in Brazil and other developing countries.
By David Gilden
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Global Access License Between
University and Biotech Benefits
Developed and Developing World
Lessons Learned:
• There is no standardized approach to
drafting or enforcing global access language
in licensing agreements.
• Having an industry partner that is likeminded
in its sense of global stewardship
is an essential foundation for a successful
agreement allowing a company to advance
technology for the developed world.
• Support from senior leadership at the
stakeholders’ organizations is important given
the unique nature of global access provisions.
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An oral amphotericin B (AmpB) formulation is showing
promising results in preclinical studies that could one
day provide the developing world with a treatment for
leishmaniasis, a devastating disease that has a significant
impact on indigent populations where the disease is
endemic. An oral AmpB formulation would allow the
therapy to be brought to the patient instead of requiring
travel to the clinic, and it does not appear to have the
associated renal toxicity of available intravenous (IV)
formulations, putting an affordable, less toxic therapy
within reach of the developing world for the treatment
of leishmaniasis.
The success to date is due in no small part to global access
principles that bind researchers, university staff and students, and
the licensee of the technology in a common bond — to ensure this
novel, lipid-based oral formulation of AmpB reaches the developing
world where, according to World Health Organization (WHO)
statistics, leishmaniasis currently threatens 350 million people
in 88 countries. The licensing deal, the first among Canadian
universities in accordance with these global access principles, was
signed in 2008 between iCo Therapeutics Inc. and the University
of British Columbia (UBC), both of Vancouver, British Columbia,
Canada. In return for the worldwide exclusive rights to develop
and sell the oral reformulation of AmpB (termed iCo-009 by iCo
Therapeutics) in the developed world as a treatment for bloodborne
fungal infections, iCo Therapeutics ensures the availability
and accessibility of a suitable formulation for the developing world
to treat leishmaniasis.
Leishmaniasis: A Global Threat
Leishmaniasis, a parasitic disease transmitted by the bite of the sand
fly, infects an estimated 12 million people today, and about two
million infections occur annually. It has a wide range of clinical
symptoms:
• Cutaneous leishmaniasis, the most common form of the
disease, causes ulcers on the face, arms and legs. While the
ulcers heal on their own, they cause serious disability and
leave severe and permanent disfiguring scars that lead to
discrimination, stigma and substandard living conditions.
Epidemics are especially devastating in refugee camps.
Kishor M. Wasan, Ph.D.
Photo by Martin Dee, with permission of UBC Public Affairs.
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• Visceral leishmaniasis, the most severe form of the disease,
attacks the internal organs, and, if left untreated, is fatal within
two years.
An ominous global trend is developing, where persons with HIV
become coinfected with visceral leishmaniasis, which accelerates
the onset of AIDS by cumulative immunosuppression and by
stimulating replication of the virus.
According to the WHO, visceral leishmaniasis is no longer
restricted to endemic areas and the number of cases of visceral
leishmaniasis and HIV coinfection will continue to rise. For
example, up to 70 percent of adult cases of visceral leishmaniasis in
southern Europe are linked to HIV infections, and 35 percent of
all leishmaniasis patients in some areas of Ethiopia are coinfected
with HIV, with an indication that it is spreading to neighboring
countries such as Sudan.
Where There’s a Will, There’s a Global Access License
The promising oral AmpB formulation was discovered in the
Wasan Lab at UBC by Kishor M. Wasan, Ph.D., professor,
Canadian Institutes for Health Research/iCo Therapeutics research
chair in drug delivery for neglected global diseases, and chair in
the Division of Pharmaceutics and Biopharmaceutics, and Ellen
Wasan, Ph.D., adjunct professor in the faculty of pharmaceutical
sciences also at UBC. The Wasans devised an oral formulation
that showed promising lab results with minimal side effects, a
significant improvement on the 50-year-old treatment that is
expensive, must be administered by IV infusion and is highly toxic.
The significance of this innovation grew when they realized it was
ideal for application in both the developed and developing world.
The next step for moving the Wasans’ discovery from the lab bench
through to commercialization might have followed the traditional
route charted by most technology transfer offices that patent and
license university-based innovations. However, in 2007 UBC’s
University-Industry Liaison Office (UILO) had just become
the first university in Canada to develop a flexible framework to
ensure it provides global access to relevant technologies. The new
Global Access Principles, developed in collaboration with key
senior administrators and the student-led UBC Chapter of the
Universities Allied for Essential Medicines, establishes practical
mechanisms and partnering strategies for UBC technologies to
maximize their societal impact.
So when iCo Therapeutics, a publicly traded biotech company,
approached the UILO about the Wasans’ discovery, they needed
to find a win-win solution that would achieve both organizations’
objectives.
“Our goal was to have the new oral AmpB formulation licensed to
a company that would agree and be able to not only develop the
formulation in the developed world for fungal infections, but also
develop the technology in the developing world for the treatment
of leishmaniasis in accordance with the Global Access Principles
adopted by UBC,” says Ian Bell, a technology transfer manager
of the UBC UILO, which assists UBC researchers through core
activities of sponsored research and technology transfer to increase
the academic, societal, environmental, economic and financial
impacts of their research.
John G. Clement, Ph.D., chief business officer and director of iCo
Therapeutics, adds, “Our business model is focused on redosing
or reformulating drugs with clinical history for new or expanded
indications. The oral amphotericin B program is an early proof of
concept of the underlying drug delivery technology and provides
iCo with an opportunity to expand our product pipeline and
provides a new way for the company to explore other drugs that
can be converted from the parenteral route of administration to the
oral route.”
The licensing negotiations — described as very productive and
positive by those involved — occurred over roughly a four-month
time frame and involved various parties, including UILO, the
UILO external legal counsel, iCo Therapeutics and its external
legal counsel.
The most critical negotiation issues involved the licensing terms
related to:
• Reasonable development time lines — With the need to move
both a developed and developing world formulation forward,
the partners established a development time line to ensure that
the company could pursue a product for the developed world
that could financially support the company, while at the same
time, ensuring that the product for the undeveloped world
would not be pushed aside or pursued in favor of the other.
• Formulation for developing world — The partners agreed
to a process whereby iCo would either solve any issues in its
obligations to create a developing world formulation, or UILO
would have the ability to step back in and access the rights to
develop the formulation for the developing world.
• Parallel imports — In an attempt to prevent or reduce the
risk of parallel imports, a matter of great concern to iCo
Therapeutics, the partners agreed that different formulations
would be developed for the developed and developing worlds.
The nature of the formulation actually lent itself to this
strategy because of the different requirements, such as disease
target, and temperature and stability.
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Once these issues and the financial terms were agreed upon,
much of the discussion centered on the appropriate global access
language, since the desire to increase global access for healthrelated
innovations and the realities of working with industry to
commercialize them takes more than a standard licensing structure.
“UBC granted iCo Therapeutics the worldwide, exclusive license
to the UBC technology,” says Bell. “Under the license agreement,
iCo’s global access obligation is to ensure availability of a
formulation of the UBC technology for treating leishmaniasis in
the developing world at a subsidized price.”
Public and Private Partners
In May 2008, the UBC UILO signed its first licensing agreement
in accordance with Global Access Principles when it partnered with
iCo Therapeutics to advance the oral formulation of AmpB. As the
Wasans’ discovery moved from the lab bench through to licensing,
it also involved several public and private organizations:
• Federal government of Canada — Provided research funding
to the inventors through the Canadian Institutes for Health
Research and the National Research Council of Canada
Industrial Research Assistance Program (NRC-IRAP),
designed to provide funding and support to Canadian smalland
medium-sized enterprises. iCo Therapeutics also received
NRC-IRAP funding to support development activities related
to the oral formulation.
• Canadian Research Network and Mathematics of Information
Technology and Complex Systems — Provided funding for a
UBC postdoctoral intern to work with iCo Therapeutics to
develop the technology further.
Since signing the license agreement in 2008, iCo Therapeutics
has moved development of the formulation forward. Some of the
work includes collaboration with the Consortium for Parasitic
Drug Development — a Bill & Melinda Gates Foundation-funded
consortia based at the University of North Carolina at Chapel Hill
— to test the oral formulation in a leishmania model. The results of
this testing showed that the oral formulation was almost 99 percent
effective in clearing the infection. iCo Therapeutics also held a pre-
IND (investigation new drug) meeting with the U.S. Food and Drug
Administration to clarify the company’s clinical plan.
iCo Therapeutics also is in the planning stages of chemistry,
manufacturing and controls, scale-up and current good
manufacturing practice, and good laboratory practice safety and
toxicology work to support a IND application.
Flexibility, Support and Willingness Key to Success
The UBC UILO has had some experience over the years with
global access and individual licensing programs and projects. One
program involves a UBC-based researcher who collects marine
and plant biota, such as sea sponges from Papua New Guinea,
and then isolates potential therapeutic compounds from them,
with a portion of economic returns going back to the country
of origin. The UBC UILO also manages some projects with the
aim of developing essential medicines for the developing world
that received a Grand Challenges in Global Health grant from
the Foundation for National Institutes of Health and the Gates
Foundation.
But now, with adoption of Global Access Principles and the
licensing agreement to allow iCo Therapeutics to commercialize
the oral formulation of the drug AmpB, UBC is part of a growing
number of universities and nonprofit research institutes that have
either implemented or are considering adopting socially responsible
licensing practices.
“Looking back over the hard work and discussions that culminated
in this licensing agreement, I think three key elements stand out
— flexibility, support and a willingness to do something good for
those who are less fortunate,” says Bell at the UBC UILO. “And, in
a way, it was the result of a perfect storm and a little luck.”
Key learnings that came out of this licensing agreement include:
• Flexible Language: This win-win scenario was based on mutual
trust and iCo Therapeutics being receptive to a creative and
flexible approach used by the UBC UILO in developing the
licensing terms and language that were acceptable to all parties.
There is not a standardized approach to drafting or enforcing
global access policy language in licensing agreements.
• Support: The UBC UILO was pleased by the support it received
for the Global Access Principles by external stakeholders during
the review process. iCo Therapeutics welcomed the global access
language in the license and its investors agreed the global access
language and relationship with UBC were a benefit to all.
• Willingness to Do Good: Having an industry partner with a
global stewardship priority is the foundation for a successful
agreement allowing a company to advance technology for the
developed world, while making the technology available to
resource-constrained countries through subsidized pricing.
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Support from senior administration, both at the university
administration and technology transfer office, also is critical to
the adoption and implementation of global access principles
that guide how licensed university-based technology may impact
the developing world. This support allowed for the drafting of
appropriate global access licensing terms and is helping to establish
a new metric to measure the effectiveness and global influence of
UBC and the UILO.
“We are very excited by the potential of iCo-009,” says iCo
Therapeutics’ Clement. “We are proud to know that iCo-009 could
save and improve the quality of life in both the developed and
developing worlds.”
By David Perilstein
To maximize the societal impact of University of British
Columbia technologies, practical mechanisms and partnering
strategies are required that:
• Enhance both the economic and societal impact of
university innovations
• Extend these impacts to broader global settings
• Ensure fair access to these technologies for the world’s poor
within an evolving framework of licensing practices, legal
concerns, business opportunity and time constraints
Broadening the societal impact of and global access to UBC
technologies requires that these concerns are addressed when
new UBC technologies are developed, patented and licensed.
To this end, while applying the university’s intellectual property
policy, UBC will:
• Promote global access by entering public-private
partnerships to develop new technologies to benefit the
developing world
• Prioritize environmentally friendly research and green
alternatives and take the lead in community sustainability
• Respect biodiversity, ensuring value return to countries of
origin
• Endeavour to ensure that underprivileged populations
have at-cost access to UBC research innovations through
negotiated global access terms whenever appropriate
As the understanding of issues relating to societal licensing
evolves, balancing ambitious objectives with legitimate business
concerns requires patience, determination and the willingness
to be both pragmatic and flexible. To support this social
licensing commitment, UBC will, where possible, employ the
following strategies:
• Build on the values of access and dissemination as
demonstrated in the open source movement in the
information technology sector.
• Promote the use of nonexclusive licensing of research tools
(for example, the West Coast Licensing Partnership on
FlintboxTM).
• Consider field-of-use and jurisdictional limitations in
exclusive licenses to exclude developing world countries.
• Negotiate developing world access at-cost to relevant
technologies that are licensed on a worldwide exclusive
basis (required for technology development).
• Continue to seek partnerships with not-for-profit and
charitable organizations to provide much-needed funding
for neglected disease area.
• Design patent strategies with development partners that
ensure quality product delivery to those most in need,
while promoting sustainable, local infrastructure.
In measuring the success of technology transfer activities at
UBC, societal impact has become a key metric alongside
standard throughput, financial and economic measurements.
Positive societal impacts include improving human and
veterinary health, supporting international biodiversity,
protection of the environment and promoting sustainable
green alternatives.
University of British Columbia Global Access Principles
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New Broad-Spectrum
Vaccine Protects Against Most
Pneumococcal Disease
Lessons Learned:
• Building a committee that emphasizes the collaborative
nature of the development work provides focused
expertise when implementing complex projects.
• Frequent, timely communication is a critical aspect of a
successful partnership’s information sharing.
• A for-profit product can be developed alongside a
nonprofit product when similar goals exist.
• People in resource-rich countries often benefit from
technological advancements designed to aid people in
developing countries.
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Courtesy of the PneumoADIP, photo by Adrian Brooks
Pneumococcal disease kills approximately 1.6 million
people every year, with more than half of these deaths
occurring to children less than five years old. The
variances in strains are compounding the problem.
“Pneumococcal disease has over 90 serotypes,” says John
Boslego, M.D., director of PATH’s vaccine development
global program. “It is the most common cause of severe
pneumonia, which is the leading killer of children less
than five years of age worldwide.” The pneumococcus
bacterium also causes meningitis, sepsis (blood
infection) and otitis media (inner ear infection).
Current pneumococcal conjugate vaccines approved for use in
children are effective against strains common in the industrialized
world and some developing countries, but they do not cover all
pneumococcal serotypes, including several strains common in
Africa and Asia. They are also expensive, which makes access to
vaccines difficult in poorer countries that most desperately need
them. While the GAVI Alliance is helping low-income countries
afford the current vaccines, new vaccines are needed both to
improve protection and affordability. Other licensed pneumococcal
polysaccharide vaccines cover an estimated 23 serotypes but are
only effective and approved for use in adults. A pneumococcal
vaccine that is affordable and offers broad serotype independent
protection for use in children in the developing world is urgently
needed.
Conjugate vaccines are complex, difficult to produce and expensive
for the populations most in need of protection from pneumococcal
disease. Since conjugated vaccines do not work against every type
of the disease or for everyone who needs protection, protein-based
vaccines could be a promising, affordable alternative that could
offer broad protection to populations that need them worldwide,
especially children in developing countries.
“The development of a common protein vaccine against the disease
holds particular promise because it could provide broad protection
by covering all pneumococcus serotypes, saving the lives of millions
of children around the globe,” says Boslego.
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To advance such a vaccine, PATH — a U.S.-based nonprofit
organization whose mission is to create sustainable, culturally
relevant solutions that enable communities worldwide to
break longstanding cycles of poor health — and the Austrian
biotechnology firm, Intercell AG, are partnering on a recombinant
protein-based pneumococcal vaccine. The partnership aligns the
goals of each organization: Intercell’s pursuit of a vaccine for the
elderly in the industrialized world and PATH’s goal of an affordable
vaccine for infants and children in the developing world. The
common interest is to develop a pneumococcal vaccine with broad
protection across the many serotypes of pneumococcal disease.
While there may be differences in the vaccine formulations for
children or the elderly, they will likely share the same antigens. By
building on this synergy, the partners are striving to achieve both
global public health and commercial goals.
Should the common protein approach prove effective, it would
offer universal coverage across all pneumococcal serotypes and
prevent serotype replacement that can occur with conjugate
vaccines. In addition, the manufacturing technology for protein
vaccines is more simple and cost-effective relative to conjugate
vaccines and could, therefore, lead to a vaccine that would be
affordable for distribution by public health systems in low-resource
countries. Finally, if successful, the vaccine could have a significant
commercial value in the developed world where pneumonia is a
major cause of morbidity and mortality in the elderly, the immunesuppressed
and post-operative populations.
The Path to Discovering a
Single Broad-Spectrum Vaccine
Assuming a standard recombinant protein manufacturing process,
it is less cumbersome and less expensive to produce protein vaccines
than complex multivalent conjugate vaccines. Intercell’s IC47
pneumococcal vaccine consists of three proteins that are highly
conserved in all 90-plus different serotypes of S. pneumoniae
including a selected panel of pneumococcal strains from different
geographic regions. “Thus the vaccine could be able to protect
against all disease-causing pneumococcal strains and isolates,” says
Dr. Andreas L. Meinke, head of Alliance and Grant Management
at Intercell AG.
Intercell AG has developed the IC47 pneumococcal vaccine
based on its proprietary Antigen Identification Program®. One of
the three antigens, PsaA, was licensed by Intercell AG from the
U.S. Centers for Disease Control and Prevention (CDC), and all
preclinical work, including the toxicity study and all manufacturing
of the three recombinant proteins was performed by or on behalf of
Intercell AG.
PATH and Intercell AG are working together through a
collaborative research and development agreement that covers all
stages of development through Phase II clinical studies, including
draft guidelines for the terms of a commercialization agreement
between the parties to be negotiated prior to the start of Phase III
clinical studies. However, the development work is funded in stages
and based on successful achievement of established milestones.
In the case of the collaboration with Intercell, PATH did a
comprehensive landscape analysis starting in 2005 with a focus on
protein vaccine candidates. Intercell had one that was attractive
to PATH so Intercell submitted a proposal and PATH agreed
to move forward with it. Because PATH believes the success of
any collaboration depends on the selection of a good partner,
PATH conducted a thorough assessment, in accordance with its
own standard operating procedure, before entering into a formal
collaboration with Intercell. During this process, PATH routinely:
• Assesses the reputation of the company, its corporate behavior
and its economic viability to ensure compatibility with PATH’s
mission and reputation;
• Reviews the scientific and technical capabilities of the
collaborator to make sure they are appropriate for the
collaboration; and
• Ensures that the public health outcomes and return on
public-sector investment will be commensurate with the effort
involved in establishing and maintaining the collaboration.
In the end, PATH and Intercell decided that a partnership would
be mutually beneficial to both entities and entered into a vaccine
development agreement in 2006. In general, PATH’s agreements
with partners including Intercell, cover, at minimum, the following
information:
• The objectives of the collaboration, the roles and
responsibilities of each partner, and the expected outcomes;
• The accountability and performance milestones that will be
used to ensure that the goals of the collaboration are met;
• A clearly defined management and decision-making structure
of the collaboration; and
• A clearly stated process for monitoring, evaluating and
terminating the collaboration.
PATH began collaborating with Intercell during the preclinical
development of the IC47 protein-based vaccine candidate in 2006
and has since committed an additional $3.6 million to support
clinical development through the second quarter of 2010. In
addition to developing the vaccine candidate, Intercell AG has also
agreed to make the vaccine affordable for children in developing
countries as part of a global access commitment under this project.
The development of the vaccine for the elderly will be carried out
in parallel using Intercell’s own funding.
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Trials and Lessons Learned
In March 2009, Intercell AG launched a Phase I first-in-man
trial of IC47 in healthy adults in Germany with support from
PATH. PATH and Intercell bring complementary expertise to the
project. They also share development costs. Funding from PATH
has covered approximately one-half of preclinical development
expenses, thus reducing Intercell’s risk. Without this funding,
Intercell would likely have emphasized developing a vaccine
for elderly people in Europe and the United States rather than
expanding the target market to also include children in low-income
countries. Successful preclinical development from 2006 through
2008 paved the way for the Phase I clinical trial in healthy adults
beginning earlier in 2009.
In partnership, Intercell and PATH have been able to further
advance the IC47 vaccine candidate by utilizing tools such as
genome sequencing data developed and made publicly available
through the work of PATH and other partners, as well as by
bringing together other collaborators in preclinical evaluation.
This project is the first at Intercell AG to be fully developed from
preclinical research to clinical testing. The trial also marks an
important milestone for PATH’s pneumococcal vaccine project in
advancing the development of a protein vaccine candidate through
preclinical studies into clinical trials.
The main two antigens were identified via Intercell’s Antigen
Identification Program, and tested together with the third antigen
from CDC in various animal models of pneumococcal disease as
recombinant proteins, produced by Intercell. The manufacturing
of the recombinant proteins for the Phase I clinical trial was done
by a contract manufacturing organization under close collaboration
with Intercell. Thus many tasks during the preclinical research as
well as development phases needed exploratory work, expert advice
and support by third parties.
Further clinical studies are currently in the planning and
preparation phase. The sites remain undetermined at this point, but
the goal is to move as quickly as possible to the target population
of children and infants in the developing world. Although it is
beyond the scope of the current agreement, the eventual goal of
the collaboration is to conduct a Phase III efficacy trial in infants
in developing countries. Intercell is also planning a separate trial in
elderly adults in developed countries.
“Our collaboration with Intercell has facilitated the advancement
of a promising pneumococcal common protein vaccine candidate
through preclinical studies into clinical trials,” says Mark Alderson,
Ph.D., director of PATH’s pneumococcal vaccine project.
One factor that makes this project unique is the pursuit of an
innovative scientific approach for which there is no proof of
concept or a previously charted regulatory pathway. As a result,
the partners have to exercise extraordinary care in designing the
Phase I and II studies and build in clear go/no-go decision points.
“Go/no-go” decision points in the PATH/Intercell collaboration
are contingent upon whether the goals of both entities can be met
and are still in alignment, as well as establishing consensus on
major project components such as the design of clinical trials and
outcomes to measure, among others.
To make the vaccine low-cost for the developing world, the
partners are working to improve production efficiency, purification
processes and stability. They invested early in assessing these issues
to mitigate risks and build back-up options in case the need arose.
“It is certainly easier than the development of a conjugated vaccine,
but there are also challenges to be addressed,” says Andreas L.
Meinke, Ph.D., of Intercell. “Similar as for conjugated vaccines,
the three recombinant proteins have to be formulated in a
common buffer with the selected adjuvant without compromising
the immunogenicity and efficacy of any of the components. In
preclinical studies this goal was achieved and, thus, we proceeded
to clinical testing.”
Courtesy of the PneumoADIP; photo by Adrian Brooks
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“In addition, assays to evaluate efficacy in clinical studies have
to be established for protein vaccines,” adds Meinke. “The
assays which have been developed for conjugated vaccines are
not readily applicable to protein vaccines. A further challenge to
the development of protein vaccines is the fact that conjugated
vaccines are already licensed and need to be used as comparator.
Thus protein vaccines will likely need to be superior to already
licensed conjugated vaccines.” A definition of superiority could
include performance and broader serotype coverage, but could
also constitute more cost-effective and simpler manufacturing that
enables global access to the vaccine.
Discussions to reach agreement on the terms of the collaboration
between PATH and Intercell took approximately one year from
first introductions and scientific discussions to completion of the
agreement and initiation of the project. PATH and Intercell are
using an iterative partnership approach for project management.
All facets of the project — including problem-solving and
decision-making — are managed collaboratively through a vaccine
development committee that meets regularly in person or via
teleconferences.
Each organization brings expertise and resources to the partnership.
While Intercell’s core expertise was originally in discovery and
preclinical development, the company has already begun building
expertise in late-stage product development. PATH provides
expertise in nonclinical development, manufacturing, clinical
development and, particularly working in developing countries,
which is where the Phase II and III trials will be performed. The
partners are sharing the development costs for the first phase.
PATH’s contribution reduces the risk Intercell might incur by
investing in a vaccine for uncertain markets in poor countries.
By Pam Baker
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Lessons Learned:
• License terms between academic and for-profit
entities can be crafted to address global access
for important medical technologies in a
meaningful way.
• Developed countries should assist the global
health effort by funding the advancement
of treatments exclusively targeted at those in
resource-constrained settings.
• Companies can successfully commercialize
products in the large markets of the developed
world to help support a sustainable solution for
those in resource-constrained countries.
• A company’s ability to use tiered pricing may be
a valuable incentive.
A Glaucoma Treatment Option
With Global Promise
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Ophthalmologists in the developed world use a variety
of available options today to treat glaucoma, including
pharmaceutical eye drops, laser procedures and surgery.
In the United States, where almost three million have
glaucoma, eye drops are the first choice for decreasing
eye pressure and eventual blindness, followed by a
combination of medications and laser treatment that
safely controls eye pressure for years.
However, in developing countries, where people have the highest
risk of developing blindness from glaucoma, varied treatment
options are almost nonexistent, leaving trabeculectomy — a
complex procedure requiring a significant amount of surgical skill
and follow-up care — as the therapeutic intervention of choice,
according to a British Journal of Ophthalmology article “Glaucoma
in West Africa: a neglected problem.” The reasons for limited
options in the developing world: availability of modern treatments
that are generally expensive compared to patients’ income, the need
to travel long distance for care, and possible lifelong treatment
and unpleasant side effects. The author, Peter R. Egbert, M.D.,
professor emeritus, Department of Ophthalmology at Stanford
University School of Medicine, wrote, “We desperately need a more
effective means of treating glaucoma… A simple, rapid, inexpensive
and effective surgical procedure would be of great benefit. What
we need is a procedure for glaucoma that is as reliable and costeffective
as modern cataract and intraocular surgery.”
A promising response to this plea involves glaucoma drainage
devices (GDDs), some of which are on the market, while others
are being developed by large biomedical device companies and
promise to offer reasonable safety and effectiveness for the control
of intraocular eye pressure. One patented GDD is the Aquashunt™,
a Yale University invention licensed with humanitarian terms to a
leading ophthalmology business, OPKO Health Inc., which started
conducting human clinical trials in South America in 2009.
If successful, inventor M. Bruce Shields, M.D., the Marvin L.
Sears professor and chairman emeritus of the Department of
Ophthalmology and Visual Science at Yale University School of
Medicine, and the Yale University Office of Cooperative Research,
both of New Haven, Conn., as well as the Miami-based OPKO
Health, expect the new GDD to provide hope not only to the 60
million people afflicted with glaucoma in the United States and
other developed nations, but especially to those in developing parts
of the world where glaucoma is a leading cause of blindness and for
which there exists no practical treatment.
Photo by Shutterstock® Images
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Glaucoma — A Group of Diseases That Steals
Sight Without Warning
Glaucoma is a large group of eye diseases that gradually steal sight
without warning. The common feature is a progressive disorder
of the optic nerve that causes a loss of peripheral vision and
“cupping” of the optic disc. Experts estimate that half of the people
affected by glaucoma may not know they have it because they are
asymptomatic, especially in the early stages of the disease when
peripheral vision loss is subtle and easily compensated for. While
the medical understanding of the nature of glaucoma has changed
in the past few years, it is a major public health concern globally.
There is little known about primary prevention of glaucoma;
however, there are effective methods of medical and surgical
treatment if the disease is diagnosed in its early stage. Through
appropriate treatment, sight may be maintained; otherwise the
progression of the condition leads eventually to severe restriction of
the visual field and irreversible blindness.
According to the Glaucoma Foundation and the World Health
Organization, glaucoma is the leading cause of bilateral irreversible
blindness worldwide and affects an estimated 60 million people, of
which more than 20 million have been positively diagnosed and are
being treated. Estimates predict this number to exceed 60 million
globally by 2010, with more than 8.4 million people bilaterally
blind from the disease.
Shaping a Humanitarian Solution for a Major
Unmet Medical Need
Despite advances in ophthalmic surgery, especially in the fields
of cataract, cornea and retinal surgery, many glaucoma specialists
recognize they need a better solution than surgery to control
intraocular pressure in patients with glaucoma. The traditional
surgical approach drains the eye fluid (aqueous humor) to a
superficial part of the eye called the conjunctival space, but this
can lead to scarring and failure, in some cases, and leakage and
infection in others.
Shields of Yale, whose research has led to more than 200 scientific
papers and book chapters, with a special focus on the mechanisms
and management of glaucoma, has invented a novel GDD
medical device called the Aquashunt as a treatment for glaucoma.
Composed of a biocompatible material that conforms to the
shape of the eye, the Aquashunt is designed as a rapid, simple and
minimally traumatic implant, making it ideal for use in both the
developed and developing world. It drains aqueous humor from the
anterior chamber to the suprachoroidal space — a space that exists
between the sclera and choroid layers of the eye.
“A lot of people are looking for better operations,” says Shields.
“But I was looking for a simple and fast glaucoma procedure that
would offer a high success and low complication rate that, once
completed, patients in the developing world wouldn’t have to make
frequent trips for checkups.”
In 2006, Aquashunt was awarded its first U.S. patent. With the
help of Yale’s Office of Cooperative Research (OCR), a startup
company, Vidus Ocular, was created to further the concept for the
developing world.
“If not for Yale’s Office of Cooperative Research, this project
would have gone no further,” says Shields. “Three OCR licensing
professionals got the patent approved, and then they worked with
me to find venture capital and a business team.”
The Management Team and Investment
Comes Together
John Puziss, Ph.D., director of technology licensing at Yale’s
Office of Cooperative Research, says the path that led the licensing
professionals to a management team and investment started with a
single conversation.
“In marketing the technology to the venture capital community,
one of our members, Loraine Lombard, pitched it to Myles
Greenberg of Collinson, Howe and Lennox, an early-stage health
care venture capital firm,” Puziss says. “Greenberg suggested talking
to ATV Capital, which, in turn, recommended Nick Warner as
an experienced engineer who would be a good addition to the
management team. Nick subsequently led us to Jim McNab, who
led us to Ben Bronstein.”
Vidus Ocular started with the one issued patent, licensed from
Yale’s OCR, three patent applications, and about $1.3 million
in funding provided by the company’s founders and individual
investors, including Jim McNab, a self-described serial investor and
entrepreneur.
“Dr. Shields is not a serial inventor but a clinical glaucoma
researcher. He is someone who has spent his life working on a
simple, well-thought-out application that is less complicated than
others being developed,” McNab says. “I got involved because I
knew we were going to have an edge on the competition.”
As a company co-founder and investor, McNab worked with
Shields and the OCR to help build a structure for the startup
company with the addition two other co-founders, physician Ben
R. Bronstein, and engineer Nicholas F. Warner, both of whom
could help Shields get a second generation device approved for use.
(While working with GMP Companies Inc. of Fort Lauderdale,
Fla., Shields had developed a first generation version of the
Aquashunt, which had successfully undergone preclinical trials in
pigs prior to the license reverting back to Yale’s OCR in 2005.)
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“We were able to get enough early-stage funding to build a
prototype, test Dr. Shield’s design and conduct successful in vitro
and in vivo studies in rats,” says McNab. “We had a compelling
story and good data, but we had a central issue: How much
money would we need to build an infrastructure and marketing
department to get to the next phase. We needed to attract more
funding.”
McNab started talking with venture capital groups throughout
the United States, but negotiations and terms were more than the
entrepreneurial company felt it could afford.
“Our goal was to quickly get this device into the marketplace so it
could be used all over the world,” McNab says. “We felt we had a
good shot at this.”
Unsuccessful with the venture capital route and unable to spark any
interest with foundations, McNab turned to ophthalmic companies
where he got “lucky” when he reached out to OPKO Health’s
Chairman and CEO Phillip Frost.
“Frost and his OPKO team recognized that the market is large
enough that it could successfully commercialize Aquashunt in
the developed world and not have to make a lot of money in
the developing world, which was the desire of Dr. Shields and a
condition of the OCR humanitarian-based license,” McNab says.
“They recognized it is the right thing to do because the Aquashunt
device is a simple, powerful idea that will have utility all over the
world. A year or two from now, I think this will be borne out.”
Yale Implements Humanitarian License Provision
On May 7, 2008, OPKO Health announced it had acquired
Vidus Ocular and retained Shields as a consultant, Bronstein as
executive vice president of R&D, and Warner as senior director,
product development. Under the terms of the agreement, OPKO
also agreed to work with Yale University on a number of initiatives
to increase access to the Aquashunt technology in the developing
world.
As part of Yale’s intellectual property management, the OCR
includes humanitarian provisions in licenses that allow for a return
on investment in more profitable markets.
“Yale’s objective in helping to fund Vidus Ocular was to create
a new venture that would focus significant resources on the
development of this important new treatment for glaucoma,” says
Puziss at Yale’s OCR. “In addition, the university wanted to find a
licensee that would commit to making Aquashunt readily accessible
to patients in the developing world.”
This sentiment was reinforced by OPKO’s Head of R&D Jamie
Freedman, M.D., Ph.D.: “We believe the Aquashunt device is
an innovative approach to the treatment of glaucoma and has
significant potential to provide clinical benefit for patients who do
not have easy access to medical therapy or for those who do fail
medical therapy.”
OPKO Health started human clinical trials with Aquashunt in 20
patients with refractory chronic forms of open angle glaucoma, in
the Dominican Republic in February 2009, followed by Mexico
in July. Once data are collected from the clinical trials and sixmonth
followup, OPKO plans to seek a CE mark for the device in
Europe conduct a clinical trial for marketing purposes in Europe,
and initiate a larger clinical trial in the United States to eventually
obtain regulatory approval for marketing from the U.S. Food and
Drug Administration.
“Even though my personal goal was to create a device that would
benefit people in desperate situations in developing countries, this
device should offer the same advantages to all, whether they live
in developing or developed nations,” Shields says. “The continued
development and validation of the new Aquashunt for glaucoma is
our top priority in our quest to eliminate the blindness of glaucoma
worldwide.”
By David Perilstein
Humanitarian Terms of a License
John Puziss, Ph.D., director of technology licensing
at Yale’s Office of Cooperative Research, says Yale and
OPKO Health Inc. settled on key humanitarian terms in
the licensing agreement for Aquashunt:
• Licensee shall make the use of licensed products in
low-income and lower-middle-income countries a
part of its Corporate Mission Statement.
• Licensee agrees to use commercially reasonable efforts
to pursue clinical testing of the licensed products in
low-income and lower-middle-income countries.
• Licensee agrees that, upon achieving $5,000,000
in cumulative profits (determined in accordance
with [Generally Accepted Accounting Principles] GAAP) from sales of licensed products, Licensee
will commit an amount equal to 1percent of net
sales, up to a maximum of $500,000 per year, in the
form of licensed products, grants and/or services, to
governments in underdeveloped regions, or not-forprofit
charitable organizations.
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The Africa Biofortified Sorghum
Project Consortium:
Food Safety and Fighting
Malnutrition in Africa
Lessons Learned:
• Engage stakeholders throughout all stages of a
project to make them more receptive to the effort
and give them a sense of involvement.
• Addressing regulatory communications and
policy concerns early is critical for long-term
success of the initiative.
• Effective internal and external communication
is key. Visible, tangible results and word-ofmouth
communication are the most effective
method to promote a project that has potential
to impact a large population.
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African Biofortified Sorghum Project Coordinator
and Africa Harvest CEO Dr. Florence Wambugu
speaks to a sorghum farmer about some of the
challenges growers face.
More than half a billion people around the world rely
on sorghum as a dietary staple. The genus of numerous
species of grass, sorghum is a unique crop in that
it grows in hot, dry environments. Its tolerance for
drought and heat make sorghum an important food
crop in Africa, where irrigation is not accessible or
affordable.
Sorghum is indigenous to the African states of Ethiopia and Sudan,
and several African states are centers of sorghum diversity. Widely
consumed through a wet cooking process similar to porridge or
baked as bread, sorghum lacks essential nutrients, such as vitamins,
iron, zinc and lysine and is not easily digested. To address the
otherwise-promising crop’s inadequacies, an African-initiated and
led consortium was established to develop a nutritionally improved
sorghum that would contribute to food security and help fight
malnutrition in Africa.
The Africa Biofortified Sorghum (ABS) Project Consortium is
led by Africa Harvest Biotech Foundation International (Africa
Harvest), an African-based international nonprofit with a vision of
an Africa without hunger, poverty or malnutrition. Its mission is to
use science and technology — especially biotechnology — to help
the poor in Africa achieve food security, economic well-being and
sustainable rural development.
“The majority of African populations cannot afford vitamins,
micronutrient supplement tablets or fortified foods,” said ABS
Project Coordinator Dr. Florence Wambugu. “In areas prone
to malnutrition, food choices and the delivery of vitamins and
micronutrients through a locally produced staple food, such as
sorghum, would have significant impact on malnutrition. ABS has
the potential to improve the health conditions for populations with
limited food choices, who eat sorghum as their main food source.”
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Africa Harvest, realizing that no single African organization has the
infrastructure or capacity to successfully undertake the scientific
endeavor required for a project such as this, formed a strategic
alliance of private, public and academic organizations. Funding
for the ABS consortium comes from the Bill & Melinda Gates
Foundation.
Team Work
The ABS consortium required expert partners in areas of
technology development, product development and management,
as well as organizations that could create an environment in Africa
that enabled the development and use of ABS. A project steering
committee manages task-oriented committees, as well as special
teams that provide support in areas such as public relations,
regulatory affairs and intellectual property rights. An external
advisory board made up of experts from key disciplines — primarily
genetic engineering, health and nutrition, general agriculture,
and development management — makes recommendations to
the project steering committee, reviews project progress and gives
strategic advice through reports and interactive meetings.
The ABS Project Manager and Director of Technical Programs
for Africa Harvest Dr. James Micah Onsando reports to the
steering committee and is responsible for implementing the
committee’s decisions. He handles administrative, sociopolitical
and management issues within the consortium and leads the Team
Leaders Management Group, which is comprised of team leaders
from each of the consortium members who meet to discuss and
agree on project implementation and strategy, set milestones,
discuss results and data, and share information.
The Technology Development group includes Pioneer Hi-Bred
International (Pioneer), which donated the initial technology;
the Council for Scientific and Industrial Research (CSIR), which
assisted in customizing and enhancing the technology for use in
Africa, and the University of California, Berkeley, which has since
left the partnership, but early on, studied sorghum digestibility and
the various processing methods. Studies of agronomic trait stability,
such as food preparation and milling qualities of transgenic ABS
are conducted by University of Pretoria in South Africa and have
been promising.
“The ABS project aims to place more nutritious seeds into the
hands of the people who need it the most — the poor — who
reside in remote areas and do not have access to fortified, processed
food,” says Lloyd Le Page, Africa Harvest board member and
biotech affairs and regulatory manager for Africa at Pioneer. “The
project is truly African: a native African crop, developed by African
scientists for Africans. We are seeing real progress and are confident
that we can reach our goals.”
To date, the Technology Development team has successfully
developed sorghum with target levels of traits in iron, zinc, lysine
and improved digestibility. The ABS#2, as this transgenic event is
referred to, has been field tested in the United States four times, in
various locations and seasons. CSIR and Pioneer are still working
on vitamin A traits.
Pioneer has successfully backcrossed the relevant traits of four
major African sorghum varieties, Macia, Malisor 84-7, Tegemeo
and Sima. Backcrossing breeds a hybrid with its parent or a
similar plant in order to produce desired traits in a plant with
characteristics of the original species. The team has also developed
an efficient sorghum transformation system, a contribution to the
international scientific community, which can be used to further
enhance sorghum by adding other desirable properties, such as
weed and pest control.
An essential goal of the technology team is to build African
scientific capacity through the training of African scientists.
To date, Pioneer has hosted six African scientists in its labs in
Johnston, Iowa. Five of these scientists have returned to Africa
and have begun leading development work in areas of technology
transfer, capacity building and the success of the project’s delivery
and impact in Africa.
A second team of consortium members focuses on product
development in Africa. The Product Development group is
comprised of the International Crops Research Institute for the
Semi-Arid Tropics (ICRISAT); Africa Harvest and National
Agricultural Research Stations (NARs), which are represented by
the Kenya Agricultural Research Institute; Environmental and
Agricultural Research Institute; and Agriculture Research Council.
ICRISAT focuses on selecting target sorghum germplasm, gene
information that is common in wide geographic regions of
Africa, conducting environmental biosafety studies and collecting
sorghum varieties for gene-band storage. NARs focus on confined
greenhouse and field studies for agronomic trait expression
and stability, selecting varieties of sorghum for breeding and
training others in open-pollinated and hybrid sorghum work.
The biosafety research of NARs is supervised by biosafety and
regulatory experts from Africa Harvest. Finally, international
consultants from Pioneer and ICRISAT supervise breeding work.
The third team is made up of Africa Agricultural Technology
Foundation, CORAF/WECARD in West Africa and Africa
Harvest. These regional agricultural research organizations
influence national policies and are important to harmonizing
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policies across country borders.
This team is focused on
intellectual property brokerage,
audit and management, and
works to ensure the global access
strategy for charitable objectives
is maintained throughout the
project’s development and
deployment. Project advocacy
for stakeholder awareness and
support in Western Africa
is managed by CORAF/
WECARD, whose vision is
to contribute to sustainable
reduction of poverty and food
insecurity in west and central
Africa through agricultural-led
economic growth and improving
the agricultural research system
of the subregion. Africa Harvest
is focused on the project’s
technical and financial management, biosafety regulations, and
overall project leadership and coordination.
In the project’s formative stages, partners established a clear
communications vision to create an enabling environment for all
partners to implement the project successfully in a timely manner.
A close-knit group of communication professionals from Africa
Harvest, Pioneer and CSIR provide direction for the project and
guide internal and external communications to ensure consortium
members speak in one voice. Consortium members are engaged
to leverage their own Web sites, newsletters and other outreach
strategies to promote the initiative within their organizations as
well as to outsiders.
Growing ABS
The ABS project has the potential to improve the nutrition of 300
million Africans who use sorghum as a staple or supplement food.
Whereas many genetically modified crop projects go years without
conducting a single field trial, the ABS project has conducted
several field trials in the United States during its four-year existence.
Project developers attribute this progress to the project’s strong
public acceptance and communication component, which helped
create an enabling environment for the project. These trials show
promising success and results that will support further studies in
Africa to target product development and delivery.
The ABS project is still in its technology development phase, which
will end after five years, in June 2010. At that time the project is
expected to achieve proof of concept and be rolled into the new
agriculture program. There may be an interim phase after this
deadline to ensure effective transition into the agricultural program.
The technological efficiency of ABS is being enhanced, so levels of
target plant traits and expressions will evolve into the final product
as the project progresses and will be carried into the second phase
of ABS: product development and deployment.
The ABS consortium has found it challenging to keep all coalition
members informed, engaged and on message. While budget
limitations make it difficult for communication professionals from
partner organizations to dedicate time and resources to the project,
project leaders and scientists have come to appreciate the role of
communication, and this issue is resolving.
Communication was especially difficult when ABS sought to
establish field trials in Burkina Faso. While most of the consortium
members are from Anglophone countries, Burkina Faso is a
Francophone country, and a language barrier had to be tackled.
Additionally, cross-cultural administrative challenges arose because
of the differing work cultures of French- and English-speaking
members. These challenges have been overcome through training,
reciprocal visits, innovative communication methods, interpreters
and commitments from both sides to learn one another’s language.
When cultural issues arose in Burkina Faso, the initiative
experienced political challenges when it applied for permits to
conduct contained greenhouse experiments. After an initial attempt
to secure permissions from the Genetically Modified Organisms
Drs. Andile Grootboom and Luke Mehlo, both from
South Africa Council for Scientific and Industrial Research,
spend time in a Pioneer lab in Johnston, Iowa.
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Executive Council, a South African regulatory body, failed, the
ABS project established a political action committee and engaged
the media to educate the public and policy-makers about the
importance of biotechnology in dealing with the country’s famine.
From these experiences, the ABS consortium took away many
lessons, including the importance of engaging key stakeholders
such as regulators and government officials prior to seeking permit
or policy approval. In the same regard, the consortium found
that scientific training of regulators is especially vital in Africa
because regulators are appointed based on the political issues
needing attention in their regions. It is crucial that regulators make
decisions based on science, rather than political motivation.
The partners also realized that engaging public and private
stakeholders, primarily scientists and sorghum farmers, throughout
all stages of a project makes them more receptive to the project
and gives them a sense of involvement. For farmers and
government officials, visible, tangible results and word-of-mouth
communication are the most effective method to promote a project
such as ABS.
The Promise of ABS for Africa
ABS has been a landmark project in Africa because it is the only
one of the Grand Challenges in Global Heath projects with
an African grantee organization (Africa Harvest) and African
leadership to steer the initiative’s vision and strategy. Among the
benefits of this African lead is that more than 80 percent of the
project budget has been spent in Africa to develop African scientific
capacity, infrastructure, technology transfer and to ensure the
creation of an enabling environment for future project deployment.
The project has successfully pioneered the concept of a consortium
of partnership among public and private, as well as representatives
from northern and southern Africa, for strategic research and
development to impact major challenges in Africa.
ABS has demonstrated professional and efficient project
management of an 11-member worldwide consortium — a
virtual institution in a sense. The success of the consortium can be
attributed to the right people working at the right capacity in the
right positions as well as consistent yet innovative approaches to
teleconferences at every level of the partnership, regular planning
meetings and effective internal communication.
By Ashley Mastandrea
Dr. Florence Wambugu explains to journalists
about the different varieties of sorghum.
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Lesotho Apparel Industry
Unites to Fight AIDS
Lessons Learned:
• In areas of high HIV prevalence, factory-based HIV
interventions promise remarkable efficiency. Such
programs can combine treatment and prevention
service for a concentrated population.
• Educating and empowering workers helps to slowly
change the attitudes of the larger community outside
the factory, where workplace programs have less
direct impact.
• Companies that buy products from factories in
resource-constrained and HIV-burdened countries
advance the global health effort by funding the
workplace prevention and treatment programs,
in turn, ensuring continuous supply of products.
Cutthroat factory competition makes it nearly
impossible for factories to fund such programs
themselves.
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Lesotho is facing an HIV crisis equal in extent to
neighboring South Africa’s but lacks the resources
of its larger neighbor. One bright spot is the surging
apparel industry, which exports most of its production
to the United States thanks partly to Lesotho’s dutyfree
status. The nation has built a reputation for ethical
labor practices, and this greatly enhances its appeal.
The industry employs about 45,000 mostly female
employees. A major threat to its stability is the 43
percent HIV prevalence among these women.
The Apparel Lesotho Alliance to Fight AIDS (ALAFA) is a special
factory-based intervention that provides workers with HIV testing,
treatment and prevention services. It has received support from
international organizations working to alleviate poverty and
the mainly U.S. retailers that purchase Lesotho’s products. The
program now includes almost all the garment factories in Lesotho.
ALAFA faces the challenges of a conservative moral atmosphere,
the female workers’ poverty and disempowerment, and the stigma
of HIV. These factors have led to difficulties in reducing HIV risk,
low HIV testing rates and late initiation of treatment. ALAFA is
making progress in these areas through its peer-educator program
and workplace medical clinics.
Getting Industry Involved in Health Care
Lesotho is an independent mountainous nation completely
surrounded by South Africa. The two million Basotho living there
are in the midst of an AIDS epidemic as calamitous as any seen
in the region. But Lesotho’s small, homogeneous nature fosters
creative solutions to the epidemic. ALAFA is one such innovation
that focuses on Lesotho’s main industry. The group’s name, which
is also the Basotho’s word for “to care for the sick,” symbolizes
both its local roots and international connections. It has united the
country’s garment factories and workforce, the largely U.S. brands
that buy from these factories, and an international organization
promoting southern Africa’s economic development. These entities
work together to provide workplace-based HIV treatment and
prevention services.
Basotho garment workers represent a highly concentrated at-risk
or already HIV-infected population. They are a cohesive social
group with broad connections to the entire community. At the
ALAFA factory, Nien Hsing Garments
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same time, the factory owners have become increasingly concerned
about the devastating impact HIV is having on the stability of their
workforce. Moreover, the U.S. brands see that funding ALAFA’s
work supports their reputation for corporate social responsibility.
There is no question that the HIV situation in Lesotho is dire.
The United Nations estimates that about 22 percent of the adult
population — or 270,000 people — is infected. The epidemic has
pushed the average life expectancy down to 40 years. Without HIV,
it would be around 66 years according to a U.S. Census Bureau
projection. The reason for this dramatic cut in life expectancy is
easy to find: Only about a quarter of Basotho needing antiretroviral
therapy (ART) actually received it in 2007. Still that percentage
has increased from the low single digits only three years earlier.
HIV testing itself is rare: About 12 percent of Basotho knew their
HIV status at the end of 2007. Again this figure represents a large
increase over 2004. Even as HIV testing and treatment become more
accessible, HIV fears and stigma remain a barrier to taking action.
When ALAFA conducted an anonymous HIV serosurvey among
apparel workers in 2007, it found that 43 percent of those taking
the test were HIV-positive. This is not a surprising result given that
the majority of these factory hands are young women living in a
high-prevalence urban environment. (Their male counterparts tend
to migrate to South Africa for the mining jobs.)
On the Road to Responsible
Competitiveness: ALAFA’s Origins
The Lesotho apparel industry, with its 40,000 to
45,000 employees, is an economic mainstay for
this poor country. Its existence is fragile, however,
because wages (at least $100 a month) are twice
what they are in competing Asian nations such as
China. The manufacturers are largely transplanted
Chinese and Taiwanese companies that could easily
move elsewhere. But the existence of a U.S. law, the
African Growth and Opportunities Act (AGOA),
has provided a special duty-free entrée into the U.S.
market, giving Lesotho a competitive edge. From
2004-2006 the industry was hit from all sides. Most
importantly, the international apparel quota system,
known as the Multi-Fiber Agreement (MFA),
ended in 2005. The result was a tsunami of Chinese
exports. At the same time, the value of Lesotho’s
currency was rising against the dollar. Finally,
AGOA’s provisions were set to expire in 2007 and
2008. Employment shrank from 54,000 to 40,000, and a halfdozen
plants temporarily closed.
The U.S. Congress eventually extended AGOA to 2015, and
Lesotho’s apparel industry rebounded. Coming up, though, is
the 2012 expiration of a key AGOA provision that allows less
developed countries like Lesotho to use fabric from the cheapest
source, not just from Africa or the United States.
The international effort to recover from the demise of the MFA
quotas garnered Lesotho considerable attention and contributed
directly to the founding of ALAFA. The MFA recuperation effort
became embodied in the MFA Forum, which holds meetings
involving governments, international organizations, private
corporations, trade unions and nongovernmental organizations.
Andy Salm directs the textile and apparel program of ComMark
Trust, a nonprofit group funded by the U.K. Department for
International Development (DFID). Salm recounts, “We got
companies and workers to go to places where the forums were held.
This raised Lesotho’s profile.” ComMark’s goal is to restructure and
expand certain trade sectors in southern Africa so that they work
to alleviate poverty. Salm has been advising the Lesotho apparel
industry since 2002.
One of Salm’s strategies was to carve out an “ethical manufacturer”
niche for Lesotho. “The industry had to clean up its act,” says
Salm. “We had to assure the international brands that if you
bought from Lesotho, there would be no bad publicity — no sweat
A peer-education session takes place during
lunch time at Precious Garments.
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shops, no labor law violations… HIV became one of the issues
that allow brands to show that they are addressing the well-being
of the people in the industry.” Salm and ComMark obtained seed
money from DFID and the Lesotho government to launch an
apparel factory-based HIV control program. This money went to
hire three South African consultants to write a feasibility report
on the concept. Also, Dagmar Hanisch was hired as project
implementation team leader and remains ALAFA’s director of
policy and prevention.
The MFA Forum made Lesotho one of its priorities. In May
2006, ComMark and the MFA Forum hosted an international
gathering in Maseru, the capital of Lesotho. The meeting was
dubbed “Destination Lesotho: On the Road to Responsible
Competitiveness Conference.” It included United Nations (U.N.)
and government officials as well U.S. garment brands, local
manufacturers and union representatives. A gala dinner at the
conference proved to be a suitable occasion to launch ALAFA in
the glare of international publicity.
Among the attendees at the conference and ALAFA launch was the
singer Bono, who developed the concept of the “Product (RED)”
clothing line. Product (RED) corporate members donate part of
the profits on their (RED) products to the U.N.’s Global Fund
to Fight AIDS, Malaria and Tuberculosis. One Product (RED)
member, the U.S. company Gap Inc., agreed to fund an ALAFA
pilot program at the 4,500-person Precious Garments facility from
which it sources both (RED)- and Gap-branded items. Edun,
another Bono ethical apparel spin-off, began producing its own
“ONE” T-shirt whose purchase price included a $10 donation for
ALAFA. In November 2006, ALAFA received a $276,000 check
from this source.
ALAFA Today
Gap and Edun have continued to support ALAFA, with additional
support from such U.S. buyers as Levi Strauss, Wal-Mart and
Nordstrom. Cathy Dix, Gap’s corporate social responsibility
manager for sub-Saharan Africa, says, “Gap Inc. supports the
ALAFA program because of its innovative and scalable approach
to addressing the HIV/AIDS pandemic. ALAFA is a unique
intervention in that it is a holistic, industry-wide initiative covering
prevention, treatment and care for those infected with the HIV
virus. It is a proven model that has changed the lives of thousands
of garment workers, both male and female.” The major portion
of ALAFA’s continuing funding has come from the UK’s DFID,
with other large grants from the European Union and the Irish
government.
Three years after its founding, ALAFA has expanded to 30 factories
covering 90 percent of the apparel workforce. That expansion
took some convincing. Bart Vander Plaetse, ALAFA’s CEO says,
“We started out with the two more-concerned companies, but the
buyers encouraged the others to join. The other companies had to
see the economic advantages. They now understand that ALAFA
creates a healthier and more stable workforce. They see they have
a greater chance of getting new orders.” ALAFA’s active support
from international buyers and donors also showed the factories
that ALAFA was a relatively low-cost way to enhance their sales
appeal as ethical manufacturers. The textile and apparel exporters’
association now sits on ALAFA’s two oversight councils along with
ComMark, government and trade union representatives, and the
international buyers and donors.
Since the apparel industry works with ALAFA in a unified
manner, it increases the potential for continuity of HIV care and
education. Other workplace HIV programs in the region center
on a single large business. The mining companies in South Africa,
for example, provide HIV care and prevention services, but only
regular employees receive HIV treatment. This leaves out the
growing number of workers employed on a contract basis and
employees’ families, which are usually distant from the mines.
These standalone programs have little impact on community
attitudes. Uptake of care is low even among the employees due to
HIV stigma and fears of discrimination. Also, individual company
programs can offer no continuity if the worker leaves the company’s
employment for whatever reason, including ill health.
One factor mitigating some of the impediments is that the
Aurum Institute has extended mining giant Anglo American’s
David Senate Tsolo works at Eclat Evergood
Textiles in Maseru as a chief supervisor, where
he is also a peer educator.
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comparatively comprehensive HIV care and treatment program
to other workplace and community sites under the auspices of the
Aurum Institute. The Aurum Institute was founded by an Anglo
American subsidiary but became an independent nonprofit in
2005. Since then, extension of corporate programs to the broader
community has become an increasing topic of discussion. That
broader community contains about 5.5 million HIV-positive South
Africans. At the end of 2008, a mere 5,200 were receiving anti-
HIV medications through Aurum’s 34 work-site programs, most of
them still related to Anglo American.
Testing: The ALAFA program consists of three in-house
components: HIV testing, treatment and prevention. Testing is
crucial because it provides the link to treatment, which is lifesaving.
Yet Basotho have shown considerable resistance to HIV
testing. A government campaign, called “Know Your Status,”
has met with only limited success due to underfunding and poor
organization. An underlying issue is the stigma attached to testing
positive. Salm recalls, “One woman related that her friends treated
her like a prostitute when she tested HIV-positive, but those people
are all dead now.”
At one point in 2008, ALAFA ran a grocery voucher lottery to
encourage testing uptake. The workers in the initial ALAFA
factories are now 70 percent or 80 percent tested, says Vander
Plaetse. ALAFA claims to have tested a total of more than 13,000
apparel workers as of May 2009. That is about 30 percent of the
entire workforce.
Treatment: The availability of treatment is critical to encouraging
testing. When workers see their colleagues dramatically recover
after receiving antiretroviral therapy (ART), HIV testing becomes
much more compelling. ALAFA originally thought to depend on
the government clinics, which dispense free ART. These clinics are
distant from the factories, though, and require long waits to see a
doctor. A factory employee would lose a whole day’s work going to
the government clinic. That is something she could ill afford and
her employer would frown on.
ALAFA in response instituted a program of factory-based clinics.
The manufacturers provide the facility and hire a nurse. ALAFA
pays the doctors. By special arrangement, the government supplies
ART without charge to these private clinics. The factory clinics
also provide a range of general health services beyond HIV —
employees do not have to be HIV-positive to make use of them.
This feature allows HIV-positive employees to visit the clinics
without publicizing their HIV status to the world. (The workers
may also see the doctors at their outside offices to ensure that their
HIV status is kept private.)
Employees who test positive for HIV are immediately linked to
the care available at the workplace clinics. About 85 percent of
the people diagnosed with HIV take advantage of these services.
ALAFA clinics are available at 20 sites to about three-quarters
of the apparel workforce, as of March 2009. They serve 3,500
HIV-positive workers, with more than 900 receiving ART. Median
time on ART was only 13 months, again according to the March
2009 report. The treatment program’s overall success had yet to be
demonstrated at that time.
ALAFA’s clinics have implemented the 2008 government
guidelines, which specify starting treatment when patients’ CD4
counts fall below 350. Patients nonetheless have been starting ART
at a median CD4 count of only 173. Patients are still entering
treatment in a very debilitated state, which limits the treatment
response rate. Presumably, this situation will improve as the
treatment program matures. Treatment options are rather limited
(mostly nevirapine plus two nucleoside analogs). That said, sharp
increases in CD4 counts have occurred. ALAFA, in March 2009,
reported that almost 90 percent of all ART-treated workers had
attained CD4 counts above 200, the upper limit for an AIDS
diagnosis.
Prevention: Peer educators run the ALAFA prevention programs,
which cover nearly all garment industry workers. The goal is to
train 500 such educators who, in turn, educate their fellow shopfloor
employees, a goal that was three-quarters fulfilled by early
2009. The subjects covered in the educators’ training include basic
HIV and AIDS information, relationship issues, family planning
and communications skills.
ALAFA factory, Lesotho Precious Garments
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Though generally sexually active, Basotho are usually reluctant to
talk about sex, and most of them are Catholic. The HIV education
represents a cultural breakthrough, not least because it is largely
oriented around women’s issues. The material generally follows the
ABC approach — abstinence, be faithful, use condoms. Vander
Plaetse comments, “We are about to go large scale with a campaign
that outlines the risks of multiple concurrent partnerships, stressing
A and B messages. But we are realists. Safe sex messages and
materials form a large part of our prevention program.”
A major issue is poverty and the resulting transactional sex that
women use to get by (to pay the rent, for example). ALAFA’s 2007
HIV prevalence survey found that multiple concurrent sex partners
(along with sexual transmitted infection symptoms and being the
family’s sole breadwinner) appreciably increase female apparel
workers’ risk for HIV.
A major constraint is the apparel workers’ cultural roots in an oral
tradition, which necessitates the creation of mostly visual or easyto-
read materials. Another problem is the short time periods that
the companies allow workers to leave their jobs to attend employee
sessions. Many companies try to fit HIV sessions into lunch
periods, which is obviously not optimal.
Vander Plaetse says, “We aim at least one big interaction moment
in factory. We’re getting a meeting once every two months. There
are also mixed status support groups. At some factories, these meet
every week, whereas in others, they are struggling to keep alive.”
ALAFA is attempting to evaluate the effectiveness of its prevention
program through a behavior change survey conducted in the first
half of 2009. Results will be out later in that year. Vander Plaetse
says, however, “I really want to have seroconversion numbers.
People who tested negative last year and then seroconverted
during our campaigns are a particular challenge — each one is
a defeat.” ALAFA’s widescale HIV testing will yield information
about seroconversion in previously negative testers. To improve
future results, ALAFA is organizing posttest clubs to support HIVnegative
persons in their efforts to stay uninfected.
A Challenging Economic Environment
Vander Plaetse notes, “We can empower the women for behavior
change. Some go back to the homesteads, where the man is still
boss. So now we have programs for the men, too.”
A major 2009 move is the expansion of the ALAFA programs
to include spouses and children. As Vander Plaetse’s comment
highlights, a rollout makes sense since the families function as
an economic as well as a social and sexual unit. Frequently one
Peer educators at China Garment Manufacturers
factory take time for a lunch time mobilization.
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member of the couple transmits HIV to the other, with the risk
particularly high for male-to-female transmission. The virus can
then infect newborns. Losing one of the parents to HIV is a
tremendous economic and emotional hardship for the survivors.
Having sick and dying children is also a great strain.
This rollout is taking place at a critical time. The South African
mines are laying off many Basotho men due to the global economic
downturn. Many will need HIV care and prevention counseling
upon their return to Lesotho. Basotho garment factories may
themselves cut back as the crisis progresses. ALAFA already has
provisions to extend health care to laid-off apparel industry
workers for six months or more. This interval will allow them
to find alternative medical providers without interruption of
care, though most will probably end up at the already crowded
government clinics.
Fortunately, the first year of the downturn did not affect the Lesotho
apparel producers as much as those in other countries. Garment
exports to the Unite States dropped 11 percent, and the industry
reduced its total employment by 2,000. “The Lesotho industry has
shown a lot of resilience, more than I expected,” says Salm.
There is also the question of whether the international brands and
other donors will be able to continue to support ALAFA at present
levels. Salm remains confident. He says, “As long as industry is
there and donors support it, the program will stay in place.
It’s a cost-effective way to deal with HIV, but it’s not within the
factories’ capacity to pay for. The competition in this industry is
cutthroat.” But ALAFA’s mainstay grant from DFID ends in 2011.
Replacement funding is not yet apparent.
The Lesotho government is the supporter of last resort since
it will have to deal with the HIV epidemic if ALAFA doesn’t.
David Rantekoa, formerly Lesotho’s principal secretary of trade
and development and now ambassador to the United States, was
instrumental in bringing the parties and resources together that
founded ALAFA. He says that the government is committed to
ALAFA’s program: “The government strongly believes that textiles
are the driver of the economy, and it is absolutely crucial to pay
attention to [the] well-being of workers in that industry.”
The Lesotho government’s proposed 2009-2010 budget calls
for a 55 percent increase in health expenditures. It is difficult to
exaggerate the low level at which the government is starting. The
latest World Health Organization country report for Lesotho —
issued in 2005 — described a grossly overstretched health system
about to face the daunting burden of AIDS. Per capita health
expenditures were only $28, and there was only one doctor for
every 16,400 Basotho. Lesotho’s economy has grown considerably
since then and so has the national health budget. Yet the 2009
health appropriation would still amount to only about $80 per
person. Lesotho remains one of the poorest countries of the world,
much poorer than neighboring South Africa but with an HIV crisis
of equal extent.
ALAFA’s workplace strategy represents an efficient way to combat
HIV in Lesotho and other poor countries with a concentrated
industrial sector composed of medium-sized corporations. These
companies are unable to develop HIV programs on their own
although they have economic and public image reasons to do
so. ComMark is considering transplanting the ALAFA model
to Swaziland, another very poor country with a textile industry
looking for an edge in its competition with South Asia. Yet the
question of the model’s sustainability remains — securing stable
funding will be critical in the years ahead.
By David Gilden
Liapeng Mpeke is a textile worker registered on
the ALAFA program and a peer educator at the
factory where she works.
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Nevirapine Single-Dose Packs
Improve Protection from
Mother-to-Child
HIV Transmission
Lessons Learned:
• Reducing rates of mother-to-child HIV
transmission in Africa, where many babies are
born at home, requires treatments that can be
administered easily by the new mother or her
birthing assistant, outside of a hospital or health
care facility.
• Simple technical changes in packaging can
increase access and usage of needed medication.
• Collaborations between corporate drug
developers and nonprofit organizations combine
the dual need for research and advocacy to
achieve these technical changes.
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In resource-restricted settings, nevirapine is a critical
drug for preventing mother-to-child HIV prevention
(PMTCT) during labor and delivery. HIV-positive
mothers take a tablet early in labor and give a liquid
formulation orally to the infants within 72 hours
of birth. In Africa, many fewer babies than mothers
receive their dose. A major obstacle has been the lack
of individually packaged doses of liquid pediatric
nevirapine. The large number of women who give birth
at home should be given such doses during antenatal
clinic visits. A collaboration among PATH, the United
States Agency for International Development (USAID),
nevirapine producer Boehringer Ingelheim, the
Elizabeth Glaser Pediatric AIDS Foundation and the
Kenya Ministry of Health set out to develop a simple
nevirapine delivery system for newborns.
The initial idea was to prepackage single pediatric nevirapine doses
at a central facility. This effort failed due to limited shelf life and
regulatory issues. Ultimately, the collaboration developed a selfsealing
laminated foil pouch designed to hold a capped oral syringe.
Clinic staff members fill the syringe with nevirapine, cap it, seal
it in a pouch and instruct their antenatal patients on how to use
it. Health care workers and expectant mothers have welcomed the
innovation. Initial signs are that more at-risk babies are receiving
nevirapine. This project is contributing to the UNICEF efforts to
develop a take-home mother-baby pack. The new pack would hold
a more potent and prolonged combination PMTCT regimen.
Project Origins
“In 2001,” recalls Adriane Berman, senior program associate at
PATH in Seattle, “after conversation with colleagues at Boehringer
Ingelheim and Population Services International, USAID
approached PATH on ways to more effectively deliver infant
nevirapine for preventing mother-to-child HIV transmission.
Nurse Emily puts the dispenser into the sealable package,
where it will stay clean and protected for weeks, until needed.
Written and pictorial instructions on the package make it easy
for a mother or her birthing assistant to use.
Photo provided by PATH
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This was part of an ongoing conversation between USAID, the
Boehringer Ingelheim pharmaceutical company and Population
Services International.” And so began a five-year international quest
leading to a simple, practical step forward in the struggle to control
the HIV epidemic.
The beginning of this decade was a breakthrough epoch for
bringing HIV treatments to developing countries. The first step,
PMTCT, was a more tractable issue than treating established HIV
infection. The U.S. National Institutes of Health trial HIVNET
012 pointed out an elementary strategy in 1999: Vertical HIV
transmission could be reduced by 41 percent merely by giving
the mother 200 mg of the anti-HIV drug nevirapine during labor
and a small liquid dose to the newborn. (Single-dose nevirapine
achieved this reduction at month 18 after birth. The reduction was
in comparison with multiple doses of AZT given to the mother in
labor and baby in the first week. All of the mothers breastfed their
babies.)
In response, Boehringer Ingelheim, the manufacturer of nevirapine
(brand name Viramune®), announced its PMTCT donation
program in July 2000. Extended indefinitely after the initial fiveyear
span, the program supplies low-income countries unable to
secure a purchased nevirapine supply.
Groups such as USAID and Boehringer’s program administrator
Axios International soon noticed that, although the program was
successful at reaching those who give birth in urban or district
clinics, it was much less successful in rural areas where many
women give birth at home. For example, the Elizabeth Glaser
Pediatric AIDS Foundation reported that at 10 African clinics,
two-thirds of HIV-positive mothers received single-dose nevirapine
from 2000 to 2003, but only about half their babies did.
Less than half the mothers in sub-Saharan Africa give birth in a
clinic, and Berman says, “In some places, the government and the
doctors didn’t trust women to take drugs home, or they didn’t have
the supplies to do it.” In addition, it was easy to hand out a single
nevirapine tablet for the mother. The newborn’s dose — which
is supposed to be taken within 72 hours of birth — was initially
0.2 ml/kg of a viscous liquid formulation. That was eventually
simplified to 0.6 ml fixed dose for take-home use. Pediatric
nevirapine comes in 240 ml and 20 ml bottles, so measuring out
the small individual quantity, packaging it and storing it at home
was extremely cumbersome, as was administering it to the baby. At
this stage, suitable packaging was not available.
The lack of nevirapine uptake helped perpetuate the overall
limitations in HIV care. “The beauty is that if you offer something,
people add other things. More and more mothers are covered in
remote areas. In general, the coverage of babies increases,” says
Michael Rabbow, director of Boehringer’s PMTCT-oriented
Viramune Donation Programme. The existence of the nevirapine
program encourages a more geographically dispersed clinic
network, more frequent antenatal visits and ancillary services such
as nutrition support.
Seeking an Elegant Solution
PATH’s formal undertaking to develop a take-home single-dose
nevirapine delivery system began in 2002 with USAID funding
through the HealthTech: Technologies for Health Program. As
the project developed, USAID was able to provide advice and
feedback from its network of field offices. It also contributed to
key decisions and provided PATH with connections to outside
organizations, including the World Health Organization (WHO),
U.S. Pharmacopoeia and other USAID-funded projects capable of
advising on the concept. Playing a more active role was Boehringer
Ingelheim. “Boehringer was the only company with approved
nevirapine [at the time], and the company didn’t want to release
the technical dossier,” says Berman. “Boehringer did the stability
testing. It was providing the drug free and was a critical partner
all the way as we moved to see what would work in field. At each
step, the company advised on what it would support.” Boehringer
receives little revenue from nevirapine because nearly all sales are
by low-cost generic manufacturers in developing countries, which
Boehringer allows despite its patents.
Photo by Shutterstock® Images
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PATH’s original idea was to provide clinics with a prefilled oral
squeeze bottle or syringe at a cost of less than 20 cents per unit. The
hope was that the unopened prefilled applicator would not only be
a great convenience for clinic staff, but would also extend the drug’s
shelf life. Boehringer currently rates the shelf life of a large unopened
bottle of liquid nevirapine as three years. That figure goes down
to six months once the bottle is open — if kept below 30º C. In
Boehringer’s tests, the nevirapine in the individual-dose containers
was stable for just two months. The problem was that the individualdose
containers had considerably more plastic per unit of drug
compared with the large multi-dose bottles. The plastic absorbed
some of the preservative in the nevirapine formulation.
In December 2004, Boehringer informed PATH that it could not
go ahead with the centrally prefilled scheme. A major problem
was that extending the shelf life of the individual-dose units
necessitated reformulating the oral solution. Besides the investment
in creating and testing the new formulation, this change would
have required new regulatory approval. In any case, creating
a facility to fill an altered packaging format meant substantial
investment in infrastructure by either Boehringer or the recipient
countries. Regulatory approval would be necessary here too.
Adapting to a Practical Solution
Meanwhile, a few Kenyan clinics were moving ahead with their
own makeshift solution. They removed the needles from standard
intravenous syringes, siphoned into them sufficient nevirapine
liquid and packaged them in the materials at hand — multiple
layers of aluminum foil, plastic bags and paper sheets plus used
medication boxes. When those materials were not available, the
mothers frequently did not receive any nevirapine to take home for
their newborns.
Boehringer made a step forward in 2005, when it began shipping
empty oral syringes along with the bottles of infant nevirapine. The
availability of standard syringes did not by itself ensure a take-home
newborn dose, however. PATH revamped its effort by focusing on
packaging the syringes. Inspired by the Kenyan makeshift model,
PATH proposed a laminated foil pouch with a self-sealing adhesive
strip. The pouch provided an area for a printed label containing
pictorial instructions and space to write the expiration date. PATH
found a manufacturer that would produce the pouch in quantity
for 8.5 cents each. It then designed a pictorial label and published a
manual for training health care personnel.
Simple as the oral syringe in a self-sealing pouch is, it still has
several drawbacks. The major one is that it requires individual
filling at the point of use rather than at a central mass-production
facility. This is inconvenient, and it was uncertain at first whether
health care personnel would embrace the process on a wide scale.
A major disappointment was the two-month shelf life, which the
sealed pouch did not prolong. If a pregnant woman has her only
antenatal clinic visit before the 32-week point, she may not receive
the nevirapine dose for her baby. Kenya and some other countries
are taking a more aggressive approach. They are giving the
newborn’s nevirapine to the pregnant woman whenever she comes
and ask that she return for a new dose in two months, believing
that something is better than nothing in any case, despite the shelf
life issue.
From Field Evaluation to Field Availability
It was therefore unclear what reception the syringe pouch would
encounter. But a USAID 2005 survey of PMTCT program managers
in Kenya and PATH on-site visits showed that the pouch was
widely regarded as an improvement over the existing situation. The
Elizabeth Glaser Pediatric AIDS Foundation, the Kenyan Ministry of
Health and Family Health International then conducted formal field
evaluations that had extremely positive results.
“Our impression was that people were really excited,” says Nicole
Buono, who is project director for Elizabeth Glaser’s Global Call
to Action, which promotes PMTCT. “The providers were more
comfortable with sending drugs home. The reality is deliveries
happen at home, and people might not come in for weeks. Without
the pouch, nurses have to bundle up the nevirapine themselves and
give instructions.”
A September 2006 stakeholders meeting in Kenya reviewed the
studies. The enthusiasm was so great that the Kenya Ministry of
Health promptly changed its guidelines to recommend distributing
take-home infant nevirapine packaged in the syringe and pouch.
PATH provided a year’s supply of the pouches to cover the rollout
program. With PATH and Elizabeth Glaser advocating for wider
distribution, Boehringer soon agreed to add the pouches to its
donation program. Says Rabbow, “Once the pouch was designed
and field tested, we knew we should add it to our package, and
I knew we could pay.” Boehringer’s shipments began in November
2007 and totaled more than 260,000 through early 2009.
The company sent a similar number of syringes in the same
period, although Buono recalls occasions when transport delays
prevented either the pouches or syringes from arriving with the
nevirapine supply.
It is difficult to evaluate the effect of the pouch on infant
nevirapine use at this writing (April 2009). Widespread pouch
availability did not occur until 2008. Rabbow points to a progress
report from Zambia’s Center for Infectious Diseases, which
states that infant nevirapine coverage increased from 58 percent
to 77 percent after the pouch arrived. Marie-Hélène Besson,
who administers the Viramune Donation Programme at Axios
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International, notes, “We will never reach 100 percent nevirapine
coverage because some mothers are not convinced it is helpful;
there is fear and stigma, family pressure.”
Future Developments
This project was successful because the partners complemented
each other’s capabilities. PATH has long experience developing
alternative health technologies feasible in resource-restricted
environments. The Elizabeth Glaser Foundation had relationships
with the Kenya clinics so that it could introduce the pouch
and survey the reaction to it. The Kenya Ministry of Health
incorporated the new packaging into its official HIV guidelines.
Boehringer Ingelheim, most importantly, already had a wide, free
PMTCT distribution system in place. Finally, PATH and the
Elisabeth Glaser Foundation had the advocacy skills to convince
the drug company to ship the pouch along with the nevirapine.
Berman concludes, “Where we ended up is not where we thought
we would go. But we ended up with a simple approach — syringe,
pouch, instructions — that facilitated sending the drug home.”
Nonetheless, many improvements could be made. A first step is
to increase coverage. A major possibility is to work with the home
birth attendants that help many mothers deliver. Besson says, “The
pouch has provided opportunity for clinics to be in contact with
traditional birth attendants [TBAs]. Some clinics have regular
meetings with TBAs and can provide the pouch to women who did
not come to the clinic late enough. This cooperation, which started
in Tanzania five years ago, is now more and more common. These
are programs beyond nevirapine distribution. Still, TBAs may be
most appropriate channel for extending this distribution.” PATH is
already working on a small box of critical birth supplies for homebirth
attendants, and that kit could easily include drugs for HIV.
PMTCT does not stop with nevirapine. The current WHO
guidelines recommend a combination preventive regimen. If the
mother is not already on antiretroviral therapy for her own health,
she is supposed to receive AZT starting at week 28 of pregnancy,
and then single-dose nevirapine plus AZT during labor. Her infant
is supposed to receive single-dose nevirapine at birth and then one
week of AZT. A Thai trial found that this combination reduced
mother-to-child transmission by 80 percent compared with
administering AZT alone to both mother and child (all infants
were formula fed). UNICEF is now working on a mother-baby
pack that would provide the WHO regimen and supplemental
medications in a single take-home box. PATH and the Elizabeth
Glaser Foundation are both consulting on the UNICEF project.
The nevirapine pouch took five years to bring to fruition, but it is
now leading to further innovation. Projects that facilitate PMTCT
have great potential to reduce infant HIV prevalence in resourcerestricted
areas even without the extensive use of combination
antiretroviral therapy seen in North America and Europe. Motherto-
child HIV transmission rates in developed countries are about
two percent. In Africa, Botswana has achieved rates only a little
higher following the WHO guidelines. This success is predicated
on Botswana’s rapidly growing PMTCT program, which is
integrated into Botswana’s extensive perinatal care program. As
a result, more than 95 percent of HIV-positive pregnant women
receive PMTCT medications.
By David Gilden
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NATNETS Succeeds in
Controlling Malaria in Tanzania
With Effective Public, Private and
Nonprofit Partners
Lessons Learned:
• Recognizing each partner’s expertise and value
is crucial in a large-scale collaboration.
• Monitoring and evaluation lead to established
best practices.
• Working locally with partners is a
valuable way to test ideas and develop best
practices, which can later be applied to a
broader geographical area.
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Malaria is the overall leading cause of death in Tanzania
with approximately 36 of 38 million Tanzanians at risk
of contracting the disease. Health care and treatment
for malaria, along with decreased economic productivity
and opportunity, costs the nation an estimated $119
million per year, 3.4 percent of gross domestic product.
For Tanzania, malaria is not only a health issue, but a
development issue.
To control malaria, which is transmitted by Anopheles mosquitoes,
Tanzanians — especially pregnant women and children under five
years old who are most vulnerable to the disease — are encouraged
to protect themselves with insecticide-treated bed nets.
NATNETS, a collaboration of government, private and nonprofit
agencies, with the goal to plan and implement a national strategy
to increase the use of insecticide treated nets (ITNs) in Tanzania,
used the successes of partners’ past programs and utilized the roles
of each organization to establish a successful and growing malaria
control program.
Led by Example
To develop NATNETS, organizers reviewed results from previous
bed net operations. The Kilombero Net (KINET) project operated
in two districts in the Kilombero Valley from 1996 to 2000.
The Ifakara Health Institute, formerly Ifakara Health Research
and Development Centre, and the Swiss Tropical Institute,
with support from the London School of Hygiene and Tropical
Medicine, implemented the bed net distribution program. The
KINET project showed an association between regular use of
ITNs and a 27 percent reduction in child mortality, as well as a 60
percent decrease in childhood anemia. ITNs also proved to have a
positive impact on reducing malaria in pregnant women.
KINET not only showed bed nets could control malaria under
such a program; it also generated initial social marketing experience
and tested an innovative voucher system. Pregnant women were
given a voucher that allowed them to buy a net at a discounted
price in participating shops.
In addition to KINET, Population Services International’s (PSI)
Social Marketing for ITNs (SMITN) project operated in four
Photo provided by the National Malaria
Control Programme, Tanzania.
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additional regions from 1998 onward. With funding from the
United Kingdom Department for International Development
(DFID) and the Royal Netherlands Embassy, a classic social
marketing program introduced two new brands of ITNs, including
heavily subsidized nets for pregnant women. SMITN also
developed and marketed subsidized insecticide re-treatment kits,
a highly innovative development that offered a new method to
promote net re-treatment.
In October 1999, a group of stakeholders from the public and
private sector met to discuss the success of these projects and the
urgent need for a national ITN policy in Tanzania. As a result of
this meeting, in 2000, the Ministry of Health and Social Welfare
(MoHSW) of Tanzania commissioned the development of a
national ITN policy. This policy was developed by the National
Malaria Control Program, the UNICEF and the Swiss Tropical
Institute, discussed by national stakeholders in August 2000, and
approved by the MoHSW in December of that same year, thus
creating a national strategic program for scaling up the use of ITNs
in Tanzania called NATNETS.
Establishing ITN Policy in Tanzania
With the formally established national policy, SMITN became
a national program and was renamed SMARTNET in 2002.
SMARTNET went further than the original program. It dropped
procurement and distribution of its own subsidized ITN brand,
called Njozi Njema, and started supporting brands owned by the
local net industry. The private sector was brought more into the
partnership.
While KINET and SMITN had inhibited the development of
local distribution networks because the commercial sector could
not compete against subsidized products, net manufacturers could
now rapidly develop their own brands. Under SMARTNET,
a memorandum of understanding was established with net
manufacturers. They would be provided with free insecticide kits if
they agreed only to sell nets bundled with kits. Manufacturers and
wholesalers were provided with transport subsidies to ensure nets
were available in remote areas, and retailers were also recruited to
participate by stocking nets.
SMARTNET, like SMITN, included an important behavior
change component that stressed the importance of nets in
preventing malaria and encouraged Tanzanian residents, especially
pregnant women and children, to use nets diligently. The campaign
messages were released through radio, TV and print marketing, as
well as rural films, road shows, posters and roadside signs. Radio
proved to be the most effective marketing tool. Multi-brand
commercial advertising also increased demand.
In 2003, the government of Tanzania, the Swiss Agency for
Development and Cooperation (SDC) and the Swiss Tropical
Institute, acting as SDC’s executive agency, partnered to develop an
ITN cell within the National Malaria Control Program. The Swiss
Tropical Institute provided experienced staff and technical support
to this cell, and SDC provided funding via the institute. From then
on, the ITN cell would be responsible, as a part of the National
Malaria Control Program and, hence, the MoHSW, for facilitating
and coordinating the NATNETS program’s overall management
and fundraising.
The ITN cell organized a NATNETS Steering Committee to
provide guidance for and oversight of the program in general, and
the ITN cell specifically. The committee is chaired by the chief
medical officer and includes the director of preventative services,
the national malaria control program manager, the ITN cell team
leader and representatives from the Swiss Tropical Institute; the
DFID; the Dutch embassy; United States Agency for International
Development, under the President’s Malaria Initiative; Population
Services International; the Global Fund to Fight HIV/AIDS,
Photo provided by the Tanzanian
National Voucher Scheme
(TNVS) partnership.
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Tuberculosis and Malaria (GFATM); Local Fund Agent (PWC);
UNICEF; and the World Health Organization (WHO). The
committee meets quarterly, more often if necessary.
Membership of the Steering Committee changes periodically to
reflect the changes in the donor partnership. With the launch of the
President’s Malaria Initiative and the World Bank’s Malaria Booster
Programme, both organizations were invited to join the Steering
Committee, while the UK’s DFID discontinued its membership
upon the conclusion of the SMARTNET program.
The Tanzanian National Voucher Concept
Don de Savigny of the Swiss Tropical Institute came up with the
idea to create a voucher system to distribute insecticide-treated
nets. De Savigny, along with Alastair Unwin of the UK’s DFID and
the National Malaria Control Program, developed a proposal for
the plan and brought it to NATNETS partners.
In June 2003, after successfully securing the first grant funded
by the GFATM, the MoHSW contracted Mennonite Economic
Development Associates (MEDA) to design a voucher system for
the distribution of insecticide-treated nets. Following the design
of the Tanzanian National Voucher Scheme (TNVS), MEDA was
contracted to implement the program.
MEDA, the logistics contractor for TNVS, which has been
involved in the insecticide-treated net sector in Africa since the
early 1990s, prints and delivers vouchers at the national level
through the Tanzanian health system via 4,432 clinics.
Initially, every pregnant woman received a voucher at the
time of her routine checkup. In 2005, the President’s Malaria
Initiative joined NATNETS to fund an infant voucher, which
was introduced the following year. Vouchers are given to a child’s
mother or caregiver when a child is brought to a clinic for measles
vaccination at nine months of age.
Pregnant women and mothers can use vouchers in any participating
shop for a $2.50 discount on a treated net. Retailers, in turn,
redeem vouchers for more nets from wholesalers. Wholesalers are
reimbursed the value of nets by the project or by manufacturers,
in the form of more nets. Four net manufacturers, A-Z Textiles,
Sunflag, Moshi Textile and TMTL, participate in the TNVS, and
250 wholesalers and 6,900 retailers are registered by MEDA to
accept TNVS vouchers. To date, more than 4.9 million vouchers
have been redeemed.
Contractual partners, who were originally selected by the
government of Tanzania’s Central Tender Board under competitive
tender in 2003 and 2004, implement the TNVS. MEDA manages
the logistics of the program. Net-use training and promotion is
handled by World Vision Tanzania, with assistance from CARE
Tanzania during the first 18 months. The London School of
Hygiene and Tropical Medicine and the Ifakara Health Institute
oversee monitoring and evaluation. A financial audit is conducted
by KPMG.
Playing Catch-up
In 2007, after much debate, ITN stakeholders decided to launch
a new campaign, the Under Five Catch-up Campaign (U5CC), to
bring long-lasting insecticidal nets to every child in the country.
The new campaign was made possible through an extension to the
Round 1 grant to Tanzania from the GFATM. In addition, the
World Bank gave a $25 million soft loan to support the campaign,
as well as a National Net Re-treatment Campaign in 2007. As a
result, the World Bank joined the NATNETS Steering Committee.
The U5CC received additional support from the President’s
Malaria Initiative and UNICEF, which received funding for the
program from the U.S. charity Malaria No More. The coordination
of the U5CC rests within the ITN cell, on behalf of the MoHSW,
through policy, grant management and supervision, and contractor
oversight.
For this campaign, which is currently under way, 7.2 million longlasting
insecticidal nets made in Tanzania (Olyset™) are distributed
Tanzanian Prime Minister Hon. Mizengo Pinda gives
long-lasting insecticidal nets to children under the
age of five, as part of a pilot program of the Under 5
Catch Up Campaign in the Mpanda district.
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to families with children who are under five years old. The nets
remain treated with insecticide for at least five years. Because the
manufacturer is local and responsible for distribution down to the
village level, local logistics are well-handled.
On a district level, the prime minister’s office and regional
and local governments are responsible for the implementation
of the program. Village and ward executive officers register
eligible children and organize distribution locally. They follow
training by World Vision Tanzania and coordinate net deliveries
through MEDA, who works with A to Z Textile Mills, the net
manufacturer.
Other implementing contractors include, CARE Tanzania, the
Ifakara Health Institute, the London School of Hygiene and
Tropical Medicine, and KPMG. PSI and The Johns Hopkins
Bloomberg Center for Communication and Programmes
implement a supporting behavior change campaign.
Maintaining a Multi-Sector Partnership
The NATNETS Steering Committee manages the program at
the policy and strategy level and meets quarterly. Members also
hold ad hoc meetings as issues arise. On the implementation level,
contractual partners meet monthly to discuss project development.
Additionally, a quarterly publication, NATNETS News, provides a
link to partners and Tanzanian stakeholders.
Government participation in the partnership was critical to
the program’s success. The Tanzanian government supported
the public-private partnership approach, exemplified in the
SMARTNET program. It also supported NATNETS submission
of the Global Fund Round 1 proposal that secured funding for the
TNVS. Government also played a key role in the implementation
of TNVS, by distributing vouchers through reproductive and child
health clinics.
An important element of the partnership’s success is the established
understanding of the need for monitoring and evaluation. Ifakara
Health Institute and the London School of Hygiene and Tropical
Medicine fulfill this role since joining the partnership in 2004. At
first, members were uncomfortable with being evaluated but were
persuaded when they realized monitoring helped determine best
practices.
For example, the evaluation of delivery strategies was taken to
NATNETS stakeholders and discussed by Steering Committee
members to determine which approach held the most promise for
the program’s future.
Clear lines of communication among partners were crucial to
the partnership’s success. Strategic and implementation issues are
discussed regularly and openly by partners to ensure each has his or
her voice heard on matters relating to the project’s operations and
future planning. Recognizing each partner’s expertise and finding
value in his or her perspectives is crucial to the success of this largescale
partnership.
Moving forward, NATNETS is focused on two campaigns, the
U5CC, taking place now and scheduled for completion in early
2010, and the Universal Coverage Campaign, scheduled for the
remainder of 2010. The goal of the Universal Coverage Campaign
is to provide a long-lasting insecticidal net for every sleeping space
in mainland Tanzania by distributing more than 14 million nets.
In the last quarter of 2009, long-lasting insecticidal net vouchers
will be introduced to pregnant women and infants and will provide
a continuing means to deliver them to newly pregnant women
and infants.
Organizers are aware that demand for new nets will decline in the
immediate aftermath of the Universal Coverage Campaign, and it
is not known how this will affect the willingness of retailers to stock
nets as they try to anticipate changes in the marketplace.
In the long-term, as existing nets wear out, there will be an
extensive consultative process conducted zone by zone among
all stakeholders to identify policy and distribution options for
distributing new nets and laying the foundation for a future “keepup”
strategy.
Photo provided by the NATNETS partnership.
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Photo provided by NetsforLife®
NetsforLife Utilizes Local Channels to
Promote Net Culture in Zambia
Incidents of malaria in Zambia have nearly tripled over the past 30
years. In 1976, the incidence rate was 121.5 cases per 1,000. The
numbers rose to 398.8 per 1,000 in 1998 and 428.0 per 1,000 by
2003. In 2006, with hospital visits to treat the infectious disease
on the rise, it was estimated that 50,000 deaths per year were
attributed to malaria.
Following a pilot program in rural Zambia (funded by
ExxonMobil) in 2005 and the publication of the proof of
concept, the NetsforLife® program partnership was founded in
2006. A unique consortium of funding partners conceptualized,
vetted, promoted, blessed and launched NetsforLife® with the
lead corporate partners of ExxonMobil Foundation, Standard
Chartered Bank, Coca-Cola Africa Foundation, Starr International
Foundation, White Flowers Foundation and Episcopal Relief
& Development as both a funding and implementing partner.
NetsforLife® distributes long-lasting insecticide-treated nets
(LLITNs) and trains people in remote communities about the
protective value of LLITNs, how to use them correctly and how to
recognize malaria symptoms and when to seek medical treatment.
The initiative works to instill a “net culture” in sub-Saharan Africa
by promoting communitywide understanding of and knowledge
about the transmission of malaria and the need for prevention.
NetsforLife® operates through faith-based organizations established
in remote communities where transportation is limited
Faith-Based Approach
In remote Africa, churches are often the only functioning
institutions and a primary source of social services. Church leaders
are held in high regard and have the presence and power to unite
communities. The NetsforLife® partnership is committed to
utilizing these established and trusted networks on the ground.
NetsforLife®’s success in closing the gap between ownership and
use is attributable to its unique ability to engage church leadership
in emphasizing malaria messaging and in recruiting church
members as volunteer Malaria Agents. These agents are trained
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through NetsforLife® and are the first line of defense in mobilizing
communities and promoting awareness to reinforce a net culture.
The high-quality training provided to the Malaria Agents and
extensive follow-up the agents perform are critical to establishing
their high levels of ownership and use in NetsforLife® communities.
This community-level investment, anchored in the local church,
facilitates sustainability and capacity building.
Corporate Approach
The original mix of partners purposefully included private-sector
players who could inject business savvy, bottom-line mentality
and intense focus on quality and results. Dr. Steven Phillips of
ExxonMobil notes Episcopal Relief & Development, as a faithbased
organization, was eager for corporate partners to participate
beyond financial sponsorship; to contribute to business core
competencies, such as assistance with on-the-ground employee
engagement, marketing and communications; and monitoring and
evaluation. He said one of the most valuable aspects of this part
of the collaboration was the ability to establish a corporate-style
system of monitoring and evaluation, something not common in
partnerships he’d seen before.
Phillips explains that, too often, programs operate without
measuring results. The ones that do measure often fail to get
data into the hands of the right people, such as donors, program
managers, fieldworkers and the communities in which programs
are run. From a business perspective, monitoring and evaluation
are critical in that they provide a sense of accomplishment, induce
further commitments and help determine next steps as well as best
practices.
“It creates a virtuous cycle of increasing support and better
performance,” Phillips says. ExxonMobil specifically funded a
monitoring and evaluation model in each of the African countries.
Seven Million Nets by 2012
The collaborative malaria prevention program began in 2006,
in eight countries. In 2009, a milestone delivery of one million nets
across 17 countries was met. The primary NetsforLife® objective
is to distribute seven million nets in 17 sub-Saharan Africa
countries by 2012.
Photo provided by NetsforLife®
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The successes of the program come from many levels of
collaboration among partners with various areas of expertise. The
NetsforLife® consortium is overseen by an executive board that
approves budgets, helps secure funding, defines communication
strategies and identifies potential partners. A steering committee
comprised of one representative from each partner organization
meets quarterly to gather each partner’s input on the board’s
decisions and to discuss operational issues.
The NetsforLife® initiative’s next challenge will be to meet the
demand that has been created for nets and education, while
adhering to established methodology and upholding monitoring
and evaluation standards. Program developers realize the initiative’s
presence is still very small in proportion to the problem.
NetsforLife® serves people in need regardless of faith affiliation
or membership within the churches from which it operates. An
integrated community development model allows the people of
the remote African communities to be involved in the process of
education and net distribution.
By Ashley Mastandrea
Photo provided by NetsforLife®
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Lessons Learned:
• Due to the similarity of symptoms, incorrect diagnoses of
diseases are common and contribute to the growing resistance
to front-line drugs.
• Building medical infrastructure in the developing world may
be critical to treating epidemic diseases, even if drugs are
available.
• Keep training local to reach nontraditional health care
providers and build developing world medical infrastructure.
• It can be critical for a developing organization to diversify
funding sources, once it has established its relevance in the
early years.
• Strong relationships among local and international partner
organizations are critical factors in establishing credibility
and ensuring wide program participation.
Nontraditional Global Health
Partners Team Up to
Fight Malaria in Uganda
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The Infectious Diseases Institute is gaining international
prominence; can the lessons learned to fight AIDS be
used in treating malaria and vice versa?
Malaria is a devastating disease that claims a child’s life every
30 seconds and kills more than one million people each year. In
sub-Saharan Africa, which accounts for more than 90 percent of
all malaria cases worldwide, the disease is particularly brutal on
the young; there, malaria is responsible for nearly 20 percent of all
deaths in children under the age of five.
World leaders have come together with a comprehensive plan to
eradicate malaria by 2015 and have pledged $3 billion to meet
this goal. In addition to providing research funding for a vaccine,
the plan aims for a reduction in deaths in the next two years by
providing mosquito nets, indoor spraying, diagnosis and treatment.
“Several organizations have made a claim that if everyone in malaria
endemic zones had a bed net, we could eradicate the disease. I
wish it were that simple,” says Carol Spahn, executive director
of Accordia Global Health Foundation, a nonprofit working to
overcome the burden of infectious diseases by building health care
capacity and strengthening academic medical institutions in Africa.
Could malaria be eliminated simply by expanding the use of bed
nets? “The answer is no. The reason is, mosquitos can still bite
you when you’re not in bed,” says Alex Coutinho, M.D., M.P.H.,
executive director of the Infectious Diseases Institute (IDI),
Accordia’s flagship program in Kampala, Uganda.
Bed nets are one very important piece in the arsenal of proven
interventions that can help prevent malaria. Others include indoor
insecticide spraying and intermittent preventative treatment for
pregnant women. But clinical training to enhance the quality
of care and counseling is an equally essential component of any
effective prevention strategy.
Recognizing this reality, Accordia, ExxonMobil and IDI joined
forces over the past four years to create the Joint Uganda
Malaria Program (JUMP), an ambitious partnership that also
includes I-Tech, Makerere University, University of California
San Francisco, the Uganda Malaria Surveillance Program and
the Ugandan Ministry of Health. The JUMP program is aimed
at reducing the burden of malaria by implementing innovative
training approaches that teach health care workers to correctly
diagnose malaria. The team-based training has shown dramatic
results in improving fever case management and reducing the
over-prescription of antimalarials — thereby reducing the problem
Anopheles mosquito
Photo by Shutterstock® Images
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of drug-resistant malaria — and building the capacity of Uganda’s
health workforce.
“The reason why an energy company is involved in a global
health partnership follows a multi-step logic,” says Steven Phillips,
M.D., M.P.H., medical director for Global Issues and Projects at
ExxonMobil. “First of all, ExxonMobil has a large footprint in
Africa. We’ve been on the continent for more than 100 years, and
we’ve been present in 25 sub-Saharan countries historically,” he
says, noting that ExxonMobil now does business in six countries
there.
Additionally, investment in oil and gas resources in Africa has been
growing. Africa now represents about eight percent of the world’s
oil supplies, but that number is expected to grow to about 12
percent.
“Starting in about 2001, we developed a very comprehensive
workplace malaria control program. However, we have to address
the reservoir for mosquitos, which is [all] human beings, not just
company people,” he says.
JUMP is an integral part of ExxonMobil’s overall corporate
responsibility program and commitment to the African continent.
ExxonMobil has funded the project at the $500,000 level each year
for the past four years, but the company’s overall commitment to
the fight against malaria is much larger.
That said, it may be the Ugandan government’s commitment that
is the real indicator of the program’s success, as the government
has adopted JUMP’s curriculum as a national standard for training
health care workers.
The JUMP program has evolved significantly since it was initially
developed. “JUMP started as a classroom-based, five-day training
program. But we discovered that sites did so much better in
terms of health outcomes after we conducted on-site support and
supervision visits that we decided that that had to be an essential
component of any training,” says Kelly Willis, M.B.A., senior vice
president for program development at Accordia Global Health
Foundation. “In doing so, we found it was more cost efficient to
have peer leaders conduct the courses, so we created a training-oftrainers
module, which has proven to be tremendously effective,”
Willis adds. As of the end of 2008, the JUMP program had trained
803 individuals in fever case management and effective diagnosis
and treatment of malaria.
A Center of Excellence
While malaria has long been a medical problem throughout sub-
Saharan Africa, the impetus behind the founding of IDI was not
malaria, but AIDS.
In 2001, a group of North American and African physicians,
who had experienced the AIDS epidemic firsthand, recognized
that Africa lacked the infrastructure to deal adequately with the
problem, so they reached out to Hank McKinnell, Ph.D., the
former president and CEO of Pfizer, who now is chairman of the
board of Accordia.
“The result was what we originally called the Academic Alliance,
which quickly became the Accordia Global Health Foundation,”
McKinnell says. That group established IDI at Makerere University
in Kampala, Uganda. To date, IDI has trained more than 4,500
health care workers from 29 countries in HIV/AIDS, malaria,
laboratory practices, research methods and other critical infectious
disease topics.
While IDI is an autonomous institution, it is integrated into
Makerere University, which, having been founded in 1932, is one
of the oldest universities in Africa. “For a long time Makerere was
the only university for doctors in the whole of eastern Africa,” says
IDI’s Coutinho.
Makerere University, which has a student body totaling around
30,000 students, produces roughly 100 doctors a year. In
the medical school, there are 23 professors, as well as 500
undergraduate and 200 graduate students, according to Coutinho.
While IDI’s development and subsequent reputation as a center of
excellence are a relatively recent phenomenon, Makerere University
has a long and accomplished history, which includes discovery of
new diseases like a tumor called Burkitt’s lymphoma, among others.
“The vision for IDI was that the driving force to combat diseases
that primarily impact Africa needs to be firmly rooted in Africa,
and Makerere was the natural place to locate it,” says Accordia’s
Spahn.
The number of IDI’s trainees has grown substantially since its
inception in 2004 to around 1,600 trainees in 2008 alone. With
this expansion, the training methods have also evolved. In addition
to the trainees who come from across Africa to participate in
specific training programs, Makerere medical students also cycle
through IDI for a two-week period and follow a patient through
the clinical care process and into their homes. This is intended to
enable the students to understand the patient’s psychosocial and
socio-economic circumstances as part of the HIV/AIDS treatment
and care process.
Accordia also sends visiting scholars to IDI, to give lectures and
do rounds with medical students, Spahn explains. “These scholars
play a critical mentoring role with young African scientists doing
research at IDI,” she says. In the last four years, IDI scholars have
published 71 articles and presented 92 research abstracts at major
infectious disease meetings around the world.
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While originally focused on AIDS through contributions from
Pfizer, ExxonMobil’s generous support allowed IDI to expand
to malaria research, prevention and care. In the first year of the
JUMP program, activity focused on building relationships and
jointly developing a comprehensive curriculum for use in multidisciplinary
team training for the care and prevention of malaria.
The second year saw the implementation of the core malaria
training program and demonstration of the value of its multidisciplinary
team-based approach to malaria training. In 2008,
the program was adapted for national scale by adding modified
field-based components for facilities with and without laboratory
capacity, external funding was secured for program expansion, and
the JUMP curriculum was formally endorsed by Uganda’s Ministry
of Health.
A New Model of Treatment
According to ExxonMobil’s Phillips, the company found that the
training approaches being developed at IDI for HIV/AIDS could
be leveraged to address malaria as well.
“We wanted to develop a module that complemented what IDI was
already doing, by developing a new curriculum for training health
professionals in malaria and disseminating it, not only in Uganda,
but throughout the continent of Africa,” says Phillips.
“But how do you test — how do you export — that technique, and
make sure that it is generalizable to other parts of Africa? Malaria
is a totally different disease, and it’s not like you can turn on a
dime. You have to spend substantial financial resources and figure
out who the curriculum is for. Malaria is primarily taken care of
by people who work in very, very remote health centers, by people
who have very little medical training,” he adds.
Another part of the problem with malaria in sub-Saharan Africa is
that, while the disease is readily treatable, resistance has spread, in
part because of frequent misdiagnosis. Treatment can take as little
as three to five days if the patient is properly treated with drugs
like artemisinin, chloroquine or primaquine. “However, the new
products are much more expensive, so we have to train the health
workers to much higher levels so they don’t waste treatment,” says
IDI’s Coutinho. “That’s because malaria is a disease that cycles
through the body, and, at different phases of the cycle, different
drugs are able to block the propagation of the parasite. For
instance, chloroquine is able to block it in the blood cells, while
primaquine blocks malaria in the liver cells,” he continues.
“In a country like Uganda, you can often find shopkeepers, or what
you would call pharmacists, filling the need for local treatment,
and we need to be sure we work with them so that they dispense
treatment in the correct fashion. We need to make sure we
constantly teach and train people on the front line,” Coutinho says.
Resistance has mainly been a problem in the last decade or so, as
doctors have encountered chloroquine resistance in as many as
30 percent to 40 percent of cases. Malaria is often confused with
hepatitis or typhoid or one of a number of other tropical diseases
when the patient has a fever.
To deal with the problem, the JUMP partnership developed a new
field training model to deliver the most effective care for malaria.
The model includes a six-day intensive course in advanced care
for and prevention of malaria and targets doctors, nurses, clinical
officers and laboratory technicians. The JUMP team includes
a medical officer, training coordinator or curriculum specialist,
laboratory technician, training assistant, data manager and a driver.
Once core teams are trained at the institute itself, they return to
their home communities to continue training and teaching others.
The JUMP team then provides on-site follow-up support.
“We found that the extra investment in providing on-site support
helped solidify the training and resulted in a stronger impact,”
Accordia’s Spahn says.
Expanding Activities and Diversifying Resources
Because of the success of the JUMP program, Accordia and
IDI hope to pilot the JUMP program outside of Uganda, to
demonstrate the model’s success in other settings. “The program
has been proven to have a positive effect on patient outcomes in
Uganda, and we believe it has strong applicability throughout
sub-Saharan Africa,” says Spahn. “It is imperative that we scale this
up as quickly as possible as a part of the broad plan to eradicate
malaria and its impact.”
Accordia and IDI are also exploring the potential replication of
the IDI model in another country. “We are trying to replicate
the institute in West Africa, perhaps in Nigeria,” Coutinho says.
“Tanzania, Zambia and South Africa already have similar institutes,
but in West Africa, there are none,” he adds.
Additionally, IDI hopes to acquire land for a new building. “We
are fundraising and identifying land; we hope to construct a new
building very soon, because the demand for training is so huge,”
Coutinho says. “The new building will be used mainly for training,
but we could also use some space for additional research. In just
five short years, we have outgrown our space.”
As part of its visionary investment in IDI, Pfizer constructed a
state-of-the-art facility in Kampala. “The building is something
you might find around the corner from you in the United States,
with a bustling level of activity,” says Lisa Foster, M.B.A., senior
director in the corporate responsibility/philanthropy team at Pfizer.
The multi-level building comes complete with an award-winning
research lab and hosts as many as 40 physicians and researchers
from the region at one time, she adds. In addition, the on-site
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computer server is protected from fire or explosion by a heatsensing
device, and the building features an air-circulation system.
“Our clinic treats up to 300 HIV-positive people per day,”
says Coutinho, adding that the building has 40 rooms, three
pharmacies, a records office and one of only six labs in Africa that
are certified by the College of American Pathologists.
Despite the fact that Pfizer solely financed construction of the
building, it has welcomed multiple partners in an effort to build
long-term sustainability. “The many different partner organizations
work very well together,” says Accordia’s McKinnell. “The reason
for diversifying is that we did not feel it was appropriate for a major
institute anywhere in the world to be dependent on a single source
of funding. Once established, like any other organization, it has to
develop its own funding sources,” he adds.
“In the early years, it was very critical that Pfizer provide a solid
base of core funding to establish IDI’s relevance, so that when
the executive director approaches other organizations to ask for
funding, donors will be receptive,” says Pfizer’s Lisa Foster.
By John Otrompke, J.D.
Infectious Diseases Institute (IDI) and
Treatment for AIDS
Establishing new methods of training providers to treat malaria
has not detracted from the Infectious Diseases Institute’s
(IDI) work in combating the AIDS epidemic. In fact, it may
contribute to this work. “People who are HIV-positive or have
AIDS are more susceptible to malaria,” says Alex Coutinho,
M.D., M.P.H., executive director of the Infectious Diseases
Institute (IDI). “On average, a patient with HIV will survive if
they also have malaria, although it may take longer for them to
get better. However, if the patient is HIV-positive and pregnant,
and gets malaria, the chances of the baby succumbing are much
more severe.”
While ExxonMobil has funded the Joint Uganda Malaria
Program and the IDI’s malaria work, the lessons learned are also
contributing to efforts to develop training for nurses and clinical
officers in integrated infectious disease management, which
combines HIV/AIDs, malaria, tuberculosis and other infectious
diseases. Accordia Global Health Foundation has recently
received a $12.5 million grant from the Bill & Melinda Gates
Foundation to study appropriate models for training lower-level
cadres of health workers, who are bearing a significant burden
of caring for patients due to the severe shortage of physicians in
Africa.
“Over the last 17 years, HIV or AIDS has gone from being a
death sentence to a disease that can be treated in some cases
for 20 or 30 years,” Accordia’s Hank McKinnell, Ph.D. says.
“We don’t have the 20- or 30-year data yet, but we certainly
have patients in Africa who have been on treatment for 10 years
or more. Today, nobody needs to die from an HIV infection
in Africa due to a lack of drugs,” he explains, adding that the
problem today is a lack of well-trained providers and adequate
infrastructure.
A Multi-Dimensional Partnership
The JUMP program is a project that involves a multi-level
partnership of more than a half dozen organizations. Each JUMP
partner brought strategic capabilities to the successful partnership,
and had its own reasons to contribute them to the project.
• Accordia sought to broaden the scope of its IDI, adding
malaria expertise to the training program there.
• For ExxonMobil, success meant a stronger strategy to
overcome the burden of malaria in Africa, proof that a novel
approach could work on a larger scale, and lessons it can
share with other partners to achieve that impact.
• For Makerere University and the University of California
San Francisco (UCSF), the partnership offered
opportunities for students and researchers to get involved in
a meaningful way, and contribute to the body of knowledge
around malaria programs. UCSF provided needed
demographic surveillance in the early part of the program.
• The Uganda Malaria Surveillance Program (a joint venture
between Makerere University Institute of Public Health,
Uganda Ministry of Health and several other academic
institutions) used the incremental funds made available
through the JUMP program to expand its own surveillance
activities.
One of the key lessons learned during the successful concept,
design and execution of the JUMP program was that
strong relationships among local and international partner
organizations are critical factors in establishing credibility and
ensuring wide program participation.
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Public and Private Partnership Helps
to Set the Standard of Care for
Multi-Drug Resistant Tuberculosis
Lessons Learned:
• Technology transfer of a drug product may require more
than sharing intellectual property. Guidance in training,
manufacturing and quality control are also critical.
• Multi-pronged strategies that address health care
infrastructure are necessary when dealing with a pandemic.
• Partnering with local physicians and working through
local ministries of health to train nurses, doctors and
hospital administrators are critical to making a measurable
impact quickly.
• A strong social support system, like that provided by
community-based care delivery, is essential to successful
drug-resistant TB treatment in resource-poor settings, where
illness and economic factors can prevent patients from
getting to where the treatment is being delivered. Nonmedical
incentives can be effective in convincing patients to
comply with medical treatment.
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When a new form of tuberculosis (TB) was raging
through the shanty towns in the Northern Cone of
Lima, Peru, Partners In Health (PIH) was on the
ground trying to find a solution.
“Our group first encountered this in Peru in 1995, but science
has known from the earliest days that you have to give multiple
drugs to tuberculosis patients or resistance can develop very
quickly, probably within the span of about a month or so,” says
Salmaan Keshavjee, M.D., Ph.D., then an anthropologist. “As a
phenomenon we saw drug-resistant TB in the 1950s and 60s, and
there was a big outbreak of it in New York and Miami in 1991 and
1992,” adds Keshavjee, who has since become a physician and is
now a senior TB specialist with PIH.
While as many as two billion people have been infected by TB,
or one-third of the earth’s population, only about nine million
people per year get active TB. The most vulnerable patients are
immunocompromised or those suffering from malnutrition, and
while patients can live for as long as 10 years with active TB, if
left untreated, “It will kill you in the end,” says Keshavjee. “In the
meantime, the TB bacillus is destroying part of your lungs and
being transmitted to other people.”
The World Health Organization (WHO) estimates that 1.8 million
people die every year from TB, making it essential that those with
active TB receive treatment. Some patients may develop a drugresistant
form of the disease; these strains require 18 to 24 months
of treatment with numerous second-line anti-TB drugs, making
treatment and compliance much more difficult. More than 70
percent of patients with the drug-resistant form of the disease can
be cured, however the growth of drug-resistant TB is outpacing
global efforts to fight it.
The multi-drug resistant form of TB, known as MDR-TB, strikes
about half a million people each year, but is still susceptible to
drugs, including capreomycin and cycloserine, two second-line
therapies made by Eli Lilly and Company. And it is because of
this experience that Lilly set out to create the Lilly MDR-TB
Partnership, initially to fill the need for these drugs by supplying
them at a concessionary price. The partnership also embarked
on a transfer of technology program to generic manufacturers in
A child with tuberculosis takes his medication
under the supervision of a community nurse in
Gugulethu, South Africa.
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high-burden countries, to enable them to produce the medicines
locally. It has since evolved into an alliance of partners — private
and public health care professionals, academics, patient- and
community-advocacy groups, international organizations, and
producers of medicines in developing regions — whose aim is to
support the WHO goal in treating 1.6 million MDR-TB patients
by 2015.
The Lilly MDR-TB Partnership consists of more than 20 global
partners, including Partners In Health, the Centers for Disease
Control, WHO, the Stop TB Partnership, the International
Council of Nurses, the World Medical Association, the
International Hospital Federation, the World Economic Forum,
the International Federation of Red Cross and Red Crescent
Societies, TB Alert, the Advocacy Partnership, the Global Business
Coalition, the Global Health Advocates, Hisun Pharmaceutical,
Shasun Chemicals and Drugs, SIA International/Biocom, Aspen
Pharmacare, Purdue University, RESULTS, and Eli Lilly.
The partnership was created following the Peruvian crisis of
the mid-1990s, according to Patrizia Carlevaro, head of Lilly’s
International Aid Unit. “Doctors Without Borders asked me if Lilly
could give them drugs for some former Soviet Union programs. We
had these older drugs which were still very effective. I then began
to think that we had to do much more than just give drugs and
that’s when the inspiration for the partnership began.”
Lilly distributes the drugs at concessionary prices, but does so
through an organization called the Green Light Committee
which monitors MDR-TB projects throughout the world so that
treatment protocols are correct and more drug-resistant strains
don’t develop. “We asked the WHO and others to put together the
Green Light Committee, to review requests for drugs in order to
make sure that the programs were using the drugs correctly to avoid
more drug resistance,” says Carlevaro.
“The Green Light Committee evaluates applications from
countries. As a mechanism, the committee evaluates countries
and approves them or not within two months,” says Keshavjee,
who currently serves as the committee’s chair. If a country requires
assistance to strengthen its program before being approved, the
committee works with it through the process.”
The Green Light Committee (GLC) is comprised of representatives
from institutions with specific programmatic, clinical, advocacy,
scientific and managerial expertise [see sidebar]. WHO is a
permanent standing member. It is charged with reviewing
applications, providing technical assistance to countries throughout
the application and implementation processes, monitoring and
evaluating GLC-approved programs to assess their progress and
continued adherence to WHO guidelines, and assisting WHO
with developing policy to control MDR-TB.
The Stop TB Partnership and WHO raise funds to sustain
the work of the committee from national and governmentsupported
agencies, regional and international organizations,
nongovernmental organizations, universities, research institutions
and other sources. In addition, a cost-sharing mechanism helps
support the efforts of the GLC initiative in countries receiving
Global Fund grants for work on MDR-TB.
To become a quality-assured provider of TB drugs, drug companies
have to go through the WHO prequalification program, a
long process that can take two years or more. One of the key
components of the Lilly partnership is transferring the technology
Lilly transfers its technology to manufacturers
in high-burden countries.
Current Members of the Green Light
Committee
(as of September 2009)
Members are eligible for participation for a maximum of two
years. An open call for membership is disseminated whenever
a vacancy occurs, and members are usually drawn from the
Stop TB Partnership Working Group on MDR-TB.
Partners In Health — Current Chair
U.S. Centers for Disease Control
Hospital General de “Francisco J. Muniz”
International Union Against Tuberculosis and
Lung Disease
KNCV (Dutch) Tuberculosis Foundation
Médecins sans Frontières
State Agency for TB & Lung Disease, Latvia
World Care Council
World Health Organization Standing Member
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to manufacture the two key drugs that can cure MDR-TB —
capreomycin and cycloserine. Lilly identified four companies in the
developing world and gave them the equipment, methodologies and
training to produce these drugs as well as the manufacturing and
marketing expertise to be able to provide the drugs to the growing
number of countries, health ministries and donor agencies in need
of these medicines for the TB pandemic. The four countries were
those with the highest MDR-TB burden, so that drug supply could
be available for the immediate needs of these nations as well as other
countries hard hit by this deadly disease.
“The technology transfer was not a transfer of intellectual property
per se, because the patent is over, since the drugs are more than 20
years old,” Carlevaro explains. “We give them all the technologies for
manufacturing, and expert production technicians went to the local
companies to teach them how to produce the two drugs,” she adds.
In addition to providing the transfer of technology, between 2000
and 2008 Lilly has supplied 2.3 million vials of capreomycin and
5.5 million capsules of cycloserine at concessionary prices to the
WHO’s program. This has provided the much-needed drugs in the
interim before the new companies were up and running.
An Emerging Economy Model
Of nine million cases of TB that occur annually, scientists now
estimate that half a million are of the drug-resistant form. The Lilly
partnership contributed to the GLC’s enrollment of around 56,000
patients to date, according to Carlevaro. While the disease is
spreading faster than it is being treated, some countries like Russia,
which have adopted the partnership model as a standard of care for
treating the disease, have seen better progress than others.
“Russia has a very well-established health care delivery system,
with sufficient physicians, nurses and resources, so our work
is more focused on training those physicians,” says Amy Judd,
director of program development in the division of Global Health
Equity at Brigham and Women’s Hospital. With a grant by the
Lilly Foundation, PIH subcontracts with Brigham and Women’s
Hospital to administer the program.
“Whenever possible, we partner with local physicians and work
through local ministries of health or the ministry of justice for the
prison system, to educate physicians in drug-resistant TB diagnosis
and treatment and advocate for effective care delivery models,” adds
Judd, who notes that, while PIH is involved in other TB work, its
partnership with Lilly is mostly limited to Russia.
Because Russia has established multi-drug resistant treatment as a
national policy, the partnership may be improving treatment for as
many as 25,000 patients per year, adds Judd. She also notes that the
country sees 120,000 new cases of TB per year, of which 20 percent
are multi-drug resistant.
“Partners In Health has doctors in Tomsk, Russia, but we’re
not directly treating patients any more. Russian health care
professionals basically run everything themselves, and since 2003 or
2004, we have been there just as consultants,” says Keshavjee.
Treatment is also more thorough in Russia than in some places,
notes Keshavjee. “In our sites in Russia, patients start in the
hospital and then are sent back to the community. With drugsusceptible
tuberculosis, patients become noninfectious in two
weeks to one month, but for the drug-resistant forms, patients
usually convert to a noninfectious stage in two months, so the
patients are kept hospitalized for between four and six months,”
notes Keshavjee.
Different Techniques Needed
Lilly also funds other partners to conduct extensive programs in
Africa and Asia. Through grants to the International Council
of Nurses, the World Medical Association and the International
Hospital Federation, integrated TB training programs have
been conducted for nurses, doctors and hospital administrators
throughout Africa. “The problem with drug-resistant TB in Africa is
especially critical,” says Lilly’s Carlevaro. “In Africa, 50 to 60 percent
of the patients with HIV die from TB. If they’re not treated, they die
very quickly, sometimes within a few weeks,” she explains.
Nonmedical measures are sometimes essential to effective
implementation of the partnership, according to Carlevaro. “The
Red Cross has more than 100 million volunteers globally, who
go house to house, providing incentives such as a kilogram of
sugar, for people who need treatment,” she says. “It seems strange
because in the developed world, if you’re sick, you are usually
willing to get treatment, especially if it’s free. In some parts of the
world, however, if you’re sick, you can’t get to the treatment. In
some cases if patients take the drugs for a few months, feel better,
and then stop, they become re-infected. So, we try to make sure
they complete their treatment.” While the course of treatment for
regular active tuberculosis takes about six months, for the drugresistant
kind it lasts up to two years,” says Carlevaro.
“The medicines can have a bad side effect profile, with almost
universal nausea and vomiting. Patients sometimes don’t have
families and social support, and they may lack nutrition, so the
Red Cross delivers food assistance and helps patients take their
medicines,” says Keshavjee.
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Coordination Challenges
The Lilly MDR-TB Partnership is active in close to 80 countries
across five continents, and virtually all partners agree that there
have been logistical challenges in working in developing countries.
When the Green Light Committee has to change its forecasts
for drug purchases, the manufacturing partners must adapt their
manufacturing schedules. On the other hand, the manufacturing
partners also rely on WHO for its quality approvals, and slow
response times and policy disagreements have sometimes frustrated
partners and those waiting to receive the medicines. Some partners
have had difficulty scheduling around grant disbursements and
project evaluation requirements.
Prequalification procedures for drug quality and safety measures
have taken more time for companies in developing countries to
master. Thus, while the supply of drugs to the developing world has
been able to meet demand to date, delays in getting one of the Lilly
partner’s manufacturing facilities approved, have been addressed so
that future supply lines will not be affected.
“What Lilly has done with their technology partnership is very
innovative,” says Keshavjee, who lead-authored a white paper in
November 2009 on barriers to solving the problem for the Institute
of Medicine last fall entitled: “Stemming the Tide of Multidrug-
Resistant Tuberculosis: Major Barriers to Addressing the Growing
Epidemic.” MDR-TB is very concentrated in southern Africa,
India, China and Russia, and Lilly has transferred its technology to
companies in each of those regions.
Lilly’s technology transfer process has been very complicated. For
example, the fermentation process required for capreomycin is a
highly challenging and sophisticated process in any country. Hisun
Pharmaceutical also had other challenges to address in safety and
quality control, and Lilly had to provide support as part of the
technology transfer.
In addition, there are sometimes problems with compliance by
the manufacturers with the quality approval process in developing
countries. “Some manufacturers don’t want to go through the
WHO process because it takes too long,” says Judd. “So, some of
the nonquality-approved products may not be good, or we have
no way of knowing whether they’re good or not.” That is why
the Lilly partnership has been critical to ensure that their partner
manufacturers will go through either the prequalification process
or approval by a stringent regulatory authority such as the U.S.
Food and Drug Administration or the European Union. Lilly itself
doesn’t need to go through the process because it is FDA-approved.
As an important milestone in the Lilly MDR-TB Partnership,
in June 2009, WHO added Lilly manufacturing partner Aspen
Pharmacare’s cycloserine to its prequalified list.
Other problems of coordination also exist, Keshavjee adds. “We don’t
know exactly how much medicine countries need,” he says. “Say
they’re going to treat 2,000 patients next year but they don’t have the
capacity or the labs, and they really end up treating 20 or 100. It’s
very difficult to forecast what’s going to be done. It’s a problem with
implementation within countries in some cases,” he says.
While coordination is a challenge, the partnership has succeeded
in multiple spheres in its fight against MDR-TB. Through its
multi-pronged approach, it has dramatically increased the supply
of essential medicines and enabled manufacturers in high-burden
countries to produce these drugs as well. However, the partnership
realizes that drugs are not enough, and partner achievements have
also been crucial in this battle.
By the Numbers
• The International Council of Nurses has trained nurses
worldwide in treating MDR-TB, with an estimated 16,000
nurses trained to date.
• Through programs led by PIH, more than 2,000 people have
been trained on TB prevention, hospital management and
clinical trainings in Russia and India alone.
• The International Federation of Red Cross held public
awareness and antistigma campaigns that have reached more
than 15,000 people in Kazakhstan, Romania, South Africa and
Uzbekistan.
• Around 2,000 Red Cross Red Crescent staff volunteers
have been trained in TB and MDR-TB, and nearly 1,000
community leaders received sensitization training.
• More than 300 clients with TB/MDR-TB signs are referred
monthly to TB institutions, while more than 3,000 household
visits have been conducted with MDR-TB prevention sessions.
• The International Hospital Federation has disseminated
TB and MDR-TB control training manuals to aid hospital
managers in more than 40,000 public and private hospitals
and clinics in some 100 countries.
The impressive achievements of these partners augment Lilly’s
effort in fighting MDR-TB by ensuring that the increased supply
of MDR-TB drugs are put to proper use through consistent
training of medical workers on an international scale. Furthermore,
the awareness and advocacy work of the partners reduces stigma
and increases awareness, which ultimately ensures that more people
seek treatment for this illness.
By John Otrompke, J.D.
150 Case Studies for Global Health
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Integrating Neglected
Tropical Disease Control:
Comparing the Experience in
Rwanda and Burundi
Lessons Learned:
• Accurate epidemiologic information is critical.
Verify conventional wisdom.
• Empower the projects teams to make decisions
and implement plans. Efficiencies in their work
should be rewarded and give rise to opportunities
to further health care initiatives.
• Advocacy in support of Neglected Tropical
Diseases control must be conducted at all levels of
society — from the highest rungs of government to
the bottom of the village hierarchy.
• The objectives of a national health program and
the national health strategy should be aligned.
• Ministry of health ownership of NTD control is
critical to its long-term viability.
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The 13 parasitic and bacterial infections that are
considered neglected tropical diseases (NTDs) afflict
a billion people, take half a million lives each year
and impose a health burden on the world that adds
up to a staggering 56.6 million disability adjusted life
years. Seven of these diseases are responsible for 90
percent of this devastation. They include (see Table
I) lymphatic filariasis (elephantiasis), schistosomiasis
(bilharzia), onchocerciasis (river blindness), blinding
trachoma (a bacterial infection of the eyes) and the
three distinct kinds of worm infestation (trichuriasis,
hookworm infections and ascariasis) collectively known
as soil transmitted helminthiases (STH). Though each
of these seven NTDs can be cured with the use of
safe and generally inexpensive drugs, they continue to
exact a grim toll on the poorest of the world’s poor.
Left untreated, the infections compromise the ability
of adults to work. They also stunt the physical and
intellectual growth of children: Those chronically
infected with hookworm grow up to earn 43 percent
less than do their uninfected peers. And so the
widespread persistence of NTDs perpetuates a cruel
cycle of disease and poverty, hampering the economic
advancement of many developing countries.
The densely populated and mountainous East African nations
of Rwanda and Burundi are no exception. Both carry a heavy
burden of NTDs but, before 2007, neither had comprehensively
determined the extent of the problem or devised a strategy to deal
with it. To address this need, the global investment firm Legatum
— whose interest stemmed from the low cost and high return on
investment in NTD control and the opportunity to apply private
sector best practices to the effort — contributed $8.9 million
for the establishment of an NTD control program in the two
countries. Legatum funneled its support through the philanthropy
advisory service Geneva Global, which manages funding to the
programs, monitors them and evaluates their progress.
The programs themselves are overseen by the Global Network
for Neglected Tropical Diseases, an initiative of the Sabin Vaccine
Institute, which, in turn, relies on the Earth Institute at Columbia
Doctor palpating to check for worms.
Photo by Lindsay Wheeler, Global Network for Neglected Tropical Diseases
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University’s Access Project in Rwanda and CBM (formerly known
as Christian Blind Mission) in Burundi to manage operations on
the ground. All of these organizations also work closely with the
Schistosomiasis Control Initiative (SCI), which provides technical
guidance to the effort (its founder, Alan Fenwick, directs the overall
program). But the key partnership of both control programs is
that with the Ministry of Health (MoH), with which each works
to conduct everything from disease surveillance to mass drug
administration (MDA) for the treatment of NTDs.
The control programs both integrate their operations with existing
programs for health intervention — namely the Mother and Child
Health Week run by the MoH in collaboration with UNICEF.
Notably, the program in Burundi had initially sought to work
through an army of community drug distributors who had been
trained by the African Programme for Onchocercaisis Control
(APOC) to distribute drugs against onchocerciasis. The approach,
pioneered by APOC, relies on community leaders and other trusted
members of society to distribute drugs in MDA campaigns.
But after a pilot round of MDA in three provinces, it quickly
became clear that adding further NTD control responsibilities to
the already full plates of community drug distributors was neither
fair nor practical. So the Burundi program too chose to integrate
its operations with those of its existing Mother and Child Health
Week, relying on trained health workers and schoolteachers to
carry out the drug distribution. Both control programs have been
deliberately structured to build in the health ministry of each
country a sense of ownership for NTD control, as well as the
technical capacity to sustain it.
This is not easily accomplished. Though lately the darling of
international donors, Rwanda continues to lack vital infrastructure
and is deeply scarred from the 1994 genocide in which an
estimated 800,000 of its citizens lost their lives. Burundi,
meanwhile, remains a cauldron of instability. Aside from its own
legacy of intertribal conflict and genocide, the country is troubled
by recurrent bouts of civil war. Indeed, fighting flared up in April
2008, even as the control program conducted monitoring and
evaluation activities. Such instability has, in general, discouraged
most donors from investing in the nation’s development.
Despite these challenges, the two control programs have conducted
several highly effective MDAs. The Burundi program has already
delivered about 13 million treatments for STH and more than a
million for schistosomiasis over the first two years of its operation.
The program in Rwanda, meanwhile, has delivered about 13
million STH treatments and more than 400,000 treatments for
schistosomiasis over that period. Notably, over the course of the
first year of operation, more than 3.2 million individuals were
Disease Causes and Consequences Chemotherapy
Schistosomiasis
(also known as snail fever or bilharzia)
200 million infected worldwide
Caused by a blood-borne fluke that is transmitted via
fresh-water snails, schistosomiasis kills more people than
any other NTD. A common sign of infestation is blood in
urine or stools. Left untreated, it can cause bladder, liver,
spleen and kidney damage.
Praziquantel
Soil-transmitted helminthiasis
Up to 2 billion infected worldwide
The term for three distinct types of worm infestation —
ascariasis, hookworm infection and trichuriasis — STH is
associated with poor sanitation and dirty water. Chronic
infestation can cause anemia, malnutrition and stunt the
physical and intellectual growth of children.
Ivermectin,
Albendazole, Mebendazole
Onchocerciasis (river blindness)
37 million infected worldwide
Caused by a parasitic worm transmitted by black flies, this
disease is characterized by intense itching, disfiguring skin
conditions and eye lesions that can lead to total blindness.
Ivermectin and Albendazole
Trachoma
84 million infected worldwide
This bacterial infection of the eyes, spread by flies and
contact with infectious discharge, is the world’s leading
cause of preventable blindness. As the infection progresses,
scar tissue develops on the upper eyelid, turning it inward.
Eyelashes scratch the cornea, causing blindness.
Zithromax
Table I: The Major Neglected Tropical Diseases of Rwanda and Burundi
Table I information was provided by the Global Network for Neglected Tropical Diseases.
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treated in Burundi and Rwanda combined at a cost per person of
approximately 51 cents (second-year calculations have not yet been
completed). Today the programs have only one outstanding item to
address on their NTD agenda: trachoma. Having established that
it is endemic in Burundi, though not in Rwanda, they are currently
applying to the International Trachoma Initiative for the antibiotics
required for treating the disease via MDAs in Burundi and as
required in Rwanda.
This case study examines how the two control programs
evolved from their planning stages through to the second year
of their operation. It focuses, in particular, on key aspects of the
partnerships — between government and global health agencies,
nongovernmental organizations (NGOs) and local communities
— that have had a significant impact on the efficiency of the
enterprise.
Starting Up
The biggest challenge both programs faced at the outset was that
there was scant information about the distribution of tropical
diseases in Rwanda and Burundi. To fill in that critical gap, each
control program began in mid-2007 to gather data for a national
map of NTDs, an effort that was integrated in Burundi, though
not in Rwanda. Prior to their arrival on the scene, onchocerciasis
was the only such disease to have been mapped across the region.
It had been found to be absent in Rwanda, but not Burundi,
where it was the focus of a collaboration between the government’s
Programme National de Lutte contre l’Onchocercose (PNLO) and
APOC.
The mapping effort in Rwanda was complicated by the fact that
the Ministry of Education did not know where all of the nation’s
schools are located, and surveys of schoolchildren are vital to the
accurate mapping of schistosomiasis and STH. As a consequence,
the mapping effort in that country also became something of a
census of Rwanda’s educational system. The ministry now has a
complete map of the nation’s schools.
The control programs’ maps revealed that the only major NTD
that isn’t an issue in either of the countries, due primarily to
their elevation, is lymphatic filariasis. STH, on the other hand, is
widespread in both, affecting as many as four in 10 people across
Burundi, and 65 percent of schoolchildren in Rwanda, with the
prevalence reaching 90 percent in some areas in that country.
Schistosomiasis, meanwhile, was found to be entrenched around
major bodies of water in both Rwanda and Burundi. Finally,
trachoma — which has long been believed not to be a problem in
either country — turned out to be highly prevalent in Burundi.
Adults waiting to receive Ivermectin
Photo by Global Network for Neglected Tropical Diseases
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The two programs also began from the outset in 2007 to address
the shortage of human resources for NTD control. In Burundi,
the MoH worked closely with CBM and SCI to train all control
program staff in the diagnosis and treatment of the major NTDs.
Staff in both countries were trained in data management and
analysis as well, building an eminently transferrable set of vital
technical skills. Beyond that, the program in Burundi saw to the
training of more than 11,000 community health workers, teachers
and community drug distributors in the treatment of the targeted
NTDs. Similarly, the Access Project in Rwanda collaborated with
the Treatment and Research Center for AIDS and other Pandemics
(TRAC+), a program of the MoH, to train more than 10,000
community health workers, teachers, lab technicians and other
national health care staff. The World Health Organization also
contributed to the effort, conducting the training of nearly 100
health care workers and control program staff members in NTD
assessment and diagnosis in both countries.
Ministries Matter
Since a nationwide project targeting onchocerciasis was already
under way in Burundi, the control program did not include the
disease in its efforts. It did, however, incorporate its operations
with those of the Mother and Child Health Week. This not only
cut costs — through the pooling of resources — but helped the
control program to learn from and build off the systems already put
in place. But what truly distinguished Burundi’s program from that
of Rwanda’s, especially in the early stages, was the involvement and
enthusiasm of its MoH.
Although beset by troubles ranging from fuel shortages to striking
doctors, the NTD control program in Burundi remained squarely
in the focus of the MoH. Key to this success was the establishment
of a leadership team in the ministry dedicated to the effort. It kept
the program running despite three changes in leadership of the
department in the span of just two years. The ministry’s commitment
was also evident in its willingness to invest precious resources to the
control program; it shared office space and provided its own vehicles,
nurses and technicians to support the effort.
This not only affected the bottom line — only eight percent
of the Burundi control program’s total expenditures in the first
year, for example, were for personnel costs. It also served to root
the initiative firmly in the MoH, which has since assumed an
unequivocal leadership role. “Ministry leadership may mean the
program is slower, less efficient and prone to internal conflicts,”
says SCI Director Alan Fenwick. “But it also means that, in the
long term, the ownership of the control program for tropical
diseases belongs to the Burundians and their Ministry of Health.”
By contrast, the Rwandan MoH took only a tepid interest in the
control program when it was launched in mid-2007. It appeared
reluctant at the outset to invest much of its limited human and
material resources in the effort, and the Access Project had to
compile its NTD team almost from scratch. As a consequence, 39
percent of the Rwandan control program’s expenditures in the first
year were for staffing.
In an effort to get the MoH more deeply involved, the Access
Project — which renamed itself the NTD/Access Project —
established with ministry staff a joint task force to sensitize people
across Rwanda’s health system on NTDs and, in some cases, to
train them in diagnosis and treatment of the diseases. Further, the
task force submitted to the ministry a strategic plan for integrating
Felix in Kirundo infected with schistosomiasis NTD control into its TRAC+ initiative.
Photo by Lindsay Wheeler
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These steps were critical. They account, at least in part, for
the increased ministry involvement in the second year of the
program. Indeed, in August 2008, the Access Project pooled
resources with TRAC+ to deworm some 3.8 million children and
expectant mothers during the annual Mother and Child Health
Week overseen by the MoH. “We’re seeing the beginnings of an
integrated health platform within Rwanda’s districts,” says Kari
Stoever, managing director of the Global Network. “That’s exactly
what we want to see from the perspective of sustainability.”
But why, in the first place, was the Rwandan ministry so much
slower to respond than the one in Burundi? This probably had
something to do with its absorption in efforts to combat AIDS,
tuberculosis and malaria — the three major epidemics of the
region, says Fenwick. But it also had to do with the lack of data
about the prevalence of NTDs in the country: the Rwandan
MoH simply didn’t think there was a big enough NTD problem
in its jurisdiction to warrant concerted action. After its leaders
saw the maps of NTD distribution, says the Access Project’s
Denise Mupfasoni, the NTD control program’s Rwanda national
coordinator, the ministry was quick to take on a more active role.
But another factor contributed to ministry’s initial reluctance:
Unlike its Burundian counterpart, the Rwandan ministry lacked
clear policy guidance on NTD control. One of the four prime
objectives of Burundi’s health development plan, after all, is to
“reduce the prevalence of transmittable and nontransmittable
diseases,” such as NTDs. “The crucial thing to remember about
any NTD program,” says Fenwick, “is that it cannot happen
without external impetus. So we needed to do our advocacy at
all levels. We needed to convince the Ministry of Health of our
target countries to write specifically in their strategic plans: ‘We
will control neglected tropical diseases and improve child health
through deworming.’”
Once senior government officials are made aware of the severity
of the problem and the low cost and relative ease of dealing with a
number of tropical diseases, says Fenwick, they are only too happy
to cooperate. And their support is invaluable, as it sends a powerful
signal of endorsement down the rungs of the national bureaucracy
that can be critical to garnering support for ground operations
from local officials.
Getting buy-in from the target population is another matter. It
certainly helped that each of the control programs had access to
existing national health care initiatives to reach as many people as
possible. The Rwanda program operated via TRAC+ and a joint
program of the MoH and UNICEF — called Mother and Child
Health Week — that delivered bed nets, vaccinations and nutrients
to mothers and young children. The Burundi control program’s
MDAs too were integrated into an almost identical program run by
its MoH and UNICEF.
All this brought people to the table. But getting them to take drugs
for parasitic diseases required a more concerted effort. The rural
populations of both countries have been disease-ridden for so long
that many people do not even consider infection with NTDs to be
preventable or, indeed, anything out of the ordinary. To get such
people to participate in the MDA, the control programs invested
generously in national media campaigns in both countries when
they launched their second major MDA campaigns in the latter
half of 2008. Thousands of posters, booklets and leaflets about
NTD prevention were directed not only at communities but used
to educate health workers and the staff of a variety of NGOs as
well. Mupfasoni suspects that without that campaign — especially
the radio messages, which had the greatest reach — most people
would have refused to take drugs in the absence of symptoms. As
it turned out, the MDA covered an estimated 80 percent of the
target population in Rwanda and 91 percent of the population of
Burundi.
Best Business Practices
From the project management perspective, says Stoever, the greatest
successes of both control programs was not just the efficiencies they
achieved — both came in well under budget in the first year of
operation — but how those efficiencies were leveraged. When project
teams find they are coming in under budget, she explains, they
often tend to panic, assuming that they will either be penalized for
overbudgeting or lose the money that they saved by dint of shrewd
planning and execution. As a consequence, there’s a high incentive to
spend such extra funds in almost any justifiable fashion.
This was something Stoever wanted to avoid. “We wanted to
be flexible and create an environment of partnership that would
reassure them that we would not be penalizing efficiencies,” she
says. After all, the donor organization Legatum had expressed
a particular interest in whether best business practices could be
applied to the NTD control programs it was underwriting.
Rewarding efficiency and initiative certainly qualified. So when the
joint program teams asked how they ought to spend their excess
money, she first reassured them that they would not lose their
funds. She then suggested they take a little time to mull over how
the money might be redirected in service of the ultimate objectives
of the control program — the elimination of the major NTDs.
The two programs returned with different prescriptions. The
Burundi team believed that the money it had saved would be best
spent to buy an extra couple of rounds of MDA, extending their
program by a year. The Rwanda team, on the other hand, felt that
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the dire shortage of potable water and basic sanitation systems
across rural areas were severely compromising NTD control. It
wanted to use the spare funds to supplement existing projects to
shore up such infrastructure, particularly in schools located in highendemic
areas. “By being open with them,” says Stoever, “we were
able to be more creative, more innovative and more efficient. When
they realized they would not be penalized for underspending, we
could open the dialogue with them about what other things we
could achieve with those resources. That’s an innovative approach
to partnership.”
The Way Forward
Still, there remains room for improvement in the processes that
made such savings possible. Although organizationally integrated
in the ministries of health, says Fenwick, neither the Rwanda nor
the Burundi control programs have figured out yet how best to
integrate the delivery of different drugs in one visit. This is in part
due to the distribution of the diseases in both countries — people
with STH may or may not have schistosomiasis, especially in areas
distant from major bodies of water.
This raises another problem, evident in the pilot phase of the
Burundi program: the burden placed on community drug
distributors who are asked to deliver drugs for multiple diseases at
different times. Since these volunteers are critical to the efficiencies
associated with a community-directed approach to MDA, their
concerns must be taken into account in any program. Indeed, the
Burundi program had to stop working with the drug distributors
trained by APOC/PNLO due to the extraordinary demands this
imposed on their time. It was fortunate to be able to integrate its
operations with those of another national health program, which
had its own cadre of drug distributors. Since the Mother and Child
Health Week is an initiative active in other countries as well, it
could be harnessed to distribute NTD treatments should those
nations wish to implement similar programs.
Today, both control programs are monitoring their impact
on NTD prevalence to fine-tune strategies. But the shortage
of adequate infrastructure remains a major challenge to the
sustainability of NTD control. Parasitic diseases — notably
ascariasis — often return to their original levels relatively swiftly
after the completion of MDAs, observes Mupfasoni. Any lasting
solution to the NTD problem in both countries will inevitably
depend on better sanitation and the widespread installation of
infrastructure for clean water.
By Unmesh Kher
Children in Burundi
Photo by Lindsay Wheeler, Global Network for Neglected Tropical Diseases
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Integrating Neglected
Tropical Disease Control:
Common Themes in
Niger and Zanzibar
Lessons Learned:
• Early engagement and active support by political
leaders aids in neglected tropical disease control efforts.
• Community mobilization hinges on buy-in from
community leaders, religious figures and local
politicians.
• Make sure that health care workers at every level of the
health system have bought into the program and are
made explicitly aware of its high priority.
• Mass drug administration must be coupled with
effective health education and other measures to ensure
adequate long-term adoption and prevent further
disease transmission.
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Neglected tropical diseases (NTDs) are a set of 13
parasitic and bacterial infections that affect more than
a billion people worldwide and take a half million lives
each year. Yet, like so many diseases that afflict the
poorest of the poor, many of them are not adequately
addressed by health agencies today, even though most
are eminently preventable and relatively easily treated.
This makes NTDs ideal candidates for national
disease control programs. And, over the past decade, a
number of such efforts supported by donors and drug
companies have been launched by government agencies
in collaboration with international nongovernmental
organizations. These programs have sought mainly
to control or eliminate one or more of seven major
NTDs (See Table I): lymphatic filariasis (elephantiasis),
schistosomiasis (bilharzia), onchocerciasis (river
blindness), blinding trachoma (a bacterial infection
of the eyes) and the worm infestations — ascariasis,
trichuriasis and hookworm — collectively known as soil
transmitted helminthiasis (STH).
Many of these programs first started conducting mass drug
administration (MDA) campaigns against individual tropical
diseases in Africa in the early years of this decade. To do so, they
often employ an approach that relies on volunteer drug distributors
who have been identified by their social peers as trusted members
of the community. The volunteers are trained by health workers
and partnering organizations to distribute the right drugs in
the right dosages to the right people and are then mobilized
during mass treatment campaigns. Such community-directed
interventions have been shown empirically to be far more effective
in reaching people during an MDA than traditional modes of drug
distribution.
As the control programs using these sorts of approaches (see Table
IIa and IIb) expanded their geographic coverage, they soon realized
that they were often trying to reach the same people in Africa;
many of the tropical diseases are endemic in the same areas, and
coinfection with NTDs is not uncommon. It was obvious that
combining basic operations, such as disease surveillance, drug
delivery and the training of volunteers and health workers in MDA
and diagnostics, would do much to boost the cost efficiencies of
the overall effort. With the encouragement of the World Health
Organization (WHO) and the Bill & Melinda Gates Foundation,
which funds many of these efforts, the various control initiatives
Photo by Shutterstock® Images
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thus began in 2006 to work closely with each other and with
national health agencies to integrate their operations.
This case study examines how that process unfolded in Zanzibar
and Niger. It explores, in particular, practices in the management
of partnerships and personnel that are likely to be critical to any
future integrated, community-directed MDA campaign against
diseases of the developing world.
The Arenas
A semi-autonomous territory of Tanzania, Zanzibar is an archipelago
of several small islands and two large ones, Unguja and Pemba,
which have a combined population of 1.2 million. Niger, on the
other hand, is a vast, landlocked country in Western Africa whose
Northern and Eastern regions lie under the Sahara Desert. As a
consequence, most of its 14 million, largely impoverished citizens
live in the South and West of the country, concentrated in the Niger
River basin, where subsistence agriculture is at least possible.
Though the two countries could not in demographic, cultural and
geographic terms be more different, they do share some similarities.
Zanzibar, like Niger, is largely peopled by the rural poor. Both
countries are also short on basic infrastructure for clean water
and sanitation. As might be expected, schistosomiasis, lymphatic
filariasis (LF) and the STHs, which all thrive in conditions of
poor hygiene and poverty, have historically been rampant in both
regions. Blinding trachoma, a bacterial infection typically found in
dry areas, is not a problem in Zanzibar, but is widespread in Niger.
The Campaign in Zanzibar
Although Zanzibar has been the focus of efforts to control parasitic
diseases for roughly two decades, the first of the control programs
relevant to this case study started only in 2001. That was when
the Global Alliance to Eliminate Lymphatic Filariasis and the
Zanzibar Ministry of Health and Social Welfare launched an annual
community-directed MDA program to eliminate LF on both islands
using drugs donated by Merck & Co. and GlaxoSmithKline. If taken
just once a year over a five-year period, those drugs — Mectizan
(ivermectin) and albendazole — eliminate not only the parasites
responsible for LF, but intestinal worms as well.
Two years later, the Gates Foundation-funded Schistosomiasis
Control Initiative (SCI) and a team from the British Natural History
Museum funded by UK’s Health Foundation, began working with
Disease Causes and Consequences Chemotherapy
Schistosomiasis (snail fever, bilharzia)
200 million infected worldwide
Caused by a blood-borne fluke that is transmitted via
fresh-water snails, schistosomiasis kills more people than
any other NTD. A common sign of infestation is blood in
urine or stools. Left untreated, it can cause bladder, liver,
spleen and kidney damage.
Praziquantel
Soil-transmitted helminthiasis
Up to 2 billion infected worldwide
The term for three distinct types of worm infection —
ascariasis, hookworm infection and trichuriasis — STHs
are associated with poor sanitation and dirty water. Chronic
infestation can cause anemia, malnutrition and stunt the
physical and intellectual growth of children.
Ivermectin,
Albendazole,
Mebendazole
Onchocerciasis (river blindness)
37 million infected worldwide
(Not prevalent in Zanzibar and almost
eliminated in Niger)
Caused by a parasitic worm transmitted by black flies, this
disease is characterized by intense itching, disfiguring skin
conditions and eye lesions that can lead to total blindness.
Ivermectin
Lymphatic filariasis (elephantiasis)
120 million infected worldwide
A parasitic worm transmitted by mosquitoes causes this
disease. The larvae of the parasites circulate in the skin,
causing intense itching, while the adult worms severely
damage the lymphatic system. Victims suffer from severe
disfiguration and incapacitation due to swollen limbs and
thickened skin.
Ivermectin and
Albendazole
Trachoma
84 million infected worldwide
(Not prevalent in Zanzibar)
This bacterial infection of the eyes, spread by flies and
contact with infectious discharge, is the world’s leading
cause of preventable blindness. As the infection progresses,
scar tissue develops on the upper eyelid, turning it inward.
Eyelashes scratch the cornea, causing blindness.
Zithromax
Table I: The Major NTDs of Niger and Zanzibar
Table I information was provided by the Global Network for Neglected Tropical Diseases.
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the ministry on a separate program to bring STH and schistosomiasis
under control on the islands. Named the “Kick out Kichocho”
program, it involved annual combined MDAs of albendazole
with praziquantel, the medicine for treating schistosomiasis. The
treatments were aimed at school-aged children on Unguja, and at
both adults and children at risk for infection on the island of Pemba.
This partnership culminated in late 2006 with the integration of the
schistosomiasis control program and the LF elimination program.
(For a full listing of partners involved in Niger’s and Zanzibar’s NTD
control programs, see Tables IIa and IIb.)
Piggybacking on the systems and human resources already
established by the LF initiative, the integrated program first
conducted a pilot study. Drugs against all three of the NTDs were
administered at the same time to 5,500 people in high-risk areas.
When it was clear that there were no adverse events from the triple
therapy, the entire eligible population of Zanzibar — totaling some
700,000 people — was treated with the three drugs. The integrated
program established for the first time that, in places where the
prevalence of the targeted NTDs has been reduced substantially,
such triple drug therapy can be given safely to people who have
had extensive exposure to the drug therapies employed. The MDAs
over the past several years have, further, had the combined effect of
virtually eliminating LF from the islands and significantly reducing
both the prevalence and the intensity of schistosomiasis and STH.
But, notably, the last two diseases persist in hotspots of infection on
the islands.
The Campaign in Niger
Niger was in a very different place when it chose to integrate its
NTD control programs. A highly effective campaign had already
succeeded in eliminating river blindness in the country. But other
control efforts had begun in earnest there only in 2003, when
the Ministry of Health (MoH) and the International Trachoma
Initiative launched a program for trachoma focused on the dry,
eastern part of the country. Next, schistosomiasis and STH were
targeted by an MoH treatment program that began in 2004 in
partnership with SCI. By 2007 the schistosomiasis and STH
program had reached approximately 6.2 million people through
annual MDAs. The control of LF, on the other hand, had never
quite progressed beyond its planning stages.
In 2007, Niger’s MoH, with funding from the United States
Agency for International Development (USAID) supported by
additional funds from the Bill & Melinda Gates Foundation, set
about integrating its independent NTD control efforts, adding
a program for LF elimination to the mix. Because Nigeriens had
not had quite as much exposure to the drugs used to treat these
diseases, triple drug therapy was not considered. But other aspects
of the community-directed MDA were amenable to integration.
This included the diagnosis of NTDs and the
prevalence mapping that is essential to both
an effective MDA and its evaluation. It also
included the delivery of drugs, the training of
trainers who would teach volunteers how to
administer those drugs and the actual training
of those volunteers. Some aspects of disease
control, however, could not be integrated —
most notably the eye surgeries for trachoma
and the hydrocele surgeries for LF. In all, some
18,000 people were trained in 2007, mainly
as drug distributors. The first integrated,
community-directed drug delivery, using
drugs donated by Pfizer Inc., Merck & Co.,
GlaxoSmithKline and UNICEF, reached 5.2
million people in 19 districts of Niger in 2007,
and approximately eight million in 26 districts
in 2008.
Harnessing Political Support
If any single thing accounted for the relatively
smooth integration of independent control
programs in Zanzibar and Niger, it was the
strong and clear backing each enjoyed from
Table IIa: Niger
Organization Role
Ministry of Health Coordinated the integrated NTD control program in Niger
USAID/RTI International USAID funded the effort through its NTD control program, which
is managed by RTI International. Niger was one of the first five
fast-track countries selected by USAID to receive funding for MDAs
against the major NTDs.
Schistosomiasis Control Initiative
at Imperial College London
SCI was established in 2002 with a grant from the Bill & Melinda
Gates Foundation to oversee programs for schistosomiasis and soiltransmitted
helminth control. SCI worked with Niger’s Ministry of
Health and Ministry of Education, providing funding and expert
advice to the nation’s disease control program.
International Trachoma Initiative ITI was founded by Pfizer Inc. and the Edna McConnell Clark
Foundation in 1998 in response to the WHO’s call to eliminate
blinding trachoma by the year 2020. It collaborates with governments
and NGOs to implement the SAFE strategy for trachoma
elimination. ITI has been working in Niger since 2001.
Global Alliance to Eliminate
Lymphatic Filariasis
Established in 2000, GAELF is a public-private partnership involved
in advocacy, resource mobilization and program implementation
for lymphatic filariasis control. GlaxoSmithKline and Merck & Co.
have pledged the albendazole and Mectizan (Ivermectin) necessary to
achieve elimination of lymphatic filariasis. Valued at more than $1
billion, these are the largest drug donations in history.
World Health Organization The WHO is the overall coordinating health authority within
the United Nations and is responsible for providing guidance to
ministries of health. Its NTD department was established in 2006.
RISEAL A nonprofit multi-disciplinary association of scientists and technicians
that provides technical advice to developing countries in West Africa
on a variety of disease control issues.
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the government. That support was, in fact, assiduously cultivated
by SCI Director Alan Fenwick and other project leaders well before
either of the programs started. “We have gone up the political
hierarchy in both countries,” says Fenwick, “and made sure that
we have buy-in at the highest levels — and that this buy-in is
replicated at every level in the chain of command.”
As a consequence of this high-level advocacy, the presidents and
ministers of health of both Zanzibar and Niger participated in the
televised launch of their NTD control programs. The signal of
political support is of critical importance, says Fenwick. A phone
call from high up the chain of command can do much to end turf
wars and other conflicts that could interfere with swift decisionmaking
or otherwise hamper the MDA.
Managing the Integration
But not all problems are best resolved through such channels.
In Niger, for example, news of integration initially caused some
consternation in the Ministry of Health. Many within the ministry
who were working on independent control programs against
trachoma, schistosomiasis or LF feared that they would lose their jobs
with program integration. That concern, at least, was relatively easily
resolved. “The main thing we had to convey was that we weren’t
thinking that one person would now be doing three people’s jobs
in the ministry,” says Fenwick. “In fact, there would be more to do
because by rationalizing the work and bringing in more funding we
were able to expand the coverage of the control programs.”
Turf too was an issue. Dr. Amadou Garba, who oversees Niger’s
NTD control efforts, recalls that such interdepartmental tussles
were addressed by reminding the vertical program managers that
they would be better able to loosen government purse strings and
mobilize resources if they pulled together. “They recognized that,
working together, we would be much stronger in our advocacy for
mobilizing the resources of the department,” says Garba. Beyond
that, everyone was aware that the USAID support was intended
for an integrated MDA program, so collaboration was required for
funding.
The managers of individual control programs had some concerns
about strategy as well. The trachoma team worried, for example,
that with all the focus on MDA, vital elements of its own approach
to disease control would be neglected. Its particular concern was
that the WHO-recommended strategy for trachoma elimination
would get short shrift. The SAFE strategy, as it is known, includes
treatment with antibiotics. But it also encompasses eyelid surgeries
to improve vision and the promotion of facial cleanliness and
environmental improvements to minimize transmission.
To address this concern, says Garba,
program managers acknowledged
that all of the diseases being
targeted arise in some measure
from contaminated water and poor
hygiene. “We worked together,” he
says, “to elaborate some messages
on hygiene and water supply and
integrate them into the program.”
Not surprisingly, Niger’s NTD
control program today also covers,
in collaboration with the vertical
control programs, the delivery of
surgeries to address the morbidity
associated with trachoma and LF.
That is not a feature of national
NTD control plans that always
gets implemented, according to
Elisa Bosqué-Oliva, who was SCI’s
program manager for Niger.
The managers within the ministry
were not the only people whose
support was deemed critical to
successful integration. In both Niger
and Zanzibar, stakeholder meetings
Table IIb: Zanzibar
Organization Role
Ministry of Health and Social Welfare Members of the helminth control teams at the ministry have been directly
involved with implementation of Zanzibar’s integrated NTD program.
Schistosomiasis Control Initiative at
Imperial College London
SCI was established in 2002 with a grant from the Bill & Melinda Gates
Foundation to oversee programs for schistosomiasis and soil-transmitted
helminth control. SCI worked with Zanzibar’s Ministry of Health and
Social Welfare, providing funding and expert advice to the nation’s NTD
control program.
Health Foundation An independent charity dedicated to improving health care worldwide, HF
helped to fund schistosomiasis control on the islands.
Natural History Museum The Wolfson Wellcome Biomedical Laboratories at the Natural History
Museum have a research interest in NTDs, particularly schistosomiasis. Its
early work in Zanzibar led to the “Kick Out Kichocho” program.
Liverpool School of Tropical Medicine This medical college houses the nonprofit Lymphatic Filariasis Support
Centre, which serves as the Secretariat for the Global Alliance for
Elimination of Lymphatic Filariasis (GAELF)
Global Alliance to Eliminate Lymphatic
Filariasis
Established in 2000, GAELF is a public-private partnership involved in all
aspects of lymphatic filariasis control. GlaxoSmithKline and Merck & Co.
have pledged all the albendazole and Mectizan (Ivermectin) necessary for
elimination of lymphatic filariasis. Valued at more than $1 billion, these are
the largest drug donations in history.
World Health Organization The WHO is the overall coordinating health authority within the United
Nations and is responsible for providing guidance to ministries of health.
Its NTD Department was established in 2006.
Ivo de Carneri Foundation The foundation, in collaboration with the health ministry, runs a public
health research laboratory on Pemba Island, which was the focal point for
SCI’s monitoring and evaluation activities.
EU Framework 6-CONTRAST A European Union funded project, CONTRAST is investigating in
Zanzibar the role of community-led programs for NTD control.
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organized from the start of the process brought all parties together
and gave them opportunities to air their concerns, explain what
they brought to the table and what they were willing and able to
contribute to the integrated program. “Integration, in my mind,”
says Fenwick, “is communication, collaboration and cooperation.”
That cooperation is of particular importance at the district
level. Health workers at this level are essential to the planning
and execution of MDAs, since they know most about the local
conditions. That includes such things as the actual population in
their area, where the schools are located and how many vehicles,
educational pamphlets and other resources might be required
to cover the region. But because the integrated MDA program
is run by a government ministry, says Bosqué-Oliva, health
workers are only paid the government per diem, which is lower
than that of some other health initiatives active in Niger. This
can understandably influence how regional workers manage their
time, often to the detriment of ministry-run programs. High-level
endorsement — including letters sent out by senior officials of the
Ministry of Health requesting that the integrated MDA be given
top priority — prevented the program from becoming a second-tier
operation for these workers.
Engaging Community Leaders
Community leaders and local politicians are another repository
of important information, and their active participation is vital to
the successful execution of community-directed MDAs. Khalfan
Mohammed, who managed Zanzibar’s integrated NTD control
campaign, recalls that, when the Ministry of Health and Social
Welfare conducted its first MDA for LF in 2001, people in certain
pockets of the islands did not turn up to take their medicines. It
turned out that many of the stragglers in these areas supported
the opposition, and the NTD control program had neglected to
consult opposition leaders in the selection of drug distributors. The
distributors were, as a consequence, not well-known or trusted in
these areas. Coverage, says Mohammed, became far more uniform
when the program reached out to leaders across the political
spectrum before conducting the next round of MDA.
Understandably, when Zanzibar launched its integrated program
five years later it gave high priority to consultations with a variety
of local opinion leaders. This ground-level advocacy was reinforced
with a large media campaign publicizing the effort. “There was
a national sense of ownership for the program that motivated
people,” says Mohammed. “The social mobilization component
played a key role in that.”
Similarly, in Niger, grassroots leaders and authority figures like
imams and respected schoolteachers were tapped for their insights
and local knowledge. Their recommendations were taken for the
selection of voluntary drug distributors. Garba points out that,
without the support of such leaders, control programs distributing
drugs donated by Western countries can arouse deep suspicions —
not least the notion that the medicines are in fact birth control pills
(Niger has both the highest infant mortality rate and the highest
birth rate in the world) or vehicles of HIV infection.
Given the intricate web of relationships that supported the two
programs, and all that could have gone wrong in their efforts,
the community-directed MDAs unfolded remarkably smoothly.
They weren’t, however, without their weaknesses. For example,
although the prevalence of both schistosomiasis and STH was cut
drastically after the MDA in Zanzibar, both diseases later surged in
known hotspots on the islands in the absence of annual treatment.
This suggests that any future program that seeks to eliminate,
and not just control, the targeted NTDs will need to pay special
attention to health education, snail control and the construction of
infrastructure for basic sanitation and water purification. Similar
challenges face the ongoing NTD control program in Niger, where
the integrated MDAs have already reached about 60 percent of the
population, and the Ministry of Health expects to accomplish more
or less full coverage of the country in 2009, and then continue this
annually for several years.
If such gains are to be sustained, partnerships central to NTD
control in both countries will also need to be expanded. In
Zanzibar, the Ministry of Education will have to step up its
involvement in NTD control as schoolchildren become the main
targets of treatment. In Niger, the Ministry of Health has already
assumed that role, but other ministries too must now become
involved. These agencies, with their knowledge of where water
and agricultural projects are planned, could provide valuable
advance notice about the risk of disease outbreaks in various parts
of the country. Such information will doubtless play a critical
role in protecting hard-won public health gains once the mass
community-directed drug administration and other measures have
lowered NTD prevalence to manageable levels.
By Unmesh Kher
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Lessons Learned:
• Strong but flexible program management that
coordinates activities, timelines and budgets
across continents is critical to achieving success.
• Technical challenges can be overcome with a
flexible strategy that allows for collaborative
approaches by the program’s partners.
• Functional working relationships with oversight
agencies and continued open communication
can help partners meet important project
milestones.
Human Hookworm Vaccine
Initiative Designs Rapid
Deployment Strategy for
Developing World
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A global public-private partnership is in the final
stages of a product development and technology
transfer program that intends to deliver the world’s first
safe, affordable and effective hookworm vaccine to a
neglected population — an estimated 3.2 billion men,
women and children who live in impoverished rural
areas of sub-Saharan African, Southeast Asia, India and
the tropical regions of the Americas and are at risk for
hookworm infection.
At the heart of this global access endeavor is the Human
Hookworm Vaccine Initiative (HHVI), founded by Peter Hotez,
M.D., Ph.D., president of the Sabin Vaccine Institute and
distinguished research professor and chair of the Department of
Microbiology, Immunology and Tropical Medicine at The George
Washington University. The HHVI is a unique nonprofit product
development partnership with The George Washington University
and based at the Sabin Vaccine Institute in Washington, D.C., with
support from the Bill & Melinda Gates Foundation. For close to
10 years this international network of university and government
partners has built the infrastructure, capacity and the operational
expertise for research, product development, scale-up and
technology transfer of multiple candidate vaccine antigens.
The result of their collaborative activities is the successful
manufacture under current good manufacturing practices (cGMP)
of two recombinant vaccine antigen candidates and the completion
of two Phase I clinical trials in the United States and Brazil,
under the oversight of U.S. and Brazilian regulatory and ethical
review bodies. The HHVI also has inaugurated a Vaccine Testing
Center that includes a clinic and field laboratory in the state of
Minas Gerais, Brazil, the site of HHVI clinical testing activities,
and embarked on the transfer of product development process to
Instituto Butantan, a public-sector vaccine manufacturer in Sao
Paulo, which produces 80 percent of the vaccines used in Brazil.
Along the way, the HHVI has overcome challenges and learned
lessons in developing a vaccine for global access in the nonprofit
sector, specifically as they relate to product design, development
and manufacture, introduction and distribution, financing,
knowledge dissemination, and intellectual property management.
Two scientists working at the
Belo lab in Brazil.
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The HHVI, with its comprehensive approach to vaccine
development, is developing a global access roadmap for neglected
tropical diseases such as human hookworm — a guide that
continues to identify key operational and technical aspects that
are essential for a successful partnership with a developing country
vaccine manufacturer.
Hookworms: A Global Plague Affecting Billions
Human hookworm infection is a parasitic infection that causes
intestinal blood loss leading to iron-deficiency anemia and protein
malnutrition, particularly in pregnant women and children. This
disease is widespread in tropical and subtropical countries where
people may defecate on the ground and where the soil moisture
is most favorable for hookworm eggs to develop into larvae
(immature worms).
The World Health Organization (WHO) estimates hookworm
disease affects 576 million people worldwide. Once a big problem
in the Southeastern United States, hookworm disease is now largely
controlled in that country. Today, most of the people at risk live
in impoverished rural areas of sub-Saharan Africa, Southeast Asia,
India and the tropical regions of the Americas.
Hookworm is transmitted via contact with infective third-stage
larvae that penetrate through the skin, frequently entering through
the hands, feet, arms or legs. Infective third-stage larvae also can be
ingested where they migrate to the lungs, are expelled by cough and
swallowed into the intestine to become adults. Adult hookworm
parasites attach to the small intestine and cause intestinal blood
loss, often sufficient to cause anemia and malnutrition. In children,
the WHO reports that chronic hookworm infection impairs
physical and intellectual development, reduces school performance
and attendance, and adversely affects future productivity and wageearning
potential.
Today, hookworm infection is controlled with deworming drugs
that have high rates of failure, re-infectivity and potential drug
resistance. However, there is evidence that a safe and cost-effective
vaccine could provide an important new tool for the control of
human hookworm infection.
HHVI: A Global Public-Private Partnership
with a Mission
As a nonprofit private development (PD) public-private partnership
(PPP), the HHVI is achieving successes in its development of a
recombinant vaccine for human hookworm infection by engaging
a network of collaborative partners with complementary strengths
under the guidance of Hotez, its director. With institutions in
North and South America, Europe, Asia and Australia, the HHVI
has devised a virtual interactive framework with strong program
management that coordinates activities, timelines and budgets.
“Unlike the traditional PD-PPP with a reliance on outside
contractors, the HHVI also has built an in-house capacity for
antigen discovery, preclinical testing, technology transfer and
clinical development within its network of nonprofit entities,
academic institutions and governmental organizations,” says Ami
Shah Brown, Ph.D., M.P.H., director, vaccine operations for the
HHVI, who jointly coordinates activities and timelines for the
technology transfer program with Maria Elena Bottazzi, Ph.D.,
director, product development, HHVI.
The HHVI’s existing partnerships are based on longstanding,
established academic collaborations between The George
Washington University in the United States, the Oswaldo Cruz
Foundation in Brazil, London School of Hygiene and Tropical
Medicine in England, Institute of Parasitic Diseases in China
and Queensland Institute of Medical Research in Australia. The
largely academic structure morphed from an academic program to
a vaccine development program when the Sabin Vaccine Institute
became involved in 2000. Instituto Butantan was the most recent
addition to the partnership as plans for technology transfer and
global access evolved.
“We’ve adopted this strategy to see whether we can shorten the
time between bench discovery and the point where a promising
vaccine candidate can be tested in the clinic,” adds Brown.
To date, successes realized by the HHVI in its mission to reduce
human suffering from hookworm can be attributed to the strengths
and capabilities each member brings to the partnership, as well as
the choice of Brazil for manufacturing and clinical testing.
“Brazil is an innovative developing country, a middle-income
country with a modest economic capacity but a high capacity to
develop, patent, manufacture, ensure safety, market new health
Canine hookworm
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products and to develop, test and introduce new health policies
that support products,” says Bottazzi. “Also, there are a large
number of people living in certain areas of Brazil who suffer from
hookworm infection.”
Management and Administration
• Sabin Vaccine Institute — Chartered as a nonprofit
organization to reduce human suffering from infectious
and neglected tropical diseases by providing greater access
to vaccines and essential medicines through programs of
vaccine research, development and advocacy, Sabin provides
management, regulatory affairs and quality assurance activities
for the HHVI collaborators.
Discovery and Testing
• The George Washington University — Staff in this
Washington, D.C., university’s Department of Microbiology,
Immunology and Tropical Medicine develops processes for
the expression, manufacture, scale-up, formulation and testing
of the hookworm vaccine candidates. These processes are
designed to maximize manufacturing yields and minimize
costs, both essential elements for a product intended for the
world’s poor.
• Queensland Institute of Medical Research — This university
team, based in Brisbane, Australia, performs research and
development activities primarily for candidate antigen early
evaluation, characterization and ranking. Staff pursues and
evaluates alternative methods to challenges encountered during
antigen discovery and early feasibility of expression, which
generate and maintain supporting data for the pipeline of
candidate antigens.
• Institute of Parasitic Diseases — Located in Shanghai and part
of the Chinese government’s Center for Disease Control and
Prevention, its staff conducts preclinical testing.
Modeling and Analysis
• London School of Hygiene and Tropical Medicine — Part
of the University of London, Britain’s national school of
public health provides the HHVI with needed statistical
and epidemiologic models and cost-effectiveness analysis for
vaccine introduction, distribution and financing — data that
are imperative to estimate the global health impact that a
hookworm vaccine could have.
Manufacturing and Testing
• Oswaldo Cruz Foundation (FIOCRUZ) — Under a
collaborative agreement with the HHVI, this science and
technology health institution, which is attached to the
Brazilian Ministry of Health, provides the epidemiological
assessment, as well as the clinical testing and development of
the hookworm vaccine.
• Instituto Butantan — A public-sector vaccine manufacturer
under agreement with the HHVI, this biomedical research
center affiliated with the São Paulo state secretary of health is
involved in technology transfer, scale-up process development
and clinical grade manufacture of the hookworm vaccine. It
provides qualified cGMP facilities, experienced staff and a
history of successful collaborations.
HHVI’s Challenges and Lessons Learned
Since January 2000, when Sabin’s Vaccine Development Program
launched the HHVI, challenges have surfaced: programmatic
transitions, financial resources and risk management, as well
as geographic distance, time zones, and differences in culture
and language. But the program has and continues to overcome
them with a flexible and committed approach to continuous
communication, strong technical capacity and infrastructure,
quality management, respect for autonomy, and transparency in
decision-making. Its successes are based on a fundamental belief in
strong partnerships and collaborations, shared intellectual property
and ownership of discoveries, and a management framework
coupled with careful technical planning.
The Sabin Vaccine Institute management team learned that
strong operational, regulatory and quality-assurance management
based on expertise, open and regular communication between
partners and well-planned and documented strategies are essential
components for a successful vaccine development program.
Faced with significant product development challenges commonly
associated with vaccine development programs — problems
in small-scale expression of promising antigens, yield, purity,
stability of proteins during process development, scale-up to
cGMP manufacture, sterility after during cGMP manufacture,
and stability of the recombinant proteins over time — The
George Washington University researchers learned to explore
alternative technologies, including bacterial, insect cell and
plant-based expression systems. While these alternative systems
present regulatory challenges, the team has found that it can
perform detailed risk assessment analyses to minimize delays in the
transition to the clinical development phases.
Major challenges during the research and development phase,
including how to determine what vaccine antigen candidate
is ready to transition into the product development, led to
complementary scientific approaches. HHVI and The George
Washington University pursued activities in addressing the
expression and purification of a soluble form of one of the lead
antigens in high yield, while Queensland Institute of Medical
Research took a second approach, using a panel of monoclonal
antibodies to target early evaluation, characterization and ranking
of candidate antigens. The staff at Queensland Institute of
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Medical Research also pursues and evaluates alternative methods
to challenges encountered during antigen discovery and early
feasibility of expression, which is generating and maintaining
supporting data for the antigen candidate pipeline.
An absence of vital data required the London School of Hygiene
and Tropical Medicine team to conduct a thorough quantitative
assessment of the global hookworm disease burden before it could
provide a cost-effectiveness analysis for the hookworm vaccine.
Approval to begin clinical testing of an investigational vaccine
in the developing world is a multi-step process. For example,
in Brazil the process requires regulatory approval by ANVISA,
Brazil’s equivalent to the U.S. Food and Drug Administration, and
ethical approval by a local ethical review committee affiliated with
the institution where the research is conducted, and by CONEP,
Brazil’s national ethical review committee.
FIOCRUZ has learned that
functional working relationships
with oversight agencies and
continued open communication
can help partners successfully
achieve downstream project
milestones.
As for a successful transfer of
product development processes
to organizations such as Instituto
Butantan, the partners found
that a framework for operational
management and careful technical
planning can overcome issues
with quality control, the ability
to achieve goals and objectives
efficiently and economically,
which can often become
stalled by evolving ethical and
regulatory requirements, as well as
inconsistent standards, practices
and criteria.
“We created this framework to
enable the shift from a largely
academic program focused on
discovery and research to a
program focused on development
and rapid movement of a
promising vaccine candidate from the bench into clinical testing in
humans,” Brown says. “The operational management and technical
planning are tools that we have had to use to effectively manage
a varied set of partners to focus on a common goal. We tend to
avoid getting caught up in ethical and regulatory requirements and
inconsistent standards by staying actively involved and engaged in
both realms.”
Shaw and Bottazzi are kept abreast of changes through their
Brazilian colleagues at FIOCRUZ and Instituto Butantan, which
allows them to respond accordingly. They’ve found this often
leads to an additional set of questions, but it keeps the important
dialogue moving forward.
Hookworm research work being conducted
at the Belo lab in Brazil
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Open communication and realistic timelines also can overcome
significant delays in timelines and milestones due to regulatory
requirements, which initially hindered the prompt exchange of
materials between the Institute of Parasitic Diseases and The
George Washington University.
HHVI’s Global Access Roadmap
The HHVI partnership has developed a strategy that is designed to
permit the rapid deployment of the human hookworm vaccine to
the developing world once efficacy has been shown. It emphasizes:
• A global health solution available at affordable prices to those
most in need in the developing world
• Knowledge gained through discovery that is promptly available
to the global scientific community
“The Human Hookworm Vaccine Initiative is the story of the
struggle of developing products and technologies in the United
States for the transfer to developing countries for manufacture and
clinical testing in the near term and building capacity for the entire
vaccine development process for the long term,” says Brown.
Adds Bottazzi, “When we first started doing our first HHVI
viability assessments, we recognized that this endeavor to develop
a vaccine for the developing world would always be a challenge.
But we also recognized that if we engaged parties in both
the developing and the developed world, we could overcome
anticipated and unforeseen challenges.”
By David Perilstein
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Faster, Better, Cheaper:
New Vaccine Promises to
Control Japanese Encephalitis
Lessons Learned:
• Collaborative efforts can help facilitate the
meeting of international development standards
and World Health Organization prequalification
requirements.
• Detailed epidemiologic and vaccine efficacy
studies provide the justification for conducting
public vaccination programs.
• Successful mass vaccination programs are greatly
facilitated by a single-injection vaccine.
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Japanese encephalitis (JE) is caused by a mosquitoborne
virus similar to West Nile fever. Epidemic to
endemic in East Asia (see map), JE is the leading viral
cause of neurologic disease on that continent. Some
30,000 to 50,000 symptomatic, febrile cases occur
annually, mostly in children under 15 years old. There
are 10,000 to 15,000 deaths among these cases. The
virus is fatal 30 percent of the time when it invades
the brain. At least half the survivors suffer permanent
intellectual or motor impairment. There are no antiviral
treatments available.
Mosquito control has not proved effective in reducing JE’s disease
burden, largely because the Culex mosquito that spreads JE is very
widespread — its breeding areas include irrigated rice paddies. It
also has a 10- to 12-day replication cycle; spraying would have
to take place in each cycle. A vaccine for JE was invented in the
1940s, but supplies have always been limited and comparatively
expensive. (Immunization costs from $12 to more than $300 per
dose depending on the country.) In addition, this vaccine is not
very immunogenic; it requires three vaccinations for high-level
protection plus boosters every year or two. The vaccine, composed
of mouse brain-derived inactivated virus, carries with it the risk
of serious allergic reactions as well as neurologic side effects.
Still, sustained vaccine campaigns, where conducted, have been
successful in controlling JE (see graph, next page).
An alternative JE vaccine appeared in 1988. It was produced by
several Chinese manufacturers including the Chengdu Institute of
Biological Products (CDIBP). This live, attenuated vaccine, known
as SA 14-14-2, requires only one or possibly two vaccinations to
provide long-lasting protection. Despite its advantages, distribution
has been largely restricted to China. The Chinese pharmaceutical
industry has historically concentrated on its huge domestic
market, which annually consumes 50 million doses of SA 14-14-2.
According to Lingjiang Yang, CDIBP’s manager for international
business and cooperation, “We wanted to internationalize the
The government of India initiated mass
JE vaccination campaigns in 2006.
Photo provided PATH
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vaccine from the very beginning. We went to international
meetings, and we consulted with the WHO [World Health
Organization]. We received licenses for South Korea and Nepal
and conducted studies there.” Yet progress was slow until Chengdu
entered a partnership with the Seattle-based nongovernmental
organization PATH.
PATH Provides the Missing Ingredient
PATH started in 1977 with a mission to bring new contraceptive
methods to women in poor countries. It has since expanded to
other health issues and has a network of offices around the world.
Its current budget approaches $200 million per year.
One of PATH’s interests is in vaccine development and
distribution. The organization received a 1998 grant from the Bill
& Melinda Gates Foundation to support its Children’s Vaccine
Program, which worked on improving childhood immunization
options for a broad range of diseases. PATH’s JE project grew
out of that effort. In 2003, the project received its own Gates
Foundation grant. (The grant ultimately totaled $35 million spread
over six years.)
“We first targeted disease awareness because JE was seriously
underdiagnosed,” recalls John Wecker, the JE project’s current
director. “We did epidemiological surveillance, bringing in new
diagnostic technology. Surveillance is critically important in
advocacy because countries are often unaware there is a problem
until faced with the data.”
Then it was a question of finding a suitable vaccine. Although there
were several new JE vaccines under development, the only one
ready for mass immunization campaigns was CDIBP’s SA 14-14-2.
The program’s staff visited Chengdu in 2004 to discuss the vaccine’s
status with CDIBP officials. China, Nepal and South Korea had
approved CDIBP’s vaccine, but the question remained whether
the previously collected data and the present manufacturing
facility met international standards. Without national regulatory
approvals, the vaccine could not be distributed in other countries.
CDIBP wanted the vaccine to receive prequalified status from
the WHO. Prequalification would allow international donor
agencies to purchase the vaccine for public programs in developing
countries. PATH was already working closely with WHO on JE
epidemiology, and this interchange expanded to include studying
the CDIBP vaccine.
“PATH offered to conduct clinical trials and help build a new
WHO-compliant production facility. In turn, CDIBP agreed to a
very good price. It was a win-win situation,” says Mansour Yaïch,
the JE project staff member responsible for the relationship with
CDIBP.
The 20-year price contract that PATH negotiated with CDIBP in
2005 to 2006 covers vaccination programs in countries with a per
capita gross national product of less than $1,000 per year. There
are 14 Asian countries at this low level, including India. CDIBP
committed itself to providing the vaccine at a specified minimal
factory-gate price for these countries’ public vaccine programs.
“The price will be similar to the measles vaccine, 20 cents or 25
cents a dose,” says Yaïch. The only allowed price increases are those
needed to keep up with inflation and changes in currency exchange
rates. Yaïch concludes, “Our agreement will enable countries to
make a long-term plan for JE vaccination.”
JE Outbreak in India
PATH and CDIBP cemented their collaboration just as India was
experiencing a spike in JE cases. About 1,800 JE-related deaths
resulted from the late-2005 outbreak. Most of these deaths were
among children living in Northeast India along the Nepal border.
The striking increase in mortality put considerable pressure on the
Indian government to launch an immunization campaign before
the next monsoon — and mosquito — season, which lasts from
June to September.
Indian manufacturers only produced the old, inactivated vaccine,
and their production capacity was low. PATH, with its large preexisting
staff in India, was able to connect the national government
with CDIBP. Chengdu provided 13 million vaccine doses to launch
an immunization campaign the following summer. India went on
to immunize 45 million children over the next three years, with the
goal of vaccinating 100 million by 2011.
“The 2005 outbreak was a special case,” says Yang. “PATH
put us in contact with the Indian government and assisted in
gaining acceptance of the vaccine.” PATH then helped the Indian
government organize the immunization campaign, including the
publication of training materials for health care personnel.
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New Clinical Studies
JE Project Spokeswoman Deborah Phillips says, “Our primary goal
was to empower the countries to decide whether JE vaccination
programs were suitable for them.” The Indian situation helped
PATH and CDIBP do just that. It provided a large store of data on
the vaccine’s efficacy and safety in a non-Chinese population.
A WHO vaccine safety committee in late 2006 reviewed safety data
from the 9.3 million children vaccinated in the summer of that year
and advised that the vaccine had an acceptable safety profile. Sixtyfive
serious adverse events were reported, including two clusters of
encephalitis-like syndromes, but the committee judged that these
were unrelated to the vaccine. The committee concluded by calling
for further, more rigorous safety monitoring.
The Indian government set up a postmarketing study that
has followed 1,400 vaccinated children. This ongoing study is
monitoring the level of immunity as well as safety over the course
of one year postvaccination. Another Indian study is checking
whether there is any possibility that the weakened JE vaccine strain
will revert to wild type and cause disease. This is a concern raised
by clusters of encephalitis like the ones noted in 2006, although
the WHO Safety Committee found that any link to the vaccine
was unlikely. In 2005, the same committee noted that the genetic
differences between the live and attenuated strain seem too great
for reversion to occur.
A third study, conducted with PATH cosponsorship, is comparing
the incidence of JE in a vaccinated juvenile population and a
matched unvaccinated group. “We need to show the Indian
government that it is getting its money’s worth. That will convince
it to maintain the JE vaccination program over the long term,”
observes Wecker.
PATH has carried out two clinical trials of the vaccine along with
local investigators. One in the Philippines studied the ability to
coadminister JE and measles vaccines (ideally at age nine months).
Coadministration would be a great convenience for vaccination
programs and parents alike. There is, however, a concern that
concurrent vaccination will interfere with the immune responses
to each vaccine. The WHO committee in 2005 asked for more
information on this question. The Philippines trial enrolled 600
children and randomized them to receive both vaccines either
separated by a month or together. The results indicated some
interference with the measles vaccine response at one month postvaccination.
There were no differences between trial arms after one
year. PATH continues to follow participants and measure longterm
protection.
Another issue raised by WHO involves the interchangeability of
the live and inactivated vaccines. Many children have received
the inactivated vaccine, which requires frequent boosters. What
happens if the live vaccine is given instead of the booster? Using the
live vaccine might prove better or worse as a booster. A PATH trial
in Sri Lanka is studying this question in 570 Sri Lanka children
previously vaccinated with the inactivated JE vaccine through that
country’s extensive JE immunization program.
Boosting Production Capacity
CDIBP’s original manufacturing plant for the SA 14-14-2 vaccine
left several things to be desired. One, it did not have the extra
capacity to satisfy international demand. Two, it did not meet
the WHO’s stringent standards for good manufacturing practices
(GMP). The vaccine could not receive WHO prequalification until
those standards are met.
The WHO GMP manual is 400 pages long. It covers the range
of pharmaceutical products, giving detailed descriptions of
manufacturing practices that best ensure high-quality products that
are free of contamination. Plant design — including cleanliness
and hygiene, inspection and testing, packaging and labeling, and
storage — has to take GMP goals into account. Job descriptions
and production procedures have to be documented in detail, with
personnel carefully trained to fulfill their assigned tasks. Lastly,
there has to be meticulous documentation at every step that the
proper practices were followed.
With technical support from PATH, CDIBP undertook the
construction of a completely new plant for the expanded
production. CDIBP financed the construction, and PATH in
2007 contracted with a French engineering company, Technip, to
Geographic distribution of Japanese encephalitis
Source: U.S. Centers for Disease Control and Prevention
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manage design, construction and equipment acquisition to meet
GMP standards. PATH also hired a number of consultants to
advise on vaccine manufacturing.
Yang says, “In China nobody has achieved GMP standards. We will
be first. This accomplishment is very important for the Chinese
vaccine industry. It will be a model for other companies.”
The facility was supposed to open in 2008 but was delayed by
the earthquake that year in Sichuan. As of the summer of 2009,
the completed plant was undergoing validation testing and
refining its manufacturing practices. The WHO-required GMP
documentation was in process, too. CDIBP’s engineers meanwhile
were planning the shift of production from the old to the new
facility. When online, the unit will be able to produce 50 million
vials a year, with each vial containing one or five freeze-dried
vaccine doses.
Toward Control of Japanese Encephalitis
This partnership has run smoothly so far, not counting the
earthquake. The main issues were that the CDIBP was not capable
of collecting the data needed for WHO prequalification, nor
could it build a high-capacity plant on its own that would meet
WHO’s GMP standards. PATH provided funding and expertise
to achieve these two ends. The main hurdle was negotiating the
details, including the guaranteed price. But the goal of expanding
distribution of the Chinese JE vaccine suited CDIBP as much as
PATH, so there were no real disputes. The test of the agreement’s
durability will come in the course of meeting high demand for the
vaccine over the years
PATH’s JE grant from the Gates Foundation ends in 2009. The
organization’s role will be diminished after that, but it will still
contribute to advancing the vaccine. “Next year will be very
critical,” says Yang. With PATH’s assistance, CDIBP plans to
apply for WHO prequalification in 2010. By the end of 2009, it
will meet with WHO officials in Geneva to go over its plans. The
pricing agreement with PATH will remain in force until 2026. A
joint PATH-CDIBP steering committee that meets annually will
review vaccine issues.
PATH’s Yaïch concludes, “For me this is really a South-South
partnership involving China, India and other Asian countries. It
will be self-sustaining. The PATH project is ending except for some
residual regulatory activity. Then the company and the countries
will be on their own.”
Countries that need assistance in funding and launching
immunization programs can obtain it from a number of
international and national aid programs, including USAID,
UNICEF and the Global Alliance for Vaccines and Immunization
(GAVI). Unlike polio or small pox, JE will persist even if there
is universal vaccine coverage. The virus establishes “amplifying”
populations in animal hosts, notably pigs and wading birds, which
support the disease’s spread (see figure below). Human vaccination
will be necessary in high-risk areas for the foreseeable future.
Three other JE vaccines — sponsored by large European
and Japanese pharmaceutical companies — are in advanced
development. In 2009, one of these, an inactivated version of the
SA 14-14-2 strain, received regulatory approval in the United
States, Europe and Australia. The new vaccines are expected to
initially fill a different marketing niche than CDIBP’s product.
Yaïch says, “CDIBP has a very affordable price. The other
vaccines will come to market at $10 or $20 per dose in developing
countries. Their producers are targeting middle-class populations
that receive their vaccines in the private sector. These companies
will not start with the production capacity that CDIBP has.” If
their prices eventually become competitive, the new vaccines will
add to the tools available for public JE control programs.
PATH is establishing an international JE working group with
WHO and other organizations associated with the JE project. The
working group will provide a permanent platform for promoting
JE vaccination. Japanese encephalitis vaccines have come a long
way since the 1940s. Keeping the disease under control will
nevertheless require a sustained effort. With the technical and
economic issues resolved, the sustainability of political will is now
the prime question.
By David Gilden
Japanese encephalitis transmission cycle
Source: TF Tsai 1994, via PATH
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Lessons Learned:
• Because of differences in stakeholders’
organizational styles and cultures, agreement
on a clear, common purpose is critical to a
successful collaboration and ongoing knowledge
sharing may require continuous effort.
• Inadequate funding can leave individual
partners stretched too thin and thus slow
results.
• Helping local medical communities recognize
the advantages of new health care technologies
will enable effective rollout.
Multi-Pronged Attack on Cervical
Cancer Detection Seeks to Speed
Detection and Treatment in
Resource-Constrained Countries
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Cervical cancer kills approximately 270,000 women
each year with nearly 85 percent of those deaths in
resource-poor settings. Routine cytological screening
of women, commonly known as the Pap smear,
has resulted in a dramatic decline in cervical cancer
deaths over the past four decades in wealthier regions.
However, screening has been much less successful in
developing regions. A key reason for continuing high
mortality in the developing world is the shortage
of practical and cost-effective, yet still high-quality,
precancer screening programs. Existing tests are
prohibitively expensive and too technical for lowresource
settings.
New technologies that allow alternative screening methods could
help overcome this obstacle. To this end, PATH developed close
partnerships with several, very different organizations to launch a
multi-pronged approach to solving the problem.
In 2000, an effort to investigate sustainable alternatives to Pap
became the Alliance for Cervical Cancer Prevention (ACCP);
member organizations included EngenderHealth, the International
Agency for Research on Cancer (IARC), Jhpiego, the Pan
American Health Organization (PAHO) and PATH, which acts
as the coordinator. Recently the alliance expanded to include
three additional members. The ACCP, with support from the Bill
& Melinda Gates Foundation, worked closely with the World
Health Organization, Harvard University, and governmental
and nongovernmental partners in Africa, Asia and Latin America
on a coordinated research agenda aimed at assessing a variety of
approaches to cervical cancer screening for low-resource settings.
The goals were to improve service delivery systems, ensure that
community perspectives and needs were incorporated into program
design, and heighten awareness of cervical cancer and effective
prevention strategies.
After initial friction generated by competitive natures and role
misunderstandings, the details of a clear, common purpose and
ACCP, CCA, PATH and others agree that the
best strategy for rapidly reducing deaths due to
cervical cancer is a comprehensive prevention
approach, focusing both on screening of adult
women and vaccination of adolescent girls.
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roles for each partner were negotiated and carefully articulated over
the first couple of years to help coalesce the ACCP. Trust between
the partners built over time, making it easier to resolve issues as
they arose. The group also agreed early on to operate under the
single Alliance logo, rather than vie for positioning of their separate
logos, which has helped build cohesiveness. Even so, partners are
listed individually in the body of documents and printed materials
so that some individual recognition is retained.
In the nine years since inauguration of the project, the ACCP
partners conducted studies comparing a number of screening
techniques including cytology (Pap), visual inspection methods
with acetic acid (VIA) or Lugol’s iodine, and a HPV DNA test.
The tests were evaluated in more than 20 low-resource settings
around the world.
VIA and HPV DNA testing have proven to be of special
interest. The ACCP found that VIA compares well to cytology
in terms of sensitivity for disease detection, yet presents clear
advantages because it requires fewer specialized personnel and less
infrastructure, training and equipment. Cervical cancer screening
using VIA can be offered in remote, less-equipped clinics, thereby
reaching more women. Another important advantage is that VIA
provides immediate results, making it possible to screen and treat
women during the same visit. Immediate treatment means that
women do not have to make an extra visit to the health center
— this reduces the number of women who are lost to treatment
because they cannot return for one reason or another.
Even so, recent data suggest that a new, low-cost HPV
test specifically designed for low-resource settings has
much better performance than either cytology or VIA
(see below).
In 2003, PATH launched a second related initiative:
the Screening Technologies to Advance Rapid Testing
(START) project designed to develop two different
biochemical HPV screening methods appropriate
for use in the developing world, including the lowcost
HPV DNA test previously mentioned. It was
important that the tests be acceptable to women and
their providers, relatively simple to use, accurate, and
affordable; cultural sensitivities to medical tests being
performed on the genitals or by male doctors on female
patients were of concern, therefore the testing method
had to be made acceptable to the population. In
addition, diagnosis and treatment, if indicated, should
be possible during the same screening visit.
In this effort, PATH developed close partnerships with
the commercial medical diagnostics company Digene,
since purchased by QIAGEN, and the World Health Organization
(WHO). Digene/QIAGEN needed access to cervical smear samples
from countries of interest, and needed PATH to manage field
research with local institutions.
PATH needed an industry partner to develop the technology
and for future manufacturing and distribution of the test.
WHO, a research and advocacy partner, was keenly interested in
technologies that could bring precancer screening to poor women.
Further, WHO plays a regulatory role, and will assess the new test
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for international procurement by United Nations (UN) agencies,
such as the United Nations Population Fund, and will prequalify
the manufacturer of the product — thus significantly increasing
access to the test worldwide.
PATH is also partnering with Jhpiego, a not-for-profit agency
affiliated with The Johns Hopkins University, to lay the foundation
for future introduction of the new test through creation of a
network of in-country training excellence centers focused on VIA
and cryotherapy.
By early 2007, PATH and QIAGEN had developed and fieldevaluated
a new, highly sensitive HPV DNA test that is portable,
could be powered with rechargeable batteries and uses reagents that
do not require refrigeration. Test results are available in less than
two-and-a-half hours, facilitating immediate treatment or referral
in the same visit.
In developing countries, however, several challenges impede
widespread adoption of new technologies. Before incorporating the
HPV DNA test into national cervical cancer prevention strategies
and plans, ministries of health need evidence that the new test is
feasible and appropriate for their health system infrastructure and
their geographic, cultural and economic circumstances. In addition,
private industry needs guidance in navigating the complexities of
product introduction in the public sector of developing countries,
which are generally perceived as high-risk, low-return markets.
To address these issues, in November 2007, PATH inaugurated a
follow-up project to START, called START-UP.
And Then There Were Three
Cervical Cancer Action (CCA) is yet a third coalition of
organizations with diverse connections to the prevention of cervical
cancer in the developing world, specifically to immunization,
cancer, sexually transmitted diseases and reproductive health,
women’s health, and HIV/AIDS. This group coalesced to advocate
for equitable and rapid access to new lifesaving technologies to
prevent cervical cancer in these countries, specifically better and
less expensive methods of screening adult women for signs of precancer
and provision of HPV vaccines to protect girls.
CCA was created in 2006; founding members include PATH,
PAHO, the American Cancer Society, the International Planned
Parenthood Federation, Cancer Research UK, the International
Union Against Cancer, the AIDS Vaccine Advocacy Coalition,
the International AIDS Vaccine Initiative, and the International
Federation of Gynecology and Obstetrics. CCA has been designed to
avoid duplicating the activities of any member organization or taking
on activities that member organizations, or other groups, are better
able to fulfill. The work of CCA is grounded in public health science,
but also evokes arguments related to economics and global equality
of access.
The CCA partners recognized that, unless there is coordination
and cooperation on a common, forward-looking mission to ensure
access to the new tools, the potential for real progress in reducing
the global burden of disease will be unfulfilled.
Certain conditions must be in place for these new prevention
technologies to become available and be effectively used in
developing countries:
• Strong scientific and public health leadership by leading
international health agencies and organizations
• Sustained political leadership and financial commitment for
a comprehensive approach to appropriately and effectively
vaccinate girls and screen and treat women
• Partnership among diverse constituents of civil society, health
professionals, medical associations, researchers, donors and
governments to support widespread access to these new tools
• Adequate supplies of the full range of HPV and cervical cancer
prevention tools from the manufacturers at affordable prices
• Leadership and action by multi-lateral agencies, including
rapid prequalification, issuance of international guidelines and
large-scale procurement for developing countries.
CCA activities have been limited by its funding model. It has
not been able to raise external funding but instead functions on
cash and in-kind contributions from CCA Governing Council
members. Lack of external funds may be, in part, a result of
the decision early on not to solicit or accept funding from the
pharmaceutical industry, even though CCA members felt that such
funding may have been relatively easy to access. The Governing
Council adopted this position to avoid any perception of conflict of
interest in its mission.
The funding CCA has obtained from some of the nine Governing
Council members over the past two years has been used to support
a small but very active secretariat. CCA members recognize the
utility of maintaining a dedicated secretariat, but it is unclear how
sustainable this shoestring budget system will be in the future.
Aside from the efforts of the secretariat, all CCA work is carried
out by members of the CCA Governing Council. These volunteers
have primary duties that sometimes force them to put CCA tasks
at lower priority. It is more difficult for some members to allocate
time to CCA than for others.
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Challenges of the Three Efforts
The three initiatives share goals but incurred separate challenges;
some obstacles were due to the nature of the partnership, others
were due to the nature of the work.
In the case of the Alliance for Cervical Cancer Protection, the
groups were brought together because of their interest in cervical
cancer prevention in the developing world, but not necessarily
because they were driven to work as part of a strong alliance. A lack
of attention to the collaborative/coordinated work of the alliance in
the early days led to friction — ACCP scientific and programmatic
discussions often were contentious and maintaining the partnership
seemed in doubt on several occasions.
For example, while some of the partners had more of a research
perspective, others were more focused on practical programmatic
approaches. This led to different tolerances for uncertainty in
the data related to use of visual inspection as a primary screening
method and use of a single-visit approach to screening and
treatment. Partners were also influenced in part by the prevailing
opinions and political climate of the regions where they worked.
It is possible that ACCP achievements could have been more
extensive had the partners agreed at the start to a coordinated
research agenda. However, given early differences in organizational
visions, the ways that the funding was dispersed and individual
personalities, agreement on an overall agenda did not seem likely.
Over time collaboration became easier. As the evidence base grew
during the following years, the partners defined their respective
roles and became accustomed to working together. In short, trust
levels increased, and the ACCP’s collective vision became more
aligned. By 2007, ACCP partners were able to articulate and
broadcast a clear set of 10 recommendations endorsed by all.
The ACCP is now exploring how a cervical cancer screening visit
can serve as a core building block for a broader menu of health
services needed by women in their 30s and 40s, such as screening
for cardiovascular disease, breast cancer, and diabetes; management
of symptoms of menopause; and other services largely unavailable
in developing countries, but which address increasingly important
public health problems.
The START program initiative and its sequel, START-UP, faced a
number of obstacles. A key challenge for QIAGEN, the industry
partner, is to develop a business model that allows the marketing of
two types of HPV DNA tests — one more technologically complex
than the other and, thus, with different pricing tiers — in different
parts of the world.
Another key challenge came from medical communities. One
aspect of country mobilization is engagement of the community
of reproductive health care providers in the country, including
the obstetrics-gynecological community. These clinicians and
researchers, many of whom are very comfortable with Pap smear
testing in urban settings, may see Pap and subsequent diagnosis
as gold standard medicine and may, in fact, make a living from
cytology. Many have not seen the results of alternative strategies
with their own eyes and remain skeptical about those alternatives.
To address these needs, PATH, Jhpiego and WHO are continuing
to promote their findings in professional journals, at international
meetings and through personal contacts in the hopes of moving
influential professionals towards a new paradigm of cervical cancer
screening in low-resource settings.
For Cervical Cancer Action, progress toward comprehensive
prevention and control has been substantial, despite key challenges
including the high current price of HPV vaccine in the private
sector and lack of global success implementing large-scale cervical
cancer screening in low-resource settings. However, the GAVI’s
recent interest in subsidizing HPV vaccine and encouraging results
using less-expensive and more rapid screening tests is galvanizing
the effort. The global conversation has evolved to the point that
country-focused discussions can become a major theme over the
next few years.
Coming to Agreement
Some member organizations are constrained in the kinds of
agreements they can sign with others. This is especially true of
UN agencies. It is for this reason that neither WHO nor IARC
felt they were able to join the coalition. UN member PAHO was
able to join, but cannot enter into some of the agreements shared
by all other groups. The coalition has had to craft agreements to
accommodate these circumstances accordingly.
By Pam Baker
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Links for Life Integrates
Programming for Food Security,
Nutrition and HIV/AIDS
Lessons Learned:
• Knowledge sharing through “learning
communities” is the key component to integrating
programs that can affect change.
• Success depends on participants having the
mechanisms to regularly explore ideas, think
together and share relevant knowledge across
local, regional and national boundaries.
• A program dependent on volunteers is challenged
by inconsistent levels of participation.
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The epidemics of HIV, hunger and poverty are
inextricably linked. Throughout Africa, these singularly
threatening assaults have converged to form a perfect
storm that affects the lives and livelihoods of individuals
and inhibits families and communities from taking care
of their most vulnerable members.
Good nutrition has been called the key to positively living with
the HIV virus. When malnutrition prevails, the immune system is
weakened and susceptibility to infections increases.
“Although antiretroviral therapy (ART) is becoming increasingly
available, treatment can fail when patients are nutritionally
compromised,” say Gwenelyn O’Donnell-Blake, food security
technical officer at Project Concern International (PCI). “Without
nutritious food to complete treatment, patients are often too ill to
successfully start ART. And, once on treatment, interruptions due
to hunger contribute to treatment failure and drug resistance.”
To promote learning and advocacy around integrated HIV and
food/nutrition security (FNS) programming, PCI and its many
nongovernmental organization (NGO) partners initiated Links for
Life, a multi-faceted development program.
Communities of Practice
Links for Life was conceived at the Africa Forum 2006, a gathering
of NGOs and international health and development organizations
from across the continent. A total of 220 practitioners from 16
countries attended this hands-on, skills-building conference that
focused on sharing up-to-date knowledge in integrated HIV and
FNS programming.
In June 2006, groups of practitioners that attended the Africa
Forum started meeting to continue sharing their experiences with
integrated programming in their own countries. Without formal
support and funding for these meetings, efforts toward continuous
sharing were short-lived. These efforts, however, led to the Links
for Life Communities of Practice (CoPs), which is currently being
piloted in Ethiopia and Malawi.
Photo by Shutterstock® Images
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These two CoPs, also known as “learning communities,” promote
organizational learning and help identify emerging practices in HIV
and FNS programming in Ethiopia and Malawi. Led by experienced
facilitators hired by Links for Life, CoP members from NGOs,
government and academic institutions working in HIV and FNS
programming meet to share their programmatic experiences and to
document what they are learning from being part of the CoP.
One of the first steps toward establishing the Ethiopia and
Malawi CoPs was to set up the Steering Committee to oversee
the communities’ inception and nurture their development.
The committee first convened for a strategic planning session in
September 2007 via a teleconference led by O’Donnell-Blake. The
committee developed the concept, put together a fundraising plan
and formulated a timeline for the initiative. Steering Committee
members include international NGOs and academic and research
institutions that work in HIV, food and nutrition security and
are also committed to promoting “integrated” HIV and FNS
programming. (A full list of Steering Committee members appears
near the end of this article.) Partners spent the next few months
securing funds to support the CoPs.
By April 2008, the Links for Life CoPs were up and running.
Practitioners attended regular meetings and learning events where
they decided on criteria for identifying promising practices in
integrated programming and set out to review some of their own
projects, as well as projects implemented by nonmembers. They
interviewed project staff and beneficiaries and reviewed monitoring
data to assess whether projects were sustainable, exhibited social
acceptance by their community, were cost effective, empowered
beneficiaries, addressed the underlying causes of poverty and met
other specific criteria set by CoP members.
“The most beneficial aspect of the CoPs is being able to gather
technical implementers from the same country to look at what is
working well,” says Tina Lloren of Save the Children Federation.
“[The CoPs have] strengthened the collaboration among incountry
networks. Equally important, the lessons learned will be
shared at the Africa Forum 2009, thus spreading the wealth of
knowledge beyond the countries’ borders.”
What Is a Community of Practice (CoP)?
A community of practice (CoP) is a group of people who
share a concern, set of problems or passion for a topic,
and deepen their knowledge and expertise by interacting
and learning from one another on an ongoing basis. CoPs
can be formal or informal, related to a career or a personal
interest or hobby.
Natalie Campbell, (former) technical advisor at CARE
USA, uses a group of pregnant women as an example of
a CoP. These women get together on a regular basis; they
share their thoughts, ideas, complaints, joys and, just as
importantly, the lessons they have learned to help them
cope with this nine-month period of their lives. These
women are unknowingly engaging in an informal CoP.
More formal versions of CoPs are used by major
international organizations to propagate learning. For
example, over the past decade, industry leaders such as
Chrysler, McKinsey & Co., the World Bank and others
have relied on CoPs to stimulate innovation, develop
social capital and nurture emerging knowledge.
An important distinction must be made between CoPs
and working groups or task forces. The latter two are
brought together by obligation to an employer to create
a product or meet a goal. CoP participants, on the other
hand, take part voluntarily. They share and learn because
they are passionate about the topic at hand, and it helps
them to improve their abilities around their practice
or discipline, whether it be career-oriented or simply
a personal interest. They are self-motivated to attend
meetings, take part in discussions and share their own
knowledge and skills.
Since participation is voluntary, it is crucial that CoP
meetings be engaging and fun for participants. CoP
members must see value in being part of the group and
understand the relevance of their participation and that of
their peers. Only with dedicated members, strong internal
leadership and a spirit of sharing knowledge, will a CoP be
successful and sustainable.
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Bringing It All Together
For these CoPs to be successful, participants need mechanisms to
explore ideas, think together and share relevant knowledge. This
took collaboration at global, regional and country levels.
About 45 organizations are involved with Links for Life, globally
as Steering Committee members and locally as CoP participants.
Organizations not only provide financial support, but also facilitate
their CoP member participation by allowing their staff to attend
meetings, engage in CoP-related activities and host CoP meetings
on a rotating basis.
To ensure CoP member participation and to guide the formation
of the groups, PCI and the Steering Committee hired a country
coordinator for each of the two countries. These individuals are
skilled facilitators and are dedicated to sharing and documenting
knowledge in integrated HIV and FNS programming.
During the early stage of developing the CoPs in Malawi and
Ethiopia, the CoP coordinators devoted significant energy to
securing commitments from CoP participants in each country.
Since participation is voluntary, the program relies on its perceived
value to each and every member and his or her organization.
Initially, country coordinators had a hard time getting participants
on board.
“The biggest challenge for Save the Children has been finding
consistent and dedicated staff to give the CoP the time it needs and
deserves,” said Lloren.
Success Follows Reconciling Challenges
Natalie Campbell, then technical advisor at CARE USA, traveled
to Ethiopia and met with both country coordinators in July 2008.
She cofacilitated a learning event for members where, as part of
an exercise, participants asked themselves why they attended CoP
meetings. Without an obvious product to produce, as they were
accustomed to, participants did not immediately see the value
of CoP membership. For many, the answer to this question has
evolved over time.
“It’s important that the country coordinators are passionate and
people-oriented,” says Campbell. “And, they need to be dedicated
to their “domain” — the CoP term for the topic or theme that
brings members together.”
Because a tradition or culture of sharing knowledge across agencies,
especially between those who compete for similar funding and
prestige does not automatically exist, trust between CoP members
initially posed a challenge. Over time, however, meetings and
learning events used participatory learning tools and methods
to create an environment that built trust and facilitated sharing
and collaborative learning. This has gone a long way toward
encouraging members to engage and invest in the CoP. Participants
have articulated tangible and intangible benefits to belonging to
their CoP.
To bolster trust, each meeting begins with one organization sharing
its recent programming successes, as well as challenges. Participants
are encouraged to bring specific issues to the group for peer-assist
exercises in which members brainstorm ideas to help others with
specific problems. When members see that their peers have valuable
solutions, they are more inclined to continue participating.
Ethiopia CoP’s monthly meeting
Links for Life CoP Steering Committee
Current Steering Committee members include Academy for Educational Development, ACDI/VOCA, Action Against Hunger, Africare,
Association of Nutrition Service Agencies, CARE USA, Catholic Relief Services, Christian Relief and Development Association, Concern
Worldwide, Consultative Group on International Agricultural Research, Family AIDS Care Trust, Friends of WFP, The George Washington
University, Global Alliance for Improved Nutrition, Global Food and Nutrition, GTZ, Helen Keller International, Kalusha Foundation,
Land O’Lakes, Mercy Corps, Nzinga International, Oxfam, PATH, Project Concern International, Save the Children, UNDP, USAID, U.S.
Department of State, World Vision, and the World Food Program.
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Another challenge to establishing and sustaining CoPs involved
relying exclusively on electronic communication. Since broadband
Internet access is inconsistent at best, coordinators have learned
to rely on handwritten communication and text messaging via
cell phones to remind participants of meetings and convey other
urgent messages. Additionally, Yahoo!® Groups were established as
an online discussion forum and repository for meeting minutes,
photos, CoP reports, calendar of events and other documents of
interest to members.
Process not Product
Early successes are evident, but a healthy CoP is a process, not
a product. Before success can be claimed, members will have to
continue to nurture and cultivate their learning communities. A
future challenge will be how to sustain and grow CoPs long-term.
Convincing organizations that learning requires resources and does
not happen spontaneously will be tough. Money is also needed to
support logistics of meetings, learning events and field-site visits, as
well as salaries for coordinators and other support staff. Partnership
and teamwork across and between all members is required for
sustained success.
When it comes to coordination of the many partners brought
together for this project, Campbell gives credit where it’s due, “I
have to give PCI, including O’Donnell-Blake, credit for being
persistent and keeping everyone organized.”
Campbell notes that a project leader cannot be a passive person.
He or she must be able to motivate people and convince donors
that this multi-organizational learning initiative is worth funding.
“Without salaried coordinators in Malawi and Ethiopia, we
could not have achieved what we have,” Campbell says. “Internal
leadership is crucial for any collaborative programmatic effort,
especially for CoPs that bring individuals and organizations from
diverse backgrounds together.”
The promising practices identified by the Malawi and Ethiopia
CoPs were showcased at Africa Forum 2009: Sharing Integrated
Solutions to HIV and Food/Nutrition Insecurity in June 2009.
CoP members will also facilitate sessions, for other practitioners, on
lessons learned from starting their own CoP. It is hoped that their
achievements will encourage other practitioners to use this unique
platform — the community of practice — to promote learning in
more aspects of HIV and FNS programming across Africa.
By Ashley Mastandrea
Kara Greenblott of Nzinga International and Gwenelyn O’Donnell-
Blake of Project Concern International contributed to this article.
Ethiopia CoP members engage in
small-group work.
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The Malawi Project:
Global Assistance Initiative to
Combat HIV/AIDS
Lessons Learned:
• Hands-on experience and resources enable
partners to provide technical assistance for the
quick implementation of vital activities.
• Sustainability should be a key aspect of
program design.
• Partner organizations can help each other
and motivate existing staff by filling human
resource gaps.
• Ministries of health should spearhead and be the
public face for major global health initiatives.
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Combating global HIV/AIDS received priority status
in 2003 with the U.S. President’s Emergency Plan
for AIDS Relief (PEPFAR), which set out to build
sustainable local capacity by supporting the training
of new health care workers in HIV/AIDS prevention,
treatment and care. Nowhere is there more need for
improved HIV/AIDS diagnosis and treatment than
in the eight African countries of Botswana, Lesotho,
Namibia, South Africa, Tanzania, Uganda, Zimbabwe
and Malawi, a fact underscored by Bingu Wa
Mutharika, Ph.D., president of the Republic of Malawi,
who has made management and prevention of the HIV/
AIDS pandemic a top priority.
Under the aegis of PEPFAR, several governmental and nongovernmental
organizations (NGOs) have been developing and
implementing training programs for this growing demand in
prevention, treatment and care programs for HIV/AIDS. One
such program is the Howard University Technical Assistance
Project (HUTAP), the second five-year cooperative agreement
that the Washington, D.C., university has signed with the Centers
for Disease Control and Prevention Global AIDS Program since
2002. Howard University is one of the leading partners involved in
building the overall laboratory capacity in Malawi.
Into its second year of the agreement, the Howard University
College of Pharmacy, Nursing and Allied Health Sciences, working
in conjunction with several other NGOs, has enhanced the
infrastructure that will provide a critical foundation on which to
build high-performing laboratory services essential to the scale-up
and success of Malawi’s newly adopted five-year AIDS treatment
plan, Prevention of Mother-To-Child Transmission (PMTCT) and
Early Infant Diagnosis programs. To date, HUTAP has:
• Trained more than 160 laboratory technicians, tutors and
managers in HIV diagnosis and disease monitoring
• Developed an HIV testing preservice curriculum
• Refurbished three training laboratories and a computer
laboratory to enhance teaching and learning of the new
curriculum content at two laboratory training schools
• Formed partnerships with other organizations in Malawi,
including the U.S. Centers for Disease Control and
Prevention’s Global AIDS Program (CDC-GAP), Ministry of
Health, William J. Clinton Foundation, the United Nations
The refurbished training lab in the Malawi
College of Health Sciences in Lilongwe.
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Children’s Fund (UNICEF), World Health Organization
(WHO) and Baylor College of Medicine to rapidly expand
access to HIV testing and treatment for pregnant mothers and
HIV-exposed infants
• Strengthened three referral hospital laboratories to provide
early infant diagnosis for HIV using DNA PCR (polymerase
chain reaction), which previously had limited use in Malawi
• Provided technical staff to address human resource gaps and
provide technical assistance to assure quality lab services or
strengthen management capacity
A Future Is at Stake
By the end of 2002, sub-Saharan Africa represented 29.4 million of
the estimated 42 million HIV/AIDS cases globally. The enormity
of this devastation caused by HIV/AIDS is best measured in the
most dire of human terms — a drastically reduced life expectancy,
a steadily decreasing workforce and the virtually unchecked
proliferation of poverty.
The HIV/AIDS epidemic in Malawi is one of the most severe
in sub-Saharan Africa, with almost one million of the nation’s
population living with HIV/AIDS, according to a 2008 update
by the Joint United Nations Programme on HIV and AIDS
(UNAIDS). The HIV/AIDS estimates for Malawi in the 2008
UNAIDS update include:
• 930,000 people living with HIV
• 11.9 percent prevalence rate in people 15 to 49 years of age
• 840,000 people age 15 and up living with HIV
• 490,000 women age 15 and up living with HIV
• 91,000 children up to 14 years old living with HIV
• 68,000 deaths due to AIDS
• 560,000 children up to age 17 orphaned due to AIDS
Organizations and Their Contributions in Malawi
Laboratory capacity and infrastructure are important in providing
HIV/AIDS care and support. As more HIV/AIDS treatments
become available, training institutions in sub-Saharan Africa are
challenged to produce more technicians to fill job vacancies, as
well as quality educational programs that address HIV testing and
monitoring needs.
To strengthen the laboratory capacity for providing quality HIV
testing services in Malawi, the CDC funds HUTAP as part of
its activities for PEPFAR. Its primary target is to improve the
infrastructure and quality of laboratory testing at central and
district-level hospitals, including refurbishment, purchasing
laboratory equipment, consumables and reagents in support of
HIV testing and training; updating skills of laboratory technicians;
and increasing human resource capacity of laboratory personnel.
Howard University has a long history of working with the Ministry
of Health in Malawi and the CDC-GAP to build the country’s
capacity in laboratory services and infrastructure. A preservice
assessment documented the need for tutors at training institutions
and hospital personnel who prepared laboratory technicians for
HIV work. Data were collected through surveys and focus groups
on available resources, curricula content, tutor training and
expertise, and skills of laboratory technicians. Site visits were made
to observe laboratory operations.
The results supported the need to upgrade the laboratory
curriculum; provide the laboratory training institutions and
hospital laboratories with equipment, reagents and supplies; and
upgrade the knowledge and skills of tutors, lab supervisors and
technicians.
HUTAP is managed in Malawi by Carol Porter, Ph.D., assistant
professor, Department of Clinical Laboratory Sciences in the
Division of Allied Health Sciences at Howard University. She is
assisted by several local Malawians involved in day-to-day activities
to address identified needs, and several members of the Howard
University faculty in the College of Pharmacy, Nursing and Allied
Health Sciences provide assistance to the project. The team is
responsible for:
• Strengthening in-service training, supervision, management
and quality-assurance programs
• Updating preservice training curricula to link it to
target testing for HIV diagnosis, disease monitoring and
opportunistic infections
• Bringing trainers and clinical instructors up-to-date on new
HIV curriculum content, educational methodology and
Training session in Lilongwe, Malawi curricula implementation
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• Creating laboratory centers of excellence at service-delivery
sites for HIV testing
• Recruiting and retaining senior-level staff to fill the lab
positions being created to implement national qualityassurance
programs for HIV, CD4 (cluster of differentiation 4)
and PCR.
“Howard University is working to build the critical laboratory
infrastructure in Malawi; educating trainers, clinical instructors
and lab technicians; hiring staff; implementing quality-assurance
programs; and helping with supplies,” says Porter. “But one partner
can’t provide everything to make a program of this magnitude
successful.”
Also joining Howard University in the CDC-funded University
Technical Assistance project are the William J. Clinton Foundation,
which provides the DNA PCR and CD4 test kits and supplies and
started a lab assistants training program in 2007 to address the
shortage of lab personnel (the first class of 80 students will graduate
in 2009); Abbott Funds; and Baylor International Pediatric AIDS
(BIPAI) at Baylor College of Medicine in Houston, which provides
clinical services, recruits pediatricians, treats infants and mentors
Malawian health staff.
The Baylor College of Medicine-Abbott Fund Children’s Clinical
Centre of Excellence (COE) was officially opened in 2006 within
the grounds of Kamuzu Central Hospital in Lilongwe, Malawi. It
serves as the outpatient pediatric HIV clinic for the hospital and a
pediatric referral center for the nation.
“Baylor’s mandate in Malawi is to assist the Ministry of Health
in the national effort to improve pediatric HIV care, which
we do through this collaboration [and] that uses each partners
comparative advantage,” says Peter N. Kazembe, M.D., chief of
pediatrics at Kamuzu Central Hospital and director of Malawi’s
first center for the care and treatment for children with HIV/AIDS.
“Baylor brought its expertise in clinical training to the initiative,
while Howard brought to the table its expertise in lab training,
management and monitoring, which were critical to developing
new skills that government hospital lab technicians needed to
diagnose the DNA PCR tests for babies under 18 months old.”
In just over two years of operation, Kazembe says clinical services
staff have registered more than 3,400 patients at the COE. This
figure does not include the children who doctors are managing in
the outreach sites (district hospital and health centers), where they
are operating nationally. From its inception, the number of children
accessing care at the COE has progressively increased to where it is
now enrolling about 100 new patients per month; the daily patient
attendance ranges from 50 to 100. The COE has an active caseload
of 2,100 patients, with 1,039 of them on anti-retroviral drugs. In
line with the family-model of approach to HIV care and treatment
that is being pioneered by the BIPAI, the COE offers care to adults
through a family clinic at the COE, which has 120 adults in active
care. It also runs a teen clinic one Saturday a month, which has
about 100 teenagers who patronize this clinic for clinical care in the
morning, followed by activities that promote their educational and
psychosocial development. Aside from working with the partners,
the Malawi Ministry of Health also supported the CDC, Baylor
School of Medicine and Howard University efforts.
“With support from UNICEF and others, we were able to
help purchase lab equipment and supplies, train nurses and lab
technicians, and provide private courier services to transport the
samples from health facilities to the labs for DNA PCR testing,”
says Reuben Mwenda, deputy director, health technical support
services-diagnostics, Malawi Ministry of Health.
Malawi’s Challenges and Critical Issues
UNAIDS states the HIV response in Africa is at a turning point,
with countries in East Africa reporting good results due to access
to testing and treatment. In Malawi, signs of positive change are
evident.
Malawi’s AIDS response has stabilized the HIV infection rates.
However, UNAIDS warns that more resolute interventions in the
areas of finance, community empowerment and political drive are
necessary to increase the effectiveness and reach of HIV prevention,
treatment and care.
DNA PCR laboratory at Kamuzu
Central Hospital lab in Lilongwe
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For several years, the CDC-GAP and its partners have provided
assistance — technical guidance, resources, training and direct
linkage to care and treatment — to strengthen Malawi’s laboratory
capacity to test for HIV and monitor diseases. In 2002, Howard
University received a $5 million grant from CDC-GAP to provide
technical assistance to support and strengthen laboratories and train
lab staff and faculty from the lab training programs at the local
colleges and universities. In 2006, the Ministry of Health in Malawi
awarded a $280,000 subcontract to HUTAP to hire lab managers
and an epidemiologist for the National HIV Reference Laboratory
and to roll out rapid HIV with western blot and CD4 testing
training.
“Since 2003, Howard University has worked closely with the
Malawi Ministry of Health and the other partners and collaborators
to progressively strengthen and broaden HIV testing and training
capacity and build a sustainable national laboratory infrastructure
with the capacity to meet both the country’s strategic plan for health
care delivery and its response to HIV/AIDS,” Porter says.
To accomplish the scale-up of laboratory services, the coordination
and involvement of partners has been critical in key areas:
• Consultative meetings with stakeholders
• Development of policies and strategic plans
• Coordination with district health officers and administrators
• Identification of funds to support activities
Challenges, though, have surfaced as in the building of this
much-needed laboratory infrastructure. It has been especially hard
with limited and inconsistent procurement systems for ordering
lab reagents and supplies, staff shortages that often hinder the
motivation of the existing staff, and few experienced lab supervisors
and managers, admits HUTAP’s Porter. To overcome these
obstacles, HUTAP, the Malawi Ministry of Health and other key
stakeholders are coordinating activities that provide critical data —
assessments, site visits and other programs — that highlight gaps
in the system and help them decide where to provide the technical
and structural support.
DNA PCR laboratory at Kamuzu Central
Hospital lab in Lilongwe, Malawi
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One example involves a strategic mentorship program that HUTAP
introduced to improve the quality of laboratory supervision in
Malawi. Mentors are hired by HUTAP as lab supervisors or
coordinators to work side by side with the laboratory supervisor on
quality control, documentation/recordkeeping, communication,
equipment maintenance and stockkeeping. Since 2008, the
mentorship program has effectively helped new lab technicians to
understand and partake in supervisory roles and responsibilities. It
also has provided essential knowledge that has enabled laboratory
staff to implement good clinical laboratory practices, improve
documentation and recordkeeping, enroll and monitor quality
assurance procedures, and enforce corrective action to remedy
deficiencies.
Other problems facing Malawi involve the critical shortage
of experienced laboratory personnel. Porter says HUTAP is
collaborating with the Ministry of Health to strategically place
staff, as they return to the workforce, in laboratories where the
demand for testing services is high and where good supervision is
essential for quality services. HUTAP also will recruit senior-level
and experienced laboratory personnel for the next couple years to
continue raising the standards of laboratory testing and training.
“Howard University is addressing lab staff shortage by hiring
people from the private sector and Southern African Development
Community region on behalf of the Ministry of Health,” Porter
says. “These hires have the right skill set to help mentor new
staff members.”
The Ministry of Health is trying to address the experience shortage
with a mandate to increase the number of lab professionals who
graduate from Malawi colleges every year.
“We’ve introduced a bachelor’s degree lab program, and we’re
encouraging those who have pursued master’s degrees to return
and use a higher quality of skills in Malawi,” says Mwenda. “We’ve
also updated lab facilities, funded automation projects, and bought
new equipment, supplies and services so there is no interruption of
services.”
The Work Continues
Today, HUTAP is working with a new, five-year $2.5 million
cooperative agreement signed in 2007 by CDC-GAP for building
laboratory capacity through preservice and in-service training. This
will be done by providing in-service and preservice training for
laboratory technicians, supervisors and medical laboratory science
students; establishing laboratory centers of excellence in HIVrelated
testing; strengthening the laboratory science curriculum;
improving teaching capability at the training institution; addressing
human resource shortages through the provision of technical and
managerial staff; and developing a national quality-assurance
system for HIV, CD4, PCR and routine laboratory testing.
“Over the past year, HUTAP felt the critical need was to train
laboratory technicians from the central and district hospitals
in CD4 testing and DNA PCR due to the rapid PMTCT and
ART [antiretroviral therapy] acceleration plans, as well as the
implementation of EID [electronic identification device] services,”
Porter said. “Now, under this new initiative, we intend to build this
laboratory capacity with lab tutors who are oriented in this area and
students who have received the necessary training at service delivery
sites throughout Malawi.”
By David Perilstein
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Standardizing Solutions to
Change the Face of Laboratory
Services in Tanzania
Lessons Learned:
• The input of local and national level governments is
critical during the design and implementation phases.
• Standardization is essential to efficient contract
management, construction, mentoring, training and
supervision.
• Training via face-to-face mentoring accelerates the
pace of change.
• Receiving donations of used equipment is not the
answer to building sustainable capacity in a new
laboratory; a supply of reagents, maintenance and
training are necessary.
• Communication is key at all levels, and the
frequency of communication needed is frequently
underestimated.
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Patients at Mt. Meru laboratory
before modernization.
In certain African countries such as Tanzania, lack of
health care infrastructure impedes progress not only in
controlling the HIV/AIDS epidemic but in the overall
provision of health services. Even when sufficient stocks
of medication are available,shortcomings with certain
ancillary services, such as laboratory testing, contribute
to the challenges of diagnosing and treating HIV/AIDS
and other diseases.
Abbott, the global health care company, was compelled to action
in the late 1990s as the HIV epidemic in Africa was worsening.
In 2000, Abbott CEO Miles White saw firsthand the issues of
crumbling infrastructure during his visit to Muhimbili National
Hospital, Tanzania’s most advanced medical institution and
university medical center. Reflecting on the experience, Miles said
“I learned more in 10 minutes at Muhimbili than I had in reading
all the newspapers and reports.”
It was evident that, in order to address HIV in Tanzania, health
system deficiencies needed to be modernized. After the visit, a
comprehensive plan was put in place to fight AIDS in Tanzania by
first addressing the weak health system that resided at the top of the
Tanzanian health infrastructure, Muhimbili National Hospital.
Abbott with the support of the government of Tanzania, began a
program to systematically improve laboratory infrastructure and
services. While the initiative is a work in progress, Abbott has
obtained measurable improvements in both turnaround time and
the quality of patient results.
“In 2007, the regional laboratories in Tanzania were devoid of
automation, similar to where we were in the U.S. in the mid-
’80s,” says Larry Wood Jr., program manager for Abbott Fund
Tanzania. Wood, who is in charge of implementation and training
in the project, explains, “Although they are relying on manual
methodologies in many cases, local laboratory staff can generate
acceptable results.”
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Abbott employee volunteer working alongside
Tanzanian lab worker.
AIDS and Other Conditions
While HIV affects the population at a rate of about 5.7 percent
throughout the country, in some places the rate goes much higher,
up to 12 percent in the Lake Victoria region, for instance. But
non-HIV patients often bear the brunt of the laboratory inequities
in Tanzania.
“When antiretroviral therapy became available for people with
HIV, laboratory services in the region were very poor, because
the outdated facilities were not equipped to deal with the influx
of patients needing ongoing disease and drug monitoring. It was
hard for any of these labs to provide adequate patient care, without
proper equipment, reagents, training and technical expertise. A
physician without laboratory results is treating the disease blindly,
unable to definitively define the best course of treatment for the
patient’s changing condition,” says Gloria Kulaya, M.D., M.P.H.,
technical manager for monitoring and evaluation for the Abbott
Fund Tanzania.
Global AIDS agencies like PEPFAR and the Global Fund tried
to improve the situation by funding the update of laboratories
and tests performed specifically for HIV patients. “This improved
services for those with HIV, which is its charter; however non-HIV
patients didn’t receive the full benefit from the rehabilitations. For
example, if you were HIV-positive, you’d get your results back
quickly; if not, you could wait at least a week for your results,”
Kulaya says.
Abbott’s first major intervention was to rehabilitate Muhimbili’s
52,000-square-foot Central Pathology Laboratory, in which the
laboratory staff struggled to keep up with the hospital’s workload
using broken and outdated equipment. The Abbott Fund installed
new chemistry, hematology and immunology instruments and
stocked the lab with reagents. In addition, the laboratory, and
eventually the entire hospital, was fully computerized. To address
the challenge of maintaining and servicing instruments, two Abbott
field service engineers were dedicated to the new laboratory. Abbott
field service personnel have access to the requisite parts and training
to ensure that instruments are available 24 hours a day, seven days a
week. In addition, the company also provides a full-time technical
adviser to work alongside the technicians and train them on the use
of quality control, instrument maintenance, reagent procurement
and general laboratory operations and management.
Abbott also funds non-Abbott instruments and reagents. Most
recently, Abbott Fund purchased a highly technical molecular
instrument to diagnose HIV in infants early enough (before 18
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months) to effectively treat them before they are overcome by the
disease. As a result of this significant investment in equipment,
training and personnel, Muhimbili is one of the highest quality and
most sophisticated laboratories in East Africa.
Creating Efficiencies Through Standardization
In 2007, with the experience of Muhimbili as a reference point, the
government of Tanzania asked Abbott Fund to consider renovating
each of its region’s laboratories; Tanzania has 20 regions and three
larger regional-level laboratories for a total of 23 laboratories that
needed immediate attention. Abbott agreed and began working
with the government to determine the implementation strategy.
Abbott Fund, a foundation funded solely by Abbott, visited each
lab together with its lab designers, architects and designated
government officials. The team makes a determination as to
whether the laboratory can be renovated or requires demolition and
completely new construction. Key to the strategy is the intent to
deliver a standardized final laboratory.
Standardization is an important aspect of the project. “From the
very beginning, we wanted to provide a standardized solution,” says
Christy Wistar, M.B.A., vice president of Abbott Fund Tanzania.
“We wanted all 23 buildings to look and feel alike.” That goal has
been partially hindered by the fact that some of the projects are
complete teardowns, while others are rehabilitations. Right now the
ratio is running about 50/50, she says.
While each of the labs differs in small ways, the overall plan to
provide a standardized design helps to maintain control of the
process and costs. As part of the program, Abbott installs safety
equipment to provide protection from infection and contamination
of laboratory staff. “The bio-safety cabinets and fume hoods are an
important component of our overall program. It’s not only about
better quality results but also better and safer working conditions
for laboratory personnel,” says Wood.
Prompt Quantification of Benefits
Of the 23 laboratories slated for renovation, eight are now
complete, five are under construction, and 10 more labs are
planned for 2010, according to Wistar. Each lab costs between
$400,000 and $500,000 dollars, she adds, a little more than
originally planned but not out of line considering inflation and an
expected three-year project investment of $10 million.
While many of the rehabilitated labs are just now coming on line,
Abbott measured improvements at one lab, the trial project in
Mt. Meru Hospital, Arusha, Tanzania. There, the number of tests
performed rose from an average of 15,000 to 134,000 per year,
while turnaround time decreased from an average of three to 14
days to less than 24 hours. The number of clients using laboratory
facilities also rose, from an average of 5,000 to 38,000 per year.
For some of the more recently completed labs, it is too early
to measure results. Kulaya says they came up with a list of five
indicators — among them the number of patients served, the
number of test requests completed, instrument status, reagent
inventory status, and turnaround time of results. The laboratories
report back to Abbott Fund on Monday of every week. Currently,
data collection is taking place manually because the monitoring
system is not yet computerized.
Overcoming Logistical Difficulties
Even in the newly modernized laboratories, shortages of training,
power or reagents sometimes mean that patient tests are not
completed.
With the exception of Muhimbili, where Abbott supplied
instruments for clinical chemistry, hematology and immunoassay,
the Tanzania Ministry of Health is supplying laboratory equipment
for the regional laboratories.
“One of the major challenges with the equipment purchased
by the government is that until recently, no plans were made for
service. Relatively new equipment can be inoperable for weeks
or months because the local distributor is not a reliable source
of service or parts. The problems are worse when equipment is
donated without provision for local procurement of consumables
or service.
State of the public laboratory in Tanzania
before modernization.
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“Through our day-to-day contact with the laboratories we’ve found
that, often due to a lack of reagents or hardware issues, relatively
new analyzers are inoperable,” says Wood. “For example, we found
an instrument where the hard drive had failed on the system after
installation, and without a service plan in place, the staff put a
blanket over the system and the associated tests were not performed
for weeks. “I can’t tell you how critical qualified service and support
are to the management of a modern laboratory,” says Wood.
As part of their training and implementation program, Abbott
provides mentors to work with lab personnel side-by-side for two
months during the start-up process to ensure the lab has good
processes and procedures in place and is able to work through
many on-site operational issues. Supervision of sites is also done
weekly by e-mail, fax or telephone to ensure the sites are running,
instruments are in good condition, and reagents and quality control
are available.
However, by far the most difficult logistical problem facing labs
in Tanzania is that of keeping reagents in supply. A reagent is
a consumable resource used with the analyzer to produce the
test result, like paper is to a printer. A busy laboratory requires
hundreds of different reagents with different expiration dates,
making laboratory inventory and procurement a huge logistical
challenge in a country like Tanzania.
At Muhimbili, Abbott provides reagents and other consumables
at no charge or they are purchased from local suppliers. Abbott
support personnel are responsible for managing inventories and
ordering supplies. In the regional labs, because it isn’t Abbott
instrumentation, two local distributors as well as the government’s
own procurement agency, are responsible for supplying the
country’s laboratory supplies.
The reagent ordering process has been a source of frustration for
the laboratory staff in Tanzania. “The main thing is that it just
takes too long, forms are filled out manually, requiring signatures
and sent by mail to the Medical Stores Department, where there is
a huge backlog of forms,” says Kulaya. In fact, often, reagents are
shipped out to the laboratories without regard to need or inventory
on site. It’s called a “push” system whereby reagents are pushed
from the Medical Stores Department to the laboratories without an
order. This inevitably ends with oversupply and storage issues for
some supplies and running out of others.
Abbott is trying out a new method of ordering reagents at the
labs, Wood says. “We’re trying to convert from a “push” system to
the more traditional “pull” system where reagents are ordered as
needed. Right now, we have a pilot program, and we should have
feedback from that within the next six months,” he adds.
Ensuring the Future Through Education in the Lake
Victoria Region
One of the regions hardest hit by the AIDS crisis, the Lake Victoria
region in the north, with its population of 13 million, may also
serve as another kind of laboratory for solving some of the country’s
global health problems. In addition to building or renovating
labs across Tanzania, Abbott is partnering with U.S.-based Touch
Foundation Inc., to increase medical education. The Touch
Foundation was working on the health care worker shortage in
Tanzania and enlisted Abbott support, when Abbott was beginning
the lab modernizations in the Lake Victoria region.
Every year, Abbott funds more than 100 scholarships for medical
technologists, for a full three-year program, at (Weill) Bugando
University College of Health Sciences in the Lakes region.
“Well-trained lab managers and medical technologists are the key
to ensuring the future of these laboratories,” says Wistar. “We
need to ensure that Tanzania has a next generation of qualified
medical technologists. Beyond training laboratory staff to use the
equipment or conduct tests and read results, Abbott’s mentoring
program is instilling a new discipline. Through daily observation
and a weekly phone questionnaire, we’re communicating that the
role of the laboratory is vital to the health care system and it’s not
acceptable to let patients and physicians down. We’ve established,
most importantly, a new sense of accountability.”
By John Otrompke, J.D.
Christy Wistar contributed to this article.
Mt. Meru laboratory after modernization.
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Lessons Learned:
• Effective research partnerships require strong
leadership and government support.
• A cooperative decision-making style enables the
sharing of technical and cultural knowledge.
• Providing career opportunities and research grants
in developing countries entices researchers to return
to their home countries after obtaining their
graduate education elsewhere.
• Collaborations that include sophisticated research
projects and advanced training of local personnel
can provide the foundation for a new, worldclass
research system in even the most resourceconstrained
countries.
Bringing Modern
Medical Science to Mali
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Guindo Oumar (left), lab manager, and Professor Anatole Tounkara,
scientific director, work together at the Center for HIV and TB
Research Program (SEREFO) in Mali.
Mali, covering a vast wedge of sub-Saharan Africa,
is one of the poorest nations in the world. Its health
problems are multi-farious, with the country’s four
million annual cases of malaria representing a severe
burden. Yet the situation is not hopeless. Mali is the
scene of an international partnership that has created a
world-class medical research center and, within it, the
seeds of a research-based modern medical system.
Back in 1989, Robert Gwadz of the National Institute of Allergy
and Infectious Diseases (NIAID), a component of the U.S.
National Institutes of Health (NIH), was busy developing the
“perfect mosquito” — a transgenic version of Anopheles gambiae in
which the malaria parasite could not breed. The idea was to flood
a local Anopheles mosquito population with the transgenic version
and eliminate the malaria threat through interbreeding. But,
Gwadz recalls, “We had no idea how to manage such a release.”
Gwadz contacted Yéya Touré, a Malian researcher with whom he
had previously worked. He received Rockefeller Foundation and
World Health Organization (WHO) funding for the initial effort.
Within two years, NIAID added its financial support and assigned
entomologist Richard Sekai to coordinate the program inside Mali.
Ogobara Duombo, a young Malian physician returning from his
education in France, together with Louis Miller, then head of the
Malaria Section at the NIAID Laboratory of Parasitic Diseases,
extended the research agenda into malaria treatment. These
efforts in 1992 became the Malaria Research and Training Center
(MRTC) within the national medical school (now part of the
University of Bamako).
Steve Smith, current director of the NIAID Office of Global
Research, says that the project’s success was initially due to the
“strong commitment in NIAID and Mali by certain individuals.
You can’t do a project like this unless there are talented researchers
with a mix of skills including science diplomacy.” Smith also notes
that the Mali government’s consistent support has been crucial. “It
is a real partner,” he says. “Other countries don’t have this piece.”
Pressed by the popular demand for malaria control measures, the
Mali Ministry of Health supported the MRTC’s creation at the
nation’s public university. It now works with MRTC researchers
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on joint projects. These include evaluation of mosquito control
measures, malaria drug resistance and the training of laboratory
technicians.
At first, the biggest problem was a lack of local resources. For
example Gwadz found that, after a fuse blew in one of the original
labs, there were no fuses for sale in the entire country. He had to
bring a suitcase full back from Paris. “There were no supplies, no
basic laboratory chemicals. Everything had to be ordered from
abroad,” he says. Electrical power was another serious problem,
with daily outages when dams were low at the start of the rainy
season.
These problems were largely resolved through the construction
of new research and training facilities, which NIAID funded over
the years. The development of reliable supply chains helped as
well. The MRTC now boasts of seven fully equipped laboratory
and office buildings in Bamako plus several field research sites,
all equipped with emergency generators. Communications are
assured by satellite dishes providing a direct Internet link to the
NIAID computer network in Bethesda, Md. Most important is
the laboratory equipment. “In some countries, we have to bring
everything we need. This is not the case in Mali. We can do flow
cytometry, PCR [polymerase chain reaction] and other advanced
techniques,” says NIAID researcher Amy Klion. International
research groups from other organizations now regularly make use of
the MRTC facilities.
Expansion to Other Diseases
Klion is an expert in filariasis, an infection of parasitic worms. The
lymphatic form of the disease, which is common in Mali, causes
severe swelling and ultimately elephantiasis. Lymphatic
filariasis is transmitted by the same Anopheles mosquitoes
that transmit malaria, leading to many coinfections.
The fact that Klion is working with the Mali project is
indicative of how it has expanded. Klion relates, “One of
Yéya Touré’s students, Yaya Coulibaly, came to work at
NIAID. He was interested in filariasis, and that was the
start of our collaboration.” The filariasis project led to a
series of investigations on insect-borne diseases, among
them leishmaniasis.
In 2002, the MRTC and the Entomology Unit of the
University of Bamako medical school jointly formed a
NIAID-sponsored International Center for Excellence in
Research (ICER). NIAID designed the ICER program
based on its experience with the MRTC. One of the
ICER program’s goals is to create locally managed,
sustainable research and training programs that build
indigenous infectious disease research capacity and
address shared scientific priorities. The main concern is diseases
of local importance. (NIAID also formed ICERs in Uganda and
India.)
An HIV/tuberculosis unit became a third part of the Mali ICER in
2002. The focus on HIV grew out of a proposal from the medical
faculty dean. HIV prevalence in Mali is relatively low (about 1.5
percent in people 15 to 49), but TB is much more common. It,
therefore, made scientific sense to include a concentration on
HIV/TB coinfection. Gwadz notes, “Mali is also safe, cooperative
and politically stable. The HIV/TB unit has proved a successful
program.”
The increasing complexity of the Mali scientific program brought
with it additional organizational complexity. NIAID now maintains
two senior science administrators at its Mali office. Since 2004, a
five-person Mali Service Center, run for now by outside contractors,
provides accounting services for the researchers in Mali.
Decision-Making Process
The Mali staff has the status of a NIAID contractor; it is not an
outside grantee. As contractors, staff members are paid directly
by NIAID within the scope of specific research projects. The
Americans and Malian consult on study designs, with Malians the
primary executors. The American collaborators visit as needed. “I
go to Mali every three months, when the data monitors go, and
also to teach techniques such as PCR,” says Klion.
Of course, the U.S. researchers have a more America-centric view
of the process than the Malians. “We have an idea, for example,
Photo provided by NIAID.
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about mosquito mating behavior, and the Malians figure out the
details based on their local knowledge,” says Gwadz.
But for the Malian researchers, “Almost the entire study is done
in Mali, including the lab work,” says Anatole Tounkara, present
dean of the medical faculty and director of the HIV/TB research
program. “It is a great thing for us that the NIAID considers us on
the same level. This is not NIAID science but our science.”
Often the Malian scientists help determine research direction.
Seydou Doumbia, deputy director of the MRTC entomology
program, cites the example of leishmaniasis. “One of our colleagues
was looking at leishmaniasis, but the NIAID people said that there
was no leishmaniasis here. So we said here are the data. And they
said, great, let’s see if we can do our vaccine study in Mali.” The
HIV/TB program has formalized this process with a joint Mali-U.S.
scientific review committee that approves research proposals from
both countries. Once fully developed, all ICER protocols must
receive final approval by Malian and NIAID Institutional Review
Boards to ensure that protocols meet international standards.
Decisions cannot go in one direction because the Malians are the
ones who have to cope with the local conditions. Hammering out
an experimental protocol is, therefore, an iterative process. The
NIAID scientists may propose a specific research idea, but the
Malian scientists refine it according to local conditions. As Sekou
Traoré, co-director of the MRTC recounts, “They [NIAID] say
what they want to do, but we can say it is not feasible. We can say
no at the initial phase, but when we have elaborated a protocol
together, turning it down is no longer an option.”
Rick Fairhurst of NIAID’s Laboratory of Malaria and Vector
Research illustrates the way the cooperation may evolve. His study
relating human genetic mutations to malaria severity in 1,200
Malian children is yielding a treasure trove of data. Fairhurst is
investigating the action of human mutations known to provide
some protection. His Malian co-investigator, Mahamadou Diakité,
is combing the same data set to find previously unrecognized
protective mutations.
Further adjustments in research protocols occur at the village level,
where studies are carried out. The Malian investigators first hold a
meeting with the local chiefs, seeking their buy-in. These meetings
are not pro forma as the chiefs usually ask very pointed questions.
Once the chiefs have approved, the investigators call a villagewide
meeting to explain the research. “We may have to alter the protocol
based on what the villagers say,” notes Klion.
Villagers obtain concrete health benefits while participating in a
study. They may receive health care that addresses the disease or
coinfection under study. Enhanced treatment for other diseases
detected in the course of the study is another possibility. These
services are provided either by the study personnel or nearby public
clinics. There are also other types of limited assistance: Klion
tells of a clinical trial in which participants received free breakfast
because the study drug had to be taken with food. When the trial
was over, the participants requested extending the free breakfasts
for another month until harvest time. “But we were unable to do
that,” recalls Klion. “It was heartbreaking.”
Creating a New National Scientific Enterprise
A critical component of the NIAID-Mali partnership is training
and education. This too is a two-way process. On the one hand,
Malians learn about conducting advanced research. On the other,
NIAID scientists receive an introduction to on-the-ground tropical
medicine research.
The training programs are multi-faceted. There is a constant
exchange between Mali and NIAID. In some cases, it is more
efficient to send people back to the United States than train them
in Mali. Malians in the United States can work side by side with
the personnel employing advanced techniques. Later, their U.S.
mentors visit Mali to see how trainees are doing. These visitors may
help adapt NIAID practices to Malian circumstances.
The ICER also organizes educational workshops held within Mali.
These cover subjects requiring broad and rapid dissemination,
such as good clinical and laboratory practices or ethical trial
conduct. Other short courses have included subjects such as basic
immunology and grant writing.
NIAID has sponsored American postdoctoral and predoctoral
fellows who go to Mali to gain experience under field conditions.
For five years, the program benefited from a grant supporting
Americans from minority groups who concentrate on tropical
medicine. About 20 grantees worked at Mali ICER research sites
for up to eight months.
Conversely, Malian medical school graduates have received
funding — from the NIH, WHO or the hosting universities
themselves — to pursue advanced degrees in the United States
or Europe. These students typically go to schools where faculty
members have an interest in pursuing the type of research that the
students have worked on in Mali. Unfortunately, this support has
been increasingly difficult to obtain.
Seydou Doumbia followed one such professional path. After
graduation from the national medical school, Doumbia worked
at the MRTC during the early nineties, collecting and analyzing
epidemiologic data on malaria. In 1994, the MRTC received a WHO
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grant to sponsor overseas study for promising doctoral candidates.
Doumbia benefited from that grant and from an NIH fellowship to
learn English while working at Johns Hopkins University. He resided
in the United States for seven years in all, receiving his doctorate from
Tulane University in New Orleans. The malaria research program
rehired him as a lead scientist when he returned to Mali. He is
now also a professor of epidemiology in the University of Bamako
Department of Public Health.
Doumbia’s story illustrates several important strengths of the
MRTC and ICER partnerships. The first is retention. Local
scientists who receive international training return to Mali to
continue their careers. The collaboration with NIAID provides
a sophisticated scientific milieu in which the young researchers
can practice what they have learned. “NIAID helps reinforce
human capacity,” says Doumbia. “Its support makes it possible for
researchers to come back to work in the country.”
An overarching benefit is that the returning scholars are able to take
up teaching positions within the medical school. As of 2009, there
were about 5,600 medical students enrolled at the University of
Bamako, double the number 10 years ago. The faculty is stretched
very thin. Tounkara, the medical school dean, has high hopes for
the returnees. He says, “If you have the human resources, naturally
they will educate other people, giving back what they have
absorbed.”
Lastly, the researchers’ international education makes them
familiar with modern scientific operations. These researchers’
presence in Mali ensures the stability of the scientific enterprise
there. This is particularly true because they have learned how to
obtain independent research grants from foreign funders. In this
way, returning science graduates form the core of a growing selfsufficient
research enterprise.
Next Steps
The Malian staff at Mali ICER now amounts to some 160
investigators, technicians and support staff. The original malaria
project started out looking at mosquito behavior and control
then expanded into epidemiology, treatment and vaccines. From
2006 to 2009, the MRTC/ICER initiated 39 human malaria
studies. Fifteen involve malaria vaccines and the rest range from
human protective factors to various drug regimens. There is also
a study looking at the immunology of filaria-malaria coinfection.
Other recent filariasis investigations include two treatment trials.
The HIV-TB unit meanwhile is conducting a long-term study
of immune responses to TB, with and without HIV coinfection.
It is now enrolling trials looking at HIV treatment response.
Among the projects at earlier stages of development are research on
leishmaniasis (an epidemiologic study possibly leading to a vaccine
trial) and the tick-borne disease, relapsing fever.
Future directions include more involvement with national
development. To relieve overcrowding at the University of Bamako,
there are ongoing discussions about building a second national
university. This would require significant expansion of the current
faculty, and the ICER has a role to play here. “There is only one
university in Mali, and I hope that we can generate more highquality
researchers able to teach in new universities as we open
them…This is my vision,” says Tounkara.
Malian researchers also mention their interest in further
emphasizing “translational research.” This research would show
how to apply scientific findings to improve community health. For
example, it is not enough to discover a potent malaria treatment
if it rapidly succumbs to drug resistance when put into clinical
practice. Translational research would find ways of administering
the drug that retain its efficacy. MRTC’s Traoré says, “We have to
strike a balance between current research and what would be useful
to the public in future. We want to be part of a new generation of
scientists that uses new technology to respond to people’s needs.”
Traoré himself is back working on the original research concept,
the genetically engineered malaria-proof mosquito. New gene
manipulation techniques make the idea more promising, and
Traoré received an independent grant from the University of Kiel
(Germany) to further develop this mosquito.
The NIAID researchers welcome a move toward such independent
research, which is a major goal of the collaboration. NIAID’s
Klion, who first worked in Mali during the late 1980s, notes that
the Malian education system historically has not encouraged selfdirected
activity among its graduates. But, she says, “There has
been a huge change in recent years. The Malians have more skills
and autonomy, with the malaria group furthest along in becoming
more independent.”
The Mali experience underscores the benefits from an international
research collaboration based on mutual respect, common scientific
objectives and shared responsibilities. The ICER is advancing to the
point where its achievements will feed on themselves, setting the
stage for further progress. The question remains as to the ultimate
health, economic and cultural benefits for the country as a whole.
These depend on Mali’s ability to apply what its scientists have
learned. Mali faces a desperate lack of resources, but the intellectual
vitality of its nascent scientific establishment promises to bring the
country into the 21st century.
By David Gilden
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Freedom of Breath,
Foundation of Life:
China’s Neonatal
Resuscitation Program
Lessons Learned:
• Government support lends credibility and
urgency to the implementation of health
programs.
• Medical organizations can help build awareness
and support for programs and set a foundation
for scale-up opportunities.
• Once a critical program goal is met, it is
essential to work on sustainability issues and
building long-lasting enthusiasm for future
growth.
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The large mannequin has an anatomic
respiratory system.
Birth asphyxia is the No. 1 cause of infant mortality
in Chinese cities and the No. 2 cause of mortality
of children less than five years old nationwide. Birth
asphyxia occurs before, during or just after birth, when
a baby is deprived of oxygen.
An estimated 17 million live births occur in China each year,
nearly four times the amount in the United States. In 2002, infant
mortality rates were documented at 29.2 per 1,000 live births, and
20.5 percent of infant deaths were attributed to birth asphyxia.
Though previous collaborative efforts attempted to bring
lifesaving technology to select regions of China, the Freedom
of Breath, Foundation of Life multi-sector partnership was the
first to successfully implement the China Neonatal Resuscitation
Program (NRP) in a systematic and sustainable way across the
country through governmental, professional and private enterprise
collaboration.
“AAP [American Academy of Pediatrics] representatives worked
for a number of years with some local Chinese agencies but were
unable to attract interest beyond specific work environments and
certainly not able to effectively discuss a public health commitment
to neonatal resuscitation,” says William Keenan, Ph.D.
In 1987, the AAP, a not-for-profit professional organization of
pediatricians, conducted the first course in the NRP in China.
Efforts to establish the NRP as a national protocol failed through
2001, when AAP hosted a luncheon meeting in Beijing with
some provincial leaders and Chinese Ministry of Health (MOH)
representatives. Enthusiasm remained low. In response, thenexecutive
director of AAP, Errol Alden, M.D., and Keenan contacted
Joy Marini at Johnson & Johnson Pediatric Institute LLC (JJPI), and
suggested they pursue an established NRP in China.
JJPI, a part of Johnson & Johnson Corporate Contributions,
is committed to saving and improving the lives of mothers and
babies. JJPI’s Marini met with Zhang Deying and Yang Qing of the
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MOH in 2002 to discuss how the private institute and government
could partner to address birth asphyxia.
The Freedom of Breath, Foundation of Life program was developed
to reduce infant mortality and morbidity by ensuring there is at
least one person trained and skilled in neonatal resuscitation at
every hospital delivery. Additionally, plans included establishing
an NRP training program at every hospital that provides obstetric
services.
To establish this program and implement NRP across the nation,
the partnership required not only governmental and financial
support, but technical expertise and the cooperation of health
professionals who would be trained and eventually would train
others. The MOH appointed the National Center for Women and
Children’s Health (NCWCH), a government organization under
the Chinese Center for Disease Control, as the implementing
organization for the program.
The NCWCH provides technical support to the MOH on policies
affecting the health of Chinese women and children. The center
also has had previous experience implementing, monitoring and
partnering with international organizations to create national
programming.
With a program leader in place, the partnership sought the
technical expertise of AAP, which, along with the American
Heart Association, developed an internationally established NRP
educational program. This gold standard program has been taught
in more than 60 countries and was the preferred method for
educating health practitioners in China.
The AAP worked closely with Chinese medical professional
associations to form the partnership’s technical team. The Chinese
Society of Perinatal Medicine (CSPM), a professional organization
of obstetricians and neonatologists, was an obvious fit for this
partnership. Members of the society are at the center of neonatal
resuscitation in Chinese hospitals, and a part of the group’s mission
is to provide continuing education to members. Past experience
with NRP training in China also made them a valuable partner.
The Chinese Nursing Association (CNA), a nonprofit professional
organization for nurses, takes a lead role in providing nurses’
professional education. By including this group, the partnership
recognized the important role of nurses in neonatal care and
resuscitation. CNA brought the idea to train midwives, who
traditionally do not receive formal training in resuscitation skills,
in addition to nurses, to ensure a skilled person is present at every
delivery.
With partners in place, a task force was formed to oversee strategy
and implementation of the program. The Freedom of Breath,
Foundation of Life initiative was an educational intervention,
based on an established NRP, in targeted provinces. Eventually, the
program would reach a national scale.
Setting the Foundation
In the United States and other countries, medical societies have
mature structures and are capable of spearheading national
programs and recommending health protocols in their field.
However, because of China’s political structure, Chinese medical
societies do not have the same administrative power and personnel.
Working closely with the AAP, the Chinese Society of Perinatal
Medicine drafted guidelines for the MOH to establish a national
NRP policy.
CSPM and AAP also collaborated to translate AAP training to fit
Chinese context. Twenty-one national health care providers, trained
by AAP, were responsible for providing technical support in each of
A baby receives resuscitation in a
neonatal intensive care unit.
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the targeted provinces. MOH and its provincial bureaus organized
training sessions with the help of local hospitals.
Twenty provinces were initially targeted based on infant mortality
rates, the presence of CSPM, funding and equipment from the
Chinese government and the need for health care capacity building.
Provinces included (see shaded sections of map): Inner Mongolia,
Yunnan, Xinjiang, Jilin, Guizhou, Shanxi, Jiangxi, Sichuan,
Liaoning, Hunan, Shaanxi, Anhui, Hubei, Gansu, Fujian, Guangxi,
Ningxia, Hainan, Chongqing and Qinghai.
Each province was required to set up a supervision team, overseen
by NCWCH, to ensure implementation and evaluation of
NRP. Provinces were also responsible for choosing the training
model that best fit their local specifications. Training was either
centralized, provided by a team of trainers, or cascading, provided
by trainees to fellow practitioners.
The CNA and the CSPM promoted NRP among their peers. This
support from the professional community helped to strengthen
the skills of health care providers from a grassroots level and keep
Chinese doctors current on the latest science and technology in the
field.
With an infrastructure established by the MOH that supports NRP
at all levels of government, the program became more widespread
and popular than previous attempts to establish NRP. Provincial
ministries encouraged and supported updated and continuous
training. Many provinces included neonatal resuscitation skills in
their obstetric service audit.
“The program helped to improve support and policy,” says
Chunmei Li of JJPI. “Before, hospitals didn’t have leadership that
thought this education was important. Now, leaders see the success
this knowledge brings.”
The popular program grew to a national scale in 2006 and 2008,
with 190 certified instructors and 44,000 practitioners trained.
Based on data from 80 hospitals sampled, the rate of birth asphyxia
has declined by more than a third, from 4.26 percent in 2003 to
2.61 percent in 2007.
China
.
Yunnan
Xinjiang Uygur A.R.
Sichuan
Shanxi
Shaanxi
Qinghai
Ningxia
Inner Mongolia A.R.
.
Liaoning
Jilin
Hunan Jiangxi
Hubei
Hainan
Guizhou
Guangxi
Zhuang
A.R.
Gansu
Fujian
Chongqing
Anhui
Graphic by Digital Vector Maps
A.R. is autonomous region.
210 Case Studies for Global Health
(As of October 2009)
www.casestudiesforglobalhealth.org
Building a Sustainable NRP in China
To maintain practitioners’ enthusiasm and continue growing the
program, the implementation plan includes a public relations
campaign and incentives for participants.
A biannual convention is held to reward notable practitioners and
provinces with exceptional training and program implementation.
Since it takes time to learn a skill and apply knowledge, it is
important to build providers’ confidence.
The convention not only encourages practitioners; it also
provides a platform to discuss program development. Facilitating
communication among participants and reorganizing the program
to accommodate best practices were vital steps to ensuring
participants’ morale.
In addition to the convention and administrative and technical
teams in each province, an interactive Web site offers another way
to connect. Maintained by the NCWCH, the Web site provides
access to training documents and updates, acts as a platform for
knowledge exchange and allows instructors to submit training
reports and other information.
The format of best-practice competition and sharing was unique
for medical training programs in China and was met with extreme
enthusiasm by participants. This model has already been and will
be replicated in other MOH programs.
Moving Training Into the Hospital Setting
To maintain an NRP and ensure skills are properly implemented in
hospitals, a hospital-based instructor program was piloted in nine
select hospitals. This pilot program, launched in October 2008,
encourages the cascading model of training and ensures a team of
qualified instructors are present at each hospital. The pilot program
also works to incorporate NRP in hospital management and
establish neonatal resuscitation in case audits and review.
While a final report of the pilot program is under way, preliminary
findings show that hospital-based instructors help institutionalize
NRP at a hospital level, neonatal resuscitation inclusion in audits
helps reinforce NRP knowledge and skills and helps identify steps
to be strengthened, and a hospital-based staff builds teamwork
among obstetric and pediatric staff.
Future plans include building long-term, sustainable NRP
through hospital-based instructor programs, implementing NRP
at township health care clinics and addressing skill maintenance
and renewal. It is hoped that NRP skills will eventually be required
for licensed obstetric service providers. The CSPM, CNA and the
Chinese Society of Obstetrics are already advocating for this policy,
and the MOH and its provincial bureaus are spearheading this
effort.
Positive results of the program are already evident in the improved
rate of birth asphyxia deaths. Providers are appreciative of the
knowledge the program has brought their institutions. They believe
their skills — and their confidence — have increased. Hospitals
have gained technology. More babies are surviving, and midwives
have the opportunity to pursue more specialized training.
Liu Jia, a nurse at Beijing Obstetrics Gynecology Hospital,
completed NRP training herself and benefited from the technology
during the birth of her son, Yang Yang.
“Every smile, every laugh, even every cry, is precious,” she says of
her son, who is about two years old now. “Yang Yang is the future
of our family. We’re so thankful for the trained team that knew
exactly what to do when he was born and did not breathe.”
“The program is saving lives and improving the health of women
and children,” says Tao Xu of NCWCH. “When I get frustrated, I
take a step back and look at the big picture. That keeps me going.”
Practitioners check neonatal resuscitation
program equipment in an operating room.
Case Studies for Global Health 211
(As of October 2009)
www.casestudiesforglobalhealth.org
A Multi-Disciplinary Partnership
The Freedom of Breath, Foundation of Life program succeeds
today due to the hard work and dedication invested by all partners
— governmental, corporate and nonprofit.
Cultural differences posed a challenge to partners. Cooperation
between Chinese and American medical teams was tested when
developing the Chinese version of AAP training materials.
The Chinese team was not familiar with copyright protocols
and guidelines for intellectual property ownership, but with
compromises from both sides, materials were created and
distributed.
Additionally, communication methods required compromise.
Initially the Chinese medical team did not understand the benefit
of both external communications, through the media, and internal
communications, through health practitioners, as a means to spread
the program’s message. In time, and after seeing some success,
the Chinese team recognized that motivating practitioners and
provincial bureaus via both modes could speed capacity building.
An ongoing challenge to the program has been securing adequate
amounts of equipment sets, which can contain more than 40 items.
Both national and provincial MOHs have provided equipment,
and some hospitals have purchased sets. Still, with such a high
demand for training, equipment can be hard to come by. The
implementation team addressed this challenge by developing an
equipment-sharing program early on. As training became more
widespread, the lending system became better known by providers
and hospitals.
Each year, teams of professionals from the CSPM and the CNA,
led by NCWCH, visit hospitals to review implementation of the
program and supervise training. NCWCH staff is responsible for
evaluating the implementation of the program. Representatives
interview health administrators and practitioners and review
supporting hospital documents. Likewise, the CSPM and the CNA
evaluate skill and knowledge advancement of hospital staff as well
as equipment and drug checks.
This long-term partnership relies on each of its member
organizations to fulfill a vital role in the successful NRP in China.
In addition to electronic communication and informal meetings
between technical partners, full partner meetings are held twice a
year to discuss and review annual implementation plans and related
activities. Partners also discuss challenges, changes and ideas for
future development.
Collaborators recognize the importance of respecting one another’s
expertise and working together with a clear goal in mind: that
quality resuscitation and early newborn care be available to every
baby born in China.
By Ashley Mastandrea
Baseline evaluation at a township clinic
“If you want to go fast, go alone.
If you want to go far, go together.”
(African proverb)
The stories presented in the Case Studies for Global Health
provide an inside look at the ways in which partners have
addressed the complex challenges of developing and delivering
effective health care for the developing world. They illustrate
the ways various stakeholders — private funders, world health
agencies, academics, pharmaceutical and biotechnology
companies, public-private partnerships, and governments —
have come together for a common purpose.
Some are success stories. Some are not. Most are works
in progress. But in every case, these are frank and honest
assessments of what was learned along the way.
ISBN #0-9778444-8-X