On March 14 2002, Médecins Sans Frontières (MSF) held a conference in New York, USA, to address the crisis in research and development (R&D) for drugs for neglected diseases.

The conference brought together over 400 people, including a large diversity of representatives of health care and research institutions from developed and developing countries, key figures from the pharmaceutical industry, drug regulators, other experts on drug development and MSF field volunteers and staff.

The conference was preceded by a two-day expert workshop attended by over 170 people from over 30 countries. The following is a summary of key issues and findings from both the workshop and conference.

Introduction

According to the World Health Report 2000, infectious and parasitic diseases—most of which are preventable or treatable—are the primary causes of death worldwide.

The unavailability of appropriate drugs to treat these diseases is a result of increasing parasite resistance, discontinued production or high cost of drugs and, not least, the lack of ongoing R&D into these diseases.

Neglected diseases are diseases that represent an enduring medical need because they face a lack of effective, affordable and easy-to-use treatments. They fall into two categories: those like malaria and tuberculosis (TB), for which some pharmaceutical market exists in wealthy countries, attracting some private R&D efforts; and diseases like leishmaniasis, human African trypanosomiasis, Chagas disease, and lymphatic filariasis, for which there is virtually no market. Fourteen million people die of infectious diseases each year, 90% of them in poor countries of the Southern hemisphere. More than 50% of this mortality is in sub-Saharan Africa and Asia.

Dr. Bernard Pécoul, Director of MSF's Campaign for Access to Essential Medicines, gave an overview of the MSF's Access to Essential Medicines Campaign's efforts over the last three years to secure availability of and access to drugs for communicable diseases.

To address the lack of research for new drugs, MSF established the Drugs for Neglected Diseases Working Group in 1999 to study the epidemiological, political, economic and regulatory environment that created the crisis in R&D. The analysis of this multidisciplinary group of some 40 experts formed the backbone of the conference.

Several diseases are particularly illustrative of the crisis in R&D. Professor Shyam Sundar from Banaras University, India, discussed visceral leishmaniasis as a classic case study of the neglected disease crisis. The disease, which predominates in Southern Sudan, India and Brazil, is fatal if untreated.

The first-line drug, Pentostam, costs US$141 for a course of treatment, is complicated to administer under field conditions and causes severe side-effects. Moreover, in northeast India, its efficacy has declined to around 70% due to drug resistance. Amphotericin B is a very important drug, but is also very expensive and can only be used in hospitals, requires four to six weeks pf treatment and often results in a high fever.

Lipid-associated Amphotericin B (Ambisome) is another effective drug, and has few side-effects; a single-dose treatment was shown to have an excellent cure rate, but the cost for this drug (ten times ordinary Amphotericin B) is prohibitive in developing countries. More research is needed to find effective and affordable treatments. A number of other promising drugs are stalled in the clinical-trial phase for lack of funding.

Sleeping sickness is another very neglected disease. It affects 300,000 to 500,000 people a year in 36 African countries and is lethal if untreated. Treatments are old, have severe side-effects and no longer work in some places. The most common second-stage treatment, melarsoprol, is a 50-year-old arsenic derivative that can have lethal side-effects and fails to cure in 5% to 30% of cases.

Production of the only alternative (and more effective) drug, eflornithine, was abandoned for several years because of lack of profit, but production was recently resumed and is being made available through an arrangement between MSF, the WHO, and Aventis, which is offering a five year donation of the drug. However, it is difficult to administer under field conditions and its long-term availability is unclear.

Two drugs, nifurtimox and megazol, are very promising but have been stalled in different stages of development; funding and targeted R&D is needed to ensure clinical trials and further development for these drugs.

Market Failure and Public Policy Failure

Els Torreele, PhD, co-chair of the Drugs for Neglected Diseases Working Group, outlined the major gaps occurring along the drug development process. While basic research often takes place in university or government labs, development is almost exclusively done by the pharmaceutical industry, and the most significant gap is in the translation of basic research through to drug development from the public to the private sector.

Another critical point is the launching of clinical trials for promising candidate drugs, a decision taken by the pharmaceutical industry which is based mainly on potential financial return to shareholders.

The situation represents not only a failure of the market but also of public policy, because society has chosen to leave pharmaceutical R&D to the private sector and to reinforce their return on investment through patents, grants, tax credits, and state-subsidized health care.

The current market-based system fails when it comes to neglected diseases of the developing world. Only a new paradigm—one that ensures that the development of new medicines for neglected diseases is a public responsibility—can change this situation in a permanent way.

Producing more drugs for neglected diseases will require building a focused, disease-specific R&D agenda, stimulating R&D according to priorities and opportunities, said Dr. Dominique Legros, director of Epicentre. Thus far, the DND Working Group has identified drug and diagnostic research priorities for visceral leishmaniasis, human African trypanosomiasis (sleeping sickness), and malaria. Its objective is to stimulate research that includes short-, mid- and long-term R&D projects that are based on knowledge of the relevant science, needs of populations and participation by the best scientists in each project location. To help carry out this agenda, the DND Working Group has proposed the creation of a new, nonprofit, drug R&D initiative.

The conference featured much debate over whether improvements to the access crisis are well underway or whether a crisis situation prevails. Work is underway in a number of developing countries and through the efforts of The Special Program for Research and Training in Tropical Diseases (TDR) at WHO, national research institutes in the United States and Europe and public-private partnerships such as MMV, GATB and IAVI.

With recent headlines about the WTO declaration at Doha and the collapse of the pharmaceutical industry lawsuit against South Africa, there has been a subtle shift in recognition of the problem of access to medicines in the developing world.

Today, there is greater opportunity for non-industry-based innovative drug research, and small research groups, including those in the South, are capable of taking on various aspects of research. But as Dr. Graham Dukes of the University of Oslo pointed out, it has not yet begun to deeply affect policy in developed countries, and there is a need to defeat Western inertia around neglected diseases.

Solutions to the R&D Crisis

A number of governmental, intergovernmental and joint public-private organizations currently have R&D projects in progress for some of the most neglected diseases. Dyann Wirth, director of the Harvard Malaria Initiative and a professor of immunology and infectious diseases at Harvard School of Public Health pointed out that some efforts to develop drugs are "there or almost there" in a number of developing countries. Conference participants discussed the important role of each type of initiative in alleviating the neglected disease crisis.

Public-Private Partnerships

One model that has grown significantly and has gained substantial government and foundation support in the past decade is that of the public-private partnership (PPP) for health. Broadly defined, these PPPs are collaborations between public and private actors in global health which aim to improve access to drugs and stimulate discovery of easy-to-use, affordable, effective drugs. As Dr. Ariel Pablos-Mendez, of the Rockefeller Foundation put it, their "shared goals are more important than shared values."

Dr. Jean-Pierre Garnier, CEO of GlaxoSmithKline (GSK), said that no one entity can have an impact on the R&D issue. There must be partnerships, based on mutual trust, respect, and clearly defined goals. GSK has given $1 billion toward immunization of millions for river blindness and other diseases, and is working on a prototype for a malaria vaccine. In a new model, GSK has received finance for the latter project from the Gates Foundation. Its Institute for Tropical Diseases in Spain is looking at leishmaniasis and diarrheal diseases among others, but funding is needed to scale up these projects.

Dr. Giorgio Roscigno the Global Alliance for TB Drug Development outlined the current health PPP environment. There are 78 registered health PPPs, nearly half are based in the public sector; one-third of these are geared toward new drug development. But little effort is devoted to sustainable solutions - one-third are geared toward arranging drug donations - and very little is being done for the most neglected diseases.

Throughout the conference, it was argued that careful attention to patient participation, the governance, and accountability of PPP's is critical. Also, because they are still a recent phenomenon, PPPs have yet to yield tangible results and their success in increasing the availability of essential drugs remains to be proven.

Governmental and Intergovernmental Involvement

Dr. Brandling-Bennet, deputy director of PAHO, outlined the key role that the WHO has played in international public health. WHO was instrumental in eradicating smallpox through a major effort from 1967 to 1978 and seeks to repeat that success through its numerous public-private partnerships aimed at reducing or eradicating other specific diseases. However, some participants in the discussion questioned whether the WHO has backed away from the bold stance it took toward disease eradication earlier in the last century.

Dr. Robert Ridley outlined TDR's programs, which encompass a high level of expertise and engage in activities ranging from basic research to applied product and implementation research and training. Most of TDR's successes have come from public-private partnerships: for example the Onchocerciasis Control Program, funded by the WHO, UNDP, with a major donation of ivermectin by Merck, has achieved an 80% drug coverage of the population at risk.

TDR has also worked on drug development programs for sleeping sickness, leprosy, and malaria. TDR, said Dr. Ridley, is focusing increasingly on partnerships for strategic goals and is seeking to create more product R&D linkages with PPPs and industry.

Speakers Dr. Gerald Keusch, Director of the Fogarty International Center, National Institutes of Health (NIH), and Dr. Eve Slater of the US Health and Human Service Department said that, although the US health budget is generally devoted to health in the US, it is increasingly interested in international health.

Since 1994, the NIH has dramatically increased funding of research with international components, and its Institute for Tropical Medicine has a $195 million budget and is focused primarily on malaria, TB, and diarrheal diseases, as well as dengue and Chagas disease. It also promotes technology transfer, reagent repositories that are available to scientists worldwide, and support for clinical trials.

Dr. Keusch said that the NIH is strongly supportive of the idea that resource-rich nations need to share resources with resource-poor nations. NIH supports scientific work on global health issues being done by young scientists from poor nations, and is increasingly engaged in partnerships with the WHO, PAHO, other regional partners, governments, and academic institutions in developing countries, particularly working on setting up ethical structures to prevent exploitation.

On the need for more resources, Dr. Michel Pletschette from the European Commission talked of the need for countries to raise their contribution to development aid. Development aid is a major area of investment for the European Union, which has been working to encourage countries to raise their contributions. The EU has engaged in small research partnerships, such as one promoting African capacity building for neglected diseases. But much more resources are required. Dr. Pletschette said that if citizens understood their governments' capacity to improve global health, they would demand that urgent steps be taken.

Capacity-Building Networks in Developing Countries

Numerous conference speakers emphasized the importance of using and building the nascent drug development capacity that exists in the developing world. Sakiko Fukuda-Parr of the UNDP said that "the solution is not an issue of access, but of production capacity in the developing world." Dr. Navaratnam of the Universiti Sains Malaysia added that certain projects could be started right away - capacity and motivation for drug R&D and production exist for example, in India, South Africa, Brazil, Thailand, and Malaysia.

But to truly develop capacity, a number of needs must be met. First, fragmented capabilities — from lead-compound discovery, to clinical trials, to actual production — must be harnessed. One potential model is for several countries of the South to unite and resolve common technical problems and maximize their capacities around targeted drug development goals.

Dr. Eloan Dos Santos Pinheiro, director of Far Manguinhos (a drug research, development, and production unit of Brazil's Ministry of Health) said her institution has helped Brazil meet its goal of providing medicines free of charge to its population; R&D decisions are based on the social or financial demand for drugs, rather than profit, and inroads have been made in developing drugs for neglected diseases. Far Manguinhos has come up with innovative ways to ensure that intellectual property rights work to the benefit of the population. However, there are still gaps in the research capacity in Brazil, and targeted capacity building is needed to bridge these.

Public Sector Drug Development: the DNDi

Dr. Yves Champey presented the DND working group's proposal to set up a not for profit Drugs for Neglected Diseases Initiative (DNDi) that will engage in targeted drug R&D for neglected diseases. Although its priority is to produce drugs rapidly, the DNDi will rely on and help create R&D networks based in the developing world and will seek to enhance capacity through its work.

The DNDi will work closely with the TDR and other initiatives to avoid duplication and will tap resources and expertise from the small number of developing countries that have established education and research centers.

The DNDi will work closely with academic and research institutions as well as regulatory authorities in industrialized and less-industrialized countries. Recognizing that few institutions are capable of translating knowledge into drug innovation, it will work on a limited and clearly defined basis with the pharmaceutical industry.

To proceed, the DNDi will require substantial funding. It will also need independence to choose partners, countries in which to operate, and compounds to prioritize. Discussions are under way with a number of co-founders including TDR and R&D institutions in France, India, Brazil, and Malaysia.

Several drug R&D projects have already been initiated in collaboration with other organizations: the pre-clinical validation of megazol for sleeping sickness, the development of two artesunate fixed-dose combinations and one blister pack for malaria, and the end-stage development and registration of paromomycin for visceral leishmaniasis.

Challenges to Overcome

Throughout the conference, regulation, funding, and capacity building in the South emerged as the key challenges facing all efforts—from small nonprofit endeavors to major industrial ones—to develop drugs for neglected diseases.

Capacity Enhancement

Dr. Navatnaram said that major pharmaceutical companies use expertise from the South, and some US generics are produced in India and Thailand. Although there has been mass technology transfer, especially to India, by way of reverse engineering of generic drugs, technology transfer through collaborative efforts is often done with little planning, and rarely involves the newest technology is often not involved.

The real key to success will be political commitment to sustainable R&D on the part of governments whose populations will benefit from new drug development. Developing countries need their local and national governments to take more responsibility to obtain needed cooperation and build infrastructure. Local political commitment, strong administrative support, and adequate, committed human resources are needed. Prof. Wirth argued that sustaining public awareness is an absolute prerequisite to such governmental commitment.

Doctors and community workers need to be involved in building drug-delivery systems to ensure rational use of drugs. Essential hands-on expertise can be gained in the course of Phase II/III clinical trials conducted in the developing world. There is potential for greater collaboration among scientists from developed and developing countries

Fighting neglected diseases requires the capacity for laboratory research, field and epidemiological research, clinical research carried out locally, and production, distribution and monitoring capabilities, said Dr. Michèle Boccoz of the Institut Pasteur. In addition, huge quantities of funding must be mobilised to produce needed drugs, and this will require greater public awareness and support. Dr Ayoade Oduala from the University of Ibadan, Nigeria, and TDR, affirmed the critical importance of capacity enhancement and capacity utilization to produce what is needed and break the existing cycles of dependency.

Regulatory Issues

Dr. Krisantha Weerasuriya, Acting Regional Adviser of the WHO Essential Drugs and Medicines Policy in New Delhi, pointed out that people in the developing world have generally benefited from the drug-regulatory framework established by the developed world.

But recently, the move from a regulatory agenda to regulatory rules, such as those set by the International Conference on Harmonization, has become a challenge for public health in the developing world. These rules threaten local regulators' autonomy to make drug decisions appropriate to their populations.

Dr. Weerasuriya argued that there should not be a globally uniform rules-based technical approach to drug quality, safety, and efficacy. Rather, these issues should be tied to country-specific public health needs. To achieve this, support will be needed for drug regulatory authorities in the developing world. Countries that have the diseases should be the decision-makers, and regional regulatory networks must be developed further.

Patents and Trade Rules

Jamie Love, Director of the Consumer Project on Technology, explained that governments support R&D through intellectual property laws, direct investment, research mandates and treaties, tax credits, and subsidies. But R&D into neglected diseases cannot be appropriated by any party for gain. Patents lead to high prices, and, when there are too many patents in one area, inhibition of research (e.g., stem cell research). Tax credits lead to decentralized decision-making but are biased against nonprofit research.

Governments could enforce corporate obligations to engage in specific R&D work, as it does in other industrial areas. Love concluded that "there is a legitimate trade issue in defining who will pay for R&D," adding that, like the landmine treaty or the Kyoto treaty on the environment, access to drugs could be the subject of trade treaties.

Workshop participants put forward the need to explore new paradigms for intellectual property rights while simultaneously identifying best current IPR practices. The assumption that patents are a prerequisite to stimulate R&D should be critically examined, especially in the context of neglected diseases.

The possible role and influence of patents on public sector research should also be looked at, and ways to protect public rights to government funded R&D need to be identified and enforced. The international legal, policy and human rights instruments should to be examined in relation to options of using treaties, and code of conduct approaches to licensing around R&D for neglected diseases could be explored.

Next Steps

A broad perspective should be taken in viewing the access crisis, looking to enhance drug research and development capacity, as well as the capacity of regulators and health systems at the regional and sub-regional levels. Advocacy for continued public and governmental awareness of the access crisis is a prerequisite.

Reviewing several key issues that emerged from the conference Dr. James Orbinski, co-chair of the DND working group, said that today's R&D activities are fragmented, with no market or public policy-driven agenda for neglected diseases. Existing capacity in the South must be utilized, coordinated and harnessed. He reiterated the need for a public sector response to the crisis in R&D for neglected diseases such as a not-for-profit drug R&D initiative. The historic advances that have taken place in TB, cancer, and AIDS have come about through strong advocacy from the public.

"As citizens, we must translate our passion into action and push our governments to make access to essential medicines a reality," Dr. Orbinski concluded.