The huge discrepancy of life expectancy between the five richest and five poorest countries is one of the greatest disappointments in the 20th century.

While wealthy nations pursue drugs to treat baldness and obesity, depression in dogs, and erectile dysfunction, elsewhere millions are sick or dying from preventable or treatable infectious and parasitic diseasesD. J. Ncayiyana, "Africa can solve its own health problems," British Medical Journal, 324:688-9, March 23, 2002.. It's called the 10/90 gap.

"Less than 10% of the worldwide expenditure on health research and development is devoted to the major health problems of 90% of the population," explains Els Torreele, co-chair of a working group that provided background recently for an initiative announced by Medecins Sans Frontieres (MSF) to fight the gap.

MSF's Drugs for Neglected Diseases initiative (DNDi) will address what MSF-USA executive director Nicolas De Torrente called "a fundamental mismatch, expressed as millions of lives lost each year, between human needs and scientific innovation." Planning began in 1999, when MSF gathered international experts to identify contributing social, political, economic and technical factors, and to suggest solutions.

The March unveiling, in a packed auditorium at the Graduate Center of the City University of New York, attracted almost 400 people - an eclectic mix including government scientists from the United States and European Union, representatives of MSF and the World Health Organization (WHO), activists and health care workers, a brave few from the pharmaceutical industry and interested others.

The challenge is clear. "Old drugs are becoming less effective, existing drugs aren't being made, and no new drugs are on the horizon," summed up James Orbinski, working group co-chair and a researcher at the Munk Centre of International Relations at the University of Toronto. Of 137 drugs in the pipeline to treat infectious or parasitic disease, one targeted sleeping sickness and one malaria. Yet eight drugs are in clinical trials for erectile dysfunction, seven for obesity, and four for sleep disorders.
 

Defining the problem

Speakers described the crisis in sweeping and highly personal terms. Harold Varmus, president of Memorial Sloan-Kettering Cancer Center, cited the huge discrepancy of life expectancy between the five richest and five poorest countries as "one of the greatest disappointments in biological sciences in the 20th century."

Morten Rostrup, president of the International Council of MSF in Brussels, described his vigil with a young malaria patient: "For two days and two nights, I fought for the life of this 22-year-old with malaria. On the third night, I finally had to fall asleep, and the patient died. Something is failing terribly."

Yet malaria and tuberculosis are among the least neglected of the neglected diseases.K. Wengelnik et al., "A class of potent antimalarials and their specific accumulation in infected erythrocytes," Science, 295:1311-4, Feb. 15, 2002.  Visweswaran Navaratnam, professor of clinical pharmacology at the University of Science in Malaysia, provided a glimpse of the effect of parasitic disease on society: "An aboriginal farmer in Borneo had eight children, and filariasis, which causes elephantiasis. He became unable to support the family. He thought that the best answer, for him, was suicide. Why couldn't I have given him an alternative? Large populations given these problems can become nonfunctional."

To assess Big Pharma's commitment to neglected diseases, in spring 2001 the DNDi working group and the Harvard School of Public Health surveyed 20 large pharmaceutical firms in the United States, Europe, and Japan. Of 11 responders, eight had done no research over the past year in tuberculosis, malaria, African sleeping sickness, leishmaniasis, or Chagas disease; seven spent less than 1% of their research and development budget on any of these disorders.

In contrast, the Pharmaceutical Research and Manufacturers of America's New Medicines in Development survey www.phrma.org.  found that, of 137 drugs in the pipeline to treat infectious or parasitic disease, one targeted sleeping sickness and one malaria. Yet eight drugs are in clinical trials for erectile dysfunction, seven for obesity, and four for sleep disorders. The most neglected diseases affect predominantly people in the southern hemisphere who do not contribute to the pharmaceutical market. Torreele identified gaps in the drug pipeline that fuel the crisis.

The most important gap is the first, between basic research and preclinical investigations, which coincides with the public-to-private sector transition, she said. Added Paris-based Yves Champey, director of the feasibility study for DNDi, "Public research is producing a wealth of new knowledge on the agents of parasitic diseases, but the ideas are not being developed into medicines. We need a means to deploy new knowledge."

The second gap is from preclinical work to clinical trials, which requires a strategic decision and commitment within a company. "If there is a candidate drug to treat Alzheimer's and one to treat African sleeping sickness, it is easy to understand which one will go on to be developed," Torreele said. The final gap arises between clinical research and delivery to patients. Said Navaratnam, "Sitting in New Jersey or Geneva and trying to understand the dynamics of an illness in Botswana is very difficult. We need to get development of drugs to the people right where they need it." And that's exactly what the DNDi will do.

Taking action

Several countries, including Brazil, Thailand, Malaysia, India, China, Mexico, Argentina, and Korea, are already revving up their domestic drug production. These countries are setting examples for and actively assisting other governments. Most newsworthy has been Brazil's production of anti-HIV drugs, which the government provides to those in need.

The death rate from AIDS has been halved since Brazilian officials took matters into their own hands in 2001, and they are helping African nations follow their exampleG. Yamey, "US trade action threatens Brazilian AIDS programme," British Medical Journal, 322:383, 2001.. Cipla, an Indian generic drug manufacturer, is selling HIV cocktails to MSF for $350 per year per patientH. E. Kettler, R. Modi, "Building local research and development capacity for the prevention and cure of neglected diseases: the case of India," Bulletin of the World Health Organization, 79:742-7, 2001. 6. P. Jha et al., "Improving the health of the global poor," Science, 295:2036-9, March 15, 2002.. It's a new way of looking at health care financing.

"The system that wealthy countries use to develop innovative drugs doesn't work for most neglected diseases," said Champey. Added Orbinski, "We have to recognize that there is no viable market for these medications. To expect the private sector to step in and do R&D is a pipe dream." Approaches to flag economic interest include the "pull" of higher royalties for neglected diseases, and the "push" of government subsidy of basic research in certain diseases.

Increasingly, public-private partnerships, such as the collaboration among GlaxoSmithKline, the University of Liverpool, WHO and the UK's Department for International Development, are working to find new treatments for multidrug-resistant malaria. David Brandling-Bennet, deputy director of the Pan American Health Organization of WHO, listed such partnerships working to target a half dozen neglected diseases. Funding for the DNDi will come from what Orbinski called "charity replacing duty." It will rely mostly on fundraising, support of foundations such as the Pasteur Institute, and philanthropy.

"DNDi is not a public-private partnership in the way it has been defined over the past few years, but a partnership for public response to the crisis of neglected disease. The partners will be close to the need, and they are willing and able to assume responsibility as part of their public duty.

No pharmaceutical companies will be founding members, although DNDi can still have contracts with industry on focused projects," he explained. This reliance on giving is necessary because many industrial and government efforts seem out of sync with reality.

For example, five drug companies offered to cut HIV drug prices to MSF, but these costs are still three times Cipla's $350 yearly price tag. Navaratnam put this into a sobering perspective: "When someone's income is 10 cents a day, a medication reduced to $5 is still unaffordable." Varmus pointed out that the US government gives one-eighth of 1% of its gross national product (GNP) for the most neglected diseases, although that may change.

How scientists can help

"Scientists can use their credibility to advocate government spending on health care in poor countries," said Varmus, recommending the WHO's final report of the Commission on Macroeconomics and Healthas a "blueprint for advocacy."

And advocacy can become action. Varmus envisioned an "international corps for global science" in which scientists would serve a year or two on the frontlines.

He concluded, "Advances in biology and medicine can and must be used to combat disease in the developing world." With the framework that the DNDi will provide, that hope is one giant step closer to reality.