5 December 2002 23:00 GMT

by Vicki Brower

Available drugs and diagnostics for diseases that plague developing nations are "outrageously outdated," said Carol Nacy, Chief Executive Officer of the Rockville, MD-based biotech company Sequella. "Tuberculosis, at the turn of the millennium, is grievously out of control," said Nacy, speaking at the Partnering for Global Health Forum in Washington, D.C., an event jointly sponsored by the Biotechnology Industry Organization (BIO) and the Bill and Melinda Gates Foundation. "How would you feel if a doctor told you she'd treat you with 50-year old medicine and 100-year-old diagnostics? You would be outraged," she said.

Sequella is one of a handful of biopharmaceutical companies that is focusing its drug development exclusively on global infectious diseases. The five-year old company is beginning with TB. Noting that in 2001, two to three million people worldwide died from this disease, more than 100 million people were tested, and almost 9 million were diagnosed with TB, Nacy observed that for a small biotech company, tuberculosis represents both an urgent global health crisis and an excellent business opportunity. As a result of successful public and private partnering (with the Gates Foundation and the National Institutes of Health, among others), Sequella described the progress of five products through its pipeline in five short years. It will begin Phase III testing of a new rapid Patch Test for active TB early next year, a therapeutic vaccine and the first of its new TB drugs will be in trials in late 2003/early 2004.

Sequella has been testing its drugs and diagnostics for the past four years in South Africa, an area extremely hard struck by the epidemic. During that period, it has trained skilled lab personnel and set up a clinical site where the epidemiology, human genetics and molecular epidemiology of TB are being studied. The team is currently preparing a site for Phase II and Phase III clinical trials. Along the way the Sequella team has learned that the need to create trust in the community through understanding - not just its health problems, but also its politics and culture - is as important as getting the science right.

Offering some historical perspective, Brian Greenwood of the London School of Hygiene and Tropical Medicine noted that when he began working in Nigeria on the prevention of meningococcal disease in 1978, no studies were conducted with regulatory oversight. The past 25 years has seen significant change: in East Gambia, where he recently worked, there is now FDA approval for trials and five ethics committees. In place, are a regulatory presence, good clinical practices, and a serious effort to deal with complex ethical issues, including informed consent and medical care delivery post-trial. An ongoing issue is whether trial participants will have access to the product being tested, however. Moving forward, what is needed is more staff, more patient education, additional training of ethics committees, and more clinical trial centers.

While conditions have changed for the better in just the past 10 years in Ghana, serious challenges remain, said Fred Newton Binka, executive director of the INDEPTH Network based at the University of Ghana, a nongovernmental organization comprised of 28 demographic surveillance system field sites in 16 countries. INDEPTH monitors 1.8 million people at a household-level as a platform for the design and evaluation of healthcare innovations and research studies.

Binka recounted experiences from trials in Ghana with vitamin A supplementation, permethrin-impregnated nets for children's sleep areas, intermittent treatment of malaria, rotavirus vaccine and tafenoquine for malaria prevention. While the Ministry of Health has forged links with universities and other partners to improve research training and disease control, regulatory practices are still thin or non-existent, there is a dearth of labs, good clinical and lab practices practice are rudimentary or lacking, and ethics boards are bare-bones, says Binka.

"There are serious inequalities in power and advantage in conducting clinical research in developing countries," agreed Sandy Thomas, director of the UK's Nuffield Council on Bioethics. Last May, the Council published a critical report on research ethics, which was precipitated by a controversial study published three years ago in the New England Journal of Medicine on the reduction of HIV transmission to infants by short-course AZT therapy. Is it ethical to develop a second - inferior - standard of care for developing countries because of a lack of resources, Thomas asked.

The Nuffield report suggests a framework of duties and responsibilities of those who design clinical trials for developing nations, identifying minimum requirements to be met in all circumstances. It encourages nations to set their own priorities for health care, and to set up their own guidelines. "The existing international - CIOMS and Helsinki - guidelines on research ethics are ambiguous, too diverse, and need revision," she said.

The Council identified the key issues of informed consent, standard of care (universal compared with what is available in a particular region), post-trial access to drugs and diagnostics, the ethical review of research, and the role of sponsors as particularly pressing. It recommended that the universal standard of care be offered to the control group after the trial; where not appropriate, the minimum is the best treatment offered by the national public health system. It also recommended that post-trial access to all should be secured for effective interventions. In spite of current pitfalls, "it is not only possible but absolutely essential to do this research in developing countries," urged Thomas.

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