Recruiting patients into clinical trials to test new drugs is rarely straightforward. Even without fiascos like the trial of TGN1412 in London earlier this year, in which six healthy volunteers suffered multiple organ failure, four out of five clinical trials in the west have been failing to enrol sufficient numbers of test subjects. For drug companies, each day a potential blockbuster remains locked up in R&D can represent $1 million in lost sales.
One response to this crisis has been to export the last phases of clinical trials to developing countries, where sick and desperate people abound. Seventy-five per cent of deaths from chronic non-communicable diseases such as heart disease, diabetes and hypertension occur in developing countries, and relatively few people there have access to any treatment for their conditions.
While the World Health Organization recognises this to be a public health disaster of staggering proportions, for contract research companies and their drug company clients it is an opportunity. Here they can easily recruit subjects suffering diseases common in the west. Merck, GlaxoSmithKline and Wyeth say that at least half of their clinical trials this year for new drugs are being conducted outside the US and western Europe.
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The potential for exploitation and for violations of research ethics is hard to ignore. Take voluntary informed consent, universally considered the cornerstone of ethical clinical research. A steady stream of people dropping out of trials is generally interpreted as confirmation of voluntary consent, with up to 45 per cent of subjects dropping out in some trials in the west. In poor countries, this phenomenon is disturbingly scarce. When Quarraisha Karim and others from South Africa鈥檚 Centre for Epidemiological Research in Durban probed the issue by questioning people already enrolled in an HIV prevention trial, they found that 80 per cent were unaware that they were free to leave the trial. Similar results were obtained in Bangladesh. Some contract-research companies go so far as to tout the low drop-out rate in developing countries as a reason to site more trials there. One New Delhi-based company boasts in its promotional literature that it retains 99.5 per cent of enrolled subjects.
鈥淭he potential for exploitation and for violations of research ethics is hard to ignore鈥�
Neither the US Food and Drug Administration (FDA) nor the European Medicines Agency (EMEA) requires that drug makers submit their clinical trial plans before they start trials abroad. In stark contrast to their approach to western trials, the FDA and EMEA simply accept the word of local ethics committees and local regulators that ethical standards have been met, despite obvious signs of unresolved conflicts of interest. In India, where Pfizer, GlaxoSmithKline and AstraZeneca have set up centres for clinical trials, government officials have announced their intention to increase the drug trials business from $70 million to $1 billion annually, and have exempted experimental drugs from customs duties, offered generous tax concessions, and weakened other restrictions to make it happen. Despite a well-documented history of transgressions in clinical research, the few rules governing medicine and the pharmaceutical industry are lightly enforced at best. 鈥淓ven if an erring company is caught red-handed indulging in illegal activities,鈥� writes Indian industry analyst Chandra Gulhati, 鈥渋t is let off鈥� with a light warning.鈥�
So what would help? For a start, requiring prior review of clinical trials by western regulatory authorities as well as independent confirmation of subjects鈥� consent. Unfortunately, the FDA and other regulatory bodies seem more interested in ensuring speedy trials than enforcing ethical standards. In 2001, the FDA refused to incorporate revisions of the World Medical Association鈥檚 premier research-ethics code, the Declaration of Helsinki, which reinforced protection for research subjects in placebo trials. In 2004, the FDA proposed dropping the Declaration of Helsinki from its codes altogether. In its place it suggested using a set of rules written by drug industry trade associations together with US, European and Japanese regulatory authorities, which focus on the technical aspects of gathering data rather than ethics.
This is a health issue, as well as one of human rights. Mistrust of western medicine is on the rise in developing countries. In Nigeria, polio vaccine was rejected as poison; in South Africa, government ministers continue to question the link between HIV and AIDS; and in Cameroon, Cambodia and elsewhere, AIDS prevention trials have been condemned and abandoned.
A boom in poorly regulated clinical trials in developing countries will only deepen this crisis of trust. One consequence will be to make drug-industry trials more difficult in the long run. More importantly, it will also threaten public health research in poor countries. That is the kind of clinical research the developing world needs more of, not less.
