FDA Puts Medical Test Subjects in Danger

by Sonia Shah

With hardly a word in the mainstream press, the FDA has gutted the rules restraining drug companies from exploiting clinical trial subjects in developing countries.

Now that 80 percent of clinical trials fail to recruit sufficient numbers of test subjects on deadline, drug companies increasingly export their trials to developing countries, where sick, undertreated patients abound. It's faster, it's cheaper and it's easier to conduct the placebo-controlled trials that companies and the FDA prefer. There is precious little oversight of these trials. Unlike for domestic trials, the FDA does not require advance notice before drug companies take their trials outside US borders. And with 90 percent of trials failing to gain FDA approval, a massive number of trials are conducted, fail and then vanish with no agency review at all -- and little public record, if any.

Until now, the FDA's sole requirement for these overseas trials is that they adhere to the Declaration of Helsinki (or local rules, on the off chance that they are more stringent). Signed by the United States and thirty-four other countries in 1975, the Declaration of Helsinki consists of several dozen pithy principles to govern ethical research on humans, and is widely considered the gold standard in research ethics. Crafted and updated by the World Medical Association, a group representing dozens of national physicians' organizations from around the globe, the Declaration of Helsinki (DOH) urges voluntary informed consent, the use of independent committees to review and oversee trials, that investigators prioritise their subjects' well-being, that research subjects be assured access to the best health interventions identified in trials and that their societies enjoy a "reasonable likelihood" of benefiting from the results of trials.

It's not a perfect document. It's very short. It's a little vague. The FDA does not bother to enforce it. Even when they know of infractions -- such as in Pfizer's trial of the antibiotic Trovan in Nigeria, which not only failed to procure informed consent but didn't even have an oversight committee in place at the time of the trial -- the FDA has done nothing and approved the drug anyway. We know of that particular trial's violations only because the Washington Post exposed them several years later. In researching a book I wrote on clinical trials in developing countries, I similarly found many examples of trials clearly in violation of Helsinki provisions that were nevertheless reviewed and approved by the FDA.

The FDA has been agitating against the DOH since the late 1990s, when the World Medical Association strengthened the document's restrictions on placebo-controlled trials, which an unlikely alliance of industry, public health and academic researchers angrily challenged. The strengthened DOH, the FDA's medical director Robert Temple railed, "doesn't look like a group of suggestions that are worth discussing." Under pressure from the agency and drug companies, the World Medical Association diluted the objectionable language about placebo trials -- increasing the document's vagueness -- but by then the FDA was on the warpath. Just as President Bush opted out of international treaties on climate change and anti-ballistic missiles, in 2001 the FDA bucked two decades of its own precedents and refused to adopt updated versions of the internationally sanctioned Declaration of Helsinki. That done, in 2004, the agency proposed dumping the DOH from its codes altogether, and on April 28 announced it would indeed be summarily excised starting in October.

In its place, the FDA will incorporate "Good Clinical Practice" rules. Good clinical practice sounds, well, good, but these rules are no replacement for the Declaration of Helsinki. Unlike Helsinki, which describes ethical principles agreed upon by the international medical community, GCP rules are bureaucratic regulations crafted by regulatory authorities and drug industry trade groups, behind closed doors. They offer little by way of ethical precept. There is no injunction, for example, that research subjects be assured access to study drugs after trials end, or that their communities have a reasonable likelihood of enjoying the benefits of the research, principles of justice enshrined in the DOH.

The FDA's move against the DOH is more than a symbolic change. With drug companies rushing to countries where the domestic regulatory infrastructure is weak at best -- India, where Pfizer and GlaxoSmithKline have set up global clinical trial hubs, being perhaps the prime example -- and the FDA turning a blind eye, the business of protecting impoverished, sick, under-treated patients from exploitative experimentation falls almost entirely upon local people convened by clinics and hospitals to sit on FDA-required ethics committees. Theirs is a nearly impossible job, much of it shrouded in secrecy. Some, from India and South Africa, spoke to me, anonymously. They told me of how their clinics and hospitals desperately need the income drug-industry trials bring in. Of how, often, their bosses sit on the committees with them, pressuring members to approve as many experimental protocols as come in. They are overworked, underpaid and poorly trained -- if trained at all -- in the principles of research ethics. Even the most courageous among them find it difficult to challenge problematic experiments and interrupt the flow of industry dollars.

And yet, they do, and when they do, they rely upon the only set of rules that their administrators and drug company clients consider legitimate: those backed by the FDA.

The last-stand oversight of local ethics committees has clearly been insufficient. A growing body of evidence, from anthropological research to case studies, suggests that the consent of trial subjects in many poor countries is uninformed, and worse, non-voluntary. Many clinical-trial companies openly promote the non-voluntariness of trial subjects in developing countries, not as a reason to conduct fewer trials, but to conduct more. (Specifically, they promote the low dropout rates, a telling signal of coercion.) Anecdotal evidence of the abrogation of the principles of justice -- the lack of access to study drugs after trials end, the inaccessibility of the benefits of research, whether because of brand-name prices or the irrelevance of the resulting drug -- abounds.

That's how bad it has been with the Declaration of Helsinki on the books. What we don't know is how many more violations have been averted by the nameless, faceless people sitting on ethics committees in developing countries, relying upon the strictures of the Declaration of Helsinki. There is no way to know how many times they've been able to extract guarantees, protections, and promises from industry researchers, or to amend experiments so that subjects' rights and safety are better protected, thanks to the principles of the DOH.

All we can know is that come October, thanks to the FDA's scrapping of the gold standard in research ethics, their already difficult work will be made more so. Research subjects in developing countries -- often the poorest, the sickest, those with the fewest options -- can only become more vulnerable.

Sonia Shah is the author of a new book on malaria forthcoming from Farrar, Straus & Giroux and the website ResurgentMalaria.com. Her book The Body Hunters: Testing New Drugs on the World's Poorest Patients is now available in paperback.
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