LAST month, the Archives of Internal Medicine published a scathing reassessment of a 12-year-old research study of Neurontin, a seizure drug made by Pfizer. The study, which had included more than 2,700 subjects and was carried out by Parke-Davis (now part of Pfizer), was notable for how poorly it was conducted. The investigators were inexperienced and untrained, and the design of the study was so flawed it generated few if any useful conclusions. Even more alarming, 11 patients in the study died and 73 more experienced “serious adverse events.” Yet there have been few headlines, no demands for sanctions or apologies, no national bioethics commissions pledging to investigate. Why not?
One reason is that the study was not quite what it seemed. It looked like a clinical trial, but as litigation documents have shown, it was actually a marketing device known as a “seeding trial.” The purpose of seeding trials is not to advance research but to make doctors familiar with a new drug. In a typical seeding trial, a pharmaceutical company will identify several hundred doctors and invite them to take part in a research study. Often the doctors are paid for each subject they recruit. As the trial proceeds, the doctors gradually get to know the drug, making them more likely to prescribe it later.
In an age of for-profit clinical research, this is the new face of scandal. Pharmaceutical companies promote their drugs with pseudo-studies that have little if any scientific merit, and patients naïvely sign up, unaware of the ways in which they are being used. Nobody really knows how often companies conduct such trials, but they appear with alarming regularity in pharmaceutical marketing documents. In the marketing plan for the antidepressant Lexapro for the 2004 fiscal year, Forest Laboratories described 102 Phase IV trials — the classification under which seeding trials fall — in a section labeled “Marketing Tactics.”
Oversight bodies like the Food and Drug Administration generally don’t view seeding trials as research scandals: seeding trials are not illegal, and the drugs in question have already received F.D.A. approval. But even after particularly egregious seeding trials have been exposed, the F.D.A. has not issued sanctions. Take the notorious Advantage study, a seeding trial of the pain reliever Vioxx conducted by Merck. According to a 2008 report in the Annals of Internal Medicine, litigation documents show that the Advantage study was conceived and managed by Merck’s marketing department. Three subjects died in the Advantage trial; five more subjects experienced heart attacks. Oversight bodies should treat the Advantage study as a violation of research ethics.
How can studies that endanger human subjects attract so little scrutiny? Forty years ago, when most clinical research took place in academic settings, the main dangers to research subjects came in service to genuine scientific aims. A large regulatory apparatus was developed to protect human subjects from the ambitions of overweening academic researchers. In the early 1990s, however, pharmaceutical companies realized that it was faster and less expensive to conduct trials in the private sector, where the driving force is not knowledge, but profit. And the regulatory apparatus designed for the old era has proved woefully inadequate for the new one.
The main source of protection for research subjects is a patchwork system of ethics committees known as institutional review boards, or I.R.B.’s. These are small, federally empowered bodies that review research proposals before they are carried out, to ensure that the studies are ethically sound. But they don’t typically pass judgment on whether a study is being carried out merely to market a drug. Nor do most I.R.B.’s have the requisite expertise to do so. Even worse, many I.R.B.’s are now themselves for-profit businesses, paid directly by the sponsors of the studies they evaluate. If one I.R.B. gets a reputation for being too strict, a pharmaceutical company can simply go elsewhere for its review.
Last week, the federal government announced that it was overhauling its rules governing the protection of human subjects. But the new rules would not stop seeding trials. It is time to admit that I.R.B.’s are simply incapable of overseeing a global, multibillion-dollar corporate enterprise. They should be replaced with an oversight system that is financially and administratively independent of the research it oversees. The system must have the power to impose sanctions, and its responsibilities must extend to fraud, bribery and corruption. Many patients volunteer for research in the hope that the knowledge generated will benefit others. When a company deceives them into volunteering for a useless study, it cynically exploits their good will, undermining the cause of legitimate research everywhere.
I’m not sure the FDA is the proper vehicle for regulation of Phase IV studies. I’d be more inclined towards criminalizing such activities myself. These people who undertake this kind of scheme know exactly what they’re doing, and are consciously stepping outside the lines of the intent of the law. That’s called "crime" in other similar situations.
Patients as commodities…