The Wall Street Journal this morning reports on a study in the Annals of Internal Medicine that uses internal Merck documents to show that the company consciously engaged in a scientifically dubious trial of Vioxx whose primary purpose was to encourage doctors to use the drug. Such trials are called "seeding" trials because they're seen as a way to plant seeds in the minds of physicians who enroll their patients in the trial to favor the drug over its competitors after the trial is over. The authors of the study have served as consultants for plaintiff attorneys suing Merck.

Any accompanying editorial by the editors of the Annals asks doctors to "just say no" to seeding trials.

Better late than never. In February 2005, on the day that the Food and Drug Administration advisory committee met to discuss whether the Cox-2 painkillers Vioxx, Celebrex and Bextra should be pulled from the market, the Center for Science in the Public Interest's Integrity in Science project (i.e., me and my assistant) released a report entitled "A Failure To Ask the Right Questions" that documented that nearly 85 percent of the Merck and Pfizer-funded clinical trials on Cox-2 inhibitors that appeared in the medical literature after the drugs were approved were seeding trials. That report involved a review of hundreds of clinical trials (including the 2003 ADVANTAGE trial that is the subject of today's Annals study), and took nearly three months of work.

Even though CSPI sent out a general press release, the study received zero press attention at the time.

I'm glad the Annals ran this study today showing that Merck's top officials knew they were engaged in running an ethically troubling clinical trial whose sole purpose was to further the marketing goals of the company. But I assure you, it wasn't just one. And it wasn't just Merck. And one didn't need smoking-gun emails obtained in litigation to know that.

What were the institutional review boards thinking when they approved this and other seeding trials? The editorial in today's Annals struck me as incredibly naive on this point:

The documents do tell us that deception is the key to a successful seeding trial. That information—once it becomes general knowledge—could be the fatal blow for seeding trials. Institutional review boards, whose purpose is to protect humans who participate in research, would probably not likely approve an action that places patients in harms' way in order to influence physicians' prescribing habits. If they knew, few established clinical researchers would participate as coinvestigators. Few physicians would knowingly enroll their patients in a study that placed them at risk in order to provide a company with a marketing advantage, and few patients would agree to participate. Seeding trials can occur only because the company does not disclose their true purpose to anyone who could say "no."

What do they expect -- that companies will put a stamp on the cover of their patient enrollment documents stating: "Warning: This is a seeding trial and serves no scientific purpose"? The ADVANTAGE trial at least had the superficial rationale that it was trying to determine if Vioxx had fewer gastrointestinal side effects than a generic over-the-counter painkiller. Had that finding been shown to the FDA's satisfaction (the original study in the Annals claimed that Vioxx led to less use of acid indigestion medicine), it would have actually helped Merck and patients. But that trial, like the others testing gastrointestinal side effects, never proved the drug sufficiently superior to other painkillers to avoid the label warning that it might cause an upset stomach in about 2 to 4 percent of patients.

Now let's look at one of the Merck seeding trials highlighted in the CSPI study:

Merck funded 12 physicians associated with the Altoona Center for Clinical Research to test Vioxx against a traditional nonsteroidal anti-inflammatory drug made by one of its rivals for arthritis of the knee. The results, published last year (2004) in the Journal of the American Geriatric Society, showed both worked, both were well tolerated and Vioxx offered slightly faster pain relief.

Somewhere there is an IRB that approved that study. Somewhere there is an IRB that needs to be investigated by the Food and Drug Administration. Trials like the one highlighted in the CSPI study, just as much if not more than the ADVANTAGE trial, are violations of the basic ethical guidelines that supposedly protect patients in clinical trials: that the trial serve a legitimate scientific purpose.

This situation cannot be remedied by more disclosure and a plea to IRBs and individual physicians to resist the commercial entreaties of drug companies. This is a matter of institutional culpability, and the responsibility of regulatory agencies to police it.