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Researchers Ignored Early COX-2 Warnings

March 16, 2005
Published studies of prescription painkillers Vioxx, Celebrex, and Bextra were largely geared to developing new uses for those drugs and were much less concerned with the question of whether they increased users' risk of heart attacks and strokes, according to a review of the medical literature by the Center for Science in the Public Interest (CSPI).

COX-2 Drugs • Bextra • Celebrex • Vioxx --- News • Celebrex May Disrupt Heart Rhythm • FDA Rejects Arcoxia As Arthritis Drug • FDA Panel Rejects Vioxx Replacement • FDA Panel Members Indebted to Drug Companies • COX-2 Painkillers Restricted in Europe • Researchers Ignored Early COX-2 Warnings • FDA to Improve Drug Safety Monitoring • FDA Convenes COX-2 Meeting • FDA Blasts Ads For Celebrex, Bextra • Feds Issue Caution On All COX-2 Drugs • British Heart Patients Told to Stop Taking Cox-2 Drugs • Researchers Warn of Dangers

That patients taking COX-2 inhibitors might be at greater risk of experiencing cardiovascular events became known in the medical community in 2001, when researchers from the Cleveland Clinic published a warning in the Journal of the American Medical Association.

Yet even after that report, none of the clinical trials published in the medical literature was designed to gauge that risk. And while CSPI found that many of the studies were funded by the drug companies themselves, even the independently funded trials failed to assess the overall cardiovascular impact of this class of drugs.

"The failure of researchers in both the private and public sectors to follow up on the critical safety questions raised in one of the earliest large trials for these drugs points out the need for an independent safety arm at the Food and Drug Administration to require such trials," said Merrill Goozner, director of the Integrity in Science project at the CSPI.

"Drug companies managed to enroll tens of thousands of patients in clinical trials aimed at selling more of these drugs, but none of them conducted a well-designed, placebo-controlled study to see whether these drugs caused heart attacks."

CSPI could determine the source of funding for 145 out of 237 published clinical trials of those drugs, known as COX-2 inhibitors. And of those 145, 103 were funded directly or indirectly by Merck and Pfizer, the companies behind the drugs, and 41 were funded by government or non-profit institutions.

Nearly 85 percent (87 of 103) of the industry-funded trials that have appeared in the academic literature since 2001 involved testing the pain relief afforded by COX-2 inhibitors for off-label uses, according to CSPI.

Just 16 (15.5 percent) of the trials funded by drug companies evaluated any type of health risk associated with the drugs, and only five (4.9 percent) of those had anything to do with cardiovascular risk. Three of those were funded by Pfizer, and sought only to measure narrow questions such as those involving drug-drug interactions among cardiovascular patients.

Public and non-profit institutions did no better at putting safety and heart health at the top of their agendas, according to CSPI. Of the 41 trials not funded by industry, just eight (19.5 percent) asked questions related to potential side effects of COX-2 inhibitors and none of those involved cardiovascular risk. Three of the trials whose funding could not be determined considered cardiovascular risk, but again, only in a narrow way.

CSPI found that the vast majority of the industry-funded trials in the literature were what are sometimes called "seeding" trials: clinical trials for common but off-label uses of drugs that have already been approved for narrower indications. Such seeding trials accounted for over 90 percent of the trials whose funding was undisclosed or could not be determined, which suggests that a high proportion of those were also industry-funded, according to CSPI.

"Drug companies are effusive in their self-congratulation over their big research and development budgets, but they tend to spend that money figuring out how to sell more drugs instead of answering these critical safety questions," Goozner said. "The idea is to get results published in a wide range of journals so that salespersons can deliver reprints to physicians in those specialties."

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

CSPI's review comes as the Food and Drug Administration is holding a three-day hearing to evaluate the magnitude of the cardiovascular risk posed by Vioxx and other COX-2 inhibitors. Its findings quantify problems finally being recognized by leading voices in the medical community.

"When clinical trials showed an increased risk of myocardial infarction, rather than consider this finding a major danger signal, the manufacturers designed trials to show efficacy for other indications and enhanced the cardiovascular safety monitoring in these subsequent trials," Dr. Jeffrey Drazen, editor of the New England Journal of Medicine, wrote yesterday.

"Had trials designed to test the question of cardiovascular toxicity directly been launched in 1999 and executed with urgency, substantial morbidity and perhaps a substantial number of deaths could have been prevented."

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