FDA Approval of Marketing the COX-2 Inhibitors

The FDA approved the marketing of Vioxx, Celebrex and Bextra last week. In light of the question of possible increased risk of MI, stroke and death compared to conventional nonsteroidal antiinflammatory drugs (NSAID's), this raises many concerns. I'd like to make some observations regarding some of those concerns.

Click here for the complete essay.The FDA approved the marketing of Vioxx, Celebrex and Bextra last week. In light of the question of possible increased risk of MI, stroke and death compared to conventional nonsteroidal antiinflammatory drugs (NSAID's), this raises many concerns. Some observations I would make regarding this decision:

1) There is significant (though not overwhelming) data from several distinct studies that suggest that the COX-2 inhibitors confer an increased risk. Such data has been known for quite some time. See Karha and Topol.

2) The COX-2 inhibitors are drugs with a MASSIVE patient base. Even a very small increase in excess risk over conventional NSAID's with regard to cardiovascular and stroke risk would correspond to a large number of excess MI's, strokes and deaths. Even a 1% increased risk in a class of drugs with many millions of users would be catastrophic.

3) The increased risk is mainly observed in patients who use higher than standard doses for longer than recommended periods. Patients likely to require COX-2 inhibitors are exactly those most likely to use them at higher doses and for longer i.e. patients with chronic pain conditions such as osteoarthritis. Furthermore, patients with chronic inflammatory arthritides such as rheumatoid arthritis (also common users of COX-2 inhibitors) are known to have increased risk of cardiovascular disease to begin with. These would be exactly the types of patients with the highest expected rate of complications from COX-2 inhibitors.

4) The COX-2 inhibitors are a class of drugs with NO demonstrated advantages over other nonsteroidal antiinflammatory drugs (NSAID's) other than fewer gastrointestinal side-effects. This reduction in GI problems can also be achieved with conventional NSAID's by adding a drug called a proton pump inhibitor (Prevacid, Nexium, Protonix, others). See Chan FK et. al. PPI's are not known to have the same cardiovascular risks.

For these reasons, the question I would ask is: what business does the FDA have in rushing their new recommendations of these drugs? The COX-2 inhibitors are most assuredly NOT lifesaving or indispensable nor do they make a revolutionary impact on the health of the public ( factors that would argue a more laissez-faire approach).

To me, this decision raises uncomfortable possibilities that require close scrutiny. Is the FDA operating under an agenda OTHER than promoting the health of Americans (and by its reputation global health)? Note the following consequences of their actions:

• This decision will have a potentially favorable impact for the defense on the outcome of large class action lawsuits of Merck and possibly Pfizer.
• The FDA's decision is a marketing bonanza for Merck and Pfizer. Right now, many patients (not to mention their physicians) are frightened to continue taking these medicines. The FDA's recommendations will surely be interpreted by such patients as a re-endorsement. While many physicians will be reluctant to represcribe these drugs, their patients will begin demanding them again.
• This decision will also empower the drug companies to step up their advertising to physicians. I can already envision the Pfizer reps that call on my institution to reaffirm the safety of their drugs with this newfound endorsement from the federal government.

To me, it is inconceivable that the risks to the public's health can possibly be worth the perceived benefits of these drugs. Currently, there are several longterm studies being performed to further characterize the risks and benefits of these drugs. Given the ready availability of alternatives to the COX-2 inhibitors, it seems so obvious that the sensible course is one of prudence.

Was the FDA under pressure from higher up to soften their position? Could their decision makers be operating under any conflicts of interest that need to be revealed? To me this decision is so unusual that such questions need to be investigated. At a minimum, the FDA needs to justify its position more clearly and more openly.

As an aside, I was rather curious as to whether or not there is a precedence for "reapproving" a drug for sale in the US that had previously been removed (Vioxx). Apparently there is only one (for a drug called Lotronex) at least since 1990. As USA Today reported, The FDA:

"restricted the drug to women with severe symptoms and for whom other treatments failed. Among other things, patients have to sign consent forms indicating they're aware of potential risks. Doctors must enroll in a program to assure they understand them."

Seems pretty restrictive to me!