Smackdown!

I'm really sorry that this is subscription only, it's definitely the sort of thing that the greedheads at the AMA (which gets most of its revenue from advertising in the journal) should make available to the public. But a lot of it is fairly technical, and I suppose it wouldn't have quite the endorphin-releasing effect on the general public that it does on me . . .

Anyway, I'm talking about hero whistleblower FDA scientist David Graham, who is now far too firmly in the public eye for them to get rid of him, as desperately as they want to. In the new JAMA (link for reference purposes only, you can't read it without a password), the good doctor lays waste to drug companies, the FDA and the congress (yup, like I said, they actually have a real job to do) over COX-2 inhibitors. Merck and Vioxx get the BFH (which the carpenters among you know stands for a particular category of Big Hammer), but the rest of them get a pretty good wacking with a 2x4. I shall summarize.

Our story begins with aspirin, which in spite of its miraculous properties is in the public domain and therefore impossible to make obscene profits off of. What to do, what to do . . .Aha! Aspirin does have one side effect, not extremely common but potentially worrisome, which is that it can cause gastric bleeding. It turns out that its anti-inflammatory and analgesic effects result from inhibition of an enzyme called cyclooxyenase (COX)2, while the gastrointestinal complications result from inibition of COX-1. So if you can design a drug that inhibits COX-2 but not COX-1, maybe you can get the good effects without the bad. You can also patent it, get exclusive marketing rights, and make a killing. (ha ha)

Of course, you also have to convince people that it's worth spending the vastly greater amount of money for patented new drugs. That requires advertising. And there is one other teeny weeny little problem. COX-1 inhibition slows blood clotting and relaxes the blood vessels, which is why aspirin protects against heart attacks. COX-2 inhibition opposes these effects, which might increase the risk of heart attacks.

Best not to think about that. In fact, there were indications of cardiovascular risk in the very first application to the FDA for approval of VIOXX, in 1998. But the FDA requires "complete certainty" before worrying about safety concerns. Indeed, in 1999, shortly after VIOXX was approved, the now-famous VIGOR study found a 500% increase in (in lay terms) heart attacks in people taking VIOXX, compared with people taking the aspirin-like naproxen. The company just claimed that naproxen protected against heart attacks, and that VIOXX wasn't actually causing them. It kept right on advertising the drug to consumers. Not until 2004, when another trial showed an increased risk when compared with placebo, did Merck withdraw the drug. It turns out, as everyone should have known, that naproxen has no cardioprotective effect. Meanwhile, Pfizer's rival drug celcoxib was found to increase cardiac risk in 2000, but Pfizer didn't tell anyone until 2005.

Merck claimed in 2004 that its trial showed that the increased risk of heart attacks didn't begin until people had been taking Vioxx for at least 18 months, but that turned out to be either a very stupid mistake or a big fat lie, which they finally admitted in 2006. (I won't go into the technicalities.)

Here's Dr. Graham's bottom line:

What should physicians do? For most patients with arthritis or other conditions who require chronic pain relief, naproxen appears to be the safest NSAID choice from a cardiovascular perspective. For patients at high risk of NSAID-related gastrointestinal tract complications, naproxen plus a proton pump inhibitor is less costly and as effective, and probably safer, than low-dose celecoxib. . .If COX-2 inhibitors cost substantially more, confer substantially greater cardiovascular risk, and offer no unique and meaningful gastrointestinal tract benefit over generic naproxen plus proton pump inhibitor, is there any point to the continued use of these drugs? Another critical area for research relates to the use of low-dose aspirin in the setting of COX-2 selective and nonselective NSAID use. It is unclear whether aspirin mitigates or abolishes NSAID-related MI risk, and, if so, how it may affect gastrointestinal tract risk. The concomitant use of aspirin would appear to contradict the premise underlying selective COX-2 inhibitor use.

Another key issue is to account for the long delay in defining the risks and benefits of COX-2 inhibitors. Part of the problem lies with FDA policies, practices, and procedures that lead it to ignore potential safety problems. Despite a priori concerns and disconcerting evidence in the preapproval application, the FDA approved rofecoxib, stating it lacked “complete certainty” that the drug increased cardiovascular risk. Such a standard does not protect consumers, is prejudicially favorable to industry and its financial interests, rewards drug companies for not aggressively pursuing safety questions, and guarantees that some drugs with major safety problems will be approved and, once approved, will remain on the market, even in the face of extensive patient harm. The failure to immediately withdraw high-dose rofecoxib from the market following publication of the results of the VIGOR trial, and to study quickly and intensively its cardiovascular risks at lower doses, increased the number of patients harmed by the drug as well as the profits made from its continued marketing. Only Congress can help prevent this from happening again by enacting legislation to create a separate and independent Center for Post-Marketing Safety within the FDA, empowered with the authority to identify and effectively deal with unsafe medicines and the companies that market them.

But guess what kids? Merck is now coming back with an application for approval of yet another COX-2 inhibitor, while Pfizers celecoxib (Celebrex) continues to be sold. Merck's claims on behalf of its new drug, as Graham shows, are based on cynical manipulation, using a trial designed to get deceptive results. They have no shame. Will the FDA?