Marcia Angell has an interesting article in the New York Review of Books on the case of Vioxx, the painkiller drug that was withdrawn after it was found to cause heart attacks. (She cites an estimate of tens of thousands of heart attacks caused by the use of Vioxx and related drugs, referring to Eric J. Topol, “Failing the Public Health—Rofecoxib, Merck, and the FDA,” The New England Journal of Medicine, October 21, 2004.) Angell writes,
In late 1998 and early 1999, Celebrex and then Vioxx were approved by the FDA. They were given rapid “priority” reviews—which means the FDA believed them likely to be improvements over drugs already sold to treat arthritis pain. Was that warranted? Neither drug was ever shown to be any better for pain relief than over-the-counter remedies such as aspirin or ibuprofen (Advil) or naproxen (Aleve). But theory predicted that COX-2 inhibitors would be easier on the stomach, and that was the reason for the enthusiasm. As it turned out, though, only Vioxx was shown to reduce the rate of serious stomach problems, like bleeding ulcers, and then, mainly in people already prone to these problems, a small fraction of users. In other words, the theory just didn’t work out as anticipated.
Furthermore, people vulnerable to stomach ulcers could probably get the same protection and pain relief by taking a proton-pump inhibitor (like Prilosec) along with an over-the-counter pain reliever. So the COX-2 inhibitors did not really fill an unmet need, despite the one seemingly attractive claim made in favor of them.
She also goes into detail on conflict of interest in the FDA advisory committees, and recommends that the FDA shouldn’t approve new drugs so hastily. This sounds like a good recommendation for Vioxx etc. (tens of thousands of heart attacks doesn’t seem good). But how many drugs are there on the other side—effective drugs that are still waiting for approval? I’m curious what Angell’s colleagues at the Harvard Center for Risk Analysis would say. Would it be possible to have an approval process that catches the Vioxx-type drugs but approves others faster?
I am in no way a fan of the FDA, but in their defense…Cox-2 Inhibitors weren’t prescribed as intended by the companies that produced them. These drugs were only in short-term trials and were shown to be very safe with few adverse effects, including gastritis and ulcers. These heart attacks occurred after long-term usage prescribed by doctors, but doctors aren’t sharing any responsibility in the problem.
More on the topic, another interesting issue is with the cost-benefit of some drugs. I worked on a study for a drug that was supposed to help obesity. It didn’t help obesity at all, but it turned out it worked wonders for anorexia. Unfortunately, there is a billion dollar market for an obesity pill but a very small market for anorexia, so the company stopped the research. Consequently, there is a drug out there that can possibly cure anorexia but since it won’t make enough money, it won’t be on the market.
Expedited drug review is probably appropriate when that drug is the first drug for the treatment of that condition or shows a clinically significant (not just statistically significant) benefit. However, if there are alternatives to the treatment of that particular disease, I would urge strong caution in approving any new drug. For example, if a drug has been shown to cure HIV and not just suppress virus, it should get expedited review. On the other hand, if that drug is one of those many “me too” drugs, then its saftey should be proven before its approval. Furthermore, if a drug gets an expedited approval, the pharmaceutical company should be required to conduct post-marketing clinical trials to confirm the safety (and efficacy) of the drug.
As far as FDA is concerned, there is something seriously wrong with it. Let me give an example of a drug 'muraglitazar'. An advisory committee for the FDA Endocrinology and Metabolic Drugs Division reviewed this drug at an open public hearing on September 9, 2005, and recommended approval of the drug as monotherapy for treatment of type 2 diabetes (by an 8:1 vote) and as combination therapy in patients with blood glucose not adequately controlled with metformin (by a 7:2 vote). This drug is a dual-PPAR agonist and can treat both diabetes and hypertriglyceridemia (a lipid disorder), a combination frequently found in patients with diabetes. FDA panel reviewed 5 clinical trials. In a subsequent study (http://jama.ama-assn.org/cgi/content/abstract/294/20/2581), pooling of the results from the same five trials found an increased risk of death, cardiovascular events, and congestive heart failure. Of course, individual trials were not powered to evaluate these adverse outcomes. One wonder, why FDA panel did not look at the data collectively.
Back to COX-2 inhibitors, if FDA approves a drug for a disease that is chronic, such as osteoarthritis, FDA should evaluate safety of that drug when taken for extended periods. Otherwise, that drug should be approved for illnesses of limited duration, such as acute pain.