The FDA gets flack from both sides. Advocates for earlier release of drugs to treat serious illnesses say the agency is too slow to approve them. More noise comes from those who believe that the FDA is too lax in allowing unsafe drugs to reach the market. There is no way the FDA is going to please everyone. People on both sides of the question are passionate and well-meaning.
Clearly the FDA has not and will not always get it right. There will never be absolute certainty about short and long term side effects of any new drug. It doesnâ€™t matter how many studies are done prior to approval.
To illustrate what problems can arise after a drug is approved, letâ€™s take a look back at the painkiller Vioxx, which was pulled off the market in 2004, and the diabetes drug Avandia, which is still on the market.
The Vioxx story
Non steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Motrin, Advil) and naproxen (Naprosyn, Aleve) work by blocking the action of COX enzymes. However, only one of these enzymes, COX-2, really matters as a target for treating pain and decreasing inflammation. But the older NSAIDs are not selective; they block COX-1 as well as COX-2. COX-1 plays an important role in keeping the stomach lining from getting eaten away by its own acid. When COX-1 gets blocked, gastritis and ulcers are more likely to occur.
Vioxx was the first of the selective COX-2 inhibitors. In theory, it should have been a safer drug to treat arthritis and other painful conditions. And the results of early studies confirmed that Vioxx was as effective as older NSAIDs with less risk of stomach ulcers and internal bleeding. So what happened?
Studies on Vioxx done prior to the drugâ€™s approval showed an unexpected finding: people taking Vioxx had a slightly higher rate of heart attack compared to people taking the older NSAID naproxen. Merck put a warning into the package insert to reflect this risk.
For all prescription drugs, package inserts contain information about known and potential side effects under three categories:
Â·Â Â Â Â Â Â Â Â Contraindications â€“ reasons you should never use the drug unless no alternative therapy is available. The drug could cause serious injury and possible death if used in this way.
Â·Â Â Â Â Â Â Â Â Black box warnings â€“ extreme caution about a serious side effect that may pertain to certain patients, a side effect that needs special monitoring by the prescribing doctor, or both.
Â·Â Â Â Â Â Â Â Â Warnings â€“ established problems when the drug is used in certain situations and alerts to serious problems that can arise in anyone taking the drug.
Â·Â Â Â Â Â Â Â Â Precautions â€“ side effects that may occur but that are not proven to definitely occur, and less serious side effects that still should be monitored by the prescribing doctor.
Merck mentioned the potential heart problem under â€œprecautions,â€ the least serious category. While the company did state that caution should be used when prescribing Vioxx in patients with known coronary heart disease, the bottom line was: â€œthe significance of the cardiovascular findings from three studies is unknown.â€
Merck pulled Vioxx off the market when additional information and new analysis of the data revealed a more definitive risk of heart attack in January, 2004.
Avandiaâ€™s turn in the spotlight
More recently, the diabetes drug Avandia has been in the spotlight because some studies show a potentially higher heart attack risk in people who take the drug versus those who take a placebo. Avandia controls blood sugars in people with type 2 diabetes in ways that should have been good for the heart, at least theoretically. It makes insulin work better, and causes less weight gain compared to insulin shots and other sugar-lowering pills.Â
It was known that people with heart failure should not take Avandia because it can make heart failure worse. Nothing about the way Avandia works made scientists expect a higher rate of blocked coronary arteries causing heart attacks. But this spring a new analysis of the Avandia studies suggested a possible increased heart attack risk. Whether this risk is real is still being debated. Meanwhile, the FDA has chosen to allow Avandia to stay on the market with a black box warning.
There are many questions that people need to consider when thinking about whether the FDA moves too slowly or too quickly: Should the FDA hold up approval of any drug when there is even a suggestion of a potential serious problem, knowing that the definitive answer may not come? Or should the FDA take a different approach â€“ if there is not definite evidence of harm, and the drug clearly has benefits, proceed with approval? What are your thoughts about the FDA drug approval process?
Howard LeWine, M.D., is a hospitalist at Brigham and Womenâ€™s Hospital in Boston, where he practices and teaches Internal Medicine. He is the Chief Medical Editor of Internet Publishing at Harvard Health Publications.
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