Have Faster FDA Approvals Caused More Drug Safety Problems? No!

by John R. Graham,

The media gave some attention to a new study, which suggests that the Food and Drug Administration (FDA) recklessly allows unsafe new prescription drugs onto the market. The research supports a longstanding suspicion that the Prescription Drug User Fee Act (PDUFA), first passed in 1992 and renewed every five years, has caused the FDA to view the research-based pharmaceutical industry as a “partner” and source of revenue, rather than a regulated industry.

Before PDUFA, the FDA was funded by general appropriations. PDUFA has allowed the FDA to increase its revenue by user fees, which drug-makers agree to pay for new drug approvals or facilities inspections. PDUFA was last renewed in 2012. At the time, I endorsed the renewal because there was no likelihood of Congress reducing the FDA’s power: PDUFA was the best way to ensure drug approvals kept moving at the FDA.

These researchers think that’s a bad thing. According to the lead author, Cassie Frank, a physician at Harvard Medical School: “The FDA is under constant pressure to rush new drugs through the pipeline to approval. In its hurry, the FDA is apparently failing to distinguish useful drugs from toxic ones, and more dangerous drugs are slipping through. By the time many drugs receive serious safety warnings, millions of Americans have already been exposed to their side effects, which can sometimes be fatal.”

This conclusion is sensationalist, to put it mildly.

The authors examined drugs approved from 1975 through 2009 and found that drugs approved after PDUFA’s passage were more likely to receive a new black-box warning or be withdrawn than drugs approved before its passage (26.7 per 100 drugs versus 21.2 per 100 drugs at up to sixteen years of follow-up).

That 5.5 percentage point difference got a lot of attention and ginned up renewed accusations that the FDA is in cahoots with the drug industry. This is the result that the authors wanted. However, an objective consideration of their analysis leads to the opposite conclusion.

First, the authors mixed black-box warnings in with withdrawals. The reason for this is that so few drugs are withdrawn that there are no useful conclusions to be made by examining withdrawals alone.

However, black-box warnings are a different outcome than withdrawals. While withdrawal indicates (to some) that a drug should never have been allowed on the market, a black-box warning indicates exactly the opposite. It is the FDA’s most strict labeling requirement, telling prescribers that the drug has severe side effects. New information has been discovered that increases the likelihood of a physician appropriately prescribing the medicine. This new information would never have been learned if the drugs had not been on the market.

Second, reporting the statistical results as percentages, instead of the raw figures, disguises an important fact: There were actually more black-box warnings and withdrawals in the pre-PDUFA 16-year sample than the post-PDUFA 16-year sample: 80 versus 76. (I had to go through the appendix with a pencil to figure this out.)

In the pre-PDUFA 16-year sample, 42 drugs had black-box warnings. Because some drugs had more than one warning, the total number of warnings was 68. Twelve drugs were withdrawn. For the post-PDUFA sample, there were 48 drugs with warnings, 58 warnings, and 18 withdrawals. (Yes, there were more withdrawals in the post-PDUFA sample, but recall that there are so few withdrawals that they have no statistical power.)

So, patients in the post-PDUFA environment need not fear that more dangerous drugs are getting through the FDA. In fact, quite the opposite is true. While PDUFA improved the speed of FDA approvals after it was passed, normal bureaucratic inertia took over and the FDA returned to its previous, sluggish performance.

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