Can Caution Be Too Risky?

Balancing risks and benefits at the FDA


Should regulators always err on the side of caution? New twists in the debate over whether antidepressants increase the risk of suicide in adolescents are starting to shed light on the risks and benefits of pharmaceuticals.

The controversy began in 2004 when a couple of British medical journals published review articles looking at the effects of selective serotonin reuptake inhibitor (SSRI) antidepressants on adolescents. Both reviews concluded that, with exception of Prozac, the risks of SSRIs outweighed the benefits for treating children and adolescents with depression. In particular, the reviews suggested that antidepressants increased the risk of suicide and suicidal thoughts in adolescents and children. Later that year, then-New York Attorney General Eliot Spitzer sued the drug company GlaxoSmithKline, alleging that it had hidden data showing that its antidepressant Paxil produced suicidal thoughts in adolescents.

Alarmed by the journal articles, the U.S. Food and Drug Administration launched its own review of the effects of SSRIs on adolescents. The FDA eventually concluded that adolescents taking SSRIs doubled their suicide risk compared to those taking placebo. So in October, 2004, the FDA scientific advisory panel voted to require that drugmakers include a "black box" warning on all SSRI antidepressants except Prozac. The warning states: "Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders." Just last month, the FDA ordered that the warning be extended to young adults between ages 18 and 24.

In 2004, GlaxoSmithKline settled with Spitzer for $2 million and agreed to publish the results of all of its clinical trials online. The company has also settled a number of other civil suits as well. Not surprisingly, the number of SSRI prescriptions for adolescents and children fell steeply after the FDA warning. Was this another triumph of public health over corporate greed? Perhaps not.

In April of this year, a meta-analysis of 27 pediatric antidepressant clinical trials in the Journal of the American Medical Association (JAMA) found that relative to placebo, antidepressants are efficacious for pediatric depression. In addition, the researchers concluded that the benefits of antidepressants appear to be much greater than risks from suicidal ideation and suicide attempts.

Two new studies in the current issue of the American Journal of Psychiatry also suggest that the FDA got it wrong—antidepressants actually reduce suicides among adolescents and young adults. One study found that the incidence of suicide attempts was "highest in the month before starting treatment, next highest in the month after starting treatment, and declining thereafter." One reasonable interpretation is that treatment begins when the risk of suicide is highest and the longer a patient receives the therapy the lower the risk of committing suicide becomes. It is also likely that the use of antidepressants is a marker for more severe depression and patients suffering from severe depression are more likely to be suicidal. The other study concluded that all age groups benefited from treatment with SSRIs. The lead author, University of Illinois at Chicago biostatistician Robert Gibbons, noted, "The risk of suicide attempt among depressed patients treated with SSRI drugs was about one-third that of patients who were not treated with an SSRI."

Excessive caution is risky, too. Back in 1992, Congress, worried about the slow rate of approvals, passed legislation imposing FDA user fees on pharmaceutical companies. Flush with these new funds the agency hired 1000 additional drug reviewers and slashed new drug review time from 30 months to 15 months. Now critics claim that the FDA is in the thrall of drug companies and is endangering the public's health by rushing dangerous new drugs onto the market. As evidence they cite the dangerous side effects of the painkiller Vioxx, the antipsychotic Zyprexa and more recently the diabetes drug Avandia. Sen. Chuck Grassley (R-Iowa) in a letter to the agency in September, 2006, declared, "Under the current FDA review system, patient safety takes a back seat to the fast approval of products." Critics like Grassley believe that the FDA should err on the side of caution.

And in fact, recent criticism appears to have made FDA regulators more timid. According to a 2005 JAMA report, "It does seem indisputable that there have been shifts in the acceptable threshold for risk/benefit for many diseases as the depth of scientific understanding increases and as information about the effects of drugs on large patient populations is more readily available." One disturbing consequence of this shift in the risk/benefit threshold is that for drugs approved in the first half of 2005, the average time from application to approval was 29 months. This is up from an average of 16 months for drugs approved in the first half of 2004. Why the slowdown? Because, as Harvard Business School professor Regina Herzlinger explains in her May 2006 article Why Innovation in Health Care is So Hard (not online): "Officials know they will be punished by the public and politicians more for underregulating—approving a harmful drug, say—than for tightening the approval process, even if so doing delays a useful innovation."

But if slower regulatory approvals are the price we need to pay for safer drugs, surely that's a good tradeoff. Not really. A fascinating 2005 study by University of Chicago economists calculated that the speed up in FDA drug approvals that occurred after 1992 may have been responsible for saving the equivalent of 180,000 to 310,000 life-years. On the other hand, the economists estimated that at worst, about 56,000 life-years were lost to drugs that were eventually withdrawn for safety reasons. Unfortunately, it's much easier to identify people who are harmed by drugs than those who are saved by drugs. In the face of this information asymmetry regulators focus on reducing lives lost to unsafe drugs rather than preventing deaths by speeding effective new therapies to patients.

Interestingly, having fallen for years since the introduction of SSRIs, the teen suicide rate jumped 18 percent in 2004 after the FDA issued its warning. Coincidence? Perhaps, but others think that the 50 percent reduction in SSRI prescriptions for depressed adolescents may be responsible. University of Illinois researcher Gibbons told Newsweek: "I think the FDA has made a very serious mistake. It should lift its black-box warning because all it's doing is killing kids." Regulators and the public have to keep in mind that erring on the side of caution can be the really risky thing to do.

Disclosure: I don't think I own any stocks in drug companies that make antidepressants. I also took Prozac for four months after my father's death in 1998 and it seemed to help.

Ronald Bailey
is Reason's science correspondent. His book
Liberation Biology: The Scientific and Moral Case for the Biotech Revolution is now available from Prometheus Books.

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