Today’s paper in PLoS Medicine reporting on a meta-analysis of clinical data on SSRI inhibitors for the treatment of depression really made a splash.
The article, by Irving Kirsch and his colleagues, showed that, when you look at data from 35 randomized clinical trials testing the efficacy of four of these “new-generation antidepressants”, the only differences between the drug and the placebo groups are seen in severely depressed patients.
Although this is not the first time that a meta-analysis has provided evidence against the eficacy of SSRIs, it is perhaps the largest study of its kind available so far, immediately fuelling existing concerns about their widespread use in medical practice.
Not unexpectedly, the companies that sell the drugs have already issued statements supporting the efficacy of their products, pointing out that the meta-analysis didn’t look at all of the available data. It wasn’t clear, however, if the companies were referring to postmarketing surveillance data, something that is entirely possible, as the paper was based strictly on data received by the US Food and Drug Admnistration (FDA) before approval of the drug.
In any case, this is not the first time that we experience this scenario. You can bet that we will now start hearing accusations of negligence against the FDA for approving medicines that don’t work. The public image of pharma companies will be further tarnished by negative claims against their products. Psychiatrists will have to reassure their patients, trying to encourage them to remain compliant. Iin fact, some associations of psychiatrists have already issued statements urging patients not to stop taking their medications until they discuss the situation with their doctors.) And people with depression? Well, I guess they’ll have every reason to be depressed.
Now, is it really the case that these drugs don’t work but in a small subset of patients? These drugs are globally available, and several world regions have their own regulatory agencies, each of which carries its own analysis of efficacy before approving a drug. Are we supposed to accuse not only the FDA, but every other regulatory agency of not doing a good job making sure that a drug works? It’s possible, but unlikely.
OK, let’s say that the lack of efficacy could not be detected with the data submitted to the regulators, but only with the large number of patients that you look at when you do a meta-analysis. Should the regulatory agencies then ask for much larger (and therefore much more expensive) trials before approving an antidepressant? Maybe, but then it might be too harsh to use a post hoc analysis that had the opportunity to look at data from at least four different companies to then rebuke the FDA for their approval of the drug or each of the individual companies for their trial design.
To my mind, the key issue now is to see what the regulatory agencies are going to do after the publication of these findings. Will they look at postmarketing surveillance data to try to confirm or rebut the alleged lack of efficacy? Will they modify their approval of the drug so that it is only prescribed to the small subset of patients in whom an effect was observed? In several Nature Medicine Editorials, some of which are here (1, 2, 3, 4, 5), we have been critical of the FDA’s leadership and commented on the need of the agency to regain the confidence of consumers. So, the publication of the PLoS Medicine paper should not necessarily be construed as a new embarrassment for the FDA, but as a fresh opportunity for the agency to show that it can respond to public concerns, and handle the situation efiiciently and wisely.