FDA Accuses GSK of Suppressing Clinical Research

We have posted quite a lot about what came to be called the "Avandia" case. This started with the publication in the New England Journal of Medicineby Nissen and Wolski of a meta-analysis focused on cardiac adverse effects of rosiglitazone (Avandia, by GlaxoSmithKline) (see post here). One of the most important aspects of this case, in my humble opinion, which we posted about here, but has not been widely discussed, is that it is a case of the suppression of clinical research.

As we posted last year, the Nissen and Wolski meta-analysis [Nissen SE, Wolski K. Effects of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356, online here] was to be the first published article to combine data from all relevant clinical trials of rosiglitazone completed to date. Although two major trials of Avandia had been published, its manufacturer, GlaxoSmithKline, had performed many other smaller trials of the drug, most of which have not been published to date. They did eventually appear on a web-site run by GSK. However, this web-site was relatively obscure, and it was not created voluntarily, but in response to a settlement of legal action that alleged GSK had suppressed clinical research about its antidepresant paroxetine (Paxil). (See Steinbrook R. Registration of clinical trials - voluntary of mandatory. N Engl J Med 2004; 351: 1820-1822, link here and our post here).

Nissen and Wolski found it, compiled the results of trials on Avandia, and combined their results with those of the few published trials in their meta-analysis.It is to the credit of Nissen and Wolski to figure out how to do this. It is not to the credit of GSK that they sat on the data from these trials, only put it on this web-site when compelled to do so, did not make any effort to publicize the web-site, and did not publish a meta-analysis done by company scientists that showed qualitatively similar results to that done by Nissen and Wolski (see post here).

Now, as first reported on the PharmaLot and WSJ Health Care blogs, the US Food and Drug Administration (FDA) issued a warning letter to GSK about its suppression of multiple studies about Avandia. (Link here courtesy PharmaLot.)

In particular, the letter asserted,

The inspection found that your firm failed to report multiple postmarketing studies involving Avandia in mandatory Periodic and/or NDA Annual Reports.

The letter listed numerous studies which GSK failed to report

Furthermore, the letter stated,

Your firm lacked appropriate knowledge of the studies associated with Avandia, resulting in the reporting deficiencies noted. Absent a clear explanation of the extent and cause of these deficiencies and an adequate plan to correct them, we are concerned that similar deficiences in the postmarket reporting for your firms other FDA-approved drugs may exist.

Thus,

The specific violations noted in this letter are serious and may be symptomatic of underlying postmarketing safety reporting failures.

So I guess I wasn't just whistling Dixie when I discussed the Avandia case in terms of suppression of research.

Let's just review why it's bad to suppress research.

First, suppression of research can distort medical decision making, leading to poor decisions for particular patients and thus bad outcomes for some of them. Patients and physicians ideally should base decisions on the best available clinical evidence relevant to the patients' problems. Suppressing evidence that is unfavorable to particular companies' products may lead to use of that product in situations in which it may do no good, or in situations in which it is more likely to produce adverse effects than some alternative. Furthermore, unreasonably delaying or attempting to suppress publication of results of clinical research betrays the trust of the research subjects. Research subjects usually volunteer with the understanding that results of research done on them would be published. Such results could only have been obtained because of their willingness to participate.

At least more cases of attempted suppression of research are now getting the bad publicity they deserve. No we need to fix the problem An obvious solution would be decreasing or abolishing control of clinical research by those with vested interests in the research coming out a certain way.