Ethics (or Lack Thereof) and Post-Marketing Studies

As I noted in HOOKED, and as has been here documented, all too often the FDA approves a new drug contingent upon the company doing a post-marketing study to address outstanding safety or other concerns, and the study never gets done. So you might imagine that the actual conduct of such a study would be an ethically good thing. Unforunately this seems not always to be the case, as discovered by a committee of the Institute of Medicine that was called together by the FDA to look at a study of rosiglitazone (Avandia). Three members of the IOM committee reported on their ethical findings in last week's New England Journal (subscription required).

I have blogged a good deal about the rosiglitazone saga (most recently, http://brodyhooked.blogspot.com/2012/06/worshiping-at-altar-of-innovation-aka.html). The study that the IOM committee addressed was called TIDE, for Thiazolidinedione Intervention with Vitamin D Evaluation, designed to compare long-term cardiovascular outcomes in diabetic patients on two different, related drugs--rosiglitazone and pioglitazone (Actos). TIDE was done in the face of existing information suggesting that rosigolitazone increased the risk of heart problems in a way that pioglitazone did not. By the time TIDE was inaugurated, clinical practice was already starting to shift away from the use of rosiglitazone in diabetes and toward pioglitazone, for the small number of patients who actually had need for a drug in this class anyway. (Drugs in this class lower blood sugar but have never been shown to have long-term, beneficial effects on major complications of diabetes, which is the whole reason to treat Type II diabetes.)

The IOM committee looked especially at two questions regarding TIDE, first, the adequacy of the consent process, and second, the adequacy of the review that was conducted by the 480 IRBs (research review committees) that all approved the trial at their respective institutions. First, the consent stank (my term not the authors'). Patients should have been told that they were at risk of getting a drug that had already been shown to be potentially dangerous, and that there might be no need for the study since clinical practice was already changing even without the results--in short, they should have been given a consent form that would have discouraged all reasonable people from being in the study at all. The consent process softpedaled all these issues.

One of the reasons that the consent process stank was related to the study design. The TIDE investigators (reporting on their trial which apparently was stopped for regulatory reasons, presumably when the IOM committee was called in to referee) noted two areas of "uncertainty" regarding the two diabetes drugs--heart effects and a relationship between Vitamin D and cancer. That latter issue presumably justified sticking in a Vitamin D component which had nothing to do with heart effects, but trying to explain about the Vitamin D in the consent process could easily have confused research subjects and diverted attention away from the heart risks. If one were inclined to be paranoid about a study designed by industry in hopes of exonerating a suspected unsafe drug, one might think that was not entirely coincidental.

On the issue of the IRB oversight, the IOM committee was perhaps more circumspect than they might have been. Rather than decide that these 480 IRBs were all of them incompetent, they preferred to imagine that they were simply not fully informed of the rationale for the study. Had they been so informed, the committee imagined that they would have realized that even if there had been decent consent (and of course there wasn't), the study would have been questionable because subjects were being put at serious risk to establish a fact that was already known and that was uinlikely to change clinical practice. The committee went on to say some wise things about the circumstances when FDA post-marketing studies are more or less justifiable.

The IOM committee made clear that when the FDA orders a drug company to do a post-marketing study, and a study is then conducted that is ethically unsound, the blame cannot be sloughed off on the drug company; the FDA has to share in the ethical responsibility. The lesson for the FDA seems to be--if you find an unsafe drug on the market, deal with it; don't kick the can down the road by pretending that you cannot do anything without more data, if getting the further data would entail doing unethical research.

Full disclosure: I am a member of the IOM but had nothing to do with this committee.

Mello MM, Goodman SN, Faden RR. Ethical considerations in studying drug safety--the Institute of Medicine report. New England Journal of Medicine 367:959-964, September 6, 2012.

Punthakee Z, Bosch J, Dagenais G, et al. Design, history, and results of the Thiazolidine Intervention  with Vitamin D Evaluation (TIDE) randomised controlled trial. Diabetologia 55:36-45, 2012.