FDA Advises GSK of Delay in the TIDE Study
This past week, the FDA announced on their website that they had informed GlaxoSmithKline (GSK), the manufacturer of the diabetes drug Avandia (rosiglitazone), that a huge study called TIDE (Thiazolidinedione Intervention With Vitamin D Evaluation) "has been placed on partial clinical hold. Under the partial clinical hold no new patients may be enrolled into the trial until further notice from the FDA. Patients already enrolled in the trial will be allowed to continue to participate. The FDA also instructed GSK to update investigators, institutional review boards (IRBs) and ethics committees involved in the TIDE trial regarding new safety information presented at the joint FDA Advisory Committee meeting held on July 13 and 14, 2010, along with information regarding the deliberations and votes of that meeting. This information can be used by investigators and IRBs to update existing informed consent information for current trial participants."
The TIDE trial was discussed by its lead investigator, Dr. Hertzel Gerstein, at that recent Advisory Committee meeting (also, see my earlier postings about the AdComm meeting here at MyDiabetesCentral). His presentation also is on-line at the FDA website.
The TIDE study is a head-to-head double-blind randomized clinical trial that studies two diabetes drugs called "glitazones"(Avandia/rosiglitazone and Actos/pioglitazone). TIDE was designed to answer the question whether adding either of these drugs in adults with type 2 diabetes who have additional risk factors for cardiovascular outcomes will decrease the chance of myocardial infarction, stroke or cardiovascular death compared to placebo. (It also investigated a second question, whether giving Vitamin D to these patients reduces death or cancer, but that's another story.) The study is sponsored by GSK, the manufacturer of Avandia, who is obviously running a risk that the study will show that Avandia will be shown to be worse than their competitor's drug (Actos, made by Takeda).
TIDE was planned to enroll about 16,000 volunteers world-wide, who would participate for 5-10 years. As of this summer, the researchers have enrolled slightly over 1000 patients when the partial hold was placed.
As the TIDE study cannot enroll any more patients until revised informed consent forms are developed, and present participants will be presented with revised inform consent forms, what will happen to the study?
First, it will be delayed. Probably not a big deal, except for the cost to the sponsor.
Second, I'd expect that a considerable number of present volunteers will back out of the study. Imagine being asked to signed a document that says "I know that one of the two drugs in this study that I might get has been shown to have increased cardiac risk, and I already have cardiac risk, and I'm willing to risk my life by participating in this study." I think the only people likely to sign such a statement are motorcyclists who don't wear helmets (and who have diabetes and have additional risk factors for heart disease).
And I'd expect some of the present investigators might choose to back out.
And some of the IRBs and ethics committees that have to review and approve clinical trials might refuse to allow the study at their institutions.
And recruiting thousands of new patients into the study may prove to be impossible, due to the same problem as for the present volunteers already in the study: when presented with the new informed consent form, who will sign on for 5+ years during which they may be receiving a drug that has repeatedly been shown to have a cardiovascular risk?
Finally, it's quite possible that the FDA's partial hold on the study is a preliminary indicator that FDA will be pulling Avandia off the market soon. Dr. Steven Nissen, who spoke against Avandia at the AdComm, has been quoted as saying that holding enrollment in the TIDE trial was "the ethically correct thing to do... I still think there's a very good chance that the FDA will decide to remove Avandia from the market," Nissen told the AP.
If so, the TIDE study will inevitably be terminated. Which will be safer for patients, but will mean that we'll never get the hard facts about just how high the cardiac risk might be from Avandia compared to Actos.