FDA Adviser Questions Surrogate Endpoints for Diabetes Drug Approvals

BANGOR, Me., Aug. 9 -- The chairman of the FDA advisory panel that reviewed the safety of rosiglitazone (Avandia) last week believes the time has come to abandon surrogate endpoints for approval of type 2 diabetes drugs
Percentage decrease in glycated hemoglobin should no longer be used as the regulatory benchmark for approval, endocrinologist Clifford J. Rosen, M.D., wrote in a perspective published online today by the New England Journal of Medicine.
"We urgently need to change the regulatory pathway for drugs for the treatment of type 2 diabetes to make clinical outcomes, not surrogates, the primary end points," he wrote.
The problem, Dr. Rosen said, is that a change in glycosylated hemoglobin level is "a relatively poor surrogate for cardiovascular outcomes in type 2 diabetes, accounting for only 5% to 15% of the variation in ischemic risk."
For example in the ADOPT (A Diabetes Outcome Prevention Trial) patients taking rosiglitazone had a greater percentage decrease in glycosylated hemoglobin than patients taking metformin or sulfonyurease "yet the risks of congestive heart failure and cardiovascular ischemia were higher (with rosiglitazone)."
If the FDA fails to make the shift from surrogate to clinical end points "with regard to diabetes drugs, we are certain to be in the same position five years from now that we are now: we will again find ourselves in possession of a new wonder drug that is designed to treat a devastating chronic disease but that may do more harm than good."
The publication comes just a week after the FDA committee, chaired by Dr. Rosen, of the Maine Center for Osteoporosis at St. Joseph Hospital, concluded that rosigliatzone was associated with a "greater risk of myocardial ischemic events than placebo, metformin, or sulfonylureas."
The panel also agreed that the drug should stay on the market with more stringent warnings added to the label and "extensive educational efforts."
The FDA convened the advisory panel in response to a cardiovascular concerns raised by the publication in May of a meta-analysis of 42 trials that found a 43% increase in relative risk myocardial infarction for type 2 diabetes patients treated with rosiglitazone.
In his article, Dr. Rosen pointed out that three meta-analyses -- one by Steven Nissen, M.D., of the Cleveland Clinic, one by GlaxoSmithKline, maker of rosiglitazone, and another by FDA staffers -- all confirmed an increased myocardial ischemic risk with the once popular drug.
Moreover, Dr. Rosen said that the meta-analyses, while far from perfect, are likely to remain the best available evidence for the foreseeable future because "none of the proposed analyses of the ongoing clinical trials [of rosiglitazone] is likely to define an absolute risk for myocardial ischemic events in patients with diabetes who are taking this drug."
Dr. Rosen noted that data from two large observational studies -- one conducted by Tricare using Department of Defense data and one by Wellpoint -- noted no appreciable signal of increased cardiovascular risk with either of the available thiazolidinediones (rosiglitazone and pioglitazone [Actos])," but those data failed to quell concerns about rosiglitazone safety.
Although they boasted large numbers -- 22,050 rosiglitazone patients and 23,768 pioglitazone patients in the WellPoint study -- the studies also highlight the methodological weaknesses of "examining events that are common and whose rates are likely to be increased only slightly by a given drug, even in a large cohort."
And those weaknesses highlight the flaws in a proposal floated during the FDA committee meeting. This was that the FDA "should fund and oversee phase 4 post-marketing studies as a means of determining the safety of approved drugs."
Any such post-marketing studies would be subject to the "inevitable effects of the many confounding variables" that undermined the reliability of the Wellpoint and Tricare studies, Dr. Rosen concluded.
Dr. Rosen disclosed that he has received lecture fees from GlaxoSmithKline and grand support from Eli Lilly, Merck, and Novartis.Additional source: New England Journal of MedicineSource reference: Rosen C J "The Rosiglitazone Story -- Lessons form an FDA Advisory Committee Meeting" N Engl J Med DOI: 10.1056/NEJMpo78167