Wednesday, August 8, 2007

The Recent FDA Meeting on Avandia

Commentary in the NEJM by the Chairman of the joint committee

Mr. B. has posted previously on Avandia – aka Rosiglitazone – a therapeutic agent for treatment of diabetes that is currently in the news. The New England Journal of Medicine has published today on some potential lessons from issues surrounding the use of Avandia. Selections from the article are given below.

Published at August 8, 2007 (10.1056/NEJMp078167)

The Rosiglitazone Story — Lessons from an FDA Advisory Committee Meeting

Clifford J. Rosen, M.D.

On July 30, 2007, the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee of the Food and Drug Administration (FDA) convened to discuss the myocardial ischemic risk associated with rosiglitazone treatment in patients with type 2 diabetes mellitus. The joint committee, which I chaired, consisted of 24 experts in cardiovascular disease, epidemiology, biostatistics, and endocrinology. After lengthy discussions, we concluded that the use of rosiglitazone for the treatment of type 2 diabetes was associated with a greater risk of myocardial ischemic events than placebo, metformin, or sulfonylureas.

Ultimately, the committee voted to recommend not that rosiglitazone be removed from the market but rather that label warnings and extensive educational efforts be instituted immediately. The committee also requested further studies, but disconcertingly, none of the several proposed analyses of the ongoing clinical trials is likely to define an absolute risk for myocardial ischemic events in patients with diabetes who are taking this drug.

The basic plot of the rosiglitazone story quickly became obvious to the advisory committee: a new "wonder drug," approved prematurely and for the wrong reasons by a weakened and underfunded government agency subjected to pressure from industry, had caused undue harm to patients. Notwithstanding this characterization, as well as the emotional nature of the hearing and the media distractions, the committee meeting attempted to demonstrate the dispassionate application of scientific evidence to public health decision making. In fact, several basic tenets emerged at this meeting that might ideally be used as guiding principles for improving the process of approving new drugs: first, the pathogenesis of disorders that require intervention must be fully understood; second, treatment options for these diseases should be clarified through an evidence-based system; and third, a uniform approach should be used to determine the societal benefits and risks associated with a given intervention.

It has been 80 years since insulin was discovered and 50 years since sulfonylureas were introduced. Since those developments occurred, tremendous strides have been made in understanding the origins and sequelae of diabetes mellitus. For example, because it accelerates atherosclerosis, type 2 diabetes quadruples the risk of macrovascular disease. And ischemic heart disease continues to be a major cause of death among patients with diabetes. Yet the results of our current therapies fall short of our high expectations for chronic disease management.

For example, we know that in type 1 diabetes, metabolic control can reduce the risk of microvascular complications. On the other hand, the two largest randomized, placebo-controlled trials in patients with type 2 diabetes, the United Kingdom Prospective Diabetes Study and the University Group Diabetes Program, failed to find a significant reduction in cardiovascular events even with excellent glucose control. Moreover, we are facing a troubling paradox: preliminary data that were presented at the meeting and published by Gerrits et al. suggest that among the thiazolidinediones — a class of drugs that has been shown to improve metabolic control — rosiglitazone may increase cardiovascular risk whereas pioglitazone may reduce it. Until we have a better grasp of the pathogenesis of atherosclerosis in type 2 diabetes, it will be difficult to design therapies to prevent this complication or even to determine how the currently available agents that act at multiple sites may affect clinical outcomes in very different ways.

Not surprisingly, glycemic control has been the centerpiece of therapeutic interventions in type 2 diabetes for many years. Within the past decade, several new drugs that result in "glycemic durability" — a reduction in the glycated hemoglobin level — have been approved by the FDA. However, change in the glycated 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. This finding represents a major dilemma for practitioners, regulatory agencies, and patients who seek the newest and best treatments for this disease.

The controversy surrounding biochemical surrogates versus clinical outcomes was also highlighted at the FDA meeting when the advisory committee reviewed one of the largest randomized trials of rosiglitazone, A Diabetes Outcome Prevention Trial, or ADOPT. In that study, the percentage decrease in glycated hemoglobin was greater with rosiglitazone than with metformin or sulfonylureas, yet the risks of congestive heart failure and cardiovascular ischemia were higher. These data suggest that 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.
This is not a radical proposal: 20 years ago, the FDA shifted its primary efficacy end point for osteoporosis drugs from bone mineral density (a reasonable surrogate for the risk of fracture) to fractures themselves.

Without a regulatory sea change with regard to diabetes drugs, we are certain to be in the same position 5 years from now that we are in 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 rosiglitazone story thus carries lessons for scientists, practitioners, and regulators alike. One can only hope that the energy generated by the advisory committee meeting will be channeled into improving the open hearing process to better serve all interested parties.

Dr. Rosen chaired the FDA advisory committee meeting on rosiglitazone on July 30, 2007; the views expressed in this article are those of the author and do not necessarily reflect those of the advisory committee or the FDA. Dr. Rosen reports receiving a lecture fee from GlaxoSmithKline and grant support from Eli Lilly, Merck, and Novartis. No other potential conflict of interest relevant to this article was reported.

Source Information

Dr. Rosen is an endocrinologist and a senior staff scientist at the Maine Center for Osteoporosis, St. Joseph Hospital, Bangor, and the Jackson Laboratory, Bar Harbor — both in Maine.

This article (10.1056/NEJMp078167) was published at on August 8, 2007. It will appear in the August 30 issue of the Journal.

If issues raised in this article are of concern or interest to you for health reasons, please consult your physician for further information. This situation is a little complicated, but I have highlighted certain sections that should be informative if you have more than a passing interest in the matter and would like to understand what is involved in this latest drug scare.

Ciao, Bonzo

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