Drug approval double-header in today’s NEJM
The New England Journal of Medicine: This Week’s Table of Contents
The NEJM must consider this week’s Perspectives concerning rosiglitazone and follow-on biologics of great public importance–they’ve made them both freely available, along with accompanying correspondence on Cliff Rosen’s rosiglitazone Perspective from FDA, GSK (Dr. Krall), and from Rosen himself.
Also, in the current issue, and also fully available for free, is correspondence refuting the association of rosi with MI. Michael Bracken from Yale calls attention to lack of concordance between the Peto odds reported by Nissen and both the risk and common odds ratios. I previously discussed why the common odds ratio was more a appropriate method to use than the risk ratio, but I didn’t discuss Peto vs. common ORs, because, well, because I didn’t. It’s an adavnatge of being my own editor. The fairly esoteric discussion necessary to explicate this letter fully leaves me bored just thinking about it, let alone motivated to write about it. However, if a dear reader feels compelled to comment on odds ratio esoterica, by all means doon’t let my lack of enthusiasm for doing so myself stop you.
First up is Dr. Rosen and dear old rosi. Rose chaired the recent FDA advisory committee hearing, in which the panel recommended, nearly unanimously, that FDA not remove rosi from the market.
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.
Off to a rousing start. Here’s more:
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.
Hmmm…Will FDA notice that Dr. Rosen forgot (benefit of the doubt) to mention that hyperglycemia is not only a surrogate marker of disease but also a condition worthy of treatment itself? You guessed it…Slam. FDA is nothing if not keenly observant. Well, that and the fact that they write the rules governing approval of antihyperglycemia drugs in the U.S. helps. Thus quote FDA:
All drugs currently approved for the treatment of diabetes are indicated to improve glycemic control. Reductions in glycated hemoglobin levels directly reflect improved glycemic control, leading to a lessening of hyperglycemic symptoms, including polydipsia, polyuria, and blurred vision. In this respect, the FDA views a reduction in the level of glycated hemoglobin as a well-validated surrogate for a beneficial effect on the immediate clinical consequences of diabetes.
Dr. Rosen’s oversight aside, his underlying observation, that for chronic-use drugs FDA must demand of sponsors more thoroughly defined safety profiles prior to marketing than they have been., is spot on If the U.S. had a highly effective postmarketing surveillance program in place, I might feel differently, but, inexcusably, the U.S. is a long way from this goal. Until then, large safety studies pre-marketing should be de rigeur for chronic-use drugs intended for large treatment populations.
The follow-on biologics Perspective is by Richard Frank of Harvard.
The prospect of the loss of patent protection for tens of billions of dollars’ worth of biopharmaceuticals increases the urgency of the need for a regulatory policy that promotes price competition and preserves the safety and efficacy standards that Americans expect from prescription drugs. In my opinion, the Hatch–Waxman framework is not sufficient to cover both relatively simple biopharmaceuticals and very large and complex molecules—a new regulatory framework is needed. Because of the need for complex, situation-specific judgments, the FDA should be granted a great deal of discretion. The conflicting goals of bolstering price competition in biopharmaceutical markets and preserving the incentives for innovation call for a nuanced policy that must be based on the best current science and key features of the economics of biopharmaceutical markets — not on the impassioned claims of the interested parties.
Couldn’t have said it better. To Senators Hatch, Waxman, Clinton et al. get on the ball. Time is a wastin’ and the world is a waitin’.
