Healthy Skepticism Library item: 10750

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Publication type: news

Hughes S.
Rosiglitazone: Policy Implications and Continuing Debate
Heartwire 2007 Jun 28
http://www.medscape.com/viewarticle/558987

Full text:

As the rosiglitazone (Avandia, GlaxoSmithKline [GSK]) controversy continues, some policy implications of the whole affair, focusing on reform of the FDA, have emerged from the written testimony of Dr Brian Strom (University of Pennsylvania School of Medicine, Philadelphia) submitted to the congressional hearing earlier this month [1].

The need for change at the FDA, highlighted by the rosiglitazone furor, is also the subject of an editorial in Science magazine by the editor-in-chief, Dr Donald Kennedy, who is a former FDA commissioner [2]. While Strom and Kennedy concur that the FDA needs better funding, they disagree on the merits of the publication of Nissen’s meta-analysis. Dr Valentin Fuster (Mt Sinai School of Medicine, New York, NY) also weighs in the rosiglitazone saga in an editorial in the July 2007 issue of Nature Clinical Practice Cardiovascular Medicine, of which he is editor-in-chief [3].

In his testimony, which has only recently been made publicly available, Strom, an expert in drug safety, says an exaggerated response to the Nissen meta-analysis is misguided. “Ultimately, this study may be proven to be correct, but it may not be. This is simply a signal, and only better science will determine whether the signal is real. The FDA gets perhaps hundreds of these signals per year, and it is its job to sort through them and determine when the signal is real. To date, at least, the two available studies, flawed but probably better, do not confirm this finding,” he writes.

But Strom makes the point that the rosiglitazone episode does have important policy implications. He says that Congress and the public need to understand that no drugs are safe, but that relatively rare side effects are not going to be detected before approval. He says there is a critical need for studies evaluating clinical outcomes with a new drug and how it compares with other drugs for the same indication, to be performed after marketing, as well as larger epidemiologic studies of the product when used in the general population.

Strom believes the US drug safety system is flawed and should be changed but says this is not the fault of the FDA. Rather, it has arisen because Congress has not seen fit to create a system that is rational. “Right now, we have crying needs for studies conducted after drug marketing. Yet the FDA does not have the regulatory authority to require such data, does not have enforcement authority if the data are not provided, and our pharmaceutical manufacturers are given no incentive whatsoever to provide it; quite the contrary. It seems hypocritical for Congress to criticize the FDA when it is doing the best it can with the limited authority and resources it was provided by Congress,” Strom writes.

Strom proposes that when a drug is initially approved, it should enter a period of conditional approval, when marketing should be restricted. Extended approval could follow when sufficient data are available to answer all drug safety questions. He says that this system would allow the drug to be used in urgent cases while giving sponsors an incentive to gather safety information quickly.

He also calls for an empowered FDA, which can demand postmarketing studies rather than have them subject to negotiation. Strom also makes the point that the FDA needs markedly increased resources to conduct and fund more postmarketing safety studies itself. He notes that while $188.5 billion was spent on prescription drugs and $11.9 billion on pharmaceutical advertising in the US in 2004, the FDA’s current extramural epidemiology contracts program has a budget of less than $1 million per year to investigate all drugs, a situation that he describes as “preposterous.”

“The public needs to be able to rely on the FDA as a neutral, scientific, credible source of information and unbiased judgment when these questions arise, as they will do with increased frequency. I call on Congress to make use of the opportunity of this public misunderstanding to make significant changes in the FDA, strengthening it in the process,” he concludes.

Kennedy supportive of Nissen publication

In his editorial, Kennedy says that public confidence in the FDA has been shaken, and its capacity to do the quality of work that all healthcare systems require, including monitoring the safety of marketed drugs, needs to be restored. He writes: “The problem is that the United States lacks a system that is adequately tuned to detect adverse reactions. . . . Event reporting is voluntary, yielding a record of dubious reliability, and there’s no national prescription record.” He suggests that information about all clinical trials reviewed by the FDA should be made publicly available at the FDA’s website and also be linked to the National Institutes of Health’s website ClinicalTrials.gov. Kennedy agrees with Strom that the FDA needs more resources and says that user fees are not the way to fund the agency, as this causes public doubt about the FDA’s relationship with industry, and user fees cannot be applied to drug safety.

But unlike Strom, Kennedy praises the publication of Nissen’s meta-analysis, saying it “revealed cardiovascular risks that had been hinted at in earlier published trials but were not statistically significant in any one trial.” Kennedy says the study, published online May 21, 2007 in the New England Journal of Medicine [NEJM] [4], illustrates the difficulty of finding important trial data. “The journal has since been attacked by the company, some physicians, and an unfortunate editorial in the Lancet, but it deserves praise instead,” he writes.

Fuster disagrees

In his editorial, Fuster and coauthor Dr Michael E Farkouh (Mt Sinai School of Medicine) say that while the public has both a right and need to know all information available with regard to drug safety, “the NEJM meta-analysis of the cardiovascular safety profile of Avandia seems a rushed and incomplete examination.”

They point out several weaknesses of meta-analyses in general and say that this particular analysis does not answer the question of whether Avandia increases the risk of heart attack or cardiovascular-related death. “Faster and incomplete publication isn’t always better, particularly when the public and political implications may be huge, as demonstrated after publication of the NEJM report,” they write.

Strom consults for many pharmaceutical companies. He has been a consultant to GSK in the past but not related to Avandia and not related to this issue. He said he was asked to write his testimony by the congressional staff and GSK had zero input. Fuster is chair of GlaxoSmithKline Research and Education Foundation for Cardiovascular Disease and recipient of a research grant. Farkouh declares no competing interests.

Strom BL. Statement for the hearing of the United States House of Representatives Committee on Oversight and Government Reform, June 7, 2007.
Kennedy D. Fixing the drug laws. Science 2007; 316:1669.
Fuster V, Farkouh ME. Faster publication isn’t always better. Nat Clin Pract Cardiovasc Med 2007; 4:345.
Nissen SE and Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356:2457-71.

The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.