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Rosiglitazone viewed through a political prism
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Patients with diabetes have telephoned and visited my office in droves during the past few months — all rattled by the news that they’d heard in the mainstream media about rosiglitazone, or Avandia, manufactured by GlaxoSmithKline. You have probably had a similar experience in your office.
This was all triggered by a New England Journal of Medicine paper by Steven Nissen, MD, chairman of the department of cardiovascular medicine at the Cleveland Clinic, and Kathy Wolski, MPH, a statistician also at the Cleveland Clinic, and an almost simultaneous Congressional hearing that used the paper as a springboard to examine the FDA’s drug safety practices.
Why has Nissen and Wolski’s article had such a profound impact?
Throughout history, man has used prisms to better understand the world around him – to view stars millions of light years away, or to view the insides of living cells. If we view the rosiglitazone situation through a “political prism,” it becomes clear that this issue may have political underpinnings.
To begin, one must take a close look at the scientific merits of the paper. The true take-home message that many patients, and apparently the NEJM and Congress, did not take home from that paper is that this single study was not conclusive. It was a meta-analysis, which only generates a hypothesis rather than proves a hypothesis. The study did not gather new information or test patients; instead it gathered results from 42 other studies. The overwhelming majority of the trials included were short term, which makes it unlikely that they could adequately evaluate cardiovascular risk. In addition, the paper excluded six trials that had no cases of myocardial infarction or cardiac death.
Next, consider the sequence of events occurring in Washington at the time the paper was released. In May, bills were being considered in Congress regarding the FDA legislation. Senate bill S-1082 was passed, and House bill HR-2900 was generating strong debate and dissension.
Nissen and Wolski’s paper was released electronically on Monday, May 21, after what may have been an accelerated review — although as of this printing, confirmation of this has not been possible. Knowing the date on which the article was submitted and comparing it to the date the article was released would help put this rumor to rest. The NEJM prides itself on transparency because it has its authors list any conflicts of interest at the end of each paper, yet information regarding submission dates and peer review remain opaque. The journal did not list the submission date on the paper, and when contacted by my staff, it did not release that information. The journal suggested contacting Nissen for the submission date. Myself and others on my staff have done this but unfortunately, the submission date is still not known.
The electronic release of the paper occurred three and a half weeks prior to the release of the print version on June 14. Historically, the NEJM has released its papers electronically three days prior to the print version being released. Releasing the Nissen and Wolksi paper so far in advance seems, therefore, highly unusual.
Why would there be such a rush to release the paper to the media? Again, viewing the situation through a political prism may help bring a reason for this into better focus. This paper was used by Congressman Henry Waxman, chairman of the Committee on Oversight and Government Reform, to argue for more government regulation of the FDA. Citing Nissen and Wolski’s paper, Waxman argued that the FDA had failed to warn Americans of the dangers involved with the use of rosiglitazone and argued that more regulations are needed to ensure that the FDA does its job.
Having served on AACE’s Legislative and Regulatory Committee for many years, I can assure you things don’t usually move quickly in Washington unless the wheels have been greased in advance. The wheels of the Congressional hearing appear to have been lubricated by Nissen and Wolski’s paper. When the paper was released May 21, Waxman immediately issued a detailed press release about the findings. The press release also listed the date and location of an oversight hearing aimed at probing the FDA’s handling of these drug safety issues. The hearing took place June 6, just 16 days after the release of the electronic version of Nissen and Wolski’s paper and a full eight days before the print version was released. Thus, the paper was used to set the stage for those arguing that the FDA negligently approved a dangerous drug and then failed to monitor it sufficiently after its release.
As it is currently structured, the FDA is a government agency operating under pressures that are both scientific and political in nature. These pressures proved to be extremely intense regarding rosiglitazone. Prior to the release of Nissen and Wolski’s paper, the FDA had scheduled an Advisory Meeting in November. This was moved to July 30.
The July 30 meeting combined the FDA Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. After reviewing all of the available data and listening to experts who testified, the panel recommended that “rosiglitazone continue to be marketed and further recommended that information be added to the labeling for risk of heart attacks.”
As a result, both drugs in the TZD class, rosiglitazone and pioglitazone (Actos, Takeda), now have black box warnings regarding the risk of heart failure. This issue is not new and has been known since release of these drugs. They will also now be contraindicated in NYHA Class III and IV heart failure.
Regarding ischemic events and rosiglitazone, the FDA will provide updates as the information becomes available. At this time, three large, well-designed, long-term, randomized controlled trials involving rosiglitazone are underway. Once completed, these studies will provide information regarding rosiglitazone and macrovascular disease, which could lead to future changes in the labeling of the drug.
The impact of Nissen and Wolski’s paper has been significant on many levels. According to an article in The Wall Street Journal, global sales for rosiglitazone last year were $3.15 billion. Within one month of the release of Nissen and Wolski’s paper, the total number of rosiglitazone prescriptions fell, as did the number written for new patients. The cost of this is not only in lost revenue for GlaxoSmithKline, but also in the burden placed on the shoulders of clinicians who spent countless hours fielding calls from anxious patients.
And how does one estimate the cost to the many patients who stopped using rosiglitazone without notifying their physician? Patients feared developing a myocardial infarction because of the drug. By stopping it and losing control they actually increased their risk of such an event occurring.
For more information:
- Richard O. Dolinar, MD, is a Senior Fellow in Healthcare Policy at the Heartland Institute, Chicago, Illinois, and is a member of the Endocrine Today Editorial Board.