Ever wonder how much of a role politics might play in medicine? If you consider an event that took place this summer, you might start to think it’s rather significant.
Patients with diabetes have telephoned and visited my office in droves during the past few months. All had been rattled by the news they’d heard in the mainstream media about Avandia, manufactured by GlaxoSmithKline, being linked to increased risk of heart attacks.
This was all triggered by a New England Journal of Medicine (NEJM) paper by Steven Nissen, M.D. and Kathy Wolski, M.P.H.–respectively, the chairman of the department of cardiovascular medicine and a statistician at the Cleveland Clinic–and an almost simultaneous congressional hearing that used the paper as a springboard for examining the U.S. Food and Drug Administration’s (FDA) drug safety practices.
Why has this article had such a profound impact?
Inconclusive Study
The Avandia issue clearly has political underpinnings.
The true take-home message that many patients, and apparently the NEJM and Congress, didn’t get from the Nissen-Wolski paper is that the study itself was inconclusive. It was a meta-analysis, which only generates hypotheses, instead of proving them.
The study did not gather new information or test patients. It gathered results from 42 other studies. The overwhelming majority of the trials included were short-term, making it unlikely they could adequately evaluate cardiovascular risk. In addition, the paper excluded six trials that had no cases of heart attack or cardiac death.
Suspicious Timing
Next, consider the events that occurred in Washington around the paper’s release.
In May, Congress was considering bills regarding FDA. Nissen and Wolski’s paper was released electronically on 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.
Though the NEJM requires authors to list any conflicts of interest at the end of each paper, information regarding submission dates and peer review data 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. I and my staff have done so, to no avail.
Greased Wheels
The paper’s electronic release occurred three-and-a-half weeks before the print version landed on June 14. Historically, the NEJM has released its papers electronically only three days prior to the print version being released.
Why would there be such a rush to release the paper to the media? Tellingly, Rep. Henry Waxman (D-CA), chairman of the Committee on Oversight and Government Reform, used it to argue for more government regulation of FDA. Citing Nissen and Wolski’s paper, Waxman argued FDA had failed to warn Americans of the dangers involved with the use of Avandia, and said more regulations are needed to ensure FDA does its job.
Having served on the American Association of Clinical Endocrinologists’ Legislative and Regulatory Committee for many years, I can assure you things usually don’t move quickly in Washington unless the wheels have been greased in advance.
Nissen and Wolski’s paper appears to have been the lubricant for the congressional hearing. When the paper was released May 21, Waxman immediately issued a detailed press release about the findings, listing the date and location of an oversight hearing aimed at probing FDA’s handling of these drug safety issues.
Immediate Response
The hearing took place June 6–just 16 days after the electronic release of the paper, and a full eight days before the print version was released. Thus the paper was used to set the stage for those arguing FDA negligently approved a dangerous drug, then failed to monitor it sufficiently after its release.
FDA operates under both scientific and political pressures. Those pressures proved extremely intense regarding Avandia. Prior to the paper’s release, FDA had scheduled an advisory committee meeting for November; afterward, it was moved up to July 30.
That meeting combined the FDA Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. After reviewing all the available data and listening to expert testimony, the panel recommended that “Avandia continue to be marketed and further recommended that information be added to the labeling for risk of heart attacks.”
Sudden Impact
As a result, both Avandia 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 New York Heart Association (NYHA) Class III and IV heart failure.
FDA will provide updates on strokes, heart attacks, and Avandia as information becomes available. Currently, three large, well-designed, long-term, randomized controlled trials involving Avandia are underway. These will provide information regarding Avandia and macrovascular disease, which could lead to future changes in the labeling of the drug.
Cost to Patients
The Nissen-Wolski paper has had a significant impact on many levels. According to The Wall Street Journal, global sales for Avandia last year were $3.15 billion. Within one month of the paper’s release, the total number of Avandia prescriptions fell, as did the number written for new patients. The cost is measured not only in lost revenue for GlaxoSmithKline but also in the burden placed on clinicians who spent countless hours fielding calls from anxious patients.
At this point it is impossible to estimate the cost to the many patients who stopped using Avandia without notifying their physician because they feared the drug would cause a heart attack. By stopping it and losing control over their conditions, they actually increased their risk of such an event occurring.
Richard O. Dolinar, M.D. ([email protected]) is a senior fellow for health care policy at The Heartland Institute.
