June 11, 2010 (Silver Spring, Maryland) — An FDA reviewer who has long warned of the cardiovascular risks of rosiglitazone wrote to FDA commissioner Dr Margaret Hamburg worried that his superiors at the FDA may be stalling or blocking the publication of observational data showing the risks of rosiglitazone (Avandia, GlaxoSmithKline) to be higher than those of pioglitazone (Actos, Takeda Pharmaceuticals) in Medicare subjects, according to Pharmalot blogger and journalist Ed Silverman.
In a May 28 email reprinted by Silverman, FDA reviewer Dr David Graham told Hamburg that the Journal of the American Medical Association (JAMA) "is very interested in our manuscript, and we would like to submit it before next Friday, June 4. [Dr] Gerald Dal Pan, my supervisor, is prepared to sign the clearance form (the paper has a disclaimer and does not represent an official FDA position) but won’t unless Dr [Janet] Woodcock and Dr [John] Jenkins approve. He is afraid to act, even though he is the 'clearing official.' "
The notion that the FDA could in any way be delaying the publication of comparative thiazolidinedione data could not come at a more sensitive time. The FDA's much ballyhooed rosiglitazone review, including a decision on the contentious TIDE trial, is now confirmed on the advisory committee schedule for July 13–14 and is widely predicted to be one of the most controversial drug reappraisals in the FDA's history.
Graham writes that the manuscript, posted online by Silverman, is completed, "except for a few minor details," and shows that in over 227 000 subjects, rosiglitazone compared with pioglitazone significantly increased the risk of stroke by 27%, heart failure by 25%, death by 13%, and AMI or death by 11%. The increased risk of AMI alone (6%) was not statistically significant. "We suspect that fewer elderly patients survive their AMI long enough to reach the hospital, so that AMI/death is a better measure," Graham wrote.
Graham's email goes on to say that, in his study, the number needed to harm was "59 patients treated with rosiglitazone for one year to produce one excess case of any of our outcomes. This translates to 48 000 excess events attributable to rosiglitazone among patients age 65 years or older between 1999 and June 2009. Given that 62% of rosiglitazone use has been in patients below age 65, the actual national impact is probably 100 000 or more."
Graham points out that his manuscript has coauthors from the Centers for Medicare and Medicaid Services (CMS), who are also anxious to see the results made public in a timely fashion given their "duty" to Medicare patients.
"The idea of being blocked from doing this by a sister agency is a source of concern to them and to me," Graham's email reads. "In late 2004, [Center for Drug Evaluation and Research] CDER management suppressed the publication of a study I conducted using data from Kaiser California that showed increased AMI risk with rofecoxib [Vioxx, Merck]. This was done in an effort to downplay the seriousness of their prior poor decision-making in leaving rofecoxib on the market. So you can understand that I am very sensitive to anything that remotely smells like suppression or censorship."
Silverman also posted a response from GlaxoSmithKline, pointing out that it is not yet clear whether Graham et al's study had yet been peer reviewed. "Until then, it would be premature to comment." Likewise, an FDA spokesperson told Silverman, "We didn't suppress this" and said that Graham's supervisor was not, in fact, "afraid" to provide authorization for the paper, which was provided in time for the June 4 deadline.
Graham has not yet responded to a request for more details from heartwire , and it is not yet clear whether, indeed, the manuscript has in fact been submitted or accepted for publication at JAMA. As previously reported by heartwire , Graham and Dr Kate Gelperin coauthored one of the documents included in the February Senate finance committee report, concluding that rosiglitazone be removed from the market.
Heartwire from Medscape © 2010 Medscape, LLC
Cite this: Rosiglitazone Critic at FDA Accuses Superiors of Stalling Publication of New Data, Says Pharmalot Blog - Medscape - Jun 11, 2010.