The US Congress House Committee on Oversight and Government Reform wrapped up its Wednesday hearing into the FDA's role in evaluating the safety of rosiglitazone (Avandia, GlaxoSmithKline [GSK]) with no clear consensus on what the cardiovascular risk of the drug may be, no definitive reprimand for the FDA and its handling of drug data, and no bipartisan agreement as to whether the controversy that exploded in late May was a "political concoction."
One clear change is in the cards for diabetes drugs in this class, however. During his witness statement, FDA Commissioner Andrew C von Eschenbach said that the FDA has issued letters to GSK and Takeda Pharmaceuticals, the manufacturer of pioglitazone (Actos), requesting labeling changes. Strikingly, this new black-box warning will have nothing to do with the recent rosiglitazone ruckus, which has centered on MI and cardiovascular death. According to von Eschenbach, the aim of the boxed warning is "to more prominently address the risks of congestive heart failure [CHF] associated with the use of these drugs in certain patients."
Takeda has issued a press release announcing the changes it will make to its label to "heighten awareness of the risk of CHF."
No definitive conclusions on safety
From the outset, committee chair Henry Waxman (D-CA) said he had "struggled to find the right tone" for the hearing and stipulated that its purpose was not so much to determine rosiglitazone's safety but to appreciate the "need for reform of the nation's drug safety laws."
"Many people watching this hearing today will be looking for answers about whether Avandia is safe," Waxman stated. "I understand and share their desire for answers, but because of the lack of data, there may be no definitive conclusions."
Instead, what emerged in Waxman's remarks, as well as presentations from the FDA, were consistent concerns about the possibility of increased cardiovascular risks with rosiglitazone that, as yet, have not been adequately highlighted in the drug labeling. As early as 1999, when the drug was first approved, the FDA's medical officer referred to concerns about "deleterious long-term effects on the heart" and called for a postmarketing study to address these issues as a condition of approval.
But the FDA, according to Waxman, "dropped the ball" by not requiring the sponsor to design and follow through with a trial that would conclusively answer the right questions about cardiovascular risks.
Pressed to say whether he felt the ADOPT study, which was the GSK postmarketing study mandated by the FDA, adequately addressed the cardiovascular concerns raised by the FDA's medical reviewer in 1999, von Eschenbach acknowledged the agency, at that time, had been more concerned about the risk of heart failure than the risk of heart attacks and that the postmarketing study agreed upon did not address the events now in the spotlight. But FDA officials repeatedly insisted that they are still in the process of reviewing data provided to them by the company, in particular a meta-analysis of randomized trials and a large epidemiological study. They are also performing their own meta-analysis using patient-level data.
"We will evaluate the results of that analysis along with the data from other sources, including the long-term controlled clinical trials . . . and the large observational study, before reaching a conclusion about the potential for an increased risk for ischemic cardiovascular events in patients treated with rosiglitazone," von Eschenbach said.
But other witnesses summoned to the hearing, namely Drs Steven Nissen (Cleveland Clinic, OH), Bruce M Psaty (University of Washington, Seattle), and John B Buse (University of North Carolina School of Medicine, Chapel Hill), charged the FDA with taking too long to review rosiglitazone's safety record and failing to mandate the necessary trials. Nissen was coauthor on a meta-analysis pointing to a significant 43% increase in MI with rosiglitazone that touched off the rosiglitazone firestorm last month [1]. Psaty was a coauthor of an editorial [2] that accompanied that study, and more recently, of another editorial [3] accompanying the publication of an interim analysis of the RECORD trial [4].
Psaty put the blame for the paucity of quality data squarely on the shoulders of GSK, which he alleges designed randomized clinical trials--DREAM, RECORD, and ADOPT--to answer "marketing questions" rather than investigate the risk of ischemic events. But he also questioned the FDA's reluctance to inform the public about key data, including those provided by GSK that led to product label revisions in Europe back in October 2006.
"The US product label still does not identify heart attack as a potential adverse reaction in the general population of diabetics," Psaty noted. "It is not clear why FDA failed to make this information public before Dr Nissen's meta-analysis was published. The primary measure of regulatory success is the timeliness of information, warnings, or withdrawals; with Avandia, FDA failed to warn or inform in a timely fashion."
Revisions warranted for drug approval process?
Some of the day's hearing focused on whether von Eschenbach specifically, or the FDA generally, supported legislation that would give the agency more power to enforce postmarketing studies, to control direct-to-consumer advertising, or to give more power to a separate drug-safety committee.
Repeatedly, von Eschenbach dodged questions requiring answers that might in any way imply shortcomings in the FDA's current approach to drug and device review. Asked by Patrick T McHenry (R-NC) about the implications of "elevating" a safety-review office within the FDA, von Eschenbach argued, instead, for "diversity of focus within the FDA that looks at these issues from different perspectives but does so in an integrated and coordinated way." Separating reviews of drug safety from efficacy would be "more destructive than constructive," he suggested.
Political machinations vs good medicine
Throughout the hearing, partisan politics reared its head, despite the insistence of some panel members--each with a different, valiant attempt to pronounce "rosiglitazone"--that patient well-being was the main reason for the hearing. Darrell E Issa (R-CA) questioned the motives of the committee and witnesses, suggesting some were attempting to "politicize science," particularly since there clearly was not enough evidence to definitively condemn or acquit rosiglitazone.
Following Nissen's testimony, Issa and McHenry grilled him as to when he first approached members of the oversight committee, whether he had shared data with members before his meta-analysis appeared in the New England Journal of Medicine, and why he had not also contacted the FDA with his findings.
"What were you doing in February when you were saying you were concerned and asked for information from a political body rather than the fundamental group that we hold accountable, the FDA?" Issa asked Nissen. "It very much looks like this was a political entity, designed to make a big public splash," he said, adding that the hearing was called for even before Nissen's meta-analysis was published. "Didn't you, in fact, make a conclusion back in February that this was, in your opinion, a potentially dangerous drug and decide that you wanted to shed light upon it using this body at a public hearing, using your article?"
Nissen flatly denied having a political motive and insisted he approached the oversight committee only in an effort to gain access to data not available in the public domain. He pointed out that the FDA is not allowed to provide the information he was looking for but in fact had access to even better, patient-level data and could presumably have come to the same conclusions he did.
"With all due respect sir, this is about patients, it's not about politics," Nissen said. "I had an incomplete result, I was looking for assistance to complete the study. When it was completed, I did what any scientist would do: I sent it for peer review and publication. Why? Because it is my scientific, ethical, and moral obligation to put such information into the public domain."
On the Democrat side, Elijah E Cummings (D-MD) chided his political opponents for questioning the scientific process. "Having been here for 11 years, I hate it when witnesses are attacked. It bothers me, particularly when they are trying to do the best they can with what they have. I believe you are all honorable men trying to be the best you can be. I hate that we have to make these accusations that people are putting politics over the health of the American people."
CV risks "comparable" to other drugs: GSK
Also called as a witness, Dr Moncef Slaoui, chair of research and development for GSK, defended rosiglitazone's safety record in the randomized controlled studies and in the large epidemiologic study commissioned by the company, published online in Pharmacoepidemiology and Drug Safety the same day as the hearing [5].
"The complete data available to date clearly support our conviction that the cardiovascular safety of Avandia is comparable to that of the two most widely used oral antidiabetes medicines," he said. He also called the interim data from RECORD, reported by heartwire earlier this week, "very reassuring" and said he was "extremely disappointed" with the editorials that accompanied it [2,6,7] for "cherry-picking" end points.
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356:2457-2471.
Psaty BM, Furberg CD. Rosiglitazone and cardiovascular risk. N Engl J Med 2007; 356:2522-2524.
Psaty BM, Furberg CD. The record on rosiglitazone and the risk of myocardial infarction. N Engl J Med 2007; DOI: 10.1056/ NEJMe078116. Available at: http://www.nejm.org.
Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes--an interim analysis. N Engl J Med 2007; DOI: 0.1056/NEJMoa073394. Available at: http://www.nejm.org.
McAfee AT, Koro C, Landon J, et al. Coronary heart disease outcomes in patients receiving antidiabetic agents. Pharmacoepidemiol Drug Saf 2007; DOI: 10.1002/pds.1443. Available at: http://www3.interscience.wiley.com/cgi-bin/jhome/5669.
Drazen JM, Morrissey S, Curfman GD. Rosiglitazone--continued uncertainty about safety. N Engl J Med 2007;357. DOI: 10.1056/NEJMe078118. Available at: http://www.nejm.org.
Nathan DM. Rosiglitazone and cardiotoxicity: weighing the evidence. N Engl J Med 2007;357. DOI: 10.1056/NEJMe078117. Available at: http://www.nejm.org.
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