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FDA panel recommendation creates mixed opinions about future of rosiglitazone
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The FDA advisory committee recommendation that rosiglitazone stay on the U.S. market as a treatment option for patients with type 2 diabetes but with restrictions on use and revised labeling has many physicians questioning the future of the diabetes drug as well as how to rank medical evidence.
Twelve of 33 members on the joint Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management advisory committee recommended the complete withdrawal of rosiglitazone (Avandia, GlaxoSmithKline). Ten recommended continued marketing with additional warnings about MI and congestive HF or restrictions such as patient and provider education; just three recommended no changes to the current labeling.
“This was not just a discussion about the safety of rosiglitazone, it was a discussion about which type of scientific evidence is more important,” Yehuda Handelsman, MD, medical director of the Metabolic Institute of America, Tarzana, Calif., told Cardiology Today.
The FDA advisory committee was presented with conflicting evidence about the CV safety of rosiglitazone from randomized controlled trials, such as the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) study, to observational studies to meta-analyses. Much of the discussion focused on RECORD, with criticisms about the open-label study design, biased mishandling of CV events and overall results.
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Source: Cardiology
Today |
“There remains great uncertainty that the results of the studies to date have been inconclusive from a scientific standpoint,” Richard G. Bach, MD, professor of medicine at Washington University School of Medicine, said in an interview. “The degree of inconsistency and discordance between studies raises great questions.”
Ranking of medical evidence
While many were focused on the decision itself, for others the quality and ranking of scientific evidence was the star of the 2-day meeting. Fraught with statistical analysis, the meeting focused on the panel debate about which level of evidence has more weight: randomized controlled clinical trials or observational studies and meta-analyses.
“I saw an attack on the scientific basis for medical practice,” Alan J. Garber, MD, a professor in the division of diabetes, endocrinology and metabolism at Baylor College of Medicine in Houston and a member of the Cardiology Today Editorial Board, said of the meeting.
“This is of great concern because in the last 30 years, we have built up an edifice called evidence-based medicine,” he said. “Now we are seeing these randomized controlled trials — the gold standard for evidence-based medicine — being attacked because what were previously thought to be inferior levels of evidence are now being elevated, such as database analyses.”
The safety of rosiglitazone has been questioned since 2007, when a meta-analysis by Steven E. Nissen, MD, and Kathy Wolski, MPH, of the Cleveland Clinic, showed that rosiglitazone was associated with a 43% increase in the risk for MI. The findings were published in The New England Journal of Medicine.
The FDA panel was also presented with results of a nationwide, observational, retrospective study conducted by David Graham, MD, FDA drug safety scientist, and colleagues that looked at outcomes of about 230,000 Medicare patients who were treated with rosiglitazone or pioglitazone. The study examined a combined endpoint of MI, stroke, HF or death and found that patients taking rosiglitazone had an 18% increased risk compared with those taking pioglitazone. The data were published in JAMA in late June.
“We have to deal with the fact that many of the clinical interventions we provide for patients are supported only on the basis of either observational data or retrospective analyses,” Bach said. He said it is difficult to appreciate the caveats and question marks that remain about the way studies such as RECORD, observational studies and meta-analyses were conducted.
Inconclusive data
At the end of the meeting, panel member Lamont G. Weide, MD, PhD, said he remained concerned about removing a drug from the market that provides benefit to some patients.
“I would hate to take away a drug without definitive evidence from the few patients who need it,” Weide, chief of diabetes and endocrinology at University of Missouri-Kansas City, said of his vote to keep rosiglitazone on the market.
Voting member Arthur J. Moss, MD, PhD, said he could “absolutely not vote for withdrawal” based on the inconclusive data presented to the panel.
“I wanted to send a message to the FDA because a proper trial [on the safety of rosiglitazone] should have been done going all the way back to 1993 — and that trial still needs to be done,” Moss, professor of medicine and cardiology at University of Rochester, N.Y., said at the meeting.
Some members voted for withdrawal and stricter restrictions on the rosiglitazone label because alternative therapies to rosiglitazone are available, such as pioglitazone (Actos, Takeda), the other thiazolidinedione on the U.S. market.
“We can still take care of diabetes if rosiglitazone is banned by the FDA in its final vote,” said Abraham Thomas, MD, MPH, panel member and division head of endocrinology, diabetes, bone and mineral disorders at Henry Ford Hospital.
This is not the first time that rosiglitazone was the focus of an FDA advisory committee meeting. On July 30, 2007, the CV safety concerns associated with the drug were discussed before a joint advisory committee, which voted 20-3 that available data suggest rosiglitazone increases cardiac ischemic risk in type 2 diabetes. The committee voted 22-1, however, that the overall risk-benefit profile of rosiglitazone supports its continued marketing in the United States.
Final vote to come
While the agency is not required to follow the recommendations of the advisory committee, it typically does.
Janet Woodcock, MD, director of the FDA Center for Drug Evaluation and Research, said the agency will evaluate the advisory committee proceedings and available regulatory options and come to a decision “as soon as possible.”
“It is always nice to say, ‘Here is the answer.’ But that is not realistic in this circumstance,” Bach said.
“The medical community and FDA are learning a lot from this experience. The problem of surrogate endpoints in clinical trials, the type of data that need to be acquired and so on requires a level of scientific rigor and careful attention to detail in trial design and conduct that will probably improve the way we study and approve drugs in the future. It was a difficult path to get here, but the lessons learned will be important in the future,” Bach said. – by Katie Kalvaitis
Note: Dr. Garber and Dr. Handelsman have reported receiving financial support from GlaxoSmithKline.
For more information:
- Graham DJ. JAMA. 2010;304:doi:10:1001/jama.2010.920.
- Home PH. Results of the RECORD clinical trial. Presented at: American Diabetes Association’s 69th Annual Scientific Sessions; June 5-9, 2009; New Orleans.
- Nissen SE. N Eng J Med. 2007;356:2457-2471.