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FDA panel favors looser restrictions for diabetes drug
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After 2 days of hearings in June, an FDA advisory committee voted to ease existing restrictions for the diabetes drug rosiglitazone.
Current Risk Evaluation Mitigation Strategy with Elements to Assure Safe Use (REMS/ETASU) restrictions require health care professionals to submit forms on each patient prescribed rosiglitazone (Avandia, GlaxoSmithKline), and patients must acknowledge that they understand potential CV risks before they can receive the drug. Rosiglitazone is available to patients only if other medications have failed.
The vote included 13 members in favor of modified restrictions, seven for removal of all restrictions, five for unchanged restrictions and one for withdrawal of the drug from the US market.
Recommendations were based on discussion of a highly anticipated, independent analysis of the FDA-requested Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial.
The agency will consider the committee’s vote before making a final decision, but is not required to follow the recommendations of the advisory committee.
Use of rosiglitazone, a thiazolidinedione indicated as an adjunct to diet and exercise for patients with type 2 diabetes, has been controversial since 2006 when data emerged suggesting potential risk for CV events including MI and stroke.
The Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory meeting was called due to “the public interest in Avandia, the extensive history of the product and the continued uncertainty of the risk surrounding this drug,” Janet Woodcock, MD, director of the FDA Center for Drug Evaluation and Research, wrote in an FDA blog.
RECORD was a 5–plus-year study of more than 4,400 patients designed to evaluate long-term effects of rosiglitazone on CV outcomes and blood glucose control compared with metformin and sulfonylureas. Initial results reported in 2009 demonstrated no increased risk for CV morbidity or mortality with rosiglitazone.
The independent readjudication of RECORD was conducted by Duke Clinical Research Institute researchers at the request of the FDA. The analysis included follow-up for mortality for 25,833 person-years, including an additional 328 person-years identified during a reevaluation. Overall, researchers reported 184 CV or unknown-cause deaths (88 rosiglitazone, 96 metformin/sulfonylurea), 128 patients with MI (68 rosiglitazone, 60 metformin/sulfonylurea) and 113 patients with stroke (50 rosiglitazone, 63 metformin/sulfonylurea). The HR for rosiglitazone vs. metformin/sulfonylurea for the endpoint of CV death/MI/stroke was 0.95 (95% CI, 0.78-1.17) vs. 0.93 (95% CI, 0.74-1.15) for the original RECORD results. Treatment comparisons for MI (HR=1.13; 95% CI, 0.8-1.59) and mortality (HR=0.86; 95% CI, 0.68-1.08) were also the same compared with the original results.
“Observed HRs and CIs from these analyses using the original RECORD or new FDA endpoint definitions showed similar treatment effects of rosiglitazone compared with the original RECORD results,” the DCRI researchers concluded in the analysis, which was published online in American Heart Journal.
During the advisory panel meeting, most members agreed that the HRs and CIs from the analyses were consistent and that the drug did not increase risk for all-cause or CV mortality. Even so, the RECORD trial design, reliability of CV endpoints, the drug’s contraindication with statins and the absence of data on MACE came under fire.
“RECORD was too inadequately designed and conducted to provide any reassurance about the CV safety of rosiglitazone,” Thomas A. Marciniak, MD, from the division of cardiovascular and renal products at the Office of Drug Evaluation I, Office of New Drugs and CDER at the FDA, said during the meeting.
Panel member T. Mark Woods, PharmD, clinical coordinator and residency program director in the pharmacy department of Saint Luke’s Hospital in Kansas City, voted in favor of REMS/ETASU modification. “While [readjudication of] the RECORD trial helped reassure us in some aspects, it also introduced new questions. For example, I think the statin issue is very much still up in the air, and given the number of diabetic patients that will end up on statins I have lingering concerns about toxicity,” he said.
Experts weigh in
Ralph G. Brindis
“Regarding safety, the story of rosiglitazone is a cautionary tale. With 14 years since the FDA approval, [the drug] is still lacking conclusive evidence,” Ralph G. Brindis, MD, MPH, FACC, president-elect of the American College of Cardiology, said during an open public hearing.
“Rehashing clinical trial data only goes so far,” Brindis said. “Improved real-time surveillance is critical.”
In a comment after the meeting, American Heart Association national spokesperson Jorge Plutzky, MD, said, “Those voting to modify current restrictions may believe it would enable researchers to more definitively assess the potential risk for heart attack and other major heart events with this drug. Many panelists expressed the need for more data, which would be difficult to obtain under the current level of restriction.”
George A. Bakris
In an interview, George A. Bakris, MD, FASH, FASN, Cardiology Today Editorial Board member, said, “After reviewing the quality of data put together by DCRI and the vote cast by the metabolic unit of the FDA, it is clear that a more definitive opinion about CV safety could not be confirmed. I applaud the effort of DCRI and the FDA committee to try and get at the truth with PPAR gamma agents, which when used in lower doses are not associated with untoward effects and the benefits outweigh the risk.”
Robert E. Ratner
Robert E. Ratner, MD, FACP, FACE, chief scientific and medical officer of the American Diabetes Association, does not anticipate that the vote will have a “major change” on the treatment of diabetes patients. “I don’t see a major future for rosiglitazone from a clinical standpoint,” he said. “The more important aspect of this particular meeting is that the agency is reinforcing the appropriate process by which data need to be reviewed and how logical decisions as opposed to emotional decisions are made.”
Future considerations
Pending the FDA’s decision, rosiglitazone will be available through the REMS/ETASU program to physicians and appropriate patients, according to statement from GlaxoSmithKline.
Only about 4,600 patients in the United States are currently using rosiglitazone, Robert Bigelow, PhD, DCRI senior statistician for the reevaluation, said at the meeting.
Disclosure: FDA advisory committee members declared no relevant financial disclosures. Bakris reports receiving grant/research support from Takeda; salary support from Medtronic and Relypsa; and consulting for Abbott, CVRx, Daiichi Sankyo, Eli Lilly, Johnson & Johnson, Relypsa and Takeda. Brindis, Plutzsky and Ratner report no relevant financial disclosures.