Keeping a patient on rosiglitazone under the REMS “will be an onerous task” and the use of the drug will be “minimal,” said Dr. Paul Jellinger, professor of clinical medicine, University of Miami, and past president of the American College of Endocrinology and the American Association of Clinical Endocrinologists. Patients can easily be switched form rosiglitazone to pioglitazone, or a non-TZD drug, such as an incretin-based treatment, he said in an interview.
Dr. Jellinger said that he thought the FDA decision was appropriate and that the FDA acted on behalf of patient safety, based on substantial amount of data. Although there was “considerable uncertainty, there remains a potential risk and there is a signal that suggests there may be a relationship.”
One of the cardiologists on the panel in July, Dr. Sanjay Kaul of the Cedars-Sinai Heart Institute in Los Angeles, said in an interview that the FDA’s decision is “the right call to keep the drug accessible but with significant restrictions that have teeth.” The decision, though, “reflects the uncertainty in the evidence – it is insufficient to either implicate the drug or exonerate it.”
During the press briefing, Dr. Woodcock said, “We still believe there is considerable uncertainty about the magnitude of the cardiovascular risk.” RECORD was an open-label trial, “and it was determined that we can’t rely on those results, even though they did not show a significantly increased risk of cardiac harm. Therefore, the questions raised by the meta-analysis have not really been answered,” she said.
The FDA also decided to terminate the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) study, also sponsored by GlaxoSmithKline, which was designed to determine any difference in cardiovascular safety between rosiglitazone and pioglitazone. In July, the FDA put TIDE on a partial hold, allowing patient enrollment but not treatment. The panel had voted 19-11 to continue the TIDE trial, if rosiglitazone remained on the U.S. market.
Dr. Rosen, who was among those strongly opposed to continuing the study, lauded the decision to halt the TIDE study because it would be unethical to continue the study and subject people to a randomized trial that involved a drug ”where we know the risk and benefit is not established beyond pioglitazone.”
Dr. Kaul was among the panelists who supported continuing TIDE. ”If you stop the study, how else are you going to resolve this uncertainty,” he said. But he agrees with the FDA decision. “The FDA had to do what they did,” but pointed out that considerable controversy over the drug remains.
Dr. Jellinger also would have liked the TIDE study to continue, and found it “unusual” that the gold standard of clinical trials, the prospective randomized, controlled study, was trumped by studies like meta-analyses.
During the press briefing, Dr. Woodcock said that the signal of increased risk “has not been completely refuted by any evidence, so we think it is prudent to restrict access and make sure that those using and prescribing the medication are aware of the facts and make the choice in an informed manner.”
It will take several months to fully implement the REMS program, Dr. Joshua Sharfstein said during the briefing. Until then, “Patients who are taking rosiglitazone should continue to do so, and consult their physician to discuss the possibility of selecting another medication without this concern of cardiac ischemia,” said Dr. Sharfstein, FDA’s principal deputy commissioner. “Once the REMS is in place, physicians will need to enroll patients before they can continue to receive the drug.”
When the REMS is active, Dr. Sharfstein reiterated, rosiglitazone will be available only to patients who cannot control their blood sugar on any other medication and who are unable to take pioglitazone for medical reasons. “Doctors will have to document this, and also that they have discussed the risks of rosiglitazone in order for the patient to receive the drug.”
Researchers had hoped the RECORD study would set the rosiglitazone risk story straight. But in July, the FDA panel tasked with reviewing the drug’s safety questioned RECORD and its adjudication of cardiovascular events. The independent review of RECORD’s adjudication at a patient record level will be done, Dr. Sharfstein said, “to catch events that occurred but which might have not been properly referred to the adjudication committee.”
In a press statement, Dr. Ellen Strahlman, GlaxoSmithKline’s chief medical officer, said, “Our primary concern continues to be patients with type 2 diabetes, and we are making every effort to ensure that physicians in Europe and the U.S. have all the information they need to help them understand how these regulatory decisions affect them and their patients.”