Rosiglitazone Restrictions Should Be Eased, FDA Panel Says

Miriam E. Tucker


June 06, 2013

The diabetes drug rosiglitazone (Avandia, GlaxoSmithKline) should stay on the market, and the current restrictions on its prescribing should be eased but not lifted entirely, according to the majority vote of a joint advisory panel to the US Food and Drug Administration (FDA).

Of the 26 total members of the FDA's Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee, 13 voted to keep rosiglitazone on the market but to ease up on various elements of the current risk evaluation and mitigation strategy (REMS) with elements to assure safe use (ETASU) program, which was initiated in 2010 because of concerns about cardiovascular (CV) safety.

Another 7 members voted to completely remove the REMS/ETASU and allow the drug to be freely prescribed again, while another 5 members voted to continue the current REMS/ETASU restrictions as they now stand. Only 1 panel member, the consumer representative, voted to remove rosiglitazone from the US market.

Under the current REMS/ETASU, special certification is required for healthcare providers who prescribe rosiglitazone. In addition, only specially certified pharmacies can dispense it, and only patients who were already taking it prior to the restrictions or new patients who cannot use any other glucose-lowering medications are eligible to take it. Medication guides for both patients and healthcare providers are also part of the program.

The number of patients using rosiglitazone in the United States has dropped from 117,349 in 2009 to 3405 during 2011–2013. Although the decline began prior to the REMS/ETASU, the drop was dramatic after it was implemented, the FDA's Justin Mathew, PharmD, told the panelists.

Regarding rosiglitazone's future, Robert J. Temple, MD, acting deputy director of the FDA's Office of Drug Evaluation, told Medscape Medical News that there is no timetable for the FDA to make a decision following this advisory committee meeting. "We're going to have to think about it. I don't think we want to take too long, but we've got to take long enough," he observed.

Vote Was Culmination of 2-Day Meeting; Opinions Still Differ

The shift in opinion since 2010 on the need for the restrictions came after a 2-day meeting at the FDA, in which panel members evaluated a readjudication of GlaxoSmithKline's Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD) study, the only randomized trial of the drug to specifically examine CV outcomes.

The findings of the original RECORD trial, which did not show an overall increased risk for CV events, had been called into question because of concerns about its reliability and interpretability. On the first day of the current meeting, panel members heard presentations about a readjudication of RECORD carried out by the Duke Clinical Research Institute (DCRI), which supported the conclusions of the original trial. A subsequent analysis of the FDA backed up the readjudication.

Most panel members said they were convinced of the integrity of the readjudication and were satisfied that accusations of malfeasance and manipulation of the data were not valid. Yet, the panel expressed considerable concerns about limitations of the original trial's open-label design and missing data.

The panel also considered results from a Cochrane-type systematic review of 28 epidemiologic trials conducted by the FDA, which found that rosiglitazone appeared less safe with regard to CV end points than the other thiazolidinedione drug on the US market, pioglitazone (Actos, Takeda Pharmaceuticals).

Given the limitations of all the currently available data, several panel members called for GlaxoSmithKline to conduct a new trial, preferably one that is large, randomized, and placebo-controlled. Others, however, felt that such a trial would be unethical and/or unfeasible.

Cardiologist Sanjay Kaul, MD, from the David Geffen School of Medicine, University of California, Los Angeles, said that at the 2010 advisory panel meeting that preceded the restrictions he had voted for continued marketing of rosiglitazone with additional warnings on the label. "At the time, I was neither reassured nor concerned about the RECORD data. The DCRI readjudication reconfirmed my uncertainty."

Dr. Kaul said he struggled with his current vote but finally went with the majority, ultimately deciding that the REMS, in whatever the final modified form, "would be a good opportunity to communicate the uncertainties to the patients in the form of a communication plan."

However, he added, "If somehow magically the stars are aligned and it is feasible to conduct the desired trial and the only way the FDA will allow that is to remove the REMS, then I would be in favor of removing the REMS."

Another cardiologist on the panel, Marvin A. Konstam, MD, chief physician executive at the CardioVascular Center at Tufts Medical Center and professor of medicine at Tufts University, Boston, Massachusetts, also voted with the majority. "The difference between now and 2010 is the readjudication of RECORD. Those results do not remove my concern about the cardiovascular safety of rosiglitazone, but in my mind they move the needle in a direction that it seems to me is appropriate to shift the burden of decision making for prescribing this drug to the physician in terms of interpreting the entirety of the data."

Dr. Konstam suggested that the REMS/ETASU might be modified by either eliminating or in some way softening the prescribing restrictions while keeping the medication guide.

But epidemiologist Susan R. Heckbert, MD, PhD, professor of epidemiology at the University of Washington, Cardiovascular Health Research Unit, Seattle, voted to continue the current REMS/ETASU with all its restrictions. "None of the conclusions from the July 2010 meeting have changed, not from the RECORD trial,  the [FDA's] meta-analysis of short-term trials, or the observational studies."

Added Dr. Heckbert, "No new results suggested any unique benefits of rosiglitazone, and no results of effects on CV end points have changed. I don't see any reason to change the current approval status of the drug. I voted to keep the current REMS/ETASU in place because I think it's reasonably effective at dealing with the CV safety signal, which is still present."

On the other end of the voting spectrum, Michael A. Proschan, PhD, a mathematical statistician in the Biostatistics Research Branch at the National Institutes of Health, voted to remove the REMS/ETASU entirely. "I'm reassured by the data from RECORD...[that] at least that it's not worse than other diabetes drugs."


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