BETHESDA, MD 27 June 2013—A panel of experts on June 6 recommended that FDA ease some of the restrictions on the prescribing of the antidiabetic drug rosiglitazone and make the drug more readily available to patients.
Of the 26 voting members of FDA's Drug Safety and Risk Management and Endocrinologic and Metabolic Drugs advisory committees, 20 supported the removal or modification of the risk evaluation and mitigation strategy (REMS) program for rosiglitazone.
This represented a change of opinion from 2010, when 17 of 32 advisers agreed that rosiglitazone required new labeled warnings, new restrictions on use, or both, and 12 others voted to remove the GlaxoSmithKline product, sold as Avandia, from the U.S. market.
In 2010 and this year, many advisers said their views were influenced by findings from the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) study. The large, randomized, multicenter trial compared rosiglitazone against metformin–sulfonylurea therapy and was completed in 2008.
GlaxoSmithKline's 2010 analysis of data from the RECORD study concluded that rates of cardiovascular-related hospitalization and death were similar whether patients used rosiglitazone or the control therapy.
But many meeting participants were skeptical of the RECORD trial's findings because of its open-label design, problems with patient follow-up, and GlaxoSmithKline's pooling of data for analysis. Conflicting data from other studies had suggested that rosiglitazone use increased both all-cause mortality and cardiovascular-related hospitalizations and deaths.
One of the outcomes of the 2010 meeting was that FDA required GlaxoSmithKline to commission an independent readjudication of data from the RECORD trial. The results of that process were presented at this year's meeting and largely supported the original findings.
"I would say that the results for myocardial infarction are indeterminate. The results for all-cause mortality seem reassuring," said Ellis F. Unger, a director in FDA's drugs division who reviewed the readjudicated RECORD data for FDA.
The new analysis satisfied many of the advisers at this year's meeting.
"Generally speaking, in 2010 I felt that I couldn't look at RECORD at all for useful information. I don't feel that way at this point," said Marvin A. Konstam, director of the cardiovascular center at Tufts Medical Center in Boston.
Konstam had voted in 2010 to remove rosiglitazone from the U.S. market. This time, he recommended keeping the drug on the market with a less-stringent REMS program.
"It may be possible in my mind to eliminate the ETASU program, or at least to soften it in a way that simply shifts the burden to the physician to use his or her judgment based on the totality of the data," Konstam said.
ETASU denotes elements to assure safe use within some REMS programs. In the case of rosiglitazone, these elements include mandatory prescriber certification, enrollment of patients who meet specific criteria, and availability of the drug only from designated pharmacies.
Mark Woods, clinical coordinator and director of pharmacy residency programs at St. Luke's Hospital in Kansas City, Missouri, voted in 2010 to withdraw rosiglitazone from the U.S. market.
This time around, Woods preferred to keep the drug on the market but change its REMS program.
"I do believe there is a very small subset of patients that potentially need to have access to this drug," Woods said. He said it would be helpful if the REMS program could be changed in ways that would provide data on adverse events in patients who use the drug.
Woods and several other advisers said they would like a new clinical trial of rosiglitazone to be conducted that would provide conclusive data on the drug's safety. He and others were hopeful that a new trial could answer concerns about a potential safety signal in people treated concomitantly with rosiglitazone and a statin.
According to FDA's briefing documents, an analysis of the readjudicated RECORD data suggested that statin users were more than twice as likely as control patients to die after starting therapy with rosiglitazone. Neither FDA's reviewers nor the independent adjudicators had a plausible explanation for this potential interaction.
"I'm skeptical, given where we are, probably, in the patent life of this drug, that we're going to see a lot of new studies," Woods noted. "But I guess that will be for the sponsor to figure out."
FDA initially approved rosiglitazone in 1999, and the drug was under patent protection until recently. Teva Pharmaceuticals on January 23 won FDA approval to market generic 2-, 4-, and 8-mg versions of rosiglitazone oral tablets, and other manufactures have received tentative approval to sell competing products.
Generic versions of rosiglitazone will be marketed under the terms of a shared-systems REMS program, according to FDA. But it's unclear whether the availability of these products will expand patients' use of rosiglitazone.
FDA analyst Justin Mathew said annual retail prescription fills for rosiglitazone-containing products peaked at 12.5 million. Sales began to fall in 2007, when data emerged about the drug's potential risks. Last year, he said, about 12,600 total prescriptions were dispensed for these products.
FDA analyst Joyce Weaver said the largest drop in prescription fills occurred after November 18, 2011, when rosiglitazone sales were restricted to four authorized mail-order pharmacies. Sales by other pharmacies since then are outside of the REMS program and involve product that should have been returned to the manufacturer and not offered for sale.
John Jenkins, director of FDA's Office of New Drugs, called the 2013 meeting "an outstanding discussion of a very complicated issue."
He said FDA staff will discuss possible changes to the marketing status of rosiglitazone, but he did not give a time frame for a decision on those changes.