FDA is replacing prescribing and distribution restrictions for rosiglitazone-containing medicines, including GlaxoSmithKline PLC’s Avandia and generics, with a requirement for prescriber training on the current state of knowledge about the diabetes drug’s cardiovascular risks.

The agency’s action amounts to a significant easing of the current REMS restrictions on the thiazolidinedione but not a complete elimination of the program’s elements to assure safe use (ETASU). It also reflects the high level of comfort the agency gained from the re-adjudicated RECORD study results, which showed no increased cardiovascular risk for rosiglitazone compared to other diabetes drugs.

Under the changes announced Nov. 25, current ETASU requirements for prescriber, pharmacy and patient enrollment in the Rosiglitazone REMS Program will be eliminated.

FDA expects the labeling and REMS changes to be finalized within six months.

The REMS and ETASU will be modified to “consist of a requirement that sponsors ensure that health care providers who are likely to prescribe the drug are provided training based on the current state of knowledge concerning the cardiovascular risk of rosiglitazone-containing medicines,” FDA said.

Sponsors of rosiglitazone-containing medicines will also be required to send Dear Healthcare Provider and Dear Professional Society letters that summarize the current state of knowledge concerning the drug’s CV risk and changes to the REMS, the agency said.

The restricted distribution REMS and a limited indication statement were required by FDA in September 2010 and finalized in May 2011 due to agency concerns and uncertainty about the drug’s cardiovascular safety Also see "Avandia REMS Limits Access To Mail Order Pharmacies Beginning In November" - Pink Sheet, 18 May, 2011..

Like the certification and enrollment requirements, the REMS provision limiting drug distribution through certain mail order pharmacies will become a thing of the past. “Patients will also be able to receive rosiglitazone through regular retail pharmacies and mail order pharmacies,” FDA said.

Opening Up The Indication

The drug’s indication statement also will be opened up to more patients, FDA said.

Rosiglitazone currently is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes who either are already taking the drug or are unable to achieve adequate glycemic control on other diabetes medications and, in consultation with their health care provider, have decided not to take Takeda Pharmaceutical Co. Ltd.’s competing thiazolidinedione Actos (pioglitazone) for medical reasons.

Under the forthcoming changes to the REMS and product labeling, “rosiglitazone’s indication for use will no longer be limited to certain patients,” the agency said. “FDA anticipates that the new indication will state that the drug may be used along with diet and exercise to improve control of blood sugar in patients with type 2 diabetes mellitus, an indication similar to other diabetes drug currently available.”

FDA said it anticipates the labeling and REMS changes will go into effect within six months.

In a statement, GSK said it welcomes FDA’s decision and “appreciates the agency’s robust review of the science with regard to Avandia. GSK maintains its view that Avandia is a safe and effective treatment for type 2 diabetes when used appropriately.” The company said it will work with FDA to update labeling and implement the agency’s decision to ease restrictions on the drug.

FDA’s actions also will have regulatory implications for Teva Pharmaceutical Industries Ltd., which received ANDA approval for single-ingredient rosiglitazone in January 2013, at which time GSK’s existing REMS was converted to a shared system. However, Teva has yet to launch its generic and may have been biding its time while FDA finalized its decision on changes to the brand product’s labeling and REMS Also see "Shared REMS Systems Show Challenges Of Standardization – Could PDUFA V Help?" - Pink Sheet, 22 July, 2013..

Aligning With The Advisors

The agency’s action to modify, but not eliminate, the rosiglitazone REMS generally aligns with the recommendations of its Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees, which met jointly in June 2013 to consider the re-adjudicated results of the RECORD trial.

In her September 2010 decision requiring a restricted distribution program for Avandia, Center for Drug Evaluation and Research Director Janet Woodcock directed GSK to commission an independent re-adjudication of the 4,400-patient RECORD trial comparing rosiglitazone’s CV safety with that of metformin and sulfonylurea Also see "FDA, EMA Decisions On Avandia Reflect The Power Of REMS" - Pink Sheet, 27 September, 2010..

RECORD was an open-label study conducted entirely outside the U.S. GSK’s analysis found no increased risk of the composite endpoint of CV death and hospitalization for rosiglitazone, with a nonsignificant 14% increased risk of myocardial infarction.

Cardiology experts within FDA disagreed as to whether the study demonstrated that rosiglitazone did not increase CV risk. In July 2010 an advisory committee generally agreed that the open-label nature of the trial and inherent biases in the study reduced the extent to which they could rely on its findings Also see "Avandia Advisory Committee Re-Review Reflects Well On FDA" - Pink Sheet, 19 July, 2010..

In her September 2010 memo, Woodcock said that every effort should be made to learn as much as possible from RECORD since it is the only large, randomized, long-term trial of rosiglitazone’s CV safety compared to other diabetes drugs. Furthermore, it was reasonable to restrict drug access while the RECORD data were further evaluated, she said.

GSK retained Duke Clinical Research Institute to perform a re-adjudication of RECORD results, which showed no statistically significant increase in the risk of mortality, myocardial infarction, stroke or major adverse cardiac events with rosiglitazone Also see "Avandia Review Endorsement Aided By Good Data, Cultural Shift On Safety" - Pink Sheet, 17 June, 2013..

Given the re-adjudicated results from RECORD, “our level of concern is considerably reduced,” CDER’s Woodcock said.

At the June advisory committee meeting, 13 of 26 panelists voted in favor of modifying the rosiglitazone REMS/ETASU. Seven voted to remove the risk management program, five favored continuing it without changes, and one said the drug should be withdrawn from the market Also see "Avandia Committee Gives Split Vote To Drug, But FDA Clear Winner" - Pink Sheet, 10 June, 2013..

In announcing the easing of the REMS restrictions, FDA said the re-adjudicated results did not confirm the signal of increased heart attack risk seen in a meta-analysis led by Cleveland Clinic’s Steve Nissen and first reported in 2007.

“Our actions today reflect the most current scientific knowledge about the risks and benefits of this drug,” Woodcock said in a statement. “Given these new results, our level of concern is considerably reduced; thus, we are requiring the removal of certain prescribing restrictions.”

TIDE Is Gone For Good

FDA also said it was releasing GSK from a requirement to conduct the TIDE trial designed to establish the comparative CV safety of rosiglitazone and pioglitazone.

The study was required by FDA in conjunction with a November 2007 boxed label warning for Avandia about CV risks. However, the study was placed under a partial clinical hold in July 2010 and a full clinical hold two months later, with FDA citing problems related to informed consent and patient access to drug given the distribution restrictions that were also being imposed at that time.

In announcing that it had released GSK from its requirement to conduct TIDE, the agency said it “has concluded that this trial is no longer necessary or feasible.” There are no additional GSK post-marketing requirements for a study comparing rosiglitazone to pioglitazone, the agency said.

FDA Replaces Avandia REMS Distribution Restrictions With Prescriber Training

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