Memorandum

FDA approves label change for GSK’s Avandia, removing many elements of REMS program – May 12, 2014

Executive Highlights

  • The US FDA has formally approved major label revisions for GSK’s Avandia (rosiglitazone), removing most of the restrictions on the prescription and dispensation of the drug.
  • The decision is based on the re-adjudication of the RECORD trial, which indicated that Avandia is not associated with an increased risk for heart attack. 
  • This move represents a major backtrack for the FDA, although we do not imagine it will breathe much life into the flagging ex-blockbuster franchise.

Late last week, the FDA communicated its approval of a major revision to the label of GSK’s Avandia (rosiglitazone) franchise, removing many key elements of the risk evaluation and mitigation strategy (REMS) for the drug. This decision followed an FDA announcement in November of the agency’s decision to remove most of the restrictions on the prescription and dispensation of GSK’s Avandia (rosiglitazone) franchise, based on the re-adjudication of the RECORD cardiovascular outcomes trial that was assessed at an FDA Ad Comm last summer (read our report). The final revised label has not yet been made public, but from the content of the FDA’s original announcement and its correspondence to GSK regarding the recent label change approval, the major changes appear to be as follows:

  1. The labels for rosiglitazone products will be changed to reflect that current evidence does not suggest an increase in cardiovascular risk (we are unsure if the alteration will involve the addition of new language, or simply the removal of the cardiovascular safety warning currently on the label).
  2. Rosiglitazone will no longer only be indicated for patients who are uncontrolled on other glucose-lowering agents. The final updated label will indicate rosiglitazone for type 2 diabetes patients to be used concurrently with diet and exercise (a comparable label for most other type 2 diabetes pharmacotherapies currently available).
  3. Providers, pharmacies, and patients will no longer be required to enroll in the REMS program for rosiglitazone in order to prescribe, dispense, or receive the drug.
  4. The manufacturers of rosiglitazone drugs (GSK) will be required to ensure that likely prescribers of the drug family are informed on the most recent knowledge regarding rosiglitazone’s cardiovascular risk.
  5. GSK will no longer be required to conduct the TIDE trial, which was to compare rosiglitazone to pioglitazone (Takeda’s Actos) and other diabetes drugs.

As background, Avandia was a blockbuster franchise for much of the previous decade, with annual sales exceeding $3 billion in 2006. A meta-analysis of small randomized control trials published by the Cleveland Clinic’s Dr. Steve Nissen (mastermind of the FDA’s 2008 CV guidance) in 2007 found a statistically significant 43% increased risk for myocardial infarction with Avandia treatment. In a landmark 2008 FDA Advisory Committee meeting that was convened in large part due to the developing Avandia story, the panel voted 14 to 2 in favor of requiring type 2 diabetes drugs to demonstrate cardiovascular safety in a hard outcomes trial or other means (read our report on that meeting, which of course led to the infamous 2008 FDA CV Guidance for diabetes drugs). By that year, sales of Avandia had already fallen by over 50% from their peak levels, but there was more bad news to come. After a 2010 FDA Advisory Committee meeting specifically on Avandia (read our full coverage of that meeting), the FDA decided to enact a strict REMS program for Avandia, which effectively restricted its use to patients that were uncontrolled on other antihyperglycemic agents. The franchise’s perceived safety profile was significantly tarnished by this series of events; sales plummeted worldwide, and the compound was pulled from the market in the EU.

In past years, however, there has been much controversy over the FDA’s interpretation of the 2007 study results, especially in light of the finding of the RECORD long-term outcomes trial (reported in 2009) that Avandia showed no increase in cardiovascular risk or hospitalization (read our initial report on the study here). In June of this year, an FDA advisory committee convened to review and discuss the results of a re-adjudication of RECORD’s results conducted by the Duke Clinical Research Institute, which most panelists found at least somewhat reassuring (read our full report for comprehensive detail on the meeting). During the final vote, 18 of the 26 panelists voted to either lift or relax Avandia’s REMS program.

Overall, we view the FDA’s decision as a significant and slightly embarrassing backtrack for the agency, one that represents somewhat of an admission of guilt regarding the initial creation of the REMS program. Unfortunately for GSK and for patients, the decision is, of course, too little, too late for the Avandia franchise. The damage to the drug’s safety reputation has been done: only a few thousand patients are currently on Avandia, and in 3Q13 (read our GSK 3Q13 Report) GSK stopped reporting sales for the franchise (which have fallen away to practically nill). We might expect a slight bump in Avandia sales following the FDA decision; the class certainly has its advocates, even very high-profile ones such as Dr. Ralph DeFronzo (read our coverage of a talk he gave on the class at CODHy Latin America 2014) and TZDs as a class are still the only approved drugs to address insulin resistance. However, safety concerns regarding bone health and weight gain that have dragged down Takeda’s Actos (pioglitazone) franchise (the other major TZD on the market) would still likely lead to reticence on the part of providers to prescribe Avandia on a large scale. Of course, rosiglitazone is now generic, meaning that the commercial potential of trying to revitalize the franchise is limited. However, now that it is generic, rosiglitazone could have renewed potential in emerging markets.

In our eyes, the Avandia saga illustrates the importance of proper framing and interpretation of clinical data, as well as the dangers of raising safety flags that are not supported by the most robust clinical data available. If the FDA and the medical community had come to this final conclusion sooner after the initial fears were raised, we can’t help but wonder whether the 2008 CV guidance would exist at all.

 

Close Concerns Questions

  • Will the reversal of the FDA’s decision lead to an upswing in interest in generic rosiglitazone?
  • Could fixed-dose combinations involving rosiglitazone once again be a possibility?
  • What will the next successful class of insulin sensitizers for type 2 diabetes be?

-- by Manu Venkat and Kelly Close