Prasugrel Delay Shifts Focus to August Advisory Committee Date

Attention will now turn to a tentative August 19-20 FDA Cardiovascular and Renal Drugs Advisory Committee meeting date as the next major prasugrel milestone after FDA extended the review of the novel anti-platelet drug by three months on June 23.

The original user fee deadline for the priority six-month review application had been scheduled for June 26; the new deadline is September 26.

The agency has yet to make public the agenda—or whether they’ll even hold a meeting—for the tentative August date. The drug's manufacturer, Eli Lilly, says it has not been notified by FDA that prasugrel (Effient) will be the subject for review at the meeting, if FDA chooses to hold one.

Whether or not prasugrel gets slated for an advisory committee review is at the center of speculation regarding the future of the potential blockbuster. A panel meeting would provide some level of clarity to FDA’s position on the application in the form of questions to the committee and public briefing documents related to the agency’s medical review of prasugrel data. However, it also adds the variable of a group of scientific experts from different disciplines questioning the merits and scrutinizing the safety concerns of the drug in a public setting.

A late August advisory committee meeting would also put FDA under a time crunch to deliver a decision by the new September deadline given the additional guidance it will have to process from the panel.

Senior FDA officials have said in the past that if the benefits of a drug are so obvious to agency reviewers and clearly outweigh the risks, an advisory committee meeting is sometimes unnecessary. However, a major drug safety issue that fosters consensus among FDA reviewers could also render convening a panel of outside experts to review the drug a needless exercise, officials have cautioned.

In renal cell carcinoma market, for example, Bayer/Onyx’ sorafenib (Nexavar) and Pfizer’s sutinib (Sutent) both were priority reviews that resulted in timely approvals without advisory committees. Both were viewed as significant advances in renal cell carcinoma therapy, an area that had not seen major advances in years.

The extension is a minor setback for Lilly and is certainly a better outcome for the company than a number of different decisions the agency could have made.

A three-month extension is relatively common for new therapies that may carry extensive postmarket requirements, such as risk management plans. The extension is triggered if the sponsor submits significant supplemental information to FDA during an ongoing review and the agency simply needs more time to comb through the additional data.

The extension keeps the application in a first-cycle review timeline. An “approvable” or “non-approvable” decision at this point would have been significantly less favorable for Lilly and require the company to re-submit the application and restart the review clock.

“We will continue to work closely with the FDA throughout the review process and continue discussions to determine if any requirements under the new FDA Amendments Act (FDAAA) will apply,” Lilly VP-global regulatory affairs Jennifer Stotka said in a statement.

Lilly’s public reference to FDAAA indicates the company may be working on a REMS (risk evaluation and mitigation strategies) program for the drug, which would further explain the extension. REMS were created under the new drug reform law to improve postmarket surveillance of drugs entering the market.

Biogen Idec/Elan’s natalizumab (Tysabri) for Crohn’s disease and Celgene’s cancer drug lenalidomide (Revlimid) are two recent examples of drugs that received three-month deadline extensions to review risk management programs but were approved promptly thereafter.

Lilly’s Phase III 13,000-patient TRITON clinical study of prasugrel produced a 19% reduction in the composite primary endpoint of cardiovascular death, non-fatal heart attacks or non-fatal strokes when compared with clopidogrel (Plavix).

However, the study also demonstrated a statistically significant 32% increase in minor and major bleeding. But when you consider the primary endpoint, those bleeds didn’t lead to deaths, heart attacks or strokes.