The third time may not be the charm. Twice before the FDA has turned down the supplemental new drug application for an acute coronary syndrome indication for Johnson & Johnson’s Xarelto (rivaroxaban). On Thursday the Cardiovascular and Renal Drugs Advisory Committee will take up the sNDA yet again, but FDA review documents posted today suggest that the company will again face an uphill battle.
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Originally, back in 2011, most observers thought the ACS indication would be a snap. The pivotal ATLAS ACS 2-TIMI 51 trial was widely praised when it came out and the FDA promptly granted priority review for the indication. But momentum, as I’ve reported before, ground to a halt when FDA reviewers raised questions about the ATLAS trial. The FDA advisory panel, highlighted by vocal criticisms from Steve Nissen and Sanjay Kaul, resulted in a vote against the ACS indication, leading to the first complete response letter. The FDA issued a second complete response letter last March but J&J restated its confidence in the trial and its commitment to pursue the indication.
The earlier rejections were based largely on the significant amounts of missing followup data from the trial. The FDA and J&J thought that this problem might be circumvented by pursuing an indication for a shorter 90-day treatment duration, since much of the missing data was for longer followup. But the short term data do not appear very convincing and the FDA reviewers make clear in the new review documents that they now have grave concerns about this approach. (For readers interested in the details and minutiae of FDA-sponsor interactions and negotiations, the briefing documents contain a series of letters from the FDA that provide a fascinating retrospective view of this complex process.)
There was more bad news for J&J in the announcement of the panel participants. Former critics Steve Nissen and Sanjay Kaul are on the roster again and will be joined by noted pharma critic Sidney Wolfe. In addition, and perhaps even more dangerous for J&J, is one of the scheduled FDA presenters, clinical reviewer Thomas Marciniak. He has become well known for his scathing reviews of rosiglitazone and the angiotensin receptor blockers in addition to rivaroxaban.