FDA Reviewers Recommend Against Approval of Rivaroxaban (Xarelto)

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FDA reviewers have recommended that the FDA issue a complete response letter for the NDA for rivaroxaban (Xarelto, Johnson & Johnson). This story will be updated later today with with more details, but here’s the bottom line from the FDA’s review:

Based on our review of the clinical data, we recommend a complete response. Reasons for this recommendation include:

  1. There is a lack of substantial evidence that rivaroxaban will have its desired effect when used as recommended in labeling. (21 CFR 314.125(b)(5)). The data from the Sponsor’s Phase 3 ROCKET trial comparing rivaroxaban to warfarin are not adequate to determine whether rivaroxaban is as effective for its proposed indication in comparison to warfarin when the latter is used skillfully (e.g., TTR >~68%, near the midpoint of center based TTR in the RE-LY study, and the US median TTR of 65% in ROCKET). In order for atrial fibrillation (AFib) patients to be protected from the risk of thrombotic events, a new drug for this indication should be demonstrated to be as effective as warfarin when it is used skillfully. This requirement is based on an FDA policy that requires drugs for conditions that are “life-threatening or capable of causing irreversible morbidity (e.g., stroke or heart attack)….” to be shown to as effective as approved agents (see Sec. This issue also implicates 21 CFR 314.125(b)(4), described in the next paragraph, because of the potential risk of additional strokes in patients who might receive rivaroxaban instead of approved treatment should rivaroxaban be approved. The FDA policy cited above and other aspects of this issue are discussed in further in Sec.
  2. There is insufficient information about the drug to determine whether it is safe for use with its proposed labeling (21 CFR 314.125(b)(4)). In the ROCKET study there was an excess of strokes in the rivaroxaban arm during the transition from blinded study drug to open label warfarin at the end of the study. The Sponsor’s proposed instructions for the transition from rivaroxaban to warfarin, developed after ROCKET was completed, have not been evaluated or shown to be safe in terms of bleeding risk or embolic risk in a clinical study. Such a study must be performed prior to approval in this case (see Section for a discussion of this issue). The study of the transition regimen could be performed as part of the study needed to satisfy the deficiency cited in paragraph 1, above.


  1. Please then tell me how many people are using Wafarin “extremely” well?

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