FDA Reaffirms Safety And Efficacy Of Rivaroxaban

–FDA says no changes needed to the rivaroxaban label.

Following a year of controversy and uncertainty relating to the anticoagulant drug rivaroxaban (Xarelto, Johnson & Johnson), the FDA has reaffirmed the drug’s safety and efficacy.

Rivaroxaban is approved for stroke reduction in patients with atrial fibrillation. The indication is based on results of the ROCKET-AF trial, which compared rivaroxaban to warfarin. New questions about the trial emerged last year when it became known that the portable device used to adjust warfarin usage in the trial had been recalled due to unreliability in some patient populations.

On Tuesday the FDA said that it had concluded “that Xarelto is a safe and effective alternative to warfarin in patients with atrial fibrillation.” The review statement echoes previous reviews from the European Medicines Authority, Johnson & Johnson (and its partner, Bayer), and the ROCKET AF investigators.

The FDA conducted three separate reviews (clinical, statistical, and clinical pharmacology) of the problem. The FDA concluded that the point of care device in the trial produced INR values that averaged 13% lower than laboratory INR values obtained from stored samples during the trial. The FDA concluded that the “estimated reductions in the rates of bleeding events in the warfarin arm were small enough so that the benefits of rivaroxaban would still outweigh its risks if efficacy were not affected.” This finding was “directionally consistent” with the earlier studies.

The clinical reviewers said there was no need to change the rivaroxaban label and that “no other major regulatory action” needed to be taken.

Asked to comment on the FDA statement, Sanjay Kaul (Cedars Sinai) said that “the results of the FDA analysis are aligned with those conducted by the EMA, sponsor and the Duke investigators. It is an inference I personally concur with. I hope the BMJ investigative reporters and the skeptical external experts are satisfied by this report.”

But the BMJ investigator, Deborah Cohen, said she still has concerns about the drug and thinks that the “whole saga raises ethical issues” that still need to be addressed. Here is her full comment:

“I’m not totally convinced this is a clean bill of health. The FDA confirmed that the device malfunctioned. They confirmed that the malfunction resulted in warfarin patients experiencing additional bleeds – the modified event rate went down. Finally, the FDA calculated that the hazard ratio for major bleeds could be as high as 1.16. (Up from 1.05 (CI: 0.91, 1.20) in ROCKET-AF).

“Although not the highest level of evidence, this finding seems to be supported in observational studies by the FDA (Graham et al).

“The FDA actually said the reason for no label change is because ‘we think that a labeling change to describe the modeling results would be very difficult to write in a concise manner…’

“But while the FDA might say that the benefit/harm ratio is acceptable, the whole saga raises ethical issues. Given Janssen knew that the device was malfunctioning – were trial participants put at unnecessary risk of major bleeds? And that surely is something that can’t be ignored.”

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