Again, FDA Advisors Deliver Solid "No" to Rivaroxaban in ACS

Shelley Wood

January 16, 2014

SILVER SPRING, MD (updated) — After an afternoon that circled again and again around missing data, subgroup analyses, and statistical power, a Food and Drug Administration (FDA) advisory committee gave a resounding "no" to rivaroxaban (Xarelto, Bayer Pharma/Janssen Pharmaceuticals) as a treatment in ACS patients, with 10 panel members voting against recommending approval. One panel member abstained.

Specifically, the FDA advisory panel was to consider whether rivaroxaban should be approved for use for a suggested duration treatment of 90 days to reduce the risk of thrombotic cardiovascular events in patients with ACS. Key to the discussion, however, was that the pivotal trial for this agent in this setting, ATLAS ACS TIMI 51 , studied the drug as chronic therapy, not as a drug that should be used over a discrete, 90-day period. Evidence for this novel proposed use, discussed today, comes from new analyses of previously submitted data on the primary end point and bleeding, as a function of time.

In other words, while the proposed use is different from that which the panel voted against in 2012, no new trials were conducted to test the drug used in this way. This was a sticking point for many panel members, who suggested that approving the drug for this time-limited use without ever specifically studying it was setting a dangerous precedent.

Dr Thomas Fleming (University of Washington, Seattle), the panel's statistician, hammered the point: one can't solve a problem of missing data by redefining the trial such that the end point relates to the period of time before patient data went missing.

En masse, the panel agreed.

"I applaud the sponsors and TIMI group for going back and doing all this follow-up; this was a tremendous amount of work. However, it didn't really add in a substantial way to the primary-end-point analysis," panel chair Dr Philip Sager (Stanford University School of Medicine, CA) stated in his concluding remarks. "Looking at the overall study, it wasn't robust enough in terms of statistical significance to be considered as a positive study, and with that, it was not possible to look at subgroups. Even if we had been able to look at the earlier time periods from a methodological standpoint, the data there in terms of missing data on benefit and efficacy really weren't very compelling."

Dr Sanjay Kaul, also zeroing in on the lack of statistical power, said he believed this analysis was not enough to support effectiveness on the basis of a single trial. That said, Kaul continued, "That doesn't mean that this information cannot be used to go forward" as the basis for future trials.

Dr Mori Krantz (University of Colorado, Denver), the lone abstaining vote, said that he had aimed for a vote in the middle. "In my mind, I think we need to open the door to the possibility of this being approved. I kind of felt that the sponsor provided a credible level of evidence. . . . I think there are clinically meaningful benefits that could be potentially derived from this drug, and I actually think that the idea of looking at a circumscribed period of time is [an] innovative [approach]."

As is often the case, some of the most colorful comments of the day fell to Dr Steven Nissen (Cleveland Clinic, OH), who at one point compared the study reanalysis to pasta being hurled against a wall to "see what sticks."

Among the many reasons Nissen voted against approval was the concern that this drug was tested on top of clopidogrel and aspirin, yet more potent thienopyridines are already approved and in use. Even if a boxed warning were added, he said he'd be very concerned about catastrophic bleeding events in people taking rivaroxaban on top of more potent antiplatelet medications.

The same concern was raised by Dr Sidney Wolfe (Public Citizen, Washington, DC), who called the approval of rivaroxaban for ACS by European regulators "not a wise approval."

"The benefits at this point are outweighed by the risk, and I think it would be a danger to put this on the market and further bother if not kill people who have already had an acute coronary event," Wolfe said.

Dr Paul Burton, vice president of clinical development at Janssen, released a statement saying: "We appreciate the thoroughness of the committee's review and continue to believe [that] rivaroxaban, in addition to the current standard of care, may help provide patients with ACS additional protection against life-threatening cardiovascular events such as death, heart attack, and stroke. We will work with the FDA to address questions raised today."

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