As rivaroxaban (Xarelto, Bayer/Johnson & Johnson) waits to take center stage at the FDA’s Cardiovascular and Renal Drugs Advisory Committee meeting Thursday, Sept. 8, the FDA has stated that it will argue against approval for the oral factor Xa inhibitor due to concerns about lacking data. Briefing documents outlined the FDA’s concerns, which centered on the fact that data surrounding rivaroxaban may be insufficient in terms of the proposed labeling—to prevent stroke in nonvalvular atrial fibrillation patients.

In the documents, the FDA argued that data from the ROCKET AF (Rivaroxaban Once Daily Oral Direct factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial are not robust enough and “do not convincingly demonstrate that rivaroxaban is as effective in preventing strokes and systemic emboli as warfarin when warfarin is used skillfully.”

The agency said that its concerns stem from the fact that comparing rivaroxaban to warfarin was not adequate, particularly to determine whether rivaroxaban is safe and effective for the current indication in comparison to warfarin when monitored appropriately.

“In order for atrial fibrillation 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,” the FDA wrote. The agency said that if the drug is approved, patients may be at greater risk of harm from stroke compared to being treated appropriately with warfarin.

While the sponsor has requested that language surrounding the drug relate to its superiority to warfarin, the FDA has outlined several reasons why this would be inadequate. For example, the FDA said that only the on-treatment analyses of the safety and per-protocol populations support superiority and said that the overall time-to-treat ratio (TTR) in ROCKET AF was relatively poor (55 percent). “Thus, the comparison to warfarin may have been biased in favor of rivaroxaban because poor INR control is associated with reduced efficacy of warfarin,” the FDA wrote.

The agency said that it would be concerned that superiority language in labeling could persuade physicians to switch patients doing well on warfarin to rivaroxaban, despite that these data do not support this switch.

The agency’s reviewer said that interpretations of the ROCKET AF trial are “complicated by the relatively poor degree of INR control in the study.”

The FDA went as far as to say that rivaroxaban should not be approved unless the sponsor is able to fork over convincing data outlining why the drug is safe and effective for the aforementioned indication. However, the reviewer noted that it may be reasonable to approve rivaroxaban as a second- or third-line treatment if an additional anticoagulant for AF patients is necessary, and said that the drug could be useful in patients who are poorly controlled on warfarin.

“However, given that dabigatran has been shown to be superior to warfarin when it is used reasonably well, and robustly non-inferior to warfarin when it is used extremely well, it seems advisable to make rivaroxaban a third-line agent, behind both warfarin and dabigatran,” FDA concluded.

Currently, rivaroxaban is approved in the European Union to prevent deep vein thrombosis in patients undergoing elective hip or knee surgery.

The committee meeting will take place from 8 a.m. to 5 p.m. at the Marriott Inn and Conference Center at the University of Maryland University College in East Adelphi, Md., Thursday, Sept. 8.