FDA Panel to Consider Rivaroxaban's Comparative Efficacy

The Food and Drug Administration’s policy requiring new drugs for serious conditions to be "as effective" as approved agents will take center stage at the Cardiovascular and Renal Drugs Advisory Committee’s Sept. 8 review of Bayer/Johnson & Johnson’s anticoagulant Xarelto (rivaroxaban) for atrial fibrillation.

The agency will ask the panel whether the oral Factor Xa inhibitor must be shown to be "as effective" as warfarin and/or Boehringer Ingelheim GmbH’s oral direct thrombin inhibitor Pradaxa (dabigatran) for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, according to FDA review documents released Sept. 6.

If the committee concludes that rivaroxaban must show similar efficacy to existing treatments and has demonstrated such efficacy, the agency asks whether a superiority claim over warfarin is warranted. Alternatively, the agency asks whether rivaroxaban should be used only in those patients who fail other anticoagulant therapy.

The committee also will be asked to comment on the adequacy of the ROCKET AF trial design and how the suboptimal use of warfarin in the 14,000-patient study impacted the interpretation of rivaroxaban’s efficacy results.

Concerns outlined in the FDA’s review documents about the suboptimal use of warfarin as a control in the clinical trial, coupled with an increase in strokes associated with transitioning patients to warfarin, suggest rivaroxaban faces a difficult regulatory path forward even if it manages to get a positive recommendation from the cardio-renal panel.

Commercial, Regulatory Challenges Ahead

The FDA approved rivaroxaban on July 1 for the prophylaxis of deep vein thrombosis in patients undergoing knee and hip replacement surgery. However, those acute indications carry limited durations of use, whereas chronic use in the atrial fibrillation population presents a far more lucrative market.

Yet, even ahead of the release of FDA’s advisory committee review documents, there were strong signs that development partners J&J and Bayer faced regulatory challenges with the atrial fibrillation claim, not the least of which was the agency’s decision to take a new drug application for a secondary indication to a panel.

Publication of results from the pivotal ROCKET AF study in August also suggested a number of areas of likely concern for the FDA and the committee. Among these were rivaroxaban’s showing of superiority over warfarin in the as-treated safety population, but not in the intention-to-treat analysis. The published data also spurred questions about how well warfarin was dosed in the comparator arm.

Even if the atrial fibrillation claim can pass regulatory muster, rivaroxaban seems poised to face commercial challenges from Pradaxa and Bristol-Myers Squibb/Pfizer’s investigational Factor Xa inhibitor Eliquis (apixaban).

Pradaxa has the first-mover advantage among the new oral anticoagulants, having entered the market in October 2010. It carries a "back-door" claim for superior efficacy over warfarin; the FDA determined that an overt claim was not warranted because dabigatran’s effect was driven by patients in the RE-LY trial’s warfarin arm whose clotting time, as measured by the International Normalized Ratio, was not well controlled.

According to the recently published results of the ARISTOTLE pivotal study, apixaban demonstrated both superior efficacy and bleeding safety over warfarin, along with a statistically significant, albeit slim, all-cause mortality benefit.

Agency Reviewers Urge "Complete Response"

These challenges notwithstanding, the FDA’s medical review released ahead of the Sept. 8 advisory committee meeting was highly negative. Reviewers Nhi Beasley, Preston Dunnmon, and Martin Rose recommended a "complete response" letter due to the need for additional efficacy and safety data.

The reviewers cited two main reasons for their recommendation that the NDA not be approved.

First, they said the ROCKET AF data were not adequate to determine whether rivaroxaban is as effective as warfarin when the latter is used skillfully. Interpretation of ROCKET AF results is complicated by the relatively poor degree of INR control in the study, the reviewers said.

The mean time in therapeutic range (TTR) in the warfarin arm was 55%, well below the TTR in other recent warfarin-controlled studies, which ranged from 63% to 73%.

TTRs in ROCKET AF varied widely by region and country, ranging from 36% in India to 75% in Sweden. The mean TTR of U.S. study sites was 63%.

"At global centers in ROCKET where warfarin was used skillfully, e.g., centers with mean TTR above [about] 68%, the study data suggest that patients had a numerically greater rate of primary end point events (stroke and systemic emboli, but most events were strokes) in the rivaroxaban arm," the reviewers said. "Such centers constituted about a quarter of the total in ROCKET, but the number of subjects at those centers was only about 15% of the total. The confidence interval around the point estimate for the hazard ratio in this subset of patients is quite wide, so there is a substantial measure of uncertainty about these data. Such uncertainty about comparability to approved therapy for stroke prevention argues strongly for the need for additional data to support approval."