FDA'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 non-valvular atrial fibrillation, according to FDA review documents released on 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 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

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 (Also see "FDA Approval Of Xarelto Bodes Well For Drug’s Future Expansion" - Pink Sheet, 11 July, 2011.).

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 an NDA for a secondary indication to a panel.

Publication of results from the pivotal ROCKET AF study last month also suggested a number of areas of likely concern for 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 ('Xarelto Atrial Fibrillation Data Suggest Lines Of Advisory Committee Inquiry,' 'The Pink Sheet,' Aug. 15, 2011).

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 "backdoor" claim for superior efficacy over warfarin; 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 (INR), 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 (Also see "Bristol/Pfizer's Apixaban Shows Mortality Benefit In ARISTOTLE, But Is It Enough To Supplant Warfarin?" - Pink Sheet, 29 August, 2011.).

Agency Reviewers Urge "Complete Response"

These challenges notwithstanding, 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 cite 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 ~68%, the study data suggest that patients had a numerically greater rate of primary endpoint events (stroke and systemic emboli, but most events were strokes) in the rivaroxaban arm," the reviewers say. "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."

Interpreting FDA's "As Effective" Requirement

Beasley, et al. seek to put the data into the context of FDA policy that requires new therapies be as effective as approved treatments when the disease at issue is life-threatening or capable of causing irreversible morbidity.

"The policy is broadly written and lacks a discussion of operational details," the reviewers say.

"For example, it does not state whether comparable effectiveness to an approved therapy used in an unskilled manner would be adequate for approval. However, if it is essential for a therapy to be as effective as an approved therapy to protect public health, it is logical that the new therapy should be as effective as the approved therapy when the approved therapy drug is used skillfully."

The reviewers said rivaroxaban should not be approved "unless the sponsor submits convincing information that it is as safe and effective for its target indication as warfarin when it is used skillfully (e.g. in the subgroup of patients at centers where TTR > ~67%), or that it is as safe and effective as another approved agent, such as dabigatran."

The reviewers leave a door open for rivaroxaban's approval for those patients whose INR cannot be well controlled on warfarin or who are unwilling to take the vitamin K antagonist.

"However, such patients have an alternative, dabigatran, which is approved for rivaroxaban's proposed indication," the reviewers point out. "Dabigatran was shown to be superior to warfarin in preventing stroke and systemic emboli in the overall results of the large global RE-LY trial (with a median TTR of about 67%), and it was robustly non-inferior to warfarin at RE-LY centers with TTR above the median."

Given the availability of dabigatran, "it seems advisable to make rivaroxaban a third-line agent, behind both warfarin and dabigatran," the reviewers say.

In the draft questions to the advisory committee, FDA notes its "as effective" policy explicitly does not apply if the new therapy is studied in a new population. The agency asks whether this exclusion applies to rivaroxaban based upon differences in the populations of the ROCKET AF and RE-LY trials.

Key among these differences was the enrollment in ROCKET of patients at higher risk for stroke, based upon CHADS scores, than those studied in RE-LY. ROCKET also enrolled more patients who had a prior stroke or systemic embolism.

A Firm "No" On Superiority

If the committee votes in favor of approval, the panel is asked to discuss whether a claim for superiority over warfarin is merited.

FDA reviewers say the sponsors' request for superiority language should be rejected for several reasons. Among these, only the on-treatment analyses of the safety and per-protocol populations support superiority. "All analyses that include follow-up of patients for at least seven days after the last dose of study, and all ITT analyses do not support superiority. We generally prefer an ITT analyses as the basis of a superiority claim."

More Data Needed On Transition Strategy

In explaining their second reason why the NDA should not be approved, Beasley, et al. point to a statistically significant increase in the rate of strokes in the rivaroxaban arm compared to warfarin while subjects were being transitioned from blinded study drug to open-label warfarin at the end of study.

Unlike in the RE-LY and ARISTOTLE trials, no provisions were made for a short period of dual therapy for patients in the rivaroxaban arm to continue anticoagulation during the lag period of INR control at the start of open-label warfarin.

"To ameliorate the risk of events after discontinuation of rivaroxaban, the sponsor has submitted proposed labeling with instructions for the transition from rivaroxaban to warfarin therapy. These instructions call for a period of concomitant treatment with both drugs under INR control (with INR measured at the end of the rivaroxaban dosing interval)," the reviewers say.

However, these instructions were developed after the ROCKET trial was completed and are based on pharmacokinetic/pharmacodynamic modeling; they have not been evaluated in a clinical trial. Given the serious risk of stroke associated with this transition period, "it seems prudent to require the sponsor to demonstrate in a clinical study in AFib patients receiving rivaroxaban therapy that the proposed transition regimen is safe and effective."

-Sue Sutter (s.sutter@elsevier.com)

Xarelto's Comparative Efficacy To Warfarin, Pradaxa Will Be Focus At FDA Panel Review

More from Archive

More from Pink Sheet