FDA advisory panel decisions

FDA panel to reconsider Xarelto for treatment of ACS

The FDA’s Circulatory and Renal Devices Advisory Committee will vote today on whether rivaroxaban should be approved for the treatment of ACS over the course of 90 days.

In May 2012, the panel recommended against that expanded indication for rivaroxaban (Xarelto, Janssen Pharmaceuticals), citing a lack of data on early patient withdrawals and deaths. Rivaroxaban is currently approved for reducing the risk for stroke and systemic embolism in patients with nonvalvluar atrial fibrillation and for the treatment of venous thromboembolism.

Results from the ATLAS ACS 2 – TIMI 51 trial (n=15,526) form the basis of the application. In this trial, rivaroxaban-combined doses were superior to placebo at reducing the risk of achieving the primary, composite efficacy endpoint of CV death, MI or stroke (HR=0.84; 95% CI, 0.74-0.96).

However, patients assigned to 2.5 mg rivaroxaban twice per day (1.3%; HR=3.46; 95% CI, 2.08-5.77) or 5 mg rivaroxaban twice per day (1.6%; HR=4.47; 95% CI, 2.71-7.36) had increased rates of non-CABG TIMI major bleeding vs. placebo (0.4%).

Shortly after the panel’s May 2012 vote, the FDA declined to approve rivaroxiban for the treatment of ACS. “The primary reasons were 1) the P-value for the primary efficacy analysis of ATLAS was insufficient to support approval and 2) the number of subjects in ATLAS for whom follow-up for the primary endpoint was incomplete was large enough that it impugned the utility of the data for interpreting the results of the trial,” FDA staff wrote in a briefing document distributed to the advisory panel.

In May 2013, Janssen sent a Formal Dispute Request to the FDA’s Office of Drug Evaluation 1 to request a reversal of the decision, but ODE-1 sided with the original conclusion that the P-value of .024 was “not strong enough to support approval on the basis of a single trial,” according to the briefing document.

In August 2012, Janssen submitted a complete response to the FDA in order to address concerns of incomplete follow-up. Among other data, vital status was obtained for 843 of the 1,338 participants for whom it was not available at the end of ATLAS, but the application was not approved. In a second complete response submitted in August 2013, Janssen proposed to limit the duration of treatment to 90 days, and provided new analysis of previously submitted data on the primary endpoint and other observed outcomes, according to the briefing document.

The FDA is not required to follow the recommendations of its advisory panels, but it usually does.

For more information:

CRDAC Briefing Document. NDA 202439/s002.

The FDA’s Circulatory and Renal Devices Advisory Committee will vote today on whether rivaroxaban should be approved for the treatment of ACS over the course of 90 days.

In May 2012, the panel recommended against that expanded indication for rivaroxaban (Xarelto, Janssen Pharmaceuticals), citing a lack of data on early patient withdrawals and deaths. Rivaroxaban is currently approved for reducing the risk for stroke and systemic embolism in patients with nonvalvluar atrial fibrillation and for the treatment of venous thromboembolism.

Results from the ATLAS ACS 2 – TIMI 51 trial (n=15,526) form the basis of the application. In this trial, rivaroxaban-combined doses were superior to placebo at reducing the risk of achieving the primary, composite efficacy endpoint of CV death, MI or stroke (HR=0.84; 95% CI, 0.74-0.96).

However, patients assigned to 2.5 mg rivaroxaban twice per day (1.3%; HR=3.46; 95% CI, 2.08-5.77) or 5 mg rivaroxaban twice per day (1.6%; HR=4.47; 95% CI, 2.71-7.36) had increased rates of non-CABG TIMI major bleeding vs. placebo (0.4%).

Shortly after the panel’s May 2012 vote, the FDA declined to approve rivaroxiban for the treatment of ACS. “The primary reasons were 1) the P-value for the primary efficacy analysis of ATLAS was insufficient to support approval and 2) the number of subjects in ATLAS for whom follow-up for the primary endpoint was incomplete was large enough that it impugned the utility of the data for interpreting the results of the trial,” FDA staff wrote in a briefing document distributed to the advisory panel.

In May 2013, Janssen sent a Formal Dispute Request to the FDA’s Office of Drug Evaluation 1 to request a reversal of the decision, but ODE-1 sided with the original conclusion that the P-value of .024 was “not strong enough to support approval on the basis of a single trial,” according to the briefing document.

In August 2012, Janssen submitted a complete response to the FDA in order to address concerns of incomplete follow-up. Among other data, vital status was obtained for 843 of the 1,338 participants for whom it was not available at the end of ATLAS, but the application was not approved. In a second complete response submitted in August 2013, Janssen proposed to limit the duration of treatment to 90 days, and provided new analysis of previously submitted data on the primary endpoint and other observed outcomes, according to the briefing document.

The FDA is not required to follow the recommendations of its advisory panels, but it usually does.

For more information:

CRDAC Briefing Document. NDA 202439/s002.