Merck & Co. Inc. may have to overcome questions about changes made to its primary efficacy studies when an advisory committee considers its platelet inhibitor vorapaxar.

FDA reviewers questioned safety-related changes made during the TRACER and TRA2P Phase III trials and Merck’s subsequent decision to narrow its target population to one where there were fewer safety problems.

The product, proposed trade name Zontivity, will go before FDA’s Cardiovascular and Renal Drugs Advisory Committee Jan. 15 Also see "FDA Panel Will Have To Resolve Bleeding Risk With Merck’s Vorapaxar" - Pink Sheet, 16 December, 2013..

Merck has proposed an indication of reduction of atherothrombotic events in patients with a history of myocardial infarction, with a demonstrated reduction in the rate of cardiovascular death, MI, stroke and urgent coronary revascularization.

The product will not be recommended for use in patients with a history of stroke or transient ischemic attack (TIA) due to an increased risk of stroke on treatment.

FDA’s clinical reviewers recommended approval based on the TRA2P trial results, which showed a daily 2.5 mg tablet of vorapaxar was better than placebo in a composite primary endpoint of CV death, MI, stroke or urgent coronary revascularization, according to advisory committee briefing documents. Vorapaxar also met a key secondary endpoint of time to CV death, MI or stroke.

But the reviewers noted that “the course of the study was complicated by major safety-based changes” in its conduct that should be considered.

After excess bleeding rates were detected in the TRACER trial, Merck, following a recommendation of its Data and Safety Monitoring Board, decided to stop it early Also see "Intracranial Hemorrhage The Culprit In Merck's Vorapaxar Trial" - Pink Sheet, 20 January, 2011.. The board also recommended patients at high risk of stroke be taken out of the TRA2P trial.

TRA2P still showed vorapaxar helped prevent additional CV events as an add-on therapy after a heart attack, but also an increased bleeding risk Also see "Bleeding Rates In TRA-2P Further Dim Outlook For Merck’s Vorapaxar" - Pink Sheet, 1 April, 2012..

Unplanned Analysis Issues

FDA statistical reviewers also indicated a concern about “unplanned interim efficacy analyses conducted,” even though the trial still achieved significance for its primary and secondary endpoints.

The original study protocol for TRA2P included one unblinded interim analysis for efficacy. Yet, there were 11 DSMB meetings between February 2008 and January 2011 where minutes included safety findings.

“It is unclear whether such unplanned unblinded interim efficacy analyses, sample size re-estimation and change of patient population might have some impact on trial integrity,” the statistical review concludes.

Merck told the agency that the DSMB received periodic aggregated safety reports that were partially blinded. At a September 2008 meeting, the board asked for treatment assignments to be included.

The company also said that total efficacy rates were being monitored as required for an interim analysis at 50% of accrued events, but “there is no indication that efficacy endpoint event rates were being monitored by treatment assignment.”

In all, there were three unblinded efficacy data examinations, in addition to the planned interim analysis, Merck told FDA. They were done in part because of safety concerns, according to the documents.

FDA is asking advisory committee members to discuss how the interim analyses impacted their interpretation of the study, as well as whether they agree with the proposed stroke and TIA restrictions.

Only one voting question is planned, on whether the product should be approved and if so, for whom.

No REMS Suggested For Bleeding Risk

Bleeding remains the primary safety issue for vorapaxar. The data clearly indicate the drug is linked to an increase in bleeding rates, including among those with a history of stroke.

Rates were lower among the proposed label population, i.e., those with a prior MI but no history of stroke or TIA, compared to the overall treated population, based on analyses of time to bleeding events in both populations.

FDA clinical reviewers noted that the findings in TRA2P related to history of prior stroke and TIA are analogous to experience with Eli Lilly & Co./Daiichi Sankyo Co. Ltd.’s Effient (prasugrel) in acute coronary syndrome patients and suggested that a similar contraindication is warranted.

FDA also indicated that vorapaxar’s effect seems to be larger as body weight increases, but has “little or negative” effect in patients weighing 60 kg or less. Clinical pharmacology reviewers also recommended avoiding use in those weighing less than 60 kg “due to unfavorable benefit-risk.”

Safety reviewers did not recommend a Risk Evaluation and Mitigation Strategy for vorapaxar. During a mid-cycle meeting, the Division of Risk Management said Merck “might consider disseminating risk information outside of a REMS,” according to the documents.

The briefing documents indicate Merck proposed a Medication Guide regarding the bleeding risk overall, the contraindicated populations, that treatment be discontinued in the event of a stroke or TIA, and that increased bleeding risk is expected among the elderly and those weighing less than 60 kg or with severe hepatic impairment.

Committee members will discuss the best way to evaluate the trade-off between the increased bleeding risks and reduced atherothrombotic events the product presents.

The draft questions for the panel also ask whether that evaluation should include subjectively assessing separate analyses of safety and efficacy, net clinical benefit analyses, or a formal weighted composite safety and efficacy endpoint.

FDA Reviewers Say Vorapaxar Approvable, But Question Study Changes

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