SILVER SPRING, MD (updated) – A Food and Drug Administration (FDA) advisory panel voted 7 to 2 that cangrelor (the Medicines Company, Parsippany, NJ), an intravenously administered antiplatelet agent, should not be approved for the reduction of thrombotic cardiovascular events in patients with coronary artery disease undergoing PCI.
Acting chairperson of the Drug Safety and Risk Management Advisory Committee Dr Philip Sager (Stanford University School of Medicine, CA) and Dr Jennifer Li (Duke University School of Medicine, Durham, NC) voted yes, but the majority of the panel had trouble with the data, with the experts arguing that the risk/benefit profile was not sufficiently strong enough to recommend approval. Specifically, some of the panel members were troubled by the totality of the evidence, noting that two clinical trials with cangrelor were negative, and despite the positive results with CHAMPION-PHOENIX , these previous studies mattered and factored into their "no" vote.
"In the background of two failed trials, and with all of the issues in almost every aspect of [PHOENIX], starting with the design, oversight with the data safety and monitoring board, how they counted efficacy, and how they counted safety, it just left me with more uncertainty," said panel member Dr Stuart Rich (University of Chicago Pritzker School of Medicine, IL). "I just couldn't defend the risk/benefit advantage here."
Also voting no, Dr Milton Packer (University of Texas Southwestern Medical Center, Dallas) said he really wanted to vote yes. "The concept behind this drug was so intuitively appealing," he said. "You have an antiplatelet drug, and the minute you turn it on, it works, and the minute you turn it off, it stops. That sounds really cool. The problem I had was that if that were the basis for approving drugs, we would always approve drugs based on surrogate end points. We would approve drugs based on what we think they ought to do and hope they would do that."
For Packer, despite looking for reasons to vote yes, including being reassured by the sponsor about questions he had about PHOENIX, he remained "uncomfortable" about the type of MIs reduced with cangrelor and the clopidogrel comparator arm used in the study. In addition, he remained troubled by the two negative trials with cangrelor. "And then you have to think about that you'll have to treat 1000 patients to prevent, maybe, three MIs or deaths at the cost of three or four major bleeds," he said. "It does not add to a favorable benefit to risk."
In addition, the advisory panel recommended rejecting the application for a cangrelor bridging indication. Specifically, the nine panel members voted against approving cangrelor for use in patients with stents at increased risk for thrombotic events who have to stop oral P2Y12 inhibition because they are undergoing surgery. There were zero votes in favor of approving cangrelor as a "bridge" therapy, mainly because the panel members again felt there wasn't sufficient evidence to provide an assessment of the risks and benefits.
The major trials investigating cangrelor, all of which were reported by heartwire , include CHAMPION-PCI and CHAMPION-PLATFORM , both of which investigated the new IV drug in ACS patients scheduled for PCI. Both were stopped early in 2009 after interim analyses suggested neither study would show a benefit. The CHAMPION-PHOENIX study was sponsored by the Medicines Company to address issues raised about those earlier trials—namely, that they were negative because of problems adjudicating new MIs in patients with elevated biomarkers at baseline.
PHOENIX was an 11 000-patient trial testing cangrelor in patients undergoing PCI for stable angina or for acute coronary syndromes (ACS), including STEMI. Overall, treatment with cangrelor reduced the composite efficacy end point of all-cause mortality, MI, ischemia-driven coronary revascularization, and stent thrombosis by 22% compared with patients treated a 300-mg or 600-mg loading dose of clopidogrel. The risk of stent thrombosis was reduced 38% and the risk of MI reduced 20%.
Earlier this week, the FDA posted a review of the cangrelor data by its own internal reviewers. One reviewer was extremely critical of the data and argued that the "CHAMPION trials do not show superiority or noninferiority of a cangrelor regimen to clopidogrel or to standard of care." Two other reviewers, however, believed the overall risk/benefit profile, which weighed the risk of bleeding vs the benefit of reducing thrombotic events, showed mixed results. They ultimately concluded, however, there was a "marginal" benefit in the PCI setting that was driven by a reduction in periprocedural MIs.
PHOENIX: An Ethical Trial?
Throughout the daylong panel, committee members grappled with understanding the PHOENIX results. While trying to come to terms with the benefits, panel members were troubled by the type of MIs prevented with cangrelor and whether or not they were clinically meaningful. Even with the uncertainty about benefits, they also struggled with identifying the most clinically significant bleeding end point. In PHOENIX, there were more bleeds with cangrelor, depending on the definition used, although the study's primary safety end point, GUSTO severe non-CABG or severe/moderate bleeding, did not differ between cangrelor- and clopidogrel-treated patients.
In addition, some committee members struggled to make sense of the benefits of cangrelor, given variations in comparator arm. Patients in the PHOENIX control arm received either a 300-mg or 600-mg loading dose of clopidogrel at the physician's discretion, while those in the cangrelor arm received clopidogrel 600 mg that was initiated immediately following the discontinuation of the IV drug.
For Dr Thomas Marciniak, the medical team leader who reviewed PHOENIX for the FDA, the trial was "unethical" because it delayed the use of clopidogrel until after coronary angiography and because it prohibited the routine use of prasugrel (Effient, Lilly/Daiichi-Sankyo), ticagrelor (Brilinta, AstraZeneca), or GP IIb/IIIa inhibitors.
The PHOENIX investigators, including Dr Robert Harrington (Stanford University, CA), rigorously defended the trial, stating that he was "quite uncomfortable" with the language used in the Marciniak review to characterize the trial and added that the study underwent multiple levels of review and was conducted always with patient safety in mind. For members of the advisory panel, none appeared to believe the study was designed unethically, although it might appear unethical "upon reflection," given that clopidogrel in the comparator arm was delayed in some patients until after PCI.
For Packer, who stressed that he does not believe the trial investigators did anything deliberately unethical, the CHAMPION-PHOENIX group should have learned a lesson from the PLATFORM trial, where clopidogrel administration was delayed until after PCI. Packer said they should have known that if cangrelor went up against clopidogrel when it was given "early" the benefit of cangrelor would be diminished.
Dr James de Lemos (University of Texas Southwestern Medical Center, Dallas) voted no but said he was sympathetic to the challenges faced by the sponsor and clinical investigators in testing a drug given for a very short period of time and in a situation where the number of clinical end points is small.
"When I look at the data in aggregate, not just PHOENIX but the other two trials, I'm just not convinced the risk/benefit is clearly favorable for clearly meaningful end points," he said. "I'm not as bothered by the control group. I think that reflects contemporary practice, particularly for stable coronary disease PCI, but I am bothered the math doesn't add up to a clear risk/benefit for this therapy."
Heartwire from Medscape © 2014 Medscape, LLC
Cite this: FDA Advisory Panel Votes No on Approving Cangrelor for PCI, Bridge Therapy - Medscape - Feb 12, 2014.