SILVER SPRING, MD ( updated ) — The Cardiovascular and Renal Drugs Advisory Committee of the US Food and Drug Administration (FDA) voted 9 to 2, with one member abstaining, that the injectable antiplatelet agent cangrelor (the Medicines Company, Parsippany, NJ) should be approved for reducing thrombotic events in PCI—a reversal from the committee's vote last year.
Today's "yes" votes included acting chair Dr Philip Sager (Stanford University School of Medicine, CA). He told heartwire from Medscape after the meeting there was "a lot of good discussion," and he was impressed that the sponsor responded several times with additional data when asked.
"Everyone was committed to making this a good meeting. And I'd say in the end that the data, taken in totality, showed that cangrelor will have an important role in the armamentarium for a subset of patients undergoing PCI," said Sager.
Some of the "good discussion" he mentioned sounded more like hearty debate as questions and concerns were brought up throughout the day regarding the trial at the center of the new drug application. CHAMPION-PHOENIX showed positive results in its cangrelor-vs-clopidogrel comparison. However, the previous CHAMPION-PLATFORM and CHAMPION-PCI trials were both negative.
Last year, the committee voted 7 to 2 against recommending cangrelor for PCI because of data problems and they felt that the risk/benefit profile was not sufficiently strong enough. The Medicines Company then underwent further sensitivity analyses and supplied a more simplified application.
Earlier this week, FDA reviewers gave a favorable review that the agent now be approved "in patients in whom treatment with an oral P2Y12 platelet inhibitor prior to PCI is not feasible and when glycoprotein IIb/IIIa receptor antagonists are not anticipated to be used." They also noted that PHOENIX was sufficient enough as a stand-alone trial to warrant approval of cangrelor[1].
However, several panel members voiced concerns both last year and this year that PHOENIX was successful only after the failure of the other two trials. "Is this a pivotal trial or just a third attempt?" asked Dr Scott Emerson (University of Washington, Seattle). "If we don't like the results, can we just fish through essentially the same population to get a better efficacy point?"
Emerson, along with Dr Julia Lewis (Vanderbilt University School of Medicine, Nashville, TN), cast the two "no" votes today. Lewis also voiced her displeasure with looking only at PHOENIX. "I have a lot of concerns that make me unwilling to accept a single trial for approval," she said.
The one abstaining vote came from Dr Thomas Fleming (University of Washington, Seattle). "Specifically in this case, it felt more comfortable to abstain because there are issues on both sides of this," he explained.
Fleming then referenced FDA draft question 5, which asked if the benefits of administering cangrelor for preventing perioprocedural thrombotic events outweigh the risk, based on further analyses conducted on PHOENIX data. The FDA reviewers had concluded in their earlier briefing documents that "the benefit of cangrelor compared with clopidogrel is small, but the risk is smaller"—which was echoed by a consensus of the panel.
"If this really is the whole story, than I can accept an approval in the context of recognizing that it's a relatively small absolute benefit with a relatively smaller absolute harm," said Fleming. "My reservations about this are that it's relative to the configuration of the comparator as it was set up."
In PHOENIX, patients randomly assigned to clopidogrel received a 300-mg or 600-mg loading dose, based on the physician's discretion. The other group received 600-mg clopidogrel immediately following discontinuation of cangrelor.
"At best, I would say that approval should be with a course of corresponding restrictions. We've only shown efficacy, if indeed we have shown it, in the context of patients where it was not feasible to be giving them a P2Y12 platelet inhibitor or a IIb/IIIa," said Fleming, before also noting his concern that data from all three of the CHAMPION trials were not being evaluated together.
The watch-dog group Public Citizen, among the organizations speaking during the open public-hearing section of the meeting, was against the recommendation of approving cangrelor in large part because of "antiplatelet mismanagement."
During the session, a group representative even quoted remarks from Dr Deepak Bhatt (Brigham and Women's Hospital, Boston, MA) in a heartwire story published in 2009 about CHAMPION-PCI and PLATFORM. The rep said the comments showed that Bhatt believed antiplatelet therapy should be given before PCI rather than after—which was not done in PHOENIX.
"If clopidogrel had been given earlier [in PHOENIX], it might have been shown to have been superior," the representative said to the panel.
Even several of the "yes" voters did so after asking many questions throughout the day about the study and treatment procedures, population, and especially the statistical data.
"I voted yes, but with great reluctance," said Dr Stuart Rich (University of Chicago Pritzker School of Medicine, IL). "I would have loved to have seen new data rather than the same data repackaged again and cherry-picked out. Certainly, I do not feel this was a vote of confidence. The only thing that persuaded me is that I know what goes on in day-to-day practice and the problems that come in. So I think some people will be helped," said Rich.
Dr James de Lemos (University of Texas Southwestern Medical Center, Dallas) voted no at last year's panel. "I remain concerned by the very narrow clinical benefit of the drug relative to the risks and what I worry will be the potential use of the drug. This would represent an addition to the armamentarium; but if it's used broadly and indiscriminately, it will not only be expensive, it will expose low-risk patients to unnecessary bleeding," said de Lemos.
"So there is a great responsibility that this gets used appropriately," he added.
Dr Jennifer S Li (Duke Translational Medicine Institute, Durham, NC) said that her vote of yes this year was easier than when she voted yes at last year’s panel. "With the earlier vote, I struggled a lot due to the issues being raised surrounding the primary end point and the comparator," said Li. "But I feel that the additional analyses were compelling, and it would be of utility to have an IV drug that has a fast on-set and off-set available in the cath lab."
Sager noted right after his vote that he felt PHOENIX was a "real-world" trial and showed "significant reductions in clinically meaningful events," especially MIs. "I think the concept that one can look at data and generate hypotheses from a failed trial and then confirm them in another trial is, in my viewpoint, what took place here. And I think that's important for drug development," he concluded.
Heartwire from Medscape © 2015 Medscape, LLC
Cite this: FDA Advisory Panel Gives 'Thumbs Up' for Cangrelor in PCI - Medscape - Apr 15, 2015.
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