The FDA's Cardiovascular and Renal Drugs Advisory Committee (CRDAC) voted 9-2, with one abstention, Wednesday to recommend approval for The Medicines Co.'s (MDCO) cangrelor, but the panel's love for the drug wasn't much lovelier the second time around.
"I surely don't feel this is a vote of confidence," panelist Stuart Rich said as he voted yes "with great reluctance." Rich, a professor at the University of Chicago Pritzker School of Medicine, echoed a few of his colleagues in expressing concerns that the single phase III trial used to support approval of the drug for use in percutaneous coronary intervention (PCI) was a repackaging of previous trials that had failed or were flawed.
Citing a small benefit for the fast-acting intravenous antiplatelet agent, some of the other committee members also voted a reluctant yes, advising the FDA to require labeling explicitly identifying patients who might benefit from the drug and specifying that clopidogrel (Plavix, Bristol-Myers Squibb Co. and Sanofi SA) was used as the comparator in the phase III trial.
The use of clopidogrel was part of the reason Julia Lewis, a nephrology professor at Vanderbilt University School of Medicine, voted against approval. Like some of the other panelists, she questioned clopidogrel as a comparator since it is no longer the leading standard of care.
Lewis said she was uncomfortable with voting for approval based on a single trial given her concerns with the design of the CHAMPION PHOENIX study. In addition to the comparator, she questioned the stable angina patient population that was studied as it wouldn't be the intended population in clinical practice. Lewis also couldn't ignore the previous trials.
Before the vote, the FDA's Robert Temple explained that in a comparator trial, the investigative drug has to show superiority to the control. If the comparator is the best active control available, it adds strength to the trial.
One of the challenges the Parsippany, N.J.-based MDCO faced in designing the trial is the variability in the practice of interventional cardiology. There are no definitive practice guidelines on the timing and dosing of P2Y12 inhibitors such as clopidogrel in PCI, Jeffrey Marshall, a MDCO consultant and director of the cardiac catheterization lab at the Northeast Georgia Medical Center, told the committee.
Although it's unclear how concomitant drugs are used in the space, the FDA has issued no guidance to help sponsors develop new drugs. So instead of having a rigid regimen for the dosing of clopidogrel in the CHAMPION PHOENIX trial, MDCO told investigators to follow their center's normal use of the drug.
While this created uncertainty among some committee members, others applauded it. Susan Leighton, CRDAC's patient representative, said that after cangrelor's first appearance before the committee, she called several patients who had undergone PCI to learn how the inhibitors were administered. She found it varied widely by location.
"This is real world," she said of MDCO's trial design. "As a patient, this is what I want to see," she added.
Others on the committee also welcomed cangrelor as a needed addition to the cardiology armamentarium. Its benefit over other P2Y12 inhibitors is its fast action. Another advantage is that its inhibitory activity disappears within an hour or so, whereas clopidogrel's activity lasts for days after the drug is stopped, often delaying necessary surgeries. The fact that cangrelor can be used and stopped quickly gives doctors flexibility until they figure out how to treat a given patient. (See BioWorld Today, March 12, 2013.)
While some of the uncertainty expressed Wednesday may have evoked déjà vu of cangrelor's appearance before CRDAC a year ago, the vote was a positive reversal. Last time, the committee voted 7-2 against approving the drug for use in PCI and voted unanimously against its use as a bridge from oral antiplatelet therapy to surgery. That meeting was followed by a complete response letter from the FDA. (See BioWorld Today, Feb. 13, 2014, and May 2, 2014.)
This time around, MDCO is seeking a narrower indication – to reduce thrombotic cardiovascular events in patients with coronary artery disease undergoing PCI who have not received an oral P2Y12 inhibitor prior to the PCI procedure and in whom oral therapy with P2Y12 inhibitors is not feasible or desirable.
The FDA seems more supportive of the drug this time, with Temple encouraging CRDAC members to submit suggestions for labeling of the drug. (See BioWorld Today, April 14, 2015.)