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By Jeannie Baumann
Jan. 7 — The FDA's approval of a Medicines Co. drug to prevent blood clots in the heart stemmed from a clinical trial that “needlessly threatened the lives of subjects assigned to the control group,” advocacy group Public Citizen alleged Jan. 7.
The group is calling for a federal investigation into the ethics of the CHAMPION PHOENIX clinical trial, a heart study that found the antiplatelet drug Kengreal (cangrelor) significantly reduced heart attacks compared to the blood thinner clopidogrel, which is available as Bristol-Myers Squbb's brand name Plavix as well as in generic versions. It also wants a separate investigation into whether the study led to any inappropriate patient care.
The principal investigators for the study defended the research, maintaining that it was thoroughly reviewed and reflects common practice. Both an investigator and a Medicines Co. spokesman also told Bloomberg BNA that Public Citizen had raised its concerns about the study as early as 2014 while a Food and Drug Administration advisory committee was reviewing the Kengreal marketing application.
The FDA approved Kengreal in June.
Kengreal treats adults undergoing percutaneous coronary intervention (PCI), a procedure used to open a blocked or narrowed coronary artery and insert a stent to improve blood flow to the heart muscle.
At issue is whether subjects in the clopidogrel arm of the study—the control group—received antiplatelet medications as soon as possible to stop blood clots from forming inside the stent.
Citing a number of guidelines, Public Citizen said these subjects should have been administered clopidogrel at least two hours prior to undergoing a PCI. Not including such a requirement in the study design led to “inappropriate delays in antiplatelet therapy,” and these delays were “exceptionally high” at Department of Veterans Affairs hospitals, it said.
“The seriously flawed trial protocol paved the way for inappropriate and shocking delays in antiplatelet therapy for subjects enrolled in the control group at all trial institutions,” Michael Carome, director of Public Citizen's Health Research Group, said in a Jan. 7 statement. “Inexplicably, the rate of such delays was extraordinarily high at the VA trial sites, making participation in the trial even more hazardous for subjects randomized to the control group at those sites compared with other sites.”
In a Jan. 7 letter to the VA Office of Research Oversight, Public Citizen said, “By designing the trial to allow investigators to routinely delay administration of clopidogrel until after the PCI procedure, control group subjects were placed at a significant disadvantage relative to the cangrelor group subjects, which ultimately increased the chances that the cangrelor intervention would appear to be superior to the clopidogrel intervention.”
Public Citizen also questioned the adequacy of the informed consent document, contending that the form didn't mention the reasonably foreseeable risks and was “uninformative” in its disclosure on the availability of alternative treatments.
The group's letter called on the VA ORO to investigate the clinical trial, which involved three VA medical centers.
In a separate Jan. 7 letter to the VA's Office of Inspector General, Public Citizen asked for an investigation into whether inappropriate care for subjects in the CHAMPION PHOENIX trial extended to clinical care of patients who didn't participate in the trial.
Deepak L. Bhatt, one of two principal investigators of the CHAMPION PHOENIX trial, told Bloomberg BNA that there's a great deal of variability in practice for administering clopidogrel before a PCI.
“Regarding clopidogrel pretreatment, the observational data have suggested a benefit, but the dedicated prospective randomized trials have not shown clear benefit, though some have shown excess bleeding,” Bhatt said in a Jan. 7 e-mail. “Clinical practice in the US mirrors this uncertain benefit/risk ratio for pretreatment, with registry data showing that approximately half of patients do not get pretreated.”
Bhatt is the executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center and a professor at Harvard Medical School. According to a presentation on the study, CHAMPION PHOENIX was a large randomized clinical study involving 153 sites in 12 countries.
Before enrolling any subjects, Bhatt said, the FDA and its counterpart agencies worldwide had to review and approve the trial design and protocol. He also noted that numerous institutional review boards, ethical boards and sites throughout the U.S. also approved the study. He said the study findings appeared in a “leading medical journal,” referring to a New England Journal of Medicine paper.
“Thus, the trial tested and answered an important scientific and clinical question,” Bhatt told Bloomberg BNA. “CHAMPION PHOENIX was a large, robust clinical trial that provided strong data supporting use of a new therapy in specific situations—and numerous regulatory agencies and practicing physicians agree.”
Robert A. Harrington, the trial's other principal investigator and chairman of the Stanford University Department of Medicine, added, “[T]hese are not new criticisms from Public Citizen. They expressed these comments at both FDA Advisory Committee meetings on the topic.” He was referring to the FDA Cardiovascular and Renal Drugs Advisory Committee, which recommended approval in April.
Bob Laverty a spokesman for the Medicines Co., echoed Harrington. Laverty told Bloomberg BNA Jan. 7, “The scientific diligence questions raised in the Public Citizen letter, were previously raised in February 2014,” and “were thoroughly dismissed by the FDA and the advisory panels and by the Office of Integrity, an independent division at the FDA.”
“The Medicines Company is proud to be associated with the VA hospital system and honored to have successfully conducted clinical research at the VA on numerous occasions,” he said. “Our products serve the military in VA hospitals and we are proud to serve those who serve our country. The news in question is very old and not about the drug.”
CHAMPION PHOENIX is a shorthand name for the “Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention (PCI),” according to ClinicalTrials.gov.
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