FDA Panel Splits Vote on Approval Recommendation for PFO Closure Device
Members of the FDA’s Circulatory System Devices Panel were split on whether a transcatheter patent foramen ovale closure device should receive premarket approval for use in patients with cryptogenic ischemic stroke caused by a presumed paradoxical embolism.
The panel voted 15-1 that the transcatheter patent foramen ovale (PFO) closure device is safe, 9-7 that it is effective and 11-5 that its benefits outweigh its risks.
St. Jude Medical, manufacturer of the PFO closure device (Amplatzer PFO Occluder), is seeking approval for an indication for percutaneous transcatheter closure of PFO to prevent ischemic stroke recurrence.
If approved, the product would be the first transcatheter PFO closure device.
St. Jude Medical is seeking approval based on the results of the RESPECT trial. In that study, the primary effectiveness endpoint was not met in the intention-to-treat analysis, but per-protocol, as-treated and post hoc device-in-place analyses suggested a 70% to 72% relative risk reduction for recurrent ischemic stroke in patients assigned the device vs. those assigned guideline-directed medical management.
Panel chair Richard L. Page, MD, of the University of Wisconsin School of Medicine & Public Health, said panel members had questions about the conduct of the study.
“There was concern over so much missing data and that confounders and selection bias may play a role,” Page said during his summary of panel deliberations.
Panel member Seemant Chaturvedi, MD, FAHA, FAAN, of the University of Miami Miller School of Medicine, voted no to all three questions.
“We are in a world of evidence-based medicine and two trials have shown that the primary endpoint was not met,” Chaturvedi said.
Panel member David Yuh, MD, of Yale University School of Medicine, on the other hand, said he voted yes to all three questions “all through the prism of the consequences of stroke.”
Other panel members voted yes to safety, but were split on effectiveness and benefit/risk ratio.
Karen Furie, MD, PhD, of Rhode Island Hospital, voted yes on safety and benefits outweighing risks, but voted no on effectiveness.
“I too had concerns over methodology and lack of statistical significance, but I also see the need,” Furie said.
Of 980 patients followed for 4 to 5 years, there were 42 primary endpoint events (18 in the device group and 24 in the medical management group). The device group had a rate of 4.5% of serious adverse events related to the device or procedure. There were 16 deaths in the device group and 10 in the medical management group, none of them related to the device or procedure.
“Through extended follow-up, there was a persistent benefit,” David Thaler, MD, PhD, chairman of the department of neurology at Tufts, said during St. Jude Medical’s presentation.
FDA staff noted during their presentation “a signal for an increased risk of atrial fibrillation and deep venous thrombosis/pulmonary embolism in subjects treated with the device.”
John D. Carroll, MD, professor of cardiology at the University of Colorado, Denver, said during the sponsor presentation that the higher rate of venous thromboembolic events in the device arm was unexpected, but that “the imbalance of warfarin therapy offers likely explanation for the imbalance in VTEs.”
Other concerns with the study expressed during panel deliberation included a high rate of patient discontinuation, particularly in the medical management group, and the prevalence of atherosclerotic risk factors for stroke among patients in both groups. Residual shunting across the patent foramen closure was also common among the device patients.
If the device is approved, St. Jude Medical will conduct a post-approval study to further investigate the rate of device-or-procedure-related serious adverse events and the rate of recurrent ischemic stroke.
Clifford J. Kavinsky, MD, PhD, FSCAI, professor of medicine and pediatrics and director of adult structural heart disease at Rush University, Chicago, spoke on behalf of The Society for Cardiovascular Angiography and Intervention during the public portion of the hearing.
SCAI “urges at least limited approval of a device for PFO closure with a multidisciplinary team approach, mandatory participation in a post-approval registry, and specific operator and institutional requirements that would lead to safe and efficacious dissemination of percutaneous PFO technology to the public and fulfill this important unmet need,” he said.
The FDA is not required to follow the recommendations of its advisory panels, but it usually does. – by Tracey Romero
Disclosure: The FDA granted a waiver to enable participation by Page, whose institution, the University of Wisconsin School of Medicine and Public Health, was a clinical site for the RESPECT trial and received reimbursement for trial-related expenses; Page was not involved with the study. The other members of the panel report no relevant financial disclosures.