A meeting of the Circulatory System Devices Panel was held on March 2, 2007. The Panel discussed and made recommendations on PFO closure devices and issues related to randomized clinical trials. The meeting was closed to the public from 10 a.m. until 12 p.m. to permit discussion of and review of trade secret and/or confidential information.
The concept of percutaneous closure of a Patent Foramen Ovale (PFO) in patients with cryptogenic stroke has been under various forms of clinical evaluation in the United States for approximately ten years, yet no prospective trial has been completed and no device has been approved under the Premarket Approval (PMA) process. Although limited marketing applications (i.e., Humanitarian Device Exemptions (HDE) applications) were approved for “high risk” populations, these applications have been recently withdrawn secondary to an increasing patient population, beyond the limit eligible for the special Humanitarian Use Designation (HUD), thus rendering them ineligible for continued marketing under HDE applications.
The purpose of this meeting is to reevaluate whether randomized trials are essential for PMA approval. If so, FDA wants the Panel to identify potential changes that may improve patient recruitment and, if not, to identify critical trial design elements for nonrandomized trials.
Call to Order
Dr. Maisel called the meeting to order at 8:00 a.m. James Swink, Executive Secretary for the Circulatory System Devices Advisory Panel, read the conflict of interest statement into the record. All members and consultants were in compliance. Based on the agenda and all financial interests reported by the Panel members and consultants, a conflict of interest waiver was issued in accordance with 18 U.S.C. Section 208 (b)(3) to Dr. Phillp Gorelick. The waiver allowed him to participate in the deliberations. Copies of this waiver may be obtained by visiting the Agency’s website at http://www.fda.gov/ohrms/dockets/ac/cdrh07.htm or by submitting a written request to the Agency’s Freedom of Information Office, Room 6-30 of the Parklawn Building.
History of PFO Devices and Regulation
FDA presented an outline of the regulatory history and a summary of the review process of PFO closure devices. This in-depth presentation included an overview of PFO from a pathological and clinical perspective, including an overview of the anatomy and physiology of PFO and Cryptogenic Stroke, a brief summary of ongoing trials, a history of HDE Approvals and Withdrawals, current therapies and previous panel recommendations. The FDA presentation also included current FDA trial design recommendations.
In the afternoon the Panel was given the opportunity to address FDA’s questions. The panel was in general agreement that Randomized Controlled Trials were needed to assure the Proof of concept for the rationale of using PFO closure devices to prevent recurrent stroke. The Panel discussed viable alternative trial designs, endpoints and barriers to enrollment:
- Off label use is a barrier to enrollment in RCTs
- Inclusion/exclusion criteria can be broadened to allow for better enrollment
- Endpoints were discussed such as blinded radiographic evidence for stroke and TIAs/extensive follow up/Randomization/2 year follow up
- Adding new sites/Referral patients to help enrollment in RCTs
- Direct patient incentives / Insurance incentives can be given to those who enroll in RCTs
- Information Management should allow for patient education on PFOs from new unbiased internet sites/patient advocacy groups and professional societies
- Alternative Trial designs such as High risk or Consecutive registries may be established to collect adjunctive data
Contact: James Swink, Executive Secretary,
(240) 276-4179 James.Swink@fda.hhs.gov
Transcripts may be purchased from: (written requests only)
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Food and Drug Administration
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