A meeting of the Circulatory System Devices Panel was held on September 20, 2007. The Panel discussed and made recommendations pertaining to trial issues for ablation devices designed to treat patients with medically refractory atrial fibrillation.
The devices are used to ablate cardiac tissue for the purposes of creating lines of block in the atria to disrupt conduction patterns responsible for atrial fibrillation. Commonly used energy modalities with which ablation takes place include radiofrequency, cryoablation, laser, high intensity focused ultrasound, and microwave. The devices are generally categorized by how the energy is delivered, that is, either percutaneous transvenous access (catheter), or surgical access under direct visualization.
The purpose of this meeting was to discuss the characteristics of the clinical trial designs of these studies that would generate valid scientific evidence to support premarket approval (PMA). If so, FDA wants the Panel make recommendations on overall trial design issues as well as specific study endpoint considerations.
Dr. Yancy 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. Clyde Yancy, Dr. David Milan, Dr. James Neaton and Dr. Cynthia Tracy. The waivers allowed all to participate in the deliberations. Copies of these waivers 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.
Atrial fibrillation (AF) is a disease that affects over two million Americans. Current standard-of-care medical therapies have a range of effectiveness that is widely variable, as reported in the literature. The devices being used include those that are approved for other purposes such as treatment of atrial flutter or supraventricular tachycardia, but have not been evaluated or approved for treatment of AF by FDA, and are being used off-label. Several manufacturers are sponsoring studies to provide a reasonable assurance of safety and effectiveness to support PMA approval for treatment of atrial fibrillation. They discussed their experiences and varying successes in executing the studies. FDA has convened meetings of this advisory panel to discuss this issues twice previously in 1998 and 2000, but many of the same issues still exist. FDA is seeking the advice of the 2007 advisory panel to continue to discuss atrial fibrillation trial design issues.
In the afternoon the Panel was given the opportunity to address FDA’s questions. The panel was in general agreement that Randomized Controlled Trials (RCT’s) would provide the best evidence to support a PMA for an ablation device intended to treat medically refractory AF. The Panel discussed viable alternative trial designs, endpoints and barriers to enrollment:
- The panel was in agreement that a RCT was the most viable clinical trial design for development of valid scientific evidence. The panel thought that the RCT design could be used to study percutaneous atrial fibrillation as either first or second line therapy. Alternative nonrandomized trial designs were discussed and felt to be problematic.
- Several mechanisms were discussed for increasing timely enrollment into the atrial fibrillation trials. It was felt that Inclusion/Exclusion criteria could be broadened in order to facilitate enrollment. Also, it was thought that separate trials are not needed for study of paroxysmal and persistent atrial fibrillation. Rather these populations could be studied collectively in the same trial.
- Effectiveness Data should reflect clinically significant outcomes and should have an objective measurement of absence of AF for the primary endpoint. The panel noted that important secondary evaluation may be AF Burden, asymptomatic recurrence of AF, and quality of life.
- Safety Data should be collected for both the treatment and control groups and compared for serious adverse events. In the final analysis, the risks of long-term drug use will have to be considered relative to the safety profile of the device.
- FDA and the panel agree with the current ACC/AHA/ESC guidelines which state “Drugs and ablation are effective for both rate and rhythm control, and in special circumstances surgery may be the preferred option. Regardless of the approach, the need for anticoagulation is based on stroke risk and not on whether sinus rhythm is maintained.”
Contact: James Swink, Executive Secretary,
(240) 276-4179 James.Swink@fda.hhs.gov
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