A meeting of the Circulatory System Devices Panel was held on March 4 and 5, 2002. On March 4, the Panel discussed, made recommendations, and voted on supplement to a premarket approval application, P920014/S016, for the HeartMate Vented Electric Left Ventricular Assist System (VE LVAS) manufactured by Thoratec, Incorporation. The device was approved for use as a bridge to transplantation in September 1998.
The Panel heard a presentation by the sponsor on the results of the REMATCH clinical trial to support the use of the device as a permanent heart pump for destination therapy. REMATCH stands for Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure. This study was a prospective, multi-center, randomized study in which 67 patients were implanted with the VE LVAS and 61 patients received maximal medication alone.
The primary endpoint was improvement in survival. Secondary endpoints were improvement in several functional measures: quality of life as measured by 5 separate questionnaires, 6 minute hall walk, number of hospitalizations, New York Heart Association Class and VO2 as measured by cardiopulmonary exercise testing. Safety was measured by the rate of anticipated and unanticipated adverse events.
Following the FDA presentation, and after questioning the sponsor, the Panel considered several discussion questions related to the PMA supplement. In particular, FDA asked the Panel to:
- Evaluate device reliability as shown in the REMATCH study and put that it clinical perspective for expanding the use of the device onto the broader market, that is out of the clinical trial setting
- Evaluate if the survival benefit shown in REMATCH was clinically meaningful
- Determine if the device provided a clinically meaningful improvement in functional status
- Discuss whether benefits of the device outweigh it's risks
- Make labeling recommendations; and
- Discuss whether additional clinical follow-up or a post market study are necessary to evaluate the long-term effects of the device.
Following these deliberations, the Panel voted 8 to 2 that the application be found 'approvable with conditions', citing concerns over device safety, and reliability. The panel also was concerned about the number of adverse events and reoperations and how to adequately inform the patient of these risks. The conditions outlined by the Panel were:
- Full analysis of existing data, with an emphasis on reliability.
- Make an analysis of the time to death or stroke
- The FDA and the sponsor should agree on new indications for use that are more specific and identify the patient population more clearly that will most benefit from the device and who will be at least risk for complications.
- An extensive post-market study. A registry format for the study was discussed.
- Clear set of written information should be available for patients that would describe the data for use of the device as a permanent pump. This information would be based on the data acquired during the REMATCH trial.
On March 5, the Panel discussed, made recommendations, and voted on a premarket approval application, P010031, for the Medtronic Corporation InSync ICD, Model 7272. The device is an implanted cardioverter defibrillator with the additional capability of biventricular pacing used in the treatment of life-threatening ventricular dysrhythmias and congestive heart failure.
The Panel heard a presentation by Medtronic on the results of the primary clinical studies used to support the safety and effectiveness of the InSync ICD. The study was a prospective, multi-center, double-blinded randomized study. The data presented to the panel was on 133 patients with Class III/IV congestive heart failure who were implanted and received treatment with the device and 124 control patients with Class III/IV were implanted with the device and did not receive resynchronization therapy.
There were 3 co-primary effectiveness endpoints:
- NYHA class
- Quality of Life score
- 6-minute hall walk distance.
These co-primary endpoints were evaluated statistically based on an adjustment for multiplicity.
The safety objectives were:
- InSync ICD generator complications
- InSync system related complications
- Left ventricular (coronary sinus) lead Model 4189
There were many secondary objectives.
Following the FDA presentation, and after questioning the sponsor, the Panel considered several discussion questions related to the PMA. In particular, FDA asked the Panel to:
- Comment on the sponsor's study design.
- Discuss the device therapy's effectiveness in treating congestive heart failure
- Discuss the effectiveness of the system as an ICD
- Discuss the safety of the system as an ICD
- Make labeling recommendations; and
- Discuss whether a post-market study should be performed and if so what should be evaluated.
Following these deliberations, the Panel voted on a motion that the application be found 'not approvable', citing many deficiencies in the data provided in the panel pack supporting the sponsor's claim of effectiveness and safety. The Panel voted 5 to 5 on this motion, with the acting chairperson breaking the tie with a vote against the motion.
A second motion was made for "approvable with conditions". The Panel again voted 5 to 5 and the acting chairperson broke the tie with a vote for the motion.
The conditions recommended by the Panel were:
- Post-approval study to obtain 12-month mortality data on the IDE cohort and to perform a 3-year evaluation of mortality and chronic lead performance, including electrical performance and adverse events, on 1000 patients.
- Medtronic should provide the complete data on:
- interaction involving the lead performance
- left ventricular lead risk and procedural safety
- remainder of the study population follow-up data
- Medtronic should provide the FDA with a document that shows the explicit original intent of the original agreed upon sample size of the study. The data set for the agreed upon sample size should be reviewed by FDA.
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