Full article reprinted from "The Gray Sheet" - November 24, 2008
Find out how Johnson & Johnson/Biosense Webster's Navistar ThermoCool saline irrigated radio-frequency ablation catheterhas the inside track to become the first ablation catheter with an FDA-approved indication for atrial fibrillation following a unanimous recommendation from the agency's Circulatory System Devices Panel.
Full article reprinted from "The Gray Sheet" - November 24, 2008
At its Nov. 20 meeting in Gaithersburg, Md., the committee voted 7-0 to recommend that FDA approve, with conditions, Biosense Webster's PMA supplement to add "treatment of drug-refractory atrial fibrillation" to Navistar ThermoCool's label.
Catheter ablation is intended to stop symptoms of cardiac arrhythmias by creating scars in the heart tissue that block specific electrical pathways. Atrial fibrillation ablation usually entails creating a circumferential lesion around the opening between the left atrium and the pulmonary vein.
Catheter ablation devices, including Navistar ThermoCool, are approved for treatment of other arrhythmias such as atrial flutter and ventricular tachyarrhythmia, but catheter ablation for atrial fibrillation is currently an off-label procedure.
Other ablation device manufacturers pursuing atrial fibrillation product labeling include Medtronic, Boston Scientific, St. Jude Medical, CardioFocus and AtriCure.
If FDA were to follow the panel's approval recommendation, Biosense Webster would be the only company allowed to market its ablation device specifically for treatment of atrial fibrillation.
"This will add a very important tool to the electrophysiologist's tool kit ... one that will be very beneficial to our patients," cardiologist David Slotwiner, Long Island Jewish Medical Center, said at the close of the meeting. Slotwiner was the panel's primary reviewer of the ThermoCool PMA supplement.
Bayesian Statistics Supports Pivotal Study Data
Biosense Webster's application is based on a 167-patient, 19-center trial comparing Navistar ThermoCool pulmonary vein isolation ablation to antiarrhythmic drug therapy alone. Patients enrolled in the study failed previous regimens of antiarrhythmic drugs.
The primary chronic effectiveness endpoint of the trial was freedom from symptomatic atrial fibrillation based on electrocardiograph data, with no changes in the patient's antiarrhythmic drug regimen during nine months of follow-up.
In the ablation arm, 53 out of 103 patients completed the nine-month follow-up without a symptomatic atrial fibrillation event, compared to 9 out of 56 patients in the control arm.
Biosense Webster originally planned the trial for 230 patients, but "encountered unprecedented challenges to timely enrollment for completion of this study," according to materials submitted to the panel. They launched the trial in October 2004 but enrolled only 11 subjects in the first year and only 53 in two years, despite screening over 2,100 patients.
Enrollment was slow partly because so many patients elected to undergo off-label atrial fibrillation ablation rather than risk being randomized to drug-therapy alone. The Circulatory System Devices panel discussed slow enrollment of AF ablation trials at a special meeting in Sept. 2007 (1"The Gray Sheet" Oct. 1, 2007, p. 9)
To accelerate completion of the study, the company added several European sites to the trial and, in late 2006, the company and FDA developed an adaptive Bayesian statistical model that would allow the researchers to accurately estimate the chronic effectiveness of ThermoCool on an interim analysis of the data.
After 167 patients were enrolled, the model showed that the chance of ablation being superior to drug therapy for the chronic effectiveness endpoint is 99.9% compared to a prespecified goal of 98%. The company was able to stop the trial based on this result and submit the data to FDA to support the PMA supplement.
"While the final sample size of 167 subjects may appear modest, the Bayesian approach provides a least burdensome, efficient and statistically valid approach," the company explains.
The panel complimented the company and the agency for finding a creative solution to the enrollment problem.
The panel's statistics reviewer, surgeon and biostatistician David Naftel, University of Alabama-Birmingham, called the company's statistical presentation "a really nice analysis plan and implementation and [FDA's statisticians] really helped to shore up a lot of the questions."
Safety Needs Confirmation In Post-Market
Biosense Webster submitted safety data from 103 patients enrolled in the ablation group plus 36 patients from the control group who eventually underwent ablation after drugs alone failed.
In that group, a total of 16 adverse events were reported within seven days after ablation for 15 patients. Overall, 10.8% of subjects experienced an early-onset serious adverse event with a statistical upper limit of 16.1%, barely missing the prespecified target for the upper value of 16%.
Several panelists said they were not very concerned with that result because none of the patients treated with the ThermoCool died or suffered stroke or myocardial infarction within a week of the procedure.
However, the panel also agreed with John Somberg, M.D., Rush University Medical Center in Illinois, that the pre-market study was too small to provide adequate information on all possible safety questions.
The panel unanimously recommended that FDA require, as a condition of approval, that the company sponsor a post-market registry of ThermoCool atrial fibrillation ablation that will be large enough to detect rare adverse events.
The company proposed a post-market study that would follow 145 new patients treated with ThermoCool for atrial fibrillation and continue to follow the 139 patients from the pre-market safety study. Under that plan, all the subjects would be followed for at least five years.
Several panelists said that the company's planned post-market study would be too small.
Seth Bilazarian, M.D., Pentucket Medical Associates in Haverhill, Mass., suggested a 500-patient study with at least seven years of follow up in which the patients' vital cardiovascular metrics including EKG would be collected each year. "That would at least give us a forward-looking idea of the safety."
Trial Results Vs. Real World
FDA asked the panel to specifically discuss the relevance of the pre-market trial results to the "real world," because there was such a wide range of success rates in the trial. One non-U.S. center had a 100% procedural success rate, while the overall success rate for U.S. centers was around 50%.
The panelists generally agreed with a suggestion from Slotwiner that the post-market study include patients from a variety of centers, including those that only perform a few cardiac ablations per year.
Also, given the apparent correlation of physician experience with the device to outcomes, the advisors recommended as a condition of approval that J&J develop a physician education program for the device.
On Slotwiner's recommendation, the panel confined its recommendations to the Navistar version of ThermoCool, because that was the only device used in Biosense Webster's pre-market clinical trials. Navistar ThermoCool has a manual, unidirectional deflection mechanism and is compatible with Biosense Webster's CARTO EP navigation system.
The company's PMA supplement also requests adding the atrial fibrillation indication to four other versions of the device: Navistar ThermoCool RMT, Ez Steer ThermoCool, Ez Steer ThermoCool andCelsius ThermoCool.
Celsius ThermoCool is not compatible with CARTO, ThermoCool RMT has a remote magnetic deflection mechanism, and the EZ Steer devices have a bidirectional deflection mechanism.
The panel declined to make a recommendation on the other four models, citing a lack of information, although the company says it has given FDA information that shows the different versions of the device are effectively equivalent.
- Reed J. Miller
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