Medical Device Daily Washington Editor

GAITHERSBURG, Maryland — The Medical Device Dispute Resolution Panel convened in April for the second time since December — the first meeting being Acorn Cardiovascular (St. Paul, Minnesota — and this gathering was to referee a dispute between the agency and Cardima (Fremont, California) over the outcome of clinical trials for the Revelation TX microcatheter, which is designed to treat paroxysmal atrial fibrillation (PAF) in patients who have not responded to treatment with at least two drugs.

Cardima once again struck out, largely because of persistent problems with data collection that, when combined with the use of patients as their own controls, pushed the panel to a 5-0 vote against the company's application. As a result, the U.S. market still has no ablation catheter approved for PAF, despite availability on the other side of the Atlantic for several years.

Cardima filed the original PMA in September 2002, and the application went to a circulatory system devices advisory committee the following May. That panel gave the application a 7-0 thumbs down, which the agency announced it agreed with in June 2003 and sent the company another non-approvable letter in May 2004. Several meetings have taken place in the interim in an effort to avoid going to the dispute panel.

The company got no help from the current chair of the circulatory systems advisory committee, William Maisel, MD, the director of pacemaker and defibrillator services at Beth Israel Deaconess Hospital (Boston), who suggested that this technology might not fare well in the market even upon approval. He said that radio-frequency ablation for AF "was very popular in the late 1990s but has fallen out of favor" because "the consensus is that it is less likely to be successful." And he criticized the specifics of the data collection: "It is critically important that you measure acute procedural endpoints, and critically important that you measure them at the time of the procedure." Maisel was the reviewer for the circulatory systems panel on the application for this device in 2003.

Maisel's views on the utility of RF ablation were not shared by all. Jaswinder Gill, MD, of London Bridge Hospital (London), argued that RF ablation is effective and is a vital tool. "Linear ablating technology offers us an advance" in the treatment of heart disease, Gill said, adding that a failure to move this technology into widespread use "would represent a great travesty." Gill said he was not compensated to appear at the meeting.

Daniel Cher, MD, who served as the medical director at Cardima in 2004, backed the sponsor's request. Cher remarked that the field is in need of a non-drug treatment for PAF, asking rhetorically, "in our population, how much good is another anti-arrhythmic drug going to do? In our opinion, not much."

The sponsor and FDA apparently agreed to allow patients to serve as their own controls for the pivotal study, a move that the agency said imposed a tighter standard of adherence to the study protocol than would have been necessary in a trial with separate controls.

The protocol required that clinical investigators (CIs) record a measurement of the electrical current applied with each ablation, a number of which went on with each procedure.

However, many CIs apparently did not record a sizeable number of their "burns," so to speak, which can be recorded by Ensight, a computer program that can be used with MRI equipment for such purposes.

The Revelation is positioned by a larger catheter also made by Cardima, the NavAblator, but this was not the mode of positioning in each clinical site throughout the trial, a situation that created problems of its own. The use of the NavAblator was also not part of the original PMA application.

The absence of data on between 65% and 70% of the ablations left FDA with insufficient data to establish "acute procedural efficacy," leaving the agency's reviewers to conclude that the possibility that a placebo effect was responsible for much of the reported efficacy could not be ruled out.

Bram Zuckerman, director of the cardiovascular devices office at the FDA's Center for Devices and Radiological Health, said there was "no pre-determined goal for the number of successes" in terms of reported absence of PAF, and pointed the panel back to the absent data in remarking that "[u]nfortunately, what you have heard is that the trial has not been conducted well."

Cher made the case that the trial results are "consistent with surgical and other ablation studies," and that the safety profile, a 5% rate of serious adverse events, is reasonable. "I think it's unrealistic to expect amplitude demonstration at each electrode," Cher said in reference to the absent data. As to the overall effectiveness of the device, he remarked that "these patients do not get better on their own, and a control group is hence not necessary."

Cher asked the panel to consider recommending approvable with this condition, but when the time came for a motion, this offer was not discussed.