Medical Device Daily Washington Editor
GAITHERSBURG, Maryland — Nervous traders drove down the stock of CryoCor (San Diego) from $4.30 to $2.77 on Monday when FDA posted documents on its web site related to the company’s application for approval of its cryoablation system to treat atrial flutter (AFL) (Medical Device Daily, June 26, 2007). Those documents strongly suggested that the company would once again be turned down by an advisory panel, as it had early last year (MDD, Feb. 6, 2006).
But the bulls more than returned in force the next day as CryoCor’s shares opened at $4.79 at the opening bell. And at just after 4 p.m. yesterday, CryoCor was trading at $4.70 on the tech-heavy NASDAQ board.
The reason for the Street’s optimism: A panel vote this time supporting the application.
After the sponsor and FDA detailed a variety of differences concerning the company studies and its endpoints, the panel voted 8-2 to forward the application to FDA with an approvable recommendation with three conditions. One was that the product label include clinical trial data on inclusion/exclusion criteria and chronic and acute efficacy definitions.
The second condition was that CryoCor provide in-person training to physicians. And the panel wants a post-approval requirement — that the firm conduct an observational study of on-label use for evaluation of short- and long-term serious adverse events and for efficacy.
The first few minutes of the advisory panel hearing seemed to augur well for the firm as no speakers showed up to argue that the device should be held off the U.S. market. (The device is available in Europe). The agency’s presentation was also not conspicuously long by FDA standards.
This hearing also did nothing to alter the perception that a change of lead reviewers at FDA is associated with products that end up under an advisory panel review (Medical Device Daily, April 26). Owen Faris, PhD, now the lead reviewer at FDA for this product, told Medical Device Daily that he was not the original lead reviewer.
The Cryoablation system is indicated for treatment of isthmus-dependent AFL in patients 18 and older, and the agency had concerns about the safety endpoint as well as the secondary efficacy endpoint. The agreement between the agency and the company on the safety endpoint, which was less than 2.5% of patients experiencing serious adverse events within seven days of the procedure, was based on a series of standards cobbled together nearly a decade ago, dubbed the objective performance criteria (OPC).
The panel discussed the OPCs at some length, with some of the physicians questioning their value and asking the sponsor why it agreed to those standards.
In an effort to clarify the OPC question, Donna-Bea Tillman, PhD, the director of the Office of Device Evaluation (ODE), told the panelists that the OPCs were assembled when FDA noticed that physicians were using radio frequency (RF) ablators for off-label uses, which was about the time that the agency conceded that controls were not necessary in trials for RF ablators for supraventricular tachycardia.
Initially, “[t]he safety endpoint was intended to be all adverse events up to seven days,” not just those related to the device, she said. Tillman was the chief of the electrophysiology branch in 1998.
On the other hand, the OPCs “are not written in stone,” according to Tillman, although she said “we think the company’s results are a bit mixed.” She told the panel that FDA is interested in feedback on the validity of the OPCs for this application.
Randall Brockman, MD, a medical officer at ODE, said that nine patients reported 10 adverse events within a week of the procedure, including one incident of cardiac tamponade. Since the trial included only 140 patients, the 2.5% rate of SAEs was exceeded.
One of the advantages of cryoablation over RF ablation is that cryoablation does not require sedation. RF burn is perceptible as pain, and patients would tend to react if not sedated, creating problems with catheter location.
Also, cryoablation catheters tend to adhere somewhat to the site of the ablation, which reduces catheter float. Another drawback to RF ablation is that overheating may lead to steam pop, which can cause stenosis and fistulas.
The secondary efficacy endpoint for the trial served as the main bone of contention between CryoCor and the agency, but it was dependent on the primary efficacy endpoint, which was that at least four of five patients exhibit bi-directional block of the atrial signal at the isthmus within 30 minutes of the procedure.
FDA and the firm agreed that the secondary endpoint would be that 80% of patients who clear the primary efficacy endpoint be free of atrial flutter at six months.
The panel’s biostatistician, Sharon-Lise Normand, PhD, a professor of healthcare policy and a biostatistician at the Harvard School of Public Health (Boston) said that a more realistic representation of the device’s value to the patient would be the percentage of all patients who were free of flutter at six months, rather than using the primary endpoint to calculate the secondary endpoint. But her position was not taken up by other panelists.
CryoCor hired an outside entity to adjudicate the weekly heart rhythm readings that patients electronically transmitted to the sponsor, a task the contractor handed off to a technician.
CryoCor saw problems in interpretation of some of the cardiograms and in a post-hoc analysis of the data, reclassified 13 of the failing patients as successes. Some of the cases were reclassified because of readings that did not distinguish between coarse atrial fibrillation and AFL, and the company cited a similar area of potential confusion between atrial tachycardia and slow AFL.
Melvin Scheinman, MD, a professor of medicine at the University of California at San Francisco , spoke on CryoCor’s behalf and pointed out that “if there was only one episode where flutter was unable to be excluded” as a possible interpretation of the cardiogram, “it was considered a failure.”
However, FDA’s Brockman said “as an electrophysiologist, it isn’t clear to me how a patient with recurrent atrial flutter can be reclassified.”