Medical Device Daily Washington Editor
COLLEGE PARK, Maryland – For the second time in as many days, a titan of the device industry met with the circulatory systems advisory committee for its approval for a device that could tilt the market toward the applicant. Boston Scientific (Natick, Massachusetts) snared a huge win in its pursuit of an expanded indication for its CRT-D units (Medical Device Daily, March 22), and Medtronic (Fridley, Minnesota) sought the same panel's approval for its MRI-compatible pacemaker, the Revo SureScan.
The panel threw several questions at the sponsor regarding several engineering considerations, but FDA came to bat on Medtronic's behalf on a couple of points, noting for one instance that the company undertook changes to address the agency's concerns. That cooperation may or may not have been decisive in gaining the panel's approval, given that the study met both its safety and efficacy endpoints.
Medtronic made use of at worst-case scenarios – or worse – in bench testing and animal models, but one panel member, Bill Maisel, MD, of the Medical Device Safety Institute (Boston) suggested that FDA and firms think about a test-to-failure approach for device failure modeling. Maisel's remark drew no overt agreement, but his views have substantial weight inasmuch as he formerly chaired the panel, and he clearly has the ear of Congress where medical device issues are concerned. Maisel appeared as an expert witness at two congressional hearings last year on the subject of medical device safety (MDD, May 14 and Aug. 9, 2009).
Sandy Wixon, Medtronic's MRI group leader, reminded the panel that MR machines generate two magnetic fields in addition to a radio frequency (RF) field. “The gradient [magnetic] field is the one with the greatest variability,“ Wixon pointed out, varying by as much as a factor of four in some procedures. Patient morphology is also an area of great variation and “has a significant impact“ on the use of MR technology, he said.
“There are no standards for pacemakers in the MRI environment,“ Wixon remarked, noting that IEC 60601, published by the International Electrotechnical Commission (Geneva) offers some details, although he said 60601 needs further development for MR applications. The chief concern here is that an RF signal may heat a lead and damage the tissue surrounding the tip, resulting in the formation of a fibrous capsule. This capsule, Wixon observed, can inhibit conduction, “producing an increase in pacing capture threshold,“ or PCT.
To deal with these interactions, Medtronic went about “creating a library of . . . human bodies,“ Wixon said, to capture a cross-section of human body types. Medtronic also “developed a set of 100 lead paths“ to depict the range of locations of pacemakers and the routes of leads. An overlay of these “maps“ produced a matrix for device-MR interaction, and the results, he said, show that the probability of a half-volt change in PCT was one in 71,000, and for a full volt change, one in 2.9 million (documents distributed at the hearing did not indicate the normal voltage range).
Worse than worst-case enough for FDA
Canine studies, Wixon said, included both worst-case and triple-worst-case modeling for the RF field intensity. “Even at extreme power levels, the increase in the pacing capture threshold would not result in an inability to“ attain capture, he said. Wixon said “a half volt change in pacing capture [as] normal,“ and that a variation of up to one volt “is not uncommon.“ The six-week evaluation of the canine models that had been exposed to triple-worst-case dosing suggested the leads would hold up. “Even at three times clinically relevant power levels . . . there is no permanent change“ to the lead's PCT, he said.
Another risk is that the RF signal can transit into the pacing unit and rebound to the lead tip, hence sparking the heart again. It was not clear how the Revo filters out such bounce-back, but Wixon said the company does not use a signal rectifier, an electronic component that permits electrical conduction in one direction only.
Regarding bench testing of the 5086 leads, Wixon stated that the unit “underwent hundreds of millions of cycles,“ equal to 10 years of life. The lead differs from its immediate predecessor, the 5076, in that Medtronic beefed up the number of filars (filament) from two to four, and the lead inner conductor is said to be designed to mitigate heating.
Bruce Wilkoff, MD, of the Cleveland Clinic (Cleveland), noted that the pivotal trial recruited 464 patients at 42 centers in and outside the U.S., and used five scanners made by three companies at a setting of 1.5 Teslas. The data presentation was simplified by the fact that of the 211 patients in the study arm (47 of the original 258 were lost to follow-up or otherwise not included in the analysis), none experienced complications attributed to the interaction between the MRI unit and the Revo and the leads. Pacing capture thresholds at a month post-MRI were statistically indistinguishable from baseline.
As for efficacy, Wilkoff noted that measures of both atrial and ventricular amplitude met statistical significance, a conclusion corroborated by both sensitivity and tipping-point analyses, the latter of which would be well received by several of the advisory committee's members.
Panel; no value in larger clinical trial
The panel seemed favorably inclined toward the application at the beginning of discussions. Michael Domanski, MD, of the National Heart, Lung and Blood Institute, said the study was “as well done as it could be, but the whole thing rests on the modeling.“ He asked why FDA is comfortable that the modeling “reflects physical reality.“
Owen Faris, PhD, the lead reviewer for the application, noted the existence of “an active, ongoing standards development effort“ for this application, and that “the sponsor's validation efforts are very consistent with what the experts from around the world“ recommend, Faris said.
“The model could be correct or completely incorrect,“ Faris acknowledged, but he said FDA and Medtronic “spent a great deal of time from the beginning“ looking at the relationship between exposures and outcomes in animal models, “and at several points along the way, we . . . asked them to make more conservative assumptions, and they did,“ Faris acknowledged. Hence, “we are very comfortable with the assumptions they made along the way.“
Despite this and other reassurances, Maisel hinted that he does not see worst-case testing as adequate. “In some other device scenarios, we've learned that worst-case testing“ is not enough, adding that “test-to-failure“ might be a better approach.
Mitchell Shein, a scientist at FDA, reassured the panel that standards are on the way, but that they are likely to be fairly generic. FDA, he said, “can't regroup all those people“ for each device-specific standard.
“Yes, we do run the risk that the device you're reviewing today will not comply with that standard,“ but “based on the science we have today, this is an appropriate device for you to review,“ Shein said.
During a discussion of the clinical trial, panelist David Naftel, PhD, of the University of Alabama (Tuscaloosa, Alabama), said, “if there were three times the patients in this study, I don't think we would have learned anything more,“ although he acknowledged concern about the patients who dropped out. “I think the tipping point analysis is elegant and it really helped me“ to compensate for the lost data. “If the study were three times larger, you'd still have the same proportion of missing data,“ and a larger study might “lure you into a false sense of security,“ he remarked. This sentiment prevailed for a sizeable majority of the panel.
As for the use of pacing capture threshold as a surrogate for tip heating, the panel seemed largely unconcerned. Andrew Aria, MD, of NHLBI, remarked, “in some ways, I like this better“ than tip temperature readings, partly because temperature measurements are difficult to perform and because PCT is a widely understood measurement. This line of thinking on the subject was not challenged.
The panel voted for approvability with several conditions, including that the label reflect that there are no data supporting any mixing-and-matching of leads and pacing generators. The panel also recommended a training program for medical professionals, although the details were left to the firm and FDA to determine.
Mark McCarty, 703-268-5690