Medical Device Daily Washington Editor
WASHINGTON – Monday's goings-on at CRT (Cardiovascular Research Technologies) 2010, sponsored by the Cardiovascular Research Institute (Washington), included an afternoon session during which a number of FDAers opted to use their microphone time to give a common-knowledge review of the functions of their offices. However, a round-table discussion offered some tidbits in exchange for the attendees' time, including a review of continued enrollment in device trials and issues in connection with harvesting of valves after the patient has expired.
One issue that arose was that of the now-notorious post-approval study (PAS), which has become more than a nuisance for device makers, having morphed into a very expensive undertaking in some instances. One of the panelists in the discussion pointed out that a registry PAS can be as costly as the pivotal study that earned the firm the PMA to begin with while an industry representative had to fend off a suggestion that firms commence with a PAS prior to FDA's decision on the PMA.
One of the questions put to FDA's Matt Hillebrenner, a supervisory biomedical engineer at the Center for Devices and Radiological Health, dealt with continued access to investigational devices. He took a moment to urge industry not to expect too much from continued access programs for trials that have concluded the enrollment required for the application, a time at which the randomization requirement is eliminated. "We rarely see randomized continued access protocols," he noted, but reasserted that "continued access is a limited continued enrollment," often undertaken to help maintain surgeons' skills and secondarily to bolster data sets. He also reminded attendees that "taking away randomization is not an implication of device approval."
Continued enrollment numbers are often pegged to the average monthly enrollment rates seen in the pivotal trial's study arm toward the end of the study, Hillebrenner observed. "There may be some procedures where the skills set required is so extensive" that the allowed number "is not sufficient" to maintain the requisite skills in all the surgeons who participated in the trial, but Hillebrenner said that there's little else FDA can do, however unfortunate this might be seen as by physicians and/or sponsors. This end-of-the-trial calculation "is the happy medium," he said, and is consistently undertaken. Allowing the number to balloon beyond that essentially "allows full-scale marketing," he said.
Panel moderator Jeffery Popma, MD of St. Elizabeth's Hospital (Boston), asked Renu Virmani, MD, of the CVPath Institute (Gaithersburg, Maryland), whether she intends to explant any samples of the percutaneous aortic valves currently in play in the U.S., namely the CoreValve, made by Medtronic (Minneapolis) and the Sapien, made by Edwards Lifesciences (Irvine, California).
"I already have started explanting" the Sapien, she said, adding that "with CoreValve ... I think the company is quite willing to set up a site" for explantation work.
As for whether she expects the valves to fibrose, hence lending some assurance of fixation into the valve body, Virmani said, "I see no fracture" in the Edwards valves at two years. The CoreValve explants she has seen were only a year old, but she said the same observation held. She also added that she noticed fractures in animal models, but that "did not lead to valve dysfunction," cautioning all the same that this state of affairs would not necessarily persist in the long run.
Virmani is not known to go out of her way to make friends of device makers, but her report certainly did not stir up any animosity on Monday. She noted that while "it is possible that crimping causes some deterioration," she nonetheless observed that "up to four years, I haven't seen deterioration," although "we have seen some inflammation."
The problem with explants, said Thomas Armitage, VP for clinical research and regulatory affairs at Medtronic, is "our ability to collect these devices," which he described as "horrible. We try to get devices back, and we're not having success."
Virmani chimed in that the recovery rate from deceased patients is "exceedingly low, less than 5% in Europe and less than 10% in the U.S." Reoperations of the affected valve offer a shot at reclamation, but the best route is to obtain them from patients when they die, which of course requires consent before the fact. "Oftentimes I think physicians don't make the effort," Virmani mused, but she averred that physicians are "the ones who have to ask." Firms and FDA can't do it, she said.
Popma seconded Virmani's observations, saying "it's a very emotional experience" to enroll in a valve trial in the first place and that doctors are consequently leery of broaching the subject when the patient consents to the trial. This might not be the only window of opportunity, however, and Popma concluded with the remark, "we're in a position to be able to do that."
Popma asked if Armitage's employer found the definitions of adverse events, such as those provided by the Academic Research Consortium and others, useful when designing a trial. "I think 'useful' is an understatement," Armitage said, adding that a good example of the utility of standard definitions is that the definition of death, simple as it may sound, is not that simple at all. "We would all benefit if there was some standard" set of definitions "so that the clinical community" can "make an apples-to-apples comparison," Armitage said.
Donna Lochner, FDA's deputy director of the division of cardiovascular devices, explained FDA's position on the question of definitions. "We can't dictate standardized definitions in most cases," she shrugged, and "we also can't comparatively say to one sponsor 'one guy did it this way so I want you to do it this way.'"
"Obviously we're supportive ... but our statutory authority is limited," Lochner continued. She took the opportunity to address how this definition dilemma influences the agency's views on data from outside the U.S. (OUS) where device applications are concerned. The definition issue is "a large factor" in the agency's willingness to just accept OUS data wholesale, she acknowledged, but other issues include "holes in the data. We will accept OUS data, but it's sometimes limited in terms of details," she claimed.
Virmani chimed in on the definition issue. "It's up to us" as clinicians to push device makers on the question, she said. "It's [a question of] how dogmatic we are." She also posted a guarded vote of approval for the ARC definition set, offering the remark, "the ARC definition is not a perfect definition," but is nonetheless "better than no definition."
Registries are becoming an increasingly common – and increasingly inexpensive – fact of life for makers of drugs and devices, making this an irresistible target for discussion. Armitage said "the bar is being raised" for registry set-up and architecture. "It used to be that ... a registry was something you could do" for a relatively modest sum of money, but "now you have to have a sophisticated database" and a well thought-out protocol. "There had better be a lot of value coming out of it for the sponsor" he warned, because of the cost. "It isn't something you can do because it's nice to have."
Popma added, "It's just as expensive to run a good registry as to run a good RCT."
Bill Maisel, MD, of Beth Israel Deaconess Medical Center (Boston), said, "I'm still a bit traumatized from the DES experience," given that he chaired FDA's cardiovascular devices advisory committee when the controversy over DES blew into the open. He asked what can be done to get a registry up and running as soon as the PMA gets the agency's imprimatur. Another panelist proposed that when industry sponsors the registry, "there is a big problem with the credibility of the data," so maybe medical specialty societies "can sponsor those types of registries." However, Maisel responded to the effect that if FDA trusts a device maker to run a clinical trial, it might as well trust the firm to handle the registry.
Armitage said that starting up a registry prior to issuance of the PMA "is a roll of the dice" and intimated that such a move could prove to be an enormously costly blunder. "It's by no means clear you're going to get approval" until FDA drops the news in a firm's lap, he said, adding that the humanitarian device exemption process for the Melody was well handled, but if FDA had said to start the registry prior to awarding the HDE, "our response would have been, 'are you assuring us we're going to get approval?'"
Armitage acknowledged that "the discussion [with FDA] needs to start as early as possible," but attested, "we're taken aback" at FDA's expectations of the PAS for Melody. "In the past year, year and a half," FDA has ratcheted up expectations for post-approval studies substantially, he said.
Mark McCarty, 703-268-5690