Medical Device Daily Washington Editor

SILVER SPRING, Maryland – The post-approval study (PAS) is one of the most frustrating parts of the development process for makers of novel devices, not just because patients are not particularly eager to enroll.

One of the speakers at an FDA symposium on the topic this past Thursday had some bad news for any sponsors who were not already aware of the situation: the typical PAS is not only old hat for physicians who are inherently more interested in the cutting edge than in bringing up the technological rear, it also does not pay particularly well compared to a pivotal trial.

On the other hand, this latter problem may ease, given the recent drop in venture capital investment in new medical technology and the impact that such a drop will have on the number of pivotal trials for new devices.

Christine Pierre, president of RxTrials (Elliot City, Maryland), gave a discussion of how clinical trial sites view participation in a PAS, noting that she had organized a meeting of clinical site supervisors recently. "All these [clinical] investigators (CIs) came to this meeting" and "the vast majority of investigators said that 'the reason I do not like to participate is the ROI,'" or return on investment, a polite way of saying the studies pay too little.

"At some point, we have to realize that an investigator's time has to have a ROI," Pierre said, partly because FDA and the National Institutes of Health (NIH) are tightening the regulatory screws. In the case of FDA, clinical investigators are subject to warning letters and worse, to disqualification from participation in trials. Furthermore, given that most pivotal trials are for new, high-risk (read; implantable) devices, "these are by and large surgeons," Pierre said, who want to be on the next pre-approval study, not a PAS.

One way in which manufacturers sometimes unwittingly – but preventably – complicate their lives, Pierre observed, is that they sometimes choose a site based on marketing considerations. "Where is it [written] that marketing is driving who these investigators are?" she asked, an odd decision given that such an approach often lands a CI who has not handled a lot of trials. "They don't even know about 21 CFR," the portion of the Code of Federal Regulations dealing with drugs, devices and clinical trials, she said of some potential CIs.

"How we choose these investigators has to be paramount," Pierre urged, informing sponsors that some CIs will sign on for a PAS because they figure it will get them in on the sponsor's next pivotal study, an idea she said some sponsors explicitly or implicitly foster. Another possible issue with poorly vetted study sites is that a clinic that is not particularly busy will take a PAS, but suddenly lose interest after signing on to do a more engrossing and more remunerative pivotal study. "Look around and talk to the coordinator at the site. She'll tell you what's really going on," Pierre suggested.

As for the money angle, any clinic that is looking at drug vs. device trials will be even less interested in a PAS. Pierre said "the compensation for a device versus a phase III drug study is approximately $3,000 less."

Danica Marinac-Dabic, PhD, director of the Office of Surveillance and Biometrics at CDRH, said during a brief presentation that the PAS is "just one of many tools" used by CDRH to assess post-approval performance. "At the time of approval, we do not have enough information about long-term performance," a situation that a PAS can rectify, she said. Another point of interest on FDA's part is how a device works "in the hands of physicians who practice in community hospitals" rather than in centers of excellence.

Physician training is an issue because of "huge variations in the use of the product" and the PAS should "assess the effectiveness of that training," she said. There are differences in how a given device works in population sub-groups, hence, "it is important to tackle those differences" in a PAS.

Dabic said that device makers should "think about the registries" if a PAS can be constructed as a continuation of the pivotal study. "We may not have to have de novo [PAS] studies if we have the infrastructure in place," she stated, adding that while registries are good tools, they often do not follow patients past 30 days, a feature that will have to be tweaked if a registry is used to conduct a PAS.

In a brief on some recent approval numbers, Dabic said that the number of approved PMAs and panel-track supplements that came with a PAS requirement rose from 15 out of 38 in 2005 (39%) to 15 out of 30 in 2008, a 50-50 split. During that stretch, the peak year in terms of sheer numbers was 20 of 44 PMA and panel-track supplements that required a PAS, or 45%. So far this year, only four of 16 PMAs and panel-track PMA supplements required a PAS.

As for sponsors' efforts to keep their PASs on track, Dabic remarked that "industry is making a huge effort. Out of 120 post-2005 studies, 117 reports have been received on time. This is really a great result." Of that number, 102 have kept with their timetables whereas 17 fell behind at one point or another with their completed PAS reports because the studies are or were moving more slowly than planned. In the last of the 120, the sponsor had yet to file a protocol for the PAS as of the date of the analysis, which was not made clear.

She broke down the studies by area, noting that cardiovascular had three studies overdue out of a total of 16, but the most conspicuous device area in terms of laggardly study reports was orthopedic, with five tardy studies out of a total of 17.

Dabic said that Medicare data could be a big help to device makers, adding that FDA and CMS are examining the infrastructure of data sharing for several purposes. "If we can show the value of going into CMS data, sponsors can do the same thing rather than sending postcards" to patients along with all the other labor-intensive follow-up to obtain the results needed to fill out a PAS data set.