BB&T Washington Editor and BB&T Staff Reports

A January investigation by the U.S. Department of Justice into industry's influence on prescribing patterns for implantable cardioverter defibrillators by cardiologists will focus on physicians as well as manufacturers, and the Heart Rhythm Society (HRS; Washington) has agreed to serve as an advisory body to the DoJ in its investigation. While manufacturers brace for a raft of bad news on this scenario, a financial analyst says the effect will be discernible, but manageable.

The ICD prescribing issue was underscored by an article appearing in January in the Journal of the American Medical Association by Sana Al-Khatib, MD, of Duke University Medical Center (Durham, North Carolina), et al, which asserted that slightly more than 22% of all ICD implants were for off-label diagnoses. Another foreshadowing of this development was the agreement reached between federal authorities and St. Jude Medical (St. Paul, Minnesota), in which the firm agreed to pay $16 million to settle allegations it paid physicians to use the firm's ICDs.

HRS said in a Jan. 21 statement it “has agreed to assist in an advisory role“ regarding the guidelines, but while the statement notes that ICDs are “99% effective in stopping life-threatening arrhythmias and are the most successful therapy to treat ventricular fibrillation,“ the primary driver of sudden cardiac death (SCD), the association also notes that it supports multi-center clinical trials “to better define the safety and efficacy“ of ICDs.

The problem for HRS is that one of its past presidents, Anne Curtis, MD, is on record as stating that the expanded use of ICDs to ward off sudden cardiac death is justified due to the low probability that the patient will live long enough to be treated otherwise. In an interview with BB&T at the society's annual meeting in 2006, Curtis said that rather than being overused, “you could argue that we're not implanting enough in the United States“ and that implant rates were “still well below“ a level that would confer a benefit. Curtis posed the question of “what is our tolerance?“ for not implanting a patient who displays only a low risk of SCD but who nonetheless suffers an event.

In a Jan. 24 report filed by Wells Fargo Securities (New York), the firm's analysts concluded that ICD makers “may have to pay manageable fines for their communications with physicians“ on Medicare reimbursement, but also that some hospitals will have to pay fines as well. The report notes that the analysts believe that the HRS announcement “will lead to a near-term correction of about 10% in the U.S. ICD market“ because electrophysiologists “will more carefully select patients to make sure they are within guidelines.“

Advisory panel floats 'class III lite' AED category

The Jan. 25 hearing of the circulatory systems advisory committee regarding a potential reclassification of automated external defibrillators (AEDs) was replete with different ideas about whether these devices should be routed through the PMA pre-market mechanism rather than the 510(k) channel. Even FDA's staff exhibited a difference of opinions as to whether PMAs should be required of this class of devices, marking a rare event in the recent history of advisory committees for medical devices.

One of the key issues was that of how to interpret the information enclosed in – or omitted from – medical device reports, but another factor that played a role in shaping the discussion was the fact that about two thirds of purportedly failed AED units are not checked to determine the cause of the failure. Most failures are picked up during routine tests rather than actual use.

The panel grappled with issues such as how a clinical trial would deal with informed consent for patients who are in no position to grant consent as well as a potential shortage of AEDs should the PMA route slow the entry of devices to market, and the upshot of the deliberations was that FDA consider a “class III lite“ category to circumvent some of these issues.

Roberta Sullivan, a medical device report analyst at CDRH, told the panel that the most common device failure mode over the past six years (2005-2010 inclusive) was that the device displayed an error message disallowing further operation of the device. This problem accounted for more than 8,000 such malfunctions and represented about 40% of the total listed by FDA, but the error message is often not specific enough to determine a cause, Sullivan said. “The second most commonly reported problem was a failure to power up,“ she noted, although this was “almost always the result of component or sub-assembly failure“ rather than a failure of the battery.

“Total reporting doubled between 2005 and 2010,“ Sullivan continued, although she acknowledged that “the reason for the reports can be debated.“ She acknowledged that among the potential contributors to this uptick were more frequent use and more exhaustive reporting. “Our preliminary recommendation is that AEDs be classified into class III and be subject to“ PMA requirements, she said.

John Sapirstein, a medical officer at CDRH, offered a different view, although he characterized his opinions as an alternative view, “not a dissenting opinion.“ He remarked on FDA commissioner Margaret Hamburg's statement in a journal article that FDA “may have to be a little more flexible“ in the coming years to adapt to the pace of scientific discovery. Among the downsides to a PMA route for AEDs cited by Sapirstein was that the rate of technological change “might outstrip the time-frame of a PMA review,“ leading to a pronounced technological lag.

The PMA route “is a relatively inflexible paradigm,“ Sapirstein asserted, proposing that “the appropriate use of regulatory authority under class II“ would effectively deal with FDA's concerns.

Sapirstein noted further that a more stringent approach “may be creating an environment in which there is a disincentive“ for small firms, which make most AEDs, “to come forward“ with devices that offer improvements over the current state of the art.

Paula Lank, VP for clinical and regulatory affairs at Physio-Control (Redmond, Washington) argued for a class II designation. “Given the ubiquity with which AEDs are distributed in the U.S.,“ she said, a slowdown in distribution might have a negative impact on availability. FDA could reclassify and strengthen the 510(k) process “with the establishment of appropriate special controls,“ Lank continued, which she pointed out “would not preclude FDA from requiring PMAs for new AEDs“ should those units raise “new questions of safety and effectiveness.“

“The vast majority of recalls are associated with purchasing controls and design controls, both of which can be mitigated with the adoption“ of special controls, Lank said. She noted that only 4-8% of AED recalls dealt with manufacturing issues. “Based on that, FDA's proposal to move to PMAs . . . is unnecessary and unduly burdensome.“ She asserted that a requirement that should the PMA requirement come into play, “there will be a substantial delay in getting devices to market“ and that “it's probable that the cost of these devices will increase.“

The first question FDA posed to the panel for discussion was whether device malfunction is the biggest issue. After brief discussion, panel chairman John Hirshfeld, Jr. MD, of the University of Pennsylvania School of Medicine (Philadelphia) reported that the panel concluded, “safety and effectiveness . . . are the principal safety issues for this device,“ but he added, “many of these devices are dormant for an extended period of time before being called into action,“ and that there may be related quality issues that have to be addressed.

When the panel took up the question of whether the device should continue as a 510(k), Hirshfeld summarized: “There's a sense that there's an advocacy for class II,“ based on “a relatively mature technology and really not subject to clinical questions about efficacy,“ but he noted that the panel also saw “a number of signals that raise questions about quality and reliability.“ He said that the aggregate effect of panel opinions “is really sort of a class 2.75.“

FDA had earlier in the day suggested that among its options might be to keep the devices in the 510(k) channel, but to add pre-clearance inspections, annual reports and reports on changes to the device that would be closer to those required for PMAs in order to maintain that status. Seemingly in reference to that proposal, Hirshfeld, said, “it's possible that what the panel is suggesting is a class III lite,“ which would include post-market surveillance activities.

Panel recommends a wider indication for Acculink

FDA and the Centers for Medicare & Medicaid Services sometimes put across the impression that they are working together, such as when they float ideas about parallel regulatory and reimbursement review, but CMS may find itself at loggerheads with FDA if the latter agency follows the advice offered by an advisory panel this week.

The circulatory systems advisory committee met on Jan. 26 to go over the application by Abbott Vascular (Abbott Park, Illinois) to expand the indication for the firm's RX Acculink carotid artery stent from patients who are at high risk for a carotid artery endarterectomy procedure to those who are at standard risk from the surgical fix for carotid artery stenosis. The application includes the use of the company's embolic protection device, the RX Accunet embolic protection device, and the panel felt that the data from the CREST (Carotid Revascularization Endarterectomy vs. Stenting Trial) study were sufficient to vote 7-3 (with one abstention) that the data suggest a reasonable safety and efficacy profile for this patient population.

The vote will put medical reviewers at CMS on the spot if FDA follows suit. CMS sometimes covers a device for an indication that FDA has not approved or cleared despite FDA's distaste for the practice, but denial of Medicare coverage for an FDA-approved device would put CMS in a delicate position, especially given the support for coverage by medical specialty societies. Still, it should be pointed out that some time may pass before FDA announces a decision, which will give CMS only slightly more wiggle room.

Abbott posted a Jan. 26 statement on its website stating that stenting and surgery “had similar safety and long-term outcomes for patients with symptomatic and asymptomatic carotid artery disease who were at standard surgical risk,“ the population CMS has been reluctant to cover. The Abbott statement goes on to state that the CREST data, accumulated over 10 years, covered more than 2,300 standard-risk patients “with symptomatic and asymptomatic disease“ and that the study arm “demonstrated non-inferiority to surgery for the primary composite endpoint of death, any stroke and myocardial infarction within 30 days of the procedure plus ipsilateral (same side) stroke from 31 to 365 days.“ Although Abbott acknowledges “7.1% of stenting patients and 6.6% of surgery patients experienced an event,“ the difference, Abbott states, was statistically insignificant.

CMS last took up the reimbursement side of this device and indication in 2009 and came out with a decision to leave matters as they were, namely to pay only for high-risk patients who demonstrated occlusion of 70% or more, although the agency offers clinical trial coverage for two other groups, namely asymptomatic with occlusion of 80% or more and high-risk symptomatic patients whose carotid arteries were at least half blocked. That was not the first review at CMS, but the data then available had many in the clinical community up in arms over the agency's reluctance to cover moderate-risk patients.

Chris White, MD, director of the Ochsner Heart & Vascular Institute (New Orleans), told BB&T at the time that he found it mystifying that CMS unilaterally undertook the review in 2009 only to leave the status quo intact. In a January interview with BB&T, White said an FDA decision probably would make the CMS hot seat a bit hotter on this issue.

White started the interview with a caveat, specifically that while “we have to have FDA first, CMS has not followed them before.“ All the same, he opined, “its going to be harder and harder for CMS to dodge this one.“

White indicated that some medical specialty societies were, as the saying goes, conspicuous in their absence, at least where the open public hearing was concerned. White is the president-elect of the Society for Cardiovascular Angiography and Interventions (SCAI; Washington) and remarked, “typically when we [speak at a panel meeting], there are several other specialty societies, but yesterday we were the only group that spoke.“

As for the panel's reaction to the CREST data, White said, “I think they were very impressed with the learning curve“ for surgeons, an observation tied to the fact that the data for safety trended better over the 10 years. “After 2005, there was a distinct learning curve“ related to cutting down on stroke in the stented patients. “One of the panelists said the learning curve“ made him “much more comfortable,“ White related.

White made the case that Medicare might have saved a few dollars over time on the patients who go the endovascular route, stating that many such patients are handled on an out-patient basis. While the time allocated in the operating room favors stenting only slightly, the surgical patient is not going home that day under any circumstances. This group, he said, is subject to “an obligatory couple of days' stay“ in the hospital, generating lots of in-stay costs.

Study says device recalls in U.S., EU, similar

The medical device industry has produced a number of studies of late in an effort to rebut allegations that FDA's regulatory and enforcement activities are deficient, and the Advanced Medical Technology Association (AdvaMed; Washington) held a conference call in January to report on the results of a study of device recalls in a continuation of that effort. The report's results were compared to a study of device recalls in the U.S., and the results suggest a rough parity in device safety despite the perceived device lag in the U.S.

The report, commissioned by AdvaMed and conducted by the Boston Consulting Group (BCG; Boston), notes that there is no centralized authority in the European Commission nations for tracking device approvals and that there is “no comparable public database that captures all medical device safety recalls in the EU as FDA does in the U.S.“

Simon Goodall, a partner and the managing director at BCG, said crafting a recall data set for Europe for comparison to U.S. data “is not an easy thing to do because in Europe, there is no central body“ that collects such data. All the same, he said, “we found . . . the annual number of recalls in Europe is almost identical to the U.S.“ even after controlling for device type. Furthermore, “we didn't' find any evidence to support the hypothesis that the EU approach to device approval led to any unsafe devices,“ Goodall noted.

The study report notes that BCG employed “a four-phase approach“ to compiling the EU data, including an analysis of national competent authority reports (NCARs) filed between 2005 and 2009, with 85% of those filed in just five nations, the UK, France, Germany, Ireland, and Switzerland. The total of slightly more than 5,000 NCARs was winnowed for duplicate reports, and any reports for a low probability of harm to the patient were dropped. After further sorting to match the severity of the EU actions for comparability to FDA recall actions, the list came to 126 recalls.

According to the BCG report, 54% of the recalls in the EU were for post-market issues whereas the remainder of 46% were for pre-market issue, which the report notes is a nearly identical pair of figures arrived at by Ralph Hall of the University of Minnesota Law School (Minneapolis), who reported last year that about 55% of U.S. recalls were for post-market issues and 45% for pre-market issues.

Using Hall's data as a comparator database, the BCG report states that the absolute number of class I recalls between 2005 and 2009 were nearly identical for the U.S. and the EU at about 21 per year, and that “the distributions across therapeutic areas and the reasons for recall are also nearly identical as well.“ Recalls of cardiovascular devices and devices falling into the category of general hospital devices accounted for most of the recalls in both geographic areas, although anesthesiology equipment rated higher in Halls' numbers than orthopedic devices whereas the BCG report discerns little difference in EU recalls for these two categories.

One of the more conspicuous charts appearing in the BCG report dealt with class I recalls by year. The data provided by BCG indicate that EU authorities announced about 23 recalls in 2005, which bumped up to 32 in 2006. Class I recalls then plummeted to seven the following year and rebounded only slightly to nine in 2008. In 2009, however, EU class I recalls skyrocketed to 41.

FDA numbers roughly track this parabolic effect, although with a burp in the middle. U.S. recalls totaled 27 in 2005 and fell to 16 in 2006. The class I recall total in 2007 rebounded to 23, but fell to 13 in 2008. The five-year high in the U.S. was in 2009, when FDA reported 35 class I recalls.

Simon said after explaining the numbers in more detail, “the interesting thing is that we're matching up recalls and if there are more devices approved in Europe, there would be more recalls“ assuming a similar rate of device safety issues. However, he acknowledged, “without a central body, it's impossible to say whether there are more devices in Europe.“

FDA offers no extra resources for device program

The Center for Devices and Radiological Health (CDRH) unveiled its Medical Device Innovation Initiative in February to substantial fanfare, but the downside of the idea is that while the Center for Devices and Radiological Health will open up a fast-track for high-priority medical devices, CDRH will enjoy no additional resources to keep other, lesser-priority devices moving through the premarket pipeline.

Jeff Shuren, MD, the director of CDRH, made note of the recent report by PwC (New York) about the leadership in device innovation enjoyed by the U.S., and he remarked that the American leadership in med-tech “didn't happen by chance,“ although he said the U.S. “won't remain the world's leader for long“ without innovative oversight.

Shuren hinted at the possibility of a fast-track for such devices at a November 2010 appearance at the American Enterprise Institute (AEI; Washington), stating at the time that FDA's interest was in devices that offer “the biggest bang for the buck“ in terms of public health. At the time, law professor Ralph Hall of the University of Minnesota Law School (Minneapolis) raised the question of “who decides what is innovation?“

Shuren noted that a number of ideas are embodied in the innovation program, remarking, “the most exciting is our proposal to establish“ an expedited review program “to target unmet medical needs.“ To that end, Shuren said CDRH would “commit time and resources much earlier in product development“ and will “choose and monitor qualified“ applications via the CDRH science council.

Shuren said CDRH would “assign a case manager“ for each product in the accelerated review program “and establish a primary review group“ to help each application along. Within 120 days from acceptance of such an application, CDRH reviewers “will develop a memorandum . . . that describes a road map“ for assessment and review of the application.

“The key features . . . will be resolving“ safety and efficacy issues early in the process, Shuren remarked, noting that clinical trial protocols will be developed jointly by the sponsor and CRDH staff. “By front-loading our resources, we can cut the time it takes“ to get these high-priority devices to market.

As for the other parts of the initiative, Shuren noted that CDRH will work to establish a “robust research infrastructure in this country“ for regulatory science, including an initiative to “creat[e] a voluntary third-party certification program for medical device test centers.“ He said FDA will recruit universities and others “in a competitive way“ that will provide industry with a resource for testing and assessing so that “we can find and fix problems earlier.“ Shuren also said CDRH will work to develop a core curriculum for college degree programs in regulatory science.

Shuren said the initiative also includes some effort to clear up the issue of what sort of clinical data gathered from outside the U.S. (OUS) might be acceptable in FDA's eyes. He said the agency will offer “clear guidance on how sponsors can best leverage data and research“ from OUS sources, although he offered no anticipated date for publication.

As for the expected impact on device application turn-around goals, Shuren remarked, “making a significant investment in the Innovation Initiative is a luxury we cannot afford,“ but “we can lay the foundation for the new paradigm“ and “take just a handful“ of applications.