BB&T Washington Editor and BB&T Staff Reports

Negotiations between industry and FDA for the device user fee schedule have traditionally been conducted behind closed doors, but this next round won't be such a private affair. Prior to the start of those negotiations, however, the process was already different as demonstrated by a public meeting the agency held in mid-September. As significant for industry, however, may be that Jeff Shuren, MD, director of the Center for Devices and Radiological Health at FDA, also told attendees that review times for 510(k) filings may be affected by the ongoing restructuring of the 510(k) program, but he also said the agency is interested in feedback from all stakeholders, including a variety of public-interest groups.

Shuren said the user fee program has allowed reviewers “to reduce the time it takes to review 510(k) submissions“ substantially, adding that “nearly 500 more 510(k)s receive a timely review each year“ than prior to the Medical Device User Fee Modernization Act (MDUFMA). However, he seemed to signal an elevation of fees with the remark that user fees “currently account for less than 20% of funding for CDRH activities covered by user fee program.“ He also hinted that other parties will have a lot of influence on the user fee schedule with the comment, “we look forward to strengthening our relationship with all stakeholders throughout the reauthorization process.“

Among the public health advocates who spoke at the meeting was Diana Zuckerman, President of the National Research Center for Women and Families (Washington), who said, “on some level, we would not care at all how high or how low user fees were if appropriations were higher.“ Still, she said, “we think the user fees are too low.“

“We also think there's no good reason why some of the largest corporations in the world . . . that pay very large user fees“ for drug applications “pay much-much, much-much, much-much less“ for device applications, adding that the “fees for the 510(k)s are especially egregious,“ given the relatively low sums required. Zuckerman stated further that the largest firms should pay for “the entire cost of a 510(k) review.“

“Even the much larger PMA user fees are disproportionately low compared“ to fees charged for new drug applications (NDAs), Zuckerman stated, arguing that the fees and the quality of the reviews “should be similar“ between the two application types. She further made the case that the lack of a requirement for a pre-clearance inspection is “something that has to change.“ FDA's recommendations for the 510(k) program include a pre-approval inspection (PAI) for clearance applications.

Boston Sci approved for expanded CRT-D indication

FDA announced in late September that it has approved the application for expanded indications for cardiac resynchronization therapy/defibrillation (CRT-D) filed by Boston Scientific (BSX; Natick, Massachusetts), an approval the company invested millions to win.

The study BSX used to support the application was MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy), which randomized more than 1,800 patients to a CRT-D unit and an implantable cardioverter defibrillator. The results of the study are that CRT-D cut the risk of death and heart failure in patients with blocked left bundle branches (LBBB) by 57% compared to patients on implantable cardioverter defibrillation alone. Roughly seven in every 10 patients in MADIC-CRT exhibited symptoms of LBBB.

BSX gained a nod from the circulatory systems advisory committee earlier this year for the expanded indication to a large number of patients with class II heart failure and a small group of patients in class I, namely those with left bundle branch block who have normal sinus rhythm and QRS intervals of at least 130 milliseconds. The clinical trial data scored superbly on safety scores, with 85% of patients on CRT-D avoiding system-related complications compared to the target of 70%. More than 90% of controls avoided those complications, but much of the difference was due to complications incurred with the use of the extra lead needed for pacing of the left ventricle.

The news may prove helpful to BSX as it tries to recoup its investment in Guidant, which started the MADIT-CRT study prior to BSX's acquisition of Guidant in a bidding war with Johnson & Johnson (New Brunswick, New Jersey) in 2006. All the same, the impact of the announcement on the firm's shares at the New York Stock Exchange was negligible inasmuch as the market had already factored the expected approval into share prices. A Sept. 17 statement by Piper Jaffray (Minneapolis) described the news as “an incremental positive“ for BSX and for “the market as a whole,“ but the gains from sales of CRT-D units, which are generally pricier than ICDs devices, may be at least partly offset by widely anticipated price pressures.

As is commonly the case, the approval comes with post-market study requirements. According to a Sept. 16 statement at the FDA web site, BSX must conduct two post-approval studies (PASs), one of which will “evaluate complications and long-term mortality benefits of CRT-D in patients with left bundle branch block,“ although the company will be able to use the National Cardiovascular Data Registry to handle that study. The second study entails further follow-up of MADIT-CRT enrollees twice a year for five more years “to assess long-term mortality benefits“ of the two device types.

Gordon Tomaselli, MD, an electrophysiologist and the chief of cardiology at Johns Hopkins University School of Medicine (Baltimore) told Biomedical Business & Technology that while there are a number of patients who can benefit CRD-T, he does not anticipate a flood of CRT-D units finding their way into patients' chests in his practice.

“I don't think there's all that much“ need for this class of device compared to some classes of electrophysiology equipment, Tomaselli said, adding, “the downsides are that you have to put in another lead, and there are potential complications,“ as the trial demonstrated.

The electrophysiologist said clinicians as a whole are not utterly skeptical about CRT-D, but not entirely sold, either. “The reigning thought is that if you have left ventricular (LV) dysfunction and a wide QRS interval, and [the patient's CHF] is mild and you don't pace, you may actually be fine,“ Tomaselli said, pointing out that the severity of congestive heart failure often abates upon the commencement of medical therapy. On the other hand, he remarked, “if the patient has a problem down the line, you can always put in an LV lead.“

FDA, CMS try to drum up interest in parallel review

The idea of parallel device review between FDA and the Centers for Medicare & Medicaid Services is a perennial that never blooms, but an announcement in the Federal Register in September indicates that hope for parallel review persists.

Some of the issues cited in the FR notice are whether CMS should be able to review a drug or device for off-label indications and whether CMS should be able to unilaterally undertake a parallel review regardless of the sponsor's wishes. The sticking point here is that premarket applications are confidential while CMS is bound by statute to disclose any coverage analyses it has undertaken. In this scenario, firms could find their applications uncloaked against the sponsor's will.

The FR notice also suggests that parallel review may drive up operating costs at CMS, adding that further user fees may be needed. Given the prospects of higher user fees based on comments heard during the user fee forum, this is another feature likely to blunt industry's appetite for parallel review.

Randel Richner, President of the Neocure Group (Newton, Massachusetts), told BB&T that the lack of progress on the idea is “all about the problem that the data that CMS wants are different from the data FDA wants.“

“There's a lot of hyperbole and rhetoric around it,“ Richner observed, but cautioned that “the reimbursement pathway . . . is heavily dependent on coding and payment systems that don't match with the timings associated with the FDA approval process. It's going to be very difficult to align those timings.“ As things currently stand, “you cant even begin to start the process with CMS until you get FDA approval,“ she remarked.

Richner acknowledged the tension between a lack of certainty as to FDA's approval of an application and the notion that a larger, more expensive study would likely be needed to cover both agencies' requirements. “I guess it is a risk you would have to take, but I believe there are ways you can probably satisfy the evidence requirements for CMS that might not require that you double what you're doing for FDA,“ she said. She added that in some cases, “I think people are going to have to invest“ in the studies needed to cover both bases.

Richner pointed out that devices “that have to go through a national coverage determination or new technology pass-through are those that are innately going to be different and more breakthrough than“ other applications. She advised that sponsors of such products “should be prepared to invest in those kinds of studies.“

All the same, the disclosure that goes with an application for coverage remains problematic for a pending PMA, Richner noted, a tension that she described as “a severe problem.“ She noted that she and a client had recently met and discussed a coverage request, remarking “we were extraordinarily reluctant to share the design of the [pivotal FDA] study with [CMS] for this very reason. It's a highly competitive field“ and “even meeting with CMS would be an indicator to the competitor as to where they stood.“

AdvaMed reviews class IIb; FDA ponders changes

FDA had originally promised that it will deliver a proposed final set of changes to the 510(k) program by the end of September, but the Advanced Medical Technology Association (AdvaMed; Washington) has staked out a definitive position on the matter in a Sept. 21 statement that leaves no doubt as to where the association stands on the matter.

Janet Trunzo, executive VP for technology and regulatory affairs at AdvaMed, said in the statement that the association's revamped proposal, which AdvaMed rewrote “to clarify our position and to distinguish it from“ the agency's conceptualization of a class IIb for some 510(k) devices, includes a recommendation that the agency stick to “a small, focused subset of class II devices that may require additional information to support a substantial equivalence determination.“

Trunzo remarked that AdvaMed is of the view that any such change would require a rewrite of the statute. The association proposes that the individual elements of a “small, focused subset“ of devices that would initially be subject to “enhanced information requirements“ might be moved off the list “as more experience is gained and the use of each device becomes well established.“

Among the device categories AdvaMed believes might be included in this subset would be permanent implants and devices that could be described as life-sustaining and life-supporting, although not all devices that could be described as such would necessarily be subjected to greater scrutiny. Among those that would be left off the list under AdvaMed's rubric would be those whose uses and technologies are well characterized as well as those with solid safety records and are the subjects of updated standards, guidances “and/or special controls that have proven effective.“ Two examples would be sutures and dental implants.

Trunzo also suggested that the enhanced informational requirements could be limited to the results of pre- and post-market clinical investigations “or other studies . . . of a justifiably comparable device.“ However, she also indicated that FDA might require that manufacturers submit the final product label at the time of clearance and require that manufacturers submit reports at three-year intervals covering design and labeling changes that ordinarily would not trigger the need for a new 510(k) filing.

The AdvaMed proposal makes the argument that the agency's concerns regarding predicate creep and the use of split and multiple predicates “all become irrelevant if there are specific evidentiary requirements that must be met regardless of the relationship of the new product to a predicate.“ Trunzo argues further that the use of “additional submissions requirements (special controls)“ would clarify the evidence that manufacturers need to submit to gain product clearance, provide greater consistency in decision-making, and “improve public confidence in FDA's decisions.“

510(k) changes may foster 'tremendous confusion'

The Advanced Medical Technology Association (AdvaMed; Washington) has offered a more complete response to FDA's proposed changes to the 510(k) program in early October after penning a critique of the proposal to split class II devices into two arms, a notion the association continues to assert would require an overwrite of the statute. AdvaMed hosted an Oct. 6 conference call during which officials at the association said that while there are points of agreement and disagreement with FDA on the full program of changes, the sheer breadth of those changes are sure to create “tremendous confusion“ and substantially inflate already-expanding 510(k) review times.

Janet Trunzo, the association's executive VP for technology and regulatory affairs, said that “given the strong safety record“ of the device clearance process, FDA would be well advised to “focus on changes that are targeted and have a corresponding public health benefit and strengthen the current system.“ She stated that AdvaMed supports 16 of the proposed changes as spelled out by FDA, and support 27 of them “with some modifications.“ AdvaMed, she said, flatly opposes 22 of the proposed changes.

All the same, Trunzo claimed that “the sheer volume of proposals, if all were actually implemented, would create tremendous confusion“ for reviewers and manufacturers, and would create sufficient additional work for the agency that it would “slow down product approvals for an extended period.“ She suggested that FDA “find a solution that works for the agency, for us and most of all for the public health.“

“Our bottom line is fix what needs fixing first,“ Trunzo said, noting that changes that address reviewer training and the de novo process as two examples, “are particularly welcome and would help to deal with the problems we're facing today.“

Trunzo said one concern at AdvaMed is the notion of redefining of fundamental terms, including a proposed rewrite of the meaning of the term “substantial equivalence.“ This, she reminded, would be achieved by consolidating the terms “intended use“ and “indications for use,“ a move she argued would “actually add confusion to the process and increase delays.“ Trunzo stated that such a move “would not be appropriate,“ but she offered no alternatives.

Trunzo noted that CDRH is considering a limit on the use of multiple and split predicates, which she said would “unnecessarily limit the range of evidence used“ to support an application and could “unnecessarily complicate“ reviews.

Regarding the off-label use issue, Trunzo said FDA would seek “the authority to consider off-label use when determining the intended use“ if the agency's reviewers suspected that an off-label use was the sponsor's actual intended use of the device. Such a move, she said, is superfluous because the agency already has the authority to cover such situations.

On the matter of the agency's interest in greater authority to rescind a 510(k), Trunzo asserted again that the agency is already equipped to deal with such concerns, stating FDA “has extensive post-market tools to remove devices . . . it deems dangerous.“ She made the case that a more extensive use of rescission “could have significant disruptive domino effects“ because the regulatory status of devices cleared using the device in question as a predicate “could be jeopardized“ even if the concerns about the removed device don't apply to those other devices.

Trunzo again took up the class IIb question, stating that a split of the class II category comes with substantial hazards. “While AdvaMed supports identifying a small subset“ of devices for which extensive data requirements might apply, she said, “we do not support the class IIb category proposed by FDA in this report.“ She observed that the FDA proposal“appears to include a much broader category“ of devices than AdvaMed sees as necessary, and is “unreasonably burdensome.“

FDA, industry will avoid lawsuit over class IIb

The Advanced Medical Technology Association (AdvaMed; Washington) has staked out a position on the changes FDA has proposed for the 510(k) program, but while the association agrees with some of the changes, AdvaMed argues that the agency needs a change of statute to impose the split of class II devices that is part of the suggested changes.

However, the certainty of that view is not universally held, as an interview conducted by BB&T, held with Howard Dorfman of the New York law firm of Ropes & Gray, made clear. Dorfman said that while one read of the statute might support that idea, there are other factors to consider, including whether FDA and industry want to get into a legal tussle. All the same, he also pointed out that the agency seems determined to make changes to the program and will attempt the split of class II devices regardless of whether one legal scholar or another sees the move as legally tenable.

“I think that the question of whether FDA has the authority is certainly open to debate,“ Dorfman said, adding that “a strong legal argument could be made on both sides.“ Dorfman acknowledged that the views of Ralph Tyler, FDA's chief counsel, may play a role in how aggressively FDA decides to pursue this issue.

Tyler argued at this year's annual meeting of the Food and Drug Law Institute (Washington) that FDA should not observe the traditional reticence to move into areas not spelled out in the statute, but should fill any gaps in the statute the agency believes is necessary to ensure public safety. “Based on Tyler's hints,“ Dorfman observed, FDA “will be aggressive,“ in this pursuit, although he speculated “that there probably will be some negotiations and discussions [with industry] with regard to what the definition of IIb will be.“

Whether device makers would undertake a public battle against FDA – let alone whether it would prevail – is completely up in the air, Dorfman indicated. He suggested also that neither party might be keen on seeing the issue hammered out in Capitol Hill hearing rooms. Part of the reason for industry's reluctance to engage in a public spectacle is that when it comes to patient safety, any position that seems to argue another viewpoint is probably tantamount to a grab of the third rail for device makers.

“It will probably be in the interest for both manufacturers and FDA to resolve the issues amicably and without the necessity of going to litigation,“ Dorfman commented.

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