BB&T Washington Editor and BB&T Staff Reports

FDA has let its enforcement and compliance intentions be known via warning letters on numerous occasions lately, and two recent FDA warning letters citing two firms regarding pre-market paperwork for their knee resurfacing systems suggest that FDA believes that its oversight of this class of devices has been less than exhaustive. In both cases, the agency notes that the recipient has no PMA or 510(k) for the device in question, but one of the devices does appear in the 510(k) database while the other seems absent from both the 510(k) and the PMA database at the FDA web site.

The July 27 warning letter to Biomet (Warsaw, Indiana) is all boilerplate other than the claim that the company has no 510(k) or PMA on file for the Signature personalized patient care system. The contours of this controversy were at the time unclear, however, given that Biomet's media relations efforts consisted only of statements to the effect that the company was working with FDA regarding the issue.

A similarly obscure situation surfaced less than a month later in the form of an Aug. 19 warning letter addressed to DePuy Orthopaedics (Warsaw, Indiana), alleging that the firm had no 510(k) or PMA for a similar product, the TruMatch personalized knee system. A search of the agency's databases for both 510(k)s and PMAs yielded no returns for the search terms “TruMatch“ or “trumatch.“ All the same, the company's web site still listed the TruMatch as an available device in mid-September.

Biomet's Signature system consists of the use of scanning software interface to be used with imaging technology, such for MRI or CT, along with patient-specific surgical guides to allow surgeons to reshape the femoral and tibial components of the knee joint. The idea is that the surgical guides help the surgeon to remove some bone and attach arthroplasty caps designed to require less removal of the native structure than is typically incurred for conventional full knee replacement. DePuy's TruMatch is a similar system.

The Biomet system is said to be the subject of a 510(k) obtained in April 2004 by Materialise (Leuven, Belgium), from which Biomet purchases the Signature. The FDA 510(k) database for April 2004 turns up two other clearances by Materialise, one of which is the April 16, 2004, clearance for the Surgicase traditional 510(k), said to be based on the predicate of the firm's SimPlant, which is cleared for use in dental applications. The second 510(k) for Materialise was the April 2, 2004, clearance for the Mimics, also based on the SimPlant predicate. The SimPlant 510(k) discusses an anatomically specific use, describing the software as being “for simulating/evaluating dental implant placement and surgical treatment options.“ However, neither the Mimics nor the Surgicase indicate a specific anatomical region for use.

The warning letter to DePuy is not clear on whether the agency believes the device requires a PMA or a 510(k) because, as was the case with the Biomet warning, FDA notes only that neither a PMA nor a 510(k) is on file. A statement from DePuy was no help in deciphering the situation, stating only that it is “reviewing the letter to understand the FDA's concerns and will respond to their request for information.“

One possible interpretation of the Biomet warning is that FDA is becoming more wary of 510(k)s citing predicates used in other anatomical locales. The language of the DePuy warning and the company's response make it impossible to know whether to extrapolate this interpretation to the DePuy warning, however. On the other hand, FDA is notoriously reluctant to allow makers of stents to bootstrap data from cardiovascular use to applications for stents for peripheral artery disease, and the anatomical specificity issue was one that cropped up in the controversial Menaflex 510(k) by ReGen Biologics (Franklin Lakes, New Jersey), which may go down in medical device history as the most controversial 510(k) application of all time.

CMS eyes more class IV VAD coverage

The Centers for Medicare & Medicaid Services recently proposed an expansion of coverage of ventricular assist devices (VADs) for use as destination devices in class IV heart failure, but appears to have no interest at present in expanding coverage to class IIIb patients. While the proposed coverage memo offers substantially less than the requester, Thoratec (Pleasanton, California) had sought, makers of VADs may come away with a slightly larger market than they currently have.

The proposal leaves intact the existing threshold of left ventricular ejection fraction (LVEF) at 25%. One proposed change would be to expand coverage to patients who have “failed to respond to optimal medical management,“ including beta-blockers and ACE inhibitors, “for at least 45 of the last 60 days,“ while the previous standard required failure to respond in 60 out of the 90 previous days. Alternatively, the patient would be balloon-pump dependent for 7 days or dependent on intravenous inotrope for 14 days, language that is not currently in section 20.9 of the coverage manual.

Another coverage tweak is that candidates will have “demonstrated functional limitation with a peak oxygen consumption“ of less than or equal to 14 milliliters per kilogram of body weight per minute, up by two milliliters from the current standard. However, the memo omits language appearing in the current coverage that says an alternate to the oxygen consumption is a “continuous need for intravenous inotropic therapy“ due to systemic hypertension, decreasing renal function or worsening pulmonary congestion.

The proposal does not explicitly make body surface area (BSA) a criterion for coverage whereas the current standard limits reimbursement to those patients whose BSA is 1.5 square meters. CMS makes note of a study by Musci, et al (2008) that “demonstrates no difference in mortality outcomes after VAD implantation for patients with low [body mass] compared to normal“ mass, and that a strong correlation between body mass and BSA allows study data to be “generalized to persons with low body surface area.“ CMS also remarks that FDA “no longer specifies a minimum BSA for implantation.“

IIIb coverage gaining acceptability

The decision to pass on the class IIIb issue for the time being might not ruffle many feathers among clinicians if some of the comments are any indication. For example, James Kirklin, MD, a cardiologist at the University of Alabama in Birmingham wrote in a March 23 comment that “the only substantive evidence relates to NYHA Class IV patients,“ but also that trial data does not provide “any basis of evidence for mechanical circulatory support in class III or IIIB patients.“ On the other hand, Richard Pierson, MD, of the University of Maryland Medical Center (Baltimore) remarked that the National Institutes of Health has proposed a trial of VADs for class IIIb patients and that “applications have been received in response.“ This, he said, “demonstrates that experts in the field believe that such a trial should be performed, and that centers are eager and willing to perform a pivotal study with NIH support.“

Douglas Mann, MD, director of cardiology at the Washington University School of Medicine (St. Louis) and the current president of the Heart Failure Society of America (St. Paul, Minnesota) told BB&T that the expanded coverage is more than appropriate. “As best as I can tell, they should cover what they say they're going to cover,“ he said, although he cautioned, “the definition of class IV [heart failure] is sometimes slippery“ because medication can resolve some of the symptoms seen in a patient upon initial diagnosis. He noted that most patients are in class IV on admission.

Mann also said it was not farfetched to argue that a broader coverage for class IV patients is overdue. “I think that the data were fairly robust for destination therapy for certain people who are not transplant eligible, but who are in and out of the hospital,“ he said, although he also pointed out that some of the problems with the first generation of VADs “were significant.“ He also commented, “the private payers have been doing destination therapy for a while. I think it is a little overdue.“

Mann said there are arguments for and against covering class IIIb patients. “The argument [for coverage] would be that these are people who are in and out of the hospital and whose cost of care is exorbitant,“ he said, stating further that their “quality of life would benefit from circulatory support.“

The argument against class IIIb use is that, like class IV, “the definition is slippery,“ which “opens the door to move too quickly to put in devices when medical management is indicated,“ Mann remarked. “Most of us who have experience . . . tend not to give up when things don't go right immediately,“ he stated of medical therapy, whereas less experienced physicians – and patients – tend to jump to surgical options.

“I think the smartest thing FDA has mandated is this registry for LVADs,“ Mann said, noting that if CMS is “persuaded by the aggregate data, they will come around and expand the indication“ to class IIIb. All the same, Mann mused, “predicting what CMS will do in the current healthcare climate is fraught with uncertainty.“

Mann had some words of praise for device makers. “I'm very excited about the device world,“ he said, although he added there is room for improvement in treatment of heart failure. He said he looks forward to devices that can be implanted “with the thought that we may be able to remove them. We see this nice marriage between devices and medicine“ that may bring this vision to fruition.

“Devices I thought would never work actually worked. It's been really rewarding to take care of patients with the armamentarium we have,“ Mann commented.

Morgan Brown, chief financial officer at VAD maker WorldHeart (Salt Lake City, Utah) told BB&T that the company is “excited with the opportunity to expand the market in destination therapy.“ However, he indicated he was not surprised that class IIIb did not get the nod.

“As expected they have not extended coverage to IIIb. As more data gets out there, they may reconsider coverage in that area,“ Brown observed. He continued: “It appears they've said there's not a clear definition of what a class IIIb patient is,“ but as definitions tighten up and device trials begin to demonstrate a benefit for such patients, “CMS will expand coverage in that space,“ he said.

FDA ponders no public notice for 510(k) rescissions

FDA held a webinar recently to deal with questions about the series of proposed changes to the 510(k) clearance process, and one development of interest is that FDA might not let industry know of its intent to rescind a 510(k) despite that any devices using it as a predicate may have to come off the market as a consequence of that rescission. Another potentially important development is that according to one member of the management team at the Center for Devices and Radiological Health, data found in patent applications may constitute information a sponsor should “reasonably“ know about, which could be boot-strapped into a requirement to disclose such information to the agency in 510(k) submissions.

Regarding 510(k) rescissions, Christy Foreman, director of the Office of Science and Engineering Labs at CDRH, said “our intent is to revisit that issue and consider additional regulations we need to clarify the process.“ However, she said that FDA has “not yet established whether that would be a public process or a behind-the-scenes process.“

The complicating factor behind this is that a rescission of a 510(k) that has served as a predicate for other applications could put the manufacturers of those products in the position of illegally marketing those products without any means by which they can be apprised of the situation. Alberto Gutierrez, director of the Office of In-Vitro Diagnostics at CDRH, said later in the call, “when a 510(k) is rescinded, those devices don't have clearance anymore and therefore are being marketed illegally.“

Gutierrez continued: “They have to either come back in with a 510(k) if they think they can provide some kind of update or a way to mitigate whatever problem was found, but as they are, they would be illegally marketed.“

The issue arose again later in the webinar, and Foreman offered more detail. She said, “we also have to look at the basis of the decision“ to rescind, giving the example of a device filing that included fraudulent information. “Many of our rescissions have been related to fraud,“ she commented, adding that a decision to rescind would not necessarily migrate to the downstream devices assuming “those three subsequent devices do perform as intended.“

Any safety issues related to the predicate “would probably go to all those devices that exhibit the same issue,“ Foreman observed, but the unanswered question is that of whether CDRH would give itself time to review data for those downstream devices if it felt the need to rescind the predicate was urgent.

Jonathan Sackner-Bernstein, associate center director of CDRH for post-market operations, said during a discussion of the proposed requirement of more exhaustive data submissions for 510(k)s that “there were often surprises that came up as a product that came up under review“ or in post-market experience, “so by asking for as much data and information as a manufacturer would reasonably be expected to know, we believe we can avoid some of those surprises.“ He gave the example of data found in patent applications as the kind of data the agency might see as falling under such a requirement.

Sackner-Bernstein later attempted to finesse his comment, claiming it “was not intended to say we want patent applications submitted. Rather it was pointing out that [such information would appear in] a document that the sponsor had in their possession that disclosed study result that were not made available to us at the time of submission.“ He said, “certainly they would know about studies they performed in support of a patent application. That's what we're presenting as a recommendation in these reports, that kind of information would come“ under a requirement for full disclosure.

As for the searchable online database for 510(k)s, Jeff Shuren, MD, director of CDRH, said the availability of such data would allow patients, doctors and industry to “see why we made a particular decision“ and that such a database would “also include pictures or a schematic of a device.“ He assured industry, however, “we're not proposing that these will be blueprints . . . but instead a schematic or a photograph of the device.“ The database would also include labeling to help sponsors determine the appropriateness of that device as a predicate.

Regarding how the CDRH action might affect 510(k) applications made to the Center for Biologics Evaluation and Research, Shuren said, “this pertains only to the CDRH program.“

On the subject of a recent study said to have demonstrated that the 510(k) program has not produced a conspicuous number of failed devices, Shuren said the study “tried to look at one particular measure,“ namely class I recalls, which he characterized as “a limited safety measure. It's helpful,“ he said, but remarked, “we're seeing that the program is becoming challenged.“

“The wheels are starting to rattle on the cart,“ Shuren claimed, adding that while the percentage of recalls “might not be a very high number,“ the question for FDA is “have we done a perfect job on safety? No.“

Shuren also said that changes to the third-party 510(k) review program are intended “to make optimal use of the third-party program“ and to address the fact that “the quality of the third-party reviews was highly variable.“ He said that almost half the applications that went through a third party ended up with an FDA review to obtain additional information. The idea here, he said, is to more clearly determine which technologies should and should not go through third parties.

FDA could reclassify two class III catheter types

FDA will probably never get any credit for being the fastest-responding of all federal agencies, and the announcement in September that it will reclassify some coronary artery catheters from class III to class II did nothing to dispel doubts about the agency's responsiveness to advisory panel recommendations.

In the Sept. 8 edition of the Federal Register, FDA states that it will reclassify two types of catheters for cardiovascular use from class III to class II, and released a draft guidance for the concomitant special controls. The FR notice states that it received a reclassification request in September 2000 from an entity the notice describes only as “COOK,“ which turns out to be a reference to Cook Medical (Bloomington, Indiana), and that an advisory committee hearing in December that year led to a recommendation that FDA allow angioplasty-only catheters to henceforth go through a 510(k) review.

FDA indicates that data collected in the decade following the panel suggest that the risks associated with catheters for stent deployment “are similar enough to the risks associated“ with straight angioplasty catheters (when dealing with de novo lesions) that special controls are adequate to deal with those risks. The agency also notes that it sees as unfounded the panel's conclusion that active post-market surveillance may be necessary for angioplasty catheters, a conclusion implicitly carried over to stent-deploying catheters.

Among the features of the proposed special controls is biocompatibility testing, which FDA recommends be done using ISO 10993, although data from a predicate can be used so long as the predicate uses the same materials and processes and is intended for the same duration of contact. FDA recommends animal testing with non-pregnant guinea pigs with concurrent controls or controls tested within three months of tests on the models.

The four-corners test paradigm holds for this guidance, as it did for the guidance on bench testing for bare metal stents, but this will not be a perfect four-corner testing regime. Balloon lengths of 10 mm and 40 mm can be employed to evaluate diameters of 2 mm, but the maximum length for a diameter of 4 mm is 30 mm. The largest diameter recommended to test the 40 mm catheter is 3.25 mm. Interested parties can e-mail FDA at dsmica@fda.hhs.gov and refer to document # 1608 for copies of the guidance.

Steve Ferguson, CEO of Cook Medical, confirmed to BB&T that “the petition was filed by Cook Medical,“ but he said the announcement “came as a surprise to me.“ As to whether anyone with Cook has had any contact with the agency on the matter over the past couple of years, he said, “not to my knowledge.“

“When we filed this petition, we were filing to demonstrate our belief that after a certain period of time, the risk profile and knowledge about the device means they should be down-classified,“ Ferguson said. He noted further, “we think reclassification ought to be a routine part of the FDA process.“

Ferguson said he does not expect to see a flood of catheter 510(k)s coming at FDA. “I think that this doesn't change“ the market, he said. Ferguson also said that industry's lack of attention to reclassification issues is to some extent a matter of self-protection. Such a request “gets into the issue that the PMA process is a protection for market share, so there's a certain amount of reluctance to engage in that,“ he mused.

Still, FDA's failure to routinely review the device inventory under its purview is a frustration of congressional intent, Ferguson stated. “At one point in time, [Congress] gave FDA a period of time to publish a list of devices“ for down-classification, but the agency never came up with the list. He made reference to the early 1990s as the time frame when Congress first expressed such an interest, about the time Congress passed the Safe Medical Devices Act of 1990.