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510(k) Caution Engulfs FDA—Predicate Choices Questioned

As FDA’s multitiered assessment of its beleaguered 510(k) program grinds on—largely hidden from public view—a possible signal that CDRH is cracking down on predicate devices cited in 510(k) submissions has come to light.

In April, ProUroCare Medical said it had received a letter from the center rejecting its predicate in a recent submission. CDRH said that it could not complete its review of the company’s ProUroScan prostate imaging system because it believed an appropriate predicate device had not been identified.

“FDA specifically noted the lack of a comparable predicate device for use as an aid in visualizing and documenting abnormalities of the prostate detected by digital rectal examination,” ProUroCare said, adding that it plans to meet with FDA to discuss its predicate selection.

If the ProUroScan system is not found to be substantially equivalent because a suitable predicate cannot be identified, then FDA may push the product into its de novo classification process. This path is intended to allow low-risk devices to be marketed under a 510(k) when there is no adequate predicate.

CDRH and the Institute of Medicine are separately evaluating the 510(k) process, which is sure to result in some revamping of predicate use. At a public meeting in February, CDRH officials outlined challenges with the current predicate system. One example cited was when companies choose a poorer performing device for the predicate even though better performing devices are available. One CDRH official explained that medical manufacturers may use the poorer performing device to make it easier to obtain a substantial equivalence determination.

“This construct may serve to inhibit device improvements for performance for the entire device class and I don’t think that serves the public health,” the official said. “We also run into cases where the original device may no longer be marketed due to subpar performance, yet this device serves as a valid predicate because at the time it was equivalent.”
And more recently, a CDRH reevaluation of ReGen Biologics’ Menaflex collagen scaffold raised questions about whether predicate devices cited by that company were adequate to demonstrate equivalence, according to briefing documents released for an advisory committee meeting in March.

Members of FDA’s Orthopedic and Rehabilitation Devices Panel said in late March that there is “evidence of reasonable efficacy” for the collagen scaffold surgical mesh used in medial meniscus soft-tissue repairs. However, they questioned the rigor of the scientific proof offered by the company for the device’s efficacy. Panel members were asked to reevaluate FDA’s 2008 decision to clear the device through the agency’s 510(k) process.

Panel chair John Kelly, an orthopedic surgeon at the University of Pennsylvania, said the group was given inadequate and low-quality evidence on the device’s effectiveness and too little information on its safety. He said the panel had concluded that the device “is reasonably safe, but it fails to pass scientific muster.”

ReGen officials told the panel they had done more research and provided more data than makers of similar devices. The reevaluation was ordered by FDA principal deputy commissioner Joshua Sharfstein after the agency said that the approval process was flawed. It was reported that, at the time of the review, then CDRH director Daniel Schultz approved the product over the objections of several agency scientists and managers.

Representatives of the medical device industry raised concerns about the reevaluation at the hearing. Orthopedic Surgical Manufacturers Association chair Susan Krasny of Stryker Corp. cautioned that if FDA could overturn an approval without a major safety issue being raised, it would lead to uncertainty in the device community. And ReGen officials said that the questions being raised about the collagen scaffold’s safety and efficacy are irrelevant to a 510(k) clearance.

In advance of the panel meeting, FDA provided a briefing document to the panel that raised questions about the adequacy of predicate devices cited by the company to demonstrate equivalence. Agency reviewers told the panel that ReGen “did not provide adequate preclinical mechanical testing data to clearly demonstrate safety against mechanical failure of the collagen scaffold device.” ReGen complained that the questions posed in the document for the panel were intended to secure a negative panel response.

Following the meeting, CDRH director Jeffrey Shuren told the media that FDA has several options following its reevaluation. These included doing nothing, applying special controls, or reclassifying the collagen scaffold as a high-risk device, which could require the company to file a PMA.


CDRH Reviewers “Pressured” to Okay CT Scans


At an FDA meeting in March, a former medical device review consultant said that he and eight other reviewers had been pressured by CDRH managers to approve CT scans for colon cancer screening despite their safety concerns. These concerns involved potential overradiation as more patients could undergo CT scans in lieu of traditional colonoscopies.

The former reviewer, San Diego-based gastroenterologist Julian Nicholas, is one of nine former and current CDRH dissident scientists who wrote to President Barack Obama more than a year ago. They wrote that “sweeping measures are needed to end the systemic corruption and wrongdoing that permeates all levels of FDA and has plagued the agency far too long.” The dissidents’ complaints are believed to have contributed to the resignation of former CDRH director Daniel Schultz.

Nicholas also said at the FDA meeting that his contract was allowed to expire late last year due to his disagreement with CDRH managers. Nicholas said he and the eight other reviewers “were pressured to change their scientific opinion” in order to move forward a submission by General Electric (GE) to expand CT scanning into colon cancer screening. The device is still under review at the center, according to FDA officials.

An FDA spokeswoman told the online FDA Webview subscription news service that allegations of retaliation by Nicholas and others were sent to the HHS’s Office of Inspector General (OIG) for evaluation. That assessment “found no evidence of potential violation of law, prohibited personnel practices, or retaliation,” she said. “FDA will continue to take seriously concerns about retaliation and support an environment conducive to effective scientific discussion and decision making.”
Disagreements by scientists are not uncommon at the agency and, in fact, are encouraged as part of the scientific process, the spokeswoman acknowledged. “FDA encourages discussion of differing scientific viewpoints because it is through such discussions that the agency makes the best judgments to protect the health and safety of Americans."

In response to the OIG review and the management complaints, FDA has hired a management contractor to help strengthen the workplace at CDRH. The spokeswoman said, "the contractor is in the process of conducting an environmental assessment of the center to solicit employee feedback and recommendations about the CDRH organization on topics including trust, interpersonal and cross-organizational communication, manager-staff relations, CDRH’s policies and processes, organizational structure, and performance.” 

The contractor may recommend establishing additional or more transparent policies and procedures, according to the spokeswoman. In addition, the contractor will help CDRH improve its capability to manage future allegations.

FDA’s meeting on CT scanning is part of an initiative launched in February to further promote safe use of medical imaging devices and reduce unnecessary radiation exposure. That move followed FDA action in December that urged CT technologists to “go back to basics” to ensure that patients receiving CT perfusion scans are not exposed to excess radiation. The agency is investigating reports that hundreds of patients in several facilities in California and Alabama received excess radiation that led to skin reddening and hair loss. The reports involved instruments produced by GE and Toshiba.

Nicholas complained that CDRH managers were not adhering to scientific and regulatory review processes while
advocating for the CT scanner’s approval. Current CDRH reviewer Robert Smith corroborated Nicholas’s allegations. “Science must not be ignored, suppressed, or distorted as that endangers the public,” he said at the meeting.

Expanding CT use to virtual colonoscopy has morphed into a turf battle between medical specialists, outsiders observe. Radiologists are supportive of the newer scanning procedure and believe the radiation dose is a minimal risk, while gastroenterologists support the traditional colonoscopy as a diagnostic gold standard.

In reaction to a public radio program, Raleigh, NC–based radiologist Philip R. Saba posted a comment on Marketplace.com that said there are certain conflicts of interest with the overutilization of medical imaging, particularly with physicians who have a financial interest in the CT scanner. “Many nonradiologists who own imaging equipment engage in the act of ‘self-referral,’” he said.

The ACR (American College of Radiology) has fought long and hard to encourage legislation against this practice, however, we have been consistently outnumbered by the nonradiologist physicians who have a financial interest in continuing the practice of self-referral (i.e., the AMA). Overutilization of imaging is indeed a problem, but we must be careful not to throw the baby out with the bath water. The radiologists are blameless in this arena, and should have a seat at the table in decisions regarding the utilization of medical imaging, as they do not control the flow of the patients.

When announcing the initiative, FDA said the amount of radiation Americans are exposed to from medical imaging has dramatically increased over the past 20 years. The goal of FDA’s initiative is to support the benefits associated with medical imaging while minimizing the risks.


Globalization Spurs More Regulator Cooperation


FDA and its European counterparts have taken initiatives to better manage the unfavorable effects of globalization on the medical device industry. This had led to greater international cooperation among regulators, particularly in the areas of compliance and postmarket surveillance. This assessment was provided at the recent Regulatory Affairs Professionals Society 2010 Horizons Conference by CDRH chief of circulatory support and prosthetics Matthew
Hillebrenner.

He moderated a session in which CDRH acting compliance director Larry Spears reminded attendees that commissioner Margaret Hamburg had recently promised swifter enforcement actions, risk-based inspection planning, and special emphasis on ensuring the integrity of the pharmaceutical supply chain.

“Risk-based inspection planning is currently based on such factors as product registration and listing data, inspection history, device classification, and recall experience,” Spears said. “But future risk models will incorporate additional factors, now being developed, such as how many different devices are produced by an individual manufacturer, as well as the nature of these products, including whether they involve complex processes that may be difficult to control.”

He noted that pharmaceutical supplies—especially active pharmaceutical ingredients—are increasingly imported and, for this reason, industry should expect enhanced import screening, including a doubling of field examinations of imports for FY 2010 with increased sample analyses.

Spears pointed out that success in maintaining the safety of the supply chain will require greater diligence and accountability on the part of manufacturers, as well as cooperation on the part of foreign regulatory authorities. He said approximately 300 foreign inspections were conducted last year—however, this number is expected to rise to 350 in 2010. Spears said the establishment of three FDA offices in China (Beijing, Shanghai, and Guangzhou) is expected to further enhance supply-chain safety, because the offices will facilitate more foreign inspections. Moreover, they will provide information and training for Chinese authorities with regard to meeting FDA regulatory requirements.

CDRH expert in global device adverse-event reporting Deb Yoder told the session that the National Competent Authority Report (NCAR) represents a significant vehicle for achieving international cooperation among regulatory authorities, and is now making an important contribution to global public health and safety. NCAR, she explained, is a device for communicating with regulatory authorities worldwide concerning “significant actual or potential risk to the global public.” Reports on medical device safety issues are generated at the discretion of individual regulatory agencies, based on perceived public health concerns including adverse events, and are disseminated internationally to cooperating regulatory agencies.

According to Yoder, the system is premised on the idea that one regulator may have unique knowledge that should be widely shared. Although there are no firm criteria concerning the nature of events or the circumstances that should dictate issuance of a NCAR (this is left to the discretion of individual regulatory authorities), Yoder said NCARs generally relate to issues that are deemed “serious,” that can lead to preventive measures, and that may affect vulnerable populations. FDA has increasingly used NCAR as a means for learning about products from other regulators when a device has been marketed abroad longer than in the United States, Yoder said.

According to the third presenter, GE Healthcare and EMEA quality assurance and regulatory affairs executive Rainer Voelksen, medical device regulation is currently undergoing significant revision, both in terms of regulatory emphasis, and as a result of recent legal and administrative changes. He explained that there is no central agency to oversee medical devices, but that regulation of devices is within the purview of the 27 “competent authorities” composing the European Union (EU). Nevertheless, the EU Commission is empowered to issue directives to guide the member states’ individual regulatory
authorities.

He pointed out that recent changes made to the Medical Devices Directive for EU members provide for software classification and stronger requirements for clinical data and clinical evaluations for approvals of medical devices. He emphasized that the EU Commission is actively engaged in the work of the Global Harmonization Task Force and maintains numerous bilateral contacts with the Chinese and other regulatory bodies. But he indicated that the lack of a centralized EU medical devices agency inhibits greater international cooperation in the device area.

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