Device Reviews Not Hostage to Safety Over Efficacy

FDA principal deputy commissioner Joshua Sharfstein insists that despite a growing industry perception to the contrary, negative headlines about the agency’s 510(k) process haven’t resulted in FDA taking an unduly cautious approach to all medical device market submissions.

Speaking by telephone to attendees at the 16th annual meeting of the Medical Device Manufacturers Association, Sharfstein acknowledged that there are “lingering issues with FDA’s medical device program.” But he asserted that under the leadership of CDRH director Jeffrey Shuren, the highest priority has been assigned to resolving program “uncertainties.”

Among these, Sharfstein emphasized a determination to allay industry “fears” that the agency is now inordinately focused on product risks at the expense of potential product benefits. “We really do take a benefit-risk approach; we try to strike a proper balance between benefits and risks,” he said. In response to an audience member’s question, he said investment in “regulatory science” can help solve conundrums posed by competing values of safety versus efficacy.

Another attendee suggested that some medical devices with inherently limited markets should be treated for regulatory purposes in the same manner as foods—that is, by foregoing extensive clinical trials, but insisting on comprehensive labeling outlining known risks and leaving the choice of whether to use such products up to physicians and patients. Sharfstein said that although this novel idea may be “interesting,” it would not provide a practical (or perhaps even legal) solution for speeding such medical devices to market.

“Effective FDA oversight is important to payers,” Sharfstein said. “Without the rigor of FDA’s approval process, payers would wonder if a product is ‘worth it,’” he noted. “FDA approval inspires consumer confidence and facilitates payment by third parties.” He said developing better, science-based ways to evaluate safety and efficacy of FDA-regulated products is the best way to make the regulatory process more efficient and less costly.

A key management tool, called FDA Track, will enhance the accountability of FDA program managers for meeting deadlines and accomplishing program goals, Sharfstein said. He indicated that a list of 300–400 performance measures is being developed to provide a basis for evaluating program efficiencies and effectiveness. He said that monthly data from FDA Track, including such information as the resolution rate for 510(k) applications, will be available on the agency’s Web site. Sharfstein invited industry comments and suggestions for improvements to FDA Track once it becomes fully operational, including suggestions for specific performance measures to be utilized.

A keynote luncheon address was delivered by Senator Amy Klobuchar (D–MN), a member of the Senate Finance and Commerce Committees, with jurisdiction over Medicare, Medicaid, and other federal healthcare programs and agencies.

Klobuchar pointed out that small business firms account for 65% of jobs in the United States, and that the medical device industry is composed predominately of small businesses. Moreover, she observed that the medical device industry is one of the few areas of U.S. manufacturing that can claim to enjoy a significant export market.

“At a time of 9.9% unemployment, it is particularly important to maintain and expand medical device exports,” she said, noting that “95% of customers [for medical devices] live outside our borders.”

AdvaMed Protests “Increasing” FDA Review Times

AdvaMed says that the time it takes FDA to complete its review of a product in the premarket approval process is troubling. The average review time has increased since the medical device industry entered into a 2002 user fee agreement—partly to speed up reviews.

AdvaMed senior executive vice president David Nexon raised the concern in comments before the President’s Council of Advisors on Science and Technology in May.

He said that FDA data show that in 2007 (the most recent year for which data are available), the average time between a product’s submission and a final agency decision was 446 days. Since the 2002 user fee agreement, the average time in review has increased by two months, Nexon added.

“It is not a good omen for the future of the U.S. device industry, or for American patients, that an increasing proportion of products appear to be undergoing clinical trials and entering the market abroad before they are introduced in the U.S.,” he said.

Nexon also commented on FDA’s 510(k) clearance process and said that AdvaMed supports the agency’s current review of that process and will recommend next year any changes it believes are necessary.

“We welcome this review because we believe the process can be improved and public confidence in it can be increased,” he said. But he also cited industry’s belief that the 510(k) process has an excellent record of protecting the public against unsafe or ineffective products, while also providing a relatively speedy path to development and approval for innovative new products.

“It is very important to the future of the industry and to continued medical progress that the 510(k) not be altered radically in a way that would unnecessarily increase the time and cost of developing new products,” he said.

CDRH’s Top Priority: Strengthening Premarket Reviews

CDRH’s biggest priority is to improve the “quality, consistency, and predictability of our regulatory decision making by strengthening our premarket review programs,” center director Jeffrey Shuren told a Minneapolis town hall meeting recently.

In addition to an ongoing assessment of CDRH’s troubled 510(k) program, he said his center is pushing this year to “improve the quality of clinical data submitted in support of premarket approval [PMA] applications, to make sure that the safety and effectiveness of high-risk medical devices are adequately supported before they enter the market.”

Shuren mentioned that earlier this year, the center coauthored a study with experts from the Beth Israel Deaconess Medical Center on the use of clinical trials to support PMAs for cardiovascular devices. “We are currently extending that review to other device types. A few weeks ago we posted our pivotal IDE [investigational device exemption] checklist that identifies important components of a clinical trial protocol that we look at during our review of an IDE. This year we will also develop draft guidance on the design of clinical studies.”

Shuren said that CDRH sees great promise in establishing a unique device identification (UDI) system to increase the agency’s ability to capture and more effectively use meaningful data on marketed devices.

“There has been much discussion about whether real-world clinical data could be routinely used in lieu of more formal clinical studies in support of a PMA or 510(k),” he said. “The condition precedent for such a consideration is the UDI, because it is essential for linking information about the device with information about a patient’s experience with the device. “ Shuren also noted that UDIs will help OEMs conduct more-efficient and effective recalls “by allowing manufacturers to more quickly identify where product subject to a recall is located in the supply chain.”

On globalization, Shuren told the audience that “over the next two to three years CDRH will develop mechanisms to exchange and make better use of medical device information from trusted foreign authorities, such as supplementing our inspections with quality systems and GMP inspections conducted by other countries under the ISO 13485 audit report.” Part of this effort includes developing a single audit program for two countries. Under such a program, Shuren said that an inspection conducted for another country would serve in lieu of an inspection by FDA and vice versa.

On compliance, Shuren said CDRH has recently developed a compliance strategic plan and a summary of this will be publicly released soon. “The CDRH compliance strategic plan—and I emphasize compliance not enforcement—is geared toward enhancing the center’s compliance capability, largely through operational improvements. Our goals include enhancing our risk-based decision making, better integrating our operations with FDA’s Office of Regulatory Affairs, and strategically allocating staff and resources to address critical public health needs.”

Shuren said that preventive measures (instead of enforcement measures) will be the focus. “Our staff needs to be armed with more than hammers and not everything we come across should be considered a nail. And our approach must encompass working with industry to prevent problems in the first place rather focusing solely on the proper use of enforcement tools,” he told the audience.

CDRH is also working with industry and others to facilitate improvements in the design of medical devices that have had safety problems across multiple manufacturers. For example, Shuren cited recent work by the center to reduce unnecessary radiation exposure from imaging devices and another initiative to improve infusion pumps.

Local device industry representatives in attendance voiced concern that CDRH’s review activities have become unpredictable and inconsistent. “We see the shift,” former Office of Device Evaluation director and now Medtronic vice president Susan Alpert said. “We see [FDA] moving toward more intense enforcement, and more discussions around safety issues versus effectiveness issues.”

The agency also heard from worried venture capitalists. Peter McNerney, a prominent Twin Cities medical technology venture capitalist, said that investors are shying away from upstart medtech companies because the FDA approval process is too hard to gauge, and too likely to shoot down new products.

“The regulatory process has become long and uncertain, and in many instances unnecessarily burdensome,” he said. “As a result, we have lost our ability to evaluate regulatory risk.” Nationwide, McNerney said venture capital investment in medical device companies declined by more than one-third over the past two years.

Frustrations over working with center reviewers could also be heard from several audience members who approached a public microphone during the town hall’s question-and-answer period. One woman said she was trying to get a device treating sudden cardiac arrest approved but faced repeated questions from an FDA reviewer about whether the device affected patients’ sense of taste.

Shuren took everything in stride, interjecting slight humor so as to not appear too bureaucratic. When a consultant handed him a proposal to fix the agency, Shuren replied: “I guess I won’t be reading the new Nora Roberts novel on the flight back home.”

FDA Moves to Intensively Regulate LDTs

In June, FDA moved to assert more intensive regulation over laboratory-developed tests (LDTs). The agency has been a longtime believer that these tests are being marketed to consumers without adequate FDA-determined assurance of safety and effectiveness.

CDRH Office of In Vitro Diagnostic Device Evaluation and Safety director of personalized medicine Elizabeth Mansfield told a high-level advisory committee that the agency “intends to establish risk-based oversight framework for all tests, not just commercially distributed tests.”

She announced this to the HHS Secretary’s Advisory Committee on Genetics, Health, and Society less than an hour before the release of a Federal Register notice announcing that a meeting on the issue was planned for July 19–20. “The agency believes it is time to reconsider its policy of enforcement discretion over LDTs,” Mansfield said.

The general expectation, Mansfield said, is that FDA will require a registration and listing period, “to figure out who is out there” and that it will do a risk-based phase-in, looking at the highest risk first. In addition, “we will take all precautions to avoid disruptions to access to tests that are currently on the market.…Our risk assessment is based on the possible harm to the patient, based on an undetected, incorrect result.”

Mansfield also indicated that the agency may “provide a low bar or a no-bar” for certain tests for which FDA is not certain that oversight beyond that already done by CMS (under the Clinical Laboratory Improvement Act or CLIA) will be beneficial. “We want to provide as much access to FDA and education as possible to labs as to how to do this, how the whole system works and so on,” she said. “You should not expect a draconian wall to go up, where today you are not regulated and tomorrow you are.”

Mansfield confirmed that genomic tests will be included in the framework. Saying that CLIA regulates labs and lab activities, but FDA regulates “things, products” and “bits and pieces,” Mansfield said, “We are going to publish a guidance that tells you where CLIA and FDA quality systems correspond, and we will be providing lots of help on getting people up to speed on this.”

She also said that FDA may “have to make some changes as well to the kind of tests that we regulate as commercially distributed, because there is a resource dependency here.” In addition, she said some tests that FDA currently regulates may not benefit from the agency’s oversight anymore because they are old technology, old tests, and low risk.