Despite a rising clamor to bring device evaluation standards closer to those used in drug evaluation, President Obama’s FDA appointees in November heightened their efforts to ensure industry that this won’t happen.

Jim Dickinson

December 22, 2010

13 Min Read
FDA Addresses Data Harmonization Concerns

Deputy commissioner Joshua Sharfstein told a think tank conference in Washington that FDA’s intention is ultimately to “harmonize” the data standards that compose a critical basis for the agency’s regulatory function. However, no consideration is being given to modeling future data standards for medical devices on those currently applicable to drug products.

“Data standards for drug evaluation cannot be a starting point for standards to be applied to medical devices,” Sharfstein said, adding pointedly: “There are enormous differences in evaluating drugs and devices.”

Some of these differences, he indicated, include the fact that in contrast to drug development, the development process for medical devices tends to be evolutionary or iterative in nature. Moreover, Sharfstein noted that designs of clinical trials for devices are typically quite different from those employed for drug evaluations.

Sharfstein’s comments were in response to a question posed at a conference titled “Regulation and Reimbursement for Medical Devices: Protecting Public Health While Fostering Innovation.” The meeting was cosponsored by the American Enterprise Institute (AEI) and the Brookings Institution’s Engelberg Center for Health Care Reform. Session moderators included former FDA commissioner Mark McClellan, currently director of the Engelberg Center, and former FDA deputy commissioner for medical and scientific affairs Scott Gottlieb, now serving as an AEI resident fellow. Both McClellan and Gottlieb were Republican appointees to the agency during the previous administration.

Ross Jaffe, cofounder of Versant Ventures, a venture capital firm that specializes in early-stage development of innovative medical devices, said funding for innovative products has declined precipitously in recent years, and that the United States is at risk of losing its position of leadership in developing such products. “The last 10 years has been a lost decade in the development of new, innovative, healthcare technologies in the U.S., with investment in this country shifting toward later-stage development,” he said.

Furthermore, Jaffe indicated that many American companies are now taking innovative ideas overseas for development and initial marketing efforts, with product “incubators” often located in Europe, Israel, and Australia. According to Jaffe, this trend is due to a combination of factors, including a lengthy FDA product review process involving greater financial risk than is typically experienced in Europe and elsewhere. A further incentive to moving new technology development abroad, Jaffe said, is the prospect for rapid growth in some overseas markets.

A survey of 204 medical device companies also pointed blame toward FDA for the decline in funding for device innovation. It was conducted by Josh Makower, a device inventor and CEO of venture capital firm ExploraMed. According to Makower, 44% of survey respondents indicated that frequent changes in FDA staff during the period that their products were under review often resulted in an unnecessarily lengthy regulatory process. The situation has meant that products can take up to two years longer to reach patients and consumers in the United States than in Europe. Similarly, 30% of respondents indicated that a lack of clarity in FDA clinical trial requirements—disagreements over what may constitute an endpoint, for example—has often resulted in considerable time and expense to product sponsors.

CDRH director Jeffrey Shuren said FDA “takes seriously” industry criticisms of agency proposals to reform the 510(k) review process, and he avowed concern over the current unfavorable climate in the United States with respect to investment in innovative medical devices. Shuren said an internal (CDRH) assessment of the 510(k) process yielded 55 recommendations for strengthening—not replacing—the 510(k), of which 40 recommendations have received support from the device industry and other “stakeholders.”

Shuren said that the agency expected to identify which of these recommendations will be adopted by the end of the 2010, with timelines for putting them into effect. Further, he said that the Institute of Medicine will deliver an independent assessment of the 510(k) process later in 2011, which is expected to lead to additional improvements.
In response to a question, Shuren said that, given the increasing complexity of many new and innovative medical devices, and the difficulty of evaluating them, he is open to consideration of de novo reviews for such products.

CDRH Regulation Called ‘Vastly Inadequate’

But the device-drug comparison drumbeat goes on. Also in November, two U.S. medical writers went to press asserting that CDRH’s regulation of medical devices is vastly inadequate, with standards much lower than those applied to drugs. In the November 2 issue of the British Medical Journal, Jeanne Lenzer and Shannon Brownlee said that CDRH’s inadequacies may have contributed to hundreds of deaths associated with Cyberonics’ vagus nerve stimulator (VNS). The device was approved in 1997 for treating treatment-resistant partial seizures. The device was later also approved for treating treatment-resistant depression.

Their report said that neither Cyberonics nor FDA have systematically investigated what role the device may have played in the deaths. “Although Cyberonics conducted postapproval studies, none of the studies submitted to FDA included mortality data,” it says. “FDA did not specifically require Cyberonics to submit mortality data as part of the follow-up study, merely to ‘characterize morbidity and mortality.’” Lenzer and Brownlee said that FDA’s lack of aggressive follow-up “is but one example of the gap in postapproval surveillance of medical devices.”
In an accompanying editorial, Harvard Medical School professor Jerry Avorn wrote,

The standards for device approval and surveillance have fallen far below those for drugs, and even those that would be dictated by common sense. It would be unthinkable for a drug company to go to FDA or the European Medicines Agency and say in effect, ‘This new drug is much like an older product we sell, except that we have added a new amine group and modified one of the side chains. Apart from that, it’s pretty close, so we won’t be doing any new clinical tests on it. When can we begin marketing?’ But this is essentially what happens with many new medical devices when they are approved.

He called on FDA to abandon the “substantial equivalence” standard used in the 510(k) clearance process and to develop better requirements for clinical review of new products.

Cyberonics chief financial officer Greg Browne told Lenzer and Brownlee that “none of the approximately 900 deaths reported to FDA were attributed to VNS therapy. Available data indicate that all-cause mortality rates for VNS therapy patients are less than half the rates in the comparable non-VNS epilepsy patient population.”

The authors concluded that FDA will only improve when it gets more staff, better funding, more authority, and more outside experts to objectively evaluate device safety.

Hamburg Tries to Assuage Industry’s ‘High Anxieties’

In a keynote address at AdvaMed’s annual conference in October in Washington, DC, FDA commissioner Margaret Hamburg acknowledged some concerns (“high anxieties”) that have been expressed by medical device manufacturers about anticipated changes in the 510(k) clearance process, as well as other uncertainties over evolving programs and priorities at the agency. However, she quickly sought to place the need for change in perspective.

The commissioner pledged to proceed carefully and in a fully transparent manner as any changes are implemented. She noted that public comments on preliminary 510(k) recommendations, which were delivered by an internal agency study group in August, have generally been supportive.

“I realize it is taking time to determine what changes are needed, but the process should be a thoughtful one, with ample opportunity for feedback from industry and other stakeholders,” Hamburg said. “Before any decisions are made, it is critical that we have a solid understanding of the root causes of problems with the current approval process.”

The extraordinary success of the medical device industry over the past decade drew high praise from the commissioner as she noted that designers of devices have scored an “80% increase in breakthrough patents” during that time period. Indeed, Hamburg described the industry as a virtual “poster child for innovation.” She pointed out that U.S. manufacturers remain first among competitors, worldwide, as exporters of medical devices. She also predicted continuing success for exporters of American medical devices, as world markets for these products expand, particularly as a result of major growth in potential customers among the rising middle classes of India and China.

According to Hamburg, important challenges that currently face the device industry are understood and appreciated by FDA—including a difficult economy with jobs moving overseas and frequently changing rules for reimbursement. She said the agency is supportive of the industry in this difficult time, “Because we all want to see safe, effective products reach the marketplace.”

As an example of a recent measure designed to assist the medical device industry, Hamburg pointed to a policy decision (“parallel review”) that allows CMS to begin making preliminary coverage decisions for some promising medical products that have yet to receive final FDA approval.

Not Many 510(k) Devices Get Class 1 Recalls

Less than 0.5% of 510(k)-cleared medical devices have been involved in Class 1 recalls between 2005 and 2009, according to a recent white paper released by the California Healthcare Institute (CHI).

The data come from a five-month study by MR3 Medical CEO Ralph Hall that found that 89 (0.45%) of 19,873 510(k)-cleared devices from that period were subject to Class 1 recalls. Forty-three (0.22%) of the same base were recalled for premarket issues. Design issues were the predominant reason for the recalls, Hall found.

In addition to Hall’s report, the CHI white paper described a discussion the institute convened in July involving former FDA chief counsel Peter Barton Hutt, former CDRH director David Feigal, and ExploraMed CEO Makower, among others.

The white paper concluded that the 510(k) process is integral to medical technology innovation and that “increased uncertainty, unpredictability, and inconsistency are beginning to take a toll.” Proposed reforms to the process, including restricting the use of multiple and split predicates, consolidating the “indication for use” and “intended use” concepts, creating a subset of Class II devices, and giving CDRH formal rescission authority, are considered controversial, it said.

The white paper urged “careful and deliberative consideration” be given to such ideas, lest the 510(k) process become “more cumbersome, complex, and costly, to the detriment of medical technology investment, innovation and, ultimately, patient care.”

Dental Amalgam More Toxic Than FDA Says

Barely a month before FDA was officially due to hear critics of its 2009 final rule that declared dental amalgam safe and effective, the agency was confronted by two new studies in November condemning the health damage caused by amalgam’s principal ingredient, mercury.

One, prepared for a mid-December special FDA advisory committee meeting on dental amalgam risks, examines U.S. public exposure to mercury and suggests that amalgam fillings expose 122.3 million Americans to quantities of mercury in excess of the safe dosage level established by the California Environmental Protection Agency in 2008. This reference exposure level is accepted by other government agencies for public protection. The other study, published in the November 15 issue of the Journal of Alzheimer’s Disease, directly links mercury in amalgam causatively to that disease.

Both studies effectively contradict an assertion made at a 2009 press conference on the new amalgam rule by CDRH dental device division acting director Susan Runner: “The best available scientific evidence supports the conclusion that patients with dental amalgam fillings are not at risk for mercury-associated adverse health effects.”

The first study is also critical of FDA’s failure to consider the additive effect of nondental sources of mercury and the compounding effects of similar neurotoxins such as lead and methyl mercury. “Neurological effects, particularly in the nervous system of the developing fetus/neonate/child, represent the most sensitive endpoint for exposures” to these neurotoxic substances, according to the study report. The report was commissioned by the International Academy of Oral Medicine and Toxicology (IAOMT), which was among the petitioners scheduled to present at FDA’s meeting December 14–15.

Noting recent literature on the effects of the three heavy metals in humans, the first study, led by Ottawa, Canada–based SNC-Lavalin’s G. Mark Richardson, says that potential neurological effects of lead and mercury on the developing brain of the fetus are likely to accumulate via the placenta and breast milk.

The study report estimates that more than 121 million Americans have an exposure level from the combined three heavy metals that exceeds the 2003–04 National Health and Nutrition Examination Survey safety standard. The researchers reached this conclusion based on criteria set out in guidance issued by both the U.S. Agency for Toxic Substance and Disease Registry and the Environmental Protection Agency.

According to the report, these substances share the following characteristics:

  • All are absorbed in large proportion into systemic circulation.

  • All cross the blood-brain and placental barriers.

  • All cause neurological toxicity.

  • Exposure to all of these substances currently exceeds individual reference exposure levels for many in the U.S. population.

Although not part of the study, the report also notes that high-fructose corn syrups have recently been found to contain high levels of inorganic mercury, with average daily intakes in the United States at 50 grams per person “due to its widespread use in numerous commercial prepared foods and sweetened beverages.”

In the second study, authors Richard Deth and Joachim Mutter present a meta-analysis of 106 case-control or comparative cohort studies to classify mercury as a causative factor in Alzheimer’s disease. Noting that the main source of mercury in the human body is dental amalgam, the authors say the mercury

evaporates at a slow rate, but is released at a higher rate, when the fillings are put in place or removed. From this source, and other, less common ones, 1.2–27.0 mcg of Hgo [elemental or metallic mercury] are taken up per day, and 1.0–22.0 mcg of Hgo are retained. Other variable factors of mercury release include the number, age, and size of the fillings, the presence of dental alloys, individual chewing habits, and drinking hot liquids, as well as bruxism.

A news release issued by the authors quoted Samueli Institute fellow Harald Walach comparing the situation to that of smoking concerns in the early 1970s. Experimental evidence of smoking’s harm existed, but human studies were inconclusive “and were under attack by groups with a vested interest. To wait until irrefutable evidence has accumulated is not the best option in view of what we already know about the toxicity of mercury,” Walach said. “The removal of inorganic mercury from ecological cycles might prove to be the easiest and most effective public health measure to contribute to the prevention of Alzheimer’s disease.”

Petitioner IAOMT issued a news release hailing the Mutter-Deth study and urging NIH to fund “realistic research” on the mercury-Alzheimer’s link. The release quoted former California first lady Maria Shriver as expressing concern that Alzheimer’s disease “will bankrupt every family in this country.”

Seeking 510(k) Clearance without a Predicate

CDRH has begun posting de novo classification letters to help medical device sponsors better understand how they can request a 510(k) clearance for a device without a predicate. The de novo process applies to low- and moderate-risk devices that have been classified as Class III (premarket approval required) because they were found not substantially equivalent to existing devices. Applicants who receive this determination may request a risk-based evaluation for reclassification into Class I or Class II categories.

The center has been considering tweaks to the de novo process as part of its 510(k) revamp. “As currently implemented, the de novo classification process tends to be associated with lengthy review timeframes and nontransparent data requirements, making it an impractical path to market for many device developers,” a recent 510(k) report said.

In October, CDRH Office of Device Evaluation acting director Christy Foreman said at an industry meeting that the center would begin posting the de novo letters as part of a pilot program under its transparency initiative. She also provided an update on other 510(k) issues, such as a revision to CDRH’s longstanding guidance on when to submit a 510(k). The guidance will no longer contain a flowchart to guide device makers through the decision process on when device changes warrant a new submission.

One of the first two de novo letters involves Erchonia Medical’s ML Scanner, indicated for use as a noninvasive dermatological aesthetic treatment for reducing the circumference of hips, waists, and thighs (down-classified to Class II). Another letter focuses on Zeltiq Aesthetics’ dermal cooling device, which is indicated for use as a noninvasive dermatological aesthetic treatment for reducing subcutaneous fat layers (down-classified to Class II).

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