BB&T Washington Editor and BB&T Staff Reports

FDA's two-day meeting on lab-developed tests (LDTs) in July was designed to elicit input from all stakeholders, and followed several letters FDA issued to several firms the previous month for offering gene testing via mailed-in samples. While the agency's management promised no decisions had been made as to how FDA might examine LDTs, two others at FDA hinted that design controls will be imposed on clinical labs.

Jeff Shuren, MD, director of the Center for Devices and Radiological Health, said that “although FDA has decided to exercise authority“ over LDTs, “we have not made any decisions about how we will exercise that authority.“ He said “it is our hope to move forward with a framework over the next few months.“

Courtney Harper, PhD, director of the division of chemistry and toxicology at CDRH, made note of the “bifurcated pathway“ for in vitro diagnostics (IVDs) and LDTs in that FDA “applies enforcement discretion“ to LDTs. She acknowledged that discretion is “not a practice that is unique to LDTs“ and asserted that the agency's exercise of “this choice does not mean the law does not apply to these products.“

Harper said that in the past, LDTs were often performed “in the context of a close relationship between the lab and the physician,“ but inferred that this relationship is breaking down because the labs using these home-brewed tests are no longer so closely tied to the healthcare facility where physicians practice.

Some biotech firms “are setting themselves up as labs,“ Harper said, which she said further truncates any relationship between doctors and lab pathologists, so “tests are more often developed for broad commercial use“ and are “aggressively marketed in some cases.“

Elizabeth Mansfield, PhD, director of the personalized medicine program at the Office of In Vitro Diagnostics at CDRH, opened her remarks by saying, “I don't think anyone would argue that we're in a new era of molecular medicine and personalized medicine,“ but said “we feel very strongly that the public needs assurances“ as to the validity and reliability of diagnostics.

“We agree LDTs provide value,“ Mansfield acknowledged, informing attendees that FDA is aware that labs “tend to be highly motivated to provide tests for unmet needs.“ Labs also, she said, “may provide specialty tests that . . . would not translate“ readily into a commercially available kit. However, she made the case that LDTs and commercially distributed in vitro diagnostics are not as distinct from each other as in times gone by, so “today the logical basis for [the regulatory] bifurcation has faded.“

Mansfield said FDA has heard from industry about an “un-level“ regulatory playing field and that a tilt toward labs means that makers of diagnostic kits for sale find that “their ability to create high quality, innovative products is being stifled“ by the ability of labs to put out services based on products that need less oversight. She pointed out that “no one from FDA goes out and says 'you're a lab-developed test.'“ The agency sees the LTD claim “being more and more used as a loophole, as a way to go to market quickly“ without appropriate oversight, she said.

Mansfield also raised the question of design controls, which are described in 21 CFR subsection 820.30. She said “formalized control of design is lacking“ in many lab environments, adding that “if you don't do design control,“ a lab's attempts to validate a test may fall short. Concurring with Sharfstein's and Shuren's earlier remarks about the lack of finality of any plans regarding compliance and enforcement, Mansfield reassured attendees, “nothing is written in stone,“ but reinforced the message that “our considerations are to provide an assurance that LDTs are safe and effective.“ She also said FDA is “considering using CLIA or other deeming inspectors“ to handle audits.

Although Mansfield said the agency intends to phase in any regulatory approach, she also said, “we don't know what a reasonable phase-in would look like.“ One of the agency's priorities is to not get in the way, she said. “We need to worry about inspections“ because of the potential disruption. “There's no intention to disrupt critical testing, so we will be working on ways“ to keep from creating workplace problems.

Janet Trunzo, VP for at the Advanced Medical Technology Association (AdvaMed; Washington), told the attendees that the association supports “timely access“ to diagnostics and “wholeheartedly agrees that a risk-based approach should be applied.“ That approach, she said, should be “based on the risk of the test“ and “the probability of harm“ in clinical use.

Trunzo also noted that the use of risk as a basis for enforcement “will also allow FDA to focus on“ tests that present legitimate issues, adding that AdvaMed “has developed a risk-based proposal“ based on tiers “as determined by several risk factors and associated risk mitigations.“

The first factor is how the item is used, and another factor is the likelihood of false positives. Another issue, Trunzo said, “is the degree of novelty of the analyte“ and the degree of training needed to use the test. The association's approach, she said, “adds objective, standard and transparent“ criteria for oversight of a test. She also said “our approach builds on the strength of the current infrastructure.“

Stupak to pursue shutdown of DTC gene testing

Companies in the business of providing direct-to-consumer (DTC) gene testing found themselves in a deep hole on a couple of points during a July 23 hearing in a House Energy and Commerce subcommittee, and at least one prominent legislator said that he intends to spur the Federal Trade Commission to close down the industry until federal agencies have agreed on a reliable set of standards regarding the meaning of gene test results.

As the hearing commenced, Rep. Bart Stupak (D-Michigan), chairman of the oversight and investigations subcommittee, acknowledged that some tests “can detect how well some drugs work or whether they will work at all,“ but can also detect propensities to disease states that are not symptomatically obvious. He said DTC testing firms “make enticing claims“ to consumers, including that “they have the ability to“ predict a propensity toward a disease state “with a simple swab from the [inside of] the cheek.“

“But how accurate are these companies' analyses?“ Stupak asked, stating that an examination of such data “may cause more harm than good“ without qualified clinical advice. Later in the hearing, Stupak expressed dubiousness regarding the value of such tests because of the wide discrepancies between interpretations of gene test results, a position buttressed by an investigation conducted by the Government Accountability Office. “I won't believe anything until all those results are the same,“ Stupak said.

After the hearing, Stupak told BB&T that he is keenly interested in suspending the operations of these firms and will be in touch with FTC on the matter. “We wish FTC would take enforcement action,“ he said, characterizing the tests as being for “nothing more than entertainment purposes.“

Vance Vanier, president/CEO of Navigenics (Foster City, California) told BB&T, “I think there's an appropriate middle ground“ between an FTC shutdown and no oversight of the DTC gene testing industry. He said a comprehensive FTC action would be “heavy-handed and does not recognize that there are good and bad actors.“ Vanier said his company employs about 50 people and that all would lose their jobs in the event of a shutdown, but he argued, “it's not an employment issue“ so much as it is “an issue of stifling investment.“ He said that a clampdown in the U.S. “would drive investment abroad,“ noting that “its these early stages“ of an industry that make or break its viability as an industry and as a contributor to the health of a national economy.

The most damaging testimony heard from witnesses during the hearing came from Greg Kurtz, managing director of special investigations at the Government Accountability Office, who presented the results of an undercover investigation on the DTC industry, including some of the “most reputable companies in the industry.“ He said the agency purchased several tests from each of the four companies and sent two samples to each firm from at least one donor for a given test. One of the samples was presented with factual information about the demographic identity of the source of the sample, and one with fictitious information.

“All five donors received conflicting results,“ Kurtz testified, noting “68% of the time, our donors received different predictions about the same disease“ (the companies whose executives appeared at the hearing said that they employ a different subset of single-nucleotide polymorphisms to determine propensities, which is the primary driver of those different test results).

Kurtz continued: “Our investigation shows that the test results . . . are misleading and in any case not of much value to consumers.“ He played clips of some phone conversations between the ersatz customers and the testing firms, one of which claimed the company had contact with Lance Armstrong, implying endorsement. Another company's representative is said to have replied to a query about the risk of breast cancer with the statement that the result of the test indicates “you'd be in the high risk of pretty much getting“ breast cancer.

Jeff Shuren, MD, director of the Center for Devices and Radiological Health at FDA, told the panel that scientific advances in human genomics hold a lot of promise, but that “the field of personalized medicine will not make good on that promise“ if tests are inaccurate and present “only a tenuous link“ between genetic predisposition and actual occurrence.

He said FDA started meeting with firms in 2007 on the DTC gene testing issue. “At that time, these tests were being marketed as antiquity determinations,“ but said they are now “making claims about high-risk medical indications.“ He said “the link between the results of the test and the disease has not been established,“ asserting further that the agency “considers all these tests to be medical devices based on claims.“

CMS proposes demo for Part B imaging DSS systems

CMS recently reported yet another demonstration project, this one to help deal with what is seen in some quarters as an epidemic of inappropriate dose levels in diagnostic imaging. The announcement came close on the heels of a two-day FDA meeting on ways to reduce imaging dose levels earlier this year, and the demo will deal with imaging conducted under Medicare's Part B physician services program.

According to CMS, the program “will test whether the use of decision-support systems . . . can reduce unnecessary radiation exposure and utilization.“ CMS states that the two-year program will focus on Part B imaging, long a bone of reimbursement contention for those concerned with the sustainability of Medicare's financial picture. The imaging modes that are part of the demo include CT for six anatomical regions, including the lumbar spine and brain, and four anatomical locations for MRI, also including the brain and lumbar spine. SPECT imaging for myocardial perfusion is also on the list of procedures for inclusion in the program, and CMS states that the tests were based on their conspicuousness for high expenditure and utilization in the Part B program. However, the availability of professional society guidelines also helped determine the mode/anatomy pairings as well.

The agency also notes that the demo will not change any coverage/payment policies and will not entail the use of prior authorization processes.

Dominique Delbeke, MD, President of the Society for Nuclear Medicine (SNM; Reston, Virginia), told BB&T that the association is “supportive of the concept. Anything that will increase the quality of care and reduce radiation exposure“ is a good idea, she said, although she cautioned, “we just have to realize that the implementation . . . will not be easy.“

Delbeke said “its certain“ that the effort “would include imaging based on appropriate use guidelines,“ but she noted that there is “some non-conformity“ between the standards promulgated by the various professional societies. These standards “certainly need more work,“ she observed. “If done right, [the demonstration] will improve patient care,“ Delbeke said, but she said “any system that's implemented“ should allow the physician to override the support system in order to tailor the procedure to the patient. Such systems, she said, “cannot take into consideration every individual.“

FDA, FCC in joint initiative for wireless health

FDA and the Federal Communications Commission (FCC) convened in July at the FCC building in Washington to go over some of the details of the still-emerging science of device-related telecommunications, and used the occasion to announce a partnership to share data and coordinate their respective regulatory mechanisms in an effort to speed telemedicine to market.

FDA Commissioner Margaret Hamburg, MD, said, “we're here because we recognize“ the importance of telemedicine to the future of healthcare, but she also implicitly made a promise on behalf of both agencies. FDA and FCC were there yesterday also “because we believe in the promise of innovation if we remove barriers.“

Hamburg acknowledged that federal regulators “know we need a strong partnership . . . between the FCC and FDA to change the paradigm“ of how products are regulated, which she said will “change the face of medicine forever.“ The former practicing physician and public health icon said telemedicine “will make an enormous difference to families and caregivers“ when the patient is treated at home. However, Hamburg warned, “we're here also because we face and will continue to face“ some fairly intractable problems in weaving electronic device communications between patients and caregivers. Hence, she said “to harness the full power of those benefits . . . we must improve the efficiency of the regulatory processes“ where FDA and FCC overlap.

Hamburg promised the much sought-after predictability, stating, “in the coming months, the FDA will issue a draft guidance“ to address mobile applications for electronic communication of device-related physiological parameters. She also promised attendees that the two-day session between the two agencies is “just the start“ of “what I hope and am increasingly convinced will be a valuable partnership“ between the agencies.

The preamble to the July 26 memorandum of understanding between the two agencies states that FDA and FCC will “work together to promote initiatives related to the review and use of FDA-regulated medical devices . . . that utilize radio frequency emissions or otherwise fall under the jurisdiction“ of FCC. The MOU states it is designed to “improve the efficiency of the regulatory processes“ and applies “only to areas where stakeholders are affected by“ both agencies.

The four areas of interest include further enhancement of information sharing efforts and the development of infrastructure and processes that will “meet the common needs“ of the two agencies as they review applications that fall under both jurisdictions.

Maisel to head new science office at CDRH

The much-anticipated changes to the 510(k) program by managers at FDA's Center for Devices and Radiological Health were reported recently via a conference call that laid out the changes and the agency's rationale for those changes, but while many of the changes were anticipated, one of the unexpected developments is that Bill Maisel, MD, director of the Medical Device Safety Institute (Boston) will serve as the inaugural deputy CDRH director for science.

During the conference call, CDRH director Jeff Shuren, MD, said the center is proposing to establish a “new governance model for ensuring quality consistency“ in regulatory decisions, and that to provide that feature, CDRH will “establish a center science council that would be composed of senior managers and review staff under a new deputy center director for science.“ He said, “today we announced the appointment of the new deputy center director,“ namely Maisel.

Shuren added that the science council “will be able to serve as a body for auditing the decisions that we make and for providing consistency in our decision making by being available to address the tougher questions regarding science.“ Maisel, a cardiac electrophysiologist who has served on the circulatory systems advisory panel, has also served as a witness at hearings for both the U.S. Senate and the House of Representatives on matters pertaining to medical devices, especially in the context of pre-emption of state regulatory purview of PMA devices (Maisel has also advocated that device makers stress-test their devices to failure rather than in worst-case conditions).

The science council, Shuren continued, will handle some of the decisions that were previously handled at the branch level within ODE and “will be comprised of people from the review level as well as managers,“ he said. These sessions can also be convened to address crosscutting issues.

The conference call covered both the changes to the 510(k) program as well as an announcement of some other changes designed to enhance CDRH's ability to stay on top of the horde of scientific advances coming out of public and private labs around the U.S. Shuren noted that the agency will open the proposed changes to public comment for 60 days and that “if there's strong support for any of the recommendations, we would be in a position to start making those changes now,“ but any controversial recommendations would be forwarded to the Institute of Medicine, which he noted is assessing whether statutory changes might be in order for device approval procedures. Shuren reminded that the IOM report “is not due out until around the summer of 2011.“

As for the 510(k) program, Shuren noted that “in recent years . . . concerns have been raised within and outside FDA“ that “the program allows devices to enter the market“ with insufficient assurances of safety and effectiveness, but he added that the changes CDRH wants to make to the program will allow the review process to “become what we call 'predictably adaptive.'“

One of the primary differences here is that the center is proposing a new sub-classification of devices to be known as class IIb. This device group, Shuren said, is a “small subset of devices where we need either clinical or manufacturing data“ to establish substantial equivalence and to ensure that new questions about safety and effectiveness are not implied. This group, which he said makes up only about 8%-10% of 510(k) filings, will be the subject of a guidance, although he did not give a hard date for the publication of the guidance.

As a method of dealing with regulatory flux, Shuren said the agency is eyeing the use of a notice-to-industry letter that would serve as a “level 1 – immediately in effect“ notification that describes the changes ODE has decided are appropriate for applications, given the emergence of new information regarding a specific device type. The changes embodied in such letters would likely find their way into a formal guidance at a later date, but the drag on formal guidance publication mandated that CDRH find a more timely approach to making its expectations known.

Shuren noted that in the past, CDHR was stuck with “either ad hoc“ changes to regulatory expectations – which resulted in manufacturers finding out their applications need more data after “they've already invested a lot of time and money“ – or formal guidances, which he observed are “very time- and resource-consuming.“

CDRH is also considering a requirement that 510(k) submitters provide a summary of “all scientific information known or that the submitter should reasonably know regarding the safety and effectiveness of the device under review,“ an accompanying FDA document states. Such a summary “would help CDRH review staff to more efficiently make decisions, and potentially avoid extensive follow-up inquiries and questions,“ one of the great sources of drag on predicate-based device applications.

The de novo device application is also up for a tweak, Shuren noted. He said that the de novo “is broken“ because it forces applicants to go through a 510(k) application, and only when the de novo interpretation is confirmed do “you go back and we talk about the data you need for the de novo.“

The section of the working group report for de novo applications suggests that CDRH work on the existing guidance “to streamline the current implementation of the de novo classification process and clarify its evidentiary expectations for de novo requests.“ The recommendation includes a suggestion of “greater pre-submission engagement between submitters and review staff,“ but also that CDRH consider “establishing . . . a generic set of controls that could serve as baseline special controls for devices classified into class II through the de novo process, and which could be augmented with additional device-specific special controls as needed.“