FDA Plans to Issue Final LDT Framework in 2016; Subcommittee Members, CMS and FDA Officials Critique Proposed Legislative Approach that Would Give CMS LDT Premarket Review Authority

By Jamie K. Wolszon & Jeffrey N. Gibbs –    

As 2015 draws to a close, the world of laboratory-developed test regulation continues in high gear. One major event featured the Center for Devices and Radiological Health (CDRH) Director Jeffrey Shuren testifying last month before the House Energy & Commerce Committee Subcommittee on Health. Dr. Shuren stated that the Agency intends to issue a final framework under which FDA would actively regulate LDTs in 2016, although he could not pinpoint when in 2016 the final guidance would be issued.

The legislative hearing provided an opportunity for subcommittee members, Dr. Shuren, and the Centers for Medicare & Medicaid Services (CMS) official in charge of managing the Clinical Laboratory Improvement Amendments of 1988 (CLIA) program, an opportunity to critique legislative proposals under which most of the premarket reviews of LDTs would occur under an expanded CLIA program, with only a limited role for FDA. Those legislative proposals have reportedly been presented to members of the Senate Committee on Health, Education, Labor & Pensions. By contrast to those competing CMS-focused proposals, the subcommittee has circulated a legislative discussion draft which would give FDA responsibility for premarket review of all “in vitro clinical tests”—regardless of whether they are LDTs or kits—using a different standard than the one currently employed. CMS would retain jurisdiction over laboratory operations such as personnel and laboratory procedures.

The day before the November 17, 2015 hearing, FDA issued a report of 20 case studies of particular LDTs and types of LDTs that it believes illustrate the need for FDA oversight of LDTs. The report appears to have been issued as a response to a request from the same congressional subcommittee at its September 9, 2014 hearing for examples of instances where LDTs had caused harm. This report has drawn its own criticism. The Association for Molecular Pathology (AMP) released a critique on December 13, 2015, which enumerated alleged flaws in the FDA report.

In another development, in October 2015, FDA issued eagerly-awaited Federal Register notices (here and here) announcing that the Agency will allow sponsors to offer direct-to-consumer (DTC) carrier screening tests without 510(k) clearance for multiple autosomal recessive disorders (excluding tests for Cystic Fibrosis, which will continue to need 510(k)s) if the company and the test adhere to detailed special controls. In a series of letters to labs (here, here, here, and here), FDA also expressed its concerns over the LDT tests that they were offering. Thus, on the LDT front, the FDA giveth – exempting a broad swath of DTC LDTs without 510(k)s, and taketh – challenging labs that offered other types of LDTs.

Returning to the November 17, 2015 health subcommittee hearing, “Examining the Regulation of Diagnostic Tests and Laboratory Operations,” the hearing was markedly different from the subcommittee’s prior hearing on FDA oversight of LDTs on September 9, 2014. As we previously reported, at that hearing, the subcommittee members grilled Dr. Shuren for hours. The November 17, 2015 hearing was much friendlier to the Agency. While a few of the subcommittee members challenged whether FDA should have any role in the regulation of LDTs, the majority of the members seemed to accept the premise that FDA should have some role. Also, unlike the prior hearing, which included testimony from members of both the laboratory and medical device communities, this hearing only had two witnesses: Dr. Shuren and Patrick Conway, Deputy Administrator for Innovation and Quality & Chief Medical Officer, Office of the Administrator, CMS. Dr. Conway manages the CLIA program.

We previously reported on two legislative proposals – one by AMP and another by laboratory accreditor the College of American Pathologists – under which either CMS or its designee would perform most of the premarket reviews of LDTs through an expanded CLIA program. As previously reported, those two proposals are similar to each other in many respects. For instance, both exempt low-risk tests from premarket review, would give CMS or third-party reviewers sole authority to review moderate-risk tests, and FDA would only get involved for high-risk tests (all high-risk tests under the CAP proposal and a subset of high-risk tests under the AMP proposal). AMP submitted a letter for the record of last month’s congressional hearing supporting its legislative proposal.

By contrast to the CLIA-centric approach in those legislative proposals, in October 2015, the House Energy & Commerce Committee circulated a discussion draft that would create a new center for in vitro clinical tests, which would report to the FDA Commissioner. Under this proposal, FDA would use a new standard – reasonable assurance of analytical validity and clinical validity – in reviewing all high-risk in vitro clinical tests, regardless of whether the test is offered by a laboratory or as a distributed product. The current standard for PMAs is reasonable assurance of safety and effectiveness. Premarket review of the test would fall to FDA; CMS would be in charge of laboratory operations.

Dr. Shuren and Dr. Conway testified during last month’s congressional hearing that legislative proposals where FDA conducts the premarket review for some tests, and CMS conducts the premarket review for other tests, would lead to duplication and inconsistency. Dr. Conway repeatedly stated that CMS does not have the resources or expertise to conduct premarket review of LDTs. In response to a question, Dr. Conway said that giving CMS responsibility for premarket review could cause a backlog that would stifle innovation.

As for FDA’s resources, Dr. Shuren mentioned that laboratories are “at the table” as part of the current negotiations between industry and FDA related to the upcoming medical device user fee reauthorization. In a December 7, 2015 letter sent by the subcommittee with questions for the record, Rep. Blackburn (R-TN) asked Dr. Shuren to provide additional detail about those user fee negotiations. “To what extent in the ongoing MDUFMA IV negotiations have any discussions included projections or proposals taken into account the anticipated increase in workload or resource needs required for regulating…LDTs within the MDUFMA program? If so, please provide the Committee with such estimates for workload and resource needs. If not, when does the FDA expect to release such estimates?”

In that same letter, Rep. Blackburn asked Dr. Shuren for timelines on the internal reviews that will precede the release of the final guidance. “Please provide the Committee with the date when [CDRH] expects to complete the Center’s internal work on the final guidance and submit to the FDA Commissioner and/or Health and Human Services and/or the Office of Management and Budget for review and approval.” The letter requests that FDA respond by close of business December 21, 2005.

Dr. Shuren did not discuss during the hearing how the final version of the framework will differ from the proposed version. He did clarify that most modifications to LDTs that had already gone through FDA premarket review would not trigger new review. “Only big changes” would require a new submission to the agency, he testified. Specifically, he said that modifications to intended use or alteration of performance specifications could trigger a new review. Of course, the size of the change is in the eye of the beholder: what is “big” to FDA may seem trivial to a lab.

Dr. Shuren provided as examples of moderate-risk tests ones for cystic fibrosis, herpes and heart failure. He said that most moderate-risk tests would be subject to FDA premarket review; however, there would be some moderate-risk tests for which special controls would suffice. He provided carrier screening as an example of a moderate-risk test where FDA does not require premarket review (other than CF).

Both Dr. Shuren and Dr. Conway expressed concern about the “deemed approved” provisions in some legislative proposals. The concept of the deemed approved provisions is that FDA or CMS or its designee would have a certain amount of time to act on a submission; if the entity did not act within a certain time, the test would be “deemed” approved/cleared. Dr. Shuren said that he is concerned that faced with such a provision, FDA would either allow a test on the market without fully vetting the test, or in the alternative, deny a good test because it does not have enough time to resolve questions. This does not seem to have been the outcome for Investigational Device Exemption applications, which similarly have a “deemed approved” provision. Dr. Shuren also stated that there is no way for a patient to know whether a test came to market because it was deemed approved because the agency ran out of time.

Asked how long it would take to review a moderate-risk LDT, Dr. Shuren responded that the current total time for FDA review of moderate-risk LDTs is “a little over 100 days.” This statement is somewhat odd because FDA currently only reviews LDTs if a sponsor voluntarily seeks approval or clearance (or in a few instances because of FDA pressure to do so). In addition, the FDA “total time” excludes the chunk of time sponsor spends responding to FDA. The average FDA review times for IVDs have been among the longest of any product category. Rep. Michael Burgess (R-TX), in his questions for the record, asked Dr. Shuren to provide details about FDA review metrics including “the number of IVD pre-market applications, de novo application, and 510(k) applications approved by the FDA annually” and “of these applications, how many are applications for modifications of IVDs previously approved or cleared by the FDA.”

Dr. Shuren also stated that FDA has “never proposed to regulate the practice of medicine” and there “actually is a statutory provision that prohibits us from doing so.” This citation to that statutory provision is interesting; some critics have argued that the agency has largely ignored that statutory provision when it comes to LDTs.

Thus, 2015 is ending on a noisy note on the LDT front. Of course, if FDA issues a final guidance in 2016, then 2015 will seem like a whisper in comparison.