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On January 13, 2017, the U.S. Food and Drug Administration (FDA) issued a (LDTs) (Discussion Paper). The Discussion Paper follows FDA’s late 2016 announcement that, contrary to the Agency’s earlier reports, it would not issue a final guidance on its proposed oversight of LDTs to allow “for further public discussion on an appropriate oversight approach, and to give our congressional authorizing committees the opportunity to develop a legislative solution.” Discussion Paper at page 1.

The Discussion Paper is the FDA’s thoughts after synthesizing more than 300 sets of comments on prior drafts of the Guidance (2014 and 2015) as well as comments and suggestions from public meetings and workshops.

Today’s Laboratory Testing

Advances in medical technology have increased the use of diagnostic tests to guide therapeutic decisions for many diseases and conditions, especially in the context of personalized medicine. In 2014, citing the need to ensure that certain diagnostic and clinical tests are accurate, consistent and reliable, FDA announced that the Agency was lifting its enforcement discretion over certain LDTs. (). The 2014 Guidance proposed a risk-based, phased-in framework for oversight of LDTs that was in accordance with FDA’s current regulation of in vitro diagnostic devices (IVDs). Any clinical or diagnostic test that is designed, manufactured and used in a single laboratory is considered by the Agency as an LDT. Historically, LDTs were manufactured in small volumes by local laboratories. These tests were used and interpreted directly by physicians and pathologists working within a single institution. In addition, traditional LDTs were manufactured using components that were legally marketed for clinical use. More recently, LDTs are manufactured with components and instruments that are not legally marketed for clinical use and rely heavily on high-tech instrumentation and software to generate results and clinical interpretations.

Noting the changes in the complexity and use of LDTs, FDA reported that the policy of general enforcement discretion towards LDTs was no longer appropriate, and that historical oversight by the Centers for Medicare & Medicaid Services (CMS) under the Clinical Laboratory Improvement Amendments (CLIA) regulations was deficient. Thus, changes in laboratory technology and its use prompted FDA to re-evaluate its prior hands-off approach to regulation.

A Risk-Based Approach to Oversight

The Discussion Paper notes that while there is a growing consensus that additional oversight of LDTs is necessary, there remains disagreement among stakeholders as to which federal agency would be responsible for any additional oversight. Discussion Paper at page 2. In contrast, most stakeholders appeared to agree on the following features:

• “A risk-based approach to oversight;
• Independent premarket review for certain tests and for some modified tests;
• A focus on analytical and clinical validity as the basis for test approval;
• Risk classification activities;
• Adverse event reporting;
• Exemption of certain categories of tests from premarket review;
• A robust laboratory quality system;
• ‘Grandfathering’ for tests available prior to a specific date; and
• Public availability of test performance information.”

Discussion Paper at page 2.

The Agency notes in its Discussion Paper that based on extensive feedback from stakeholders, “several alternatives to what FDA proposed in 2014 should be considered, including:

• Exempting LDTs already on the market from all FDA oversight except for adverse event and malfunction reporting (‘grandfathering’), and exempting traditional LDTs … and LDTs for public health surveillance from all oversight;
• Not adopting proposals requesting laboratories to notify FDA of their LDTs on the market because FDA generally would no longer need to classify LDTs currently on the market as the result of ‘grandfathering’;
• Providing additional time before FDA would begin actively overseeing certain regulatory requirements; and
• Shortening the overall phased-in timeframe.”

Discussion Paper at page 3.

FDA’s 2017 Proposed Approach

The Agency continues to advocate a “risk-based” approach to LDT oversight. FDA’s prospective oversight proposes focusing on new and significantly modified high and moderate risk LDTs. Previously marketed LDTs would not be expected to comply with most or all FDA regulatory requirements. Discussion Paper at page 4. However, new and significantly modified LDTs in certain categories would not be expected to comply with premarket review, quality systems, and registration and listing requirements unless necessary to protect the public health. These “exempt” categories include: low risk LDTs; LDTs for rare diseases; traditional LDTs. LDTs intended solely for public health surveillance; certain LDTs used in CLIA-certified labs; and LDTs intended solely for forensic use.

Because LDTs currently on the market would be “grandfathered” thereby reducing the overall workload on laboratories and FDA, premarket review of new and significantly modified LDTs could be phased-in over 4 years rather than a period of 9 years that was proposed in the 2014 Guidance Document. The new 4 year phase-in would follow the following timeline:

1. Year One: Serious adverse event and malfunction reporting for all LDTs except traditional LDTs, LDTs intended for public health surveillance, some stem cell/tissue/organ transplantation LDTs, and LDTs intended solely for forensic use;
2. Year Two: Premarket review for new/modified LDTs with the same intended use as IVD approved under a PMA;
3. Year Three: Premarket review for new/modified LDTs with the same intended use as a Class II device subject to 510(k) clearance; and
4. Year Four: Premarket review for new/modified LDTs that do not fall into the above categories.

Discussion Paper at page 5.

The Discussion Paper also reviews the evidence standards for FDA’s premarket review of the categories of tests suggested for additional oversight. In addition, the Agency proposes expanding its third party premarket review program to include eligible LDTs, noting programs such as New York State’s Clinical Laboratory Evaluation Program. With respect to postmarket surveillance of LDTs, the Agency recommends that laboratories would initially report serious adverse events for all tests except the exempted categories of tests noted above under “Year One” implementation of the review.

Looking Ahead

FDA’s 2017 proposal, as outlined in the Discussion Paper, maintains the Agency’s original focus on the public’s access to reliable, safe and effective medical technologies without unnecessarily discouraging innovation and increasing the cost of providing these technologies. The Discussion Paper notes that while the report does not represent the formal position of FDA nor is it a final version of the LDT guidance documents published in 2014, it is hoped that its publication will continue to advance further public discourse.