Laboratory Developed Tests Should Be Carefully Regulated

Position:

We as clinical laboratory professionals agree that laboratory developed tests (LDTs) must be regulated to ensure their accuracy and overall patient safety. We ask Congress and the Administration to provide stakeholders in the laboratory community with sufficient time to develop a consensus regulatory approach for the oversight of LDTs.

With estimates that FDA may have to review 60,000 or more LDTs, we are concerned that the guidance advanced by the FDA and the draft legislation offered by the House Energy and Commerce Committee may exacerbate the slow, resource-intensive FDA oversight that manufacturers have complained has constrained the ability to update and modify commercial test kits in a timely manner. Thus, we believe that enhanced oversight requires a coordinated, streamlined, patient-centered modernization of the oversight by FDA as well as by CMS.

Rationale:

LDTs are defined by the FDA as in vitro diagnostic tests that are designed, manufactured, and used within a single laboratory. In 2014, the Food and Drug Administration (FDA) released draft guidance to provide enhanced oversight of LDTs. FDA proposed a three-tier risk-based framework for this oversight. High-risk (class III medical devices) and moderate-risk (class II) LDTs would be subject to premarket review requirements (i.e., premarket notification, or 510(k) submissions), FDA registration, listing, and reporting requirements. Low-risk LDTs (class I) and LDTs for rare diseases or unmet medical needs would be under FDA enforcement discretion for applicable premarket review and quality systems requirements; they would be required to comply with registration and listing and adverse event reporting within six months of the release of FDA’s final guidance. FDA anticipates its oversight review process for existing LDTs will take 9 years, starting with high risk LDTs then moderate risk LDTs after year 5.

The FDA will focus its initial efforts on reviewing LDTs that have identical intended uses as FDA-approved or -cleared companion diagnostics or class III medical devices as well as LDTs that determine the safety or efficacy of blood or blood products. Among those tests identified as low risk are those for rare diseases and “traditional LDTs,” which the FDA’s identifies as those using only legally marketed components, requiring non-automated interpretation, and used in the care of patients within a single health care organization.

The agency has yet to release final guidance to clarify test risk-classification and has said it will rely on expert advisory panels to help classify tests based on risk. FDA also suggested allowing third-party reviewers to play a role in reviewing lower-risk LDTs. Another element of FDA’s proposal concerns demonstrating the analytical (already required by CLIA) and clinical validity (not currently required).

Overview of Alternative Regulatory Approaches:

Most stakeholder groups have agreed with FDA’s risk-tiering approach and the need to verify analytical and clinical validity; however, there has been significant disagreement among laboratory professionals over which agency, FDA or the Centers for Medicare and Medicaid Services (CMS), should have oversight and how much oversight they should have. Alternative oversight proposals have been released by the Diagnostic Test Working, the College of American Pathologists, and the Association for Molecular Pathology.

The Diagnostic Test Working Group (DTWG), a coalition comprised of diagnostic manufacturers and large reference laboratories, would task FDA with oversight for “in vitro clinical tests (IVLT)” design, development, validation, platform manufacturing, and preparation of reagents. CMS would have oversight for typical laboratory activities, such as preparing reagents, developing lab operating procedures, pre-analytical processes, test performance and results reporting. This plan would create a new Center for in Vitro Clinical Tests at FDA. This proposal substitutes “reasonable assurance of safety and effectiveness” with “reasonable assurance of analytical validity and clinical validity”andrequires premarket review for high- and moderate-risk testsand premarket notification for low-risk tests.

The College of American Pathologists (CAP) has proposed a CLIA-centric plan, with authority for high-risk LDTs under FDA’s jurisdiction. All other risk-tiers would be under the oversight of CMS/deemed accrediting agencies. Like the FDA plan, CAP would require LDTs to establishtheir analytical and clinical validity. CAP would require premarket review and post-market review for high-risk tests.Moderate risk tests would also be subject to premarket review. Low-risk tests would be monitored via the normal CLIA inspection process. CAP’s plan would also subject high-risk tests to post-market review requirements. Modifications to FDA-approved tests would be reportable, with significant modifications reportable to FDA and lesser modifications reportable to CMS/third parties. CAP’s plan grandfathers tests in use prior to April 1, 2003.

TheAssociation for Molecular Pathology (AMP) has also proposeda CLIA-centric plan. One of the key differences between the CAP and AMP plans is that the AMP plan would provide almost no role for the FDA. An FDA role would be an option for laboratories seeking review of multi-analyte algorithm-based assays (MAAAs). Plan requires premarket review of high- and moderate tests. AMP requires review of modifications to FDA approved tests if changes increases risk profile or significantly alters performance. AMP recommends changes to CLIA for proficiency testing, inspection, recordkeeping and reporting of laboratory errors.

Congressional Efforts:

The House Energy & Commerce Committee has released two draft bills using the DTWG framework. The Senate Health, Education, Labor and Pensions Committee is working on draft legislation; however it has not yet been released. It is believed that the Senate HELP Committee may utilize a hybrid model incorporating various elements of the aforementioned proposals.

For further information on this issue, please contact Patrick Cooney at 202-347-0034 x101 or via email at .