FDA Releases Laboratory Developed Test Oversight Proposed Rule

The U.S. Food and Drug Administration (FDA) published a proposed rule in late September for the purposes of providing oversight of laboratory developed tests (LDTs). The implications of the rule are staggering.  The FDA estimates that half of existing LDTs could require premarket review, and most if not all LDTs could at least be required to comply with FDA regulatory controls, such as premarket notification, performance standards, post-market surveillance, and labeling requirements. U.S. House of Representatives Energy and Commerce Committee Chair Karen McMorris-Rodgers said the new rule “will stifle innovation of diagnostics, such as those used to detect rare diseases. By adding new costly regulations, patients could lose access to diagnostics that identify potentially fatal conditions.” Many in the laboratory community, particularly in academic medical centers, are concerned that the rule could pose significant challenges to their laboratories’ operations.

LDTs are generally defined by the FDA as an in vitro diagnostic (IVD) that is “intended for clinical use and that is designed, manufactured, and used within a single laboratory that is certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and meets the regulatory requirements under CLIA to perform high complexity testing.” This definition would give the FDA sweeping authority over LDTs, including authority over FDA-approved tests that are modified and validated by a medical laboratory, per CLIA. As one example, during the COVID-19 pandemic, many laboratories modified FDA-approved tests using different reagents or other supplies because of massive supply chain disruptions.

The FDA had been anticipating that it would secure oversight over LDTs via the Verifying Accurate Leading-edge IVCT Development Act, or "VALID Act." However, when that legislation failed to secure congressional approval last year, it opted to pursue a regulatory approach. Interestingly, both Senator Bill Cassidy, MD (R-LA), the senior Republican on the Senate Health, Education, Labor and Pensions Committee, and House Energy and Commerce Committee Chair Karen McMorris-Rodgers (widely credited as blocking the VALID Act from being approved by Congress last year) released statements opposing FDA’s release of its proposed rule, click here and here, respectively. During Congress’s consideration of the VALID Act last year, ASCP was active in opposing this legislation, supported by our grassroots network sending more than 10,000 letters to members of Congress.

Under the proposed rule, FDA would amend its regulations to make explicit that in vitro diagnostic products (IVDs) are devices under the Federal Food, Drug, and Cosmetic Act (FD&C Act) including when the manufacturer of the IVD is a laboratory. In conjunction with this change, the FDA proposes to phase out its general “enforcement discretion” approach for LDTs so that IVDs “manufactured” by a laboratory would generally fall under the same enforcement approach as other IVDs, except where meeting certain requirements under CLIA may be leveraged (see below for details). To implement the new regulatory scheme, the FDA is planning a five-stage phase-in over a four-year period.

FDA has moved away from the risk-tiering framework of VALID; instead, LDTs will be classified as either Class I, II, or III devices. Moreover, the rule will not “grandfather” tests that are currently on the market. A small number of testing exemptions from oversight are included in the proposed rule. These and other differences from the VALID Act seem to account for the FDA’s estimate that 50 percent of LDTs (generally those classified into either class II or class III) could require premarket review. This is a far higher portion of LDTs requiring premarket review than FDA previously suggested would be necessary under VALID. Former FDA Commissioner Scott Gottlieb, MD had estimated that only 10 percent of LDTs would require remarket review.

The FDA is proposing a few carve-outs in the proposed rule. The FDA proposes to maintain enforcement discretion for “1976-type LDTs.” The FDA defines these as tests that use “manual techniques (without automation) performed by laboratory personnel with specialized expertise; use of components legally marketed for clinical use; and design, manufacture, and use within a single CLIA-certified laboratory that meets the requirements under CLIA for high complexity testing”, e.g., immunohistochemistry. In addition, the FDA proposes to maintain enforcement discretion for human leukocyte antigen (HLA) tests, provided they are "designed, manufactured, and used in a single laboratory certified under CLIA that meets the requirements to perform high-complexity histocompatibility testing when used in connection with organ, stem cell, and tissue transplantation to perform HLA allele typing, for HLA antibody screening and monitoring, or for conducting real and 'virtual' HLA crossmatch tests."

The FDA indicated interest in stakeholder comments on several key issues, including whether the FDA should exercise enforcement discretion “with respect to premarket review and some or all quality standards (QS) requirements, for LDTs that are being offered as of the date of issuance of this proposed rule and are not changed with respect to indications for use or performance after that date.” While the Agency has not proposed to provide “grandfathering” for tests currently on the market, this statement indicates the agency may be receptive to such a request. The FDA only seems interested in considering this for tests classified as Class I and II devices, however. In addition, the FDA appears interested in stakeholder input on whether “leveraging programs such as the New York State Department of Health Clinical Laboratory Evaluation Program…or those within the Veterans Health Administration (VHA)” are appropriate.

The FDA is proposing to phase in implementation of its rule in five stages over four years, after which IVDs offered as LDTs generally would be expected to meet applicable requirements. The following outlines the FDA’s proposed five-stage process:

- Stage 1: End the general enforcement discretion approach with respect to medical device reporting (MDR) requirements and correction and removal reporting requirements one year after the FDA publishes a final phaseout policy, which the Agency intends to issue in the preamble of the final rule.

- Stage 2: End the general enforcement discretion approach with respect to requirements other than MDR, correction and removal reporting, QS, and premarket review requirements two years after the FDA publishes a final phaseout policy.

- Stage 3: End the general enforcement discretion approach with respect to QS requirements three years after the FDA publishes a final phaseout policy.

- Stage 4: End the general enforcement discretion approach with respect to premarket review requirements for high-risk IVDs 3½ years after the FDA publishes a final phaseout policy, but not before October 1, 2027.

- Stage 5: End the general enforcement discretion approach with respect to premarket review requirements for moderate risk and low risk IVDs (that require premarket submissions) four years after the FDA publishes a final phaseout policy, but not before April 1, 2028.

ASCP’s Commission on Science, Technology, and Policy is reviewing the proposed rule and will be preparing formal comments. ASCP does not believe that the 60-day comment period provides sufficient time for stakeholders to fully assess the rule’s impact on laboratory testing operations and its impact on patient care. ASCP will be asking the FDA to extend its comment period, preferably to 120 days. ASCP will also be working with other laboratory organizations to voice many serious concerns about the proposed rule.

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