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Proposed Regulation Changes to Laboratory Developed Tests | Avania

On September 29, 2023, FDA proposed to extend the definition of an in vitro diagnostic (IVD) to include laboratory developed tests (LDTs), making LDTs subject to the same FDA review process as IVDs. This has significant implications for LDT laboratories, IVD manufacturers, and medical professionals.

Increased FDA Oversight of Laboratory Developed Tests

Historically, FDA has not enforced regulatory requirements for most LDTs, in a policy termed as “enforcement discretion.” However, advances in the technology used in LDTs such as NGS, broader distribution, and increasing usage of LDTs in making important healthcare decisions in fields such as oncology, propelled by the large volume of EUA requests for COVID-19 diagnostics that were not designed or validated properly, raised FDA’s concerns regarding the safety and effectiveness of LDTs. On September 29, 2023, FDA proposed to amend the definition of IVDs to “include when the manufacturer of these products is a laboratory” with a phased approach for compliance beginning one to four years after the final LDT rule is published.

  • Stage 1: One year after the final rule, FDA will end enforcement discretion regarding Medical Device Reporting (MDR) and correction and removal reporting requirements.
  • Stage 2: Two years after the final rule, FDA will end enforcement discretion for requirements other than MDR, correction and removal reporting, quality systems (QS), and premarket review.
  • Stage 3: Three years after the final rule, FDA will end enforcement discretion for QS requirements.
  • Stage 4: Three and a half years after the final rule, but not before October 1, 2027, FDA will end enforcement discretion regarding premarket review for high risk IVDs.
  • Stage 5: Four years after the final rule, but not before April 1, 2028, FDA will end enforcement discretion regarding premarket review for moderate and low risk IVDs.

Industry Response to Changes in LDT Regulation

Upon release of the proposed rule, FDA provided a 60-day public comment period. Roughly 6,700 public comments were submitted in response, with a significant majority opposing the rule.

Prominent laboratory groups were against the rule, including the American Clinical Laboratory Association (ACLA) and National Independent Laboratory Association (NILA). The groups raise concerns that labs could struggle to comply with the increased financial and regulatory burden, reducing or delaying patient access to testing and slowing the development of novel tests. For example, the only diagnostic tests currently offered to confirm the presence of fentanyl and xylazine are LDTs. LDTs are also often used to measure vitamin levels, hormones, or presence of trace and toxic elements, where no FDA-cleared assay is available.

However, there has been some support from IVD manufacturers and from professional organizations, specifically in the field of oncology. The American Society of Clinical Oncology (ASCO), the country’s largest group of oncology providers, issued support for the proposed rule, arguing that FDA oversight of LDTs is “necessary to ensure the safety and effectiveness of LDTs used for directing critical treatment decisions.”

Supporters argue that the proposed rule will standardize LDT quality, enhance patient safety, and prevent tests with limited clinical performance studies and medical relevance from being used for diagnosis.

Legal Considerations on FDA Authority

Multiple groups have questioned FDA’s legal authority to unilaterally expand its regulatory jurisdiction, pushing for legislative action from Congress to determine FDA’s jurisdiction and potential litigation. The ACLA, representing the largest commercial reference laboratories in the U.S., challenged FDA’s authority to categorize LDTs as medical devices, proposing that the inherent nature of LDTs as services offered by trained laboratory professionals, rather than physical products, sets them apart from conventional medical devices. The LDT rule was received for review by OMB on March 1, 2024, and is expected to be published within the next few months. So far, there has been no indication of legislative action from Congress, and we may soon see the LDT rule challenged in court.

FDA Reclassification of High Risk IVDs

On January 31, 2024, the Center for Devices and Radiological Health (CDRH) announced the intent to initiate the reclassification process for most IVDs that are currently class III (high risk) into class II (moderate risk), where there is sufficient information to establish special controls for the test. This follows on the heels of the proposed LDT rule, likely due to the downregulation of IVDs helping FDA manage the significant increase in workload upon implementation of the final LDT rule. The proposal specifically called out companion diagnostic tests and infectious disease tests, which are a significant proportion of tests that the LDT rule seeks to target.

For the device industry, reclassification reduces the financial and regulatory burden of affected tests, allowing manufacturers and laboratories, upon the LDT rule, to seek marketing clearance through pre-market notification (510k or De Novo pathways) rather than pre-market approval (PMA), which is the most stringent type of FDA medical device review.

Presently, the reclassification process has been initiated for three types of infectious disease diagnostic tests:

  • Nucleic acid and serology-based IVDs for diagnosis or management of hepatitis B patients
  • Serology-based ICDs for detection of human parvovirus B19
  • Cell-mediated immune reactivity IVDs for identification of biological responses associated with tuberculosis infection

It is expected that many more tests will be added to this list as the LDT rule is finalized.

How Avania Can Help

This is a time of significant regulatory uncertainty for LDT manufacturers. At Avania, we help clients navigate this evolving regulatory landscape by supporting LDT manufacturers through a customized analysis of requirements to transition to an FDA-regulated IVD and strategic planning to meet changes in regulatory requirements, FDA submissions, and continued post-market activities. This includes planning QMS activities to meet FDA QSR requirements, a review of instrument and assay validation data and recommendations for FDA clearance, development and execution of a customized regulatory and clinical strategy, and organizing pre-submission interactions with FDA to confirm pre-clinical and clinical testing requirements as well as managing regulatory submissions.

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