On May 6, 2024, the FDA published its final rule on laboratory developed tests (LDTs) in the Federal Registrar, marking a pivotal turn in FDA’s long-running battle to move away from its traditional stance on enforcement discretion for LDTs. FDA must now navigate the complexities of implementing the issued phase-out period, which could be further complicated if legal opposition ensues.
The LDT proposed rule published on September 29, 2023, amassed nearly 7,000 comments from stakeholders. In response to this feedback, there were substantial changes in the issued LDT Final Rule. Let’s look at what has remained the same and what has changed between the LDT Proposed Rule and LDT Final Rule:
What Is the Same?
IVD Definition:
The LDT Final Rule revises the definition of IVDs under 21 C.F.R. § 809.3(a) to include “when the manufacturer of these products is a laboratory.” This language was implemented exactly as initially proposed in the LDT Proposed Rule.
Phase-Out Policy:
FDA’s LDT Final Rule outlines a phase-out period to gradually enforce pre-market and post-market regulatory requirements over a four-year period. The phase-out period is broken up into five stages, and remains largely consistent with the proposed rule but includes some minor adjustments:
Stage 1 (Effective May 6, 2025)
- Compliance with Medical Device Reporting (MDR) requirements (21 C.F.R. Part 803), correction and removal reporting requirements (21 C.F.R. Part 806), and complaint handling requirements (21 C.F.R. Part 820.198).
- Change from Proposed Rule: Complaint handling requirements was moved to Stage 1 from Stage 3, emphasizing its importance for effective MDR compliance.
Stage 2 (Effective May 6, 2026)
- Compliance with registration and listing requirements (21 C.F.R. Parts 607 and 807), labeling requirements (21 C.F.R. Parts 801 and 809), and investigational use requirements (21 C.F.R. Part 812) for LDTs involved in clinical investigations.
- Change from Proposed Rule: The final rule explicitly includes registration, listing, and labeling, and adds investigational use requirements due to previous confusion about FDA’s enforcement approach.
Stage 3 (Effective May 6, 2027)
- Compliance with all outstanding Quality System (QS) Requirements (21 C.F.R. Part 820):
- Note: At the time Stage 3 is effective, FDA intends to implement the integrated QMSR regulation (aligned with ISO 13485) (Feb. 2, 2026). Therefore, labs should plan to have ISO 13485 certified QMS that aligns with the QMSR by this date.
- Change from Proposed Rule: Complaint handling requirements was moved to Stage 1. FDA also expects labs to retain manufacturing records (21 C.F.R. Part 820, Subpart M), prior to reaching Stage 3.
Stage 4 (Effective Nov. 6, 2027)
- Compliance with pre-market review requirements for high-risk LDTs, including submission of pre-market approval (PMA) applications, humanitarian device exemptions (HDE), or biologics license applications (BLA). If a submission is received before this stage begins, FDA will continue to exercise enforcement discretion during the review process.
- Note: FDA has recently issued a communication that they are planning on down classifying many “high-risk” IVDs. As such, in the final LDT rule, they comment that they anticipate very few IVDs will be PMAs and they will issue further guidance about various IVD types before this phase comes into force.
- Change from Proposed Rule: No change.
Stage 5 (Effective May 6, 2028)
- Compliance with pre-market review requirements for moderate and low-risk LDTs, including submission of pre-market notification (510(k) notification) or de novo request. If a submission is received before this stage begins, FDA will continue to exercise enforcement discretion during the review process.
- Change from Proposed Rule: No change.
What Has Changed?
Carve-Outs:
FDA has introduced several carve-outs in its enforcement discretion phase-out policy in the LDT Final Rule. The carve-outs are a result of FDA’s acknowledged resource limitations and their goal of mitigating the financial impact of the rule as well as minimize disruption to patient care. These carve-outs do not exempt all requirements, and FDA stated in the rule that they reserve the right to amend these carve-outs at their discretion. All requirements that are applicable to each category must be implemented according to the phase-out policy stages described above.
Key carve-outs include:
1. Currently Marketed LDTs: Applies to LDTs marketed before the LDT Final Rule was published on May 6, 2024.
- Exempted Requirements: Pre-market review and most QS requirements, except for recordkeeping
- Requirements Enforced:
- MDR (21 C.F.R. Part 803)
- Corrections and removals reporting (21 C.F.R. Part 806)
- Registration and listing (21 C.F.R. Parts 607 and 807)
- Labeling (21 C.F.R. Parts 801 and 809)
- Recordkeeping (21 C.F.R. Part 820 Subpart M)
FDA has asked that all labeling, including test protocols, menus, and reports be submitted to them. They plan to use this approach to monitor and identify any problematic LDTs on the market. FDA intends to focus its review on performance summaries and claims of superiority and will act if labeling is found to be false, misleading, or lacking in safety and effectiveness assurances.
2. Tests Meeting Unmet Needs: LDTs manufactured and performed by a lab integrated within a healthcare system to meet an unmet need of patients receiving care within the same healthcare system for which there is no FDA-cleared test available.
- Exempted Requirements: Pre-market review and most QS requirements, except for recordkeeping
- Requirements Enforced: Recordkeeping (21 C.F.R. Part 820 Subpart M)
3. Nonmolecular Antisera LDTs: Tests for rare red blood cell antigens where such tests are manufactured and performed in blood establishments, including transfusion services and immunohematology laboratories, and where there is no alternative available to meet the patient’s need for a compatible blood transfusion.
- Exempted Requirements: Pre-market review and most QS requirements, except for recordkeeping
- Requirements Enforced: Recordkeeping (21 C.F.R. Part 820 Subpart M)
4. LDTs Approved by New York State (NYS) Clinical Laboratory Evaluation Program (CLEP): Moderate-risk and high-risk tests that have received approval through NYS CLEP. Since LDTs are evaluated for both analytical and clinical validity under CLEP, FDA considers this approval process sufficient to mitigate the risk of inaccurate and unreliable tests and can substitute effectively for FDA’s pre-market review requirements.
- Exempted Requirements: Pre-market review
- Requirements Enforced: MDR (21 C.F.R. Part 803), corrections and removals reporting (21 C.F.R. Part 806), registration and listing (21 C.F.R. Parts 607 and 807), labeling (21 C.F.R. Parts 801 and 809), and all QS requirements (21 C.F.R. Part 820)
Enforcement Discretion
FDA only specified 3 categories of LDTs that would continue to receive full enforcement discretion in the LDT proposed rule. These continue to fall under the full enforcement discretion under the LDT Final Rule as well:
1. 1976-Type LDTs: These tests resemble those available in 1976 (at the time of enactment of the Medical Device Amendments of 1976) and involve manual techniques, legally marketed components, and are performed in a single CLIA-certified lab.
2. Human Leukocyte Antigen (HLA) Tests: Used for organ, stem cell, and tissue transplantation within a single CLIA-certified lab.
3. Forensic Tests: Intended solely for law enforcement purposes.
Additionally, FDA has included a new category in the LDT Final Rule, which will also receive full continued enforcement discretion:
4. Tests Within the Department of Defense or Veterans Health Administration: Tests that are manufactured by and performed within these entities.
Comparison of Compliance Requirements — Currently Marketed vs. New LDTs
The most notable exception in the enforcement discretion phase-out in the LDT Final Rule by far is currently marketed LDTs. Let’s compare the compliance requirements that differentiate currently marketed LDTs from new LDTs introduced after the LDT Final Rule’s enactment.
| Stage | Effective Date | Compliance Requirements in LDT Final Rule | Currently Marketed LDTs | New LDTs |
|---|---|---|---|---|
| 1 | May 6, 2025 |
| All requirements apply. | All requirements apply. |
| 2 | May 6, 2026 |
| All requirements apply. | All requirements apply. |
| 3 | May 6, 2027 | Remaining QS requirements (21 C.F.R. Part 820) | Only applicable QS requirement is records requirements (21 C.F.R. Part 820, subpart M), in addition to complaint handling implemented by Stage 1 date.* | Full QS implementation is required by this date. |
| 4 | Nov. 6, 2027 | Pre-market review requirements for high-risk LDTs (i.e., PMA, HDE, or BLA) | No requirements apply.* | All requirements apply. |
| 5 | May 6, 2028 | Pre-market review requirements for low- and moderate-risk LDTs (i.e., 510(k) notification or de novo request) | No requirements apply.* | All requirements apply. |
Industry Response
Despite FDA’s efforts to moderate its initial more stringent proposal, industry response to FDA’s LDT Final Rule has been largely critical. James Boiani, an IVD, drug, and medical device attorney, voiced that while FDA had scaled back from its initial proposal in response to industry concerns regarding test disruption and availability moderated its initial stance, many stakeholders remain opposed.1
The American Clinical Laboratory Association (ACLA), along with other lab organizations such as the National Independent Laboratory Association (NILA), the American Association of Bioanalysts (AAB), the Association for Diagnostics and Laboratory Medicine (ADLM), and the College of American Pathologists (CAP), expressed strong opposition.2-5
Within Congress, legislators who supported the Verifying Accurate Leading-edge IVCT Development (VALID) Act, proposed in 2021 to enforce FDA oversight for all IVDs, including LDTs, have criticized the rule. However, legislators have recognized that the FDA’s action was due to Congress not yet acting on the matter.6
In contrast, AdvaMed, a prominent medical device industry group, welcomed the rule as a substantial advancement, although it urged legislative action through the VALID Act to further streamline IVD regulation.
What’s Next for LDT Regulation?
Despite FDA’s changes to the LDT Final Rule, the issue of LDT regulation seems destined for further deliberation in Congress. Boiani and others predict that although the FDA has been responsive to industry feedback, the contentious and ambiguous nature of the rule suggests that litigation is likely, which may prompt Congressional action.1 This could occur through new legislation, potentially through the VALID Act, or as part of negotiations for the Medical Device User Fee Amendments (MDUFA) reauthorization which is set to expire in 2027.
The future of LDT regulation will likely remain a focal point for Congress, stakeholders, and the FDA. Ongoing discussions and potential legal challenges are likely to influence how LDTs are regulated moving forward, underscoring the need for a balanced approach that addresses both industry concerns and patient safety.
How Avania Can Help
This is a time of significant change and uncertainty for LDT labs. At Avania, we offer specialized support to navigate this evolving landscape and assist in transitioning LDTs to FDA-regulated IVDs. Our services include strategic regulatory and clinical planning, preparation for FDA submissions, and managing post-market activities. We also help orchestrate QMS activities to meet FDA QS Regulation requirements, review instrument and assay validation data for FDA clearance, and facilitate pre-submission interactions with the FDA to ensure compliance with testing and submission requirements.