On September 29, 2023, the U.S. Food and Drug Administration (FDA) made public a potentially game-changing proposal concerning the regulatory framework for laboratory-developed tests (LDTs). Understanding the nuances and implications of these changes is paramount for specialists in regulatory affairs and the clinical development arena.

The FDA is proposing a change to its regulations to explicitly classify In Vitro Diagnostics (IVDs) as devices under the Federal Food, Drug, and Cosmetic Act (FD&C Act), irrespective of the manufacturer being a laboratory that previously conducted business and was certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA). This change is driven by the intent to consistently regulate all producers of such devices.

Historical analysis shows that after the 1976 Medical Device Amendments, the FDA typically “exercised discretion” in the enforcement of most Laboratory Developed Tests (LDTs) and seldom used this discretion. However, with LDTs now more integrated into pivotal healthcare decisions and using advanced technology to serve a broader audience, their associated risks have significantly escalated compared to 1976. The proposed phase-out of this enforcement discretion is envisioned to fortify public health and promote the development of innovative IVDs, ensuring they adhere to safety and efficacy standards.

At the core of the new FDA Proposed Rule is the redefinition of IVDs to encompass those manufactured by laboratories, leading to a more uniform regulation in line with other IVDs. The FDA’s authority for this rule revision springs from multiple sections of the FD&C Act, covering a spectrum from defining the device to its overarching regulation.

According to FDA, the changes are poised to yield significant benefits, mainly for patients, by mitigating the health adversities stemming from problematic IVDs identified as LDTs. These benefits are estimated to oscillate between $1.81 billion and $86.01 billion annually, given varying discount rates. Moreover, the FDA says there would be indirect advantages, such as minimized legal expenses and reduced costs for healthcare systems due to these IVD issues.

However, laboratories are expected to bear costs, projected between $2.39 billion to $19.45 billion annually, to align with these statutory and regulatory requisites. FDA will shoulder certain costs, but anticipated user fee offsets will trim these expenses to an estimated range of $103 million to $1.06 billion each year.

Breakdown of FDA’s New Proposed Rule 

Premier Research has identified five essential modifications that regulatory and clinical development specialists must acquaint themselves with.

1. Expanded Definition: FDA aims to reshape the boundaries of IVDs within 21 CFR Part 809.3. By expressly incorporating LDTs, the proposal suggests viewing IVDs as devices under the FD&C Act even when manufactured by a laboratory that was previously regulated under CLIA. This redefinition underscores the intent to bring LDTs into the same regulatory fold as other medical devices.
2. Rigorous Compliance Ahead: If LDTs fall under the IVD umbrella, they would be subject to the FDA’s medical device regulatory requirements. For regulatory affairs specialists, this implies heightened diligence to ensure that LDTs align with premarket review standards. Clinical development experts would need to navigate the potential complexities arising from this regulatory shift, particularly in terms of trial design and evidence generation.
3. Re-evaluating Existing LDTs: The proposal does not automatically “grandfather” any of the LDTs currently in use. This means re-evaluation and potentially recalibrating existing LDTs to align with the new stipulations. Regulatory affairs specialists must be prepared to undertake a comprehensive review of LDTs already in circulation and devise an appropriate strategy.
4. Exemptions: Despite its overarching reach, the proposal does carve out exemptions. Forensic tests and human leukocyte antigen tests, for instance, won’t be subsumed under the new regulations. Regulatory professionals need to be well-versed with these nuances to advise their organizations effectively.
5. Implementation: FDA recognizes the challenges this major shift can bring. They propose a phased approach to transition away from their policy of enforcement discretion for LDTs. The rollout is spread across five phases over four years (see below). The final two phases will zero in on premarket review prerequisites. The exact commencement of this phase-out will be determined by the publication date of the FDA’s final phase-out policy. This sea change will necessitate a proactive strategy from regulatory professionals, ensuring compliance at each step.

Proposed Timeline

Phase1 (1 year after publication)	End of Enforcement Discretion for: Medical Device Reporting (MDR). Correction and removal reporting requirements.
Phase 2 (2 years after publication)	End of Enforcement Discretion for: All requirements other than MDR, correction and removal reporting, Quality System (QS), and premarket review. LDT Requirements: Registration and listing. Labeling. Investigational device exemptions.
Phase 3 (3 years after publication)	End of Enforcement Discretion for: QS requirements (good manufacturing practice for medical devices).
Phase 4 (3.5 years after publication; no earlier than October 1, 2027)	End of Enforcement Discretion for: Premarket review for high-risk IVDs. Regulation Update: Class III LDTs will now fall under full Premarket Approval (PMA) requirements as per the FD&C Act.
Phase 5 (4 years after publication; no earlier than April 1, 2028)	End of Enforcement Discretion for: Premarket review for moderate-risk and low-risk IVDs needing premarket review. Regulation Update: Class II LDTs (and Class I LDTs needing premarket review) will adhere to the full 510(k) premarket notification and de novo requirements under the FDCA. The FDA generally will not enforce against LDTs with 510(k)s and de novo applications submitted within this 4-year window until the review of the submission is finalized.

Note: The specific dates will depend on when the FDA publishes its final phase-out policy. Adjust the timeline accordingly once that date is confirmed.

Public Comment and Active Participation Encouraged

FDA has set December 4, 2023, as the deadline for public comments on this Proposed Rule. It’s an opportunity for regulatory and clinical development experts to voice their insights, concerns, and recommendations, potentially shaping the final rule. Premier expects a significant response from clinical laboratories doing business in the United States.

Lab Industry Reaction and Historical Insights

The American Clinical Laboratory Association (ACLA) stands as a significant dissenting voice. They challenge the FDA’s authority to categorize LDTs under its medical device framework, contending that the inherent nature of LDTs sets them apart from conventional medical devices. From a regulatory perspective, ACLA posits that legislative action, bespoke to LDTs’ specific attributes, is the more fitting route—drawing parallels to distinct legislative frameworks that govern areas such as food, supplements, and cosmetics.

Regulatory affairs and clinical development professionals can anticipate several actions to the FDA’s Proposed Rule from ACLA including:

1. Formal Response: ACLA is poised to articulate its concerns through formal channels, urging FDA to reconsider the proposed regulatory approach.
2. Legislative Engagement: The association will likely amplify its advocacy by liaising with Congress. Their goal? To champion legislation that’s dialed into the unique nuances of diagnostics, providing a clearer regulatory path for specialists in the field.
3. Stakeholder Collaboration: In the complex realm of diagnostics, a multidisciplinary approach is crucial. ACLA is expected to foster collaborative dialogues, bringing together patient groups, laboratory experts, and industry thought leaders to mold a cohesive stance.
4. Revisiting the VALID Act: Given ACLA’s historical alignment with the VALID Act, regulatory professionals might see renewed efforts around this legislation or the inception of a new legislative draft, aiming for bipartisan alignment.
5. Distinguishing LDTs from Medical Devices: A focal point in ACLA’s advocacy will be delineating LDTs from traditional medical devices. This distinction will be pivotal in conversations, offering regulatory affairs and clinical development experts a clearer understanding of the terrain they navigate.

For those navigating the intricate corridors of regulatory affairs and clinical development, understanding ACLA’s position and potential actions is invaluable in strategizing and forecasting the regulatory trajectory for LDTs.

Furthermore, it is useful to note the FDA’s prior attempt in October 2014 when they introduced a comparable proposal entitled “Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs); Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical Laboratories.” At that time, the agency encountered substantial opposition and received an abundance of feedback from various stakeholders, including ACLA, the College of American Pathologists, the Association for Diagnostics and Laboratory Medicine (formerly known as the American Association of Clinical Chemistry), as well as numerous individuals and hospital systems.

In response to the input received, the FDA carefully reconsidered its draft guidance, weighing factors such as the extensive presence of LDTs on the market and the practical challenges associated with implementation. This deliberation ultimately led FDA to revert to its original stance of maintaining regulatory discretion. While the current proposal in 2023 may suggest heightened determination on the FDA’s part, this historical context, combined with persistent enforcement difficulties, raises questions about the practicality of successfully implementing these proposed changes, even if pursued through a phased approach. Top of Form

Conclusion

The recent proposal concerning laboratory-developed tests (LDTs) is a manifestation of the shifting dynamics in healthcare, reflecting a conscious effort to harmonize regulatory approaches and protect public health. While the changes aim to bolster the safety and efficacy standards for IVDs, they also entail an increased onus on regulatory and clinical development professionals to ensure alignment with the evolving framework.

The projected benefits for patients are significant, but the associated costs for laboratories and the potential backlash from industry bodies like the ACLA underscore the complexity of this regulatory transformation. As the deadline for public comments draws near, an informed, active, and collaborative response from all stakeholders will be paramount in shaping a balanced and effective regulatory landscape for the future.

Premier Research is a clinical research, product development, and consulting company that is dedicated to helping biotech, specialty pharma, and device innovators transform life-changing ideas and breakthrough science into new medical treatments. Our team is helping clients navigate the changing regulations and clinical research. Our expertise gives us the ability to develop customized and tailored strategic plans, mitigate regulatory risks, and optimize marketing success. Contact us today to find out how we can support your program.