Laboratory developed tests (LDTs) are in vitro diagnostics (IVDs) for clinical use, developed, manufactured, and processed within a single CLIA-certified laboratory. LDTs have operated without strict regulatory oversight for years, as the FDA has exercised general enforcement discretion over these typically small-scale and low-risk tests. However, as LDTs have expanded in scope and complexity, the regulatory landscape is changing.
What is CLIA? In the U.S., The Centers for Medicare & Medicaid Services (CMS) oversees all laboratory testing on humans (except research) through the Clinical Laboratory Improvement Amendments of 1988 (CLIA). The CLIA program ensures laboratories meet specific quality standards for testing accuracy, reliability, and timeliness of patient results.
This past May, the FDA issued a final rule on LDTs. Over a four-year period, the FDA will be phasing out its general enforcement discretion approach for certain LDTs and increasing its regulatory oversight of these tests. This means many LDTs coming to market after May 6, 2024, will no longer benefit from the enforcement discretion policy and will have to submit a premarket review to obtain FDA clearance. There are exceptions, as specific IVDs (discussed below) will be exempt from this phaseout policy, but for the most part, moving forward, LDTs will require premarket authorization.
Historical Context of LDT Regulations
To understand the regulatory framework for LDTs, it’s best to look at the historically complementary roles of CLIA and the FDA. LDTs can only be offered by laboratories certified under CLIA, ensuring they meet high testing quality and laboratory management standards. CLIA certifies the analytical quality of tests conducted in a lab but does not scrutinize the clinical validity of individual tests themselves.
The FDA started regulating in vitro diagnostics (IVDs) for safety and effectiveness in the 1970s. Since then, while they have maintained their right to regulate LDTs, the FDA has chosen not to enforce oversight for these low-risk, locally-offered diagnostics, leaving it up to CLIA to ensure analytical quality and the ordering physician to manage the clinical piece.
Of note, the exact same clinical tests, when manufactured and marketed commercially (i.e., beyond a single lab site), are regulated by the FDA as medical devices. This has led some to see marketing a test as an LDT as a regulatory loophole.
However, since the 1970s, LDTs have evolved into more complex and automated tests. They may impact critical healthcare decisions in diagnostics, therapeutics, and prevention. And with new technologies enabling the shipping of viable samples, some LDTs now serve large, diverse, cross-country populations. This has raised concerns about their safety and effectiveness at this scale and prompted the FDA to reevaluate the regulatory landscape for LDTs.
Over a decade of meetings with stakeholders, drafted guidance, and a discussion paper culminated in the FDA’s final rule on LDTs, issued on May 6, 2024. This rule means a more structured oversight approach for LDTs to keep pace with these medical tests’ advancing complexity, scope, and relevance.
Some LDTs Will Require Premarket Review
In their final rule, the FDA explicitly states that in vitro diagnostics (IVDs), including those manufactured by single laboratories, are medical devices, and the FDA regulates medical devices to ensure they are safe and effective for providers and patients.
This subjects many IVDs offered as LDTs to more stringent regulatory controls, ensuring they meet the rigorous premarket requirements applied to commercial medical devices.
Key Takeaways of the FDA’s Final Rule:
- Increased Oversight: The final rule ensures LDTs meet the same high standards expected of commercially available medical devices, emphasizing patient safety and test reliability.
- Risk-Based Framework: High-risk LDTs, such as those used for diagnosing severe conditions, may require more rigorous premarket review and post-market surveillance. Moderate-risk LDTs could see tailored oversight that balances patient safety with the need for innovation. Low-risk LDTs continue with reduced regulatory requirements, reflecting their lower potential negative impact on patient care.
- Phaseout Policy: Gradually eliminating enforcement discretion for certain LDTs over four years ensures a smooth transition to the new regulatory regime without disrupting clinical practice.
- Exceptions to the Rule: Enforcement discretion will continue for specific targeted tests, such as 1970s-type LDTs offered manually and on a small scale in a single lab, or HLA tests performed in a single lab for organ, stem cell, or tissue transplants, or tests for forensic purposes. See the FDA’s final rule for a summary of exempt IVD categories.
These changes represent a significant shift in how LDTs are regulated, potentially significantly influencing the development and use of these necessary diagnostic tools in healthcare.
Impact of Regulatory Changes
The regulatory changes for LDTs have elicited mixed responses from the healthcare industry. Many have expressed concerns about the potential impact on innovation and access to essential diagnostics. There is apprehension that increased regulation could stifle the development of new tests, particularly those targeting rare conditions or personalized medicine applications.
The FDA plans to “grandfather in” LDTs already on the market. This means they will allow existing LDTs marketed before May 6, 2024, to continue without needing premarket review, unless significantly changed. This ensures continued access for healthcare professionals and patients to the essential LDTs they currently rely on.
Key Concerns and FDA Responses to laboratory developed Tests (LDTs)
| Concern Area | Challenges or Concerns | How the FDA is Responding |
|---|---|---|
| Rare Disease Testing | Many LDTs are designed for rare diseases, where there may be little to no commercially available tests. For example, rare genetic conditions often rely on LDTs developed by specialized labs because the market size is too small for commercial test developers to justify the cost. Increased FDA regulation could impose significant costs and delays in developing these tests, potentially limiting access for patients who rely on them. | The FDA acknowledges that certain LDTs are crucial for diagnosing rare diseases and has implemented targeted enforcement discretion policies for tests meeting unmet needs, especially when no FDA-authorized test is available. For example, LDTs developed within healthcare systems to address specific patient needs will receive more lenient oversight, helping to ensure continued access to critical tests without immediate full compliance requirements. |
| Personalized Medicine and Oncology | LDTs are critical in personalized medicine, particularly in oncology, where tests are tailored to identify specific mutations that guide treatment. For instance, tests identifying specific cancer mutations (e.g., BRCA1/2) are developed and used in labs without FDA oversight. Stricter regulations could hinder these tests' rapid adaptation and customization, impacting patient care. | The FDA has recognized the importance of LDTs in guiding personalized treatment decisions, especially in oncology. While the new rules impose stricter requirements, the FDA has indicated it will be exercising targeted enforcement discretion for specific high-need areas, ensuring that essential tests remain accessible while the transition to compliance occurs gradually. |
| Academic and Research Labs | Many academic and research hospitals develop LDTs for highly specialized applications, often as part of ongoing clinical research. The costs and administrative burdens associated with FDA approval could stifle this research environment, slowing the development of cutting-edge diagnostics often first introduced as LDTs. | The FDA has included certain exemptions for LDTs developed and used within academic and research labs, especially if they fulfill a unique need that commercially available tests cannot meet. This approach supports ongoing research and innovation while gradually introducing regulatory standards. |
Addressing Concerns for Small Businesses
Some worry about how these changes will affect small businesses in the LDT space. In response, the FDA has developed a guidance called the Laboratory Developed Tests: Small Entity Compliance Guide to help small entities understand the new regulations. This guide offers plain-language explanations of compliance expectations and details how the FDA’s targeted enforcement policies will apply to different categories of LDTs.
Ensuring access to reliable LDTs
LDTs fill an essential diagnostic need within the healthcare field. Providing a regulatory environment where they remain widely available while ensuring patient safety and access to accurate information is essential. As the regulatory landscape for LDTs evolves, the imperative to balance innovation with safety and effectiveness becomes increasingly clear. Ensuring that LDTs are reliable and accessible is crucial for advancing healthcare and responding to emerging public health needs.
The Future of LDT Regulations
The ongoing dialogue between the FDA, healthcare providers, industry stakeholders, and potential legislative actions is shaping a future where regulation supports the dynamic nature of LDT development. This balanced approach aims to safeguard patient health while maintaining the momentum of medical innovation, promising a regulatory framework that nurtures the growth of vital diagnostics in alignment with the highest standards of patient care.
Does the final rule apply to my current or future LDTs?
There are many nuances to the final rule. If you’re wondering whether your LDT will need FDA premarket authorization, your best resource for specific questions is the rule itself, which includes a preamble and over 300 responses to comments from concerned stakeholders. Alternatively, you can connect with an FDA consultant with expertise in medical devices.
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