The article describes in brief the key points related to the regulatory framework for laboratory-developed tests.
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The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of healthcare products, has published a small entity compliance guide dedicated to laboratory-developed tests. The document provides an overview of the applicable regulatory requirements, as well as additional clarifications and recommendations to be taken into consideration by the parties involved in order to ensure compliance.
At the same time, provisions of the guidance are non-binding in their legal nature, nor are they intended to introduce new rules or impose new obligations. Furthermore, the authority explicitly states that an alternative approach could be applied, provided such an approach is in line with the existing legal framework and has been agreed with the authority in advance.
This guide reflects the FDA’s current position on Laboratory Developed Tests (LDTs). It outlines the requirements and provides recommendations for laboratory manufacturers to ensure compliance with FDA regulations.
Introduction
On May 6, 2024, the FDA introduced a final rule published in the Federal Register, titled “Medical Devices; Laboratory Developed Tests” (89 FR 37286), known as the LDT Final Rule. This rule clarifies that in vitro diagnostic products (IVDs) are classified as devices under the Federal Food, Drug, and Cosmetic Act (FD&C Act), including when these products are manufactured by laboratories.
The rule underscores that the definition of a device in the FD&C Act does not distinguish between different types of manufacturers. With this amendment, the FDA is introducing its general enforcement discretion approach for LDTs, thereby aligning the regulatory expectations for laboratory-manufactured IVDs with those for other IVDs.
The preamble to the LDT Final Rule elaborates on this phase-out policy, detailing the enforcement discretion policies for specific categories of laboratory-manufactured IVDs, including currently marketed IVDs offered as LDTs and LDTs addressing unmet needs. This policy is intended to enhance public health protection by ensuring the safety and effectiveness of LDTs while considering patient access and reliance.
Regulatory Background
The Medical Device Amendments of 1976 (MDA) introduced a comprehensive regulatory framework for devices intended for human use under the FD&C Act. Historically, the FDA exercised enforcement discretion and did not enforce many regulatory requirements on most LDTs, such as establishment registration, product listing, medical device reporting, current good manufacturing practices (CGMPs), and premarket review.
At the time of the MDA’s implementation, LDTs were typically produced in small quantities by local laboratories, primarily for diagnosing rare diseases or other specific local needs. These tests often used manual techniques and were performed by specialized laboratory personnel within single institutions, utilizing components already legally marketed for clinical use.
Over the years, the LDT landscape has evolved significantly. Modern LDTs now rely heavily on advanced technology, complex instrumentation, and software for generating results and clinical interpretations. They are often performed in laboratories outside the patient’s healthcare setting and in high volumes for diverse populations.
Many LDTs are produced by large laboratory corporations and used nationwide, involving components not legally marketed for clinical use. These tests play critical roles in diagnosing serious conditions, predicting disease risk, and informing treatment decisions, which increases the associated risks.
Additionally, the growing reliance on high-tech instrumentation and software in LDTs has raised concerns about cybersecurity vulnerabilities. LDTs connected to Laboratory Information Management Systems (LIMS) and other IT infrastructures pose risks of unauthorized access to sensitive patient data, including genetic information, which could have national security implications.
FDA’s premarket review process aims to mitigate such cybersecurity risks by working with manufacturers. The FDA also addresses these issues through medical device reporting and corrections and removal reporting requirements.
Given these developments, the FDA has recognized the necessity of revising its general enforcement discretion approach for LDTs. Recent information has reinforced the need for change, leading to the issuance of the LDT Final Rule.
This rule explicitly states that IVDs are considered devices under the FD&C Act, regardless of whether they are manufactured by laboratories. The FDA is phasing out its general enforcement discretion approach for LDTs and adopting targeted enforcement discretion policies for specific categories of laboratory-manufactured IVDs.
Overview
The FDA’s final rule amends its regulations to clarify that IVDs are considered devices under the FD&C Act, including those manufactured by laboratories. This amendment reflects the definition of devices in the FD&C Act, which does not differentiate based on the manufacturing entity.
The amended regulation (21 CFR 809.3(a)) states:
“In vitro diagnostic products are those reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body. These products are devices as defined in section 201(h)(1) of the Federal Food, Drug, and Cosmetic Act (the act) and may also be biological products subject to section 351 of the Public Health Service (PHS) Act, including when the manufacturer of these products is a laboratory”.
The LDT Final Rule also outlines a phaseout policy for the FDA’s general enforcement discretion approach for LDTs. Over a four-year period, IVDs manufactured by laboratories will be subject to the same enforcement approach as other IVDs, ensuring consistent compliance expectations.
This phaseout includes specific enforcement discretion policies for certain categories of laboratory-manufactured IVDs, such as currently marketed IVDs offered as LDTs and LDTs designed to meet unmet needs.
Compliance Recommendations
According to the guidance, laboratories developing IVDs should prepare to align their practices with FDA regulations.
Key recommendations include:
- Establishment Registration and Product Listing: Ensure that laboratories register their establishments and list their products with the FDA.
- Medical Device Reporting: Implement systems for medical device reporting to ensure timely communication of any adverse events or issues.
- Good Manufacturing Practices: Adhere to current good manufacturing practices to maintain high standards of quality and safety.
- Premarket Review: Engage with the FDA for premarket review to address any concerns related to the safety and effectiveness of new LDTs.
- Cybersecurity: Incorporate robust cybersecurity measures to protect patient data and prevent unauthorized access or modifications.
Conclusion
In summary, the present FDA guidance outlines the key requirements for the entities involved in the manufacturing and use of in vitro diagnostic medical devices to be taken into consideration in order to ensure compliance with the existing legal framework.
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