FDA’s regulations define IVDs as 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, and intended for use in the collection, preparation, and examination of specimens taken from the human body.
FDA has generally considered an LDT to be an IVD that is intended for clinical use and that is designed, manufactured, and used within a single laboratory that is certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and meets the regulatory requirements under CLIA to perform high complexity testing.
In implementing the Medical Device Amendments of 1976 (MDA), FDA typically exercises enforcement discretion and therefore does not usually enforce the applicable requirements for most LDTs. This is because when the MDA was first passed, LDTs were mostly manufactured in small volumes by laboratories that served their local communities. They were typically intended for use in diagnosing rare diseases or for other uses to meet the needs of a local patient population, or were generally similar to well-characterized, standard tests. They also tended to employ manual techniques (and did not use automation) performed by laboratory personnel with specialized expertise; to be used and interpreted by physicians or pathologists in a single institution responsible for the patient (and who were actively involved in patient care); and to be manufactured using components legally marketed for clinical use, such as general purpose reagents or immunohistochemical stains marketed in compliance with FDA regulatory requirements. As a result, at that time, FDA typically exercised enforcement discretion and would not have requirements for most LDTs.
Today, however, LDTs have changed radically, with many relying on high-tech or complex instrumentation and software to generate results and clinical interpretations. They are typically used in laboratories outside of the patient care setting and are often produced in large batches for large and diverse populations. Many LDTs are manufactured by laboratory companies that sell tests nationally because they accept specimens from patients across the country and run LDTs in large quantities in a single laboratory.Today’s LDTs are also more commonly manufactured using instruments or other components that are not legally marketed for clinical use and are more commonly used to inform or guide key therapeutic decisions for a wide range of screenings for both common diseases and for a wide range of life-threatening, complex disease areas, such as cancer, neurological disorders, cardiovascular diseases, infectious diseases, and rare diseases.
False-positive test results from LDTs incorrectly indicate that a patient has a disease or condition, which may delay diagnosis and treatment of the true disease or condition, lead to unnecessary interventions, and cause unnecessary suffering. And false-negative results may lead to disease progression and, in some cases, no opportunity for life-saving treatment and the spread of infectious diseases.
Various scientific literature and multiple complaints, adverse event reports, and allegations from the public have made FDA aware of serious problems with IVDs provided as LDT.
The FDA never selectively promotes laboratory innovation at the expense of public health. Rather, heightened regulation based on test characteristics and safeguards is created to protect public health.
FDA has been aware that there are already other mechanisms (e.g., medical expertise of laboratory personnel or CLIA requirements) for adequate oversight of LDTs. However, while LDT laboratories are subject to CLIA, which is primarily administered by the Centers for Medicare and Medicaid Services (CMS), CLIA is not a substitute for FDA oversight.CLIA establishes requirements for laboratories and laboratory personnel related to operations, inspections, and certifications, with a focus on the proficiency of laboratories in performing clinical tests. Among other requirements, clinical laboratories typically must possess CLIA certification, which corresponds to the sophistication of the tests performed prior to accepting human specimens for testing. However, under CLIA, CMS does not regulate key aspects of laboratory test development; does not assess the performance of tests prior to making them available to patients and healthcare providers; does not assess clinical validity, does not evaluate clinical effectiveness, does not regulate certain manufacturing activities, does not provide human subject protections for patients involved in testing clinical research trials, and does not require adverse event reporting. As a result, the focus, scope, and purpose of CMS’ and FDA’s regulatory programs differ.
2.1. Amend 21 CFR §809.3.
FDA are proposing to update the definition for in vitro diagnostic products, “IVDs are devices under the FD&C Act including when the manufacturer of the IVD is a laboratory” to include laboratories as manufacturers of the IVD.
2.2 The phaseout policy
The FDA also recognizes that many laboratory-manufactured IVDs are currently being marketed as LDTs, and that a sudden change could have a negative impact on the public (both patients and industry). In particular, FDA understands that the medical community and patients have been using these IVDs and that it will take some time for manufacturers to reach compliance.FDA also recognizes the need to consider the limited resources of the FDA agency itself. Therefore, FDA proposes to phase out the general enforcement discretion for LDTs in five stages.
It is important to note that the following three tests do not have general enforcement discretion and this proposal does not include these tests below:
(i) Tests for blood donor screening or human cell, tissue, and cell and tissue product (HCT/P) provider screening tests required for infectious disease testing under 21 CFR 610.40 and 1271.80(c), or blood group and Rh factor testing under 21 CFR 640.5.
These tests are a critical part of ensuring the safety of blood and blood components and HCT/P by preventing the spread of infectious diseases and incompatible transfusions that could lead to life-threatening conditions.
(ii) Tests for emergencies, potential emergencies, or significant threats declared under Section 564 of the FD&C Act. Such diseases carry significant risks and erroneous results could have serious implications for disease progression and public health decisions.
(iii) Direct-to-consumer testing. FDA’s general enforcement discretion does not apply to tests intended for consumer use, given the greater risk these tests pose to patients.
In addition, for some specific categories of tests, FDA proposes to continue to apply the current general enforcement discretion approach:
(i) “1976-type LDTs”: these tests share common characteristics with the LDTs offered in 1976: manual techniques (no automation) performed by laboratory personnel with specialized knowledge; use of legally marketed ingredients intended for clinical use; and design, manufacture, and use in a single CLIA-certified laboratory that meets the CLIA requirements for high complexity testing.
(ii) HLA Testing: The FDA has preliminarily determined that histocompatibility laboratories performing transplant HLA LDTs meet CLIA’s regulatory requirements for transplantation with organs, stem cells, and tissues. They are unique in that they are typically developed and tested in emergency, patient life-saving situations. If organs, stem cells, or tissues are available, physicians must often make rapid transplant decisions based on their understanding of the patient’s condition and the extent of the mismatch between the donor and the patient.
(iii) Tests for Forensic or Law Enforcement Purposes Only: Such tests are subject to the protections and requirements associated with the judicial process in a law enforcement environment, and therefore carry less risk associated with test accuracy and sample collection, which often do not exist in the home, workplace, insurance, and sports environments. In the process, test accuracy may be improved.
(iv) Tests for Public Health Surveillance: these tests differ from others in that (1) the samples are systematically collected for the sole purpose of analyzing and interpreting health data related to disease prevention and control, and (2) the results of the tests are not reported to the patient or his or her health care provider. The results of these tests are typically used for trend analysis in populations.
The phase-out policy consists of five key stages:
(i) Stage 1: End the general enforcement discretion approach with respect to MDR requirements and correction and removal reporting requirements 1 year after FDA publishes a final phaseout policy, which FDA intends to issue in the preamble of the final rule.
(ii) Stage 2: End general enforcement discretion with respect to requirements other than MDR, correction and deletion reporting, QS, and premarket review requirements 2 years after FDA issues the final phase-out policy.
(iii) Stage 3: End the general enforcement discretion approach with respect to QS requirements 3 years after FDA publishes a final phaseout policy.
(iv) Stage 4: End the general enforcement discretion approach with respect to premarket review requirements for high-risk IVDs 3 1/2 years after FDA publishes a final phaseout policy, but not before October 1, 2027.
(v) Stage 5: End the general enforcement discretion approach with respect to premarket review requirements for moderate risk and low risk IVDs (that require premarket submissions) 4 years after FDA publishes a final phaseout policy, but not before April 1, 2028.
III. Current Situation
The policy is currently in the Proposed Rule stage, where public and industry comments are being collected, and will need to be converted to a Final Rule and approved by Congress and the Government Accountability Office (GAO) before it can truly take effect.
