Laboratory-Developed Test Oversight FAQs

The CAP filed the amicus brief to urge the court to vacate the FDA regulation on the oversight of laboratory developed tests (LDTs). The CAP opposes the FDA regulation as written because pathologists and laboratories fear these regulatory restrictions from the FDA will make it difficult for laboratories to continue to develop and provide LDTs and, thus, impair and delay the diagnosis of disease and treatment of patients.

A steering group comprised of the CAP President, President-elect, Secretary-Treasurer, and present and former members of the Board of Governors led the drafting of the CAP amicus brief. The steering group included the current chairs and vice-chairs of the Council on Accreditation, Council on Scientific Affairs, Council on Government and Professional Affairs, and Council on Informatics and Pathology Innovation. The Board of Governors decided to submit an amicus brief in July after the lawsuit by the American Clinical Laboratory Association was filed on May 29. Board members then worked with the CAP’s attorneys from the law firm Sidley Austin to draft the filing from August and until its submission on October 7.

The CAP’s position on LDTs reflects its membership, which is solely comprised of board-certified pathologists, and their duties as physicians to provide high quality diagnostic services to their patients. Other organizations may have a different view on this issue because of their diverse membership, but we all agree the court should vacate the FDA regulation on LDTs. The CAP has continued to advocate for a balanced, risk-based approach to the federal oversight of LDTs that promotes continued innovation, meets patient needs, minimizes regulatory burden on laboratories, and ensures that each test is valid, safe, and reliable. Through our experience running the world’s largest laboratory accreditation program, we are aware of rare laboratories offering LDTs that are not appropriately validated analytically or clinically. For this reason, we believe there is a limited role for the FDA in regulating the highest risk LDTs.

The CAP urged the US District Court to avoid implying that LDTs constitute the practice of medicine because medical practice is regulated by the states and not the federal government. Arguments that attempt to define LDTs as the practice of medicine also pose scope-of-practice concerns for physicians.

While many pathologists are involved in the important work of developing and overseeing the quality and performance of LDTs, a host of other highly skilled nonphysician laboratory professionals contribute to developing and overseeing the laboratory use of LDTs (see pg. 13). The CAP’s filing states:

“If laboratory testing constitutes the ‘practice of medicine,’ questions regarding ‘scope of practice’ for laboratory professionals and how that should be expanded or circumscribed at the state level (where the practice of medicine is regulated) could arise. It might also compromise the ability of non-physicians—i.e., those who are not licensed to practice medicine—to oversee such lab testing at all. Finally, deeming LDTs to constitute the “practice of medicine” would also raise a host of coverage and reimbursement issues under the Medicare and Medicaid statutes.” (See pg. 13).

The Centers for Medicare & Medicaid Services (CMS) regulates laboratories that perform testing on patients in the United States through the Clinical Laboratory Improvement Amendments of 1988 (CLIA). The CMS establishes the quality standards for all laboratory testing to help ensure the accuracy, reliability, and timeliness of patient test results. However, CLIA does not regulate the scientific principles behind, or the clinical validity of, laboratory tests and the CMS does not have the expertise to ensure these tests work clinically. The CMS and FDA agree that the FDA has the expertise to oversee the clinical validity of tests. As recently as January 2024, the FDA and the CMS clearly delineated each federal agency’s authority and areas of expertise: the CMS regulates laboratory operations for patient testing, and the FDA oversees test development and production.

CLIA needs periodic targeted regulatory updates to keep pace with recent technology – not a broad, disruptive legislative overhaul that would threaten patient access to clinical laboratory tests. Re-opening CLIA legislatively could have far-reaching and unintended consequences that could undermine the framework under which all clinical laboratory testing is done in the U.S. In particular, CLIA modernization legislation could have a disastrous effect on community laboratories and those serving rural areas where new unfunded mandates and regulatory burdens could threaten to close laboratories.

The CAP’s position on LDTs is guided by what is in the best interest of patients. Many patient advocates strongly support FDA oversight of LDTs because of medical decisions being made based on the results of LDTs, as well as the risks associated with some extraordinarily complex LDTs the quality of which is difficult to impossible to independently verify. The CAP has sought to focus FDA oversight on those high-risk LDTs, while allowing lower-risk tests to meet significantly more limited oversight requirements. Striking such a balance would protect patients and allow innovative tests to continue to be developed under an oversight framework that is the least burdensome for laboratories. The CAP is advocating for Congress to give the FDA a new, more appropriate role in LDT regulation going forward.

1976 type tests have the following characteristics:

• They use manual techniques without automation performed by lab personnel with specialized expertise.
• They use components legally marketed for clinical use.
• They're designed, manufactured, and used in a single high complexity CLIA lab.

Tests with these three characteristics generally fall within the 1976-type enforcement discretion policy. FISH and IHC tests often have these three characteristics and in those cases would fall within the policy.

Tests using automation, including automated staining methods, automated plate readers, or automated interpretation would not have the first characteristic, because they would not be considered manual techniques without automation—and they would not be in the policy. Tests with components that are labeled Research Use Only (RUO) would not meet the second characteristic, because appropriately labeled RUO IVD products are not legally marketed for clinical use.

Some IVDs manufactured and first offered by laboratories after the date of issuance of the regulation (May 6, 2024) may fall within a targeted enforcement discretion policy described in the regulation. The FDA refers laboratories to the regulation for complete details, but the table above provides a high-level view of the different enforcement discretion policies. The phaseout policy details when compliance with the different requirements would be expected. For example, in phase one beginning May 6, 2025, the FDA expects compliance with medical device reporting requirements, correction and removal reporting requirements, and complaint files. In phase two, May 6, 2026. The FDA expects compliance with requirements that are not covered during the other stages of the phase out policy, including registration and listing, labeling, and investigational use requirements.

Stage three is in 2027 and the FDA expects compliance with quality system requirements. For LDTs specifically, the FDA expects compliance only with design controls, purchasing controls, acceptance activities, CAPA, and records requirements. And then premarket review would begin for high-risk tests in November 2027 and for moderate- and low-risk tests to which premarket review requirements apply in May 2028. The FDA does not intend to enforce premarket authorization requirements after a complete PMA, 510(k) or De Novo application has been submitted, if it's submitted on time according to this phaseout until the FDA completes its review of the submission. Given that such IVDs that are introduced during this transition period may already be on the market and available to patients when laboratories go to the FDA for review, the FDA does not intend to interrupt access at the point when a submission is made. IVDs for which a PMA, 510(k) or De Novo request is submitted prior to the applicable timeframe will remain under enforcement discretion for the pendency of the FDA review, whereas those that are submitted after the applicable timeframe detailed in the phaseout policy would not fall within the enforcement discretion policy and FDA clearance or authorization would be expected prior to such test being offered.

If an IVD was offered as an LDT prior to May 6, 2024, and is not modified in a way that changes its indications for use, alters the operating principle, includes significantly different technology, or adversely changes the performance or safety specs, then the FDA intends to exercise enforcement discretion and generally not enforce premarket review and most quality system requirements. This enforcement discretion policy is not limited to manual tests. Additionally, for tests that have certain characteristics that are common among LDTs offered in 1976, the FDA intends to exercise enforcement discretion with respect to all applicable requirements. The characteristics of tests under this enforcement discretion policy are that they use manual techniques without automation performed by lab personnel with specialized expertise. They use components legally marketed for clinical use, and they're designed, manufactured, and used in a single high-complexity CLIA laboratory.

If the same laboratory is offering the same LDT before and after publication of the final rule, the LDT generally would fall within the currently marketed IVD offered as an LDT policy, so long as the IVD is not modified, or modified in a way that does not change indications for use, alter the operating principle, include significantly different technology, or adversely change the performance or safety specs of the IVD.

TDM tests, including mass spec based TDMs, are IVDs. TDM tests manufactured by laboratories are covered by the final rule and the phaseout policy described in the regulation.

FDA premarket review timelines are negotiated with industry in connection with our medical device user fee reauthorization process. The FDA generally meet timeframes for MDUFA decisions that are negotiated with industry, including for IVD submissions outside of our experience in the pandemic. The FDA says this process aligns with the timeline for reauthorization discussions around our next user fee cycle, providing an opportunity for us to negotiate fees and goals for premarket reviews with our stakeholders.

The FDA intends to exercise enforcement discretion with respect to premarket review for LDTs that are approved, conditionally approved, or within an approved exemption from full technical documentation by New York CLEP. As described in the regulation, this policy applies to the version of the LDT approved by New York. Therefore, if a test is not approved by New York, it would not be in this policy.

Currently marketed IVDs offered as LDTs, the ones that are marketed prior to May 6, 2024 the FDA intends to exercise enforcement discretion with respect to both premarket review and most quality system requirements. Now, for new IVDs offered as LDTs that weren't marketed prior to May 6, 2024, the FDA expects compliance with applicable requirements, premarket review, quality system, etc, consistent with the stages in the preamble. However, if such a new IVD falls within an enforcement discretion policy described in the preamble, we intend to exercise enforcement discretion as described in that policy. The New York policy relates to general enforcement discretion with respect to premarket review requirements.

The FDA is using its existing risk classification to determine the risk categorization for LDTs. This existing framework established classifications for approximately 1,700 different generic types of devices and grouped them into 16 medical specialties referred to as panels. Each of these generic types of devices is assigned to one of three regulatory classes based on the level of control necessary to assure the safety and effectiveness of the device.

CLIA risk categorization is different from the FDA’s as all LDTs are considered high-complexity tests under CLIA while the FDA may classify LDTs from low-, moderate-, and high-risk tests.

Since 2009, the CAP has advocated for a regulatory framework that enhances patient safety, maintains quality laboratory testing, and promotes innovation without creating significant regulatory burdens on pathologists. LDTs have become more complex and unique presenting greater risk to patients that a tiered classification system could provide a balance streamlined approach and focus federal oversight on the highest risk LDTs.

The CAP accreditation checklists contain requirements for test method validation and adverse event reporting, which are used to ensure CLIA compliance. CAP-accredited laboratories may leverage the checklists to meet the FDA requirements. The 2024 accreditation checklist edition will not contain any new changes in response to the FDA LDT final rule

The CAP continues to watch the FDA LDT Final Rule and timeline closely and will reevaluate any necessary updates for future checklist editions.

At the federal level, the government does not define the practice of medicine; the practice of medicine is defined at the state level. As some laboratory-developed tests are created and developed by nonphysicians in the laboratory, the CAP does not believe creation of an LDT solely translates to, or constitutes, the practice of medicine.

Quality system requirements are outlined by the FDA in its regulation. The CAP has advocated for the FDA to recognize that most of the requirements are similar to those overseen by the laboratory director and that the individual be considered as the CEO of the laboratory.

The FDA action is independent of payment policy decisions. We don’t believe there will be a related effort to revise CPT coding.

The CAP will provide resources and education for each phase to assist CAP members and laboratories compliance with the rule (see the information above).

The CAP is now reviewing the final regulation and determining our next steps. We will continue to keep our members and laboratories updated on this and other concerns regarding the FDA oversight of LDTs as new information becomes available.

The FDA is using its existing authority to regulate LDTs. The CAP and CLIA auditors are not approved by the FDA to conduct inspections currently. The CAP will continue to engage the FDA to ensure clinical laboratories have the least burdensome approach for compliance the final rule.

Since 2009, the CAP has advocated for a regulatory framework that enhances patient safety, maintains quality laboratory testing, and promotes innovation without creating significant regulatory burdens on pathologists. LDTs have become more complex and unique presenting greater risk to patients that a tiered classification system could provide a balance streamlined approach and focus federal oversight on the highest risk LDTs.

CLIA regulations defined test complexity for clinical laboratory testing. The CMS CLIA program states modifying waived or moderate complexity test (including modifications in its intended use) is considered uncategorized for CLIA purposes and therefore becomes a high complexity test.

As a deemed accreditor, CAP must be equivalent or more stringent to the CLIA regulations to maintain its deemed status.

No, medical device adverse event reporting is required for deaths, serious injuries and malfunctions. Proficiency testing (PT) is the testing of unknown samples sent to a laboratory by an HHS-approved PT program. Most sets of PT samples are sent to participating laboratories on a scheduled basis (usually three times per year). After testing, the laboratory reports its sample results back to their PT program. The program grades the results using the CLIA grading criteria and sends the laboratory their scores. The CMS and accreditation organizations routinely monitor their laboratories’ performance.

Publications produced by the CAP are driven by its members and leaders who volunteer on various councils and committees. At present, the CAP does not distinguish between LDTs and IVDs in most of its programs – thus, it would be difficult to compose a publication addressing the topic suggested in the question.

The Verifying Accurate Leading-edge IVCT Development (VALID) Act is bipartisan, bicameral legislation that creates a new comprehensive regulatory framework for clinical laboratory tests that includes laboratory-developed tests (LDTs).

Here are the main features of the bill:

• Create a risk-based system of oversight utilizing tiers (low-, moderate-, and high-risk) to target FDA oversight.
• Exempt all existing LDTs from FDA premarket review. The FDA may only review an LDT’s validation if there is a safety concern for patients.
• Utilize mitigating measures to shift LDTs to lower tiers of regulation. These measures include such practices as appropriate labeling, performance testing, submission of clinical data, clinical studies, and posting information on a website.
• Offer exemptions from the FDA premarket review process. These exemptions include LDTs in the low-risk category, low volume tests, modified tests, manual interpretation tests, and humanitarian tests.
• Prohibit the FDA from infringing on the practice of medicine.
• Direct the FDA to avoid issuing or enforcing regulation that is duplicative of regulation under CLIA.
• Require the FDA to conduct public hearings on LDT oversight.
• Establish an effective date five years from now in 2027.
• Establish a process by which user fees will be created via negotiations between the agency and the industry, and is subject to congressional approval.

Patient and physician advocacy groups have called on Congress to move the VALID Act forward. For example, 18 advocacy groups urged Congress to prioritize the VALID Act in 2021. Those groups were: the American Cancer Society Cancer Action Network, the American Society of Clinical Oncology, Cancer Support Community, Emerson Collective, FORCE: Facing Our Risk of Cancer Empowered, Friends of Cancer Research, Global Liver Institute, LUNGevity Foundation, Lymphoma Research Foundation, Muscular Dystrophy Association, National Center for Health Research, National Consumers League, National Organization for Rare Disorders, Prevent Cancer Foundation, Theresa's Research Foundation, Triage Cancer, and US Public Interest Research Group.

Laboratory organizations such as the Association for Molecular Pathology, the American Association for Clinical Chemistry, and Association of Pathology Chairs have expressed opposition to the VALID Act. In general, the groups have opposed FDA regulatory oversight of LDTs and cite other reasons for opposing the bill.

The CAP supports many of the provisions in the VALID Act. Our most recent letter details provisions that the CAP supports and suggests other areas for improvement. The CAP expects that the legislation will continue to be modified throughout the legislative process and will be reviewing any additional changes to the bill.

The effective date in the legislation would be October 1, 2027.

The actual effective date in the legislation would be October 1, 2027; however, in the interim, the FDA would be given authority to intervene to review specific LDTs in the market if a patient safety issue is identified with those LDTs. The FDA has this authority today and is exercising that authority, but the legislation specifies this and establishes the limits of FDA authority.

No. The legislation specifically denies the FDA any authority to infringe on the practice of medicine. We understand that some pathologists consider their involvement in the development of laboratory tests to be part of their scope of practice. We have to keep in mind that scope of practice is regulated by the states and not the federal government.

The VALID Act requires documentation of clinical validation activities and outlines how those creating LDTs can demonstrate clinical validity. It doesn’t define which professionals can or cannot perform those activities. To assert that development of laboratory tests is a pathologist scope of practice issue would mean only physicians can perform these clinical validation activities, which we know to be performed by other laboratory professionals. This is acknowledged by the VALID Act.

The VALID Act stipulates those provisions in the bill will not affect a provider’s ability to administer or prescribe an approved in vitro clinical test, or otherwise limit the practice of medicine.

Modifications of tests are also exempt from premarket requirements if those modifications do not affect the analytical or clinical validity the test or change the intended use. For example, modified tests will be exempt when the modification is under an approved change protocol. If a modification adversely impacts compliance with applicable mitigating measures or the test is restricted to any high-risk or moderate-risk test that pose patient safety issues, it will require a regulatory submission.

The VALID Act explicitly states that the Secretary of the Health and Human Services should ensure there is no duplication between CLIA and FDA requirements.

No. The VALID Act does not set specific user fees. Congress would need to grant the authority for the FDA to charge fees. In general, Congress has established several exemptions from user fees (class I and some class II medical devices are exempt from premarket review and payment of an associated fee). Congress has also given small businesses (those with gross receipts below a specified amount) reduced premarket fees or will waive fees altogether.

In the CAP’s letter, we state: While the legislation does not establish the user fees, the CAP believes that if user fees are set too high, it will limit the development of LDTs by clinical laboratories and impede innovation by laboratories which are financially stressed. The CAP encourages minimal user fees, particularly for low and moderate risk LDTs which are already in widespread use.

Laboratory-developed tests have been a concern of patients for many years. One incident that initially led to advocacy by patient advocates surrounded the OvaSure Yale Ovarian Cancer Test in 2008. OvaSure was an LDT intended to be used to identify high-risk women who might have ovarian cancer. It was later determined that 1 in 15 women with a positive test would in fact have ovarian cancer while the other 14 had false-positive tests. There have been several other similar instances involving LDTs through the years. In January 2022, a group of nearly 100 members of Congress expressed serious concern to the FDA over reports of high false-positive rates in noninvasive prenatal test (NIPT) genetic screenings for rare genetic disorders. The FDA responded by writing “[m]any newer LDTs, including the NIPTs described in the New York Times article, are more complex, used broadly, and intended for higher-risk uses.”

During the COVID-19 pandemic, the Department of Health and Human Services (HHS) and FDA also reported that there were more than 500 emergency use authorization (EUA) requests from laboratories. In an analysis of 125 EUA requests for COVID-19 molecular tests, the FDA found two-thirds had either design or validation issues. Most validation issues were related to improperly designed validation studies such that the FDA couldn’t tell if the tests worked or not. Additional follow-ups found performance issues had been masked by improperly performed validation studies.

No. There have been multiple drafts of the VALID Act over a period of several years. Initial discussion about the VALID Act followed a roundtable in 2019, which was when members of Congress discontinued work on another LDT oversight bill referred to as the DAIA Act. The current version of the VALID Act is the third major iteration bill.

For over a decade, federal agencies and Congress have been considering how to design a regulatory framework for LDTs. It is important to understand that both the FDA and CMS currently use third-party accreditors and every proposal on LDT oversight through the years has included a role for third-party accreditors — whether under the CMS or FDA – because neither agency has the workforce and infrastructure to regulate LDTs without outside help. Some proposals by other organizations have also assumed that CAP would be selected to be a third-party accreditor for LDTs, but the CAP has not made that assumption.

If the FDA is granted authority to regulate LDTs, any laboratory organization could apply for third party status, including the CAP. The CAP has not assessed this, and a potential third-party role is not guiding CAP advocacy on this issue.