With the new LDT final rule, FDA works to clarify what emergency response will look like going forward

Tests, diagnostics, and emergency response: Past experience

• Quick intro: In vitro diagnostics (IVDs) and Laboratory Developed Tests (LDTs). In the U.S. life sciences regulation and oversight framework, diagnostic products are regulated as medical devices. IVDs are defined at 21 CFR 809.3(a), which specifies that IVDs 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” and that they are medical devices. LDTs are a subset of IVDs that have historically been under “enforcement discretion” from the FDA where the agency has maintained that they are IVDs and therefore subject to the medical device regulations. However, it has not required compliance with the device regulations for these products under the understanding that these products are low-volume, low-risk, and used only in clinical laboratories that are certified by the Centers for Medicare and Medicaid Services (CMS) for “high-complexity” testing under the Clinical Laboratory Improvement Amendments (CLIA) regulations.
• On April 29, 2024, FDA released a final rule revising this enforcement discretion approach, largely reversing course on the historical enforcement discretion. The rule amends 21 CFR 809.3(a) (i.e., the IVD definition cited above) to specifically state that IVDs include products “when the manufacturer of the IVD is a laboratory” – and that, therefore, these products are medical devices. Under that new final rule, LDTs will generally be treated as IVDs and be subject to the medical device regulations going forward, with a five-stage phase-in of regulatory requirements over four years. While there are some exceptions in the forms of new enforcement discretion policies and particular matters of scope, the general intent of the rule is that LDTs, which FDA is calling “IVDs currently offered as LDTs,” will face increased regulatory scrutiny in coming years. [Read AgencyIQ’s full analysis of the LDT final rule here.]
• The role of LDTs in emergency response: Because the FDA did not historically require that LDTs be submitted for pre-market review, clinical laboratories that develop LDTs could provide more agile response than IVDs regulated as diagnostics. However, there have been limits to the FDA’s enforcement discretion for LDTs that is now being phased out; in particular, in declared emergency situations, the LDT enforcement discretion did not apply. This means that when there is an Emergency Use Authorization (EUA) declaration, the agency has generally required even LDTs to be submitted for agency review via the EUA pathway. As a reminder, the Public Health Emergency (PHE) and EUA declarations were not formally de-coupled as separate authorities until 2013 under the Pandemic and All-Hazards Preparedness Reauthorization (PAHPRA) of that year; before PAHPRA 2013, a PHE had to be in place before the EUA pathway could be opened, and the EUA pathway could only remain open so long as there was an active PHE. This is no longer the case, and the EUA pathway is independent of the PHE system. Under an EUA declaration, codified at section 564 of the Federal Food, Drug and Cosmetic (FD&C) Act, the FDA may grant “authorizations” to new products (or unapproved uses of existing products) in a more streamlined way and with less evidence than its typical market access pathways require, with these “EUA authorizations” in place only so long as the EUA declaration is still in force (i.e., has not been withdrawn by the U.S. Department of Health and Human Services).
• This policy was largely informal, rather than codified in guidance. As AgencyIQ described in 2020 amidst the Covid-19 pandemic, the policy that LDTs do require EUA submissions during an emergency was largely based on precedent. Former FDA Commissioner Scott Gottlieb pointed to the agency’s actions during the Zika virus outbreak as a reference to the policy when asked, although this policy is not specifically addressed in the FDA’s 2017 guidance on the EUA system and related emergency authorities. In comments on that guidance, clinical laboratory stakeholders including the Infectious Diseases Society of America and the Association for Molecular Pathologists (AMP) both highlighted the role that clinical laboratories play in emergency response. IDSA observed that “clinical laboratories may have special expertise suited to developing diagnostics to an outbreak that may be critical in circumstances where the testing capacity of public health agencies is overwhelmed. However, these clinical laboratories have limited financial and administrative resources and little familiarity with the EUA process. IDSA understands the need for high standards for an EUA, but remains concerned that these laboratories may be unable to navigate an EUA request in time to support a response to an outbreak.”
• While FDA’s perspective evolved and was refined during the Covid-19 pandemic, it was generally the agency’s understanding EUA submissions were required (following some disagreement with leadership in the Trump administration about this position), a stance later affirmed in Covid-19-specific guidance documents that directed all LDTs offered for Covid-19 to submit an EUA. Given that laboratory developers had limited experience with dealing with the FDA, the agency did provide some flexibility – for example, laboratories with Covid-19 LDTs did not always need to submit a full, formal EUA to the agency, but could instead submit a copy of their CLIA documentation in certain circumstances.
• With the new enforcement policy outlined in the LDT final rule, FDA also sought to clarify its emergency response expectations. The rule clearly lays out FDA’s current policy, which is that “FDA’s general enforcement discretion approach generally has not applied to LDTs” when there is an EUA declaration and the EUA pathway is opened. However, given the updates to and eventual elimination of the “general enforcement discretion approach” that will be implemented under the final rule, this week, the agency released two guidance documents “in parallel to this rulemaking” that will explain the process for the role of LDTs (under the new parlance, IVDs currently offered as LDTs), going forward in emergency response.

The two new draft guidance documents outline enforcement policies in advance of and during an EUA declaration

• The guidance documents cover two separate but related topics: The first focuses on enforcement policies without an EUA declaration – either in advance of a formal declaration being made or when an emerging threat is geographically contained and does not rise to the level of a full national emergency situation. The second focuses on what any additional enforcement discretion policy will look like going forward after an EUA declaration has been made.

First up: What will happen when there isn’t an EUA declaration?

• As noted above, the agency foresees two general scenarios as to when there is a need for an “immediate public health response” but no EUA declaration: the time between when am emerging threat is identified and it is either resolved or an EUA declaration is made. With the general enforcement discretion for LDTs being phased out, “the FDA is issuing this guidance with our enforcement policy for “immediate response” tests.” The final rule calls this an “enforcement policy for certain IVDs for immediate response,” and refers sponsors to the new guidance for information on how an enforcement discretion policy would apply in these scenarios.
• In general, the guidance outlines a new enforcement discretion for pre-market review requirements – albeit limited in scope and applicability – that would apply for new (or adjusted) unauthorized tests in times of emergency response. The guidance lays out the types of tests that would be eligible for an enforcement discretion, the entities that could fall under the enforcement discretion, and what expectations would still apply even without pre-market review requirements.
• “Immediate response” tests are defined as: (1) those intended to detect or diagnosed a “newly identified, previously unknown, or unusual [chemical, biological, radiological, and nuclear] CBRN agent or agents; or a known agent or agents that result in a newly identified or unusual clinical presentation”; (2) tests needed for emergency response when there is “no adequate, approved/cleared/authorized, and available alternative test”; AND (3) the test is “intended to help ensure the government’s coordinated and effective public health response.” Notably, no tests with “home specimen collection or at home” testing capabilities would be considered “immediate response” tests, so those test types would theoretically require an EUA (once the option becomes available, as applicable).
• The policy is limited to only certain test developers. There are two categories of test developers to which this policy may apply: certain high-complexity CLIA labs, and labs within/partnered with the Centers for Disease Control and Prevention (CDC). Labs in the first category must be individual high-complexity CLIA laboratories that have experience with the FDA, meaning that they “ha[ve] demonstrated the ability to develop a similar diagnostic test consistent with FDA regulatory requirements.” The FDa further describes these labs as having “an FDA-cleared, approved, or authorized test with the same underlying technology.” Further, these labs must be either a U.S. Government (USG) laboratory or a state/local public health laboratory, or “operating under an agreement (formal or informal) with the USG. In the second category, “immediate response” tests can come from the CDC “for use by CLIA-certified laboratories” that are either within CDC, part of CDC’s Laboratory Response Network (LRN), or have an agreement with CDC. The CDC/Defense Department (DoD)’s LRN is a national security-focused laboratory network that qualifies certain member public health/DoD laboratories to respond to certain high-risk “agents of concern.”
• Validation, notification and transparency: The agency will expect tests, even those without pre-market review, to provide some information. First, information about the test’s validation should be “completed prior to testing and that summary validation and performance information [should] be made publicly available.” While the specifics of the validation methods will depend on the technology type, the agency is recommending a minimum of 30 positive and 30 negative samples, with publicly available information on sensitivity, reactivity and specificity. These validation data could additionally be leveraged for an EUA, should a declaration be made. Next, an applicable laboratory would need to provide a notification to the FDA that they will be initiating testing with their “immediate response,” including information on how they meet the criteria, information on the test, their regulatory experience and standing, as well as the link to their “publicly available” summary validation data. For transparency, the agency indicates that the test reports/ordering information (as well as the labeling) should “prominently disclose” that the test is neither reviewed nor authorized by the FDA.
• How long does the “immediate response” last? As noted above, the “immediate response” period can conclude in circumstances where the emergency situation is resolved before there is an EUA declaration, or when an EUA declaration is made. However, the agency goes on to set a one-year time limit on how long tests can be offered as “immediate response,” stating that if no EUA declaration has been made by that time, the agency would “anticipat[e] that the public health rationale for the enforcement policy… will no longer apply at that time,” and at the 12-month mark the agency would expect either a premarket submission or for the test to be pulled.
• If there is an applicable EUA declaration, the “immediate response” test would need an EUA. However, the test can continue to be offered “while the laboratory manufacturer prepares and submits an EUA request to FDA” – which, per the guidance, should happen within 21 days of the declaration – and then while the EUA is under review with the FDA. This is actually a longer period than some policies implemented under the Covid-19 emergency, which generally allowed developers up to 15 days to submit an EUA post-notification (or 10 days for certain tests).

Next, what about enforcement discretion when there is an EUA declaration?

• This draft guidance document focuses on enforcement discretion policies that would apply even when there is an EUA declaration in place. As the guidance explains, enforcement discretion can work as an add-on to EUA authorized tests, as “for certain tests, FDA may find it appropriate to also issue an enforcement policy regarding the distribution and use of certain unapproved tests for which EUAs have not been issued to help further expand access to such tests as quickly as possible,” citing experience during the Covid-19 and mpox responses.
• Rather than specifics of what such an enforcement discretion would look like, the agency instead outlines a set of “factors” it would consider in determining whether an additional enforcement discretion would be appropriate even when there is an EUA declaration already in place. Going forward, however, any specific parameters would be laid out in additional guidance tailored to the context of a particular emergency to further describe what, exactly, the FDA will have discretion about enforcing (e.g., pre-market review, adverse event policy). The guidance does go on to flag some concepts it would expect to be addressed in an enforcement discretion policy, which largely reflects the ideas addressed in the “immediate response” guidance, such as test validation and labeling, time-based constraints on when the policy would be applied, and what enforcement actions the agency would still take.
• Factor 1: Need. As described in the guidance, the FDA “intends to look at the testing needs of the emergency response,” including “the number of, and access to, FDA-approved/authorized tests available and how time sensitive the need for a test is.” These considerations will reflect information like transmission levels, the potentially exposed population, the volume of tests required to meet epidemiologic need, and “the type of test best suited to assist in the response.”
• Factor 2: Known or potential risks. “FDA intends to consider the risks to public health when unauthorized, and potentially inaccurate, tests are used,” it states. The FDA indicates that it will weigh a variety of risk-associated factor (e.g., complexity of the technology), as well as the seriousness of the emergency condition and concepts like “the experience of test manufacturers” who would be eligible for an additional enforcement discretion. As noted above, the non-EUA enforcement discretion for “immediate response” tests is only open to labs that have experience with the FDA (or are part of the LRN); these concepts would likely be applied here as well.
• Factor 3: Availability of alternatives. The guidance explains that the agency would consider not only whether alternative options exist (including FDA-authorized/approved versions of a test) but also their “adequacy” – for example, manufacturing capacity for the authorized/approved alternatives.
• Factor 4: Risk mitigation. To lessen potential risks associated with unauthorized tests, the FDA says that an enforcement discretion policy would likely take into account the developer experience (e.g., whether they have an authorized test or other regulatory experience) or participation in certain government programs – such as the National Institutes of Health (NIH) Rapid Acceleration of Diagnostics (RADx) Independent Test Assessment Program (ITAP). Further, an enforcement discretion policy would likely include information about labeling statements and validation, testing information “and submission of an EUA request within a reasonable period of time.”

What’s next?

• These draft guidance documents codify some of what CDRH developed as best practices during the Covid-19 emergency response, such as a preference for test developers with regulatory experience dealing with the FDA and those leveraging federal validation programs like ITAP, considering “manufacturing capacity” as a factor influencing the way the agency views availability and need, and a time-limited basis for the flexibilities to be in place (as well as specific timeframes for the submission of an EUA, as applicable). In general, these new guidance documents clarify that the policies will apply in advance of a new or emerging threat, which is likely to increase preparedness overall, in comparison to merely relying on precedent and Covid-19 experience.
• The draft guidance documents are likely intended to formally address some concerns with FDA’s efforts to expand oversight of LDTs. As AgencyIQ has previously discussed, some have argued that LDTs are more agile than other IVDs and are therefore an important part of emergency response. In particular, Sen. RAND PAUL (R-Ky) introduced legislation during the Covid-19 pandemic specifically stating that “regulation of laboratory-developed testing procedures may hamper the medical management and public health response to infectious disease outbreaks and pandemics.” With these new guidance documents in place, laying out the FDA’s policy on what a continued enforcement discretion would look like in case of emergency, the agency may be wanting to get ahead of these types of criticisms on its final rule.
• We are still awaiting one more draft guidance from the FDA on what the emergency response system will look like for test developers going forward. Looking at CDRH’s guidance agenda, there’s one more draft guidance on deck for this year on the subject of tests in emergency response: “Validation of Diagnostic Tests for Emerging Pathogens following a Declaration and Determination under Section 564.” This document, when available, will spell out what the FDA will expect to see in EUA submissions going forward, helping to set the stage for what diagnostic test developers can expect should another emergency require an EUA declaration.
• Further, the 2017 guidance (cited above) on EUA authorities may be due for a refresh as well, especially since the new drafts may need to cite this older document when they’re finalized. The 2017 document could do with some updating based on the lessons learned during the Covid-19 pandemic – during which the FDA used the EUA pathway more than it ever had before.
• These are draft guidance documents, which means they’re open for public comment through July 5, 2024. The documents, when final, will not apply until there is an identified emergency

To contact the author of this item, please email Laura DiAngelo ( [email protected]).
To contact the editor of this item, please email Kari Oakes ( [email protected]).

Key Documents and Dates

• • Enforcement Policy for Certain In Vitro Diagnostic Devices for Immediate Public Health Response in the Absence of a Declaration under Section 564: Draft Guidance for Laboratory Manufacturers and Food and Drug Administration Staff
  • Consideration of Enforcement Policies for Tests During a Section 564 Declared Emergency: Draft Guidance for Industry and Food and Drug Administration Staff