A quick history of FDA’s approach to LDTs and recent rulemaking efforts
- Laboratory developed tests (LDTs) are a kind of in vitro diagnostic (IVD) product. Historically, the FDA expressed an “enforcement discretion” over LDTs, not requiring these products to comply with the medical device requirements like most other IVDs, under the longstanding assumption that LDTs are developed and used in a single high-complexity laboratory for a comparatively low number of patients. [See a full AgencyIQ explainer of the history of this policy issue here.]
- Over the last decade, the FDA has signaled increasing concerns with LDT use, development and performance. In short, the agency has argued that LDTs are more numerous, complex, and reflect a more complex model than they did in the past when FDA’s enforcement discretion approach was first proposed. While both the FDA and Congress worked to develop legislation that would have created a new regulated product category encompassing LDTs and IVDs, this legislation was ultimately not passed despite significant efforts at the end of 2022, at which point the FDA committed to moving ahead with regulation.
- In October 2023, the FDA issued a proposed rule to bolster its regulation of LDTs. Under the existing statutory frameworks underpinning FDA’s authority, IVDs are regulated as medical devices. FDA’s proposed rule would update the definition of IVDs in regulation to explicitly include LDTs, therefore codifying the agency’s long-held interpretation that LDTs are a kind of IVD, and therefore a medical device. The policy would end the longstanding enforcement discretion for LDTs, bringing them into the device framework to be regulated through that system along with other IVD products. The proposal outlines a “staged” approach to ending the enforcement discretion in which different regulatory requirements would apply over five different stages: Stage one (device reporting and reports of correction and removal); Stage two (registration an delisting, labeling and investigational use requirements); Stage three (quality system requirements); Stage four (pre-market review for high-risk products); and Stage five (pre-market review for moderate and low-risk products).
FDA’s rule has just cleared the last step before publication
- On April 23, 2024 the White House’s Office of Information and Regulatory Affairs (OIRA) announced that it had finished its review of the rule and cleared it for release by the FDA. OIRA is the White House’s regulatory review body, and is charged with reviewing major policies before they are released to the public. Now that OIRA’s review of the rule is completed, the FDA may publish the LDT at its discretion. Based on past FDA actions, it seems likely that we could see this rule published later this week, or potentially next week.
- FDA has indicated it wants to move quickly on passing this regulation, and so far the rule has advanced extremely quickly. The FDA’s proposed LDT rule had a 60 day comment period, which the agency declined to extend. At the time, the FDA stated that given the history of this particular policy debate, there has already been enough time to comment on LDT policy: “The extensive background of public comment on this topic and the public health benefits of proceeding expeditiously” were factors in deciding not to extend the comment period. Further, the FDA’s Spring 2024 Unified Agenda indicated a target publication date of April 2024 for the final rule. On March 1, the White House Office of Information and Regulatory Affairs (OIRA) received the final version of the LDT rule from the FDA.
Simultaneously, OIRA also cleared two emergency response-related diagnostics policies
- Also on April 23, two FDA draft guidance documents on emergency response cleared administrative review at OIRA. These include a draft guidance document on considerations when there is a declared emergency and Emergency Use Authorization (EUA) declaration for tests, as well as another draft document on what test developers can expect when an EUA declaration has not yet been made, but as part of “immediate public health response.” These were submitted to OIRA for review on March 5, 2024.
- Notably, LDTs’ role in emergency response has been a sticking point for critics of the FDA’s efforts to increase its oversight of LDTs. Because LDTs historically do not have to be submitted to the FDA for review before deployment, some have argued that they are more agile than other IVDs and can therefore be more rapidly responsive in emergency situations; For example, 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.”
- It’s worth noting, however, that the FDA’s existing risk-based enforcement discretion doesn’t apply in emergency situations; In effect, when there’s a declared emergency situation – like a public health emergency (PHE) or an emergency use authorization (EUA) declaration – the FDA requires that LDTs, like other IVDs, be submitted for review before being marketed. The new guidance documents will likely clarify what, if any, enforcement discretion or flexibility the agency intends to use in the next case of an emergency, or where/when the diagnostic industry can expect to find information on next steps should this occur.
Some other questions about implementation: What we’re watching in the final rule
- There are a number of things to watch for in the final rule, including potential carve-outs for certain types of entities (e.g., academic medical centers), the introduction of a “grandfathering” system (which was not included in the proposed rule), and clarification on several key terms (e.g., “1976-type LDTs”). [See AgencyIQ’s analysis on “Top questions on FDA’s proposed LDT rule: Carve outs, capacity and quality systems,” here.]
- Keep an eye on Congress: Further, some legislators are showing renewed interest in this area; while there hasn’t been meaningful movement on a bill to reform diagnostics regulation overall, Sen. BILL CASSIDY (R-La.) issued a call for comments on the proposed rule, while lawmakers in the House held a hearing to discuss perspectives. The rule is likely to be met with significant opposition, which may kick off further policy debates – and potentially, legal action.
- The LDT rule also has implications beyond those directly for clinical laboratories/firms with laboratory business units. Beyond the emergency implications, the LDT rule is likely to affect diagnostic developers, device manufacturers and drug companies who may be exploring (or are currently invested in) companion diagnostics (CDx). The rule is also likely to cause challenges for the FDA’s Center for Devices and Radiological Health (CDRH), which will need to deal with an influx of LDT applications for review and pre-review work (such as early-stage meetings with companies). Application reviews for LDTs are likely to be the responsibility of CDRH’s Office of Health Technology 7 (OHT7, the diagnostics office), a division within the Office of Product Evaluation and Quality (OPEQ). However, OHT7 is currently without a permanent Director following the retirement of TIM STENZEL at the end of last year.
- The FDA has taken some action to address some of these concerns – but the actual impact is still TBD. A key assumption from the proposed version of the LDT rule was that the agency expected most LDTs would be “moderate risk,” or Class II, medical devices. Consequently, FDA expected that these devices would primarily be reviewed under the agency’s 510(k) pre-market notification pathway. However, all LDTs are technically Class III devices under current policy, considered “high risk” because of their regulatory status. In late January 2024, CDRH announced a new initiative to down-classify “most” Class III IVDs, saying that the agency’s thinking on the overall risk categorization of diagnostics had changed. Particularly for LDTs, this would help establish precedent that most IVDs, including LDTs, are Class II going forward, and would not need to submit a Pre-Market Approval (PMA) application to the FDA as part of the rule’s implementation.
- That move was also targeted at the CDx issue. CDx are a type of device, usually a diagnostic, that are used to inform safe and effective use of specific drugs. Unlike combination products, which receive a single authorization for the drug/biologic and the test that would inform its use, CDx are authorized as medical devices separately from the drug or biologic whose use they inform. While co-development is the ideal situation (i.e., the CDx and the drug are ready for approval at the same time), the FDA can approve a drug without its needed CDx in certain circumstances, as laid out in a 2014 guidance, and potentially with a post-marketing commitment for CDx approval. When drugs are approved without a CDx authorization, LDTs fill the gap – but this flexibility would be cut off under the LDT rule. The down-classification initiative specifically cites that CDx are likely candidates for a move from Class III to Class II, but re-classification of a medical device is a burdensome process, and there hasn’t yet been any news on CDRH’s expected cadence for re-classification.
To contact the author of this item, please email Laura DiAngelo ( [email protected]).To contact the editor of this item, please email Alexander Gaffney ( [email protected])
Key Documents and Dates
- Medical Devices; Laboratory Developed Tests
- Consideration of Enforcement Policies for Tests During a Section 564 Declared Emergency; Draft Guidance for Industry and Food and Drug Administration Staff; Availability
- Enforcement Policy for Certain In Vitro Diagnostic Devices for Immediate Public Health Response in the Absence of a Declaration under Section 564
- Lawmakers signal renewed interest in diagnostics policy
- CDRH diagnostics update: An IVD down-classification initiative, CDx and LDTs, and next steps for diagnostics regulation