Summary:
The article discusses ongoing legal challenges to FDA’s regulation of Laboratory Developed Tests (LDTs) amid significant administrative changes, alongside new guidances relating to AI-enabled medical devices and proposed nicotine regulations.
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The multi-decade battle over FDA’s power to regulate Laboratory Developed Tests (LDTs) had its day in court earlier this week. On February 19, 2025, Judge Sean Jordan in the Eastern District of Texas heard oral arguments in American Clinical Laboratory Association (ACLA) and the Association for Molecular Pathology’s (AMP) lawsuit against the Department of Health and Human Services. ACLA and AMP are both challenging the legal validity of FDA’s Final LDT Rule that was issued last July. The arguments lasted nearly three hours. Judge Jordan began with asking the parties a foundational question: how do you define LDTs? Without giving any indication of which way he was leaning, he asked multiple follow-up questions of both sides on topics ranging from the roles of analytical and clinical validity to the history of the FDCA and CLIA. Citing the May 6 compliance date for Stage 1 of the LDT Rule, both ACLA and AMP asked that Judge Jordan issue his ruling expeditiously. Judge Jordan said he would issue a decision as soon as possible.
Perhaps most notable in yesterday’s argument, though, was what didn’t happen. Given the numerous changes in policy by the Trump administration, there had been much speculation that the government would now take a different position on this Biden-era rule. It did not. Department of Justice counsel strongly defended the rule throughout the hearing. Interestingly, counsel focused his arguments exclusively on parrying legal attacks, rather than arguing why the rule was necessary to protect patients. In contrast, AMP and ACLA both asserted that the rule would harm medical care. Perhaps anticipating a less than favorable outcome, DOJ counsel several times asked to be allowed to submit a brief on the question of the remedy in the event of an adverse ruling.
As our readers will recall, the LDT rule will bring, by FDA’s estimates, hundreds of thousands of laboratory tests under FDA’s regulatory purview. Despite this impending massive change in regulatory scope, the President and his Department of Government Efficiency (DOGE) fired hundreds of FDA employees this past weekend. Many of the fired employees were within the Center for Devices and Radiological Health—the Center that is tasked with regulating all devices, including in vitro diagnostics, which FDA argues includes LDTs. These firings will stretch the Center’s resources to take on its existing workload, let alone handle thousands of complex and innovative LDTs. We have previously raised concerns about the number of resources that will realistically be needed for CDRH to regulate LDTs.
A major concern for laboratories, particularly those who have introduced new tests since the final rule was issued, will be availability of resources to review pre-submissions ahead of the Stage 4 and 5 implementation dates. Notably, the last question Judge Jordan asked of ACLA was on this specific point. Judge Jordan asked ACLA for confirmation that he understood correctly that pre-market submission was the major burden for labs and that while pre-market submission compliance dates are still several years away, labs should be preparing now to meet FDA’s pre-market expectations. ACLA, of course, confirmed that was true.
Labs that will need to gain clearance/approval for their tests will need to begin the process soon to ensure they understand FDA’s expectations for analytical and clinical validity. (That, of course, is not unique to labs with LDTs; kit manufacturers also need to obtain those insights well before they begin studies.) The process for gaining this alignment is through the pre-submission program. The last time CDRH was significantly resource constrained (i.e., during COVID), however, the Center stopped reviewing nearly all pre-submissions. A surge in pre-subs from labs combined with a shortage of qualified reviewers will almost certainly lead to significant delays in getting feedback, or, as happened during COVID, receiving no feedback at all. If this happens, laboratories will not be able to anticipate what data FDA wants.
The first phase of the rule, which takes effect in less than three months, requires laboratories to have certain policies and procedures in place to begin handling complaints, reporting Medical Device Reports, and reporting corrections/removals. While not terribly informative, under the prior administration, FDA held a webinar to outline the requirements of this Stage.
FDA had been scheduled to hold a webinar on the Stage 2 (May 2026) requirements related to the investigational device requirements for LDTs later this month. Since the new administration took office, however, the webinar page has been taken down from FDA’s website. This raises the question of whether and to what extent, if the rule moves forward, will FDA provide any tools to help laboratories as they seek to comply with these new requirements.
The LDT Rule itself provides no operational guidance, but only a definition. The preamble to the Rule references planned or possible guidances more than 200 times, highlighting nearly a dozen areas for guidance development. In fact, FDA has three guidances on its “A list” planned for this fiscal year that are specifically related to the LDT Rule or IVD labeling. It’s unclear at this time whether any of these guidances will be issued, if the rule moves forward.
In addition, we understand that at this time FDA is unable to consult outside experts. This restriction could significantly affect the Agency from learning from clinical and technical experts about the benefits and risks of certain tests as well as interpreting the clinical context of MDRs that it would start to receive if Stage 1 goes into effect. As those that have worked with FDA know, the Agency is not an expert on all disease states or technologies. This knowledge gap may be further exacerbated with MDRs for novel LDTs. This inability to consult external experts could make communicating with FDA on important topics of safety and effectiveness even more challenging.
Taken together, should the rule go into effect, CDRH may be even less prepared for LDT regulation than it was a short time ago. Thirty-three years after FDA first said it could regulate LDTs, we now wait to see if the court will allow the rule to stand.
The government is currently funded through March 14th, 2025. Come Monday March 17th, if Congress does not pass a budget or continuing resolution, the FDA will enter a shutdown and shutter many offices and programs while Congress works out their inter-party squabbles on national priorities. While the political process plays out many FDA employees will be furloughed and told to not report for duty.
The question that is always on the mind of folks in FDA-regulated industries is, “what does that mean for my application/inspection/meeting?”
What does it mean for FDA staff? If your position is exempt from appropriations, you may be asked to remain at your station and working while other FDA employees are furloughed. Most of FDA’s reviewers are exempt, while compliance, policy, and administrative support are typically furloughed.
What does it mean to be furloughed? When you are furloughed, you are expressly forbidden from working as you are not being paid. One’s furlough status during a shutdown can also be in flux. If you are a reviewer and you run out of user-fee work, you become furloughed until the shutdown ends or if user-fee work is assigned to you. Furloughed staff from other programs can be brought back into working status on an “as needed” basis to specific tasks.
Examples:
A manager has three approval letters to review and a binder of lot release papers. Once those reviews are complete, the manager is furloughed for the rest of the day and goes home.
A critical amendment to an IND is received. The staff required to process the submission are recalled from furlough to input the submission into the system so it can be reviewed by staff. Once processing is complete, the staff are returned to furlough status.
Drugs/Biologics/Devices/Tobacco (CDER, CBER, CDRH, CTP) – These centers are largely supported by user-fee programs that support their review staff. This means that while most of the FDA will be in shutdown mode, submissions under these agreements proceed as normal. The monies collected from the user-fee programs give FDA months of additional runway in the event of a funding lapse by Congress. The amount of runway that FDA has is dependent on the user-fee program. Each user-fee program is its own separate pool of money that is used to fund the review operations. During the 5-week shutdown in 2018/2019, PDUFA funding was the most robust and could have funded several months of review operations. Based on my own experience as a reviewer during the 2018-2019 shutdown, reviewers with active user-fee files continued their jobs without interruption.
What happens to my NDA/PMA/BLA/510(k)/IDE/IND under review? You should not expect a meaningful change to your review progress as a result of a short or moderate-length shutdown. It is only if a shutdown lasts a couple of months or more that programs may begin to run out of funding and have to furlough review staff. Some behind the scenes activities do get more difficult as some of the supporting program staff will be furloughed.
What happens to my Pre-submission or Type A/B/C/D Meeting? While these meeting requests do not have a specific user-fee tied to them, they are under the umbrella of the user-fee agreements and the staff working on these submissions are not furloughed. You should expect written response-only and teleconferences to proceed largely uninterrupted, but face-to-face meetings may not be possible due to support staff furloughs.
What happens with Inspections and Compliance? For normal surveillance operations, those inspections are largely, if not entirely, funded by appropriations. If the shutdown were to occur on Monday March 17th, inspectors may be recalled from active or on-going inspections to be placed on furlough. For pre-license or pre-approval inspections, the outcome of a shutdown is less draconian as these are under the auspices of a user-fee program.
Example: I was scheduled to conduct an international pre-license inspection in early February 2019, and we continued planning for that activity assuming that the shutdown was not going to last until that date. In the event that the shutdown was still in effect, management indicated that the inspection could still proceed, but there would be significant logistical challenges with many of the necessary folks to sign-off on items being caught in the furlough.
For most of the compliance staff, when a shutdown hits, they are furloughed as compliance operations are generally not under a user-fee program. There can/will be exceptions to this as there are programs and specific projects that are critical to health, but one should not count on calls or emails being returned until after the shutdown ends.
Will FDA accept new submissions while shutdown? Submissions to FDA that have an associated user-fee will not be accepted during a government shutdown as they do not have the ability to process the payments (PMAs, 510(k)s, PFUDA Program Fees). For the submissions that do not have an associated user-fee (INDs, IDEs, Pre-submissions, certain supplements), these submissions may be accepted and reviewed. User-fee submissions sent to FDA will be placed “in the queue” for formal processing and acceptance after FDA returns to normal operations.
If you are preparing a submission to FDA in the next few weeks, you may want to consider the ramifications of the March 14th government funding deadline and plan accordingly.
FDA recently released its final guidance for Predetermined Change Control Plans (PCCPs) for Artificial Intelligence-Enabled Device Software Functions (AI-DSF). The final guidance hasn’t changed much from the draft guidance with respect to the type of modifications FDA considers applicable for a PCCP and the required components of a PCCP. The most noteworthy change is the title, which has been broadened to include AI-DSF, not just the subset of AI known as machine learning (ML). FDA defines Artificial Intelligence (AI) as a “machine-based system that can, for a given set of human-defined objectives, make predictions, recommendations, or decisions influencing real or virtual environments.” Machine Learning is defined as a “set of techniques that can be used to train AI algorithms to improve performance at a task based on data.” Consistent with the title change, the draft guidance’s references to ML-DSF have been replaced with AI-DSF, which is now defined as a “device software function that implements an AI model” and omits references to ML models and techniques.
As we’ve previously blogged, a PCCP is a mechanism established by Congress under the Food and Drug Omnibus Reform Act (FDORA) to streamline post-market changes to medical devices. Sponsors can include a PCCP as part of their pre-market submission that describes an approach for making certain types of device modifications after the device is marketed. If FDA agrees to the PCCP, such changes can be made without a supplemental marketing submission.
While a PCCP can address many types of post-market device changes, FDA specifically recognizes that software development is an iterative process, and software developers continually try to improve and update devices. Therefore, this guidance builds on FDA’s commitment to “develop and apply innovative approaches to the regulation of [AI-enabled devices].”
Scope of Permissible PCCPs
The final guidance describes the scope of post market modifications to AI-DSF that are appropriate to include in a PCCP. In general, a modification must be within the device’s intended use and maintain the indications for use in order to be included in a PCCP. The final guidance does leave some ‘wiggle room,’ stating that “certain modifications to the indications for use” may be appropriate for inclusion in a PCCP. Examples of modifications to AI-DSF that may be appropriate for a PCCP include modifications to inputs, input sources, compatibility, and interoperability. However, the guidance states that FDA will evaluate a PCCP on a case-by-case basis, in light of the “benefit-risk profile” of the specific device when deciding if the proposed modification can be authorized in the marketing application, noting that “certain modifications that may be appropriate for inclusion in a PCCP for one device may not be appropriate for inclusion in a PCCP for another device.” The guidance encourages sponsors to engage with FDA using the Q-Submission Program prior to submitting a PCCP in order to obtain FDA feedback on if the proposed modification is suitable for inclusion in a PCCP and what information the PCCP will need to include.
Consistent with the draft guidance, the final guidance takes the position that PCCPs are only appropriate for the following submission types:
Pre-market approval (PMA): Original, Modular, 180-day PMA supplement, Panel Track PMA supplement, Real-Time PMA Supplement (only when FDA agrees the review can be achieved in real-time)
De Novo
510(k): Traditional and Abbreviated
Unfortunately, the final guidance continues to exclude Special 510(k)s. In fact, eSTAR does not allow a PCCP to be included in a Special 510(k); attempting to do so results in the message “if you are establishing a PCCP this should not be done in a Special 510(k).” Modifications to previously authorized PCCPs can be submitted via a Special 510(k), and eSTAR recommends that the manufacturer submit a clean copy and redline of the PCCP as an attachment.
The final guidance emphasizes the importance of having a quality system in place, stating that FDA “may under certain case-by-case circumstances withhold clearance of a PCCP submitted in a 510(k) based on findings in the regulatory history of the manufacturer that demonstrate failure to comply with [Quality System regulation (QSR)].” An analogous limitation is contained in the Special 510(k) guidance, which states that a Special 510(k) should not be submitted if the manufacturer has received a violative inspection report following a recent QS inspection that identified “observations related to design controls that are relevant to the design changes.” We wonder if the Agency will similarly reject a PCCP if a manufacturer has demonstrated a failure to comply with design controls, especially those related to design changes.
Components of a PCCP
The guidance identifies the following elements for inclusion in a PCCP:
Modification Description
Modification Protocol
Impact Assessment
Modification Description
The Modification Description should describe the planned modification and the performance specifications. FDA recommends including only a “limited number” of modifications in the PCCP. The description should be sufficiently specific to allow verification and validation as defined in the Modification Protocol. The manufacturer should, in addition to stating whether the modification will be implemented manually or automatically, include details such as:
End user actions needed, if any to implement the change,
Timing of implementation,
Extent of implementation in the install base, and
Include references to expected labeling changes.
Modification Protocol
The Modification Protocol should describe the methods for developing, verifying, validating, and implementing the modifications described in the Modification Description. Manufacturers should develop the Modification Protocol consistent with their quality system and should follow their risk management processes. FDA expects four elements to be included in a Modification Protocol:
Data management practices,
Re-training practices,
Performance evaluation protocols, and
Update procedures.
FDA may request additional information during the review of the PCCP.
For most manufacturers, verification and validation protocols may only cover performance evaluations against pre-determined acceptance criteria, and they may need to pull data management practices and re-training practices from their development plans. Verifying and validating update procedures may be in a separate protocol from performance testing and should be included in the Modification Protocol section of the PCCP. Update practices and training of end users also need to be addressed.
Data management practices should include how the manufacturer plans to obtain and use training, tuning, and test data to support each AI-DSF modification. FDA provides definitions for the three datasets. Although data scientists sometimes refer to the tuning dataset as the ‘validation dataset,’ FDA encourages using terminology consistent with the Agency’s Artificial Intelligence Glossary. Test data should be independent of the training and tuning data and come from multiple sites representing the intended use population.
Re-training practices should identify the “objective of the re-training process,” describe the AI model and the AI-DSF modification, and identify any “triggers for re-training.”
Performance evaluation protocols should include the planned verification and validation activities for each AI-DSF modification separately and, in total, including all planned modifications. This will ensure each AI-DSF modification does not have an adverse impact on the overall device performance. The Modification Protocol should “affirmatively state that if there is an unresolvable failure in performance evaluation for a specific modification (e.g., the predefined acceptance criteria for a specific modification are not met), the failure(s) will be recorded, and the specific modification(s) will not be implemented.” The final guidance clarifies that only an “unresolvable failure” should preclude implementation; if the failure is resolvable the modification may be implemented after retesting. Additionally, a failure is NOT considered unresolvable “if a root cause analysis of the failure reveals it is not related to specific aspects of the PCCP.” In such cases, performance testing may be conducted again.
The update procedures should include how the AI-DSF modifications will be implemented and communicated to end users. The update procedures should include plans for required labeling changes and training provided to end users. The final guidance added information on updating the UDI as part of the planned labeling changes when there is a new version of the device. In addition, the final guidance recommends the Modification Protocol include the manufacturer’s “post-market surveillance plans and procedures,” which reflects a change from the draft guidance’s recommendation for “real-world monitoring.” The final guidance adds that such post-market surveillance plans “may include real-world monitoring and notification requirements if the device does not function as intended pursuant to the authorized PCCP.” Post-market surveillance plans and procedures (PMS) are a requirement under ISO 13485 which will be adopted into FDA’s Quality Management System Regulation in 2026. PMS requires manufacturers to gather information from various sources, evaluate the data for trends, and integrate the data into product development, risk management and design updates. This change in language seems to suggest a more formal approach to monitoring to ensure the modified AI-device remains safe and effective.
FDA recommends that the PCCP include a traceability table containing each proposed AI-DSF modification and the location within the Modification Protocol for each of the four elements described above.
Impact Assessment
The Impact Assessment documents the benefits and risks of implementing the AI-DSF and the mitigations for the identified risks. The Impact Assessment should:
Compare the version of the device with each modification implemented individually to the version of the device without modifications implemented;
Discuss the benefits and risks, including risks of harm and unintended bias, of each individual modification;
Discuss how the verification and validation activities proposed within the Modification Protocol continue to reasonably ensure the safety and effectiveness of the device;
Discuss how the implementation of one modification impacts the implementation of another; and
Describe the cumulative impact of implementing all modifications.
The final guidance goes beyond considerations of harm and includes unintended bias when discussing the benefits and risks of the modification. The guidance states that the Impact Assessment can be a stand-alone document, incorporated into the manufacturer’s Risk Assessment, or included in the Modification Protocol.
The final guidance includes references to combination products and indicates the Impact Assessment should address the impact of the device modification to the biologic or drug constituent part.
Post Authorization
When FDA grants marketing authorization for a device that includes a PCCP, the PCCP will be referenced by title and version number in the authorization letter. Details of the PCCP will be publicly available (i.e., PMA summary of safety and effectiveness document (SEED) and approval order, 510(k) Summary, De Novo decision summary). FDA recommends that the following information be made public regarding the PCCP as appropriate: planned modifications, testing methods, validation activities and performance requirements to meet before implementation, and means by which users will be informed of the implementation of the modification.
Modifications that deviate from the authorized PCCP and are implemented without a market authorization may render the device “adulterated and misbranded” and result in enforcement action by FDA, including “seizure on injunction.”
If you need to modify the PCCP, you must submit a revised PCCP to the FDA for authorization prior to implementing the modification. As stated previously, when submitting a revision to an authorized PCCP, you should provide both a clean copy and redline of the revised PCCP and also include a reference to the submission that authorized the prior version of the PCCP.
The final guidance hasn’t changed much from the draft guidance with respect to the type of modifications eligible for a PCCP or the required components of a PCCP. Consistent with the draft guidance, it contains a significant level of detail on the fundamental principles that should govern the design and development of AI-based software. The placement of this information is odd and would seem to fit better in the recently released draft guidance on AI-DSFs: Lifecycle Management and Marketing Submission Recommendations (Lifecycle Management guidance). Manufacturers of AI-based software would expect to find this level of detail in the Lifecycle Management guidance would not think to look for additional details in the PCCP guidance. Ideally, the Lifecycle Management guidance would have been finalized before the PCCP guidance, however since that is not the case, it would seem to make sense to transfer design and development information from the PCCP guidance into the Lifecycle Management guidance or, at the very least ensure the Lifecycle Management guidance cross-references the PCCP guidance, where applicable.
During the final week of the Biden administration, on January 15, 2025, FDA issued a proposed rule that, if finalized, would establish a maximum nicotine level in cigarettes and other combusted tobacco products, including most cigars and pipes, through its authority under Section 907 of the FD&C Act to adopt tobacco product standards. This proposed rule follows FDA’s March 2018 advance notice of proposed rulemaking (ANPRM) regarding a potential maximum nicotine level for cigarettes.
The rule, if finalized, would set the maximum level of nicotine at 0.7 milligrams of nicotine per gram of tobacco. This is a dramatic reduction (nearly 2500%) from the average 17.2 milligrams of nicotine per gram of tobacco that many cigarettes currently contain, according to one study that FDA cited in the proposed rule.
More specifically, the proposed rule would apply to combusted cigarettes (including roll-your-own) tobacco, cigars (excluding premium cigars due to a court order that excluded premium cigars from FDA’s legal authority), and pipe tobacco (excluding waterpipe tobacco). It would not apply to electronic nicotine delivery systems (ENDS) smokeless tobacco products, nicotine pouch products, or other non-combusted tobacco/nicotine products.
FDA’s primary purpose of the proposed rule is to take aim at what it considers to be at the heart of the country’s leading cause of preventable deaths: nicotine addiction. FDA did not mince words in the opening line of the proposed rule’s executive summary, stating that each year, 480,000 people die prematurely from a smoking-attributable disease, and “[n]early all these adverse health effects are ultimately the result of addiction to the nicotine in combusted tobacco products” (emphasis added). FDA’s focus on combustion is significant. Although the Agency has long been concerned with the effects and influence of smoking on children and young adults, the proposed rule does not apply to noncombusted products that contain nicotine, such as ENDS. In addition, although the 2018 ANPRM contemplated only applying to combusted cigarettes, FDA was concerned that users would then turn to other combusted tobacco products, thereby “undermining the public health benefits” of its proposal. Now, the current proposed rule covers the combusted tobacco products that FDA describes as “the most toxic and widely used tobacco products.”
Relying on findings from the case, United States v. Philip Morris USA, Inc. et al., FDA stated that cigarette companies have designed the levels of nicotine in its products to “create and sustain addiction.” By making cigarettes and other tobacco products less addictive (FDA specifically stated that the rule is intended to make these tobacco products “minimally or nonaddictive”), FDA intends to work towards the intertwined public health goals of helping current smokers quit, preventing others (and particularly young people) from becoming addicted smokers, and reducing tobacco-related diseases and deaths. FDA predicts that the proposed rule, if finalized, would prevent approximately 48 million youth and young adults from initiating habitual cigarette smoking by 2100, and would allow more than 12.9 million additional people to quit smoking cigarettes within one year after implementation of the proposed standard.
Acknowledging the possibility that reducing the level of nicotine in cigarettes will simply result in people smoking more cigarettes to get the same nicotine yield, FDA referenced studies showing that extended use of “very low nicotine content” (VLNC) cigarettes does not result in more cigarettes smoked per day. In addition, FDA went all-in with its reduction plan, which it calls an “immediate nicotine reduction approach” (i.e., a single-target approach to reach the proposed maximum nicotine level) as opposed to introducing an incremental reduction plan, in order to avoid “compensatory smoking” (for example, taking deeper puffs) and increased manufacturing costs (i.e., manufacturers would not need to formulate multiple products and prepare and submit premarket review applications at each phase of a gradual reduction approach).
This proposed rule would also require manufacturers of products covered under the rule to employ various new procedures for compliance, including analyzing nicotine levels using methods that have been validated in an analytical test laboratory, designing and implementing sampling plans for each batch of product, and establishing procedures for dealing with nonconforming products. The proposed rule would also impose additional requirements on tobacco manufacturers, such as using a manufacturing code and recordkeeping. FDA provided various ways that the nicotine reduction can be achieved, including tobacco blending, chemical extraction, genetic engineering, and different farming methods. The effective date of any final rule based on this proposed rule would be two years after the final rule is published, providing tobacco manufacturers with some time to get into compliance with the final rule’s requirements, sell remaining stock of finished tobacco products, and subject applications for new tobacco products that comply with the finalized product standard.
Strong opposition is expected from the tobacco industry, including legal challenges to the rule, if finalized. Even if the rule ultimately survives any such challenges, whether FDA will also attempt to reduce the levels of nicotine in e-cigarettes will remain an open question, although we note that the Agency hasn’t always had the best luck in that area, and given the Trump administration’s recent withdrawal of FDA’s proposal to ban menthol cigarettes, it seems at least possible that the new administration could similarly withdraw this proposed rule.
Comments on the proposed rule may be submitted until September 15, 2025.
In early January, FDA released a draft guidance document titled Artificial Intelligence-Enabled Device Software Functions: Lifecycle Management and Marketing Submission Recommendations. FDA has issued discussion papers and guidance on use of Pre-determined Change Control Plans for devices enabled by artificial intelligence. However, up to now the agency has said little about the content sponsors should include in an original marketing application for an AI-enabled medical device. As a consequence, sponsors of submissions for such devices have been surprised by lengthy requests for additional information from FDA during premarket review.
By way of background, the Draft AI Guidance defines AI-enabled devices as devices that include one or more AI-enabled device software functions (AI-DSF). An AI-DSF is a device software function that implements one or more “AI models” to achieve its intended purpose. An AI model is a mathematical construct that generates an inference or prediction based on new input data. The Draft Guidance acknowledges that there are some differences between the terminology used by FDA and the broader AI community, so it is important that all stakeholders review definitions and make sure they are speaking FDA’s preferred language when preparing device documentation. While the Draft AI Guidance does not include a glossary of AI-related terms, such a glossary is available on FDA’s website.
The Draft AI Guidance is lengthy, containing 64 pages of information and examples to help sponsors improve the quality of the device documentation. The Draft AI Guidance provides information on both recommendations on the documentation and information that should be included in marketing submissions as well as recommendations for the design, development, deployment, and maintenance of AI-enabled devices that may be generated as part of following quality system procedures and useful to support premarket authorization.
Appendix A of the Draft AI Guidance provides a helpful overview of documentation that should be submitted in a marketing application for an AI-enabled medical device. More detailed descriptions are included in the body of the Draft AI Guidance, and other Appendices include detailed discussion of transparency design, performance validation, and usability evaluation considerations, and also provide examples of a Model Card and 510(k) Summary with Model Card.
The Draft AI Guidance includes a section on validation of AI-enabled devices, stating that validation should demonstrate both the ability of the device to meet performance specifications and the ability of users to interact with and understand the device. Performance validation should use data collected from different sites than were used for collection of training data. A statistical analysis plan, including a plan for subgroup analysis, is also recommended to pre-specify plans to analyze validation results. Appropriate subgroups for analysis will vary based on the intended use of the device but should generally include patient sex, gender, age, race, ethnicity, disease variables, clinical data site, data acquisition equipment, and, if applicable, conditions of use (including skill level of the user when relevant), device configurations, and other relevant confounding factors that may impact device performance. Validation of an AI-enabled device should also include, when feasible and appropriate, an evaluation of its repeatability and reproducibility, which may include testing using phantom, simulated, contrived, or clinical data.
The Draft AI Guidance includes recommendations for postmarket device performance monitoring. FDA notes that performance of AI-enabled devices may change over time in the real-world environment and states that sponsors may include a monitoring plan in the marketing application to support FDA’s evaluation of risk controls. While acknowledging that information on a sponsor’s quality system regulation (QSR) compliance is not generally included in a 510(k) submission, the Draft AI Guidance notes that it may be appropriate for the Agency to review information about the sponsor’s quality system during review of a 510(k) submission. The Draft AI Guidance states that inclusion of a postmarket device performance plan in a marketing application is an option for providing “reasonable assurance of the device’s safety and effectiveness” and “to ensure adequate ongoing performance . . . [to] support a determination of substantial equivalence.” That being said, the Draft AI Guidance also acknowledges that for a 510(k) submission, a postmarket performance plan would not be required absent a special control calling for the plan. For a De Novo classification request, a postmarket performance plan may be required by FDA and included as a special control for the device type going forward. Finally, a performance monitoring plan may also be a condition of approval for devices subject to premarket approval. The Agency is encouraging sponsors to include a postmarket performance plan even when not strictly required and recommends sponsors discuss these plans in a pre-submission.
To support transparency of the AI-enabled device, the Draft AI Guidance discusses content of device labeling and the public submission summary. A Model Card is noted as a means of providing appropriate information in both places. A Model Card is a short document that provides key information about an AI-model. Model cards are used in the broader AI-industry and may be helpful to communicate information about an AI-enabled device. FDA recommends that an AI model card include device identification information, device regulatory status, a description of the device’s use, a description of the device’s performance and limitations, a discussion of potential risks, and a description of data used to develop the device.
FDA has been reviewing AI-enabled devices for years and sponsors of many of these submissions have received lengthy pre-submission feedback and requests for additional information related to the topics covered in the Draft AI Guidance. Given this, having FDA’s expectations laid out in the Draft AI Guidance is a good step, though the level of detail required for a submission for an AI-enabled device is extensive and burdensome. FDA’s expectations for data management practices seem particularly challenging and will be discussed in a follow-up post.
FDA plans to host a webinar to discuss the Draft Guidance. It was originally scheduled for Tuesday, February 18, 2025, but has recently been postponed. Comments on the Draft AI Guidance are due by April 7, 2025.
Last December, Congress narrowly avoided a shutdown by significantly paring down the originally proposed 2025 Appropriations bill, slashing away hundreds of programs and laws. The Rare Pediatric Disease (RPD) Priority Review Voucher (PRV) was caught in the crosshair once again. This time, however, the program, which has helped incentivize the development of dozens of pediatric rare disease therapies since 2012, was not renewed.
Our colleagues have recently blogged about the RPD PRV, its four-year sunset date, and the political drama that it frequently gets caught in. With the current lapse in authorization, FDA may only award RPD PRVs for applications that have received an RPD designation before December 20, 2024, and—unless reauthorized before then—may not award any RPD PRVs after September 30, 2026. Below, we discuss some of its downstream impacts on the PRV landscape.
An Increased Interest in the Tropical Disease PRV Program?
As our readers may already know, FDA maintained three PRV programs to incentivize the development of therapies for underfunded diseases: the RPD PRV program, which sunset last month, the Medical Countermeasures (MCM) PRV Program, which sunset in October 2023, and the Tropical Disease PRV Program. The Tropical Disease PRV program was not only the first priority review voucher program created by Congress, it is also the only one drafted without a sunset provision.
In 2006, David Ridley, Henry Grabowski, and Jeff Moe proposed a voucher in an article in Health Affairs as an incentive to develop therapies for “neglected” infectious and parasitic diseases that affect hundreds of millions of people in the developing world. The authors suggested that the developers of such therapies would receive a “priority review voucher” that they can sell to manufacturers of blockbuster drugs. The Tropical Disease PRV program was born the very next year as part of the Food and Drug Administration Amendments Act of 2007 (FDAAA) and expanded in 2014, which experts heralded as a “game-changer” for tropical disease therapies. In the eleven years from 2009 to the end of 2019, FDA awarded 11 tropical disease PRVs for the development of therapies for diseases such as malaria, tuberculosis, dengue, and river blindness. But as the other PRV programs were created, the value of each voucher decreased, and the interest and investment in tropical diseases dropped. Over the last 5 years, only three more drugs or biologics received a tropical disease PRV. As of the start of 2025, tropical PRVs represent less than 20% of all the PRVs granted.
The Uncertainty Around the RPD PRV Program May Re-open the Investment for Tropical Disease PRVs
Of all the PRV programs, the RPD PRV program was the most productive. By our analysis, seventy percent of all priority review vouchers that have been awarded since 2009 were awarded to sponsors that developed therapies for rare pediatric diseases. While lapse of this program may raise concerns about the end of the Tropical Disease PRV, such a result is highly unlikely.
First, the Tropical Disease PRV program is the oldest one on the books and was the only one that was drafted without a sunset clause. To axe the Tropical Disease PRV Program, Congress would have to draft legislation to change the current law and then pass it through both Congressional bodies rather than simply let it expire like it did with RPD and Medical Countermeasures. This seems like a tall order, especially when one considers that the original law was passed in 2007 with only seven votes against it in the House and unanimously in the Senate, and it was expanded unanimously in both chambers in 2014.
Second, the Tropical Disease PRV program is the only program that has seen a small, but regular expansion since its creation. As recently as 2020, FDA added Brucellosis, a zoonotic infection, to the list of tropical diseases for which sponsors are eligible for receiving a PRV. This suggests FDA’s continued interest in the program, making it unlikely to appeal to Congress to repeal it.
Finally, we note that if the RPD PRV program never returns, we would expect to see a large effect on the Tropical Disease PRV program in the form of increased value of each new PRV. With no more RPD or MCM PRVs, there will be fewer PRVs for purchase (since RPDs made up 70% of the market), which would likely cause the price on the secondary market of each of the remaining PRVs to increase. As a result, both Tropical Disease PRVs and any un-used other PRVs (as all PRVs earned can continue to be redeemed notwithstanding the end of the program) have the propensity to shoot back up in cost, perhaps to those $300+ million values we saw in 2020.
Only time will tell how much companies will be willing to pay for PRVs once they become even more scarce.
Tropical diseases affect hundreds of millions of people around the world. This might be the time for investors to bring their attention back to therapies for tropical diseases—they might get rewarded with a much more valuable voucher for it.
We recently blogged about a new December 2024 draft guidance about accelerated approval (the “December 2024 draft guidance”). That post largely focused on endpoints as well as the broader context for when accelerated approval is appropriate. However, as we note in that post, the design, timing of initiation, and timely conduct of confirmatory trials are also important considerations in FDA’s determination of whether accelerated approval is appropriate.
As a result of reforms enacted by the Food and Drug Omnibus Reform Act of 2022 (“FDORA”), FDA’s authority to approve as well as withdraw an accelerated approval was given new regulatory “teeth” to ensure that confirmatory trials are conducted expeditiously. FDA’s withdrawal authority when a confirmatory trial is not conducted with “due diligence” was expanded to include that FDA could “specify the conditions for a postapproval study . . . which may include enrollment targets, the study protocol, and milestones, including the target date of study completion.” FDORA also gave FDA new authority to require that confirmatory trials be “underway prior to approval, or within a specified time period after the date of approval.”
To this end, the December 2024 draft guidance and a companion guidance published January 7, 2025, Accelerated Approval and Considerations for Determining Whether a Confirmatory Trial is Underway (the “January 2025 draft guidance”) describe FDA’s latest thinking on what it means to conduct a confirmatory trial with due diligence. These draft guidances also discuss how the Agency plans to interpret whether such a study needs to be underway at the time of approval and, if so, whether it is “underway.” They also present a more intense focus on the timelines for confirmatory study initiation and completion as well as the feasibility of those studies to verify clinical benefit within those timelines.
For instance, the December 2024 guidance goes beyond the 2014 Expedited Programs for Serious Conditions – Drugs and Biologics guidance (the last to deal substantively with accelerated approval) to describe FDA’s expectation that sponsor’s take a proactive approach to ensuring confirmatory trials are completed within specified timelines. Similarly, the December 2024 draft guidance reiterates prior positions that confirmatory trials should generally be underway at the time the marketing application is submitted but also states that this recommendation becomes a requirement by the time of approval “except in limited circumstances.” However, it left unanswered what “underway” means, noting an intention to address this authority in the now published January 2025 draft guidance.
This blog post focuses on interpreting these new authorities with respect to timely conduct of confirmatory trials. We discuss, first, the way FDA articulated its thinking regarding what it means to conduct a confirmatory trial with due diligence and then how FDA intends to interpret that a study is underway. While the first topic is addressed primarily in the December 2024 draft guidance, the considerations and policies FDA articulates in the January 2025 draft guidance are also relevant. The January 2025 draft guidance, however, provides a more focused discussion of the timing of confirmatory studies and how that might impact approval.
Conducting with “Due Diligence”: How Sponsors Attend to the Resources, Monitor Progress, & Modify Study Designs to Complete Confirmatory Trials on Time
FDA’s authority to require confirmatory trials for a drug approved via accelerated approval have long included the ability to withdraw the drug for failure to conduct such trials with due diligence. However, the meaning of “due diligence” has long been a question.
In its new guidances, FDA advises that sponsors should consult with the Agency regarding confirmatory trial design and conduct as early as possible with enough time to allow the trial to be underway at the time of approval. Sponsors should seek agreement on timelines for enrollment and completion, as well as that the design of the trial will ensure that it will be completed in these timelines. Considering FDA’s new authority to specify the conditions for such confirmatory trials (e.g., enrollment targets, study milestones), the December 2024 guidance states that FDA will specify these conditions “no later than the date of accelerated approval.”
The guidance provides key recommendations for sponsors that speak to the concept of conducting the trial with due diligence:
Ensure all needed resources are provided to meet the specified timelines.
Diligently monitor trial progress and be prepared to make appropriate modifications when enrollment is below expected levels or the trial is otherwise not progressing as intended (e.g., adding resources or sites, making other appropriate protocol changes).
Take steps to facilitate high retention including by incorporating patient perspectives into the design of such trials.
FDA appears to be signaling that due diligence may not strictly mean abiding by completion timelines but also taking the steps necessary to try to make that happen. However, the due diligence requirements are only part of the equation, which is made clear by the publication of an entirely separate guidance interpreting FDA’s authority to require a confirmatory study be “underway” at the time of approval.
Accelerated Approval Can Be Denied if the Confirmatory Study Is Not “Underway” at the Time of Approval
As mentioned above, FDA can require a confirmatory trial to be “underway” prior to approval or within a specified time period following approval. The law did not define the term “underway,” which left some uncertainty as to what it meant (e.g., early planning steps, activating sites, opening enrollment, first patient dosed, halfway enrolled, fully enrolled) as well as to when FDA would, or would not, require a confirmatory study to be underway and whether that could change based on different circumstances.
In the intervening period of time, we have seen some hints as to how this might function. In November 2022, shortly prior to FDORA’s enactment, ADC Therapeutics announced that its plan to submit a BLA in 2023 for camidanlumab tesirine for relapsed or refractory Hodgkin lymphoma was delayed due to FDA’s “strong guidance” that a randomized confirmatory study “must be well underway and ideally fully enrolled” at the time of BLA submission. The study had not yet been initiated at the time of the announcement. In March 2024, FDA issued two complete response letters (“CRLs”) for Regeneron’s application for odronextamab for two lymphoma indications due to the enrollment status of the confirmatory trials. At the time of these CRLs, only a safety lead-in stage had been initiated for the confirmatory study, not the randomized confirmatory efficacy phase.
In contrast, although we are not aware of any examples of a confirmatory study having no patients enrolled at the time of approval since FDORA’s enactment (except for unique situations), we have seen a range of confirmatory study timing that has not prevented accelerated approval. On the low end of what could be considered underway was FDA’s approval of Amtagvi (lifileucel) in February 2024 for previously treated unresectable or metastatic melanoma. As stated in the Clinical Review memo, as of January 16, 2024, one month prior to approval, five subjects of a planned 670 were randomized and only two had undergone tumor resection, and 10 out of a planned 120 study sites were activated.
What Does “Underway” Mean?
The January 2025 draft guidance is intended to answer the question of what “underway” means, and the answer is … it depends. A confirmatory trial is considered to be underway when:
1) the trial has a target completion date that is consistent with diligent and timely conduct of the trial, considering the nature of the trial’s design and objectives. This target completion date is informed by the natural history of the disease, availability of alternative treatment, anticipated recruitment timeline, and the projected timeline for efficacy analysis(es);
2) the sponsor’s progress and plans for postapproval conduct of the trial provide sufficient assurance to expect timely completion of the trial. Specific considerations include participant enrollment to date (including the current and projected rate of enrollment), as well as the anticipated timeline for complete enrollment; the number of active sites to date and projected rate of additional site activation; and
3) enrollment has been initiated.
The January 2025 draft guidance also explains that when a single trial is designed to support accelerated approval with an earlier endpoint and verification of benefit with a longer-term endpoint, FDA will generally consider the confirmatory trial underway so long as the trial is expected to complete in a timely manner.
When Might a Study Be Required to Be More or Less “Underway?” And When Might a Study Not Be Required to Be “Underway?”
Certain factors may require some confirmatory studies to be more “underway” than others. For example, the January 2025 draft guidance states that randomization, which is often required to verify clinical benefit, may make confirmatory studies more difficult to conduct postapproval, particularly if there is a placebo arm. This is because patients may be less likely to enroll in a trial due to the potential to be randomized to the placebo arm or a potentially less effective active-comparator arm, while the newly approved treatment is commercially available. In such cases, if the Agency determines that continued enrollment/retention will be especially challenging, FDA may require enrollment to be complete at the time of approval.
Additionally, sponsors should consider factors that may adversely affect accrual, including the approval itself. The impact of approval may be greater if the confirmatory trial is in the same population as the approved indication, and not, for example, in an earlier disease stage. In such cases, the January 2025 draft guidance recommends that “all or a significant portion” of enrollment should be completed prior to accelerated approval. Given the impact of a potential approval to U.S. recruitment and retention, sponsors should also prioritize U.S. recruitment prior to approval, which should be closer to completion at the time of accelerated approval.
On the other end of the spectrum, the January 2025 draft guidance described certain circumstances where the confirmatory study may not need to be underway at all. Where randomization is not required due to, for example, “clinically relevant endpoints and disease natural history” in a rare disease context, the Agency has fewer concerns related to study completion if it is not underway prior to approval. Additionally, for some rare diseases “with very small populations with high unmet need,” there may be “unique challenges” with initiating confirmatory trials prior to approval.
FDA Expectations on Gaining Alignment & Setting Early Benchmarks
The January 2025 draft guidance recommends that, shortly after the End of Phase 2 meeting, there should be agreement between FDA and the sponsor on the design of the confirmatory trial. In practice, this seems ambitious, if not outright impractical, for situations where a novel surrogate or intermediate clinical endpoint is being considered. In our experience, the focus of discussions at this stage is on filling gaps in the evidence to support that the endpoint is reasonably likely to predict clinical benefit. Discussions of the confirmatory study are often considered by FDA to be premature as there is not yet alignment on use of the accelerated approval pathway. In fact, often the very evidence that enables the endpoint to serve as the basis of an accelerated approval comes from a Phase 3 study, where the predictive value of the endpoint can be assessed using the interventional study data. It is also very difficult for sponsors to take the necessary steps to ensure a confirmatory study is underway with such uncertainty clouding the possibility of the accelerated approval itself.
Additionally, the January 2025 draft guidance provides that sponsors should propose early benchmarks to assist FDA in its determination of whether a study is “underway,” which may include recruitment goals, extent of site activation, and proportion of primary endpoint events accrued. Meeting these benchmarks prior to the accelerated approval action date would provide FDA with greater assurance of the trial’s feasibility and timely completion. If proposed benchmarks have not been met, FDA will consider whether accelerated approval is appropriate, taking into consideration any justification and plan to address delays.
Our Concluding Thoughts
The publication of the January 2025 draft guidance so close on the heels of the December 2024 draft guidance is critically important to helping sponsors navigate FDA’s new accelerated approval authorities. The absence of any specific guideposts for how FDA intended to define “underway” or “due diligence” since FDORA had resulted in significant confusion for sponsors. We now have a framework for how FDA plans to enforce these requirements, which is anchored to setting timelines for trial initiation and conduct. Consistent with recent FDA actions noted above, the guidances are signaling the Agency’s intention to use these authorities to ensure that clinical benefit be verified as quickly as possible and, if there is concern a program will not, to deny the initial accelerated approval. FDA has great discretion in what its expectations are for a study to be underway and conducted with due diligence. We now know that FDA can expect full enrollment of the study in some cases and merely expect initiation of enrollment in others.
We are also interested in the circumstances where FDA may not require a confirmatory study to be “underway.” One such situation is where randomization is not required in the context of a rare disease. As such, it appears that whether randomization will be required to confirm clinical benefit is very important for sponsors to know early in development, as this fact alone could shift the expectations for the confirmatory study from not needing to have begun enrollment at the time of approval to as much as full enrollment at the time of approval. We would encourage FDA to engage on confirmatory study design and share expectations as early as possible.
FDA also notes that a confirmatory study might not be required to be underway at the time of accelerated approval in the setting of diseases with “very small populations” with high unmet medical need. Additional clarity about how FDA intends to interpret “very small” would be very meaningful to sponsors in the rare disease space. Rather than draw a bright line, it would be helpful to consider the full clinical context in rare, serious diseases with unmet medical needs.
It also appears that in making its determination of whether a study is underway at the time of an accelerated approval action, much may depend on early benchmarks. While a footnote in the January 2025 draft guidance shares that the topic of “enrollment targets” and “milestones” will be discussed in another forthcoming guidance, we would advise sponsors to be realistic, but also conservative, in proposing justifiable benchmarks. It is difficult to predict with certainty how a trial will progress. We would also encourage FDA to be flexible in basing any adverse decisions on sponsors missing benchmarks and consider the factors expressed in the December 2024 draft guidance on whether the study is being conducted with due diligence even from that early stage. An agreement, a documented good faith effort, and open dialogue between sponsors and the Agency about such efforts and the difficulties encountered, we think, should carry significant weight in the short term to avoid regulatory action that may affect the availability of important treatments for patients.