The American Conference Institute’s 3rd Annual Forum on Advanced Therapeutics is scheduled to take place from March 19-20, 2025, at the Seaport Hotel in Boston, MA.  The conference will bring together industry leaders to explore evolving market trends, regulatory frameworks, and intellectual property strategies shaping the future of advanced therapeutics. From funding innovations and AI in drug discovery to navigating legal and compliance challenges, this conference will provide you with the opportunity to gain the insights you need to drive scientific advancements to global market success.

This collaborative endeavor drives forward the most groundbreaking developments in advanced therapeutics, marrying scientific discovery with strategic business and legal acumen for global impact. Attend to engage with leading industry thought leaders and legal pioneers who will illuminate the path from groundbreaking research to global market success.

Conference co-chairs include Derek Johnson (Managing Director and General Counsel, Portal Innovations) and Lulu Wang (Head of IP, Orna Therapeutics).  Hyman, Phelps & McNamara, P.C.’s Charles Raver will speak during a panel discussion, titled “Preparing to Launch Preparing to Launch: Designing Your Commercialization Blueprint for Advanced Therapies and Companion Diagnostics,” where the panelists will provide actionable insights into creating a streamlined pre-commercialization plan that aligns regulatory compliance with commercial objectives.

FDA Law Blog is a conference media partner. As such, we can offer our readers a special 10% discount. The discount code is: D10-999-FDA25.  You can access the conference brochure and sign up for the event here.  We look forward to seeing you at the conference.

As anticipated, the International Council for Harmonization (ICH) published the Good Clinical Practice (GCP) guideline E6(R3) Principles and Annex 1 on January 6, 2025. While ICH E6(R3) was still in the development phase, the FDA released a draft guidance in May 2023 in the form of the draft ICH E6(R3).  No word yet on whether FDA will issue guidance endorsing the final ICH E6(R3). The European Medicines Agency (EMA) has adopted  E6(R3) Principles and Annex 1 to take effect on July 23, 2025, and other ICH member nations and regions are still in the process of adopting E6(R3). Meanwhile, Annex 2, which provides guidance on pragmatic and decentralized clinical trials as well as trials incorporating real-world data, is expected to be finalized by ICH later in 2025.

This Revision 3 has been a long-awaited update and modernizes clinical trial conduct by  integrating evolving technologies and emphasizing a Quality by Design framework along with Risk Proportionality. E6(R3) specifically acknowledges the rise of innovative trial designs such as adaptive and decentralized methods, while also encouraging the use of electronic informed consent and remote monitoring. The guideline expands its focus on data governance and clearly defines the roles and responsibilities of sponsors, investigators, and service providers.  Ultimately, the guideline encourages a risk-based and proportionate approach to clinical trials that prioritizes the safety and rights of study participants while ensuring robust data quality.  Below, we explore some of the key themes seen in the changes.

Quality by Design

One of the most significant shifts in E6(R3) is its endorsement of a Quality by Design approach, requiring sponsors to proactively identify and mitigate risks throughout the trial lifecycle. This aligns with the broader trend toward risk-based monitoring and oversight extending risk-based principles to trial planning, design, conduct, monitoring, and reporting.

Risk Proportionality

A new Risk Proportionality section has been added under Principles, emphasizing that “[c]linical trial processes, measures, and approaches should be implemented in a way that… avoids unnecessary burden on participants and investigators.”

More Varied Clinical Trial Designs

To address a “one-size-fits-all” approach to clinical trials, E6(R3) expanded the approach to trial design to allow for more varied trial designs including adaptive designs and recognition of technological advances in trial design and conduct such as remote monitoring.

Clarification of Roles and Responsibilities

The Roles & Responsibilities section was added to provide clearer expectations for all trial stakeholders. Notably, sponsor oversight and accountability is enhanced with investigators required to be qualified through education, training, and experience and they must demonstrate sufficient resources and facilities to properly conduct the trial, reinforcing ethical standards and patient protections through strengthened oversight for the clinical trial and documentation.

Patient Safety

Annex 1 also includes more detailed sections outlining  the responsibilities and functions of the  Institutional Review Board/Independent Ethics Committee (IRB/IEC), sponsor and investigator with an emphasis on the rights and safety of trial participants.

Focus on Data Integrity

The Data Governance section of Annex 1 provides comprehensive guidance for investigators and sponsors on managing data integrity, traceability, and security throughout the clinical trial lifecycle recognizing the increasing complexities and importance of data security. It emphasizes that “the quality and amount of the information generated in a clinical trial should be sufficient to address trial objectives” and emphasizes that systems and processes must be designed and implemented in a way that is proportionate to the risks to participants and the reliability of trial results. Key processes include ensuring the protection of trial participants’ data confidentiality, managing computerized systems appropriately, safeguarding critical trial elements (such as randomization and blinding), and supporting key decision-making steps like data finalization and unblinding. Additionally, the guidelines require robust procedures covering the entire data life cycle—from data capture, with appropriate metadata and audit trails, to data correction, transfer, and eventual finalization for analysis.

Implications for Future of Clinical Research

R3 represents an important evolution in GCP, shifting away from a prescriptive model toward a more flexible, risk-based approach. By integrating modern trial methodologies and technologies, it provides a framework for conducting clinical research more efficiently while maintaining the highest standards of ethics, data integrity, and patient safety.

As stakeholders begin implementing R3, many questions remain regarding its practical application. How regulators will interpret and enforce its provisions may not become clear for some time. Until then, sponsors and investigators should carefully review their trial protocols, monitoring strategies, and data management systems to align with this new landscape and take advantage of the new approaches.

The American Conference Institute’s popular “FDA Boot Camp” – now in its 43rd iteration – is scheduled to take place from March 19-20, 2025, at the NY Bar Association in New York, NY . The conference is billed as the premier event to provide folks with a roadmap to navigate the difficult terrain of FDA regulatory law.  And it is exactly that!

The conference equips legal professionals without prior regulatory experience, as well as life sciences executives involved with FDA-regulated products, with a comprehensive understanding of fundamental FDA principles.  This is achieved through firsthand insights, real-world examples, and case studies from FDA-regulated products.

This year’s conference co-chairs are Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst, and Morgan, Lewis & Bockius LLP’s Maarika L. Kimbrell. They will be joined by an esteemed panel of top FDA regulatory leaders covering essential topics, including:

• Navigating the Approval Process for Drugs and Biologics
• Clarifying the Clinical Trial Process for Drugs and Biologics
• Understanding the Structure of the FDA and the Roles of Its Three Major Centers: CDER, CBER, and CDRH
• Hatch-Waxman and BPCIA Fundamentals: Understanding Follow-On Products and the Rules for Generic Entry
• Good Manufacturing Practices (cGMPs): Discovering the Unique Role of cGMPs in the Post-Approval Process
• Advertising, Promotions, and Related First Amendment Concerns
• Understanding the Scope of FDA Enforcement Authority and Actions

FDA Law Blog is a conference media partner. As such, we can offer our readers a special 10% discount. The discount code is: D10-999-FDA25.  You can access the conference brochure and sign up for the event here.  We look forward to seeing you at the conference.

The ongoing DOGE-led reductions to the federal workforce and recent sweeping policy changes have spawned many questions for compliance officers and quality managers in FDA-regulated companies. How will the cuts at FDA impact inspections and enforcement? Will there be a heightened appetite for mergers and acquisitions in the space? How will the imposition of tariffs and a burgeoning trade war affect domestic drug production and companies’ supply chain demands? Does the stand down of FCPA enforcement mean that it’s okay to bribe foreign officials now?

With all the change we are witnessing in the American model of regulation and governance, it might be tempting to ask if we are suddenly living in a post-compliance world.

The answer to that is still “no,” the current state of world and governmental events notwithstanding. For one thing, the possible answers to our rhetorical questions above are not final yet and will take years to sort out. Also, to be sure, quality still matters in the drug and device industries. M&A rises and falls on due diligence along with other factors like market conditions and growth opportunities, so compliance and quality are vital links in any deal chain. Trusting suppliers is still fundamental to any drug or device manufacturer. And the Department of Justice will still pursue viable civil and criminal cases, if not under the FCPA then under other statutes like the False Claims Act, Title 18 fraud and conspiracy, and even RICO.

So, yes, compliance and quality still matter, a lot. And they still matter to companies looking for certainty and security in turbulent times. Organizations should want to instill good habits in their employees to make compliance easy and rewarding, looking both internally and externally.

Communication of an organization’s compliance culture is key because a significant disparity often exists between how C-suite executives and lower-level employees perceive it. A 2025 study reported by Radical Compliance found that while senior management often believes in the robustness of their ethical culture, employees at other levels do not.

Some communication techniques may be better at emphasizing the importances of compliance and quality, to make the associated good habits easy, and to ensure that a company’s program is well designed, is applied earnestly and in good faith, and works in actual practice.

Clarity of purpose is a good place to start. If a compliance or quality program exists only as bargaining chip to use with regulators, that’s not a formula to instill good habits. But company leaders must look to their own values and understand and embrace them before they can communicate them on to the rest of management and down the chain. In other words, communicating specific ideas and concerns that apply to a specific business model are more likely to be effective than trying to improvise about vague or inconsistent issues.

Tailored messaging is vital, because at no company is “the chain” comprised of people that think and act uniformly. They have different duties, different concerns, and will react to different triggers. A one-size-fits all approach to communication of important principles is therefore less likely to be successful.

Dialogue is also key. It can be difficult to maintain interest during one-sided, one way instruction. Engagement with employees makes feedback—and thus interest—more likely and consistent. And, frankly, it is a useful tool to manage potential whistleblowers by addressing concerns before they mushroom. One of the most crucial aspects of compliance communication is creating an open line, both up and down the chain.

Finally, effective compliance and quality communication is not a one-off event. It’s on ongoing conversation aided by effective, recurrent training that serves as a continuous reminder and puts good habits within easy reach. Again, it’s also a useful tool to manage problems when they do arise. It’s hard to communicate in a crisis, but when one hits, the ongoing conversation should ideally lead to remedies that are easier to implement.

Bad compliance and quality habits are like the cookies in the cupboard you might be trying to cut back on: if you never introduce them into your home, plant, or management offices, the risks they pose go down. Good habits that include effective, thoughtful communications provide clarity, understanding, and by hopefully avoiding crises, profitability. But the conversation probably works best when it goes from the C-suite to the shop floor and back.

HPM Counsel John W.M. Claud is the former Assistant Director of the Corporate Compliance and Policy Unit at the U.S. Department of Justice’s Consumer Protection Branch. These are condensed thoughts from his speech “Communicating Regulatory Impact to Your Organization: Advanced Procedures for Compliance Success,” which he delivered at the 2025 Q1 Productions Life Science Regulatory Intelligence & Strategy Conference.

As the device industry is well aware, one of the greyest areas in device regulation (of which there are many) is determining when changes to a 510(k)-cleared device trigger the need for a new clearance.  FDA requires a new 510(k) clearance when a modification to an existing 510(k)-cleared device (or other existing device subject to 510(k) requirements) “could significantly affect the safety or effectiveness of the device.” See 21 C.F.R. § 807.81(a)(3). Manufacturers must evaluate device changes in the first instance to determine whether a new 510(k) is needed or, instead, whether documentation of the change and rationale for not seeking 510(k) clearance is sufficient. This evaluation can be challenging and getting it wrong can mean a manufacturer could run into trouble if FDA later determines that its justification for not seeking clearance is inadequate.

To help in evaluating device changes, manufacturers commonly refer to FDA’s guidance “Deciding When to Submit a 510(k) for a Change to an Existing Device,” which provides FDA’s interpretation of the changes it believes could significantly affect the safety or effectiveness of a device. The guidance includes examples of changes and flowcharts that frequently make their way into formal company procedures. But this guidance has its limitations. Many of the examples FDA provides are obvious cases (at either end of the spectrum) that are unhelpful in evaluating changes that are neither clearly significant or insignificant. Additionally, manufacturers typically need to conduct a risk-based assessment of device changes to determine whether they significantly affect the safety or effectiveness of a specific device. Such assessments are highly individualized and difficult to map onto the few examples provided by FDA in its guidance.

Manufacturers should, therefore, welcome any additional source of examples of device changes to aid in evaluating their own. One potentially underutilized resource for this is FDA Warning Letters (WLs). Industry commonly thinks of WLs as only citing quality system violations.  While quality system violations are often cited, we identified more than eighty WLs that appear to cite companies for failing to seek clearance for device changes that FDA believed could significantly affect safety or effectiveness.  These letters offer real-world examples of device changes that FDA believed required a new 510(k) or internal documentation that FDA found inadequately evaluated such changes.

For example, in an October 13, 2023 WL to ReNovo, Inc., FDA stated that several of the company’s products required a new 510(k) due to “smaller diameter shafts,” “smaller diameter lumens,” “smaller tip elements,” and/or “longer shafts” than the originally cleared products. Based on FDA’s guidance, dimensional changes only require a new 510(k) if a risk-based assessment identifies new or significantly modified risks resulting from the changes.  In the WL, though, FDA faults the company for “not evaluat[ing] how cleaning and re-sterilization of the additional OEM models with different designs could affect the performance specifications and reliability of [the new device models].”

Likewise, in a November 8, 2022 WL to Abbott Point of Care Ltd., FDA found that several changes to an in vitro diagnostic device could affect the safety or effectiveness of the device, including:

1. Process change for IgM component that replaced monoclonal antibody product in a live animal with production in cell culture.
2. Increase in the amount of caprine and murine IgG and introducing murine IgM in the sample inlet.
3. Change in reagent from one that requires reconstitution to one that is already in solution.
4. Change in cartridge and gasket diameters to accommodate a new sensor chip.

FDA also found that analytical sensitivity and precision testing provided by Abbott was inadequate to confirm the impact of such changes on the clinical performance of its device. Instead, FDA stated that a direct comparison of the modified and original device was required and key performance data, such as clinical accuracy, should have been documented to support the design changes.

As these two WL examples demonstrate, FDA’s determination that a new 510(k) is required may not be based on the inherent significance of a change and may, instead, be based on the lack of documented data supporting that a change does not significantly affect safety and effectiveness. This underscores the importance of these evaluations and the value of reviewing relevant WLs to identify common gaps in documentation that can lead to FDA requiring a new 510(k).

*              *              *

Determining whether a device change requires a new 510(k) is a critical aspect of regulatory compliance. While FDA guidance, and the flowcharts and examples it contains, are essential tools, WLs provide an untapped source of real-world insights into FDA’s expectations. By analyzing WLs, manufacturers can better understand the types of changes that require a new 510(k) and avoid common gaps in generating the data and documentation in cases where a new 510(k) is not required. Notably, FDA’s public WL database only goes back to 2020.  This can limit the type of information that can be gained from WLs.  Thus, when evaluating your next set of device changes and whether a new 510(k) is needed, you may want to consult a third-party database (or an advisor that has access to such a database) to help with this search.

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)[1] 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 (see our prior post here).

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 (see our prior post here).  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.  The materials from this webinar are still available on FDA’s website (here).

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 (which FDA says includes LDTs) labeling (see here).  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.

[1] Hyman, Phelps & McNamara represents AMP in this litigation.

A recent DEA decision revoking the registration of a Louisiana pharmacy sheds light on the Agency’s approach to crediting one expert’s testimony over that of another expert during an administrative hearing.  The discussion of the Agency’s expectations of the form and substance of expert witness testimony is a must-read for entities or individuals facing a DEA order to show cause hearing.  Finally, the decision explores DEA’s current thinking on a pharmacist’s corresponding responsibility when resolving red flags.

In Neumann’s Pharmacy, LLC, 90 Fed. Reg. 8039 (Jan. 23, 2025), DEA reviewed evidence from an administrative hearing and upheld the Administrative Law Judge’s (“ALJ’s”) recommended decision to revoke the registration of a pharmacy that DEA alleged dispensed controlled substances to patients without resolving numerous red flags of diversion.

The hearing involved dueling expert testimony on the pharmacy standard of care in Louisiana from both DEA and the respondent.  While on paper the respective credentials of each of the experts would indicate a balance of authority, or maybe even weigh in favor of the pharmacy’s expert (DEA’s expert had prior disciplinary history), the ALJ and DEA Administrator each found the testimony of the government’s expert more credible.  Without the benefit of the hearing transcript, it appears from the Administrator’s decision that the testimony of the pharmacy’s expert was “unclear and contradictory” because that expert offered “contradictory testimony about whether the standard of care requires pharmacists to document the resolution of red flags.” 90 Fed. Reg. at 8039.

In a footnote explaining why the Agency credited the DEA expert over the pharmacy’s expert where they disagreed, the Administrator explained that, unlike the DEA expert, the pharmacy expert “did not actually articulate many portions of the standard of care until she was testifying about a specific patient.”  Id. at 8039 n.8.  While the pharmacy took exception to this criticism and argued that an expert should testify as to specific circumstances, DEA rejected this argument, stating that “it is also important for an expert witness to summarize certain fundamental principles of the standard of care to help the Agency assess whether the expert’s opinions are consistent with State and Federal law and to help the Agency adjudicate any disagreements among experts regarding the standard of care.”  Id.  According to the Agency, the pharmacy’s expert testimony was “often vague and amorphous,” allowing for “opportunistic conclusions” about specific patients.  Id.  Notably, this discussion does not cite any prior Agency precedent governing expert testimony standards.

What’s the take away?  Well, for respondents putting on standard-of-care expert testimony at a DEA hearing, this decision offers some insight as to the Agency’s expectations.  Expert testimony should start with a clear and robust articulation of state and federal law pertaining to the proper standards of care.  Only then should an expert delve into the application of those “fundamental principles” to the specifics of a patient’s medical file or dispensing history.  And if that is the standard, respondents facing a show cause hearing should hold the DEA to the same measure.

It’s worth taking note of the Agency’s position on two other points involving the pharmacist’s “corresponding responsibility” and duty to resolve red flags of diversion (a reminder from prior decisions).  First, DEA does not need to prove that the prescriptions in question were not issued for a legitimate medical purpose under the standard set forth in 21 C.F.R. § 1306.04(a), but only that the pharmacy failed to exercise its corresponding responsibility to ensure that the prescriptions were legitimate.  Id. At 8047.  Second, DEA does not credit “undocumented, post hoc justifications” of why the pharmacy dispensed a particular prescription.  Id.  The pharmacy is expected to document that the diligence took place prior to dispensing.  Failure to do so will be held against the pharmacy in a show cause hearing.

In sum, DEA administrative hearings are nuanced, and the procedures—including for the admission of expert testimony—require specialized knowledge of the process to avoid unnecessary pitfalls.  This is especially the case when dealing with federal and state standards of care for prescribing and dispensing.

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?”  The answers below are based on my experience as a reviewer and compliance officer at FDA during the 5-week 2018/2019 government shutdown.

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 (MDUFA, PDUFA, BsUFA, GDUFA). 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 17^th, 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 (see our prior blog post on the draft guidance here).  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 (see our prior blog post here). 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:

1. Compare the version of the device with each modification implemented individually to the version of the device without modifications implemented;
2. Discuss the benefits and risks, including risks of harm and unintended bias, of each individual modification;
3. Discuss how the verification and validation activities proposed within the Modification Protocol continue to reasonably ensure the safety and effectiveness of the device;
4. Discuss how the implementation of one modification impacts the implementation of another; and
5. 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. In fact, the final guidance includes an example of a combination product in Appendix B.

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), which we blogged about here. Unlike the PCCP guidance, which is focused specifically on post-market changes, the ostensible focus of the Lifecycle Management guidance should be a comprehensive foundation for the design and development of AI-enabled devices. 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. In HPM’s next blog we will take a deep dive into setting up a successful data management strategy, which is critical to achieving market authorization for both the device and any associated PCCPs.

On January 21, 2025, the Trump administration withdrew FDA’s proposed ban on menthol cigarettes, which the Biden administration initially introduced in 2022.  This move is the latest step in FDA’s long, uncertain, and controversial journey to ban menthol cigarettes.

For some background (which is covered in more detail in one of our previous posts on the subject), in 2009, Congress specifically exempted “tobacco or menthol” when it prohibited all other flavored cigarettes under the Family Smoking Prevention and Tobacco Control Act (TCA)’s “Special Rule for Cigarettes.”  The bill’s legislative history noted several unique features of menthol and mentholated cigarettes, including “the large number of Americans who smoke menthol, the disproportionate prevalence of menthol cigarettes among African Americans, the racial and ethnic differences in lung cancer incidence, and the uncertainty about the potentially negative consequences of an immediate menthol ban. . . .” H.R. Rep. No. 111-58, at 38-39 (2009).  Given these features, the TCA authorized FDA to ban or modify the use of menthol in cigarettes based on scientific evidence, and required FDA to study and report on the impact of the use of menthol cigarettes on the public health through a newly created Tobacco Product Scientific Advisory Committee (TPSAC). 21 U.S.C. § 387g.

Despite TPSAC’s conclusion in 2011 that “[m]enthol cigarettes have an adverse impact on public health in the United States,” TPSAC did not recommend, and FDA did not take, any regulatory action until 2013, when FDA issued an advance notice of proposed rulemaking (ANPRM) to obtain more information regarding the potential regulation of menthol in cigarettes. 78 Fed. Reg. 44,484 (July 24, 2013).  As an aside, TPSAC and its 2011 report were not without controversy; although later overturned by the D.C. Circuit Court, the lower court entered a scathing opinion stating, among other things, that TPSAC’s findings and recommendations were “at a minimum, suspect, and, at worst, untrustworthy” (see our posts on the District Court and Circuit Court decisions for more details).

Around five years later, in November 2018, the Trump administration announced its own plans to ban menthol cigarettes, which faced significant opposition and was ultimately abandoned.  In April 2021, in response to a citizen petition to prohibit menthol cigarettes and a court order directing FDA to respond, FDA announced its commitment to issue a proposed product standard to prohibit menthol as a characterizing flavor in cigarettes “within the next year.”

FDA met its deadline and issued its proposed rule in April 2022 (at the same time, the Agency issued a proposed rule prohibiting all characterizing flavors, other than tobacco, in cigars).  After FDA extended the comment period and missed deadlines to finalize the rule, in April 2024, the Biden administration announced that it would indefinitely delay issuance of the final rule.  However, at a House Energy and Commerce Committee hearing last September, the director of FDA’s Center for Tobacco Products stated that “FDA has not abandoned the menthol product standard…it’s presently with the White House and continues to be a priority for us.”

Since the withdrawal, public health groups and other advocacy organizations have pledged their continued commitment to achieve a ban on menthol cigarettes.  Given the new administration’s withdrawal, it seems possible that it may similarly withdraw the Biden administration’s proposed rule to establish maximum nicotine levels in combusted tobacco products (see our post on that proposed rule here).  The future of these regulatory efforts is uncertain, but for now, we wouldn’t hold our breath on either.

Drug manufacturers won’t be receiving their first invoices for Medicare Part B and Part D inflation rebates until later this year, but rebates have been accruing since first quarter 2023 for Part B rebates and October 2022 for Part D rebates.  To help our readers learn more about these rebates before they confront the first invoices, we’ve prepared a memo summarizing CMS’ final rule on the two Medicare inflation rebate programs, which was issued on December 9, 2024.  The memo is available here.

In addition, on Tuesday, February 18, Hyman, Phelps & McNamara will be co-hosting a webinar on the CMS final rule with Riparian LLC.   The webinar will explore the legal and operational considerations for drug manufacturers.  Among other topics, the webinar will discuss Part B and Part D inflation rebate calculations, invoicing and reconciliation timelines and processes, and CMS enforcement tools.  More details are available below.

For those readers who lack the time or patience to read our memo or to listen to the webinar, a summary chart comparing the Part B and Part D programs is available here.

Webinar Details:

Date:  Tuesday, February 18, 2025

Time:  12:00 PM to 1:30 PM ET

Presenters:

• Alan Kirschenbaum, Director, HPM
• Sophia Gaulkin, Associate, HPM
• Cynthia Hwang, General Manager, Riparian LLC
• Susan Dunne, Managing Director, Riparian LLC

Please click here to register.  Once you register, you’ll receive instructions by email on how to access the webinar.  We hope you’ll join us!

One of the most significant issues facing hospitals and other facilities is the diversion of controlled substances meant for patients by physicians, pharmacists, nurses and other trusted healthcare employees.

Recent employee diversion of significant controlled substance quantities from hospitals has resulted in large civil monetary settlements, some in the millions of dollars, and costly compliance remediation programs to resolve allegations.  Controlled substances are a necessary component in providing medical care to patients, and recent employee diversion incidents illustrate the continued vulnerability of hospitals.  Hospitals that fail to fulfill their obligations under the federal Controlled Substances Act and DEA regulations pose serious health risks to patients for undertreatment and worse, and to employees for overdose and death.  Employee diversion can also result in unwanted local and national publicity.

I will be presenting “Recent Hospital Employee Diversion: Mistakes Made, Lessons Learned,” focusing on this timely topic, at the World Conference Forum’s 2025 Opioid & Fentanyl Abuse Management Congress in San Diego on February 20th.  Attendees will learn:

• How employees in some high-profile cases were able to divert significant controlled substance quantities
• Red flags that hospitals were missed

• Safeguards to minimize internal diversion risks
• Best practices for maximizing diversion detection

I am also hosting a workshop entitled “Everything You’ve Always Wanted to Ask a (Former) Diversion Investigator But Were Afraid to Ask” the same day.

Click here to learn more about the Opioid & Abuse Management Congress.

The rare pediatric disease priority review voucher program remains in its sunsetting state – the current authority only allows for granting of such vouchers if the drug was designated as a drug for a rare pediatric disease not later than December 20, 2024, and for which a “rare pediatric disease product application” is approved not later than September 30, 2026.

However, as we suggested in a recent blog post, the statute did not actually provide any limitations on FDA’s authority to grant rare pediatric disease designations, only its authority to grant vouchers.  As such, we urged companies to continue to request, and FDA to continue to grant, rare pediatric disease designations in the hopes that Congress would extend the program once again, as it seemed quite close to doing in December.

In the meantime, the Pink Sheet confirmed that FDA was continuing to review rare pediatric disease designation requests.  However, we were not aware of any actual grants of rare pediatric disease designations past the December 20, 2024, deadline – until recently.

On February 5, 2025, a press release caught our eye – Arbor Biotechnologies announced that ABO-101, its investigational therapy for the treatment of primary hyperoxaluria type 1 (PH1), received a rare pediatric disease designation.  While this press release did not specify the date that it was granted, it noted that it “closely follow[ed]” FDA’s clearance of its IND.  In an earlier press release on December 19, 2024, Arbor Biotechnologies had announced FDA’s clearance of its IND for PH1.  As such, this seems very likely to be an example of FDA granting a rare pediatric disease designation even after the December 20, 2024, deadline.

While this press release caught our eye, we went back and looked to see if there were others we had missed.  It turns out that there have been several recent press releases announcing rare pediatric disease designations following the deadline of December 20, 2024.  These include (with date of announcement):

• January 8: ViGeneron GmbH, for its investigational therapy for retinitis pigmentosa caused by mutations in the CNGA1 gene
• January 20: PYC Therapeutics, for its investigational therapy for retinitis pigmentosa type 11
• January 22: Tikun Therapeutics, for its investigational therapy for familial dysautonomia
• January 22: MeiraGTx, for its investigational therapy for Leber congenital amaurosis due to GUCY2D mutations
• January 23: NS Pharma, for its investigational therapy for Duchenne muscular dystrophy with confirmed gene mutations amenable to exon 50 skipping therapy
• January 28: SEED Therapeutics, for its investigational therapy for solid tumor indications

This may not be an exhaustive list, especially given that FDA does not announce the issuance of rare pediatric disease designations.  However, given the timing of these announcements, it appears likely that at least some of these represent FDA granting rare pediatric disease designations following the December 20, 2024, deadline.

It is important to note that even prior to the deadline, a rare pediatric disease designation was not a guarantee for a priority review voucher.  Sponsors were still required to include a request in their NDA/BLA, and the application had to meet the relevant criteria described in 21 U.S.C. § 360ff for a “rare pediatric disease product application” at the time of approval.  However, rare pediatric disease designations granted after December 20, 2024, seemingly such as the ones listed above, are currently explicitly excluded from eligibility for a rare pediatric disease priority review voucher – absent future congressional action.

We also note that the statute (at 21 U.S.C. § 360ff(d)(2)) technically states that sponsors “shall” request rare pediatric disease designation “at the same time” as a request for orphan drug designation or a fast track designation.  In guidance, FDA explained that there may be circumstances where a sponsor does not wish to submit a rare pediatric disease designation request at this time; in such cases, FDA stated its willingness to accept and review such designation requests (so long as they are received prior to NDA/BLA filing), but noted that the typical statutory 60-day response deadline does not apply.  As such, sponsors may find themselves in a situation where, in order to receive a timely response to a rare pediatric disease designation request, they have to submit one at the time of a planned orphan drug designation or fast track designation request without knowing whether a priority review voucher will ultimately be available.  This is, understandably, a difficult situation for sponsors.

We wish to applaud FDA for continuing to grant these designations, and we congratulate the sponsors in their efforts.  While the program is currently closed without a qualifying ticket for entry, these sponsors have set themselves up well to take advantage of the program should Congress reauthorize it and bring these zombie designations back to life.  We remain hopeful that this will happen in the near future.

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 (see our previous posts here, here, and here), 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 (Draft AI Guidance).  FDA has issued discussion papers (see our posts here and here ) and guidance on use of Pre-determined Change Control Plans (PCCPs) for devices enabled by artificial intelligence (AI) (see post here and stay tuned for a post on the newest final guidance).  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 (copied here) 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.

Copy of Appendix A in Draft AI Guidance:  Table of Recommended Documentation

Ensuring transparency and reducing bias over the total product lifecycle are recurring themes of the Draft AI Guidance.  AI-enabled devices may pose challenges to user understanding due to the opacity of many models.  Transparency of AI-DSF information to device users ensures that important information is both accessible and functionally comprehensible.  Bias, in the context of AI, refers to the potential for an AI-enabled device to produce incorrect results in a systematic, but sometimes unforeseeable way, such as when an AI-model relies on data correlations that do not map to biologically plausible mechanisms of action.  This can affect safety and effectiveness of the AI-enabled device in all or a subset of the intended use population.

The Draft AI Guidance discusses data management practices at length, which is not surprising as data management practices are an important means for identifying and mitigating bias and the performance and behavior of AI-enabled devices rely heavily on the quality, quantity and diversity of data used to train and tune the AI-DSF. For both training and test data, the sponsor should provide information on data collection, the reference standard (representative truth), data annotation, data storage, management and independence of data, and representativeness.  For training data only, information on data cleaning and processing should also be provided (i.e., test data should not be cleaned).  Details of model development should also be provided in a marketing submission.

The AI Draft 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.