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  • Gone in a Puff of Smoke? FDA’s Proposed Rule on Maximum Nicotine Levels

    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.

    Categories: Tobacco

    AI May Make Your Device More Efficient, but Be Prepared to Spend More Time on Design Documentation

    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

    Guidance Section and Recommended InformationRecommended Section in Sponsor’s Marketing Submission
    Section V Device DescriptionDevice Description
    Section VI.A User InterfaceSoftware Description
    Section VI.B LabelingLabeling
    Section VII Risk AssessmentRisk Management File of Software Documentation
    Section VIII Data ManagementData for development: Software Description of Software Documentation

    Data for testing: Performance Testing

    Section IX Model Description and DevelopmentSoftware Description
    Section X.A Performance ValidationClinical and non-clinical testing: Performance Testing

    Software verification and software validation: Software testing as part of verification and validation of Software Documentation

    Section XI Device Performance MonitoringRisk Management File of Software Documentation
    Section XII CybersecurityCybersecurity
    Section XIII Public Submission SummaryAdministration Information

    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.

    Categories: Medical Devices

    Can the Tropical PRV Have Its Moment (Again?) – Not all Priority Review Vouchers are Created Alike: What the Potential Loss of the Rare Pediatric PRV Could Mean for the Tropical Disease PRV Program

    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 here and here, 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.  See Table 1.  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.

    Tropical PRV Award DateDrug Name (Sponsor)IndicationSale Price (‘000,000), (Transfer Date)*
    Apr 2009Coartem (Novartis)Malaria(used)
    Dec 2012Sirturo (Janssen)MDR pulmonary TB(used)
    Mar 2014Impavido (Paladin)Leishmaniasis$ 125 (Nov. 2014)
    June 2016Vaxchora (Pax Vax Bermuda)Cholera vaccine for travelers$ 290 (June 2016)
    Aug 2017Benznidazole (Chemo Research)Chagas diseaseUNK
    June 2018Moxidectin (Medicines Dev’t for Global Health)Onchocerciasis, or river blindnessUNK (May 2019)
    July 2018Krintafel (GSK)P. vivax malaria relapse
    Feb 2019Egaten (Novartis)Fascioliasis(used)
    May 2019Dengvaxia (Sanofi)Dengue disease vaccine
    Aug 2019Pretomanid (TB Alliance)MDR pulmonary TB
    Dec 2019Ervebo (Merck)Ebolavirus vaccine$ 100 (UNK)
    Aug 2020Lampit (Bayer)Chagas disease caused by T. cruzi$ 98 (Nov 2020)
    July 2021Fexinidazole (Sanofi)Human African trypanosomiasis (sleeping sickness)
    Nov 2023Ixchiq (Valneva)Chikungunya vaccine$ 103 (Feb 2024)

    *The information presented is based on publicly released information, including GAO and RAPS. The authors do not give any guarantees for the accuracy of this data.

    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.

    Pharmacy Law and Licensing Highlights 2025

    In reviewing some new 2025 pharmacy rules/laws a couple interesting changes caught this blogger’s attention:

    • As of December 30, 2024, Missouri has rolled out new rules related to prescription drug delivery requirements.  The rules were implemented to enhance patient safety protections via revised drug handling, packaging, and delivery requirements.  The rules include changes to the notification process, medication packaging, the handling of reports, and safety issues.   Please see the Missouri Board’s general, non-exhaustive summary addressing these changes at Prescription Delivery Guidance. See rule at 20 CSR 2220-2.013.
    • The Massachusetts Board of Registration in Pharmacy published its heavily anticipated licensure requirements for nonresident pharmacies, with licensing applications being accepted starting on January 1, 2025.  Now, all nonresident pharmacies will need to be licensed in order to dispense prescription drugs to patients in Massachusetts.  This also includes additional requirements for pharmacies that engage in sterile and complex nonsterile compounding.  There is a grace period, however, and nonresident pharmacies will have until March 31, 2025 to secure licensure.  Massachusetts will begin enforcement against non-licensed pharmacy dispensing beginning on May 1, 2025.  Please note these helpful Nonresident Pharmacy Licensure FAQs
    • California Pharmacists can continue to provide oral therapeutics to patients after a positive Covid-19 diagnosis.  The most common drug Californians may be looking for this winter is Paxlovid®.  California pharmacists are still able to provide the oral therapeutics without requiring you to visit your primary care physician through January 1, 2026.  There are some specific procedures and rules related to change, which you can review at this link: California BOP 2025 Pharmacy Laws
    • This is not a new law, but instead more of a comment for persons involved in state licensing.  The California Board of Pharmacy updated many of the application forms and guidelines in late 2024.  Specifically, the change of ownership/location documents are quite a bit different and include some new and helpful information to assist applicants wading through the very confusing and cumbersome licensing process.  Most of the forms in California were several years old, so be sure to check their website to review the most updated forms.

    Hyman, Phelps & McNamara, P.C’s licensing team will continue to track these issues and keep blog readers informed about state and federal licensing/registration issues that could affect them.

    FOIA Requires Transparency of Instructions to FDA Staff, Even When Those Instructions Are to Pause Communications with the Public

    During the Regulatory Freeze Pending Review and  the HHS Immediate Pause on Issuing Documents and Public Communications, our thoughts turned to the principles underlying the Freedom of Information Act (FOIA).  As the DOJ FOIA Guide explains in its introduction:

    The United States Supreme Court has explained that “[t]he basic purpose of [the] FOIA is to ensure an informed citizenry, vital to the functioning of a democratic society, needed to check against corruption and to hold the governors accountable to the governed.”

    Since its enactment, Congress has strengthened FOIA’s disclosure provisions, most recently in 2016.  Among those 2016 changes were the requirement “for public inspection in an electronic format” of certain categories of documents, including two categories included in an earlier amendment: “(B) those statements of policy and interpretations which have been adopted by the agency and are not published in the Federal Register;” and “(C) administrative staff manuals and instructions to staff that affect a member of the public.” A new, third category was also added, “copies of all records, regardless of form or format – . . . (II) that have been requested 3 or more times” (bold added).

    These statutory changes combined with the “foreseeable harm” standard in the FOIA exemptions, gave the statute some additional teeth. But even prior to the amendments, the text of the statute, on its face, provided real time access to government records.  FOIA imposes timelines of days, not months or years, for responses.  That has been significantly undermined at FDA and other agencies by administrative backlogs, and a safety valve that Congress provided for exceptional circumstances.  As a result, requests to FDA routinely take a year and a half to two years.  Moreover, courts generally provide the agency with more time to complete its review.

    But those seeking to use FOIA to hold the Executive to the letter and spirit of the law are not without some tools.  First, as a general matter, unlike many suits against the government, in a FOIA case, a district court reviews the agency’s decisions de novo and “the burden is on the agency to sustain its action.” 5 U.S.C. § 552(a)(4)(B).

    Second, while the “exceptional circumstances” safety valve appears in the section of the statute regarding FOIA requests, there is no corresponding language in the section stating that an agency “shall make available for public inspection in an electronic format” certain records.

    Last, given FOIA’s broad standing, jurisdiction, and venue provisions, a complainant can put the Executive to its paces, in “the district court of the United States in the district in which the complainant resides, or has his principal place of business, or in which the agency records are situated, or in the District of Columbia.”  Any one of those courts “has jurisdiction to enjoin the agency from withholding agency records and to order the production of any agency records improperly withheld from the complainant.”

    The Regulatory Freeze Pending Review is a standard tool of incoming administrations, and the HHS pause is, according to the memo, set to expire on February 1.  The pause memo is not available on the HHS website, but hopefully incoming leadership, once settled, will take FOIA’s disclosure obligations to heart.  If not, regulated industry may need to consider new ways to obtain, for example, “instructions to staff that affect a member of the public,” along with other critical information about agency policy and operations that affect it.

    Categories: Miscellaneous

    When is a Confirmatory Trial “Underway” or Conducted with “Due Diligence” Enough for Accelerated Approval? FDA Explains Its New Authorities

    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. This condition was included in the final rule for the original regulations, 21 CFR § 314 Subpart H (see the December 11, 1992 Federal Register, 57 FR 58958) as well as when the pathway was codified in the Federal Food, Drug, and Cosmetic Act by FDAMA (21 USC § 356(c)) in 1997. 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:

    1. Ensure all needed resources are provided to meet the specified timelines.
    2. 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).
    3. 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 (e.g., rare disease settings). 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.

    What We’re Watching for in the Senate Confirmation Hearings to Consider Robert F. Kennedy, Jr. to be Secretary of HHS

    The confirmation hearings for Robert F. Kennedy, Jr. to lead the Department of Health and Human Services kick off at 10 am on January 29 and promise to have a packed agenda. With oversight over FDA, the Centers for Medicare & Medicaid Services, the National Institutes of Health, and the Centers for Disease Control and Prevention, if confirmed, Kennedy’s portfolio would be vast. Aside from his many high profile claims about vaccines, what he perceives as corruption at FDA, and the President’s license for him to go “wild” on health, Kennedy’s specific policy views about how FDA should administer its day-to-day oversight of drugs, medical devices, food, dietary supplements, cosmetics, and tobacco have not been publicly detailed.

    The Senate Finance Committee will hold the first day of hearings, which will then move over to the Health, Education, Labor and Pensions Committee on Thursday. Only Finance will vote to send his nomination to the full Senate.

    We don’t know if the hearings will get into management of FDA. In addition to Kennedy’s anti-vaccination stances, controversial takes on nutrition, and his own potential conflicts, Kennedy is likely to face questions about the sudden freeze on federal spending and proposed federal employee buyouts. Before the events of the last week, perhaps the best preview of the questions Kennedy is likely to face came from Sen. Elizabeth Warren, who sent him a letter with 175 questions designed to probe his policy positions.

    In addition to the hot-button topics, Warren’s letter asks Kennedy to be ready to address more nuanced, FDA-specific issues. As HHS Secretary, Kennedy would not have day-to-day FDA responsibilities. The President has nominated Dr. Marty Makary, to be FDA Commissioner, a position that also requires Senate confirmation. Those hearings have not yet been scheduled. That said, given Kennedy’s public statements, how he might affect FDA is certainly confirmation hearing-worthy. For example, she asks Kennedy if he’ll “interfere in any FDA decision regarding review or approval of vaccines,” or if he would “overrule the FDA if you disagreed with its determination that a drug or vaccine was safe and effective.” Questions like this might offer insight we haven’t seen yet into how FDA might operate under a Kennedy-led HHS.

    Other FDA-specific questions from Warren may also come up. In her letter, Warren posed these questions to Kennedy:

    1. How will you ensure that food and medicine are safe for consumption given your plans for deregulation?
    2. Do you still plan to fire FDA employees as you alluded to in your October social media post? To the extent you intend to fire any FDA employees, what will be your standard for doing so?
    3. What “gold standard” of scientific review do you have planned for the FDA?
    4. What is your plan to protect the independent scientific decision making of agencies like the FDA from political interference?

    Kennedy may also face questions about the basis for his assertion that the agency is part of a “corrupt system.” Kennedy has been critical of FDA’s reliance on user fees to fund its mission, saying they give Big Pharma too much influence. Will Kennedy try to overturn the user fee system that’s been in place since 1992? Will he wait until the next PDUFA reauthorization in 2027 to instill additional changes at the agency? A better question still may be whether the Senators get that far down on their list of questions to Kennedy, diving into the minutiae of policy and funding when so many other splashy topics accompany this particular nominee.

    We’ll see if the hearings move beyond the numerous political talking points into the specific nitty-gritty of how he would manage FDA’s statutory mission to protect public health and safety. Much more to come on this.

    Categories: Miscellaneous

    SIUU-SIUU-Sudio: FDA Finalizes Guidance on SIUU and Distribution of Off Label Information

    Who among us, upon reading FDA’s draft guidance on the distribution of off label information and their coining of the acronym SIUU (standing for Scientific Information on Unapproved Uses) did not automatically think of Phil Collins’ classic song Sussudio?  (Other than anyone under 50, that is.  In any event, you whippersnappers should look up the album No Jacket Required – it’s a classic.)

    In any event, in the waning days of the Biden Administration, the FDA finalized this gem.  And in all seriousness, the finalization of this guidance is somewhat historic given that industry has been relying on various versions of draft “Good Reprint Practices” guidance since 2009.   This final guidance (16 years in the making!) is very similar to the draft guidance with a few notable exceptions:

    • FDA expanded the list of source publications that can be used as the basis of firm generated presentations to include all the source publications that are permitted as SIUU (answering the call of all who read the draft guidance and wondered why reprints were given more weight than medical texts).
    • FDA deleted the requirement that SIUU be “clinically relevant” and left only the requirement that the information be “scientifically sound” (thank you FDA – on behalf of industry, we are still getting used to the SASS standard from the CFL guidance and yet another evidentiary standard imposed on product communications was a bit much).
    • FDA acknowledged that “scientifically sound” studies can include early stage studies and other studies that were not accepted under the draft guidance (can we get a “hallelujah?”).

    Other than these changes, reorganizing the guidance, and including a definitional section, the final version is quite similar to the draft.  One other notable change is that the final guidance discusses the in person distribution of SIUU which was absent from the draft.  The guidance states:

    FDA recommends that firms ensure that the personnel who are engaged in sharing SIUU communications have specialized training in providing truthful, non-misleading scientific information about unapproved uses of the firms’ approved medical products.  A firm’s personnel who are sharing SIUU communications should also be trained to handle potential questions that may arise about the information they are sharing or know how to direct the questions to personnel who are best qualified to respond (e.g., medical or scientific/technical representative or department).  (Guidance at 19, n.49)

    This is notable as it suggests that the personnel engaged in sharing SIUU apparently do NOT have to be within the medical affairs department.  This vague set of instructions may cause companies to ask what precisely the limits are for in  person sharing of SIUU.  We know with certainty, however, that promotional communications and scientific communications must lead “separate lives” so to speak.

    While not a remarkable change from the draft guidance, we welcome the loosening of some of the restrictions as noted above.  Even if it is against all odds we welcome anything that more closely aligns FDA’s regulatory positions with the First Amendment.

    FDA Recommends Disclosure of Plant Source in Draft Guidance on Labeling Plant-Based Alternatives

    Readers of this blog likely are familiar with the ongoing, often contentious battle over the labeling of plant-based foods (see, e.g., here, here, and here).

    Nearly two years after FDA issued draft guidance on Labeling of Plant-Based Milk Alternatives and Voluntary Nutrient Statements, on January 6, 2025, FDA released draft guidance document on plant-based labeling, Labeling Plant-Based Alternatives to Animal-Derived Foods.  This latest draft guidance outlines the Agency’s recommendations for naming and labeling plant-based foods that are marketed and sold as alternatives for animal-derived foods that fall within FDA’s jurisdiction—namely, plant-based alternatives to eggs, seafood, poultry, meat, and dairy products (except milk).

    Most notably, FDA recognizes that plant-based alternatives may use the name(s) of animal-derived foods, provided that using such terms would not cause the labeling to be false and misleading, particularly as to the source(s) of the food.  In addition, FDA recommends that specific plant source(s) be included in the statement of identity of plant-based alternative food products, regardless of whether the name of the product is accompanied by “plant-based,” “vegan,” “meat-free,” or similar, or whether the name has modified spelling (e.g., “Chik’N”).

    The draft guidance lays out the law, regulation, and FDA’s thoughts on naming foods. Under the Federal Food, Drug, and Cosmetic Act (FDC Act) and FDA’s implementing regulations, FDA has established definitions and standards of identity for certain foods.  Products that purport to be or are represented as a food for which FDA has established a definition and standard of identity must conform to that definition and standard, and their labels must bear the name specified in the definition and standard.  For foods that do not have established definitions and standards of identity (i.e., “non-standardized foods”), their labeling must bear the common or usual name of the food, if such a name exists.  In the absence of a common or usual name or other name established by federal law or regulation, food sold in packaged form must be labeled with an appropriately descriptive term or a fanciful name commonly used by the public.  The description or name of the food (i.e., the statement of identity) must not be false or misleading.

    In the draft guidance, FDA acknowledges that many plant-based alternative foods do not have common or usual names.  Therefore, they must be labeled with a statement of identity that accurately describes the food.  In determining whether a plant-based alternative food product’s name accurately describes the food, FDA considers (a) whether the name accurately identifies or describes the basic nature of the food or its characterizing properties or ingredients, (b) whether the name uniform among identical or similar products, and (c) whether the name is confusingly similar to the name of any other food that is not reasonably encompassed within the same name.  Using these criteria, FDA explains that the names of classes or subclasses of foods should distinguish one class or subclass from another (e.g., plant-based alternatives to yogurt that are soy-based should bear names that distinguish these products from those that are almond-based).

    The existence of a standard of identity for an animal-derived food does not foreclose the use of that term in a plant-based alternative.  As described in the guidance, the name can be modified to clarify how the product differs from the food subject to the standard. Perhaps most obvious, the labeling may not suggest that animal source(s) are present or have been used as ingredients.  FDA specifically recommends that, if the labeling of a plant-based alternative food includes the name of a standardized food as part of the statement of identity, the name of the standardized food be qualified by the type of plant source, e.g., “Chickpea-Based Fish Sticks” or “Dairy-Free Soy-Based Cheddar Cheese” instead of “Plant-Based Fish Sticks” or “Plant-Based Cheddar Cheese”.  In addition, consumers should be able to readily observe the particular plant source of a plant-based alternative food when reading the product label.

    For a plant-based alternative food derived from several plant sources, FDA recommends a statement of identity that includes the primary plant sources so consumers can more easily identify them and distinguish the food product from similar foods that may be derived from other plant sources.  Specifically, in case of more than one plant source, FDA recommends that the predominant plant source by weight be stated first.

    FDA’s guidance seems generally consistent with its regulation on naming foods.  It also appears consistent with the draft guidance on the labeling of plant-based milk alternatives, where FDA also recommended that the names of plant-based milk alternatives be qualified with the plant source from which it is derived.  It seems a “win” to the extent that FDA is confirming the use of traditional animal nomenclature for the naming of plant-based alternatives.  However, given the similarities between these draft guidance documents, similar comments may be expected.

    Comments on the draft guidance may be submitted until May 7, 2025.

    HPM Grows Its Ranks of Directors, Counsel, and Associates as it begins its 45th Anniversary Year

    Hyman, Phelps & McNamara PC, (HPM), which will mark its 45th Anniversary on March 17, 2025, is pleased to announce that it is increasing its directors, counsel, and associates as it starts the year.

    • Kalie E. Richardson has been promoted to Director.
    • Mark Tobolowsky has been promoted to Counsel; and
    • Esther Petrikovsky is joining the firm as an Associate.

    “While HPM prides itself on being the largest dedicated FDA law firm in the United States, it is small by design, so it is the quality of each of these individuals and what they contribute to the firm that is most exciting,” said HPM managing Director J.P. Ellison.

    • Richardson, who focuses her practice on state and federal regulatory strategy and compliance, primarily for pharmaceutical manufacturers and wholesale distributors, has been with the firm 7 years and has proven herself invaluable to colleagues and clients alike. “Kalie is the quintessential HPM lawyer. She puts the firm and clients first and is solution-oriented,” said founder Paul M. Hyman.
    • Tobolowsky, who has been with the firm 3 years, focuses on assisting clients with legal and regulatory considerations for the development of new drug and biologic products as well as with post-marketing compliance. Mark’s work often deals with therapies for rare and serious diseases that face unique challenges and, therefore, require unique solutions. “Mark’s promotion to Counsel reflects the value that he brings to the firm and his clients based on expansive and diverse experiences in the drug development arena,” commented HPM Director James Valentine.
    • Petrikovsky, a 2022 Georgetown law grad, who was articles editor for the Food and Drug Law Journal in law school, joins HPM from a national law firm. She already has broad-based exposure to a variety of FDA regulated products.  “Esther is a natural fit at HPM given her background. We expect her to hit the ground running,” said Deb Livornese, HPM’s Director responsible for recruiting.

    “HPM’s success over the past 45 years is solely a function of the quality of the people at the firm.  It’s gratifying to see such a talented group continuing that tradition,” noted founder Robert A. Dormer.

    Categories: Miscellaneous

    Is FDA Man’s Best Friend’s Best Friend?

    On January 7, 2025, FDA announced that back on November 12, 2024, the Center for Veterinary Medicine (“CVM”) issued Warning Letters to six online retailers marketing unapproved new animal drug products that purported to treat and control seizures and epilepsy in dogs and cats.  At minimum, this autumnal burst of Warning Letters from CVM is notable because CVM only issued a total of 22 Warning Letters in 2024—at least that have been made public by the Agency.

    In each November 2024 Warning Letter, FDA explains that it reviewed the target company’s online promotion from October through November 2024—including Facebook, Amazon, and other third-party webpages—and determined that the six companies were marketing and selling unapproved new animal drug products in violation of the federal Food, Drug, and Cosmetic Act (“FDCA”).  Half of the products were available for purchase on Amazon, indicating that FDA is keeping an eye on Amazon sales.

    The six target companies, including their FDA-cited violative products, are:

    • Energetic Essences, LLC d/b/a Pet Essences (Seizures formula(s))
    • Evolution Pets (SeizureGuard Plus and Life Span Arthritis & Mobility Advanced Enzyme Therapy)
    • HD Frenchies, LLC/Bully Baum (HDBully Baum No Seize, Can-B-Gone – Cancer Oil Extract, and Brain & Neurological)
    • Intermarket Industries Inc. d/b/a Doc Ackerman’s Pet Products (Doc Ackerman’s – Epilepsy & Seizure Formula)
    • Nutrition Strength Ltd. EOOD (Dog Seizure and Epilepsy Supplement and Blood Support for Dogs)
    • Vet Select Formula, Inc. (Vet Select Nuroplex Capsules, Vet Select Nuroplex – 2oz Homeopathic Spray, and Vet Select Nuroplex – Full Treatment Pack)

    New animal drug products must be approved by FDA via a New Animal Drug Application (link), Abbreviated New Animal Drug Application (link), Conditional Approval (link), or have an index listing (link).  21 U.S.C. §§ 360b, 360ccc, 360ccc-1.  The marketing of a new animal drug product which has not been approved by FDA through one of these three regulatory pathways or included in an index listing renders the product adulterated.  21 U.S.C. § 351(a)(5) (“A drug … shall be deemed to be adulterated … if it is a new animal drug which is unsafe within the meaning of section 360b of” the FDCA.); see also id. § 360b(a) (requiring that, for a new animal drug to be legally marketed, it must have been approved by FDA via one of the aforementioned pathways).  The marketing of an unapproved and therefore unsafe, adulterated new animal drug is a violation of the FDCA.  Id. § 331(a) (listing as a prohibited act “[t]he introduction or delivery for introduction into interstate commerce of any … drug … that is adulterated or misbranded.”).

    Here, the companies marketed their products as intended to treat idiopathic seizures or epilepsy in dogs and cats.  FDA found that each of the companies were marketing products that were unapproved new animal drug products because the products at issue were “intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease” and/or “intended to affect the structure or any function of the body of … [an] animal.”  Id. § 321(g)(1), (v).  Notably, FDA has only conditionally approved two animal drugs to treat idiopathic epilepsy in dogs—KBroVet-CA1 and Fidoquel-CA1.  Because FDA established the products at issue were unapproved new animal drugs, the Agency found the products to be unsafe and adulterated and the companies to have committed a prohibited act per the FDCA.

    It will be interesting to see whether CVM carries this flurry of activity into 2025, especially as it relates to online retailers, which have quickly become hubs for pet-related products.  We will continue to monitor and report on further developments.

    As 2024 Closed, FDA Issued a Proposed Rule on Asbestos Testing; Implementation of MoCRA Remains Much Slower Than Planned

    A little over two years ago, the Modernization of Cosmetic Regulation Act (MoCRA) was (at long last) enacted.  The passing of the law which, among other things, amended the Federal Food, Drug, and Cosmetic Act to include requirements for facility registration and product listing, safety substantiation, adverse event reporting, and requirements for FDA to issue several new regulations, brought excitement and anxiety.  Excitement that after about a decade the FDC Act finally was amended giving cosmetics more legitimacy; anxiety because MoCRA seemed a substantial change for many involved in the business of cosmetics. There remains much uncertainty about the practical aspects of the new requirements.

    As we previously reported, MoCRA includes various provisions requiring that FDA develop regulations within a specific time frame.  A brief review of FDA actions (or lack thereof) in 2024 shows that FDA failed to meet any of the statutory deadlines set by MoCRA.  FDA’s report card therefore shows a big Incomplete.

    MoCRA includes several self-executing requirements, such as registration and product listing, adverse event reporting requirements and labeling for adverse event reporting.  However, MoCRA also requires action by FDA.  Notably, the law requires that FDA develop three major rules within specific time frames.  MoCRA mandates that FDA develop a regulation regarding the testing for asbestos in talc (statutory deadline for proposed rule  Dec. 29, 2023), a regulation for fragrance allergen labeling (statutory deadline for proposed rule June 29, 2024); and good manufacturing practice regulations (statutory deadline for proposed rule Dec. 2024).  FDA has failed to meet all deadlines for these three MoCRA rules.

    Just on the cusp of 2024, on Dec. 27, 2024, almost a year after the statutory deadline, FDA published a proposed rule for asbestos testing of talc.

    The proposed rule on asbestos testing describes the test methods that, if finalized, manufacturers of talc-containing cosmetic products must use to detect and identify asbestos in these products. FDA proposes to require that manufacturers test a representative sample of each batch or lot of a talc-containing cosmetic product or of each batch or lot of the talc ingredient to be incorporated in the cosmetic product for asbestos using both Polarized Light Microscopy (PLM) (with dispersion staining) and Transmission Electron Microscopy (TEM)/Energy Dispersive Spectroscopy (EDS)/Selected Area Electron Diffraction (SAED). Alternatively, manufacturers may rely on a certificate of analysis for each batch or lot from a qualified talc supplier prior to using the talc in a talc-containing cosmetic.  Not surprisingly, reliance on a supplier is acceptable only if the supplier used both PLM and TEM/EDS/SAED to test the talc.

    FDA recognizes that the proposed testing method is different from what most of the industry has used thus far.  According to FDA, the requirement for the use of both PLM and TEM/EDS/SAED is consistent with established scientific opinions recognizing the limitations of PLM which may result in false negative test results.  FDA added the requirement to use TEM/EDS/SAED to ensure sensitivity and specificity.  According to FDA, “combining TEM, which enables detection of smaller fibers, with PLM, which enables testing of larger samples, gives the best chance of detecting asbestos.”

    FDA proposes to require that manufacturers keep records of testing for asbestos that show test data, including raw data (including microscopy images, spectra, diffraction patterns and bench sheets), and describe, in detail, how samples were tested.  If the manufacturer chooses to rely on a certificate of analysis from the talc supplier, the records must include any certificate of analysis from the supplier for testing of the talc used to make the finished product, and documentation of how the manufacturer qualified the supplier.  Records written in English (or when requested an English translation) must be made available for inspection and copying to an authorized FDA representative within one business day, upon request.  FDA proposes to require that records must be retained for a period of 3 years after the date such records were created.

    Presence of asbestos at any level in a cosmetic product, or in talc used in a cosmetic product, causes that cosmetic product or talc to be adulterated under the FDC Act. In addition, failure to operate in compliance with the testing or recordkeeping requirements would cause the talc containing cosmetic products to be adulterated under the FDC Act.

    Comments to the proposed rule must be submitted by March 27, 2025

    Target dates for the two other rules that FDA must issue pursuant to MoCRA, have been pushed to January 2025 for the proposed rule for fragrance allergen labeling and to October 2025 for the proposed rulemaking for good manufacturing practices.  If FDA meets those deadlines, 2025 will be a busy year for both FDA and industry.  Hopefully, FDA will also find time to develop guidance for industry answering the many questions that remain about MOCRA’s requirements for adverse event reporting and related labeling requirements, as well as MOCRA’s safety substantiation standard for cosmetics.

    Categories: Cosmetics

    To Be or Coco-Not To Be: That’s One Question Answered in FDA’s Final Guidance Documents on Food Allergens

    On January 6, 2025, FDA released two final guidance documents on food allergens: Questions and Answers Regarding Food Allergens, Including the Food Allergen Labeling Requirements of the Federal Food, Drug, and Cosmetic Act (Edition 5), and Evaluating the Public Health Importance of Food Allergens Other Than the Major Food Allergens Listed in the Federal Food, Drug, and Cosmetic Act.

    Questions and Answers Regarding Food Allergens, Including the Food Allergen Labeling Requirements of the Federal Food, Drug, and Cosmetic Act

    This final guidance replaces previous draft and final guidance documents on food allergen labeling that FDA issued in November 2022, which we discussed in a previous post.  Among other changes, the final fifth edition revises and updates questions and answers related to allergen labeling.  The most significant changes from the draft guidance are described below:

    • Tree Nuts: FDA clarified that only 12 tree nuts are considered tree nuts for purposes of allergen labeling due to the “robust body of scientific evidence support[ing] their inclusion in the list.” These are listed in Table 1 of the final guidance:
      1. Almond
      2. Black walnut
      3. Brazil nut
      4. California walnut
      5. Cashew
      6. Filbert/Hazelnut
      7. Heartnut/Japanese walnut
      8. Macadamia nut/Bush nut
      9. Pecan
      10. Pine nut/Pinon nut
      11. Pistachio
      12. Walnut (English, Persian)

    Missing from this list are several tree nuts that FDA had included in the “non-exhaustive” list in that draft guidance.  Notably, coconut is now omitted, meaning it is coco-not considered a tree nut for allergen labeling purposes. This is a significant turnaround from FDA’s historical position, prompting at least one FDA Law Blogger to wonder, “FDA, do think you just fell out a coconut tree? You exist in the context of all that came before you.”  The context here is that, for more than a decade, FDA has held that coconut is an allergen for labeling purposes.  In its previous final guidance document, Questions and Answers Regarding Food Allergens, Including the Food Allergen Labeling and Consumer Protection Act of 2004 (Edition 4), FDA specifically listed coconuts on its list of tree nuts that are major food allergens.  Failure to list coconut as an allergen has also been mentioned in several warning letters (see, e.g., here) and as the reason for several product recalls, including a recent Class I recall in April 2024 (see also, e.g., Class II recalls in 2018 and 2022 for listing coconut as an ingredient but failing to disclose coconut in the allergen statement).

    In addition, FDA walked back its previous position on certain parts of a plant that bears tree nuts.  In its draft guidance document, FDA stated that roots, leaves, stems, bark, or other parts of the same plant that bears tree nuts, but which are distinct from the tree nut portion of plant, are not considered major food allergens.  The final guidance adds more nuance, confirming that an ingredient derived from other parts of the same plant that bears tree nuts (or other sources of major food allergens for that matter) are subject to food allergen labeling requirements only if the ingredient is or contains proteins from a major food allergen.

    • Milk and Eggs: FDA has broadened its interpretation of both “milk” and “eggs,” which it historically interpreted as from a domesticated cow and from a domesticated chicken, respectively. For purposes of food allergen labeling, FDA now considers “milk” to include milk from domesticated cows, goats, sheep, or other ruminant animals.  Similarly, FDA now considers “eggs” to include eggs from domesticated chickens, ducks, geese, qual, and other fowl.
    • Allergen-Free Claims: FDA addressed “allergen-free” claims, confirming that firms may make voluntary statements on product labeling that certain allergens are absent from the product. Although there are no regulations on the specific conditions to make such a claim, the claim must be truthful and not misleading.  Importantly, although the final guidance makes clear that food allergen labeling requirements do not apply to allergens that may be present unintentionally due to cross-contact (e.g., from the use of shared equipment during the production process), FDA expects that a product with an allergen-free claim contains none of the major food allergen, including unintended allergens due to cross-contact.

    Evaluating the Public Health Importance of Food Allergens Other Than the Major Food Allergens Listed in the Federal Food, Drug, and Cosmetic Act

    Under Section 201(qq) of the Federal Food, Drug, and Cosmetic Act, “major food allergens” include milk, eggs, peanuts, wheat, soybeans, fish, shellfish, tree nuts, and effective Jan. 1, 2023, sesame.  This final guidance describes FDA’s approach to evaluating food allergens not included in this nine-item list (i.e., non-listed allergens) to inform decisions on potential regulatory requirements for such allergens.

    The final guidance largely matches FDA’s draft guidance from 2022, which focuses on immunoglobulin E antibody (IgE)-mediated food allergies.  In the final guidance, however, FDA stated that it also intends to evaluate food allergens acting through other mechanisms that may raise public health concerns.  Consistent with the draft guidance, FDA will continue to evaluate the public health importance of food allergens on a case-by-case basis, taking into account the four following scientific factors:

    1. Evidence of IgE-mediated food allergy;
    2. Prevalence of an IgE-mediated food allergy in the U.S. population;
    3. Severity of IgE0mediated food allergic reactions; and
    4. Allergenic potency.

    In addition, FDA explained that it generally intends to evaluate additional data and information, including, for example, the prevalence and amounts of the food allergen in food that is not disclosed on the labeling, food product characteristics and production practices, and patient-centered studies or other patient-centered information, when applicable.

    Any interested party may submit a citizen petition requesting that FDA evaluate the public health importance of a non-listed food allergen, establish regulatory requirements based on the public health importance of such an allergen, and/or disclose how it generally intends to evaluate the public health importance of such an allergen.

    FDA Issues Draft Guidance on Accelerated Approval: A Substantial Evidentiary and Procedural Overhaul to this High-Profile Pathway

    On December 5, 2024, FDA published a new draft guidance on accelerated approval providing a much needed and substantial update to its guidance on the pathway.  FDA’s application and use of accelerated approval has evolved dramatically since it was first developed by the Agency to help address the HIV/AIDS epidemic in the late 1980s.  Since that time, it was formalized in FDA regulations (21 CFR § 314 Subpart H) in 1992, codified in the Food, Drug, & Cosmetic Act by FDAMA (21 USC § 356(c)) in 1997, revised by FDASIA in 2012, and described in guidance, most importantly, in the 2014 Expedited Programs for Serious Conditions – Drugs and Biologics (“2014 Guidance”).  However, it has been recent circumstances, such as, reforms enacted by FDORA in 2022 (as well as FDORA’s requirement to publish new guidance; see HPM’s previous coverage here) and our observations of the evolving ways in which FDA has been applying its accelerated approval authority across a wide-range of areas of drug development that has driven our desire to see FDA provide new guidance on the topic.

    The new draft guidance, Expedited Program for Serious Conditions — Accelerated Approval of Drugs and Biologics, is intended to replace much of the 2014 Guidance’s discussion of the topic.  However, the 2014 Guidance cannot be ignored entirely.  FDA’s interpretation of several threshold criteria for eligibility (serious condition, available therapy, unmet medical need) will continue to rely upon the 2014 Guidance.  What will be replaced and is described in more detail in the new guidance is (1) FDA’s overarching view of the pathway’s applicability, (2) interpretation of what constitutes an accelerated approval endpoint, that is, a surrogate or intermediate clinical endpoint, (3) the evidentiary standard for demonstrating that such an endpoint is reasonably like to predict clinical benefit, (4) recommendations and policies regarding confirmatory trials, and (5) the procedures governing the withdrawal of accelerated approval.  Despite including guidance on confirmatory trials and FDA’s authority to require them, the Agency decided to publish an additional guidance focused solely on how it is interpreting the authority to require that such trials “be underway prior to accelerated approval or within a specified time period after the date of accelerated approval.” As such, we will publish a separate blog post focused on confirmatory trials and how FDA is interpreting this key provision of its accelerated approval authority.

    Background on Accelerated Approval

    The key concept, an ingenuity of FDA itself that has been around since the beginning of accelerated approval, is to allow earlier access to a promising therapy for a serious condition with an unmet medical need based on an endpoint that is reasonably likely to predict clinical benefit.  Accelerated approval endpoints can take one of two forms: (1) a surrogate endpoint that is reasonably likely to predict clinical benefit or (2) a clinical endpoint that can be measured earlier than irreversible morbidity or mortality (i.e., an intermediate clinical endpoint) and that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit.  Whether a surrogate or intermediate clinical endpoint (ICE), the endpoint to support accelerated approval is one that can be assessed more rapidly than the ultimate clinical benefit; this is what enables earlier patient access than would be possible while generating the evidence to support a traditional approval, which is typically infeasible.  Such clinical benefit is defined as “a positive therapeutic effect that is clinically meaningful in the context of a given disease,” is supported by a positive benefit-risk profile, and is, generally, a measure of how a patient feels, functions, or survives.

    The FDCA requires that FDA also consider the “severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments” when determining whether a program meets criteria for accelerated approval.  It also gives FDA authority to require that the sponsor conduct one or more postapproval studies to verify and describe the predicted effect on clinical benefit, to require pre- and post-approval submission of all promotional materials, and, in certain circumstances, to withdraw approval using expedited procedures for products approved via accelerated approval.

    The most recent statutory reforms gave FDA additional authority to set conditions for postapproval studies, such as enrollment targets, the study protocol, and milestones for study conduct and completion, in addition to creating a new obligation for sponsors to submit 180-day progress reports on meeting their postapproval study conditions.  These reforms also gave FDA authority to require that postapproval studies be underway at the time of approval, expanded FDA’s enforcement authority to include failure to comply with the postapproval study conditions and reporting requirements, and laid out the procedures for expedited withdrawal.  Lastly, the reforms enacted by FDORA required that FDA publish guidance on early consultation with FDA to identify novel surrogate or intermediate clinical endpoints, use of novel trials designs for postapproval studies, the expedited withdrawal procedures, and considerations related to the use of surrogate and intermediate clinical endpoints.  FDA’s December 5, 2024 draft guidance on accelerated approvals appears intended to cover each of these topics even if not by dividing them precisely along those lines.

    FDA’s Overview of When Accelerated Approval is Appropriate

    The new draft guidance explains, that there are two circumstances in which the accelerated approval authority would most clearly apply: (1) when the course of the disease is long or (2) the clinical event that is relevant for demonstrating benefit occurs infrequently.  While these examples could be interpreted to mean that the key consideration is the amount of time needed to accumulate enough evidence of benefit, FDA’s authority does not limit use of accelerated approval only to such circumstances. The new guidance states, for instance, that “accelerated approval may be considered where an effect on a surrogate endpoint could be shown in a smaller number of patients” than would be required to show an effect on a clinical outcome. To us, FDA’s application of accelerated approval in numerous other instances, such as benznidazole for Chagas disease, Oxbryta for sickle cell disease, Qalsody for SOD1 ALS or Kebilidi for AADC deficiency, demonstrate that, while accelerated approval determinations are highly circumstance specific, the authority can apply to a wide-range of development pathways and disease areas.

    Moreover, it was also interesting to see how FDA discussed the concept of unmet medical need in the limited fashion that it did in this new guidance. As noted earlier in this post, the new guidance is intended to replace previous guidance in most respects except that FDA’s interpretation of what constitutes a serious condition, available therapy, and an unmet medical need will continue to rely upon the 2014 Guidance. However, while FDA reiterated its interpretation that the statutory requirement to take “into account . . . the availability or lack of alternative therapies” and the regulatory requirement that the drug provides “a meaningful therapeutic benefit over existing treatments” means that accelerated approval is only available to therapies that address an unmet medical need, it chose to highlight one telling example of how a sponsor might satisfy this criteria even when there are available therapies – when the new therapy has similar efficacy but a different mechanism of action compared to the available therapies.

    This nod to innovation stands as something of a reminder to sponsors to not ignore disease areas simply because treatments exist and that expedited pathways are still available to those willing to pursue new therapeutic modalities and approaches.  This may also help to derisk parallel product development amongst multiple products for the same condition, where another product in development may gain traditional approval or another product already on the market under accelerated approval may confirm clinical benefit prior to completion of clinical trials to support accelerated approval (e.g., in Duchenne Muscular Dystrophy).  It will be important for FDA to communicate to sponsors its views on whether a product would address an unmet medical need on mechanistic grounds to help ensure greater certainty for investment in the development of therapies for these serious conditions.

    On the other hand, sponsors must be aware of several limitations articulated by FDA that may prevent or limit the use of accelerated approval.  First, patients may be exposed to safety risks from a drug that subsequently fails to demonstrate clinical benefit.  Second, given the potential for reliance upon smaller or shorter clinical trials (than would be typical for traditional approval), there may be less information at the time of approval about rare or delayed adverse events.  Third, accelerated approval should not be considered if the completion of an adequate and well-controlled postapproval clinical trial to verify and describe the clinical benefit is infeasible.  Each of these risks and considerations will influence FDA’s decision-making with respect to accelerated approval.  Moreover, the infeasibility of conducting an adequate and well-controlled postapproval clinical trial becomes ever more important because FDA has authority to withdraw an accelerated approval using expedited procedures if the sponsor either fails to conduct the study with due diligence and according the conditions stipulated by FDA, or that study fails to verify the clinical benefit of the product.

    FDA’s recommendation to sponsors for how to handle such risks will sound like something of a common refrain (and for good reason) at this point – communicate with the Agency early and often during development.  In particular, the guidance states that sponsors should discuss (1) potential eligibility, (2) proposed surrogate or intermediate clinical endpoints, (3) clinical trial designs, and (4) the planning and conduct of confirmatory trials.  Notably, FDA in this guidance was quite keen to convey their concern that sponsors not overlook the importance of the postapproval confirmatory studies, reemphasizing in a footnote following these recommendations that the “accelerated approval pathway will not be an option for every serious disease with an unmet medical need, particularly when evidence is insufficient to support use of a surrogate endpoint or intermediate clinical endpoint, or when an adequate and well-controlled confirmatory trial would be infeasible” (emphasis added).

    Accelerated Approval Endpoints and Evidentiary Criteria to Support Accelerated Approval

    As noted above, the endpoints for accelerated approval can fall into one of two categories – a surrogate endpoint or an intermediate clinical endpoint, either of which must be reasonably likely to predict clinical benefit to support an accelerated approval. Moreover, an application (NDA or BLA) based upon a surrogate or intermediate clinical endpoint seeking accelerated approval must still meet the substantial evidence of effectiveness standard and contain sufficient information to demonstrate that the drug is safe for use under the conditions of the proposed labeling. However, as the new guidance helps to explain the additional burden of accelerated approval is to provide “adequate evidence” that the endpoint is reasonably likely to predict clinical benefit and goes on to provide a number of factors for sponsors to consider.

    For those somewhat familiar with accelerated approval and surrogate endpoints, you will find that the guidance reiterates a now well-established framework. Surrogates are generally biomarkers, such as laboratory, radiographic, imaging, physical, or other measures that are thought to predict benefit but are not inherently measures of clinical benefit. Surrogates fall into one of three categories in terms the strength of the evidence to support their predictive capacity:

    1. validated surrogates (e., one that is known to predict clinical benefit and could support traditional approval);
    2. reasonably likely surrogates (e., one that is reasonably likely to predict clinical benefit and could support accelerated approval); and
    3. biomarkers that do not qualify as either (e., markers for which there is insufficient evidence to demonstrate is predictive capacity or simply lack predictive capacity based upon the available data).

    In contrast, FDA articulated its most detailed guidance to date on the use of; intermediate clinical endpoints (ICE). Beyond reiterating the key criteria, a clinical endpoint that can be measured earlier than irreversible morbidity or mortality (IMM) and is reasonably likely to predict an effect on IMM or other clinical benefit, the new guidance states that there is a “threshold” consideration before relying upon an ICE. FDA will consider “whether the demonstrated therapeutic effect on the [ICE] alone would be a basis for traditional approval” because accelerated approvals based on an ICE will be considered “only when it is critical to confirm the effects on IMM or other clinical benefit” (emphasis added). The new guidance provides two examples of when an ICE may be appropriate:

    1. following demonstration of “a short-term benefit in a chronic disease [but] a longer duration of effect is necessary to demonstrate a clinically meaningful benefit,” and the short-term benefit is reasonably likely to predict “a longer duration of effect;” and
    2. the ICE demonstrates clinical benefit on a “less serious or earlier symptom of serious disease, but the benefit observed is anticipated to predict a favorable disease outcome.”

    Notably, the first example provides clarity about a long-standing point of confusion regarding accelerated approval using an ICE – that is, the same clinical measure (captured at two different timepoints) can serve as both the ICE (accelerated approval endpoint) and as the measure of ultimate clinical benefit (traditional approval endpoint). While examples of this approach are uncommon, it stands out to us that FDA included this example in its guidance. Of note, the 2004 accelerated approval of natalizumab (Tysabri) for relapsing-remitting multiple sclerosis was based on the Kurtzke Expanded Disability Status Scale (EDSS) score at one-year; two-year EDSS data were used to verify and describe the clinical benefit for conversion to traditional approval. Further, the recent approval of Kebilidi for AADC is likely to follow this approach, suggesting that FDA may be gaining some comfort with type of ICE-clinical benefit relationship.

    Regardless of the type of endpoint, surrogate or ICE, the critical consideration for FDA and sponsors will be whether there is “adequate evidence” that the endpoint is reasonably likely to predict clinical benefit. The new guidance goes on to describe that such determinations will (of course) “be a matter of judgment that will depend on the biological plausibility of the relationship between the disease, the endpoint, and the desired effect, and the empirical evidence to support that relationship.” Such empirical evidence may come from a variety of sources, such as epidemiological, pathophysiological, therapeutic and pharmacologic, but it is not limited to such sources should new innovative methods or tools provide supportive empirical evidence.

    The guidance goes on to warn that “pharmacologic activity alone” cannot provide adequate evidence and that clinical data “should be provided.” FDA’s use of “should” here is interesting because the guidance also stated that in the context of certain rare disease development programs (e.g., gene therapies) “where there is (sic) data supporting a relationship between the therapeutic target and the surrogate” clinical data may not be necessary. FDA could, for instance, decide that the “totality of the evidence” (which may include compelling nonclinical data) may be sufficient to determine that a surrogate endpoint is reasonably likely to predict clinical benefit.  This may represent an important difference in the application of accelerated approval between CDER and CBER, as many therapeutic approaches regulated by the drug center have similarly targeted mechanisms to traditional gene therapy but are not mentioned (e.g., antisense oligonucleotides, small interfering RNA).

    Irrespective of disease area, FDA will consider “all relevant evidence and may consult external experts” or convene an advisory committee when deciding whether the available evidence supports the relationship between the accelerated approval endpoint and clinical benefit. FDA considers the strongest supportive evidence to be data from interventional studies showing that “the extent of change” in the surrogate correlates with “the extent of improvement” in the measure of clinical benefit. However, the guidance acknowledges that such data may be unavailable in certain settings, such as for rare diseases. For such cases, other sources of information, including nonclinical animal data, epidemiological data, and other clinical data will be considered “to determine if the convergence of evidence supports” the endpoint as reasonably likely to predict clinical benefit.

    Finally, FDA provided several factors it considers important to consider:

    1. How well understood is the relationship between the pathophysiology of the disease and the surrogate endpoint.
    2. How reliable and consistent is the epidemiological evidence supporting the correlation between the surrogate and the clinical outcome.
    3. Has the predictive relationship between the surrogate and clinical benefit been demonstrated in an interventional clinical trial previously, and whether the intervention was in the same or a closely related pharmacologic class.
    4. Does the relationship between the surrogate and the clinical outcome require achieving a certain magnitude or duration of effect on the surrogate to predict a clinical benefit (or is otherwise necessary to support a favorable benefit-risk assessment).

    A Few Concluding Thoughts

    As we noted in a few places throughout this post, FDA’s new guidance frequently acknowledges that some flexibility or adjustments to the evidentiary bar may be necessary and warranted in the context of rare diseases. Repeatedly, the guidance stressed that accelerated approval determinations are case-by-case and circumstance-specific. Our experiences and observations of this space further underscore each of these points. However, we were pleased to see FDA acknowledge, explicitly in the context of rare diseases and implicitly in the context of common diseases, that deciding whether the evidence supports a determination that an endpoint is reasonably likely to predict clinical benefit can be based on a totality of evidence approach. In the context of common diseases, FDA may require more and stronger interventional data showing “the extent of change” on the accelerated approval endpoint correlates with “extent of change” in the measure of clinical benefit but nonetheless appears to acknowledge in this new guidance that other information can supplement such data in a meaningful way.

    We were also excited to see FDA provide more explicit discussion of ICEs than had been included in previous guidance. That being said, the guidance does leave some ambiguity with respect to what extent FDA’s discussion of the evidentiary criteria applies solely to surrogates or can reasonably be extrapolated to ICEs as well. This portion of the guidance begins by discussing both surrogates and ICEs collectively or simply refers to “an endpoint that is reasonably likely to predict.” However, as the guidance turned to more specific factors and detailed discussion, the focus changed to surrogate endpoints. While we are disappointed by this potential ambiguity, it is our experience that much of FDA’s discussion of the evidentiary criteria can apply to both surrogates and ICEs, with the important caveat that each determination is circumstance-specific.

    FDA’s new accelerated approval guidance is a must read. The discussion provides a wide-ranging and much needed update on FDA policies and interpretation of its accelerated approval authorities. Moreover, given its rich and exciting content, it is a topic we expect to return to time and again.

    Want to Hear More about Accelerated Approval?

    This blog post focused largely on the selection and justification of suitable endpoints for accelerated approval, as well as a discussion of the broader context where accelerated approval would be appropriate.  Undergirding the program is timely initiation and completion of confirmatory studies, which serves to limit the extent of patient exposure to drugs that may not ultimately demonstrate clinical benefit.  FDA intends to use its new statutory authorities under FDORA to set conditions for accelerated approval related to confirmatory studies, including that such studies may be required to be “underway” prior to approval.  Failure to meet these conditions may prevent approval or result in withdrawal of the accelerated approval.  Shortly after publishing the draft guidance that is the subject of this blog post, FDA published a second draft guidance that provides further context to considerations for determining whether a confirmatory trial is “underway” prior to approval, which we will cover in a subsequent blog post.

    FDA Inspections: Lesson 1 – Interviewing Employees

    This is the first in a series of blog posts on tips for successfully handling an FDA inspection.  Using publicly available examples, these “lessons” will illustrate potential pitfalls and strategies for interacting with FDA during and after an inspection.  

    Although FDA has long taken the position that it has broad authority in how it conducts its inspections, it was not until 2012 that Congress put some teeth behind FDA’s policy position.  As part of the Food and Drug Administration Safety and Innovation Act (known as FDASIA) and later under the FDA Reauthorization Act of 2017 (known as FDARA), a drug or medical device can be deemed adulterated if a regulated company “delays, denies, or limits an inspection, or refuses to permit an entry or inspection.”  FD&C Act § 501(j).  A foreign food manufacturer that “refuses to permit entry of [FDA inspectors} to inspect such factory, warehouse, or other establishment” can be subject to an import alert under section 807(b) of the FD&C Act.

    But what exactly constitutes delaying, denying, limiting or refusing an FDA inspection?  FDA has published Guidance defining examples of circumstances applicable to a drug or medical device company, as well as separate Guidance applicable to foreign food manufacturers.   Much of the debate on this issue centers on whether FDA can take photographs during an inspection (see our previous blog post).  But a recent Warning Letter raises new questions for regulated companies on whether FDA can interview company employees, and if so, how companies should handle these requests during an inspection.

    On December 17, 2024, FDA issued a letter to Brands International Corporation, a drug manufacturer located in Ontario, Canada, citing it for limiting and delaying FDA’s inspection based on the following conduct:

    • The Quality Manager “shoving and shouting at our investigators for conducting the inspection without [his] presence”
    • Laboratory staff refusing to open a drug stability chamber “based on [the Quality Manager’s] hostile behavior”
    • Upon FDA asking questions of the Quality Control Supervisor, the Quality Manager “interrupted and stated that only he can explain and answer the requests”
    • While FDA was interviewing an employee regarding mold samples, the Quality Manager “began berating the employee, who then left the room”

    Although delaying, denying, limiting or refusing the drug inspection was not the only violation cited in the Warning Letter – it also included several cGMP violations and potential cosmetic violations – the “limiting the inspection” violation was listed first, and thus considered by FDA to be the most significant violation.

    Very rarely have we seen a Warning Letter call out the behavior of a single individual, and no less the Quality Manager, who is the public face of the company to FDA during inspections, for being uncooperative and hostile to FDA and the company’s own employees.  Here, the FDA investigators documented several instances in which the Quality Manager appeared directly responsible for preventing company employees from talking with FDA about their responsibilities or responding to direct questions from FDA about areas in which FDA has authority to inspect.  Note that the relevant Guidance document for drug manufacturers (like Brands International) is silent on the issue of employee interviews, but the Guidance applicable to foreign food manufacturers is explicit that FDA considers a company to have refused an inspection if it acted unreasonably in preventing the FDA investigator from talking to pertinent staff to collect evidence.

    Examples of where we would generally consider preventing the FDA investigator from fully conducting an inspection include:

    . . .

    The owner, operator, or agent in charge refuses to allow the FDA investigator to collect evidence to document potential violations (e.g., to take photographs as necessary; to collect samples; talk to pertinent staff; or to collect food labels and labeling).

    FDA Guidance, at 8 (emphasis added).  Now, guidances are generally not legally binding, unlike statutes or regulations.  But because this Guidance was specifically authorized by statute, it may carry more weight in a court.

    To be clear, FDA cannot coerce employees to testify during an inspection – certainly every Law & Order fan is familiar with the Constitutional right to remain silent – and there is at least some doubt as to the Agency’s legal authority to interview any employee it wants during an inspection.   But it appears FDA will assert that it has a right to question employees, presumably under the statutory provisions cited above, and FDA has the leverage (even if not explicit legal authority) to pressure companies to make their employees available.

    How should FDA-regulated companies handle interview requests during an FDA inspection?  As a practical matter, we recognize there are few FDA-regulated firms that are ready and willing to contest the Agency in court over this issue.  (If so, please call us.)  There are tactful ways to accommodate FDA’s request and set appropriate limitations to ensure FDA does not overstep its inspectional mandate.  First, companies should designate the personnel who are authorized to respond to FDA’s questions during an inspection.  Written procedures should clearly state parameters for discussions with FDA, including prohibiting FDA from conducting a private interview with an employee who is not properly designated.  If FDA asks for an interview of a non-designated employee, companies can still be cooperative with the request but insist that designated personnel are present during those interviews and that FDA limit its questions to those that are directly within the employee’s job description and responsibilities.  Wholesale refusal to allow an employee to respond to direct questions from FDA only raises more questions and distrust from the FDA investigator.  Even if not cited in a Warning Letter, the FDA investigators are instructed to document in their Establishment Inspection Report incidents of hostile or uncooperative interviewees (see Investigations Operations Manual, at section 5.3.13), which can be publicly released.   Companies should train (and remind) employees on inspection readiness.

    So Lesson #1, companies can control the extent in which FDA talks with personnel, but should do so based on established procedures and a cooperative attitude.