FDA Regulatory News and Trends - April 9, 2024

Welcome to FDA Regulatory News and Trends, designed to help you identify significant legal developments and navigate the evolving business, legal, and regulatory world.

Revised guidance on handling and retention of bioavailability and bioequivalence testing samples.

• On March 27, 2024, FDA issued a guidance titled, “Handling and Retention of Bioavailability BA and Bioequivalence BE Testing Samples.” 
  
  
• Section IV.B. of this guidance is issued as final guidance. It supersedes the Agency’s compliance policy related to the quantity of bioavailability (BA) and bioequivalence (BE) samples retained under 21 CFR § 320.38(c) described in the final guidance, “Compliance Policy for the Quantity of Bioavailability and Bioequivalence Samples Retained Under 21 CFR 52 320.38(c)” from August 2020, and statements related to quantity of reserve samples in section IX. “Number of Reserve Samples for BA and BE Testing of the draft guidance Nasal Aerosols and Nasal Sprays for Local Action” from April 2003.
  
  
• The remainder of the guidance is issued as draft guidance. FDA highlights (1) how the test article and reference standard for BA and BE studies should be distributed to the testing facilities, (2) how testing facilities should randomly select samples for testing and material to maintain as reserve samples, and (3) how the reserve samples should be retained. 
  
  
• Interested parties should submit comments on or before May 28, 2024. 
  
  

RWE for non-interventional studies for drug and biological products.

• On March 19, 2024, FDA issued a draft guidance titled, “Real-World Evidence: Considerations Regarding Non-Interventional Studies for Drug and Biological Products.” The draft guidance provides recommendations to sponsors who plan to use non-Interventional studies to demonstrate the safety and/or the efficacy profile of drug and biological products. Examples of non-interventional study includes observational cohort studies, case-control studies, and self-controlled studies, among others. 
  
  
• To enable FDA to evaluate proposals for non-interventional studies, FDA advises sponsors to provide information on study attributes including research question and hypothesis, rationale for using the proposed non-interventional study design, choice of study design, proposed selection of data sources to address the study objective and hypotheses, results of any preliminary or feasibility studies, proposed approach to support causal inference, and description of how ethical considerations are addressed.
  
  
• Interested parties should submit comments on or before June 20, 2024.
  
  

FDA publishes AI and medical products paper. 

• On March 20, 2024, FDA’s medical product centers jointly published a paper entitled, “Artificial Intelligence and Medical Products: How CBER, CDER, CDRH, and OCP are Working Together.” 
  
  
• The paper outlines four priorities for cross-center collaboration to promote consistency across the FDA: 1) fostering collaboration with third parties; 2) developing policies that provide regulatory predictability and clarity for the use of AI to support innovation; 3) promoting the development of standards, guidelines, best practices, and tools for the medical product lifecycle; and 4) supporting research related to the evaluation and monitoring of AI performance. 
  
  
• According to the paper, FDA plans to issue final guidance on marketing submission recommendations for predetermined change control plans, draft guidance on life cycle management considerations and premarket submission recommendations for AI-enabled device software functions, and draft guidance on considerations for the use of AI to support regulatory decision-making for drugs and biological products.
  
  
• The paper also reaffirms FDA’s commitment to promote health equity by promoting the responsible development, deployment, and use of AI in medical products.
  
  

Updates to premarket cybersecurity guidance.

• On March 13, 2024, FDA released draft guidance proposing select updates to its "Cybersecurity in Medical Devices: Quality System Considerations and Content of Premarket Submissions” guidance document. 
  
  
• FDA is proposing to add a new section to the guidance addressing the cybersecurity information that the Agency considers generally necessary to support obligations under section 524B of the Food, Drug and Cosmetics Act (the section that provides FDA with authority to require cybersecurity information as part of certain medical device regulatory oversight, including the FDA’s ability to require a post-market monitoring plan for cybersecurity vulnerabilities in pre-market submissions).
  
  
• Of note, updates in the draft guidance indicate that a new 510(k) would be expected to address currently identified cyberthreats, rather than simply relying on the historic state of knowledge and testing used in respect of the predicate device. Additionally, according to the draft guidance, grandfathering will not be possible – modifications to existing devices will need to account for premarket cybersecurity requirements.
  
  
• FDA has scheduled a webinar to discuss the proposals on April 30, 2024, and any comments on the draft should be submitted to the docket by May 13, 2024 to ensure consideration before FDA begins work on the final version.
  
  

CDRH proposes draft guidance on the evaluation of devices causing heating and cooling of tissue.

• On March 15, 2024, CDRH released a draft guidance document entitled, "Evaluation of Thermal Effects of Medical Devices that Produce Tissue Heating and/or Cooling." This guidance applies to devices that produce tissue temperature changes (ie, heating and/or cooling) as an intended or unintended consequence of use.
  
  
• In the draft guidance, CDRH provides recommendations on appropriate types of testing and methodologies used for assessing the effect on tissue from these devices, which would in turn be leveraged to support marketing authorization. It also discusses the potential use of computational models for performing such testing.
  
  
• Device manufacturers developing products that could cause tissue temperature changes (eg, via light, electromagnetic energy, ultrasound, or battery heating) should review the guidance and consider whether testing must be supplemented to align with the guidance, should it be finalized. FDA is currently accepting comments on the draft at docket # FDA-2024-D-0664.
   
  

CDER establishes new Quantitative Medicine Center of Excellence.

• On March 25, 2024, CDER announced the establishment of a new Center of Excellence (CoE) for Quantitative Medicine (QM). CDER defines QM as "exposure-based, biological, and quantitative modeling and simulation approaches derived from nonclinical, clinical, and real-world sources to inform drug development, regulatory decision-making, and patient care."
  
  
• The goal of this center-wide effort is to facilitate and coordinate the continuous evolution and consistent application of QM across the center. Patrizia Cavazzoni, M.D., CDER Director, explained that, "given the tremendous growth in QM, we see many opportunities to strengthen collaboration across CDER by centrally coordinating outreach, education, scientific and regulatory policy, to facilitate the consistent use of QM approaches during drug development and to inform regulatory decision making.”
  
  
• CDER will host a public workshop to share more about the new CoE on April 25, 2024. Those interested can register for the workshop on FDA's website.
  
  

Final guidance on controlled correspondence.

• On March 18, 2024, FDA issued final guidance entitled, “Controlled Correspondence Related to Generic Drug Development,” finalizing its December 2022 draft update guidance which had replaced guidance of the same name issued in December 2020.
  
  
• The guidance provides information on the process by which generic drug manufacturers and related industry can submit to FDA controlled correspondence regarding generic drug development, as well as details on the Agency’s process for providing communications in return. The document also describes the process by which manufacturers and industry can submit requests to clarify ambiguities in FDA’s controlled correspondence response and the Agency’s process for responding to those requests.  
  
  
• While the final version contains mostly non-substantive editorial modifications, FDA added that it allows questions about whether a product is considered a combination product. It also removed the recommendation for submitting cover letters with correspondence and omitted a previous statement regarding the default Level 2 categorization of requests requiring input from the Office of Research and Standards Clinical Safety and Human Subject Research Team.
  
  

Clarification on OTC labeling changes.

• On March 13, 2024, FDA issued draft guidance entitled, “Annual Reportable Labeling Changes for New Drug Applications and Abbreviated New Drug Applications for Nonprescription Drug Products.”
  
  
• The draft guidance provides recommendations to applicants of approved new drug applications (NDAs) and abbreviated new drug applications (ANDAs) for nonprescription drug products on documenting minor labeling changes in an annual report to ensure that consumers have timely access to the most current labeling, thus helping ensure the product’s safe and effective use. The guidance also provides examples of editorial and other minor labeling changes that may be submitted annually.
  
  
• The Agency intends for these recommendations to assist industry in understanding the circumstances in which it would be appropriate to document minor changes in the applicant’s next annual report rather than submitting a prior approval supplement or “changes being effected” supplement, thereby reducing burden on industry and FDA. 
  
  
• Interested parties are invited to comment on or before May 13, 2024.
  
  

Updated draft guidance on the Q-Submission Program.

• On March 15, 2024, FDA issued an updated “Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program: Draft Guidance for Industry and Food and Drug Administration Staff.” When final, the guidance will supersede “Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program,” issued on June 2, 2023, and “Guidance on PMA Interactive Procedures for Day-100 Meetings and Subsequent Deficiencies - for Use by CDRH and Industry,” issued on February 19, 1998.
  
  
• The primary change FDA made in the updated draft guidance is incorporating a discussion on PMA Day 100 Meetings rather than cross-referencing to the 1998 guidance. 
  
  
• FDA is obligated, under section 515(d)(3)(A)(i) of the Food, Drug, and Cosmetic Act, to meet with a premarket approval (PMA) applicant, upon their written request, no later than 100 days after the receipt of an original PMA application has been filed.
  
  

Proposed ban of certain electrical stimulation devices.

• On March 25, 2024, FDA took the rare step of proposing a ban of electrical stimulation devices (ESDs) intended to reduce or stop self-injurious or aggressive behavior. See the Federal Register Notice.
  
  
• ESDs deliver electrical shocks through electrodes attached to an individual’s skin to attempt to reduce or stop harmful behaviors (ie, through aversive conditioning). FDA has determined that such devices present an unreasonable and substantial risk of illness or injury.
  
  
• FDA previously attempted to ban these devices in 2020. However, the manufacturer of these devices challenged FDA’s authority to ban devices for specific intended uses without banning the device for all intended uses in US Court of Appeals for the District of Columbia Circuit. The Court vacated FDA’s ban on July 6, 2021. Congress subsequently granted FDA the authority to ban a device for one or more intended uses in the Food and Drug Omnibus Reform Act of 2022 (FDORA).
  
  

Final rule on food contact notifications.

• FDA issued a final rule to amend its regulations on how and when the Agency may determine that a food contact notification (FCN) is no longer effective.  
  
  
• A food contact substance is considered “added” when it can reasonably be expected to migrate into a food. FCNs were established to replace the more burdensome food additive petition process. If FDA does not object to an FCN, it is considered safe for its intended use and remains in effect until the Agency revokes its determination.
  
  
• Prior to this final rule, FDA could only determine that FCN is no longer effective based upon safety concerns.  The changes in this rule will allow the Agency to determine an FCN is no longer effective for reasons other than safety (eg, abandonment of use).  These changes also enable manufacturers or supplier an opportunity to provide input before the Agency reaches a determination that the FCN is no longer effective.  FDA believes the new rule will allow the agency to more effectively respond to new information on the safety and use of food contact substances. 
  
  
• An Inventory of Effective Food Contact Substances can be found on the FDA’s website.
  
  

New import alert for chemical contaminants, including PFAS.

• On March 20, 2024, FDA issued an import alert for human food products regarding detectable levels of chemical contaminants that may present a safety concern to human health.  
  
  
• This alert allows FDA to prevent entry of human food products into the US if they are found to be contaminated with a broad range of human-made chemicals including benzene, dioxins, and polychlorinated biphenyls (PCBs), and per- and polyfluoroalkyl substances (PFAS), among others. Specific firms and their food products found with levels of chemical contaminants that may pose a risk to human health may be subject to detention without physical examination (DWPE) under this import alert. 
  
  
• In its announcement of this new import alert, FDA discusses its 2022 survey for PFAS in seafood and states its plan for additional survey of molluscan shellfish this year.  FDA notes that this import alert can be used to refuse entry of food like seafood contaminated with PFAS.