FDA Regulatory News and Trends - October 9, 2023

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

Final guidance on cybersecurity in medical devices.

• In September 2023, FDA released a final guidance entitled, “Cybersecurity in Medical Devices: Quality System Considerations and Content of Premarket Submissions.” Superseding the Agency’s 2014 draft document, the final guidance provides FDA’s recommendations regarding device design, labeling, and documentation to include in premarket submissions for wireless and network-connected medical devices that may pose cybersecurity risk. 
  
  
• FDA did not have explicit statutory authority to require cybersecurity information in regulatory submissions until the Food and Drug Omnibus Reform Act went into effect in the last year; however, this final guidance, intended to “promote consistency, facilitate efficient premarket review, and help ensure that marketed medical devices are sufficiently resilient to cybersecurity threats,” aligns closely with the 2022 revised draft version – definitions have now been updated, and sections related to cybersecurity risk assessments and interoperability were added for clarity.
  
  
• Although there is no defined implementation timeline, FDA provided in the guidance that it intends to work collaboratively with sponsors that currently have a premarket application pending or that submit after initial publication of this guidance as part of the submission review process.
  
  
  

Final guidance on the conduct of clinical trials of medical products during major disruptions.

• The COVID-19 pandemic made obvious the potential for disasters and public health emergencies (PHEs) to cause major disruptions in clinical trials for medical products. In response, FDA has revamped its “Considerations for the Conduct of Clinical Trials of Medical Products During Major Disruptions Due to Disasters and Public Health Emergencies” final guidance, which includes Q&A items and considerations to assist sponsors, institutional review boards (IRBs), and clinical investigators in maintaining trial safety and compliance, while mitigating the risk of major disruptions to clinical operations.
  
  
• In 2020, FDA issued a prior iteration of this guidance as it pertains to trials conducted during the COVID-19 PHE and subsequently updated its recommendations as the pandemic continued. The revised guidance now extends applicability of the Agency’s current thinking to clinical research conducted during disasters and PHEs beyond COVID-19, from hurricanes and military conflicts to infectious disease outbreaks and bioterrorist attacks. 
  
  
• Overall, many of the COVID-19-era policies are carried over for immediate implementation, but with more generalized guidance as to considerations for continuing trials, policies, and procedures to account for potential disruptions to trials, and documentation recommendations for studies impacted by a disaster or PHE.
  
  
  

Final guidance on postmarketing requirements and commitment annual status report submissions.

• In September 2023, FDA released a final guidance entitled, “Annual Status Report Information and Other Submissions for Postmarketing Requirements and Commitments: Using Forms FDA 3988 and FDA 3989.”
  
  
• Under section 506B of the Federal Food, Drug, and Cosmetic Act (FDCA) and its implementing regulations at 21 CFR 314.81(b)(2)(vii) and 601.70, drug and biologics sponsors must submit an annual report to FDA providing the description, schedule, and status of their postmarketing requirements and commitments (PMR and PMC). This final guidance, which closely mirrors FDA’s 2018 draft guidance document, outlines recommendations for completing and submitting reports – specifically, through Forms FDA 3988 and 3989 – which may relate to PMR/PMC studies or clinical trials concerning a product’s clinical safety, clinical efficacy, clinical pharmacology, and nonclinical toxicology.
  
  
• While the views reflected in the guidance are likely unsurprising for many in industry, the recommendations therein align with FDA’s more recent focus on enforcing PMRs and PMCs – including through its added authority granted by the Food and Drug Omnibus Reform Act – and holding applicants accountable for timely completing these studies.
  
  
  

CDRH releases two draft guidance documents for weight loss devices.

• On September 15, 2023, CDRH published two draft guidance documents addressing weight loss devices: “Medical Devices with Indications Associated with Weight Loss – Clinical Study and Benefit-Risk Considerations“ and “Medical Devices with Indications Associated with Weight Loss – Non-Clinical Recommendations.”
  
  
• The first guidance focuses on clinical study and benefit-risk considerations. According to the document, CDRH recommends that pivotal studies include no more than 50 percent of data from outside the US due to the general difficulty in applying foreign effectiveness data for weight loss products to the US population. In addition, the center recommends sham-controlled studies, as the placebo effect has been identified as a significant factor in weight loss studies. Finally, the guidance discusses pediatric populations, acknowledging the increased prevalence of childhood obesity.
  
  
• The second guidance focuses on the non-clinical side. The guidance document provides insight into the center’s thinking on a slew of topics, such as labeling, sterility, biocompatibility, software, and bench testing. Importantly, it provides recommendations related to the design and conduct of animal studies, acknowledging that, “[d]ue to limitations of bench models, animal studies may be warranted to support medical device premarket submissions” for weight loss devices.
  
  
• CDRH specifies six product codes to which these guidance documents are intended to apply: intragastric implants (LTI), aspiration therapy systems (OYF), neuromodulators (PIM), oral removable retainers (ONY), ingested space occupying devices (QFQ), and endoscopic suturing devices (QTD). Companies developing devices under these product codes should review the draft guidances for insight into the direction of CDRH’s thinking and consider providing feedback at docket FDA-2019-N-4060. 
  
  

 
Draft guidance for confirmatory evidence.

• On September 19, 2023, FDA issued a new draft guidance, entitled, “Demonstrating Substantial Evidence of Effectiveness Based on One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence.” This document complements two draft guidances published by FDA: “Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products,” dated December 2019 (the 2019 Effectiveness draft guidance), and “Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products,” dated May 1998 (the 1998 Effectiveness guidance).
  
  
• The September 2023 guidance outlines key factors to consider when assessing whether a single adequate and well-controlled clinical investigation and confirmatory evidence are sufficient in demonstrating substantial evidence of effectiveness. The guidance further discusses the use of data drawn from one or more sources (eg, clinical data, mechanistic data, animal data) to substantiate the results of one adequate and well-controlled clinical investigation.
  
  
• FDA provides several examples of types of data that could be considered confirmatory evidence, such as clinical evidence from a related indication, mechanistic or pharmacodynamic evidence, evidence from a relevant animal model, evidence from other members of the same pharmacologic class, evidence from natural history, real world data/evidence, and evidence from expanded use of an investigational drug. As always, FDA emphasizes the importance of early engagement with the Agency. 
  
  
• Interested parties should submit comments by December 18, 2023. 
  
  
  

IRB review of individual patient expanded access submissions for investigational drugs and biological products.

• On September 11, 2023, FDA issued a final guidance for Institutional Review Boards (IRBs) and clinical investigators, titled, “Institutional Review Board (IRB) Review of Individual Patient Expanded Access Submissions for Investigational Drugs and Biological Products.” This guidance provides recommendations regarding the key factors and procedures IRBs should consider when reviewing individual patient expanded access submissions, including for reviews conducted by a single member of the IRB, to fulfill their obligations under 21 CFR part 56. 
  
  
• FDA recommends IRBs to (1) establish procedures for a single IRB member to review a non-emergency individual patient expanded access submission if a waiver of full IRB review is requested, and (2) focus the review on assessing the risks and benefits for the patient involved. 
  
  
• FDA additionally recommends the following factors when reviewing individual patient expanded access submissions: (1) qualifications of the investigator, (2) the inclusion of adequate provisions for soliciting age-appropriate assent from children and permission from a parent or guardian, and (3) the inclusion of all required information within the informed consent document.
  
   

Regulatory considerations for prescription drug use-related software.

• On September 18, 2023, FDA issued a draft guidance, titled, “Regulatory Considerations for Prescription Drug Use-Related Software.” This guidance describes how FDA intends to apply its drug labeling authorities to certain software outputs that are disseminated by or on behalf of a drug sponsor for use with a prescription drug or a combination product. 
  
  
• FDA intends to consider several factors when determining whether the end-user output should be regulated as FDA-required labeling or promotional labeling. Factors include (1) whether the prescription drug use-related software provides a function that is essential to the safe and effective use of the product, (2) whether evidence is provided to support a clinical benefit when the prescription drug use-related software is used, and (3) whether the prescription drug use-related software relies on data directly transferred from the device constituent part of a combination product. 
  
  
• FDA characterizes a prescription drug use-related software by the software function/design and its intended use. The guidance provides examples of prescription drug use-related software functions and end-user output, as well as examples of device software functions that are regulated by FDA under an appropriate CDRH marketing submission and where the end-user output is considered promotional labeling. 
  
  
• Interested parties should submit comments by December 18, 2023. 
  
  
  

CDRH updates guidance on its Breakthrough Devices Program.

• On September 15, 2023, CDRH published an update to its “Breakthrough Devices Program” guidance. Originally published on December 18, 2018, the document provides insight into CDRH’s program, which centers around certain medical devices and device-led combination products that facilitate more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions.
  
  
• The September 2023 update supersedes the previous guidance and provides additional information on four areas: (1) how the program applies to devices that promote health equity, (2) considerations taken in device designation, (3) designation for non-addictive medical products to treat pain or addiction (an obligation under the SUPPORT Act), and (4) disclosure of breakthrough status after marketing authorization.
  
  
• Device manufacturers considering pursuing breakthrough designation are encouraged to review the updates to this guidance and consider applicability to their product. In addition, those looking for more information can tune in to CDRH’s upcoming November 14, 2023 webinar on the topic.
  
  
  

CDRH releases guidance on its VIP program of third-party audits of manufacturers.

• On September 15, 2023, CDRH published a guidance document, titled, “Fostering Medical Device Improvement: FDA Activities and Engagement with the Voluntary Improvement Program.”
  
  
• This guidance describes a newly implemented Voluntary Improvement Program (VIP), through which manufacturers can coordinate with CDRH to complete a third-party audit of their operations. This program builds on the framework piloted through FDA’s 2018 Case for Quality Voluntary Medical Device Manufacturing and Product Quality Pilot Program (CfQ Pilot Program) and allows manufacturers to receive outside input on opportunities for improvement to their operations.
  
  
• Of note, the third-party auditor does not release complete audit findings with CDRH, but does share high-level appraisal scores for each assessed practice area, by firm name and location, as well as deidentified, aggregate information from the program.
  
  
• Companies manufacturing medical devices regulated by FDA are encouraged to review this guidance and the accompanying website, and consider whether participation in the program may be beneficial to their manufacturing operations.
  
  

 
CDRH releases a biocompatibility guidance on how to implement ISO 10993-1.

• On September 8, 2023, CDRH published a guidance document, titled, “Use of International Standard ISO 10993-1, ‘Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process.’”
  
  
• This lengthy guidance addresses several biocompatibility issues raised in the ISO 10993-1 standard, which is focused on determining the potential for an unacceptable adverse biological response resulting from contact of the component materials of a device with the body. The document outlines risk-based approaches to determining whether biocompatibility testing is needed, chemical assessment recommendations, and recommendations for when certain materials only contact intact skin.
  
  
• Companies performing biocompatibility testing are encouraged to review this guidance for applicability to their product and consider attending FDA’s upcoming October 12, 2023 webinar on the topic.
  
  
  

Draft guidance on alternative tools for assessing manufacturing facilities. 

• On September 22, 2023, FDA released a new draft guidance, entitled, “Alternative Tools: Assessing Drug Manufacturing Facilities Identified in Pending Applications.”
  
  
• The draft guidance explains how FDA intends to use alternative tools to assess manufacturing facilities identified in a marketing application, including a new drug application (NDA), abbreviated new drug application (ANDA), biologics license application (BLA), or supplement to these types of applications.  Alternative tools include remote interactive evaluations (RIEs), records requests, and review of existing inspection reports from trusted foreign regulatory partners through mutual recognition agreements.  
  
  
• The draft guidance notes that, due to the success of innovative approaches in using alternative tools during the COVID-19 public health emergency, FDA intends to continue risk-based use of these tools in advance or in lieu of preapproval inspections (PAIs) and prelicense inspections (PLIs).  When determining whether to use alternative tools, FDA will evaluate all risks and urgencies on a case-by-case basis and consider various factors, including the facility’s drug inspection history (by FDA or a trusted foreign regulatory authority), the application-specific risks, the type of product and whether it addresses an urgent need, and the feasibility of an inspection.  
  
  
• The comment period for this draft guidance ends on November 21, 2023.  
  
  
  

Draft guidance on formal meetings between FDA and sponsors of drug and biologic products.  

• On September 22, 2023, FDA released a new draft guidance, entitled, “Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products.”  This draft guidance replaces the previous guidance issued on December 29, 2017.
  
  
• The draft guidance outlines the Agency’s recommendations to the drug and biological drug product industry on formal meetings with FDA related to the development and review of new products.  It discusses the principles of good meeting management practices and describes standardized procedures for requesting, preparing, scheduling, conducting, and documenting formal meetings.  
  
  
• The guidance document explains the various types of meetings under PDUFA that occur between requestors and FDA staff, including Type A, Type B, Type B (end of phase, or EOP), Type C, Type D, and Initial Targeted Engagement for Regulatory Advice on CDER and CBER ProducTs (INTERACT), as well as the various types of meeting formats, including in person face-to-face, virtual, teleconference, and written response only.  
  
  
• The comment period for this draft guidance ends on December 21, 2023.
  
  
  

FDA seeks comments on its electronic portal for the upcoming cosmetic registration and listing deadline under MoCRA.

• Under the Modernization of Cosmetic Regulation Act (MoCRA), no later than December 29, 2023, facilities that manufacture or process cosmetic products distributed in the US must register with FDA and submit to the Agency a cosmetic product listing with information on each cosmetic product produced in that facility. Relevant information includes the product’s ingredients, the facility registration number of each facility where it is manufactured, the name and contact number of the responsible person, the name of the cosmetic product as it appears on the label, and the product listing number assigned (if any).  
  
  
• FDA has developed a portal – Cosmetics Direct – to encourage electronic submission of this registration and listing information, though paper submissions will still be accepted.  The Agency has provided links to screenshots for each submission method and is seeking comments on ways to enhance the information collection methods, as well as the feasibility and burden of these methods.
  
  
• Stakeholders will have until October 18, 2023 to comment provide comments to FDA.  More information MoCRA’s registration and listing requirements can be found on FDA’s newly launched Registration & Listing of Cosmetic Product Facilities and Products website.  
  
  
  

CFSAN adds a chapter on food allergen programs to its draft guidance on hazard analysis and risk-based PCHF.

• The Center for Food Safety and Applied Nutrition (CFSAN) has added a chapter on food allergen programs to its “Draft Guidance for Industry: Hazard Analysis and Risk-Based Preventive Controls for Human Food” (PCHF Rule).
  
  
• The PCHF Rule requires facilities to establish and implement a program to ensure that food is protected from major food allergen cross-contact and that the finished food is properly labeled with respect to the major food allergens. 
  
  
• This new draft guidance provides additional information on how to meet the requirements for establishing, monitoring, and verifying a Food Allergen Program, including information about:
  
  
  • Allergen cross-contact controls, which will supplement the allergen controls in CGMPs in part 117, subpart B (prerequisite program).
    
    
  • Label controls, including detailed information on how to develop and manage the implementation of allergen labeling requirement.
    
    
  • Supply chain programs, which should generally treat major allergens as a hazard that may bring serious adverse health consequences or death to humans (SAHCODH), such that the default verification activity is an annual audit.
    
    
  • Allergen advisory statements (ie, ”may contain [allergen]”), which should only be used when adherence to CGMP measures and allergen cross-contact controls cannot fully prevent the presence of allergens.  
    
    
  • Training, including a list of relevant training topics.
    
    
• The guidance also provides in-depth examples of food allergen programs for several product categories.
  
  
• Comments should be submitted by March 25, 2024 to ensure consideration for the final guidance.
  
  
  

CFSAN adds a chapter on acidified foods to its draft guidance on hazard analysis and risk-based PCHF.

• CFSAN has issued an additional chapter on acidified foods to its PCHF Rule draft guidance.
  
  
• Chapter 16 on Acidified Foods helps to explain how manufacturers of acidified foods can use procedures, practices, and processes that they have established to meet requirements in the acidified foods regulations to also meet requirements under the preventive controls for human foods rule.
  
  
• This new draft guidance focuses on the overlap among several requirements in the acidified food regulations and the PCHF Rule, including requirements for:
  
  
  • Qualifications of personnel with responsibility for supervision and oversight
    
    
  • Written food safety plans
    
    
  • Hazards analysis
    
    
  • Preventive controls
    
    
  • Supply chain controls
    
    
  • Recall plans
    
    
  • Records 
    
    
• FDA provides a useful Quick Reference Guide to highlight the relationship between specific acidified food requirements and the corresponding PCHF requirements.  
  
  
• Comments should be submitted by March 25, 2024 to ensure consideration for the final guidance.