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3 January 202316 minute read

FDA Regulatory News and Trends

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

FDA finalizes guidance on enforcement approach for homeopathic drugs. On December 7, 2022, FDA released a final guidance titled Homeopathic Drug Products, which finalizes the draft guidance, Drug Products Labeled as Homeopathic, initially released in 2017 and updated in 2019. The final guidance is substantially similar to the revised draft from 2019, incorporating only minor changes for clarity and transparency. For example, the final guidance clarifies that, although the CARES Act, enacted in March 2020, created a new regulatory pathway for OTC medical products under Section 505G for administrative orders to make GRAS/E determinations for certain nonprescription drugs marketed without approval, no GRAS/E determinations will be made for homeopathic drugs under section 505G because section 505G does not apply to homeopathic drug products. Accordingly, all homeopathic drug products are subject to the premarket approval requirements of the FD&C Act. The guidance states that FDA intends to prioritize enforcement and regulatory actions on unapproved products that fall into one of the following categories:

  1. Products with reports of injury that raise potential safety concerns
  2. Products containing ingredients associated with potentially significant safety concerns
  3. Products for routes of administration other than oral or topical
  4. Products intended for the prevention or treatment of serious and/or life-threatening diseases or conditions
  5. Products for vulnerable populations and
  6. Products with significant quality issues.

While FDA intends to prioritize its resources on enforcing products in these categories, the guidance also states that “this guidance is intended to provide notice that any homeopathic drug product that is being marketed illegally is subject to FDA enforcement action at any time.” The guidance also notes, however, that FDA “anticipates that many homeopathic drug products will fall outside the categories of drug products that FDA intends to prioritize for enforcement and regulatory action” as described in the guidance.

FDA publishes new website resource for augmented and virtual reality (AR/VR) in medical devices. On December 7, FDA published a new webpage devoted to AR and VR medical device subject matter. The webpage offers definitions for the terms AR and VR, which mirror those used by FDA in its July 2022 Patient Engagement Advisory Committee (PEAC) meeting on AR/VR issues. Notably, there is no more formal definition of these terms in FDA regulation. The webpage features discussion on how AR and VR are impacting medical devices, offering preliminary insight into FDA’s thinking on the potential benefits and risks presented by these technologies. Additionally, the webpage includes a list of authorized (via de novo and 510(k) pathways) medical devices that incorporate AR and VR, which may be a useful source of regulatory precedent for device developers in this space. The webpage is emblematic of the growing thought and work FDA is putting into the area of AR/VR.

FDA issues first draft guidance on Voluntary Malfunction Summary Reporting Program for Manufacturers. Device manufacturers, user facilities and importers are required to report certain adverse events and device malfunction issues to FDA as part of the Agency’s safety surveillance. In 2018, FDA released the final VMSR rule which allowed certain medical device manufacturers to submit summary, rather than individual, malfunction reports for their devices on a quarterly basis through the FDA’s Voluntary Malfunction Summary Reporting (VMSR) Program. The Program, which began as the Medical Device Reporting on Malfunctions pilot in 2015, was developed to streamline the reporting process for some non-permanently implantable, life-supporting or life-sustaining devices – the pilot produced a report format that was effective regardless of firm size, reducing report volume by more than 87 percent without sacrificing substance. The recent draft guidance is intended to further clarify the VMSR Program and its major principles: electronic summary submission format, information transparency, prompt communication of imminent hazards, avoiding duplicative submissions and streamlining reporting processes. The guidance also expands on the program’s eligibility determination process and conditions for participation, including the Agency’s policy to assess eligibility of new product codes once they have been in existence for two years. Consistent with the established program, manufacturers may still be required to submit individual reports in specific situations, including events that necessitate remedial action to prevent unreasonable risk of substantial harm to the public health, malfunctions that are subject to device recalls, determination by the FDA that individual reporting is necessary to address a public health issue, situations in which the manufacturer is no longer eligible or situations in which a new type of reportable malfunction occurs. The draft guidance comment period ends February 7, 2023.

FDA publishes Report on Risks and Benefits to Health of Non-Device Software Functions. The 21st Century Cures Act of 2016 recently updated Federal Food, Drug, and Cosmetic Act provisions on determining whether FDA has oversight of a product based on its function(s). Under the revised provisions, certain software functions do not qualify as a medical device, including administrative support functions; wellness programs unrelated to the diagnosis, cure, mitigation, prevention or treatment of a condition; electronic patient records; and lab results storage, transfer and display. However, some products, primarily in the digital health space, include both medical device functions and non-medical device functions, which may be regulated by other agencies in addition to the FDA. Under Cures, Congress directed FDA to report every two years on non-device health information technology functions, including any associated uses, risks, benefits or best practices. The 2022 Non-Device software report describes an increase in related digital health R&D and concludes that, while adverse events from non-device software may be underrepresented in the report, non-device functions generally have a positive impact on patients. The bi-annual report highlights the benefits and increased research related to e-prescriptions, electronic health records, efficient handling of lab data and results, and the proliferation of health and wellness apps amidst the pandemic. Lastly, the report touches on clinical decision support software (CDS) functions, particularly alerts and alarms, and recommendation listings, despite potentially being categorized as a device CDS (and therefore falling outside the scope of the report). While the report involves FDA’s assessment of software functions it does not oversee, the document provides some insight into the Agency’s role in non-device regulation as well as the interactions between medical device and non-device functions, which may implicate evolving FDA policy in areas such as multiple function devices.

FDA proposes to replace the current IND annual reporting requirement with the annual FDA development safety update report (FDA DSUR). On December 8, 2022, FDA issued a proposed rule titled Investigational New Drug Application Annual Reporting. The proposed annual FDA DSUR regulation is more comprehensive than the IND annual report currently required under FDA regulations. Importantly, the format and content of the FDA DSUR are consistent with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), which is described in FDA’s ICH guidance for industry entitled E2F Development Safety Update Report (E2F DSUR) (August 2011). The proposed rule is FDA’s most recent effort to increase International Regulatory Harmonization in light of the increasingly complex and global nature of pharmaceutical industry operations and related regulatory oversight. FDA lists 17 major provisions of the proposed rule and provides a side-by-side table, comparing the major differences between the current regulatory requirements for the IND annual report and the regulatory requirements for the proposed FDA DSUR. The proposed rule, if finalized, would enable FDA to identify and review new safety signal information more efficiently, create a more efficient reporting process and allow regulatory authorities worldwide to access to the same data more promptly. Interested parties should submit comments on the proposed rule by March 9, 2023.

FDA proposed to expand the current IND exemptions to include clinical studies of food, dietary supplements and cosmetic products. On December 9, 2022, FDA issued a proposed rule, Investigational New Drug Applications; Exemptions for Clinical Investigations To Evaluate a Drug Use of a Product Lawfully Marketed as a Conventional Food, Dietary Supplement, or Cosmetic. The proposed rule is an attempt to resolve concerns raised in response to the final guidance on Investigational New Drug Applications—Determining Whether Human Research Studies Can Be Conducted Without an IND (2013 IND Guidance), including the stayed portions of the guidance. The proposed rule offers two investigational new drug exemption pathways: the Self-Determined Exemption and the FDA-Determined Exemption. Under the Self-Determined Exemption pathway, a sponsor of a clinical study to evaluate a drug use of a food or cosmetic product that is lawfully marketed in the US is exempt from the IND requirements if certain conditions are met regarding (1) the intent of the investigation; (2) compliance with requirements and restrictions regarding institutional review, informed consent and promotion and commercial distribution of investigational drugs; (3) the route of administration of the product as used in the investigation; and (4) protection of subjects’ health, safety and welfare. Under the FDA-Determined Exemption pathway, the sponsor can submit a request to FDA if the investigation did not meet one or more of the self-determined exemption’s health, safety and welfare criteria, but did meet all other criteria for the self-determined exemption. In the alternative, FDA can exempt a study on its own initiative if the sponsor submits an IND but FDA determines that the study met the IND exemption decision. Interested parties should submit comments on the proposed rule by March 9, 2023.

US District Court for the Southern District of Florida grants a motion for summary judgment by Zantac manufacturers in a multi-district litigation related to the presence of N-Nitrosodimethylamine (NDMA) in Zantac. The court granted the motion for summary judgment concurrently with its decision to exclude expert witness testimony that plaintiffs relied on to support their claims that the presence of NDMA in Zantac led to a swath of health issues. In its ruling, the court found that NDMA testing of Zantac pills by Plaintiffs’ expert was unreliable, and it took issue with factors that the experts considered when offering testimony. Ultimately, without reliable expert testimony that Zantac can cause the cancers that the plaintiffs alleged, the court granted summary judgment on their claims. A number of state court cases related to NDMA remain in place, but the decision to exclude expert witness testimony in this case marks a major victory for the Zantac manufacturers. FDA issued a series of alerts to patients and healthcare professionals related to the presence of nitrosamine above the Agency’s acceptable intake level in various medications starting in 2019 and issued a final guidance regarding nitrosamine impurities in 2020 (updated in 2021). Zantac’s manufacturers and generic manufacturers of ranitidine removed their products from the market following FDA’s nitrosamine alerts. The court considered FDA’s alerts and standards in its decision, but determined that one of the experts wrongfully interpreted FDA’s acceptable daily intake for NDMA when considering the risks NDMA posed to patients.

FDA finalizes E19 a Selective Approach to Safety Data Collection in Specific Late-Stage Pre-Approval or Post-Approval Clinical Trials, Guidance for Industry. The FDA recently published E19 A Selective Approach to Safety Data Collection in Specific Late-Stage Pre-Approval or Post-Approval Clinical Trials, Guidance for Industry. The guidance document seeks to align FDA’s standards regarding the use of selective safety data collection for clinical trials with international standards – specifically ICH guidelines. Selective safety data collection refers to the reduced collection of certain types of data in a clinical trial after thorough consideration of factors that would justify such an approach. Selective safety data collection enhances clinical trial efficiency, and FDA hopes that, by finalizing these standards, it may facilitate the conduct of large-scale efficacy and safety clinical trials with large numbers of participants and long-term follow-up. The guidance document outlines factors that contribute to a conclusion that the safety profile of a drug is sufficiently characterized to justify selective safety data collection and the data that should be collected when engaged in selective safety data collection. The guidance also examines, among other topics, the point at which a sponsor should discuss selective safety data collection with regulators and situations where the practice is appropriate. The guidance goes on to discuss implementation of selective safety data collection in different situations. For example, the guidance discusses the implementation of the practice for some populations in a clinical trial while using comprehensive data collection for others.

FDA issues new draft guidance on content of human factors information in medical device marketing submissions. FDA has issued a new draft guidance intended to help stakeholders and the Agency determine what human factors evaluation information should be included in marketing submissions for medical devices, including 510(k)s, de novo requests, PMAs (including supplements) and humanitarian device exemption applications. The draft guidance includes definitions relating to human factors and uses flowcharts, tables and text to guide submitters through a risk-based approach to recommend what human factors engineering information a submitter should include in their marketing submission; FDA refers to this risk-based approach as the Human Factors (HF) Submission Category. The draft guidance also lays out a seven-part recommended structure for presenting the human factors engineering information to FDA. Finally, the draft guidance provides hypothetical examples of scenarios to illustrate FDA’s risk-based approach to determining the HF Submission Category using the flowchart and its companion text. The draft guidance was developed taking into consideration stakeholder feedback on FDA’s prior draft guidance entitled List of Highest Priority Devices for Human Factors Review and supersedes same. When finalized, the guidance is intended to complement the Agency’s existing guidance, Applying Human Factors and Usability Engineering to Medical Devices, which FDA further intends to harmonize to conform with the latest draft guidance. The Agency anticipates it will take 60 days to operationalize the draft guidance; any marketing submissions received during that time need not, but may, include the new information described therein.

FDA hosts a virtual public meeting to address its role in the AAFCO feed ingredient definition process. Registration is now open for FDA’s virtual public meeting on February 9, 2023 to address the Agency’s role in the Association of American Feed Control Officials (AAFCO) feed ingredient definition process, which establishes and publishes AAFCO definitions for ingredients used in animal food. Under a memorandum of understanding between FDA and AAFCO, FDA provides scientific and technical advice on the suitability of new or modified ingredients to support the AAFCO feed ingredient definition process. While AAFCO’s ingredient definitions are not federal regulations and do not have the force or effect of federal law, most states incorporate the ingredients listed in the AAFCO Official Publication (OP) into their state laws, thereby facilitating the interstate marketing of animal food ingredients. Additional information about registration for the meeting, as well as how to submit written comments to the docket, can be found here.

FDA finalizes its 2017 draft guidance on Best Practices for Convening a GRAS Panel. FDA has finalized its 2017 draft guidance on Best Practices for Convening a GRAS Panel. Under the FD&C Act, any substance that directly or indirectly becomes a component or otherwise affects the characteristics of any food requires premarket approval by the agency, unless the substance is generally recognized as safe (GRAS) among qualified experts based on publicly available evidence (ie, that there is reasonable certainty that the substance is not harmful under the intended conditions of use). While a GRAS panel is not required and, in many cases, may not be necessary, some proponents wish to use a GRAS panel to provide acceptance of their GRAS conclusion. This guidance clarifies the difference between a GRAS panel and an FDA advisory committee and highlights best practices to help those interested in convening a GRAS panel, including identification of appropriate members, steps to reduce the risk of bias and ensuring the supporting information is publicly available.

FDA gives guidance to industry on how to list major food allergens. On November 30, FDA issued two guidance documents about food allergen labeling requirements, intended to help the food industry meet the requirement to list all significant food allergens on the labels of FDA-regulated foods. Federal law currently identifies eight foods as major food allergens: milk, eggs, fish, crustacean shellfish, tree nuts, peanuts, wheat, and soybeans. The Food Allergy Safety, Treatment, Education, and Research Act of 2021, adds sesame to the list, effective January 1, 2023, making it the ninth major food allergen recognized on the United States. The draft guidances include Q&As for manufacturers to help them meet the existing legal requirements. FDA said, “Food labels are a powerful tool to help protect consumers with food allergies. Consumers can avoid ingredients they may be allergic or sensitive to in a food by looking for specific allergen labeling and reading the ingredient list.”

FDA extends comment period on “healthy” rule. On November 30, FDA announced that it is extending the comment period for its proposed rule that would define the term “healthy” as a nutrient claim for a food. The proposed rule appeared in the Federal Register on September 29. The new deadline for comments is February 16, 2023. The agency said that it is extending the comment period by 50 days in response to a request from stakeholders to allow additional time for interested persons to develop and submit comments. The proposed rule would make more foods eligible to use the “healthy” claim, such as nuts and seeds, higher-fat fish (such as salmon), certain oils and water.

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