FDA Regulatory News and Trends - April 3, 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.

New guidance on animal studies for medical devices. On March 23, 2023, the Center for Devices and Radiological Health (CDRH) released a guidance document related to animal studies titled, “General Considerations for Animal Studies Intended to Evaluate Medical Devices.” The document applies to animal studies intended to assess device safety in premarket submissions and provides useful insight into what FDA recommends for a wide range of animal study issues, including personnel, study planning and conduct, test facility selection, animal housing, records and reports, and submissions to the Agency. The document supersedes and greatly expands upon a 2010 guidance that was specific to cardiovascular devices. It also notes that FDA maintains a memorandum of understanding with the Animal and Plant Health Inspection Service, an agency within the US Department of Agriculture, and the National Institutes of Health that facilitates coordination and cooperation on animal welfare issues.

Overhauled Part 11 Q&A draft guidance. FDA has published a revised draft guidance titled, “Electronic Systems, Electronic Records, and Electronic Signatures in Clinical Investigations: Questions and Answers.” This replaces a similarly titled 2017 question-and-answer draft guidance with wide-ranging updates. The latest publication is effectively a rewrite which takes recent technological advances into account. In particular, the revised draft guidance considers how data obtained remotely using digital health technologies (DHTs) can comply with Part 11. Other notable updates include expanded discussions around the implementation of audit trails and recommendations regarding a risk-based approach for validating electronic systems. The recent release also includes a more fulsome glossary, setting out definitions for various new key terms which are aligned with other recent FDA guidance documents. When finalized, the guidance will supersede FDA’s May 2007 guidance on Computerized Systems Used in Clinical Investigations. For those interested in submitting feedback on the revised draft guidance, comments are due by May 15, 2023.

Warning Letter issued to pharmaceutical "broker" ElectRx. On March 2, 2023, FDA's Center for Drug Evaluation and Research issued a Warning Letter to ElectRx and Health Solutions LLC (ElectRx) for causing the introduction of unapproved new drugs and misbranded drugs into interstate commerce. In its letter, FDA explained that ElectRx “acts as a broker between foreign pharmacies and employee-sponsored health insurance plans to provide enrolled employees with prescription drugs.” FDA found that ElectRX had a practice of substituting drugs prescribed by the employee's physician with unapproved versions from foreign sources. With certain exceptions that do not apply here, new drugs may not be introduced or delivered for introduction into interstate commerce without prior approval from FDA, as described in section 505(a) of the FD&C Act [21 U.S.C. § 355(a)]. The Agency noted several risks associated with that practice, including that subjects may have dangerous drug interactions and that physicians may make decisions under the impression that the originally prescribed drug is being used.

Draft guidance on accelerated approval of oncology therapeutics. On March 24, 2023, FDA published a draft guidance titled, “Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics.” Commonly used for oncology and hematology indications, the accelerated approval pathway provides patients with serious and life-threatening cancer based on surrogate or intermediate clinical endpoints. The new draft guidance is part of FDA’s recent effort to rein in accelerated approvals. Specifically, the proposed guidance favors randomized controlled trials over single-arm trials and provides two recommendations on how sponsors can conduct randomized controlled trials. First, sponsors can “conduct separate randomized controlled trials – one trial with an early endpoint (e.g., response rate) to support the accelerated approval of the drug and a second trial powered for a longer-term clinical endpoint (e.g., progression-free survival (PFS) or overall survival (OS)) to verify clinical benefit.” Alternatively, “sponsors could design a single randomized controlled trial to support accelerated approval, that is also powered for the longer-term clinical endpoint with follow-up in the same trial to verify clinical benefit (i.e., “one-trial” approach).” Besides trial design, the draft guidance also encourages sponsors to enroll patients in the early stage of their diseases, a shift from previous practices where accelerated approval primarily focuses on patients with advanced-stage – or refractory – disease.

Revised guidance on medical food. On March 15, 2023, FDA published revised guidance on medical regulation and frequently asked questions. This is the third edition of this guidance document, which was updated to “include updates on allergens.” Specifically, question 6, which addresses labeling requirements for medical foods, was updated to require “allergen information” when necessary. In addition, questions 8 and 9 were updated to reflect regulatory information and the two recent FDA guidance documents regarding food allergens.

International Council for Harmonisation (ICH) adopts guideline for gene therapy products.  On March 17, 2023, ICH announced that the guideline, “S12: Nonclinical Biodistribution Considerations for Gene Therapy Products,” reached step four in ICH’s process, meaning that the guideline is now ready for jurisdictions to adopt.  This topic was endorsed by the ICH Assembly in June 2019, and a draft guideline was released in June 2021.  The guideline is intended to provide harmonized recommendations for the conduct of nonclinical biodistribution studies in the development of gene therapy products, and it includes recommendations for nonclinical biodistribution study design as well as considerations for the interpretation of data to support nonclinical program development and clinical trial design.  The guideline was drafted in accordance with the “3Rs” – reduce/refine/replace – to avoid the unnecessary use of animals in nonclinical studies. 

With the PHE declaration expiration imminent, FDA clarifies the effect on the Agency’s pandemic-related guidance. This month, FDA issued a notice titled, “Guidance Documents Related to Coronavirus Disease 2019 (COVID-19),” intended to provide clarity on the fate of 72 public health emergency-related guidance documents, as the PHE declaration is set to expire in May. In its immediately-in-effect guidances that were issued as part of the pandemic response, FDA has stated that the guidances are in force “for the duration of the public health emergency (related to Covid-19).” As relevant needs and circumstances evolved throughout the COVID-19 PHE, and as early-pandemic issues have stabilized, certain FDA guidances must be amended or withdrawn. Accordingly, FDA has categorized its guidance documents into those that will immediately expire with the PHE; those to be revised to remain in effect for 180 days following PHE declaration expiration; those to be revised during that 180-day period; and those that will not be revised but will remain in effect, because they are not tied to the end of the PHE. Through this evaluation and classification of guidance documents, FDA expects to provide stakeholders time to transition from policies adopted and operations implemented during the COVID-19 PHE.

FDA requests comments on annual reporting requirements for custom devices. On March 13, 2023, FDA issued a call for public comment on the requirements for annual reporting for devices qualifying under the custom device exemption to premarket review. Section 520(b) of the Food Drug and Cosmetic Act lists several criteria defining a custom device, but, in essence, these devices are created or modified in order to comply with the order of a physician or dentist to treat a unique pathology or physiological condition that no other device is domestically available to treat. In addition, the production of the device must be limited to no more than five units per year. Annual reporting is required for this type of device, and the recent FDA request for comments seeks input from industry on the requirements for content in the annual reports. Comments are due by May 12, 2023.

FDA announces conforming changes to its regulations to incorporate the amended definition of “tobacco product.”  In March 2022, the Consolidated Appropriations Act of 2022 amended the term “tobacco product” in the Food, Drug and Cosmetic Act to capture synthetic nicotine products (eg, “products that contain nicotine from any source”), which were left out of the Family Smoking Prevention and Tobacco Control Act (TCA)’s original definition (“made or derived from tobacco”).  The definition amended reflected the first re-opening of the TCA since it became law in 2009, giving FDA jurisdiction for the first time to regulate tobacco products.

Covis withdraws Makena from the market. Following months of uncertainty, Covis Pharma, manufacturers of Makena, will withdraw its preterm birth drug from the market. Last year, the Obstetrics, Reproductive and Urologic Drugs Advisory Committee voted 14-1 that the drug should no longer remain on the market.  The FDA has not indicated that it would remove the drug from the market following the October advisory committee vote, but Covis, in a recent letter to FDA, mentioned a proposed wind-down plan and a desire to orderly withdraw its product from the market in the next few months. While FDA still has not issued a final determination on Makena’s market status following the advisory committee vote, accelerated approval application holders have been monitoring the situation with great interest. Makena’s struggles with confirmatory trials and FDA’s activity served as a measuring stick for what steps FDA might take with other accelerated approval drugs that struggle to demonstrate efficacy in confirmatory trials. By voluntarily removing its product from the market, Covis avoids becoming the first company to have a product unilaterally removed from the market by FDA through the process outlined in the accelerated approval rules.