Add a bookmark to get started

9 December 202214 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 requests input on regulatory and scientific issues related to potential naloxone Rx-to-OTC switch. Naloxone is a prescription-only emergency overdose treatment that, over time, has become increasingly accessible to the public. While these products still are not available over the counter, FDA recommends liberal prescription of the drug in light of the opioid epidemic public health emergency, since naloxone helps prevent death from opioid overdose. While the Agency has approved some naloxone kits for “community use,” and state laws have provided greater access to the product – often through third-party prescriptions – access to naloxone continues to be limited in some communities. This has prompted the FDA to open the door to sponsors interested in developing certain nonprescription naloxone products through an Rx-to-OTC switch, exempting the drugs from prescription-dispensing requirements. But this also raises several issues on which the agency is currently requesting input. Until January 15, 2023, the FDA is seeking comments on whether there might be a sufficient “clinically meaningful difference” between OTC and prescription versions of naloxone products for simultaneous marketing and the potential disruption to prescription access that might result upon OTC version approval (due to misbranding). The Agency is also asking for input on what sort of evidentiary support should be used to demonstrate that a prescription is not required, and, more specifically, what data would be needed to support safe and effective use of naloxone injection for various administration routes and doses. According to the Federal Register notice, the FDA likely plans to move ahead with any potential OTC naloxone approvals and to work with sponsors of existing prescription products to mitigate potential disruptions to access that could result from the switch.

FDA publishes draft amended Environmental Assessment for AquAdvantage Salmon. In November 2015, the FDA approved AquaBounty’s AquAdvantage Salmon (AAS), which grows more rapidly than conventional, farm-raised Atlantic salmon due to its intentional genomic alteration. Subsequently, FDA approved two supplements under the same new animal drug application – and prepared corresponding environmental assessments (EAs) – allowing for an AAS grow-out and the production of AAS eyed eggs at facilities in the US and Canada (in 2018 and 2019, respectively). As a result of a 2020 lawsuit challenging FDA’s environmental impact evaluations on the original approval, a court ordered FDA to reconsider its prior “no effect” determination and to perform an additional review of the AAS, particularly to evaluate whether AAS could be introduced into the wild and whether they pose any potential danger to wild salmon populations. Last month, FDA announced the availability of its responsive draft amended Environmental Assessment for AAS, in which the Agency has again concluded that there is a “negligible likelihood” that AAS would cause significant harms to the US environment. FDA is seeking public comment on the draft amended EA through January 17, 2023 and will also be soliciting input through a virtual public meeting on December 15, 2022.

FDA publishes a brand-new MAPP. The FDA has issued a new Manual of Policies and Procedures (MAPP) 5015.13, Quality Assessment for Products in Expedited Programs. Effective on December 7, 2022, the MAPP outlines policies and procedures on how the Office of Pharmaceutical Quality (OPQ) will offer regulatory flexibilities contemplated in 21 CFR 314.105(c) in order to overcome the CMC readiness challenges faced by products with accelerated clinical development timelines. Products with breakthrough therapy (BT) designation, fast track (FT) designation, eligible for the CMC readiness pilot program, or deemed “mission critical” are within the scope of this MAPP. However, accelerated approval or priority review alone would not be sufficient for this MAPP to apply. OPQ will conduct a risk assessment in applying the regulatory flexibility options and the final decision will be determined on a case-by-case basis. Factors considered by the OPQ include “clinical, nonclinical, and manufacturing information provided to meet the standards for approval regarding safety, effectiveness, and quality, including Current Good Manufacturing Practice (CGMP) requirements.” In addition, the sponsor’s compliance with relevant modern pharmaceutical principles, such as International Council for Harmonization (ICH), will be considered. The sponsor’s past compliance history, including inspection reports from foreign entities, will also be evaluated. Based on the facility risk assessment, OPQ can recommend accepting the facility, mitigating identified facility risks using remote regulatory, or conducting preapproval inspections (PAI) or pre-license inspections (PLI).

FDA offers greater marketing flexibility to certain sponsors of COVID-19 therapeutics. On October 27, 2022 FDA sent a memorandum to sponsors of COVID-19 therapeutics marketed under EUAs, offering greater flexibilities in advertisements and promotional materials of these products. Previously, FDA established stringent conditions on advertisements and other promotional descriptive printed matter for currently authorized COVID-19 therapeutics. For example, for all COVID-19 therapeutics, CDER stipulates that “No descriptive printed matter, advertising, or promotional materials relating to the use of Drug X under this authorization may represent or suggest that Drug X is safe or effective when used for <<authorized use>>.” Recognizing the stringent conditions may hinder sponsors’ ability to inform safety and efficacy data to health care providers and patients, the recent memo revised the agency’s approach by allowing dissemination of truthful and non-misleading printed matter, advertising, and promotional materials containing scientific information related to the authorized use of the product. The previous condition of authorization is now updated to reflect this recent change accordingly.

FDA-commissioned Medical Device Cybersecurity Playbook updated for 2022. At FDA’s request, MITRE has published an updated version of its 2018 Medical Device Cybersecurity Playbook to guide hospitals and other healthcare delivery organizations in maintaining operations in the face of growing ransomware attacks, the increased connectivity of medical devices, and continually evolving healthcare technologies. The playbook outlines how health delivery organizations (HDOs) can develop a primary cybersecurity preparedness and response program, and also provides a customizable framework which organizations can use to supplement their existing plans to better limit disruptions in the continuity of clinical care and the potential for direct patient harm stemming from medical device cybersecurity incidents. The 2022 version includes more explicit alignment with the Hospital Incident Command System for managing complex incidents as well as enhanced communications guidance, action options, considerations for handling widespread impacts and extended downtimes, and an appendix of resources. As part of the playbook update, a Quick Start Companion Guide was also developed to orient users in quickly identifying the key parts of the playbook to turn to during a cyber incident.

FDA finalizes guidance on referencing the definition of medical device. The Safeguarding Therapeutics Act (STA), which was signed into law on January 5, 2021, modifies section 201(h) of the Federal Food, Drug, and Cosmetic Act by moving the definition of “device” from section 201(h) to section 201(h)(1) and adding a section 201(h)(2) to provide a new definition of “counterfeit device.” FDA typically references the definition of “device” by referring to section 201(h) in statutes, regulations, guidance, other statements of policy, judicial filings, warning letters, untitled letters, and many other public documents, and with the changes under the STA, those references could cause confusion as to whether FDA means the definition of “device,” the definition of “counterfeit device,” or both. In order to minimize this potential confusion, FDA released a guidance, Referencing the Definition of ‘Device’ in the Federal Food, Drug, and Cosmetic Act in Guidance, Regulatory Documents, Communications, and Other Public Documents. on December 16, 2021, which was finalized on November 14, 2022. The guidance clarifies that generally, FDA’s reference to section 201(h), in both previous and future documents, should be interpreted as referring to the definition of “device,” not “counterfeit device,” and it recommends that industry follow the same approach. The guidance notes that, going forward, FDA may use the new citation 201(h)(1) or 201(h)(2) when referring to certain parts of the definition of “device.” The guidance also clarifies that reference to 201(h) in FDA documents discussing enforcement discretion does not mean that enforcement discretion extends to counterfeit devices, even if counterfeit devices may themselves meet the definition of “device.” The finalized guidance is largely the same as the draft guidance, but the final guidance adds examples of how FDA may use different citations under different circumstances.  

FDA to host public workshop on the appropriate use of consensus standards for medical devices. On December 7, 2022, FDA will host a webcast public workshop, “Appropriate Use of Consensus Standards,” to obtain public input on the appropriate use of voluntary consensus standards in premarket submissions for medical devices. The FDA Standards and Conformity Assessment Program plans to obtain input on three main questions: (1) Are there existing resources that FDA could improve to better assist medical device submitters with the use of standards in their device submissions (eg, guidance, websites)? If so, how can they be improved?  (2) What tools do medical device submitters need to help facilitate the use of FDA-recognized standards in their medical device submissions? and (3) What resources do medical device submitters need to encourage the appropriate use of standards in medical device submissions? Registration is required to attend the workshop, and registration must be complete by 4:00 pm ET on December 6, 2022.

FDA announces cybersecurity Modernization Action Plan. In response to the uptick in cybersecurity threats against FDA’s IT infrastructure during the pandemic, FDA has announced a Modernization Action Plan (MAP) in relation to cybersecurity, designed to help modernize FDA’s structures, processes, and systems. This cybersecurity MAP (or CMAP) joins three other MAPs (one for technology, one for data, and one for enterprise modernization). The CMAP outlines a series of strategic priorities for FDA’s enhancement of cybersecurity defenses, to protect data and capabilities. The priorities include enhancing interoperability and secure data exchange, promoting software assurance best practices, building a “zero trust” approach with integrated counterintelligence measures, leveraging artificial intelligence and machine learning to flag potential vulnerabilities, and investing in the agency’s cybersecurity workforce. FDA is hosting a digital transformation symposium in early December, which should provide some understanding on what had been accomplished under the MAPs to date and what can be expected going forward.

President Biden signs Medical Marijuana and Cannabidiol Research Expansion Act. On December 2, 2022, President Joe Biden signed HR 8454, the Medical Marijuana and Cannabidiol Research Expansion Act, into law. The Act establishes a new registration process for conducting research on marijuana and for manufacturing marijuana products for research purposes and drug development. Specifically, the Act creates a pathway for marijuana research without violating the Controlled Substances Act through a registration program with the US Department of Justice; requires DOJ to assess and address any shortages of supply of marijuana for research purposes; encourages communication between patients and physicians about the potential harms and benefits of cannabis; clarifies that companies can manufacture FDA-approved drug products; and requires HHS and the National Institutes of Health to report cannabis medical research.

New dietary ingredient denied over previous IND. The FDA issued a letter to a dietary supplement manufacturer rejecting a filing of a new dietary supplement ingredient, β-nicotinamide mononucleotide (NMN) due to another company’s prior submission of an Investigational New Drug Application (IND) for the same ingredient. The FDA also issued a follow-up letter to the manufacturer detailing certain findings in support of its rejection. The FDA explained that, under section 201(ff) of the FD&C Act, if an article has been authorized for investigation as a new drug for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public, the article may not be marketed as or in a dietary supplement unless the article was marketed as a dietary supplement or as a food before being authorized for investigation as a new drug. Because FDA received an IND for NMN before the ingredient was legally marketed as a dietary supplement ingredient, NMN could not be marketed as a new dietary supplement ingredient. FDA would not reveal the date it used as a reference for NMN’s use as an ingredient in an IND and would not release information about NMN INDs since those are considered confidential. Furthermore, FDA did not find arguments about previous marketing of NMN in the United States and Japan to be persuasive. The FDA found that previous marketing of NMN was done illegally since NMN had not been authorized as a new dietary ingredient. The FDA also stated that foreign marketing does not suffice to meet the prior marketing clause in section 201(ff) and that FDA cannot monitor sales or interpret statutes in other countries for the purpose of section 201(ff).

FDA requires in-progress and “ideally fully enrolled” Phase 3 study for accelerated approval filing. ADC Therapeutics reported that during a Type C meeting with the FDA in October, the FDA told the manufacturer that in order to submit its BLA for a pipeline biologic, the company must have a confirmatory Phase 3 study well under way and that ideally the trial would be fully enrolled at the time of the BLA filing. The biologic is being studied as a treatment for Hodgkin’s lymphoma.  The company announced that, due to the FDA’s statements regarding a fully enrolled trial during the Type C meeting, the company would have to evaluate its options for the investigational product. The company claims it would take two years to fully enroll the trial, but it was hoping to submit an accelerated approval application some time in 2023. The FDA’s comments come in the midst of FDA’s increased scrutiny of the accelerated approval pathway. FDA Commissioner Robert Califf has stated that the agency should require drugmakers to begin confirmatory trials before approval and has commented that the agency needs “more teeth” to withdraw accelerated approvals. He will have the chance to bare these teeth as he considers Makena’s withdrawal, which was recommended by the Obstetrics, Reproductive and Urologic Drugs Advisory Committee a few months ago.

First pre-market consultation for a human food made from cultured animal cells. On November 16, FDA announced it had completed its first pre-market consultation for a human food made from cultured animal cells. Through its voluntary pre-market consultation process, the agency evaluated a submission from UPSIDE Foods for food made from cultured chicken cells and had no further questions regarding the firm’s safety evaluation. This process included FDA’s evaluation of the firm’s production process and the cultured cell material made by the production process, including the establishment of cell lines and cell banks, manufacturing controls, and all components and inputs. Because this is a poultry product, a transition to USDA’s Food Safety Inspection Service (FSIS) will take place during the cell harvest stage, per the 2019 formal agreement between the two agencies. Under that agreement, FSIS will oversee the post-harvest processing and labeling of human food products derived from the cells of livestock and poultry, while FDA will oversee these activities for the fish and seafood products it regulates. FDA’s announcement is significant as it paves the way for future cell-cultured products. In its press statements, FDA is encouraging additional firms to reach out to the agency “often and early” in the development phase, well in advance of any formal submission. The agency has also stated that it will be issuing draft guidance to assist firms in preparing for the voluntary consultations.

Long-awaited traceability rule. On November 15, FDA issued the long-awaited Final Rule: Requirements for Additional Traceability Records for Certain Foods which establishes additional traceability recordkeeping requirements for those that manufacture, process, pack or hold certain foods. More specifically, the final rule identifies Key Activities or Critical Tracking Events (CTEs) along the supply chain where records containing Key Data Elements (KDEs) will have to be created and maintained for foods on the Food Traceability List (FTL). While the final rule is limited in scope by statute, it sets the stage for the agency’s ultimate vision of end-to-end traceability across the food supply. For additional information, see our alert.

Print