FDA Updates its Approach to Genomic Alterations in Animals

On May 1, 2024, the U.S. Food and Drug Administration’s (FDA’s) Center for Veterinary Medicine (CVM) announced that it has revised and issued Guidance for Industry (GFI) #187 in two parts: final GFI #187A, “Heritable Intentional Genomic Alterations in Animals: Risk-Based Approach” and, a companion draft GFI #187B, “Heritable Intentional Genomic Alterations in Animals: The Approval Process.” GFI #187A articulates CVM’s updated risk-based approach to heritable intentional genomic alterations (IGAs) in animals, which provides for greater flexibility in the development and commercialization of IGAs in animals, drawing from precedent over the course of many years. Draft GFI #187B provides technical guidance on CVM’s approval process for IGAs in animals. FDA also released a Memorandum of Understanding (MOU) with the U.S. Department of Agriculture (USDA) to clarify the roles and responsibilities of each agency in the regulation of IGAs in animals subject to USDA jurisdiction,^[1] which is a subject that has been in flux since the previous administration. CVM’s overarching goal in issuing these materials is to modernize its approach to evaluating and facilitating the development of innovative animal and veterinary products including by expanding flexibility and improving predictability and efficiency. In addition, CVM underscores that IGAs in animals hold great potential for a range of uses, including animal disease resistance, control of zoonotic disease transmission, improved animal welfare, and increased food production and quality.

Background

For over 15 years, CVM has regulated IGAs in animals under the new animal “drug” provisions of the Federal Food, Drug, and Cosmetic Act (FDCA), as explained in its GFI #187, which CVM first issued as draft guidance in 2008 and subsequently finalized in 2009. As originally issued, GFI #187 outlined CVM’s approach to regulating genetically engineered (GE) animals containing heritable recombinant DNA constructs.

Based on advances in biotechnology, CVM updated IGF #187 in early 2017 to include animals with IGAs developed through genome editing and other newer techniques within the scope of the guidance. As the application of IGAs in animals has grown, particularly in livestock, CVM’s regulatory approach has drawn criticism from some groups as being overly burdensome and ill-suited to animal agriculture. In 2018, as part of FDA’s Plant and Animal Biotechnology Innovation Action Plan, CVM announced that it would release updated guidance to clarify its approach to the regulation of IGAs in animals based on risk-based categories. On December 28, 2020, however, USDA’s Animal and Plant Health Inspection Service (APHIS) and Food Safety and Inspection Service (FSIS) issued an Advance Notice of Proposed Rulemaking (ANPR) proposing a framework for oversight of GE animals intended for food and other agricultural purposes governed by USDA rather than FDA, pursuant to USDA’s statutory authorities under the Animal Health Protection Act (AHPA), Federal Meat Inspection Act (FMIA), and Poultry Product Inspection Act (PPIA). Proponents of the shift in oversight argued, among other things, that USDA was better suited to oversee such animals based on its program for reviewing GE plants. Less than three weeks later, and in the final days of the Trump Administration, on January 19, 2021, USDA and HHS released an MOU shifting regulatory responsibility for GE animals that are intended for food and other agricultural purposes from FDA to USDA, without rulemaking or agreement from FDA. In response, then-FDA Commissioner, Dr. Stephen Hahn, stated that “FDA does not support the Memorandum of Understanding” and “has no intention of abdicating [its] public health mandate.”^[2] While the Biden Administration did not implement the MOU, it did, via USDA, reopen the comment period for the ANPR in March 2021, indicating it could take some action to shift oversight from FDA to USDA.

FDA-USDA MOU on IGAs in Animals

The MOU released on May 1, 2024, which is signed by officials from both FDA and USDA, settles the jurisdictional limbo between the agencies by keeping the primary regulation of IGAs in animals under FDA, while clarifying and expanding the roles and responsibilities of USDA particularly during FDA’s premarket review process. The MOU states that under the FDCA, FDA reviews and approves premarket approval applications for IGAs in animals and reviews other IGAs to determine whether, based on a review of data and information, it intends to exercise enforcement discretion over premarket approval requirements for such IGAs (as described in FDA GFI #187A). As part of its review, FDA ensures that IGAs are safe to the animal and humans that eat foods derived from the animal, and that they are effective for their intended use.

USDA, including its various branches, maintains primary oversight over the safety, inspection, and labeling of foods derived from amenable species as well as other matters subject to USDA regulation. More specifically, FSIS is responsible for ensuring the safety of foods derived from amenable species including those with IGAs and that their labeling is truthful and not misleading, under the FMIA, PPIA, and the Egg Products Inspection Act. APHIS is responsible for preventing the introduction or dissemination of any pest or disease of livestock including those produced from IGAs in non-amenable species, pursuant to the AHPA. Lastly, USDA’s Agricultural Marketing Service (AMS) is responsible for implementing and enforcing the National Bioengineered Food Disclosure Standard including as applied to food products from animals with IGAs.

Under the MOU, FDA and USDA will exchange information about pending submissions for FDA approval or review of IGAs in amenable species and other animals subject to USDA jurisdiction. The MOU outlines the types of information and feedback FDA and USDA should provide to each other during the review process as well as related timelines. For example, FDA will notify USDA of the opening of an investigational or veterinary master file for an IGA in an amenable species, and USDA will determine whether FSIS, APHIS, or AMS should be included in consultations that the agencies “have determined should be held jointly with the developer.” For amenable species, FSIS also will review information provided by FDA on food safety and quality, and provide comments, if any, to FDA. For non-amenable species, upon first notification from FDA, USDA will determine whether it needs any technical sections or additional information to evaluate potential impacts on livestock health and will subsequently notify FDA of any disease concerns or whether there is a requirement under the AHPA for a developer to obtain a permit for any animals with IGAs. FDA and USDA will also meet to discuss the submission at various timepoints throughout the approval process.

CVM’s Risk-Based Approach to Heritable IGAs in Animals, GFI #187A

GFI #187A outlines CVM’s updated risk-based approach to regulating heritable IGAs in animals including how it will determine whether to exercise enforcement discretion. CVM delineates three categories of IGAs in animals based on risk:

• Category 1: No application expected, no prior review. CVM intends to exercise enforcement discretion over premarket approval requirements for IGAs in: (1) animals of nonfood-producing species that are regulated by other Federal government agencies (e.g., IGAs in insects regulated by APHIS); and (2) animals of nonfood-producing species that are raised and used in contained and controlled laboratory conditions for research (e.g., mice and rats). These IGAs are adequately regulated or pose negligible risk because the animals containing them are not likely to enter the food supply or the environment. Accordingly, CVM does not expect developers of such IGAs in animals to submit an application for approval or data on risk profile prior to marketing.
• Category 2: No application expected following prior review of risk factor data. CVM intends to exercise enforcement discretion over premarket approval requirements for other IGAs (including those in food-producing animals) if it determines that the IGA does not present a safety concern after reviewing risk factor information submitted by the developer. This information should compare the modified animal against an appropriate comparator (e.g., an unmodified comparator of the same species), and should include the methodology used to generate the IGA, characterization of the genomic sequence, and information on animal safety, food safety, and potential environmental impacts. In addition to posting a list of IGAs in animals for which it has made a Category 2 determination, CVM also describes certain types of IGAs that should fall within this category, including:
  • IGAs in food animals that are equivalent to genomic sequences in animals of the same species with a history of safe use in animal agriculture food production; and
  • IGAs in animals that are theoretically achievable through conventional breeding, result in no change to food composition or identified risks to humans, animals, or the environment, and for which the intended use does not affect animal or human disease or other health outcomes.

  For other types of IGAs, CVM will make a case-by-case determination as to whether the IGA belongs in Category 2 and lists several factors it will consider. CVM intends to respond to Category 2 determination requests within 180 days of receipt. CVM notes that in the future, it may issue additional guidance on Category 2 IGAs as well as information to help developers seeking to demonstrate that their IGA fits within this category.

• Category 3: IGAs for which FDA expects to receive an application for pre-market approval. For IGAs that do not fit within Category 1 or 2, CVM expects the developer to submit an application for premarket approval (i.e., a new animal drug application) pursuant to section 512 of the FDCA and CVM’s implementing regulations at 21 CFR part 512. GFI #187B provides guidance on the approval process as well as information needed to support an application.

CVM’s Technical Guidance on the Approval Process, Draft GFI #187B

The purpose of this draft guidance is to provide technical guidance for those IGAs in animals that go through the premarket approval process (i.e., Category 3 IGAs). The draft, in general, maintains the core elements of the 2017 draft GFI#187, including by providing guidance on requirements and procedures for investigational uses, premarket approval (including pre-approval assessments, specific application requirements, and related environmental assessments), and post-approval responsibilities. To ensure FDA considers comments to this draft GFI, comments should be submitted by July 31, 2024 (unless FDA extends the comment period).