FDA Finalizes Guidance on its Approval Process for Intentional Genomic Alterations in Animals, Proposes Framework for Regulating Alterations in Food-Producing Disease Models

On January 7, 2025, the U.S. Food and Drug Administration’s (FDA or Agency) Center for Veterinary Medicine (CVM or Center) announced the availability of two Guidances for Industry (GFI) regarding heritable intentional genomic alterations in animals: (1) Final GFI#187B, Heritable Intentional Genomic Alterations in Animals: the Approval Process (Final GFI #187B), and (2) Draft GFI #251, Heritable Intentional Genomic Alterations in Animals of Food Producing Species for Use as Models of Disease (Draft GFI #251). While Final GFI #187B largely follows the draft version, the final guidance provides further detail on key topics, including the types of intentional genomic alterations (IGAs) that may be included in a single application and the data and information that sponsors should provide as part of CVM’s pre-approval assessment process. Draft GFI #251 articulates CVM’s policy on heritable IGAs in food-producing animals that are intended to be marketed for use as models of human or animal disease in biomedical research under contained and controlled conditions. Together, these GFIs further describe CVM’s approach to regulating IGAs in food-producing animals in commercial and research settings. Interested parties should submit comments on Draft GFI #251 by March 10, 2025.

Final GFI #187B – Heritable Intentional Genomic Alterations in Animals: the Approval Process

Background

As we previously reported, CVM announced in May 2024 that it had revised and reissued its guidance on the regulation of heritable IGAs in animals, GFI#187, into two parts. The first part—final GFI #187A, “Heritable Intentional Genomic Alterations in Animals: Risk-Based Approach”—outlines CVM’s updated risk-based approach to regulating heritable IGAs in animals, including circumstances in which FDA intends to exercise enforcement discretion with respect to the marketing and distribution of an IGA in animals without prior approval. GFI#187A delineates three categories of IGAs in animals based on risk and states that CVM expects developers to submit applications for premarket approval (i.e., new animal drug applications) for “Category 3” IGAs. The second part of GFI#187 is GFI #187B, “Heritable Intentional Genomic Alterations in Animals: The Approval Process.” GFI #187B provides technical guidance on CVM’s approval process for IGAs in animals and was first issued as a draft guidance. 

As stated in Draft GFI #187B, CVM solicited comments on the draft guidance to enable it to update, and make as efficient as possible, the approval process for IGAs in animals. Specifically, CVM invited comment on (1) how a developer can demonstrate the durability of a heritable IGA over time in situations where collection of data on multiple generations of animals is difficult or not possible, (2) possible strategies a developer could utilize to address the approval requirements for multiple heritable IGAs under a single approval, (3) which areas of current good manufacturing practices and good laboratory practices specific to the production of heritable IGAs in animals require additional clarification, and (4) which process improvements would make the approval process easier to navigate.^[1]

CVM received around 5,000 comments on Draft GFI #187B. After considering these comments, CVM issued Final GFI #187B on January 7, 2025.

Key Updates in Final GFI #187B

While Final GFI #187B largely follows the draft guidance, CVM provides further clarification on the following key topics.

What types of IGAs may be covered in a single application

CVM maintains its position that each specific IGA is a separate article subject to approval requirements, but the Center may consider multiple IGAs in a single application. Final GFI #187B clarifies the circumstances under which CVM may consider a specific combination of multiple IGAs under a single application. For example, CVM may consider multiple IGAs in one animal species under a single application if all of the IGAs are present in the commercialized animal and they contribute to the same intended use. CVM also may consider IGAs in multiple lines or breeds of animals under a single application when such lines or breeds are not significantly genetically different. CVM continues to recommend that sponsors interested in including multiple IGAs or lines of animals in a single application first contact CVM to further discuss this regulatory option.

Environmental considerations regarding investigational use of IGAs in animals

With respect to the investigational use of IGAs in animals, CVM retains its recommendations regarding shipping and labeling investigational animals and their products, animal disposition, investigational food-use authorizations, and environmental considerations. CVM clarifies that for requests for categorical exclusion from the requirement to provide an environmental assessment, sponsors should provide, at minimum, a description of the number of containment measures and their redundancy. CVM continues to underscore that such considerations will vary depending upon the animal.

Pre-approval assessment process

While CVM’s technical guidance on the specific information that should be included in applications largely mirrors the draft guidance, CVM provides further clarification on its recommended process for completing pre-approval assessments for IGAs in animals. Specifically, CVM supplements its recommendations on the data and information that should be provided regarding molecular characterization of the lineage(s) of animals with IGAs and phenotypic characterization of animals with IGAs. In addition, CVM clarifies that durability plans should include validated genotypic and phenotypic durability methods, and the Center provides further explanation regarding the difference between the two. CVM also explains that its evaluation of the product characterization components of the application (i.e., product identification, molecular characterization of the IGA and of the lineage(s) of animals with the IGAs, and phenotypical characterization of animals with IGAs) should inform the scope of the food safety evaluation. More specifically, CVM evaluates the impact of the IGA and any unintended alterations that result from the introduction of the IGA into the animal’s genome, as well as the animal’s overall health with respect to food safety. For example, if the IGA results in the expression of a protein in a food-producing animal’s edible tissues, CVM may expect the sponsor to provide information regarding the digestibility and stability of the protein in the human gastrointestinal tract and its potential for causing human allergy.

Import tolerances

CVM retains its discussion of the applicability of FDA’s import tolerance authorities to safe residue levels of IGAs in animals and any substance formed in or on food as a result of use of the IGA. The Center further clarifies that an IGA that is the subject of an import tolerance may be one that is approved in another country or its use may otherwise be lawful in another country, and that any entity (e.g., the sponsor, a government entity, or a private organization) may request such an import tolerance.

Draft GFI #251 – Heritable Intentional Genomic Alterations in Animals of Food Producing Species for Use as Models of Disease

Background

CVM also issued Draft GFI #251 on January 7, 2025. Draft GFI #251 outlines the factors CVM will consider in determining whether it will exercise enforcement discretion with respect to the requirement for premarket approval for IGAs in animals of food-producing species that are intended for use as models of disease in biomedical research under contained and controlled conditions (IGAs in animal models of disease). In general, CVM considers IGAs in animal models of disease to fall within “Category 2” under its risk-based approach outlined in GFI #187A^[2] because animal models of disease are unlikely to enter the food supply or to escape and establish themselves in the environment.

Key Elements of Draft GFI #251

In describing the scope of the draft guidance, CVM maintains that if a species, such as swine or rabbits, “is food-producing, then all members of that species are considered food-producing even if particular breeds are lines are not ordinarily raised for food” and even if the animals are solely used in biomedical research settings. 

Under Draft GFI #251, CVM intends to consider several factors related to safety, exposure/ release risk, and other safety issues when making a Category 2 determination. With respect to safety, CVM will consider, among other things, (1) whether there is anything about the IGA itself that may pose an unintentional human, target animal, or environmental risk; (2) whether the IGA contains new sequences or deletes existing sequences that can indirectly affect the health of the animal (e.g., create a disease condition other than the intended one); (3) whether appropriate control and oversight is in place to ensure the adequate health and wellbeing of altered animals; (4) whether there are concerns over the disposition or disposal of the animals with the IGAs that could pose human, animal, or environmental risks. 

Regarding exposure/release risk, CVM will consider questions regarding (1) containment of altered animals; (2) developer commitments to keep the altered animals out of the human and animal food supply; (3) procedures in place when shipping altered animals; and (3) systems for disposing of animals, carcasses, and materials derived from altered animals. On the topic of other safety issues, CVM will determine whether the developer of IGAs in animals, or any recipients of such animals, encountered unanticipated safety problems. 

CVM intends to make a Category 2 determination and send a written response within 180 days. CVM states that it intends to update its guidance to reflect newer technologies, as well as improvements to existing technologies, as necessary.

CVM also notes that any inquiries or information concerning the applicability of the Draft GFI #251 or the categorization of a specific IGA should be submitted to a Type VII Veterinary Master File, which does not require the payment of user fees, rather than an investigational file. CVM describes the use of Type VII Veterinary Master Files for this and other purposes for which an investigational file is not necessary in the recently-released Draft GFI #260, Type VII Veterinary Master File for Research and Development and Risk Reviews.

Interested parties should submit comments on Draft GFI #251 by March 10, 2025.

If you have any questions concerning the material discussed in this client alert, please contact the members of our Animal Food and Drug practice.