The U.S. Food and Drug Administration (FDA) Center for Veterinary Medicine (CVM) is advancing ahead in growing the regulatory landscape for developers and sponsors of animals with investigational intentional genomic alterations (IGAs). In the past three years, the FDA has approved four animals with IGAs, a significant uptick compared to the three approvals in the prior 11 years. While the FDA CVM began approving requests for Investigational Food Use Authorization (IFUA) for animals with investigations IGAs in 2009, the recent acceleration of approvals reflects the FDA’s interest in keeping up with this ever-growing industry. Developers and sponsors of animals with IGAs for food use who are interested in bringing food product into the U.S. food supply chain can look to the guidance below during their IFUA process.

Alphabet Soup: IGAs and IFUAs with CVM

The FDA CVM is responsible for reviewing requests for IFUAs for animals with investigational IGAs. IGAs in animals are changes made to an animal’s genetic code using advanced methods, like genome editing or rDNA technologies. When it comes to regulating the use of IGAs in animals for food, developers and sponsors must obtain an IFUA from CVM, which allows things like meat, milk, eggs, and honey (sometimes referred to as edible tissues) to be used as food if they come from treated investigational animals, meaning they contain an IGA. 

This regulation also extends to genetics passed on through breeding. For example, not only is a pig that contains investigational IGA in the genome as a result of genome editing considered a treated investigational animal, but if that pig were to breed with a nonaltered counterpart, the byproduct of that breeding would also be considered a treated investigational animal. This means that food product from either of these animals cannot enter the food supply without prior FDA authorization through an IFUA.

Past Approvals

From 2009 through 2015, the FDA approved three applications for animals with investigational IGAs. In 2009, the FDA approved the first IFUA for an animal with investigational IGAs—goats that were genetically modified to produce a protein in their milk intended to be used for anticlotting treatment in humans. The protein in the goat milk, antithrombin, is sometimes in short supply or unavailable for pharmaceutical use because of a shortage of human plasma donations. In 2015, the FDA approved chickens that were genetically modified to produce a drug in their eggs. The drug, Kanuma (sebelipase alfa), is a recombinant human enzyme marketed by Alexion Pharmaceuticals. It replaces a faulty enzyme in people with a rare, inherited condition that prevents the body from breaking down fatty molecules in cells. Also in 2015, the FDA approved the first animal with IGAs for eating—AquaAdvantage Salmon, that were genetically modified to grow more rapidly than conventional, farm-raised Atlantic salmon.

After a five-year lull, in 2020, the FDA approved a first-of-its-kind IGA in a line of domestic pigs (referred to as GalSafe pigs) which can be used for food and human therapeutics. This was the first animal with IGAs that the FDA had approved for both human food consumption and as a source for potential therapeutic uses. The IGA in GalSafe pigs is intended to eliminate alpha-gal sugar, which is found in red meat, on the surface of the pigs’ cells. As a result, GalSafe pigs are intended to be safe for consumption by people with mild to severe allergies to alpha-gel sugar. Also in 2020, the FDA approved a treatment for adults and adolescents with hemophilia, which contained an active ingredient obtained from rabbits genetically modified to produce the active ingredient in their milk.

Just two years later, in 2022, the FDA approved for marketing (including food) PRLR-SLICK cattle, a type of cattle with investigational IGAs intended to make its hair shorter and thus more resistant to heat stress. This was the FDA’s first low-risk determination for enforcement discretion for an IGA in an animal for food use. The developer of PRLR-SLICK cattle said it plans to make products from the cattle available for purchase as soon as 2024. And, on May 12, 2023, the FDA approved Washington State University’s application to market German-style sausages made from pigs that were gene-edited to improve their reproductive capacity.

The increased speed of approval—four approvals in the past three years, as opposed to three approvals in the prior 11 years—and the first approval of food from animals with IGAs shows promise for the regulatory progression of genetically altered animals for food.

IFUA Requests: Who, What, Where, When, Why, and How

Who and Why to Apply?

Any developer or sponsor of a genetically altered animal for food use with an investigational file established with the FDA can apply for an IFUA, either for human food or animal food (also called rendering). Before issuing a letter authorizing the food use of a specific set of animals, the FDA carefully evaluates data to ensure that there are no potential safety risks associated with the consumption of these food products, aiming to guarantee the safety of the food that enters the human food chain. IFUAs are beneficial to developers because they prevent wastage. Instead of disposing of animals or their products, IFUAs allow them to be used for food. This promotes efficient resource utilization and supports sustainable practices in agriculture and biotechnology.

What to Include?

IFUA requests for animals with investigational IGAs should justify that food derived from animals with IGAs is not expected to pose a food safety concern and should include information on the characterization of the IGA; description of the animals with IGAs; and potential food consumption-related hazards to humans and animals.

CVM has provided guidance on the types of data and information that may be submitted and that they review in IFUA requests, noting, however, that these were not requirements—just examples of what might support an IFUA request and what helps CVM in its regulatory decision making. 

General Information

• Assess the safety concerns associated with consumption of food derived from animals with IGAs (both direct and indirect toxicity) by identifying and characterizing hazards, as well as looking at exposure to hazards.
• Conduct food safety evaluations that involve assessing any potential direct or indirect effects on food safety from the genotypic/phenotypic changes; and whether food derived from the animal with an IGA is comparable to that without an IGA.
• Review basic descriptive information, such as: species and class of animals intended for food; number of investigational animals planned to introduce to the food supply; genotypic information (e.g., zygosity); and generation (if applicable).

IGA Information

• Review information that describes overall nature of the IGA and how it was introduced into the animal (also called hazard identification and characterization review), including: description of the alteration (e.g., insertion, deletion, or substitution of DNA sequences that may or may not result in an expressed protein with novel function or loss of function, inactivation, or a knockout of a gene); any introduction of exogenous DNA that may impact food (e.g., rDNA construct); intended phenotype in the animal; whether, if offspring were produced, the genotype and phenotype will be inherited as expected in the offspring; and whether the IGA correctly targeted the desired locus with expected alteration.
• Review animal safety information, including: health records, observations, and psychological status of the animals compared to animals without IGAs; animal safety information used to assess direct/indirect toxicity that may have resulted from the IGA; and, if available, data from generation(s) close that intended for slaughter.

Food Safety Concerns

• For human food, assess potential human food safety concerns, such as: whether the IGA affects the compositional content of the edible product, including justification based on genomic or expression data and compositional or nutritional content of the edible tissues derived from the animals with IGAs compared to unmodified animals; and whether the IGA will result in consumption of a human allergen or toxic substance(s);
• For rendering, assess potential hazard for animal food, such as: how potential hazards will be mitigated (e.g., time, temperature, pressure in rendering process); whether the potential hazard concentrate in the resulting rendered material, and if so, what stream it is likely found in (e.g., meat and bone meal, feather meal, fat product); and if potential hazard cannot be mitigated, whether the potential hazard is likely to bioaccumulate in tissues—thereby posing a human food safety concern.

CVM also encourages developers and sponsors to reach out to CVM ahead of applying for an IGA for discussions on the specific data expectations for a particular product. 

When, Where, and How to Apply

IFUA requests are submitted electronically to CVM’s submission gateway known as eSubmitter. Once an IFUA request is submitted for animals with IGAs, the submission is then routed to the Division of Animal Bioengineering and Cellular Therapies, and an animal biotechnology reviewer will be assigned the lead reviewer for the request. Following their review of the request, CVM will send a letter granting or denying the IFUA request, or in some situations, may request additional information in order to complete the evaluation. CVM says that developers should allot three to four months between when they submit the request and when they plan to send animals for slaughter or rendering. 

Regarding additional requirements, opening an investigational file for the development of IGAs in animals is considered an agency action under the National Environmental Policy Act (NEPA), which triggers the need to prepare an environmental assessment (EA) or submit a claim of categorical exclusion (CE) from the requirement. CVM recommends that developers complete their obligations under NEPA (either submitting an EA or claiming a CE) prior to requesting an IFUA.

CVM’s typical practice is to request information on all facilities that would house animals with IGAs prior to shipment in order to address environmental containment and exposure risks. However, CVM said it is working to streamline this approach to increase efficiency. If an IFUA is granted, the U.S. Department of Agriculture (USDA)’s Food Safety and Inspection Service (FSIS) will be notified by the FDA if the slaughter of the animal authorized is subject to inspection by FSIS. The developer or sponsor must also notify FSIS and the FDA 10 days before sending the animals to slaughter.

Lastly, developers and sponsors will need to report to CVM any adverse reactions that may suggest a safety hazard with the IGAs in animals intended for food.

Are You a VIP?

In 2009, at around the same time of the first animal with investigational IGAs approval, the FDA created its Veterinary Innovation Program (VIP), which sits within CVM and focuses on providing greater certainty in the regulatory process, encouraging development and research of innovative public health products, as well as supporting an efficient and predictable pathway to the approval of IGAs in animals. The VIP provides intensive assistance and enhanced review efficiency for developers of IGAs in animals, including intensive interaction with CVM project managers, a CVM review team, pre-investigational development, pre- and post-review feedback, as well as the ability to stop the typical 180-day clock during the review of major technical section submissions. To determine whether a certain product can be in the VIP, the FDA recommends contact CVM as early as possible in the development process.

Key Takeaways for Developers and Sponsors

If a developer or sponsor of animals with investigational IGAs is interested in bringing food from those animals into the U.S. food supply chain, they will need to request an IFUA with CVM. They should reach out to CVM at least three to four months before they plan to slaughter or render to ensure they have the proper information necessary for CVM to decide their IFUA request, including certain requirements under NEPA and through the USDA. Wilson Sonsini’s FDA regulatory practice can help you through this process. 

We will continue to monitor CVM guidance and developments for the regulation of food from animals with investigational IGAs. The field of genetically altered animals for food use sits at the active intersection of biotechnology, sustainability, and agriculture, for which Wilson Sonsini is squarely qualified to counsel on. If you have any questions, please contact Georgia Ravitz, James Ravitz,  Eva Yin, Paul Gadiock, Marissa Hill Daley, or any member of the firm’s FDA regulatory, healthcare, and consumer products practice.

Georgia Ravitz and Marissa Hill Daley contributed to the preparation of this Wilson Sonsini Alert.