Q: What is the FDA doing to regulate intentional genomic alterations in animals?

A: On January 19, 2017, the FDA released draft revised Guidance for Industry (GFI) #187, “Regulation of Intentionally Altered Genomic DNA in Animals,” and requested public comment regarding the regulation of intentionally altered genomic DNA in animals, including animals produced through the use of genome editing technologies and genetic engineering. This draft revised guidance expands the scope of the existing GFI #187 to address animals with intentional genomic alterations (IGAs) developed through use of genome editing technologies, as well as techniques such as the introduction of rDNA constructs through genetic engineering. The public comment period is now closed.

Q: What is genome editing?

A: “Genome editing” is a term used to describe a relatively new set of technologies that enable one to make precise changes in the DNA of a plant, animal or other living organism. For example, such technologies can be used to introduce, remove, or substitute one or more specific nucleotides (letters in the DNA code) at a specific site in the organism’s genome. Genome editing is being performed using, for example, clustered regulatory interspersed short palindromic repeat associated nucleases (CRISPR), zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and oligonucleotide-directed mutagenesis (ODM).

Q: What is the difference between genome editing and genetic engineering?

A: Genome editing is a much more precise method of making changes to the genome of a plant, animal, or other living organism than methods used previously to make such changes. It also allows for the intentional addition, substitution, or deletion of specific nucleotides (letters in the DNA code) in an organism’s genome. Genetic engineering generally allows for the introduction of new DNA (referred to as a recombinant DNA or rDNA construct) into an organism to alter that organism’s genome, but generally without control of the location in the genome in which the insertion of that rDNA construct would occur. With genome editing, researchers and developers of products can direct the changes they wish to make to specific locations.

Q: When did the FDA first issue guidance on the regulation of genetically engineered animals?

A: The FDA first issued draft guidance on the regulation of genetically engineered (GE) animals and their products in 2008. (FDA used the term “GE” to describe the animals within the scope of that guidance to reflect the technology in use at the time. Because IGAs now can also be produced through newer technologies, we are using the more inclusive term, IGA.) After a public comment period, the agency issued final guidance #187 in 2009 to help industry understand the existing statutory and regulatory requirements as they apply to GE animals and to inform the public about the process FDA is using to regulate them.

Q: Why did FDA issue revised draft guidance #187?

A: As previously described, recent developments in science have resulted in new technologies that can be used to alter the genome of an animal in a way that is different from what FDA addressed as “genetic engineering” in the 2009 guidance.

This draft revised guidance issued in 2017 explains the FDA’s current thinking on regulation of IGAs in animals and clarifies the circumstances where, based on low risk, FDA does not expect sponsors to submit applications for approval. FDA is working to finalize the revised draft guidance. 

Q: How does the agency regulate IGAs in animals?

A: FDA generally regulates IGAs in animals, including IGAs produced by genetic engineering and genome editing, under the new animal drug provisions of the FD&C Act and FDA’s regulations for new animal drugs. What this means in practice is that FDA ensures that the IGA is safe for the animal, safe for anyone that may consume food from the animal, and that it is effective, i.e. it does what the developer claims it will do. For IGAs that we approve, we also assess the environmental impacts of approving the application and determine if any potential impacts are significant.  FDA’s review is science- and risk-based. Where we determine that an IGA product poses a low risk, we intend to exercise enforcement discretion and we do not expect that sponsors will submit an application for approval.

Q: When should developers of IGAs in animals first come to FDA?

A: Because the science around IGAs is rapidly developing, the FDA welcomes potential sponsors to consult with us about appropriate regulation of products. We encourage developers to contact us if they have any questions regarding whether the agency believes the IGAs in animals that they are developing are sufficiently low risk that we do not expect submission of an approval application or, if we do expect submission of an application, what type of data we expect in support of the application. For these reasons, we recommend that developers first come to the agency early in the development process; we can then work closely with them during the investigational phase of the development to ensure that animals do not inadvertently enter the food supply, and that data sets to address safety requirements are developed efficiently and appropriately.

Q: Are animals with IGAs “drugs”?

A: No, these animals themselves are not drugs. The agency regulates IGAs that are introduced into the animals’ genomes as new animal drugs because the IGA is intended to affect the structure or function of the altered animal. FDA determines whether the IGA that is contained in the animal is safe to the animal, safe to anyone that consumes food from the animal, and that it is effective.

Q. Why are plants and animals with intentionally altered genomic DNA being regulated differently?

A: There are different provisions of the law that apply to intentional genomic alterations in plants and animals. New varieties of plants produced with biotechnology, including genome editing, are regulated by three different agencies with different statutory mandates: the US Department of Agriculture, Animal Plant Health Inspection Service (USDA APHIS) regulates for plant pest risk under the Plant Protection Act; the Environmental Protection Agency regulates plant incorporated protectants under the Federal Insecticide, Fungicide, and Rodenticide Act; and FDA regulates for food safety under the Federal Food, Drug, and Cosmetic Act (FD&C Act). In the case of products of animal biotechnology, FDA regulates IGAs in animals under its FD&C Act authority. FDA’s regulation of these animal products differs from its regulation of plant products because, under the law, FDA’s review for animals includes determining whether IGAs are safe to the target animal, in addition to a determination of food safety (for food-producing animals), and efficacy. This review of target animal safety is appropriate for products in animals whereas, for plants, FDA’s review is concerned with food safety, not plant safety.

Q: What are the elements of the approval process for IGAs in animals as described in GFI 187?

A: The draft revised guidance recommends the following with respect to approval applications for IGAs in animals, which do not differ significantly from those in current, final GFI #187:

• Product definition: a broad statement characterizing the animal, and the claim being made for the animal;
• Molecular characterization of the IGA: a description of the IGA and how it was produced;
• Molecular characterization of the animal lineage: a description of the method by which the genomic alteration was introduced into the animal and how it is passed on to any offspring;
• Phenotypic characterization of the animal: comprehensive data on the characteristics of the resulting animal and its health;
• Durability assessment and plan: the sponsor’s demonstration that the alteration is stable, and that it will remain the same over the lifetime of the product, while continuing to have the same effect.
• Environmental impact and food safety: the assessment of any environmental impacts, and for food-producing animals whose genomes have been intentionally altered, an assessment of the safety of food derived from those animals for humans and animals;
• Claim validation: a demonstration that the IGA achieves its intended effect.

Q: Is food from animals with IGAs being held to a different standard than food from plants produced from the same technologies?

A: Under the FD&C Act, food must be safe for consumption regardless of whether it is derived from plants or animals, or whether the genome of the plant or animal it is derived from has been intentionally altered. Although the regulatory process for food from animals with IGAs is different from that for food from plants with such altered DNA, as dictated by different statutory requirements, ultimately, they both must be safe to be marketed legally in the United States.

Q: What is the role of the various components of FDA with respect to IGAs in animals?

A: The FDA’s Center for Veterinary Medicine (CVM) is responsible for evaluating the safety and effectiveness of the IGA in the animal. This includes the effects of the IGA on the safety (i.e., health) of the resulting animal, as well as on the safety of foods from these animals, where relevant. In addition, CVM evaluates whether the IGA results in the effects that have been claimed (e.g., that the animal has a particular, different fatty acid profile or that a biopharm animal produces the pharmaceutical it is supposed to produce).

For animals producing substances to be used in or as drugs, biologics, or devices for use in humans, the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), or the Center for Devices and Radiological Health (CDRH), respectively, review such products. For animals producing substances to be used in or as veterinary biologics, USDA/APHIS regulates the veterinary biologic. In addition, CVM will consult with the Center for Food Safety and Applied Nutrition (CFSAN) on food safety issues during its review if a particular question arises for which CFSAN has expertise.

Q: Is FDA working with other federal agencies on the regulation of products developed through genome editing?

A: FDA works closely with EPA and USDA/APHIS on various issues related to the regulation of products of biotechnology, including on genome editing. We intend to work cooperatively with other relevant agencies that may also be considering their policies or approaches related to genome editing applications within their jurisdictions.

Q: Why are some federal agencies proposing to regulate the products of genome editing differently from FDA?

A: There may be some differences among the agencies in how the products of genome editing are regulated. These are due in part to differences in the underlying statutory authorities and how those authorities relate to the kinds of risks that the products of genome editing may pose. (See response to question above, “Why are plants and animals with intentionally altered genomic DNA being regulated differently?”) Consistent with the Coordinated Framework for the Regulation of Biotechnology, we intend to work cooperatively with other relevant agencies that may also be considering their policies or approaches related to genome editing applications within their jurisdictions.

Q: How are animals with IGAs different from their conventional counterparts?

A: From a scientific perspective, the only intrinsic difference is that these animals contain an intentional alteration of the genome achieved using modern molecular technologies that gives them a new trait or characteristic, such as producing a pharmaceutical, being resistant to a disease, or growing faster. The degree of difference between these animals and their counterparts that do not have intentional genomic alterations will depend on the nature of new trait that the resulting animal possesses.

Q: Will these animals pass their new traits on to their offspring?

A: It depends. IGAs in animals that are developed to be passed on to their offspring are referred to as “heritable.” In general, IGAs are introduced at the early embryo stage or in cells that go on to make embryos that develop into the altered animal. The altered genome is heritable because it will be in every cell of the resulting animal, including those that are responsible for making sperm and egg for the next generation.

In other cases, IGAs are not intended to be inherited—for example, IGAs used for gene therapy in animals. These genomic alterations are not found in the germ cells of those animals, and their offspring will not contain the genomic alteration.

Q: How does FDA address potential environmental risks associated with IGAs in animals? Are concerns different for different kinds of animals?

A: Any potential environmental issues would be a function of the traits introduced into those animals and the conditions under which those animals would be raised. For example, a biopharm animal intended to be kept in a contained environment poses a different set of risks from an animal with an IGA that is intended to be released into the environment. FDA will consider potential environmental effects on a case-by-case basis as required by the National Environmental Policy Act. In general, we recommend that early in development sponsors consult FDA about potential environmental issues and that they consult with FDA prior to developing their approaches to environmental assessments so that we can agree on the risk questions to be addressed and the resulting scope of the environmental review.