Q: What is the FDA doing to regulate animals with intentionally altered genomes?
A: On January 18, 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 animals with intentionally altered genomic DNA, including animals produced through the use of genome editing technologies or genetic engineering. This draft revised guidance expands the scope of the existing GFI # 187 to address animals with intentionally altered genomic DNA developed through use of genome editing technologies, as well as techniques such as rDNA in genetic engineering.
Q: What does the FDA mean by “intentionally altered genome/genomic DNA”?
A: The FDA defines these terms as alterations introduced into the DNA of an organism using modern molecular technologies, such as genetic engineering (also referred to as recombinant DNA technology) and genome editing.
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 allowed 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. In the Notice of Availability accompanying the draft revised GFI# 187, FDA is asking for public comment, including on whether there are classes of animals with intentionally altered genomic DNA for which there is little to no significant risk to the health of the animals or to uses of such animals resulting from the changes to their genomes.
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. 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 is the FDA issuing 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 explains the FDA’s current thinking on how the agency plans to regulate intentional genomic alterations in animals, clarifies FDA’s requirements and recommendations for producers and developers of these animals and their products, and describes how the new animal drug provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act) apply with respect to these animals. This draft revised guidance applies to the intentionally altered genomic DNA in both the founder animal in which the initial alteration event occurred and the entire subsequent lineage of animals that contains the genomic alteration.
FDA has requested comment in the Notice of Availability accompanying this guidance on whether there are categories of intentional genomic alterations in animals that are low risk. Based on the comments received, FDA may modify the approach described in this draft revised guidance. Additionally, as part of a commitment under the September 2016 National Strategy for Modernizing the Regulatory System for
Biotechnology Products, FDA, together with EPA and USDA, commissioned an independent study by the National Academy of Sciences (NAS) titled, "Future Biotechnology Products and Opportunities to Enhance Capabilities of the Biotechnology Regulatory System.” FDA will also consider the findings of this study when finalizing the guidance.
FDA has also determined that it would be appropriate to announce concurrently the availability of draft guidance GFI 236, which clarifies that products intended for preventing, destroying, repelling or mitigating mosquitoes for population control are excluded from the new animal drug definition, including those mosquito-related products with intentionally altered genomic DNA.
Q: How does the agency regulate animals with intentionally altered genomic DNA?
A: FDA generally regulates animals with intentionally altered genomic DNA, including genetically engineered animals, under the new animal drug provisions of the FD&C Act and FDA’s regulations for new animal drugs. This guidance is intended to help developers understand the statutory and regulatory requirements as they apply to these animals, including those of the National Environmental Policy Act (NEPA), to inform the public about the process FDA is using to regulate animals with intentionally altered genomic DNA, and to gather input from the public and developers. Before finalizing the guidance, FDA may modify its regulatory approach in response to comments it receives.
Q: Is the FDA planning to regulate animals that are developed using genome editing technologies differently from how the agency regulates genetically engineered animals as defined in current Guidance #187?
A: Draft revised guidance #187 clarifies that FDA’s regulatory approach encompasses animals with intentionally altered genomic DNA—whether the product of genetic engineering or “genome editing.” The agency is seeking comment on this draft revision, as well as the questions asked in the Notice of Availability for this draft revised guidance regarding scientific evidence indicating whether certain categories of genome edited animals will pose little to no significant risk. Based on the comments received, the agency will consider whether and how to adapt the approach described in the draft revised guidance.
In general, the agency considers genomic alteration to meet the definition of a New Animal Drug, unless otherwise excluded, because it is intended to affect the structure or function of the animal. However, the agency has not and does not intend to enforce the Investigational New Animal Drug or New Animal Drug Application requirements for certain animals, including those of non-food-species that are raised and used in contained and controlled conditions, such as laboratory animals used in research.
Q: When should developers of animals with intentionally altered genomic DNA, including genetically engineered animals, first come to FDA?
A: Because the science around genomic alterations is rapidly developing, the FDA welcomes potential sponsors to consult with the agency regarding appropriate regulation of their products. We encourage developers to contact FDA if they have any questions regarding whether animals with intentionally altered genomic DNA that they are developing, including genetically engineered animals, will need FDA premarket approval, whether FDA may exercise enforcement discretion over such articles, or whether another federal agency may regulate them instead. For these reasons, we recommend that developers first come to the agency early in the development of such animals; we can then work closely with them during the investigational phase of the development of these animals 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: Is FDA’s regulation of animals with intentionally altered genomic DNA and their products consistent with how FDA regulates conventional new animal drugs?
A: Yes. Because intentionally altered genomic DNA in animals, unless otherwise excluded, meets the definition of a drug under the FD&C Act, the same laws and regulations under which we regulate conventional new animal drugs also apply to these products. A major purpose of the guidance is to explain how the law and its implementing regulations apply to such animals.
Q: Are animals with intentionally altered genomic DNA “drugs”?
A: No, these animals themselves are not drugs. Rather, the agency is regulating animals with intentionally altered genomic DNA as containing new animal drugs. The FD&C Act defines a drug, in part, as “an article intended to affect the structure or any function of the body of … animals.” Unless otherwise excluded, an intentional genomic alteration is intended to affect the structure or function of an animal, and therefore, meets the definition of a new animal drug, regardless of whether the resulting animals are intended, for example, for food or to produce pharmaceuticals or any other substances.
Q: Why has the FDA asked the public to provide scientific evidence as to whether different classes of animals produced using genome editing and their products may pose low to no significant risk?
A: Some alterations that can be made using genome editing may make only subtle changes in the animals, or introduce traits that are the same as or very similar to those found in nature in similar breeds or species. Some investigators claim that these changes could occur via breeding, albeit with much longer time necessary between the initial breeding and the final animal with the desired alteration, and should therefore be subject to no more oversight than traditionally-bred animals. However, because the definition of the regulated article still encompasses the intentional alterations that results in animals with these traits, the agency seeks scientific information (i.e., specific data and information) to determine whether such alterations pose low to no significant risk. FDA may alter its regulatory approach depending upon the information it receives in response to this request for comment.
Q. Why are plants and animals with intentionally altered genomic DNA being regulated differently?
A: Animals with intentionally altered genomic DNA are, in general, regulated under the new animal drug provisions of the FD&C Act because the intentional alteration meets the definition of a drug, unless otherwise excluded. Food from genome edited plants is regulated under the foods provisions of the FD&C Act. FDA has issued a Request for Comments seeking public input to help inform its regulatory approach to human and animal foods derived from plants produced using genome editing (see Foods derived from plants produced using genome editing). FDA is maintaining a product-focused, science-based regulatory policy, in accordance with the specific legal standards applicable to each type of product (e.g., animal drugs, human medical products, food) under its jurisdiction, and consistent with relevant overarching U.S. Government policy principles. FDA is also taking steps to provide guidance and information to developers and actively communicate with the public.
Q: What are the elements of the new animal drug approval process for animals with intentionally altered genomic DNA as described in GFI 187?
A: The draft revised guidance recommends including the following steps for animals with intentionally altered genomic DNA, which do not differ significantly from those in current GFI #187:
- Product definition: a broad statement characterizing the animal, and the claim being made for the animal;
- Molecular characterization of the intentional alteration: a description of the intentional alteration and how it was produced;
- Molecular characterization of the lineage of the animal : a description of the method by which the alteration was introduced into the animal and whether it is stably maintained over time;
- 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 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 animal fulfills the claims for the characteristics that the animal is intended to exhibit.
Q: Is food from animals with intentionally altered genomic DNA being held to a different standard from 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 intentionally altered genomic DNA 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: Are certain kinds of intentional genomic alterations, including insertion of rDNA constructs at certain locations, considered “safe”?
A: All changes to genomic DNA and the resulting animals will be considered on a case-by-case basis. FDA has requested scientific evidence from the public to help the agency make decisions regarding the potential for some classes of animals with intentionally altered genomic DNA to pose minimal or no significant risk. Before finalizing the guidance, FDA may modify its regulatory approach in response to comments it receives, particularly in light of any data demonstrating low to no significant risk for certain alterations.
Q: What is the role of the various components of FDA with respect to animals with intentionally altered genomic DNA?
A: The FDA’s Center for Veterinary Medicine (CVM) is responsible for evaluating the safety and effectiveness of the regulated article (e.g., the intentionally altered genomic DNA, including rDNA constructs) in the animal, as it does for conventional new animal drugs. This includes the effects of the article (e.g., rDNA construct or other intentional alteration such as a deletion or substitution) 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 these animals express the traits 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) has responsibility for reviewing its respective product. For animals producing substances to be used in or as veterinary biologics, USDA/APHIS regulates the veterinary biologic. CVM will consult with the Center for Food Safety and Applied Nutrition (CFSAN) on food safety issues if a particular question arises for which CFSAN has expertise.
In the accompanying Notice of Availability for draft revised GFI #187, the agency specifically asks the public for scientific evidence regarding the risk level that certain classes of animals with intentionally altered genomic DNA may pose. Before finalizing the guidance, FDA may modify its regulatory approach in response to comments it receives, particularly in light of any data demonstrating low risk for certain alterations.
Q: Is FDA working with other federal agencies on the regulation of products developed through genome editing?
A: Regulatory oversight of genome editing and its applications is being considered within the umbrella of ongoing work under the White House Office of Science and Technology Policy (OTSP)-initiated effort to modernize the federal regulatory system for biotechnology products. The U.S. Government initiated an effort in 2015 to ensure public confidence in the regulatory system for biotechnology products and improve the transparency, predictability, coordination, and, ultimately, the efficiency of that system.
In September 2016, OSTP issued a proposed Update to the Coordinated Framework (CF) for the Regulation of Biotechnology (the Update to the CF), which clarifies the current roles and responsibilities of, and coordination among, FDA, EPA, and USDA/APHIS, and a National Strategy for Modernizing the Regulatory System for Biotechnology Products (the Strategy), which sets out a vision for ensuring that the federal regulatory system is prepared to assess future products of biotechnology. In January 2017, OSTP finalized the Update to the CF.
Consistent with the Update to the CF and the vision enunciated in the Strategy, FDA continues to work closely with EPA and USDA/APHIS on various issues related to biotechnology, including on genome editing. We note that APHIS has proposed to revise its regulation regarding genetically engineered organisms that may pose plant pest or noxious weed risks. 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. That is one of the reasons why, in its request for comment, FDA is asking for scientific information to demonstrate whether there are classes of genome edited animals that will pose low to no significant risks. FDA may modify its regulatory approach depending upon the data or information on risk that it receives. Under 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 intentionally altered genomic DNA 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 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 new trait that the resulting animal possesses. From a regulatory perspective, however, the intentional alteration in the genome, unless otherwise excluded, meets the definition of a new animal drug under the FD&C Act and is therefore subject to FDA oversight as such.
Q: Will these animals pass their new traits on to their offspring?
A: It depends. Animals with intentionally altered genomic DNA that are developed to pass their new genomic alterations and resulting traits on to their offspring are referred to as having heritable traits. In general, most animals with intentionally altered genomic DNA have those changes made 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, animals may contain genomic alterations that are not intended to be inherited—for example, animals being treated with gene therapy. These DNA alterations and constructs are not found in the germ cells of those animals, and their offspring will not contain the genomic alteration.
Q: How does the guidance address potential environmental risks associated with animals with intentionally altered genomic DNA, including genetically engineered 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, fast-growing salmon to be grown in contained environments pose a different set of risks from cattle engineered to be resistant to an endemic disease and grazing on an open range. FDA will consider potential environmental effects on a case-by-case basis. In general, the guidance recommends 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 asked and the resulting scope of the environmental review.
Q: What kinds of post-approval monitoring does the draft revised GFI 187 recommend?
A: These are similar to the post-approval requirements for sponsors of conventional new animal drugs. Developers are required to register with the agency, provide a list of all animals whose genomes have been intentionally altered that they have produced and keep records of any additional information they develop related to the safety of the intentional genomic alteration and the claim on which the approval was based. We recommend that sponsors work closely with the agency as approval nears to be clear on the post-approval requirements and recommendations.
We also note that as part of the approval process, the guidance recommends the development of a durability plan by sponsors and approval of that plan by the agency. The draft revised guidance recommends that sponsors develop a plan for monitoring the genetic makeup and characteristics (i.e., the genotype and phenotype) of the animals with intentionally altered genomic DNA subject to the new animal drug provisions to ensure that any such animals that enter commerce over time are equivalent to the animals that were approved. The responsibility for the durability plan does not extend beyond the sponsors.
Q: How will FDA enforce regulatory compliance?
A: FDA will use the same enforcement mechanisms it uses with respect to conventional new animal drugs: inspections to ensure compliance with regulatory requirements and, where FDA finds a lack of compliance, the agency may take actions including seizure or obtaining a court injunction against further marketing.