Q: What is genetic engineering?
A: Genetic engineering generally refers to the use of tools of modern biotechnology and molecular biology to introduce new genetic material, or delete or alter existing genetic material to introduce intended, new traits or characteristics.
Q: What is a genetically engineered animal?
A: A genetically engineered (GE) animal is one that contains additional or altered genetic material (e.g., recombinant DNA (rDNA)) through use of modern biotechnology tools that’s intended to give the animal a new trait or characteristic. Examples of the kind of GE animals that are being developed are provided below.
Q: What kinds of GE animals are being developed?
A: Many kinds of GE animals are in development.
- Biopharm animals are those that have undergone genetic engineering to produce particular substances, such as human insulin, for pharmaceutical use.
- Research animals may be engineered to make them more susceptible to particular diseases, such as cancer, in order to gain a better basic understanding of the disease for the development of new therapies or in order to evaluate new medical therapies.
- Xenotransplant animals are being engineered so they can be used as sources for cells, tissues or organs that can be used for transplantation into humans.
- Companion animals that are modified to enrich or enhance their interaction with humans (i.e., hypoallergenic pets).
- Disease resistant animals may be used either for food use or biopharm applications. These animals have received modifications that make them resistant to common diseases, such as mastitis (a very painful infection of the udder) in dairy cows, or particularly deadly diseases, such as bovine spongiform encephalopathy (BSE).
- Food use animals have been engineered to provide healthier meat, such as pigs that contain healthy omega-3 fatty acids at levels comparable to those in fish.
Q: How are GE animals regulated?
A: FDA regulates GE animals under the “new animal drug”1 provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and FDA’s implementing regulations for new animal drugs. This guidance is intended to help industry understand the requirements that are established by statute and regulations as they apply to these animals, including those of the National Environmental Policy Act (NEPA), and to inform the public about the process FDA is using to regulate GE animals. The guidance does not create any new obligations. It clarifies how the regulations apply to GE animals.
Q: What’s the difference between animal clones and GE animals?
A: The animal clones that were the subject of FDA’s risk assessment on animal cloning (released in January of 2008) are “just clones”—that is, they are copies of individual conventionally-bred animals, and do not contain any rDNA constructs. What can be confusing is that an animal clone can be genetically engineered (i.e., have an rDNA construct introduced into it), and a GE animal can be reproduced by cloning. Our guidance covers GE animals, irrespective of whether they were reproduced by cloning. It does not cover animal clones that do not contain an rDNA construct (“just clones”).
Q: Why is FDA regulating GE animals differently from animal clones?
A: Clones are really just genetic copies of the animals from which they are produced. The purpose of the FDA risk assessment was to determine whether cloning posed any new risks to the health of animals and whether animal clones posed new food safety risks. The conclusion of that risk assessment was that there are no new risks associated with those animals, that food from cattle, swine, and goat clones, and the progeny of the clone of any species traditionally consumed as food was as safe to eat as that from conventionally bred animals, and that no new regulatory requirements are necessary beyond those that apply to other, conventionally-bred animals. By contrast, GE animals have changes to their genetic material that may potentially affect the health of the GE animal or the safety of food from the GE animal. Therefore, there are risk-based reasons for FDA to require their approval.
Q: Will GE animals be regulated the same if they’re used for food or if they’re intended to produce pharmaceuticals for people?
A: GE animals are subject to premarket oversight whether they are intended to be used for food or to produce pharmaceuticals or other useful products. There may be some differences in what the actual oversight process entails depending on the kinds of risk(s) the GE animals may pose, and the kinds of uses for which they are intended. In addition, the pharmaceuticals produced from GE animals must be approved through the same process as applies to other pharmaceuticals. In general, we do not anticipate that biopharm animals will be used for food.
Q: What kind of post-market surveillance will there be?
A: Post-market surveillance will vary depending on the GE animal. However, as with conventional new animal drugs, the guidance tells sponsors (individuals or companies submitting GE animal applications to FDA for review) that in their application they should demonstrate that the rDNA construct is stable in the animal over time, and that the GE animal retains the new characteristics over time. As with conventional drugs, if additional information shows that there are safety concerns, or if the GE animal no longer has the characteristics claimed for it, FDA can take steps to have the GE animal removed from the market.
Q: Will FDA be looking at effects on the health of animals?
A: Before FDA can approve a new animal drug, it must determine that the drug is safe for the animal receiving it. Therefore, before we can approve a GE animal, we must determine that the rDNA construct is safe for the animal containing it. To do that, we look at the health of the animal. In the guidance, we provide recommendations on how developers can assess the health of their animals.
Q: Is food from GE animals in the food supply?
A: On November 19, 2015, FDA approved an application related to AquAdvantage Salmon, a GE Atlantic salmon. Although these salmon will be bred in Canada, and raised in Panama, food from these salmon will be imported into the U.S. For details on the kinds of studies that were conducted to assess food safety, please see the Freedom of Information Summary, Section IX.
We will not approve any GE animal for food use unless we find that the food from those GE animals is safe. It would be illegal to introduce food from an unapproved GE animal into the food supply without FDA permission. We work closely with GE animal producers to make sure that they keep good records of their animals and that none enter the food supply without FDA approval.
Q: Will food from GE animals be labeled?
A: The FDA recognizes that many consumers are interested in whether food ingredients are derived from genetically engineered plants or animals, and is also publishing guidance for manufacturers who wish to voluntarily label their foods as containing or not containing such ingredients. If food from a GE animal is materially different from its non-engineered counterpart (for example, if it has a different nutritional profile), the difference would be material information that would have to be indicated in the labeling. Marketers may voluntarily label their foods as coming from GE or non-GE animals, as long as the labeling is truthful and not misleading. FDA oversees labeling of most fish and seafood, of milk and other dairy products, and of whole eggs in their shells. The U. S. Department of Agriculture’s Food Safety and Inspection Service (FSIS) generally oversees labels used for meat, poultry, and other egg products.
Q: Will GE animals be labeled?
A: Developers of GE animals will need to have labeling accompanying the animals. The guidance recommends that the labeling describe the GE animal (e.g., common name/breed/line, genus, species, GE animal line, rDNA construct), and its intended use. Where the labeling for a GE animal contains animal care or safety information (e.g., husbandry or containment), we recommend that the labeling accompany the animal throughout all stages of its lifecycle.
Q: What other agencies are involved in the regulation of these animals?
A: Depending on the species and use of the animal in question, the U.S. Department of Agriculture’s Animal and Plant Health Inspection Service (APHIS), FSIS, the Environmental Protection Agency, and others may play a role in the regulation of GE animals. FDA is working very closely with these agencies and Departments to coordinate the regulation of these animals.
Q: What about environmental effects?
A: Environmental evaluation that meets the requirements of NEPA is required prior to any approval. We expect that the environmental risks that may be posed by GE animals will differ on a case-by-case basis. For example, the concerns raised by a GE cow that is resistant to mastitis will be very different from the concerns raised by a GE fresh-water fish that is engineered to grow more rapidly. We will work closely with individual GE animal producers to make sure that their environmental assessments address all of the potential risks these animals may pose.
Q: Can food from biopharm animals be eaten?
A: In general, biopharm animals are not intended to be eaten: they are engineered to produce a therapeutic substance, and their value is in that product and not the meat or milk from the animal. Given the relatively small numbers of any particular line of biopharm animal, the large amount of food safety data that is required to be provided to FDA for each GE animal line intended to enter the food supply, and the kind of food safety issues that pharmaceutical chemicals present in such animals would generally pose, it would be very unusual for developers of biopharm animals to want to enter their animals into the food supply. Without FDA approval for food use, it would be illegal for a company to direct any of its GE animals into the food supply. It is much more likely that these animals will be disposed of in a way that does not involve human food use when they have reached the end of their lives.
However, if a developer provided sufficient evidence of safety and FDA approved the biopharm animal for food use, then the decision on whether to enter it into the food supply would be a marketing issue for the food producer and the developer and not a food safety issue.
Q: What are the potential benefits of GE animals for consumers?
A: Many GE animals in development are intended to have direct benefits to consumers. For instance, biopharm animals are being developed to produce various pharmaceuticals for humans or other animals such as clotting factors, growth factors and inhibitors used in cancer therapy, some of which cannot now be produced in sufficient quantities to meet medical needs. Some GE animals are under development to produce healthier food. And other animals are under development to have indirect benefits to consumers, such as decreased environmental impact by excreting lower levels of pollutants in their wastes.
Q: Are there any GE animals on the market now?
A: In 2003, FDA chose to exercise enforcement discretion for a GE aquarium fish that fluoresces in the dark. FDA made this decision in part because the fish (Zebra danio) is not a species used for food, and in part because the agency was able to determine that it did not pose any additional environmental risks compared with conventional Zebra danios. (Zebra danios are unable to survive outside the very warm waters of the tropics, which effectively limits the ability of an escaped or released fish to affect the U.S. environment.)
Additionally, there are many different kinds of GE rats and mice used in laboratory research throughout the world.
In addition, as described below, FDA has approved three GE animal-related applications. The first was in 2009, when FDA’s Center for Veterinary Medicine approved a GE goat that produced a human biologic in its milk. The Center for Biologics Evaluation and Research approved the human biologic, ATryn. In November 2015, FDA approved an application related to AquAdvantage Salmon, a GE Atlantic salmon. In December 2015, FDA’s Center for Veterinary Medicine approved a GE chicken that produces a human biologic in its eggs. The Center for Drug Evaluation and Research approved the human biologic, Kanuma (sebelipase alfa).
Q: How long have GE animals existed? Why did FDA step in when it did?
A: The first GE animal, a rabbit, was produced in the 1980s. Since that time, the field has grown enormously. FDA has been monitoring and evaluating the development of GE animals and believes that it is important now to provide the growing industry with a clear and transparent regulatory path. We also think it’s important to let other stakeholders, including the public, know our policies and requirements on this issue. Because we are a science-based public health agency, we are using a rigorous regulatory approach to ensure the public health, while providing GE animal developers a path by which they can bring innovative products to the market. In addition, the Codex Alimentarius, an international food safety standards organization sponsored by the United Nations, adopted a guideline on assessing the safety of food from GE animals. We therefore realized it was a good time to ensure that developers, both in the U.S. and around the world, understood what FDA’s regulatory requirements are regarding GE animals and food from such animals.
Q: Do GE animals look different from other animals?
A: Despite some of the doctored photographs that you may have seen circulating on the internet, adding a new gene to an animal does not result in outlandish physical combinations, such as a bird with the head of a rabbit. Genetic engineering simply doesn’t work that way.
Almost all GE animals will look the same as their conventional counterparts, although there are some products in which the point of the GE process is to make the animal look slightly different (such as the GloFish).
Q: Are the offspring of a GE animal also considered GE?
A: In general, most GE animals that are being developed at this time are intended to pass their new GE traits on to their offspring. Such traits are called heritable. The initial GE animal and all of its descendants that have inherited the GE trait are called GE animals. Other GE animals have “non-heritable” traits, meaning that none of the offspring will have the trait. This guidance deals only with GE animals bearing heritable traits.
Q: Is it possible that GE animals could displace or replace the conventional species?
A: Over time, it is at least theoretically possible that certain GE traits might be widely adopted. For example, were ducks and chickens developed that could not carry or transmit avian influenza, it is possible that many producers of such animals, particularly in vulnerable parts of the world, would want to introduce that trait throughout their flocks. Such a trend would be no different than what already has occurred with the popular conventional livestock breeds currently used in agriculture. Such widespread adoption of any particular GE trait would likely be quite unusual.
It also would be extremely unlikely for any GE animal to accidentally displace conventional animals. Most developers of the GE animals will likely control their breeding opportunities to further their business interests. For example, GE animals producing pharmaceutical products must be carefully confined in controlled conditions, such as limited access barns, to ensure that diseases or other contaminants do not make their way into the final pharmaceutical products.
Q: Is there a chance that this technology could be used on humans?
A: Gene therapy has been used to attempt to treat various human diseases since 1990, and is subject to strict FDA oversight under a process different from that described in this guidance. Human gene therapy is currently limited to non-heritable therapies; that is, people who receive the new genes as part of the gene therapy can’t pass them on to their children. To date there have been no gene therapies approved for humans, although several clinical trials are ongoing.
Q: What exactly does the review process of a GE animal entail?
A: The guidance recommends a review process that includes seven categories:
- Product definition: a broad statement characterizing the GE animal and the claim being made for the GE animal;
- Molecular characterization of the construct: a description of the rDNA construct or other genomic alteration and how they are produced;
- Molecular characterization of the GE animal lineage: a description of the method by which the rDNA construct or other genomic alteration was introduced into the animal and whether they are stably maintained over time;
- Phenotypic characterization of the GE animal: comprehensive data on the characteristics of the GE animal and its health;
- Durability plan: the sponsor’s plan to demonstrate that the alteration will remain the same over time, and continue to have the same effect;
- Environmental and food/feed safety: the assessment of any environmental impacts, and for GE animals of food species, an assessment of the safety of food derived from those GE animals is safe to eat for humans and/or animals;
- Claim validation: a demonstration that the GE animal has the characteristics that the developer says it has.
Q: When will the first approvals be granted?
A: FDA has approved three GE animal-related applications. The first was in 2009, when FDA’s Center for Veterinary Medicine approved a GE goat that produced a human biologic in its milk. The Center for Biologics Evaluation and Research approved the human biologic, ATryn. In November 2015, FDA approved an application related to AquAdvantage Salmon, a GE Atlantic salmon. In December 2015, FDA’s Center for Veterinary Medicine approved a GE chicken that produces a human biologic in its eggs. The Center for Drug Evaluation and Research approved the human biologic, Kanuma (sebelipase alfa). No additional applications for GE animals will be approved until FDA determines that the rDNA construct in the animals is safe for the animals and is effective, i.e., that the GE animals do indeed possess the traits that they were intended to express, and that, if the animals are intended to be used as food, the food is safe to eat. All approvals will be handled on a case-by-case basis, and as with any approval, it is difficult to estimate how long it will take to produce the data for the agency to evaluate, and when any one of those reviews will be completed.
Q. How will FDA inform the public about new GE animals, its decisions on them, and the science behind those decisions?
A. The agency is interested in increasing the transparency of its deliberations and actions. In particular, we intend to seek input from experts and the public where there is significant public interest in an issue, and FDA believes the public may have relevant data or information to contribute. Additionally, as is the case for all NADAs, after completion of an NADA, the agency will post a Freedom of Information summary of the information in the NADA file, including information used to assess safety (to the animal and for food or feed, if appropriate) and in support of the claims made by the sponsor.
We have developed a number of consumer-appropriate publications to help inform consumers and other stakeholders about the technology and the agency’s regulations of these animals. These are available on the FDA website.
FDA’s new animal drug approvals (including for GE animals) are published in the Federal Register, codified in the Code of Federal Regulations, and posted on its website at Animal Drugs @ FDA. Following approvals, FDA will also provide electronic access to a summary of all information (other than confidential business or trade secret information) used in FDA’s decisions as part of the freedom of information summary routinely published upon approval.
Q: What about the ethics of genetically engineering animals?
A: The issue of ethics is an extremely complicated one. On the one hand, the standard for approval does not explicitly include ethics—FDA must regulate on the basis of safety and effectiveness. However, many people would consider animal health and safety to be a subcategory of the broader term “ethics.” To that end, the regulatory approach described in this guidance closely examines animal health and requires a finding of safety to animals, and so we believe that we are addressing those particular concerns.
We do, however, recognize that genetically engineering animals may raise non-scientific social concerns that may fall under the heading of “ethics.” We note that these issues are not within the scope of the guidance. We do, however, continue to participate in various venues in which these issues are discussed so that we can ensure that the discussions are based on fact and not on erroneous assumptions regarding the technology or its outcomes.
Q: Where can I get more information about genetic engineering and the GE Guidance for Industry?
A: The Guidance for Industry is available on FDA's website.
1The new animal drug approval requirements are described in the Code of Federal Regulations under 21 CFR 514.