Genetic engineering

The Technology

Q: What is genetic engineering?

A. Genetic engineering generally refers to the use of recombinant DNA techniques to introduce new characteristics or traits into an organism. It entails producing a piece of DNA (the recombinant DNA or rDNA construct) and introducing it into an organism so that new or altered traits can be imparted to that organism. The genes and other segments of DNA that are part of the rDNA construct may be obtained from other organisms, or synthesized from scratch in a laboratory. Genetic engineering enables people to introduce a much wider range of new traits into an organism than is possible by conventional breeding. It has been widely used in agriculture, for example to make crops resistant to certain pests or herbicides, in medicine, for example to develop microbes that can produce pharmaceuticals for human or animal use, and in food to produce microorganisms that aid in baking, brewing, and cheese-making.

Q: What kinds of GE animals are in development?

A. Many kinds of GE animals are in development. At this time, the largest class of GE animals is being developed for biopharm purposes that is, they are intended to produce substances (for example, in their milk or blood) that can be used as human or animal pharmaceuticals. Another group of GE animals are under development for use as sources of scarce cells, tissues, or organs for transplantation into humans (xenotransplant sources). Yet others are intended for use as food and may be disease resistant, or have improved nutritional or growth characteristics. And others include animals that produce high value industrial or consumer products, such as highly specific antimicrobials against human and animal pathogens (e.g., E. coli 0157 or Salmonella).

Q: How are GE animals different from conventional animals?

A. From a scientific perspective, the only intrinsic difference is that GE animals contain an rDNA construct that gives them a new trait or characteristic, such as producing a pharmaceutical or growing faster. The degree of difference between a GE animal and its conventional counterpart will depend on the new trait that the GE animal possesses.

Q: Do all GE animals pass their new traits on to their offspring?

A: In general, most GE animals are developed so that they will 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. This guidance specifically addresses only GE animals that have heritable GE traits.

In general, most GE animals contain an rDNA construct that was introduced into early embryos or cells that go on to make embryos that develop into the GE animal. These constructs are heritable because they will be in every cell of the resulting animal, including those that are responsible for making sperm and egg for the next generation.

The term "GE animal" thus includes all the animals descended from the initial GE animal that have inherited the rDNA construct.
This is different from the term "animal clone," which does not include the sexually-derived offspring of animal clones.

In other cases, GE animals contain rDNA constructs that are not intended to be inherited for example, animals being treated with gene therapy. These rDNA constructs are not found in the germ cells of those animals, and their offspring will not contain the rDNA construct. In many ways, non-heritable constructs are very similar to conventional new animal drugs, because they may persist in the body for some time, but are not passed on to the next generation.

Q: What's the difference between animal clones and GE animals?

A: Animal cloning is a method of asexual reproduction, and results in the birth of one animal (the animal clone) that is a genetic copy of another animal. If the animal clone becomes a parent, its children are not clones, because they will have been born through sexual reproduction. So, the two things to remember about an animal clone are that (i) they are animals born as a result of asexual reproduction, and (ii) they have no new genes in them, that is, they are the same as the animal of which they are a copy. For more information, see Animal Cloning.

Genetic engineering is a method of introducing new genes into an animal. Thus, it is a method of altering an animal, not copying it. A GE animal contains new DNA (the rDNA construct) that gives the animal new traits. If the rDNA construct is stably inherited, then future generations of the initial GE animal will also contain the rDNA construct, and will also be GE animals. So, while cloning is a method of reproduction, genetic engineering is a method by which the genetics of an animal can be altered.

The animal clones that were the subject of FDA's previous risk assessment 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, i.e., non-GE animal clones (or "just clones").

Q: What are the known/potential benefits of genetically engineering animals?

A: The benefits depend entirely on the traits that are introduced. For example, scientists are attempting to develop GE cattle that are resistant to bovine spongiform encephalopathy, widely referred to as "mad cow disease." Some GE animals will grow more quickly, requiring less feed. Some GE animals have been altered to reduce their environmental impact by virtue of producing a lower level of pollutants in their wastes. Other GE animals may have improved fat composition, for example, increased levels of omega-3-fatty acids, providing a more healthful nutrient profile. Perhaps most importantly, scientists are developing GE animals that will produce certain human pharmaceuticals that are very difficult to produce in sufficient quantities by other means. An example of this is the potential ability to completely change the way in which certain chronic diseases, such as bleeding disorders, are treated. Currently, because clotting factors are so rare and difficult to obtain, people are treated only following acute attacks. If there were to be an increased supply of these clotting factors from GE animals, patients might be able to have much of their bleeding controlled by the regular administration of the medicine. In that way, these patients would potentially have a more normal ability to control bleeding.


The Regulatory Process

Q: What is the Agency issuing?

A: The Agency is issuing a guidance to provide an opportunity for public comment on FDA's current thinking on the regulation of genetically engineered (GE) animals and their products. The guidance document is intended to help industry understand the existing statutory and regulatory requirements as they apply to GE animals and their products and to inform the public about the process FDA is using to regulate them.

Q: How does the agency regulate GE animals and their products?

A: FDA regulates GE animals under the new animal drug provisions of the Federal Food, Drug, and Cosmetic Act (FFDCA), and FDA's regulations for new animal drugs. This guidance is intended to help industry 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 GE animals, and to gather input from the public and the regulated industry.

Q: Is FDA's regulation of GE animals and their products consistent with how FDA regulates conventional new animal drugs?

A: Yes. We are using the existing laws and regulations under which we regulate conventional new animal drugs and applying them to GE animals. A major purpose of the guidance is to explain how those regulations apply to GE animals.

Q: Are GE animals "drugs"?

A: No, GE animals are not drugs. Rather, the agency is regulating GE animals under the new animal drug provisions of the Federal Food, Drug, and Cosmetic Act (FFDCA). The FFDCA defines a new animal drug as "an article (other than food) intended to affect the structure or any function of the body of … animals." A recombinant DNA (rDNA) construct intended to affect the structure or function of an animal meets the definition of a new animal drug, regardless of whether the resulting GE animals are intended for food, or to produce pharmaceuticals or any other substances. As a short hand we sometimes refer to regulation of the article in such GE animals as regulation of the GE animal.

Q: Do all components of the new animal drug approval process apply to foods imported into the U.S. that are derived from GE animals raised in other countries?

A: No, not all components of the NADA process apply to foods imported into the U.S. The guidance notes the possibility of applying for an import tolerance instead of a new animal drug approval in such situation.

Q: What are the elements of the new animal drug approval process?

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 and how it is assembled;
  • Molecular characterization of the GE animal lineage: a description of the method by which the rDNA construct was introduced into the animal and whether it is 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 modification 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 intended for food, that food from those GE animals is safe to eat for humans and/or animals;
  • Claim validation: a demonstration that the GE animal does fulfill the product definition stated in the beginning of the review process.

Q: Why is the agency issuing this guidance now?

A. The agency has been regulating these animals under the new animal drug provisions of the Act since developers first approached us with GE animals. Based on our interactions with developers, we believe we now have a good idea of the kind of guidance that would be most helpful to industry. We also believe that publishing the guidance will give the public a better understanding of FDA's role in this important and developing area. Finally, with the recent adoption of the Codex Alimentarius 1 Guideline for Assessing the Food Safety of Food from rDNA Animals (June 2008; icon), which provides internationally-recognized recommendations for assessing the safety of food from GE animals, we believe that it is important that developers around the world fully understand the rigorous regulatory requirements that these animals and the food products from them will have to meet in the United States.

Q: Why is the agency issuing a guidance and not a regulation?

A: Existing statutory requirements and FDA's existing regulations for new animal drugs are applicable to, and appropriate for, GE animals. Therefore, we do not believe we need new law or regulation at this time to address GE animals and their products. However, we intend to issue additional guidance to describe the applicability of the new animal drug approval requirements to GE animals and their products.

Q: What is the legal basis on which GE animals are being regulated?

A: Under the Federal Food, Drug, and Cosmetic Act (FFDCA), "articles (other than food) intended to affect the structure or any function of the body of man or other animals" are defined as drugs. An rDNA construct that is in a GE animal and that is intended to affect the animal's structure or function meets the definition of a new animal drug. This is true regardless of whether the animals are intended for food or for some other purpose such as to produce pharmaceuticals. The FFDCA generally makes it unlawful to introduce unapproved new animal drugs into commerce. Therefore, premarket approval requirements apply to GE animals before they are marketed, and potential significant environmental impacts, if any, must be examined before approval as required by NEPA. The implementing regulations for new animal drugs are also applicable to rDNA constructs in GE animals.

Q: Does issuing a Guidance for Industry imply that this approach is voluntary?

A: No. A product that meets the definition of a new animal drug is generally required by statute and regulation to have an FDA-approved New Animal Drug Application prior to marketing. In order for FDA to approve such an application, the FFDCA requires that the sponsor demonstrate that its product is safe and effective. Although the Guidance does not itself impose any new requirements, we are issuing it to explain how existing statutory and regulatory requirements apply to GE animals and their products, and to provide recommendations on how sponsors may meet these responsibilities.

Q. Are all GE animals subject to regulation under the new animal drug provisions of the Act?

A: Yes, any animal containing an rDNA construct intended to alter its structure or function is subject to regulation by FDA prior to commercialization. However, based on risk, there are some GE animals for which the agency may not require an approval. In general, these include laboratory animals used for research. On a case-by-case basis, the agency may consider exercising enforcement discretion for GE animals of very low risk, such as it did for an aquarium fish genetically engineered to fluoresce in the dark. The agency does not anticipate exercising enforcement discretion for any GE animal of a species traditionally consumed as food, and expects to require approval of all GE animals intended to go into the human food supply.

Q. Why is the agency taking a different approach for GE animals from the one taken for clones?

A: In the case of clones, the agency first needed to determine whether food from clones posed any additional risks compared with food from more conventionally bred animals. Following the completion of a comprehensive risk assessment, the agency was able to determine that cloning fell on the continuum of assisted reproductive technologies, and that cloning poses no new risks to the health of animals involved in the cloning process or to food from cattle, swine, or goat clones or the progeny of clones of any species traditionally consumed as food. Additionally, clones are not different from non-clones with respect to their DNA; only the method by which they are produced is different. Therefore, FDA determined that no additional regulatory oversight was necessary.

In contrast to clones, GE animals have intentionally been changed. That change may affect the health of the animal, as well as the safety of food from the animal. Therefore, there are risk-based reasons for FDA to require their approval.

Q: Why is this different from the way in which GE plants are being regulated?

A: There are a number of reasons for the difference. One overarching reason is that, unlike in some other countries, the US has not considered it appropriate to create a "novel food" regulation. That is, the US does not subject foods from GE organisms to a specific new regulation simply because of their GE status. Rather, the US has so far found that its existing laws can be applied to provide appropriate regulatory controls over GE foods. And because US law generally treats plants and animals differently, and treats food from plants differently from food from animals, the regulatory procedures for GE plants will, of necessity, differ from the regulatory procedures for GE animals.

Another reason is that, unlike plants, animals can transmit diseases to humans, and in some very notable cases, are the origin of viral diseases in humans (e.g., swine flu). Depending on the nature of the modification to an animal, including the nature of any DNA sequences used to introduce or insert the rDNA construct into the animal, genetic engineering can enhance (or minimize) risks to human health. Although food from plants can be contaminated with human pathogens (usually from animals), and can thereby cause human illness, plants themselves ordinarily do not transmit human diseases. Genetic engineering does not change this. Therefore, GE animals can pose human health risks that would not arise with GE plants. The different regulatory approaches address these different risks.

Q: Is the safety of food from GE animals being held to a different standard from the safety of food from GE plants?

A: Food sold in the United States must be safe, whether it is from plants or animals, and whether it is GE or non-GE. Although the regulatory process for food from GE animals is different than that for food from GE plants, as dictated by different statutory requirements, ultimately they both must be safe to be legally marketed. In fact, the food safety assessments are quite comparable, with some appropriate differences to accommodate the key differences between plants and animals, and look at the same information as recommended in the respective Codex guidelines that provide internationally-accepted recommendations for assessing the safety of foods from GE plants and GE animals.

Q: Are there special concerns related to GE animals that are not concerns for GE plants?

A: Most of the food safety issues are the same. However, all animals, including GE animals, can cause zoonotic diseases (animal diseases that cross over to humans) because some viruses and microorganisms from animals can infect humans. Because it is possible to genetically engineer animals using viruses or segments of DNA that can recombine and possibly transfer to humans or other animals and cause disease, there are some specific issues that must be evaluated in GE animals that are not relevant in GE plants. Addressing potential risks of introducing and spreading livestock pests or disease is also within the scope of USDA's APHIS regulatory authority, as described in its RFI.

Q: Are there GE animals in the food supply?

A: FDA has not approved any GE animals for food (or for any other purpose). During the pre-approval investigational phase, there are strong statutory and regulatory prohibitions against unreported movement of GE animals as well as against their disposal in the food supply unless explicitly approved by the FDA. In addition, there are strict requirements for good record-keeping during the investigational phase.

FDA has been working closely with developers of GE animals to ensure that they are aware of the regulations, particularly with respect to disposition of investigational animals. In June of 2003, FDA issued a letter to the presidents of all US land grant universities informing them of their responsibilities to inform investigators at their universities that they should contact FDA if they were conducting investigations with GE animals of species traditionally consumed as food. Additionally, they were asked to remind their investigators of their responsibilities regarding animal disposition and record-keeping. To date, FDA has neither received requests for nor granted any food use authorizations for investigational animals containing rDNA constructs.

Now that this guidance has been issued, FDA staff will be engaging in an extensive outreach program to contact researchers in academic, commercial, and government laboratories who may be working with GE animals to educate them about their responsibilities and obligations.

Q: What is the role of the various components of FDA over GE animals?

A: The Center for Veterinary Medicine (CVM) is responsible for evaluating the safety and effectiveness of the rDNA construct in the GE animal, as it does for conventional new animal drugs. This includes the effects of the rDNA construct on the safety of the GE animal as well as on the safety of foods from the GE animal, should the GE animal or parts of it be used for food or animal feed. In addition, CVM evaluates whether the GE animal has the properties claimed for it (e.g., that the GE 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 approving its respective product. FDA intends to issue future guidance to describe more fully the intra-agency process that will be used for animals producing such substances. For animals producing substances to be used in or as veterinary biologics, 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 that CVM lacks.


Interactions with Other Branches of the USG and Other Countries

Q: How does the FDA propose to address GE insects?

A: We expect that other agencies also may have responsibilities associated with the oversight of GE insects. We are currently in discussions with other agencies, including EPA and USDA's APHIS, to determine the best approach for the general oversight of GE insects, and may jointly issue future guidance to address GE insects.

Q: APHIS is also overhauling its plant biotech regulations. Is all this activity a signal that the United States is taking a new, more restrictive approach to biotechnology regulation?

A. No. FDA and APHIS are both simply bringing their biotech procedures up to date, to accommodate the newer kinds of GE products now under development, and to reflect the agencies" experience in oversight of GE organisms and their products. Our regulations will continue to evolve to address developments in technology.

Q: What are the roles of APHIS and USDA's Food Safety Inspection Service (FSIS) with respect to GE animals?

A: Under the Animal Health Protection Act (AHPA), APHIS is authorized to protect the health of U.S. livestock. Based on that authority, APHIS may broadly consider the potential effects of animals with GE traits on the health of the overall U.S. livestock population. APHIS is reviewing whether there are any complementary activities with respect to U.S. livestock health that APHIS should consider under the AHPA. Additionally, under the Virus-Serum-Toxin Act, APHIS licenses veterinary biological products, including those derived from genetic engineering to ensure they are pure, safe, potent and efficacious.

Under the Federal Meat Inspection Act (FMIA), the Poultry Products Inspection Act (PPIA) and the Egg Products Inspection Act (EPIA), FSIS ensures that meat, poultry, and egg products are safe, wholesome, and properly labeled based on tolerances (maximum allowable amounts) set by FDA on new animal drug residues in such products. FDA and FSIS are discussing how to adapt their existing procedures so that they will fully accommodate the needs of both agencies in addressing GE animals intended to go into the food supply.

Under the Animal Welfare Act, USDA already addresses animal welfare concerns of certain animals. Under this act, APHIS has authority to ensure the humane care and treatment of certain animals used in biomedical research and for exhibition (which would include any livestock), or that are bred and sold commercially (excluding livestock).

Q: Are there any GE animals or food products from them currently in the US market or elsewhere?

A: The only GE animals known to be sold commercially in the U.S. are laboratory animals used primarily in medical research, and a type of aquarium fish that glows in the dark. There is a human pharmaceutical licensed in Europe that is produced in GE animals in the U.S. We are not aware of any foods from GE animals sold in the U.S. or elsewhere. We have been working with GE animal developers since the 1990s and have always made clear, including in a letter to all land grant universities, that food from GE animals could not be sold unless approved by FDA.

Q: How many GE animals are there in the US?

A: We are not aware of any GE animals of species traditionally consumed as food in commerce now. GE animals that are currently in commerce are those over which FDA is exercising enforcement discretion, and include a non-food GE aquarium fish, and GE laboratory rodents that are sold to aid in research around the world.

All of the remaining GE animals in the US are therefore investigational, or research, animals. It is difficult at any one time to know exactly how many GE animals are on the ground, as some are being born, and others are being sacrificed as part of safety or effectiveness studies required for approval. Nonetheless, one of the primary clarifications that the guidance provides is that developers of GE animals of any species traditionally consumed as food must notify the agency that they are developing such animals, and cannot introduce them into the food supply without prior authorization from FDA.

During the investigational or research phase, sponsors (the developers of GE animals) are required to keep records of the amount of drug being developed. The guidance interprets that as meaning the number of GE animals being developed, whether they are being shipped, and the method of disposition. Further, all investigational animals must be labeled, or clearly identified as such, and be accompanied by a label indicating that they are not for human use without FDA approval. These records must be maintained for two years after the investigation concludes or an approval is issued. FDA has the right to inspect sponsor facilities and records with no advance notice. GE animals cannot be introduced into the food supply without explicit agency approval.

Q: Will the agency be recommending a supply chain management program similar to that for clones?

A: The supply chain management program for clones is an industry-sponsored program being developed in coordination with USDA's Marketing and Regulatory Programs mission area. It is intended to provide a verifiable system to ensure that if suppliers should choose to exclude clones from their food production stream that they can do so based on animal identification and tracking. FDA's role in this program is close coordination and assistance with technical issues. Should a similar system be set up for any particular GE animal, we will be available to work closely with interested parties should they require technical advice.

Q: Are GE animals or their products being developed in other countries? Have any been commercialized?

A. Yes, GE animals are being developed actively in many countries for both food and biopharmaceutical uses. For example, there have been multiple publications from Canadian developers of genetically engineered fish that grow more quickly, and pigs with smaller environmental footprints, as well as GE animals intended to produce human pharmaceuticals. In New Zealand, dairy researchers are looking to rDNA technology to affect the relative level of certain proteins in cows" milk to make it more suitable for cheese-making. China has a major agricultural program that employs rDNA technology to make more animal-based food available, and scientists from African countries are collaborating with aquaculturists in the US to develop GE tilapia that will grow quickly. Growth enhanced fish are also being developed in Cuba. Scientists at the Roslin Institute in Scotland are developing GE chickens to produce pharmaceuticals in their eggs, as are other scientists in Korea. This is a very active area of research, and we expect that many products are likely to start reaching regulators, and then the market, within the next decade.

With respect to commercialization, many GE laboratory animals are in use in research laboratories around the world, including those GE laboratory animals that are sold to laboratories to perform various kinds of testing.

Q: How do other countries regulate GE animals and their products?

A. Usually, when countries have premarket approval requirements for GE foods or "novel foods," the requirements are the same whether the food comes from GE plants or GE animals. We anticipate that, like the U.S., most countries will evaluate the same information as that recommended in the Codex Alimentarius guideline on assessing the safety of foods from rDNA animals. We do not know what, if any, other requirements countries will put in place regarding GE animals.

Q: What if a marketer wishes to import food into the US from a GE animal from another country?

A: FDA has a mechanism by which it can evaluate the safety of food from GE animals developed abroad and can establish an import tolerance to enable import of such food. In general, the information necessary to establish such import tolerance would be found in the sections of this guidance relevant to evaluating food safety and would be consistent with the information recommended for review in the Codex Guideline for the Conduct of Food Safety Assessment of Foods Derived from Recombinant-DNA Animals.

Q: Does the United States anticipate trade disruptions related to the development and commercialization of GE animals?

A. By the time GE animals enter the food supply, they will have received FDA approval and will have gone through a food safety assessment that reviews information consistent with the information recommended for review in the international rDNA animal food safety guideline recently adopted by the Codex Alimentarius. FDA anticipates working with the trade agencies to develop a coordinated outreach program and to answer scientific questions from its counterpart regulatory agencies in other countries, as a way to help minimize or prevent trade disruptions.

Unlike the release of the Cloning Risk Assessment, which determined that no further regulation was needed for certain clones and clone progeny, the release of this guidance clarifies that premarket approval is required prior to the introduction of GE animals or their products into commerce, and describes the rigorous regulatory process that must be completed. Given the recent adoption of the Codex guideline, we believe that the international community is well aware that such animals are under development and that there is a consensus approach for assessing the safety of food from them.

Q: Is the United States part of any international activities associated with GE animals?

A: The US is an active participant in a number of international organizations that address GE animals or their products, including Codex Alimentarius and OIE (the World Organization for Animal Health).


What's the Agency asking for in the Guidance?

Q: When should developers of GE animals first come to the agency?

A: Developers are always welcome to contact the agency if they have any questions regarding whether the GE animals they are developing will need premarket approval, or whether FDA may exercise enforcement discretion over them. We recommend that developers first come to the agency early in the development of GE 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: Are certain kinds of rDNA constructs considered "safe"?

A: All constructs and the resulting GE animals will be considered on a case-by-case basis. At this time, we do not believe that certain constructs will be predetermined to be "safe" or "not safe".

Q: What happens during the research phase of developing a GE animal?

A: The agency refers to the "research phase" as the "investigational phase" of the development of GE animals containing rDNA constructs. During this phase, developers (referred to as sponsors), in general, can use various rDNA constructs and intermediates to arrive at a construct in an animal that they believe will serve as the progenitor of the line of GE animals that they wish to develop. We will work with sponsors to ensure that records are kept appropriately, that investigational animals are disposed of in a safe manner that potential environmental risks are assessed, and that data and information suitable to a New Animal Drug Application (NADA) are being developed.

Q: What kinds of information are required for an NADA submission?

A: In general, the guidance recommends that sponsors begin by developing a product definition. This is a short statement that describes the GE animal being produced, the rDNA construct in the GE animal, and the claim being made for the GE animal (i.e., the new trait that the animal is expected to have). The guidance recommends that sponsors fully characterize the rDNA construct that they will be using, including its ultimate location and stability in the genome of the GE animal's lineage. In addition, the guidance recommends that sponsors evaluate the durability of the construct (i.e., determine whether it is stably maintained and expressed) in the resulting GE animals, ultimately over multiple generations. The guidance also recommends ways in which sponsors can meet the statutory requirements of safety as related to the health of the animal, and food or feed safety if animals are intended to enter the food supply. In addition, the guidance describes sponsors" responsibilities under the NEPA to provide an assessment of potential environmental risks. Finally, the guidance provides recommendations to help sponsors meet their statutory requirements to validate the claim that is being made to demonstrate the effectiveness of the rDNA construct (i.e., that it does what the sponsor claims).

Q: How does the guidance address potential adverse effects on animal health?

A. The guidance recommends that the developer submit data and information addressing the health of the GE animals, including veterinary and treatment records, growth rates, reproductive function, and behavior. The guidance also recommends submission of data on the physiological status of the GE animals, including clinical chemistry, hematology, histopathology, and post-mortem results. And the guidance recommends submission of data addressing whether the rDNA construct or its expression products cause any direct or indirect toxicity to the animals.

Q: Does FDA address animal welfare issues? How do they differ from animal health issues?

A: Animal welfare generally refers to how animals are treated, including the conditions under which they are housed. To the extent that such issues affect animal health or the safety of products from the animals, FDA does take such issues into account in its review. However, other unrelated animal welfare issues are not within the scope of the guidance. USDA addresses animal welfare concerns of animals, other than livestock and laboratory animals. Laboratory animal welfare concerns are generally the subject of local Institutional Animal Care and Use Committees and the Association for Assessment and Accreditation of Laboratory Animal Care.

Q: How does the guidance address potential environmental risks associated with GE animals? Are concerns different for different kinds of animals?

A. Any potential environment-related issues would be a function of the traits or characteristics introduced into those animals, and the conditions under which those animals would be grown. For example, fast growing salmon to be grown in contained environments pose a different set of risks from cattle engineered to be resistant to a disease such as mastitis. FDA will consider potential environmental effects on a case-by-base 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: Will it be safe to eat the food from GE animals?

A. FDA will only approve food from GE animals that is safe to eat. FDA's food safety evaluation will look at the same information as that recommended internationally by Codex Alimentarius in its newly adopted guideline.

Q: How will FDA evaluate the safety of meat or other food products from GE animals? How does the guidance compare with the recently approved Codex Guidelines for the Food Safety of Foods from rDNA Animals?

A: The FDA guidance essentially recommends the same information for evaluating food safety that the Codex Guideline does: the characterization of the rDNA construct, the safety of the new substance produced as a result of the rDNA construct, the health status of the GE animals, and a demonstration that the composition of food produced from the GE animal is safe.

Q: How does the guidance address the issue of disposal of GE animals, carcasses, or parts?

A: Animals or edible products from them containing unapproved new animal drugs may not be put into the food or feed supply without prior FDA authorization during the investigational phase of development. The same food safety standard is applied to investigational GE animals as for investigational animals treated with conventional new animal drugs. As part of the approval process, FDA will make clear whether edible products from particular GE animals are suitable to enter the food or feed streams. FDA will enforce these decisions with regard to GE animals the same way it enforces them with animals treated with conventional new animal drugs. At this time, based on the kinds of animals currently under development, and apart from restrictions pertaining to use in food or feed, FDA does not anticipate that it would have any reason to impose special disposal limitations on GE animals, carcasses, or parts.

Q: Does the guidance have recommendations pertaining to mandatory tracking and labeling of GE animals?

A: The guidance does not have recommendations pertaining to mandatory tracking of GE animals. Developers of GE animals must, however, 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: Does the guidance have recommendations regarding the labeling of food from GE animals? Does such food have to be specially labeled?

A: The guidance doesn't explicitly address labeling of food from GE animals. FDA does not require that food from GE animals be labeled to indicate that it comes from GE animals, just as food from GE plants does not have to be labeled to indicate it comes from GE plants. However, if food from a GE animal is different from its non-engineered counterpart, for example if it has a different nutritional profile, in general, that change would be material information that would have to be indicated in the labeling. Food marketers may voluntarily label their foods as coming from GE or non-GE animals, as long as the labeling is truthful and not misleading.

Q: What kinds of post-approval monitoring does the guidance 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 GE animals they have produced, and keep records of any additional information they develop related to the safety of the rDNA construct 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 guidance recommends that sponsors develop a plan for monitoring the genetic makeup and characteristics (i.e., the genotype and phenotype) of the GE animal to ensure that the GE animals that enter commerce over time are equivalent to the GE 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.


Related Issues

Q: What about ethics? Will FDA consider these in its risk management decisions?

A. The issue of ethics and biotechnology is complex. Our experience with other animal-based new technologies such as cloning and the introduction of rBST has shown that most people include animal health in their articulation of what constitutes "ethics". We note that the new animal drug approval requirements described in the guidance require a finding of safety to animals, and so we believe that we are addressing those particular health and safety-related concerns. As for issues associated with other 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. How will FDA work to inform the public about new GE animals, its decisions on them, and the science behind those decisions?

A. At present, we intend to hold public advisory committee meetings prior to any GE animal approval. We may revisit that policy in the future as we gain more experience with reviews of GE animals.

If we intend to exercise enforcement discretion with respect to specific animal lineages, we plan to post a statement describing that intent on our website.

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.

1 The Codex Alimentarius Commission was created by the Food and Agriculture Organization and the World Health Organization of the United Nations to develop, among other things, internationally harmonized guidelines that can be used to ensure fair trade standards and coordinate food standards on an international basis.