Q: Why did the Agency issue this guidance when they did?
A. FDA’s Center for Veterinary Medicine (CVM) regulates GE animals under the new animal drug provisions of the Federal Food, Drug, and Cosmetic Act (FFDCA). As GE animals approach commercialization, we thought it was important to issue guidance to clarify our regulatory process, and to gather input from the public and the regulated industry. In addition, we thought publishing the guidance was timely in light of the recent adoption of the Codex Alimentarius guideline on assessing the safety of food from GE animals (2008).
Q: How does “guidance for industry” differ from regulations?
A: Regulations set out legally enforceable requirements. Guidances describe the agency's interpretation of, or policy on, a regulatory issue such as interpretation of statutory or regulatory requirements. Guidances are not themselves legally binding. Rather, they usually provide recommendations on how best to comply with statutory or regulatory requirements. The agency believes that the existing statutory authorities and regulations are sufficient to regulate these animals, and that providing guidance will help sponsors1 understand how these requirements apply to these animals.
Q: Is my GE animal considered to be a “drug”?
A. No, your GE animal is not a drug. Rather, the agency is regulating GE animals under the new animal drug provisions of the 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: What about all of the GE mice in my research laboratory?
A. As stated in the Guidance, FDA is not recommending that researchers working with non-food laboratory animals for research purposes contact the agency. You are still responsible for determining whether your research falls under any NIH guidelines for recombinant DNA research, as well as any institutional animal care and use committees that you may have, and any rules that may be established, as the result of participation, to maintain AAALAC accreditation. If you have any questions about whether your laboratory animals must obtain agency approval, contact FDA and we will be happy to answer your questions and provide you with assistance. In addition, you are responsible for meeting all other applicable federal, state, local, tribal, and municipal requirements, for example with respect to the disposal of animals or their wastes.
Q: Does this take the place of other laws governing my GE animals?
A. No. The guidance is FDA’s current thinking on how the FFDCA and the National Environmental Policy Act (NEPA) apply to GE animals. Other laws, regulations and guidelines would include any institutional NIH guidelines, USDA’s Animal Welfare Act, laws administered by USDA’s Animal and Plant Health Inspection Service (APHIS) and Food Safety Inspection Service (FSIS), and any other authorities administered by other agencies and departments.
Q: Does issuance of this guidance change how I interact with CVM regarding my INAD for a GE animal, and will I need to wait for issuance of a final guidance before I can get approval of a NADA?
A: This guidance explains how the existing laws and regulatory requirements apply to GE animals. The guidance does not itself impose any requirements, but instead provides recommendations for how sponsors can meet the legal and regulatory requirements under FFDCA and NEPA. We cannot predict when any approvals will be completed, but the timing of such approvals is unrelated to the issuance of the final guidance. If you are already working with CVM under an INAD or have submitted an NADA, you should find the information in the guidance consistent with FDA’s approach thus far.
Q: I have a biopharm animal; do I have to communicate with CVM in addition to CDER or CBER? Whom should I contact first?
A: You should contact CVM early in the process. The final product (e.g., the pharmaceutical), will be reviewed for approval by the product center at FDA responsible for that final product. What may be new to you is that CVM will be involved with evaluating the GE animal itself. We encourage biopharm sponsors to contact CVM as early in their research and development as possible so that we can provide assistance with developing a regulatory submission, as well as coordinating with other FDA centers. We welcome frequent and regular conversation with sponsors, especially well before any pre-IND phase of development. One of the first guidances we anticipate issuing following this guidance will address the administrative and review processes regarding biopharm animals.
Q. Why does CVM need to review GE animals that I’m developing as biopharm animals?
A. GE animals can pose risks to the food supply as well as to human and animal health. We recognize that biopharm animals will be highly valued and, from a business point of view, unlikely to be used for food; however, the agency would still need to determine that sponsors of these animals not approved for use in food have sufficient safeguards in place to ensure that they will not inadvertently enter the food supply.
Q: I haven’t made an animal with a heritable change, I am conducting gene therapy on animals; what should I do?
A: You should still contact CVM.
Q. How should I dispose of my investigational GE animals?
A. We recommend that investigational animals be disposed of by incineration, burial, or composting, and that appropriate records be kept of animal identification and disposition. 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. Under an INAD, however, you may request an Investigational Food Use Authorization from the agency. In order to receive such an authorization, you must submit sufficient data to demonstrate that food from these investigational animals is safe to eat or use for animal feed, and the agency must explicitly issue such an authorization, which would allow you to send your animals to slaughter or rendering for feed.
Q. If I’m not sure what to do, whom should I contact?
A: If you have any questions we invite you to contact the agency through either the phone number or address provided on the title page of the guidance. We are happy to help.
Q: Must I notify FDA that I am working with GE animals?
A. In general, yes, particularly if you are working with a species traditionally consumed as food. However, based on risk, there are some GE animals for which the agency may exercise enforcement discretion and not require an approval. For example, FDA is already exercising, and intends to continue to exercise, enforcement discretion for non-food species laboratory animals used for research. On a case-by-case basis, the agency may consider exercising enforcement discretion for other non-food species GE animals of very low risk. 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. The agency does not anticipate exercising enforcement discretion for any GE animal of a species traditionally consumed as food.
Q: How early in my research should I contact FDA?
A: You are always welcome to contact us if you have any questions regarding whether the GE animals you are developing will need premarket approval or whether FDA may exercise enforcement discretion over them. We can then work closely with you during the investigational phase of the development of these GE animals to ensure that animals do not inadvertently enter the food supply, and that data to support approval are developed efficiently and appropriately.
Q: What should I do first?
A: The first thing you should do is to contact CVM, and we will assist you in answering the questions you have specific to your animal. If you are working with a species not traditionally consumed as food, we may determine that, based on risk, FDA may exercise enforcement discretion over your GE animal. If not, or you are working with a species traditionally consumed as food, you will need to work through the INAD/NAD process with the Animal Biotechnology Interdisciplinary Group.
Q. What do I do if I believe FDA should exercise enforcement discretion over my GE animal?
A: You should contact the Animal Biotechnology Interdisciplinary Group, Project Manager at 240-402-0713, and work with that office in determining what kinds of data you should submit to enable the agency to determine whether it may be willing to exercise enforcement discretion over your non-food GE animal. The primary questions that the agency recommends you be prepared to address include whether there is anything about the rDNA construct that poses a human, animal, or environmental risk such as sequences that can cause human or animal disease either intrinsically or by recombination; whether, in the event of an environmental release, the GE animal poses any more environmental risk than its non-GE counterpart; and whether there are concerns about the disposition of GE animals that could pose public health risks. The agency will review the data on these issues, and then determine whether there are any other safety questions that have not been adequately addressed. As noted above, if we intend to exercise enforcement discretion over specific lineages of GE animals, we plan to post a statement describing that intent on our website.
Q: What do I do if I need to establish an Investigational New Animal Drug file?
A. First, contact the Animal Biotechnology Interdisciplinary Group at 240-276-8245 to make sure that you do need to go down the INAD/NADA path. To establish an INAD, you will need to send a letter to CVM containing such a request. In, or attached to that letter, please provide us with some background information regarding the species of animal used, the rDNA construct being used, and the intention of the modification. We recommend that this information be at approximately the level of detail that would normally be required for an NIH grant application. These requests should be sent to
Center for Veterinary Medicine
Document Control Unit, HFV-199
Animal Biotechnology Interdisciplinary Group
7500 Standish Place
Rockville, MD 20855
Q: What is a sponsor?
A: An animal drug sponsor is defined as “either an applicant named in an animal drug application . . . or a person who has submitted an investigational animal drug submission . . . .” All developers, producers, manufacturers, researchers, etc. who establish an INAD with CVM are considered, and referred to as sponsors.
Q: Will I have to pay User Fees?
A: Generally, sponsors of new animal drugs pay certain fees that support the review of products and applications. The fees include sponsor fees, establishment fees, and application fees. We anticipate that many GE animal sponsors would qualify for a small business or other waiver from these fees. More information regarding user fees.
Q: How often can I talk with CVM about my research?
A: There are no limits to how often you can talk to or meet with CVM regarding your product development. In fact, we encourage sponsors to meet with us frequently so that we can make the process of data gathering and preparation of your submission more efficient for both you and the agency.
Q: Are there milestones on the way to approval that I can use to gauge my progress?
A. As we complete our evaluation of the individual components of your New Animal Drug Application described in the guidance, we issue letters saying that you have satisfactorily completed that portion of the process. Our feedback from sponsors to date indicates that they find these letters helpful to indicate internal milestones of progress that they may share with others if they wish.
Q: I’ve been working on my project for a while already, but haven’t contacted anyone at FDA; what should I do now?
A. Please contact us using the information provided in the answers preceding this one. Once we determine whether FDA might be willing to exercise enforcement discretion over your research or if you should establish an INAD/NADA, we can help you organize your data for submission and review.
Q: I have questions about how this guidance specifically applies to my GE animal. Can I contact the agency to get help?
A: Yes, we encourage sponsors to consult with the agency to determine specifically how this guidance applies to their individual research. All of our reviews are conducted on a case-by-case basis, so we would be pleased to work with you on your particular research application.
Q: What kinds of information are required for an NADA submission?
A: In general, the guidance recommends that you begin by developing a product definition. The product definition is a short statement that characterizes the GE animal being produced, the rDNA construct in the GE animal, and the claim being made for the GE animal (i.e., the trait that the animal is expected to express). The guidance then recommends that you characterize the rDNA construct in the GE animal. In addition, the guidance recommends that you 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 you can meet the statutory requirements of safety to the health of the animal, and food or feed safety if animals are intended to enter the food supply. The guidance further describes your responsibility under the National Environmental Policy Act (NEPA) to provide an assessment of potential environmental effects. Finally, the guidance provides recommendations to help you meet your statutory requirements to validate the claim that is being made to demonstrate the effectiveness of the rDNA construct (i.e., that it does what you claim).
Q: How does the guidance compare with the recently adopted Codex Guidelines for the Food Safety of Foods from rDNA Animals?
A: The FDA guidance essentially recommends evaluation of the same information on food safety that the Codex Guideline does: the characterization of the rDNA construct, an evaluation of the health status of the GE animals, and a demonstration that the composition of food produced from rDNA/GE animals does not pose any food consumption risks.
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. Sponsors 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: How about labeling of food from GE animals?
A: FDA does not require that food from GE animals be labeled to indicate that it comes from GE animals, just as it does not require that food from GE plants be labeled to indicate that 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. Marketers may voluntarily label their foods as coming from GE or non-GE animals, so 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. Sponsors are required to register with the agency, and provide a list of all GE animals they have produced, 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.
1We refer to all producers, developers, manufacturers, researchers, and other stakeholders who file an application with CVM as “sponsors.”