I. General Overview of Status
On September 18, 2008, the Food and Drug Administration (FDA or the agency) released Draft Guidance for Industry #187: Regulation of Genetically Engineered Animals Containing Heritable rDNA Constructs via the Docket’s Division. The guidance document clarifies that the Federal Food, Drug, and Cosmetic Act (FFDCA or the Act) new animal drug provisions and its implementing regulations apply to the recombinant DNA construct in genetically engineered (GE) animals. 1This draft document was open to public comment for a period of sixty days; the comment period closed on November 18, 2008.
FDA’s Dockets Branch received and logged in comments according to the date of receipt. Once entered into the Docket’s system, each comment was forwarded to the staff of FDA's Center for Veterinary Medicine (CVM or the Center), for review by the Center’s scientific staff. In this response document, we provide a general summary of all of the public comments we received, and our response to them.
All comments are available for the public to review at regulations.gov, docket number FDA-2008-D-0394. Alternatively, comments may be viewed at the Division of Dockets Management, 5360 Fishers Lane, Room 1061, Rockville, MD 20852, or by calling 240-402-7500 for assistance in finding a particular comment.
II. Overview of Comments
According to the Dockets Branch, the Draft Guidance # 187 received a total of almost 29,000 comments as of mid-December 2008. Of this total, approximately 28,000 either were form letters or simply made general statements about GE animals or the guidance. Of these, the vast majority opposed the genetic engineering of animals. The remaining 797 comments contained specific suggestions or criticisms. Of these, approximately 60 were what we consider to be substantive, because they provided detailed analyses, recommendations, or opinions. They came from consumers, academics, animal advocacy groups, trade and professional associations, consumer and environmental groups, foreign governments, other federal and state government agencies, developers of GE animals, meat producers and purveyors, and pharmaceutical companies.
III. Summary of Comments followed by FDA’s Responses (By Topic)
As noted above, most of the form letters and single-issue comments that FDA received opposed the use of genetic engineering in general, and the genetic engineering of animals in particular. Many comments also expressed concern about animal welfare. Whether animals should be genetically engineered, as an ethical matter, is outside the scope of this guidance. The purpose of the guidance is to describe how the Act’s new animal drug provisions and FDA’s implementing regulations apply to GE animals. FDA’s authority over new animal drugs includes review of the effects of such drugs on the health of the animals. To the extent that animal welfare encompasses animal health, FDA does include such issues in its review.
The following were the principal issues addressed in the comments:
- The adequacy and appropriateness of using the NADA provisions to exert regulatory oversight of GE animals;
- The need for transparency and for allowing public input into oversight of GE animals;
- The need for interagency collaboration, both on the federal level and between the federal and state/local levels;
- Potential federal preemption of state requirements;
- The adequacy of FDA’s approach to address animal health and safety;
- Food safety;
- Biopharm animals;
- Food labeling;
- Environmental safety;
- Moral, ethical, socio-economic, and animal rights issues relating to the genetic engineering of animals; and
- The Bioterrorism Act
Below, we address these issues.
A. Adequacy and Appropriateness of using the NADA Provisions to Regulate GE Animals
A number of comments, particularly from the regulated industry, expressed the view that the NADA provisions of the Act gave FDA appropriate tools to oversee GE animals. Other comments noted that the NADA provisions were not designed to cover GE animals, or rDNA constructs in GE animals. The definition of a drug, in section 201(g) of the Act, includes "articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals;" and "articles (other than food) intended to affect the structure or any function of the body of man or other animals." Because this definition applies to the rDNA construct intended to alter the structure or function of an animal, and for the reasons explained in the guidance, the NADA provisions of the Act apply to GE animals. See Guidance at 4-5. We believe that these provisions are adequate to address the safety concerns associated with such animals. Our experience to date in reviewing pending, but not yet approved, applications is that the NADA requirements work very well as a means of regulating GE animals.
A number of comments questioned why FDA issued a guidance, noting that regulations rather than guidances are needed to set out regulatory requirements. We note that requirements that apply to new animal drugs are established by statute and implementing regulations. The guidance document explains how those existing provisions apply to GE animals. We do not believe it necessary to promulgate new regulations because the existing regulatory structure is adequate to review the safety and effectiveness of GE animal-related applications. In addition to describing and clarifying statutory and regulatory requirements, the guidance recommends the types of data and other information needed to fulfill the regulatory requirements. Issuance of a guidance document is an appropriate means to convey such recommendations. See 21 CFR 10.115 (guidance documents describe the agency's interpretation of or policy on a regulatory issue).
A number of comments noted that the NADA process does not allow for much public input, and that often the public does not know a new animal drug is under review until FDA approves it. Commenters stated that such lack of transparency is particularly inappropriate for products of a new and controversial technology such as the genetic engineering of animals. Other comments stated that developers of GE animals have the same need and deserve the same right to protect their confidential commercial information as do developers of conventional human and new animal drugs.
We are taking steps to increase the transparency of the GE animal review process. For example, we intend to hold public advisory committee meetings prior to approving any GE animal. Although we may revisit that policy in the future as we gain more experience with reviews of GE animals, we will keep in mind the public's desire for information regarding GE animal reviews.
On January 9, 2008, CVM participated in a public meeting of the FDA Blood Products Advisory Committee on the Biologics License Application (BLA) for recombinant human antithrombin III produced in the milk of GE goats. At this meeting, with the sponsor's agreement, CVM provided a summary of its review of the NADA pertaining to the GE goats, as well as a summary of the environmental assessment (EA) submitted in support of the NADA. For GE animals intended for food or other non-biopharm use, we intend to hold advisory committee meetings dedicated to consideration of the GE animal NADAs and environmental reviews.
New animal drug approvals are published in the Federal Register, codified in the Code of Federal Regulations, and posted on FDA's website at Animal Drugs @ FDA. We will also post a detailed summary of the information on which the approval is based in our FOIA Electronic Reading Room.
We also plan to post statements describing our intent to exercise enforcement discretion with respect to specific GE animal lineages on our website.
C. Interagency and Federal-State Collaboration
A number of comments address the complementary aspects of FDA’s oversight with that of other federal agencies, such as the Animal and Plant Health Inspection Service (APHIS), the Food Safety Inspection Service (FSIS), the Environmental Protection Agency (EPA), the U.S. Fish and Wildlife Service (FWS) and the National Marine Fisheries Service (NMFS). Some liked the fact that the guidance mentioned that FDA would coordinate with other agencies as appropriate, while others requested that FDA develop formal agreements with various agencies to ensure appropriate collaboration and oversight. Some commenters were particularly concerned that FDA’s authority and its technical expertise were not adequate to address certain environmental issues, such as fish raised in ocean net pens or wildlife animals intended for release into the wild, and suggested that FDA should make use of or rely on other federal or state agencies to address such issues. Still other commenters were concerned about FDA’s oversight of GE insects, believing that such oversight would be better left to other agencies such as APHIS and EPA.
FDA appreciates the importance of collaboration and cooperation with other agencies to make use of all available expertise and legal authorities. We already work closely with APHIS and EPA on jurisdictional issues relating to GE insects and expect that one or the other of those agencies will have the lead in oversight of a variety of types and uses of GE insects. FDA continues to hold discussions with experts in NMFS and FWS on aquaculture issues relating to GE fish, and with APHIS and FSIS on various oversight issues relating to GE livestock. Additionally, § 1007 of the Food and Drug Administration Amendments Act of 2007 requires FDA to consult with NMFS to produce a report on any environmental risks associated with genetically engineered seafood products, including impact on wild fish stocks.
FDA experts work closely with experts from other agencies, and from other countries, in multiple fora, including in international multilateral organizations such as Codex Alimentarius, the World Organization for Animal Health (OIE), and the Organization for Economic Cooperation and Development (OECD). FDA and USDA co-chair the Group on Quality Assurance in Aquaculture Production of the U.S. interagency Joint Subcommittee on Aquaculture. And, as noted in the final guidance, FDA intends to work with other relevant federal and state agencies should it receive a request for investigation or approval of a GE wildlife animal ultimately intended for release into the wild. Thus, we believe FDA's ongoing collaborations with other agencies address the commenters' concerns.
We also believe it is important to note that, contrary to some commenters' assertions, FDA has considerable expertise in aquaculture, at both the regulatory and research levels. For further information on FDA’s expertise in aquaculture, please see Aquaculture and Office of Research for FDA publications and activities relating to aquaculture.
D. Federal Preemption
Some comments requested that the guidance include information on the relationship between federal and state requirements, whether FDA oversight of GE animals preempts state limitations on GE animals including food labeling requirements or outright bans. The guidance notes that FDA will cooperate with state agencies as appropriate and that developers may be subject to other federal, state, local and tribal requirements that apply to their products. In general, whether FDA requirements for GE animals preempt state or local requirements will depend on the nature of the particular state or local requirements. If a state law requirement makes compliance with both Federal law and state law impossible, or would frustrate Federal objectives, the state requirement would be preempted. See Geier v. American Honda Co., 529 U.S. 861 (2000); English v. General Electric Co., 496 U.S. 72, 79 (1990); Florida Lime & Avocado Growers, Inc., 373 U.S. 132, 142-43 (1963); Hines v. Davidowitz, 312 U.S. 52, 67 (1941). For example, a state law requirement for mandatory labeling that is misleading because it suggests that food derived from a GE animal is materially different from its non-GE counterpart in an instance where there is no such difference would conflict with the misbranding provisions of the FFDCA.
E. Animal Health and Welfare
Some of the commenters stated that the genetic engineering of animals was unacceptable for reasons related to animal health and welfare. Some comments suggested that the agency had not gathered sufficient scientific information on the health and welfare of GE animals to determine the long term safety and stability of the construct across generations. Their recommendations included a moratorium on the use of GE animals until additional animal safety and health studies had been concluded along with the creation of risk assessment and post-market surveillance plans. Some comments indicated that the low frequency of rDNA integration resulting in healthy GE individuals with the desired phenotype would result in the use of increasing numbers of animals to produce viable GE offspring.
Under the Act and FDA’s implementing regulations, new animal drugs, including rDNA constructs, cannot be approved unless they are found safe for the animal. 21 U.S.C. § 360b(d). We therefore review animal health very carefully as part of the NADA approval process, and will not approve an application unless it meets the animal safety standard. Further, because the site at which an rDNA construct is located can affect the health of the animal, the guidance notes that, in general, FDA considers each animal lineage derived from a separate transformation event (or series of transformation events) to contain a separate new animal drug subject to a separate new animal drug approval.
Additionally, we note that USDA’s APHIS addresses animal welfare under the Animal Welfare Act (AWA). The AWA requires institutions performing research on animals to establish Institutional Animal Care and Use Committees (IACUCs) to oversee and evaluate all aspects of the institution's animal care and use program. Their purpose is to ensure that research or investigational animals are not exposed to unnecessary risk, and that the animals’ health and welfare are adequately protected. IACUCs are interdisciplinary groups of individuals that must include at least one veterinarian and one member of the public representing community interests. The AWA also specifies that an APHIS veterinarian must annually inspect facilities in which such research is being conducted.
F. Food Safety
Many comments focused on the need to ensure that food from GE animals is safe, and raised a variety of potential food safety concerns. Some commenters recommended that FDA harmonize its food safety review with that of the Codex Alimentarius’ Guideline for the Food Safety Assessment of Food from recombinant DNA Animals, while others complimented FDA for having done just that. A number of commenters requested that FDA institute a mandatory premarket approval system for food from GE animals, while others praised FDA for having established just such a system. Some comments requested that FDA establish registration and tracking systems for GE animals and detection methods for food from such animals.
Under the FFDCA and FDA’s implementing regulations, a new animal drug cannot be approved for use in food animals unless FDA determines that the drug and anything formed in or on the food because of use of the drug is safe for consumption. 21 U.S.C. § 360b(d). As part of that safety determination, FDA evaluates the potential toxicity and allergenicity of the rDNA construct and its expression product(s) (the drug and its residues), as well as the potential unintended effects arising from the presence of the rDNA construct, consistent with recommendations in the Codex Guideline for the Food Safety Assessment of Food from rDNA Animals.
With respect to methods to ensure that GE animals are identifiable, we believe a tracking system for GE animals is not warranted. The Act and its implementing regulations require that an NADA include a method of detection that can be used to identify the rDNA construct in the GE animal, except when data or other adequate information establish that it is not reasonable to expect the new animal drug (the construct) to become a component of food at concentrations considered unsafe. 21 U.S.C. § 360b(d), 21 CFR 514.1(a)(7). The guidance recommends that this labeling include the product definition, which contains information describing the animal (e.g., common name/breed/line, genus, species, GE animal line, rDNA construct) and its intended use.
G. Biopharm Animals
A number of comments addressed FDA oversight of animals genetically engineered to produce human or animal pharmaceuticals or medical devices for humans ("biopharm" animals). Most expressed support for the regulatory process for such animals described in the guidance, as well as support for FDA to publish a guidance with more detail on that process, particularly regarding coordination and cooperation between CVM and the FDA center responsible for review and approval of the human pharmaceutical. One comment stated that CVM oversight of biopharm animals was unnecessary because it was duplicative of oversight by the FDA center responsible for the human pharmaceutical, as well as of oversight by APHIS of animal health. It stated that start-up companies had limited resources and could ill afford complying with duplicative requirements.
We appreciate the concern of start-up companies that regulation not be duplicative and unnecessarily onerous. CVM and the other relevant FDA centers are working closely together to ensure that the regulatory process for biopharm animals is as coordinated and streamlined as possible, consistent with our statutory obligations. As noted above, we are also working with APHIS to ensure appropriate coordination and communication. To date, our experience indicates that the process for biopharm animals is working smoothly and is not creating an undue burden on sponsors. We intend to publish additional guidance in the future on oversight of biopharm animals. This guidance will discuss the process in more detail, particularly with respect to coordination between CVM and the FDA Center responsible for oversight of the extracted product to be used in humans or other animals, and will provide interested stakeholders the opportunity to comment on that regulatory process.
H. Food Labeling
The issue of labeling food from GE animals comprised a significant proportion of comments submitted to the agency. Most comments urged the agency to require mandatory labeling of food products from GE animals, citing a consumer "right to know." Some comments took the opposite view, even recommending that FDA ban voluntary labeling to indicate that a food did not come from a GE animal.
Under section 403(a)(1) of the Act, a food is misbranded if its labeling is false or misleading in any particular way. Section 201(n) of the Act further defines misleading labeling. Labeling meets that definition if it fails to reveal facts that are material in light of representations made or suggested in the labeling, or material with respect to consequences that may result from the use of the food to which the labeling relates under the conditions of use prescribed in the labeling, or under such conditions of use as are customary or usual. Historically, the agency has generally interpreted the scope of "materiality" to mean information about the attributes of the food itself. Thus, if food from a GE animal is different from its non-engineered counterpart (for example, if it has a different nutritional profile), the difference could be material information that would have to be indicated in the food labeling. FDA does not consider the methods used in the development of bioengineered foods, including GE animals, to be "material" information. 2Food marketers may voluntarily label foods as being derived from GE or non-GE animals, as long as the labeling is truthful and not misleading.
I. Environmental Issues
A number of comments discussed a variety of environmental risks potentially posed by certain uses of some GE animals, and questioned whether FDA had adequate legal authority or appropriate technical expertise to address such environmental concerns properly.
The risks described in the comments included the possibility that if certain GE animals were released or escaped into the environment, they could have a competitive advantage over a wild species, or could interbreed with and transfer their GE traits to wild or domestic non-GE counterparts. The potential approval of GE fish for use in net pens in open waters was cited as being of particular concern because of the potential for escape. These concerns extended to possible effects on other wild populations of fish and to negative economic impacts on fisheries. Some comments urged that the agency not approve any applications for GE fish, particularly Atlantic salmon that would be grown in net pens. Some comments stated that GE fish might be able to be grown safely in land-based recirculating systems.
The comments questioning FDA’s legal authority to address environmental risks noted that the agency does so through its implementation of the National Environmental Policy Act (NEPA), and that NEPA does not give the agency authority to deny approval of an application. Additionally, as noted previously in the section on interagency and federal-state collaboration, a number of comments stated that other federal and state agencies have authority and expertise that could help address some environmental issues. Commenters also urged the agency to ensure that that NEPA evaluations are made public in accordance with the requirements of the Act and its implementing regulations.
FDA recognizes that certain uses of some GE animals could pose environmental risks, and is aware of its obligations under NEPA to assess such risks. It is true that NEPA is a procedural requirement and does not give FDA new authority, such as to prohibit an activity solely because it would harm the quality of the environment. However, it has been our experience that developers of new animal drugs will choose to mitigate potential environmental impacts so that FDA can come to a finding of no significant impact on the environment for an NADA approval. They prefer such mitigation to waiting for FDA to complete an environmental impact statement for a product whose approval will have a significant environmental impact. For example, for GE animals such mitigations may include multiple, redundant containment systems (e.g., physical containment such as barriers, and biological containment such as sterilization). The agency's environmental assessment under NEPA will review risks under those contained conditions, taking into account the implications of escape, establishment, and introgression. Further, although the agency has extensive expertise in environmental assessment, including for fish, other federal and state agencies have overlapping or complementary authority and expertise that could be helpful in addressing such risks. We intend to consult with those agencies when appropriate, to ensure that such risks are adequately characterized and mitigated. Finally, it is our intent to make the results of environmental reviews public.
J. Requests for further clarifications
A number of comments asked for clarification of a variety of issues addressed in the guidance. These included: (1) how FDA distinguishes between the GE animal as drug and the GE animal as food; (2) whether the definition of "animal" includes aquatic animals such as fish and shellfish and invertebrate animals such as insects, crabs, and nematodes; (3) whether FDA will do separate INAD and NADA reviews and approvals for each species of GE animal; (4) how FDA will evaluate potential environmental hazards and risks, considering the differences in the viability, fecundity and cross ability among animal species; (5) whether import tolerances can be established for import of live animals as well as for import of food from animals; (6) whether import tolerances could be established for food from animals treated with recombinant live vaccines not approved in the U.S.; and (7) whether the Minor Use, Minor Species Act (MUMS) provisions of the FFDCA apply to GE animals.
- Drug/Food Distinction: As noted in the guidance, the rDNA construct intended to affect the structure or function of the body of the GE animal is the new animal drug. A live GE animal contains the drug; in addition, the developer may make drug claims for the construct (i.e., the GE animal is intended to express a particular substance in its milk, or the GE fish is intended to grow faster than a conventional fish). Therefore, the drug authorities of the FFDCA apply. Live animals may also be food, U.S. v. Tuente Livestock, 888 F. Supp. 1416, 1424 (S.D. Ohio 1995), and, of course, certain products derived from animals, such as meat, are food. Therefore, the food authorities of the FFDCA could also apply.
- Animal Definition: The FFDCA does not define "animal." The common definition for animal is any organism in the kingdom "animalia." Organisms within animalia include fish, shellfish, insects and other arthropods, and nematodes. As noted above, we will work with other agencies that have complementary oversight of particular types and uses of GE animals to ensure that the most appropriate regulatory tools are used.
- Reviews for Each Species: As noted in the guidance, FDA’s NADA reviews are for each animal lineage derived from a separate transformation event. INAD files, however, may contain information on multiple versions of the rDNA construct with different copy numbers or insertion sites under one INAD. The kinds of data and information necessary to support an approval are specific to the type and use of the GE animal lineage under review, so each evaluation will be performed on a case-by-case basis, and not for whole species. There may be multiple NADAs, each reviewed separately, for one animal species.
- Environmental Reviews: Similarly, FDA will conduct environmental reviews on a case-by-case basis for each lineage of GE animals that is the subject of an NADA. These assessments will take into account the nature of the rDNA construct, the phenotype of the resulting GE animal, the containment conditions under which the sponsor proposes to operate, the potential environmental consequences of release or escape into the environment, and any other information that is relevant to the application.
- Import Tolerances for Live Animals: If live animals, such as lobster, are presented for import, FDA would determine whether an import tolerance has been established for the edible portions of the animal under section 512(a)(6) of the Act, which allows FDA to establish a tolerance for a drug that is not approved for use in the U.S. 21 U.S.C. § 360b(a)(6).
- Import Tolerances for Food from Animals Treated with rDNA Vaccines: Most animal vaccines, whether rDNA vaccines or conventional, are regulated by USDA/APHIS under the Virus-Serum-Toxin Act, 21 U.S.C. §§ 151-159. The requirements relating to import of food from animals treated with vaccines is the same irrespective of whether the vaccine is from a recombinant DNA organism, is itself a recombinant DNA organism, or is a conventional vaccine. Sponsors should contact USDA/FSIS to determine requirements for importation of food containing residues from animals treated with a vaccine. In general, if the food does not contain residues of the vaccine, there would be no special regulatory requirements for such food.
- MUMS: The conditional approval and indexing provisions for minor use and minor species new animal drugs do not apply to GE animals (which are referred to as "transgenic animals" in the MUMS legislation). See 21 U.S.C. § 571(a)(3) ("A person may not file" a conditional approval application for "a new animal drug that is contained in, or is a product of, a transgenic animal."); 21 U.S.C. § 572(a)(2) ("The index shall not include a new animal drug that is contained in or a product of a transgenic animal."). Minor use and minor species NADAs for GE animals may be eligible for designation under section 573 of the Act, however. 21 U.S.C. § 573. For more information on MUMS, see Minor Use/Minor Species.
K. Moral, Ethical, Socio-Economic, and Animal Rights Issues
As noted above, the vast majority of comments expressed opposition to the genetic engineering of animals. Comments gave a variety of reasons for this opposition, including that manipulating the genomes of animals in ways that could alter their fundamental natures was, in and of itself, unethical or immoral, that experimenting with animals was wrong, that genetic engineering may have adverse social and economic consequences, that it is not possible to predict what such technology might lead to, and that in general, FDA should ban rather than facilitate the genetic engineering of animals.
We recognize that many commenters have strong views on these subjects; however, they are largely outside the scope of FDA's authority. The statutory and regulatory review and approval requirements for NADAs ensure that only drugs that are safe and effective are approved. In this guidance, our goal is to describe how the existing new animal drug regulatory structure applies to GE animals. The moral, ethical, and socioeconomic issues outlined above do not fall within the scope of the guidance. It is FDA's intent, however, that the regulatory approach described in the guidance will provide a predictable science-based framework that will ensure the safety and safe use of GE animals.
L. Bioterrorism Act
One comment claimed that FDA was not allowing food from GE animals to be labeled as being derived from a GE animal, and that such a prohibition violated religious freedom (noting that FDA allowed labeling to indicate that a food was kosher). It also said the absence of GE-specific labeling would prevent FDA from fulfilling its legal mandate to protect the US food supply and would prevent consumers from reporting problems specific to food from GE animals. The comment also claimed that the FDA approach to oversight of GE animals did not accommodate the requirement of Section 306 of the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 (BT Act) that records be kept to identify the immediate previous sources and the immediate subsequent recipients of food. It also claimed that no testing is available to allow FDA to determine if food from a GE animal is adulterated.
As noted above in the discussion on labeling, FDA does not prohibit voluntary labeling of food from GE animals. The requirements for labeling food from GE animals are the same as the requirements for labeling food from non-GE animals. Voluntary labeling is allowed so long as the labeling is truthful and not misleading.
Identification of food as being derived from a GE source is not within the scope of the BT Act. As described in the guidance, the NADA process mandates a food safety assessment to ensure that the effects of the rDNA construct in the GE animal does not adversely affect the safety of food from the animal. If consumers find safety problems with a food, they can report that problem to FDA or to USDA as appropriate, irrespective of whether the food came from a GE or non-GE animal.
1 Note that, as in the guidance document, as a short hand we refer to regulation of the article (the new animal drug) as regulation of the GE animal.
2 See FDA’s 1992 "Statement of Policy: Foods Derived from New Plant Varieties" (57 FR 22984); FDA's response to the Center for Food Safety's March 21, 2000 citizen petition regarding GE foods (Docket No. 2000-1211/CPI) (CFS 2000 CP) at 7-8.