1. Regulating Transgenic Animals (Following the Risks) Fred H. Degnan fdegnan@kslaw.com

2. Coordinated Framework: Key Concept: A Federal “Safety Net” Subject all transgenic crops and animals to science-based regulation For animals, ensure animal safety and regulatory compliance of all resulting products

3. Coordinated Framework: Basic Theme Agencies may rely on existing statutory authority for regulating the safety of food and the safety and effectiveness of drugs (for people and for animals) regardless of the “process” by which such foods and drugs are produced. The regulatory upshot: products of biotechnology are subject to the same general food safety and drug safety and effectiveness requirements as more traditional products.

4. Coordinated Framework Federal Policy Announced –OSTP notice and request for comments –Regulatory policies: FDA, EPA, USDA, OSHA –Research policies: NIH, NSF, EPA, USDA –51 FR 23302 (June 26, 1986)

5. Coordinated Framework Federal Policy Upheld –Complaint dismissed FOET v. Johnson (DDC 1986) –First of several challenges to be filed since 1986 against the Coordinated Framework or actions taken by agencies under the Framework All challenges dismissed or withdrawn

6. Animal Biotechnology: Federal Regulatory Authorities FDAFood, Drug, and Cosmetic Act USDA (FSIS, APHIS) Animal Health Protection Act Animal Damage Control Act Animal Welfare Act Meat, Poultry and Egg Inspection Act

7. CEQ and OSTP 2001 Case Studies re: Coordinated Federal Framework for Regulating Products of Biotechnology For transgenic animals: case studies identified FDA’s new animal drug rubric as the primary mechanism for control and entry into other possible regulatory control systems (new drug regulation, biologic regulation, etc.)

8. Animal Health Protection Act (AHPA) Parallels in many ways the Plant Protection Act AHPA allows APHIS to regulate movement of any article or “pest” Movement is defined to include “release into the environment” AHPA includes authority for broad remedial (post- market) action, from rulemaking to seizure and destruction Recognizes “potential” to act as or to harbor a “pest”

9. AHPA Definitions “Pest” defined very broadly, as one of several listed organisms, that can cause injury, damage or disease in livestock, including an arthropod, virus, vector, infectious agent, etc. “Article” can be any pest or disease, or anything that could harbor a pest or disease. “Livestock’ is any farm-raised animal.

10. AHPA and Transgenic Animals: Possible Applications Could apply to transgenic livestock containing a “pest” or made susceptible to a “pest” Could provide basis for “permit” system for field trials Could theoretically be used to develop tracking and identification system for GE livestock

11. Animal Welfare Act (AWA) Requires minimum standards of care and treatment for animals bred for commercial sale, used in research, transported commercially, or exhibited to the public.

12. AWA Application Applies to all research mammals other than rats and mice. Does not apply to lab rats, birds or mice, to cold- blooded animals, or to farm animals. Applies to research facilities, dealers, and exhibitors of these animals. Applies to animals derived through biotechnology in the same way as applied to other animals.

13. Animal Damage Control Act (ADCA) Grants APHIS authority to control “injurious animal species.” Congress has indicated this includes authority to protect agriculture, natural resources, property and public health and safety.

14. ADCA Activities Controls West Nile virus, rabies, etc. Controls predators of livestock and endangered species. Controls birds that interfere with aviation. Action need not address entire species, e.g., predatory wolves, coyotes.

15. ADCA Authority Should certain animals derived through biotechnology prove injurious to agriculture, the environment, or public health or safety, the ADCA provides authority to control those animals.

16. Federal Meat and Poultry Inspection Acts Authority over the processing and slaughter of most animals Authority to ensure resulting products are not “adulterated” Applies to meat and poultry products derived from transgenic animals

17. USDA Authorities Summary Post Market –authority to respond to may problems that could arise Pre-Market Authority –animal biotechnology may not use “pests” to same extent as plant biotechnology as donors, recipients, or vectors –“field trials” are not “clinical studies” to assess efficacy, safety (to humans and animals)

18. New Animal Drug Rubric The fundamental focus of the new animal drug rubric is threefold: Is the new animal drug safe for the animal? Is the new animal drug effective - does it cure, treat or prevent disease in the animal or does it affect the animal’s structure, i.e., promote growth? If the drug is for a food-producing animal, is the resulting food safe for you and me to eat?

19. Overview of New Animal Drug Rubric If “new animal drug,” then: –requirement for submission to FDA of investigational new animal drug application (INADA) for all clinical research protocol development with FDA bioresearch monitoring authority –submission of new animal drug application (NADA) demonstration of safety to animal demonstration of safety of any resulting human food demonstration that the drug is “effective” demonstration of safety to people and other animals –post-market control authority submission to FDA of adverse reaction reports subject to FDA inspection with or without cause

20. New Animal Drug Rubric If a new animal drug is used without FDA approval the drug itself violates the law, any food from animals having received the drug is per se violative, and manufacturers and users of the drug are subject to being enjoined or prosecuted for marketing and using the drug.

21. Animal Drug? A substance is an animal “drug” if it is intended to cure, mitigate, treat or prevent disease in animal or it is intended to affect the structure or function of the body of an animal (e.g., to promote growth)

22. New Animal Drug? If a substance is an animal drug it must, by law, go through a pre-market approval system unless it is “generally recognized” by qualified experts as safe (“GRAS”) and effective (“GRAE”) for its intended use(s). “GRAS” and “GRAE” status are only granted when there are adequate publicly available data and information supporting expert recognition.

23. Animal Drug? New Animal Drug? A genetic construct capable of –speeding up the growth of an animal = “an animal drug” (effect on structure & function of body) or –imparting disease resistance = “an animal drug” (effect on preventing disease) A genetic construct that is a drug is a “new animal drug” if neither GRAS nor GRAE

24. The NADA Approval Process and Transgenic Animals NADA paradigm and transgenic animals; not a perfect fit conceptually: –clearly not contemplated by framers of FDC Act –questions re: process and governing criteria remain unanswered But, it offers, in large part –opportunity for comprehensive regulation –opportunity to systematically address complex issues involving the interplay of human food safety and animal health concerns –opportunity for coordination with CDER and CBER

25. FDA Approach to Regulation of Animal Biotechnology Essential Premise: “Follow the Risk”

26. Where To Look For Hazards and Risks Risk to Humans –food consumption –vector-based risks Risk to the Transgenic Animal –insertional mutagenesis (unanticipated) –product-specific effects (anticipated) Risk to Non-Target Animals –feed consumption –vector-based dynamics concerns –population dynamics concerns

27. Sources of Hazards: Construct Preparation Characterization of construct History and origin of materials –transgene, promoter, vector, etc. Vector propagation Sequence of transgene, promoter, vector Characterization of transgenic animal –expression of construct –animal health issues

28. A Closer Look at the INAD Process Governed by regulations, 21 CFR Part 511 Much opportunity for discussion between sponsor and CVM Sponsors submit “product development plan” Sponsors develop and agency reviews study protocols Opportunity for pre-submission review and conference “Edible products” of “treated” animals may be authorized for food use

29. Investigational Animal? All animals involved in the study of the gene construct including: –actual transgenic animals; –potentially transgenic animals (e.g., “no-takes”) –non-transgenic progeny of transgenic animals; –surrogate dams, breeding partners, and contemporaneous comparators.

30. INAD Process: Does It Work For Transgenics? Logical entry into regulatory system at clinical research stage Provides foundation for comprehensive data collection –full NADA (e.g., for growth promotion drugs) –dealings with CBER, CDER (e.g., for production of human biologics or drugs) Suffers from lack of publicly available road map with mile posts –what, exactly, is the process? –what testing needs to be conducted and information needs to be filed? –what is nature of review for different types of applications –what is coordination process for dealing with CBER, CDER? –absence of road map hinders reliable estimation of the cost of compliance Relies on agency/industry dialogue

31. Environmental Safety FDA relies on “safety” authority to require that use, manufacture or disposal must not pose a significant environmental impact: Hazards to humans associated with manufacturing –occupational exposure –emissions Hazards to humans associated with administration to animals Hazards to humans and animals from use and disposal

32. Environmental Assessment FDA has stated that, under the FDC Act, it may: Require environmental safety instructions on product labels Impose conditions to ensure mitigation of environmental impact (sterilization; “recovery plans”) Refuse to approve in the fact of unmitigatable environmental impacts adversely affecting the health of humans or animals

33. Animal Biotechnology: Science-Based Concerns (2002) (NAS) “Environmental issues are the greatest science-based concerns associated with animal biotechnology … in large part due to the uncertainty inherent in identifying environmental problems early on and the difficulty of remediation once a problem has been identified ….” “The release or escape of genetically engineered animals could result in a transgene spreading through reproduction with wild type individuals of the same species.” The … potential allergenicity of the newly introduced proteins might be a concern.” “Of the genetically engineered animals that survive, many do not express the inserted gene properly, often resulting in anatomical, physiologic, or behavioral abnormalities.” Specific concern expressed with regard to the oversight of arthropods.

34. Wish List for FDA: Administrative Actions Confirm administrative commitment to new animal drug rubric; Develop guidances and criteria governing the safety of food resulting from transgenic animals; Develop a specific transgenic animal enforcement/inspection program beginning with the INAD process and including commercialization.

35. Wish List for FDA: Administrative Actions (cont.) Update existing relevant regulations and policies regarding clinical investigation, GMP controls, etc. to specifically apply to transgenic animal development and production; and Develop guidances or regulations regarding FDA’s authority to impose environmental mitigations and the types of mitigations appropriate in given circumstances.