Appendix B
Regulatory Framework for Animal Biotechnology

BACKGROUND

The regulatory framework for animal biotechnology consists of the agencies, statutes, regulations and policies under which: (1) standards are established for the care and treatment of animals used in biotechnology research and testing activities, (2) decisions are made about market access and conditions of use for the commercial products of animal biotechnology, and (3) government post-approval oversight is provided to verify that marketed products are in compliance with regulatory requirements.

The regulatory framework’s standards and procedures for making market access decisions are particularly important to the study because they establish the general scope of the questions regulatory agencies will need to ask about the commercial products of animal biotechnology.

This discussion assumes that the initial products of animal biotechnology will involve: (1) modifications that affect the performance of the animal or attributes of products derived from the animal through the action of the expression product of an inserted gene; (2) animals modified to produce drugs, biologics, or other substances of commercial value; or (3) cloned animals.



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Animal Biotechnology: Science-Based Concerns Appendix B Regulatory Framework for Animal Biotechnology BACKGROUND The regulatory framework for animal biotechnology consists of the agencies, statutes, regulations and policies under which: (1) standards are established for the care and treatment of animals used in biotechnology research and testing activities, (2) decisions are made about market access and conditions of use for the commercial products of animal biotechnology, and (3) government post-approval oversight is provided to verify that marketed products are in compliance with regulatory requirements. The regulatory framework’s standards and procedures for making market access decisions are particularly important to the study because they establish the general scope of the questions regulatory agencies will need to ask about the commercial products of animal biotechnology. This discussion assumes that the initial products of animal biotechnology will involve: (1) modifications that affect the performance of the animal or attributes of products derived from the animal through the action of the expression product of an inserted gene; (2) animals modified to produce drugs, biologics, or other substances of commercial value; or (3) cloned animals.

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Animal Biotechnology: Science-Based Concerns The regulatory framework and the questions agencies will ask will vary depending the nature of the modification and the intended use of the resulting product(s). AGENCIES The Animal and Plant Health Inspection Service (APHIS) of USDA has jurisdiction over livestock used in biomedical research, teaching, or testing, to oversee compliance with the regulations for animal care and use promulgated by APHIS under the Animal Welfare Act (9 CFR Parts 1–4). The Office of Laboratory Animal Welfare of the National Institutes of Health (NIH) has responsibility for the general administration and coordination of the Public Health Service Policy (1996) on the Humane Care and Use of Laboratory Animals, including livestock and poultry used in biomedically-related research activities. The Center for Veterinary Medicine (CVM) in the Food and Drug Administration (FDA) has asserted primary jurisdiction over the first two categories of anticipated products of animal biotechnology noted in the background section above for purposes of making market access decisions, and setting conditions of use, but CVM’s jurisdiction is not exclusive. The Centers for Drug Evaluation and Research (CDER) and Biologics Evaluation and Research (CBER) in FDA also have jurisdiction over the products in category 2 to the extent they involve human drugs or biologics. The Center for Veterinary Biologics in the USDA’s Animal and Plant Health Inspection Service (APHIS) has jurisdiction over products in category 2 to the extent they are modified to produce animal biologics. The Center for Food Safety and Applied Nutrition (CFSAN) in FDA has jurisdiction over milk, eggs and other edible products (other than meat and poultry products) to oversee compliance with limits on residues in the edible tissue and ensure the general wholesomeness and safety of the food. The Food Safety and Inspection Service (FSIS) in USDA has jurisdiction over meat and poultry derived from genetically modified animals to oversee compliance with residue limits and ensure the general wholesomeness and safety of the food. It is unclear whether any agency has jurisdiction to make market access decisions or establish conditions of use for cloned animals. FDA has said that it may have jurisdiction over human cloning through its new drug authority and that it expects human cloning experiments to be covered by investigational new drug applications (IND’s). CVM has not taken a public position on its regulatory jurisdiction over animal cloning, but it is for now constrained not to take a position that is different in principle from the FDA position on human cloning. CFSAN and FSIS have jurisdiction to oversee the general

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Animal Biotechnology: Science-Based Concerns wholesomeness and safety of the edible tissue of a cloned animal, just like any other animal. STATUTES The Animal Welfare Act (1966) provides APHIS with the authority to regulate warm-blooded animals used for biomedical research, teaching, and testing, with the exception of rats, mice, and birds. Agricultural animals used in agriculturally related (i.e. food and fiber) research, testing, or teaching, are specifically excluded by Congress from regulation under the Animal Welfare Act. The Health Research Extension Act (1985), “Animals in Research”, requires that guidelines be established for the proper care and treatment of vertebrate animals used in biomedical and behavioral research, and that assurance be provided that each applicant for a grant or contract from the National Institutes of Health or other national research institute complies with these guidelines. The Health Research Extension Act provided the statutory mandate for adoption of the Public Health Service Policy (see below). Under this Act, the NIH may suspend or revoke a grant or contract in the case of noncompliance. The animal drug provisions of the Federal Food, Drug, and Cosmetic Act (FDCA) provide the basic authority for CVM’s oversight of products in categories 1 and 2. FDA considers the expression product resulting from the genetic modification of an animal to be a “new animal drug” under section 201(v) of FDCA. New animal drugs must be licensed by FDA under section 512 of the FDCA based on a showing that the products are safe and effective for their intended use. “Safe” has reference to the safety of man or animal (section 201(u) of FDCA). The general food safety provisions of the FDCA, the Federal Meat Inspection Act, and the Poultry Products Inspection Act provide CFSAN and FSIS authority to oversee the wholesomeness and safety of edible tissue from genetically modified animals. The new drug provisions of FDCA (primarily section 505) and biologics provisions of the Public Health Service Act (primarily section 351) provide CDER and CBER authority to regulate (by requiring premarket scientific review and licensing) the safety and effectiveness of human drugs and biologics produced by genetically modified animals and to ensure that they are produced under conditions that ensure their purity and potency. The Virus, Serums, and Toxins Act (VSTA) provides APHIS the authority to regulate the safety and effectiveness of animal biologics to ensure safety and effectiveness.

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Animal Biotechnology: Science-Based Concerns The National Environmental Policy Act (NEPA) requires all agencies to conduct an environmental assessment (EA) and, when there may be significant impact on the quality of the human environment, an environmental impact statement in connection with agency actions. Under NEPA, CVM would conduct an EA in connection with its approval of genetically modified animals under its animal drug licensing authority and seek measures to ameliorate any anticipated adverse environmental effects. NEPA does not override the market entry standards of the FDCA, and CVM is not legally empowered to deny approval of an animal drug based on its NEPA assessment. CVM asserts that its animal drug authority permits it to regulate the environmental impacts of genetically modified animals to the extent they adversely affect, directly or indirectly, the health of humans or animals. This presumably would include requiring mitigation actions and monitoring of environmental impacts. While NEPA is intended to provide for public consideration of the environmental impact of government actions, the FDCA’s animal drug authorities and regulations make the licensing process confidential between the applicant and the agency and preclude disclosure of information contained in the new animal drug application (NADA) confidential until the product is approved. REGULATIONS APHIS has issued regulations under the Animal Welfare Act (9 CFR Part 1–4) setting forth procedures for the oversight of the use of mammals (except purpose-bred rats and mice) in biomedical research, teaching, and testing. The regulations require certain minimum standards of housing and care, and also stipulate that research, teaching, or testing activities involving animals first be approved by an Institutional Animal Care and Use Committee. Although the Animal Welfare Act potentially applies to all warm-blooded animals, APHIS has so far chosen not to regulate birds; hence poultry used in biomedical research are not regulated under the Act. FDA has issued detailed regulations governing the animal drug approval process as it applies generally to animal drugs (21 CFR Parts 510–514). These were written prior to the advent of animal biotechnology. There are no FDA regulations specifically addressing animal biotechnology. Similarly, FDA has issued procedural regulations for its human drug and biologics programs but no regulations specifically targeting products derived from genetically modified animals. APHIS has issued procedural regulations governing its regulation of animal biologics under the Virus, Serums, and Toxins Act (9 CFR Parts 101– 118). FDA has issued regulations under NEPA, setting forth the procedures for EA’s and EIS’s (21 CFR Part 25).

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Animal Biotechnology: Science-Based Concerns POLICIES AND OTHER GUIDANCE The Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals (1986) describes the general standards and procedures to be used by institutions to comply with the provisions of the Health Research Extension Act, including approval of research activities involving animals by an Institutional Animal Care and Use Committee. The PHS policy also requires compliance with the Animal Welfare Act and the standards outlined in the Guide for the Care and Use of Laboratory Animals (1998) published by the Institute for Laboratory Animal Resources. The Federation of Animal Sciences Societies has issued guidance for the oversight of food and fiber research and teaching using animals, the Guide for the Care and Use of Agricultural Animals in Agricultural Research and Teaching (the Ag Guide). Adoption of these guidelines by an institution is voluntary. The Ag Guide is recognized as a resource document by USDA-APHIS and in the Guide for the Care and Use of Laboratory Animals, and as a primary reference document by the Association for the Assessment and Accreditation of Laboratory Animal Care International (AAALACI), the major animal care accrediting body for U.S. research institutions. CVM has issued informal guidance through articles and speeches on its general approach to overseeing animal biotechnology under its animal drug authority but has not issued any formal policy statements or guidance. CBER has issued scientific guidance to the industry in the form of “Points to Consider in the Manufacture and Testing of Therapeutic Products for Human Use Derived From Transgenic Animals” (1995). FSIS has issued a points-to-consider document on “Safety Evaluation of Transgenic Animals from Transgenic Animal Research.”