*Table I, Parts III and IV should be consulted for additional information pertaining to specific regulations and to modern biotechnology products.

FOOD AND DRUG ADMINISTRATION (FDA)

Under the Federal Food, Drug, and Cosmetic Act (FFDCA), FDA, within the Department of Health and Human Services (DHHS), has oversight responsibility for human and other animal foods and their ingredients, dietary supplements, color additives, human and other animal drugs, cosmetics, not discussed here, and medical devices. In accordance with section 351 of the Public Health Service (PHS Act), as well as under the FFDCA, FDA also regulates human biologics, such as blood, vaccines and certain cells, tissues, and their products. Other human cells, tissues and their products, interstate conveyance sanitation, and human communicable disease agents are regulated instead under section 361 of the PHS Act pertaining to the prevention of human communicable diseases. Similarly, DHHS, specifically the Centers for Disease Control (CDC), handles through a permit, detention, inspection, and quarantine scheme, the importation from foreign countries of articles that can cause human communicable diseases and, through a registration system, the possession, use, and transfer of so-called select agents and toxins that have the ability to pose severe threats to human health. The select agents and toxins are regulated under the Public Health Security and Bioterrorism Preparedness and Response Act of 2002.

New drugs are regulated by the Center for Drug Evaluation and Research (CDER) within FDA, typically through a variety of premarket approval mechanisms, depending upon whether the drugs are versions of so-called innovators or copy some aspect(s) of the innovator drugs. All new drugs are approved through a new drug application (NDA) mechanism, although copies or generics are approved through the abbreviated new drug application (ANDA) process, and other versions that are not precise copies, among other drugs, through a so-called 505(b)(2) NDA application. Experimental human uses are handled through the use of an investigational new drug application (IND), which must be submitted at least 30 days in advance of clinical testing. Similar approval and experimental applications exist for veterinary drugs regulated by the Center for Veterinary Medicine (CVM), namely, a new animal drug application (NADA), abbreviated new animal drug application (ANADA), and investigational new animal drug (INAD). Veterinary drugs used in food animals are regulated more stringently than those used in other animals, such as companion animals. Human biologics are typically regulated by the Center for Biologics Evaluation and Review (CBER) and are subject to premarket approval in the form of a biologics license application (BLA); experimental uses are also subject to INDs. A major difference between biologics regulation and other drug or device regulation is the usual requirement of lot-by-lot release by CBER. For a detailed discussion of biologics regulation, refer to the Publications section of this website.

Human medical devices are handled by the Center for Devices and Radiological Health (CDRH) utilizing a classification system involving Class I, Class II, or Class III. Class I devices are subject to the least degree of regulation, while Class III are subject to the greatest control including the approval of premarket approval applications (PMAs), similar to the NDA submission for new drugs. Class I devices are those products for which safety and effectiveness can be assured through general controls involving the general adulteration and misbranding provisions of the FFDCA. Class II devices are those for which general controls alone are insufficient or for which special controls, including postmarket surveillance, and other mechanisms can assure their effectiveness. Class III devices are those whose safety and effectiveness cannot be assured by general or special controls and are generally life-supporting, life-sustaining, or present a potentially unreasonable risk of illness or injury. Before a Class III device may be marketed, FDA must approve a PMA.

Some Class I and most Class II devices must go through a 510(k) premarket notification process, which must be submitted 90 days in advance of marketing. An investigational device exemption (IDE) is required prior to beginning a significant risk study in human beings, whereas as non-significant risk studies do not require prior FDA approval although other requirements such as informed consent exist before the trial may begin. There also are several exemptions from FDA's IDE regulations, which apply to certain in vitro diagnostic products (IVDs), if they are labeled appropriately, the testing is not invasive, and does not require an invasive sampling procedure that presents significant risk, among other requirements. IVDs required for blood donor screening and related blood banking practices are usually licensed under the BLA process as biological devices. Some IVDs and other devices are handled by the Center for Biologics Evaluation and Research (CBER) but regulated as medical devices using the 510(k) or PMA process.

The Center for Food Safety and Applied Nutrition (CFSAN) regulates certain foods, such as medical foods, foods with health claims, dietary supplements, and infant formulas, somewhat differently than other foods or ingredients thereof. Another federal agency is particularly responsible for the regulation of meat, poultry, and egg products. Generally, new food and color additives are subject to premarket approval by CFSAN through the use of a food additive petition or a color additive petition. This includes such additives used in non-human animal foods sometimes called animal feeds. Food ingredients that are not color additives and that are generally recognized as safe (GRAS), among experts qualified by scientific training and experience to evaluate the safety of food, do not require premarket clearances. New dietary ingredients that are part of dietary supplements are subject to notification requirements at least 75 days prior to marketing.

FDA has proposed a GRAS notification procedure which it has been utilizing informally to acknowledge a company's determination of GRAS status. Previously, typically, GRAS affirmation petitions (GRASPs) were submitted to obtain FDA feedback on GRAS status. Although specific regulations list certain GRAS substances, such ingredients can be marketed even if they do not appear on such lists. A similar GRAS notification system does not yet exist for non-human animal food ingredients, although CVM still allows GRASPs and uses a so-called "no objection" letter to clear ingredients that it believes do not pose safety problems. Non-human animal food, such as pet food, is subject to additional regulation at the state level.

With respect to food ingredients, there are types of additives, including direct food additives, secondary direct food additives, and indirect food additives, which can be regulated differently in terms of safety and functionality data requirements. The first of these types applies to ingredients added directly to food for the purpose of having a technical effect in that food, whereas a secondary direct additive has a technical effect on food during food processing but not in the finished food. An indirect additive is intended to have a technical effect in food contact material, such as food packaging materials. Food contact materials are subject to a special system of clearances involving food contact notifications (FCNs). Regulations exist that cover investigational food additives, although they are seldom applicable or utilized. FDA does not usually require premarket clearances of whole foods, although a voluntary consultation process has been established for bioengineered food plants (see Part III).

ENVIRONMENTAL PROTECTION AGENCY (EPA)

Under the Toxic Substances Control Act (TSCA), EPA exercises significant authority over the testing and marketing of "chemical substances," particularly those that are new. Although the title of the law suggests it only applies to toxic chemicals, its scope is much broader. The statute was enacted in 1976 just when the debate about the safety of recombinant DNA work was beginning. At that time existing federal regulatory authority over conventional chemicals under many other environmental and public health laws was limited either to a particular use or medium of exposure and TSCA was perceived to fill the regulatory void. It does this primarily through a process under section 5 called premanufacture notification (PMN), which is required for new chemical substances 90 days in advance of their manufacture for commercial purposes. Since a "chemical substance" is defined broadly as "any organic or inorganic substance of a particular molecular identity," not surprisingly, TSCA is exceptionally all encompassing. Only certain substances regulated under other laws are explicitly excluded, such as chemicals used directly as foods, food additives, drugs, cosmetics, medical devices, and pesticides. Products covered by TSCA are handled by the Office of Prevention, Pesticides and Toxic Substances (OPPTS), specifically the Office of Pollution Prevention and Toxics (OPPT).

TSCA applies potentially to a wide variety of activities, in some cases from pure research and development (R&D) work, to use and disposal of a chemical substance or mixture. Although it covers the "manufacture" of a chemical substance or mixture, which implies large-scale production for monetary gain, the term "manufacture" is much broader and can include laboratory experimentation. For example, EPA has long held that "manufacture for commercial purposes," which is regulated under sections 5 and 8 of TSCA, does not necessarily exclude manufacture or processing of a chemical in small quantities for R&D.

Unless R&D is exempted from regulation by a specific provisions of TSCA, it can constitute "manufacture," although chemicals manufactured and used in purely academic-type research activities have yet to be regulated under TSCA. On the other hand, coverage of such chemicals is possible if the purpose of R&D is to obtain a commercial advantage. Activities such as test marketing or use of a chemical as an intermediate in the manufacture or processing of another commercially valuable substance thus are considered production "for commercial purposes."

Only section 5 governing, for example, PMN and portions of section 8 involving reporting and retention of information, contain R&D exclusions that limit their applicability to manufacture and processing for commercial purposes. Thus, both pure R&D conducted only for purposes of scientific interest and R&D performed for profit are potentially exempt from coverage of section 5 and portions of section 8. Other provisions, such as sections 4, 6, and 7, that contain no exemptions for R&D and do not restrict the meaning of "manufacture" to commercial operations cover all types of R&D, at least in theory.

TSCA provides EPA with comprehensive authority to regulate all aspects of chemical production and distribution, from prohibiting manufacture to requiring special types of labeling. Four key sections of the statute provide EPA with comprehensive authority. Under section 4, testing of chemicals can be mandated to ascertain their health and environmental effects. TSCA requires notification ninety days in advance of the intent to manufacture for commercial purposes a new chemical substance, to give the agency time to assess the safety of the chemical before environmental or human exposure occurs. It also provides EPA with certain follow-up authority in the event inadequate data exist about the health or environmental hazards associated with exposure to new chemicals or, where enough safety data exist, to control the manufacture and distribution of new chemicals manufactured for commercial purposes that pose an unreasonable risk of injury. Finally, various provisions of TSCA, which govern reporting and retention of information on chemicals manufactured for commercial purposes, authorize EPA to promulgate rules requiring the submission of data not only on production and exposure levels, but also on use and health and environmental effects. Section 5, the heart of TSCA, allows EPA to regulate chemicals before they are synthesized for commercial purposes. Premanufacture notification is required only for "new" chemical substances, which are those not on the "Inventory of Chemical Substances."

Not all new chemicals require a PMN, however; excluded are impurities, by-products made for no commercial purpose, and incidental chemical products. Test marketing exemptions (TMEs) are granted if no unreasonable risk to health or the environment is presented. EPA must grant or deny the exemption within 45 days and can impose restrictions.

Pursuant to section 5(h)(3) of TSCA, small quantities of chemicals manufactured or processed for commercial research or development purposes are exempt from PMN, provided all persons are notified of any health risk that may be associated with such substances. The purpose of this exemption is to ensure that R&D work is not impeded. EPA defines the term "small quantities" flexibly, to mean amounts that are no greater than reasonably necessary for R&D purposes, and which are used under the supervision of technically qualified individuals. A limited amount of distribution in commerce is permitted under the R&D exemption, subject to the foregoing restrictions. The R&D exemption from PMN is especially important in the biotechnology area, as discussed elsewhere.

Once PMN is provided, in the absence of EPA action under other TSCA authority subject chemicals are placed on the TSCA Inventory upon submission of a commencement of manufacture notice. Section 5(e) enables the agency to issue orders to limit production of a substance pending the development of more information, among other reasons. Also, section 8(e) requires substantiated risk notification pertaining to substances that present substantial risk of injury to health or the environment.

Section 5 also provides EPA with an additional screening authority unique to TSCA. A significant new use rule (SNUR) may be issued for any TSCA chemical substance. After the issuance of a SNUR promulgated with notice and opportunity for comment, prior notification to EPA is required before a manufacturer can manufacture a SNUR chemical for significant new uses. SNURs may be established for individual chemicals, for chemical categories, and for both new and existing chemicals. The purpose of the SNUR notice requirement is to furnish EPA with the opportunity to evaluate the intended use of a substance and, if necessary, give the agency time to prohibit or limit use before it begins. Through use of SNURs, EPA controls the manufacture of chemicals on the basis of such considerations as exposure, volume, use, or method of manufacture.

EPA has adapted PMN and SNUR requirements to apply to certain genetically engineered microorganisms. These include MCANs and SNUNs, respectively, as well as TERAs for experimental environmental releases (see Part III).

Pesticide regulation under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) involves prior review of experimental work, usually through experimental use permits (EUPs), and premarketing approval in the form of product registration, as well as the establishment under the FFDCA of tolerances or exemptions therefrom for residues of pesticides occurring in human or other animal food. The Office of Pesticide Programs within OPPTS, particularly the Biopesticides and Pollution Prevention Division (BPPD), is responsible for all regulatory activities associated with biologically-based pesticides, including those developed using modern biotechnology methods. Unlike the FDA area, many specific pesticidal and TSCA regulations have been developed for certain products of modern biotechnology (see Part III).

U.S. DEPARTMENT OF AGRICULTURE (USDA)

The Food Safety and Inspection Service (FSIS) oversees foods and their ingredients that are meat and poultry products under the Federal Meat Inspection Act and Poultry Products Inspection Act, as well as egg products under the Egg Products Inspection Act. Meat, poultry, and processed egg products are regulated by means of inspection of establishments for sanitation, inspection of animals before and after slaughter, product inspection and prior approval labeling requirements. FSIS requires the approval of experimental animals before they can be slaughtered. FDA and FSIS have executed a Memorandum of Understanding regarding the regulation and acceptability of ingredients used in meat and poultry products, which can involve premarket clearances of new food additives.

The Animal and Plant Health Inspection Service (APHIS) has extensive authority pertaining to the health of plants and non-human animals imported and transported in the United States. APHIS is involved in regulation of the imports and exports of such animals and animal products as well as of plants, including their interstate movement. In other words, it is concerned with pests or diseases of plants and non-human animals, including invasive species. The relevant laws are too numerous to list, except to say in the context of modern biotechnology products that the key laws had been the Plant Quarantine Act, the Federal Plant Pest Act, and the Federal Noxious Weed Act in the plant area and a variety of similar laws in the non-human animal area. These and some other statutes were collectively repealed either in 2000 by the Federal Plant Protection Act or in 2002 the Federal Animal Health Protection Act. Nevertheless, relevant regulations remain pretty much the same, particularly pertaining to products of modern biotechnology methods. The laws and regulations involve quarantine, inspection and permit requirements pertaining to imports, domestic movement, and environmental release and in many cases can be overlapping.

APHIS' Veterinary Services' (VS) National Center for Import and Export regulates the movement, including import and export of animal and animal products such as tissues and blood; and APHIS' Plant Protection and Quarantine (PPQ), handles the import, export, and interstate movement of plants, plant pests, and plant products that are not genetically engineered. APHIS' Biotechnology Regulatory Services (BRS) regulates the importation, interstate and environmental release into the environment of genetically engineered organisms that may pose a risk to plant health; and APHIS' Veterinary Services' Center for Veterinary Biologics (CVB) oversees veterinary biologics such as vaccines and diagnostic kits. Under the Agricultural Bioterrorism Act of 2002, VS and PPQ also regulate the possession, use, and transfer of select agents primarily in the non-human animal and plant areas, respectively. Veterinary biologics used for therapeutic, prophylactic, or diagnostic purposes are licensed under the Virus, Serum, and Toxin Act of 1913 (VSTA) through an authorization process for experimental uses and the use of establishment and product licenses for commercial uses that are designed to ensure product safety, purity, potency, and efficacy.

With respect to BRS, USDA was the first federal department or agency to develop modern biotechnology product-specific regulations, starting in 1986 with the announcement of the Coordinated Framework for Biotechnology Regulation. These regulations, which govern the introduction into the environment of recombinant DNA plants, are discussed more in Part III.

Other important USDA agencies that have been involved in regulation of products of modern biotechnology methods include the Grain Inspection, Packers and Stockyards Administration (GIPSA) the Agricultural Marketing Service (AMS). Although neither GIPSA nor AMS exercise premarket clearance powers, they play an important role in biotechnology regulation.

In most relevant part, GIPSA's Federal Grain Inspection Service (FGIS) is involved in facilitating the marketing of U.S. grain and other commodities under the U.S. Grain Standards Act (GSA) and the Agricultural Marketing Act of 1946 (AMA). They provide important standards in the marketplace called grades and related testing methods to assess commodity quality and quantity. Grading provides value to the consumer in terms of assuring uniformity. There also are user fee services involving official inspection and weighing services. GIPSA has conducted a number of biotech-related activities (see Part III).

AMS, through its Seed Regulation and Testing Branch, enforces most importantly the Federal Seed Act (FSA). FSA is largely a truth-in-labeling law that governs interstate shipments of agricultural and vegetable seed, including standards for seed certification. Labeling requirements can relate to purity, germination, and other quality and a few safety related factors, such as noxious weed content. It also provides for a fee a voluntary testing service for determining seed quality. AMS also administers the National Organic Foods Production Act of 1990 that provides for certification, quality, and other standards that must be met pertaining to the production and handling of foods labeled as "organic."