FDA

The Food and Drug Administration (FDA) is a regulatory and research agency within the US Department of Health and Human Services that is responsible for "protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, ... cosmetics, and products that emit radiation." FDA's broad statutory authority stems from the Federal Food, Drug, and Cosmetic Act of 1938 (FFDCA), as amended.

FDA's programs are organized into a number of centers and offices, each with its own regulatory, research and/or enforcement mandate. In the context of regulatory toxicology, most animal use and/or testing requirements at FDA can be linked to the following divisions:

• Center for Biologics Evaluation and Research (CBER), which regulates the licensing of vaccines, blood products, animal-to-human xenotransplants, and other human biologics
• Center for Devices and Radiological Health (CDRH), which is responsible for pre-market approval of new medical devices and radiation-emitting electronic products
• Center for Drug Evaluation and Research (CDER), which regulates the licensing and labeling of human pharmaceuticals
• Center for Food Safety and Applied Nutrition (CFSAN), which monitors the safety and labeling of cosmetics, food additives, processed foods and shellfish
• Center for Veterinary Medicine (CVM), which regulates veterinary drugs and devices, pet foods and livestock feeds
• National Center for Toxicological Research (NCTR), which conducts intramural R&D and provides scientific support to other FDA centers and offices

Cosmetics

The marketing of cosmetics in the US is regulated by the Office of Cosmetics and Colors within FDA's Center for Food Safety and Applied Nutrition pursuant to the Federal Food, Drug, and Cosmetic Act and the Fair Packaging and Labeling Act. In contrast to most other products regulated by FDA, cosmetics––including shampoo, soaps, perfumes, makeup, moisturizers, lipsticks, nail polish, hair colors, toothpastes, and deodorants––are not subject to specific testing requirements or pre-market approval by the agency. However, the FFDCA broadly prohibits the marketing of adulterated or misbranded cosmetics, including any product (other than a hair dye) that "bears or contains any poisonous or deleterious substance which may render it injurious to users under the conditions of use prescribed in the labeling thereof, or under conditions of use as are customary and usual."

Food Additives

The Federal Food, Drug, and Cosmetic Act requires that manufacturers and packagers of processed foods demonstrate the safety (i.e., "reasonable certainty of no harm") of all chemical additives and/or other materials that come into contact with food prior to marketing. Pre-market review of the safety of food/color additives and food contact materials is provided by the Office of Food Additive Safety within FDA's Center for Food Safety and Applied Nutrition.

FDA guidance for the toxicological assessment of food ingredients (also referred to as the Redbook) prescribes often extensive toxicological testing based on "concern levels" as determined by chemical structure and cumulative human exposure. Commonly required study types include the following:

• Acute oral toxicity
• Short-term (28 day) toxicity in rodents and non-rodents
• Subchronic (90 day) toxicity in rodents and non-rodents
• Chronic (1-2 year) toxicity in rodents and non-rodents
• Mutagenicity and genotoxicity
• Carcinogenicity (including possible in utero exposure phase)
• Reproductive toxicity
• Developmental toxicityNeurotoxicity
• Immunotoxicity
• Metabolism and pharmacokinetics
• Human clinical and/or epidemiology

Exceptions to the above testing requirements are provided under a 1958 amendment to the FFDCA for two broad groups of substances:

Substances that FDA or the US Department of Agriculture had determined safe for use in food prior to 1958.
Ingredients generally recognized as safe (GRAS) based on a long history of use and/or published scientific evidence.

Foodborne Illness

Foods of animal or plant origin may present intrinsic hazards due to microbiological contamination (e.g., Salmonella), for which general analytical methods have been developed by FDA's Center for Food Safety and Applied Nutrition. Separate methodologies have also been established for testing of oysters, scallops and other shellfish for toxins that can cause sickness ranging from indigestion to paralysis and death. Current FDA standards generally prescribe the use of often-lethal animal tests to detect three different classes (paralytic, amnesiac and diarrhetic) of shellfish toxins, yet also permit the use of validated, non-animal techniques such as the Lawrence method of high performance liquid chromatography under certain circumstances.

Human Biologics

A biological product, as defined under the Public Health Service Act, can include a "virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product ... applicable to the prevention, treatment, or cure of a disease or condition of human beings." The PHS Act requires that all human biologics be licensed, appropriately labeled, and proven "safe, pure, and potent." Responsibility for ensuring the safety and efficacy of biologics intended for human use in the US rests with FDA's Center for Biologics Evaluation and Research.

A company wishing to begin clinical trials of a biological product must submit an Investigational New Drug application to FDA, describing the product, its method of manufacture, and quality control tests for release. In the case of a vaccine, manufacturers must demonstrate the following characteristics:

• Purity, meaning that it is not contaminated with viable bacteria, viruses or fungi
• Safety, meaning that it is not dangerous or harmful – which is usually determined by means of "abnormal toxicity" or similar studies, in which groups of animals are injected with a vaccine and monitored for clinical signs of toxicity
• Potency, meaning that it is effective in preventing infection – which is usually determined by means of a "challenge study," in which groups of animals are first inoculated with a vaccine and are then exposed to a virulent strain(s) of the organism against which the vaccine is intended to protect. Animals are then monitored for clinical signs of the infectious disease in question, which may involve considerable pain, suffering, and ultimately, death

A further pre-marketing requirement involves three phases of clinical trials in human volunteers to demonstrate safety and efficacy in the species of ultimate interest. If successful, a Biologics License Application is submitted for review by FDA regulators, as well as the agency's independent Vaccines and Related Biological Products Advisory Committee.

Even after a vaccine is licensed, FDA may require manufacturers to submit the results of their own tests for potency, safety, and purity for each vaccine lot and/or samples of each vaccine lot to the agency for testing. It is estimated that approximately one-third of all animal use in toxicology occurs in the biologics sector.

Relevant alternative methods validated to date include ELISA batch potency tests for erysipelas and human tetanus vaccines, as well as a toxin binding inhibition (ToBI) test for human tetanus vaccine.

Human Pharmaceuticals

The Federal Food, Drug, and Cosmetic Act provides for an extensive pre-market approval process for all pharmaceutical products––including generic, over-the-counter and prescription drugs––to ensure their safety and effectiveness for human use. Responsibility for the regulation of human pharmaceuticals in the US rests with FDA's Center for Drug Evaluation and Research.

US regulations and guidance for pharmaceutical safety assessments have been harmonized with those of other major pharmaceuticals markets (i.e., Europe and Japan) under the auspices of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Harmonized ICH guidelines for the safety assessment of human medicines call for a wide array of pre-clinical (animal) studies before a drug candidate is deemed safe for human clinical trials. Commonly required animal tests include the following:

• Toxicokinetics and pharmacokinetics in rodents and/or other species
• Single-dose studies in rodents, and occasionally dogs and primates
• Subacute (14-28 day), subchronic (90 day) and/or chronic (90+ day) studies in rodents, dogs, and occasionally primates
• Reproduction segment I––fertility studies in rodents
• Reproduction segment II––prenatal developmental toxicity in rodents and rabbits
• Reproduction segment III––postnatal development in rodents
• Mutagenicity and genotoxicity studies of at least 2 varieties
• Carcinogenicity studies in rats and transgenic mice
• Immunotoxicity in rodents
• Triggered specialized studies (e.g., phototoxicity and pyrogenicity)

Drug candidates that exhibit favorable toxicological profiles in pre-clinical testing may be candidates for human clinical trials. This step requires the submission of an Investigational New Drug application to FDA, detailing the results of animal pharmacology and toxicology studies, manufacturing information, and clinical protocols and investigator information. Contingent upon approval from FDA and an institutional human research ethics committee, up to three phases of human trials may be undertaken. For pharmaceutical products determined to be safe and efficacious in human trials, the final step prior to US commercialization is the submission of a New Drug Application, which must include sufficient information for the FDA to determine that (i) a new drug is safe and effective for its proposed use, (ii) the benefits outweigh the risks, and (iii) the proposed labeling requirements and the manufacturing methods and controls are adequate. Federal law also requires that all prescription and over-the-counter drugs marketed in the US satisfy the quality standards established by the US Pharmacopeia. Once on the market, there are post-market surveillance controls with which a manufacturer must also comply.

Preclinical testing of new pharmaceutical candidates consumes many thousands of animals, and is required for both the active medicinal ingredient(s) as well as any variants in a formulation or delivery system. Yet despite these costs, the FDA acknowledges that "a new [human] medicinal compound entering Phase 1 testing, often representing the culmination of upwards of a decade of preclinical screening and evaluation, is estimated to have only an 8 percent chance of reaching the market." Such high failure rates have called into question the accuracy of animal studies in predicting human clinical outcomes and prompted calls for greater acceptance and use of alternative methods such as in vitro and "omic" techniques in preclinical safety testing, as well as alternative clinical approaches such as human microdosing.

Medical Devices

The Federal Food, Drug, and Cosmetic Act broadly defines medical devices as including any "instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is ... intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals...." Responsibility for ensuring the safety and effectiveness of medical devices lies with FDA's Center for Devices and Radiological Health.

FDA classifies medical devices based on the level of control necessary to assure the safety and effectiveness of the device:

• Class I devices present minimal risk to the user, such as tongue depressors, bedpans, elastic bandages, examination gloves, and hand-held surgical instruments and other similar types of common equipment. Devices in Class I are subject only to general controls, which cover issues such as manufacturer registration, good manufacturing techniques, proper labeling, pre-market notification, and general reporting requirements.
• Class II devices require additional special controls to assure safety and effectiveness. Examples include surgical and acupuncture needles, suture material, dental implants, infusion pumps, and x-ray machines.
• Class III devices require pre-market safety and efficacy review and approval by FDA because they are "purported or represented to be for a use in supporting or sustaining human life or for a use which is of substantial importance in preventing impairment of human health." Examples include heart valves, implanted cardiac pace-makers and cerebral stimulators, and bone and breast implants.

FDA regulations for pre-market approval applications require the submission of summaries of all "nonclinical laboratory studies" as well as "clinical investigations involving human subjects" undertaken to demonstrate the safety and efficacy of a device for human use. However, specific testing requirements are not specified. Federal law also requires that all medical devices marketed in the US satisfy the quality standards established by the US Pharmacopeia. Once on the market, there are post-market surveillance and reporting requirements with which a manufacturer must also comply.

Nutritional Supplements

Vitamins, minerals, herbs or other botanicals, amino acids, and substances such as enzymes, organ tissues, glandulars, and metabolites are regulated under the Dietary Supplement Health and Education Act of 1994 (DSHEA) by FDA's Office of Nutritional Products, Labeling, and Dietary Supplements, a division of the Center for Food Safety and Applied Nutrition. In contrast to most other products regulated by FDA, nutritional supplements are not subject to specific safety/efficacy testing requirements or pre-market approval by the agency. Responsibility for ensuring that a nutritional supplement is safe rests with the manufacturer, who is only obligated to notify FDA prior to marketing a supplement containing a new dietary ingredient. FDA is responsible for: (1) monitoring the market for potentially unsafe products and/or those that make false or misleading label claims; (2) investigating reports of adverse effects; and where appropriate, (3) taking action to remove unsafe products from the market.

Veterinary Pharmaceuticals

The marketing of veterinary pharmaceuticals and medicated livestock feeds in the US is regulated by the FDA's Center for Veterinary Medicine pursuant to the Federal Food, Drug, and Cosmetic Act (FFDCA). FFDCA requires that animal drugs and feeds be safe and effective, and that edible animal products derived from treated animals be free of unsafe residues.

FDA is responsible for the pre-market review and approval of all veterinary pharmaceuticals. US requirements for veterinary pharmaceutical safety assessments have been harmonized with those of other major pharmaceuticals markets (i.e., Europe and Japan) under the auspices of the International Cooperation on Harmonization of Technical Requirements for Regulation of Veterinary Medicinal Products (VICH). Some VICH guidelines call for a wide array of animal studies, including the following:

• Subchronic (90 day) and chronic (2 year) toxicity in rodents and/or dogs
• Reproductive toxicity in two or more generations of rodents
• Developmental toxicity in rodents and/or rabbits
• Genotoxicity studies of at least 3 varieties
• Testing for effects on human intestinal flora
• Pharmacological effects
• Immunotoxicity
• Neurotoxicity
• Carcinogenicity studies in rats and mice
• Triggered "special" studies

Data from these studies are submitted to FDA in the form of an Investigational New Animal Drug application, on the basis of which further testing may be required to demonstrate:

• Safety and effectiveness of the candidate drug in the target species
• Safety for human consumption of drug residues in food derived from treated animals
• The effect of animal drugs on the environment

For veterinary pharmaceuticals determined to be safe and efficacious, the final step prior to US commercialization is the submission of a New Animal Drug Application, which must include sufficient information for the FDA to determine that (i) a new drug is safe and effective for its proposed use, (ii) the benefits outweigh the risks, and (iii) the proposed labeling requirements and the manufacturing methods and controls are adequate. Once on the market, there are post-marketing surveillance controls with which a manufacturer must also comply.

Toxicological Research

Much of FDA's intramural research activity is centralized within the National Center for Toxicological Research, which is mandated to conduct "innovative, integrative research to support and anticipate FDA's current and future regulatory needs." A substantial proportion of NCTR research involves animal use. For example, NCTR maintains more than 80 animal breeding and holding rooms, a non-human primate research center, a phototoxicology research center, and an infectious disease biocontainment laboratory for use by its various research divisions. At the same time, NCTR has established a number of Centers of Excellence to further the development and application of new (-omic and in silico) technologies into FDA programs.

Alternatives Policies & Actions

FDA does not appear to have a specific policy on animal welfare or the 3Rs. However, the agency has undertaken a number of initiatives that are germane to the 3Rs. Perhaps the most far-reaching of these is the Critical Path – a "national effort to modernize the scientific process through which a potential human drug, biological product, or medical device is transformed from a discovery or "proof of concept" into a medical product." The Critical Path initiative aims, among other things, to develop a "better safety toolkit ... that can more reliably and more efficiently determine the safety of a new medical product," and was the impetus for the creation of Centers of Excellence for in silico and –omic technologies under NCTR. In addition, informatics and computational safety analysis staff in FDA's Center for Drug Evaluation and Research have helped pioneer many of the in silico models now widely used within the agency. Other 3Rs-relevant activities include FDA's participation in ICH, VICH, and the US Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM).