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 [for humans], medical devices, our nation’s food supply [including dietary supplements], 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. The Tobacco Control Act of 2009 expanded the FDA’s regulatory authority to cover the manufacture, distribution, and marketing of tobacco products.
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, the primary divisions overseeing animal use and/or testing requirements at FDA are:
Laws, Regulations, Guidance:
FDA regulations carry “the full force of the law.” The agency’s regulatory authority is defined primarily by the following US laws:
Through the Center for Food Safety and Applied Nutrition (CFSAN), the FDA works to “assure that the food supply is safe, sanitary, wholesome, and honestly labeled.” The agency establishes performance standards and toxicity testing protocols for assuring the safety of food additives and nutritional supplements, and the absence of contaminants.
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. The Office of Food Additive Safety within FDA’s Center for Food Safety and Applied Nutrition provides pre-market review of the safety of food/color additives and food contact materials.
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:
Exceptions to the above testing requirements are provided under a 1958 amendment to the FFDCA for two broad groups of substances:
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.
Foods of animal or plant origin may present intrinsic hazards due to microbiological contamination (e.g., Salmonella); for these the FDA’s Center for Food Safety and Applied Nutrition has developed general analytical methods. 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 of shellfish toxins (paralytic, amnesiac, and diarrhetic), yet also permit the use of validated, non-animal techniques such as the Lawrence method of high performance liquid chromatography under certain circumstances.
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:
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, as many as three phases of human trials may be required. 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 (1) a new drug is safe and effective for its proposed use, (2) the benefits outweigh the risks, and (3) 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 Pharmacopeial Convention. 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 in vitro and "omic" techniques in preclinical safety testing, as well as new clinical approaches such as human microdosing (Phase 0).
A biological product, as defined under the Public Health Service (PHS) 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:
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.
In 2010, the Patient Protection and Affordable Care Act amended the Public Health Service Act to "create an abbreviated licensure pathway for biological products that are demonstrated to be ‘biosimilar’ to or ‘interchangeable’ with an FDA-licensed biological product." This amendment is also referred to as the Biologics Price Competition and Innovation Act of 2009.
The Act stipulates that, "to have a product reviewed as a biosimilar or interchangeable, manufacturers must submit a 351(k) biologics license application (BLA) that includes, among other things, information demonstrating biosimilarity based upon:
In some cases, the FDA might determine that one of these elements is unnecessary; manufacturers are therefore encouraged to "contact the appropriate review division to obtain input on a proposed development program."
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:
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.
The FDA has regulatory authority over products that emit radiation, such as medical and therapeutic devices (e.g., diagnostic and treatment radiography, mammography, surgical lasers), security x-rays in airports and office buildings, laser pointers/players/printers, cell phones, and microwave ovens. For safety purposes, many of these devices must meet specific performance standards.
Oversight is conducted through the FDA’s Center for Devices and Radiological Health (CDRH), which established the "Radiological Health Program" to "protect the public from hazardous or unnecessary radiation exposure from radiation-emitting electronic products."
The program accomplishes this by:
The program is a cooperative effort between numerous stakeholders "including States and other Federal agencies, professional organizations, academic institutions, users, manufacturers, and consumer groups."
CDRH has created an educational tool, "CDHR Learn," to provide industry with "comprehensive, interactive, and easily accessible" information about the steps required to bring new medical radiation-emitting devices to market.
The marketing of veterinary pharmaceuticals and medicated livestock feeds in the US is regulated by the FDA’s Center for Veterinary Medicine (CMV) 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.
The FDA’s Office of New Animal Drug Evaluation (ONADE) is responsible for reviewing information submitted by sponsors of new animal pharmaceuticals, and for determining whether the new drug should be approved by the CVM for marketing. At the beginning of the approval process, the drug sponsor contacts ONADE to open an Investigational New Animal Drug file and discuss data requirements.
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:
Data must document:
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 (for generic copies of existing animal drugs, an Abbreviated New Animal Drug Application is available), which must include sufficient information for the FDA to determine that (1) a new drug is safe and effective for its proposed use, (2) the benefits outweigh the risks, and (3) 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.
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 (FFDCA) and the Fair Packaging and Labeling Act. In contrast to most other products regulated by FDA, cosmetics––including shampoo, 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." The FDA also invites participation by manufacturers, packers, and distributors in its Voluntary Cosmetic Registration Program (VCRP). "The VCRP assists FDA in carrying out its responsibility to regulate cosmetics. FDA uses the information to evaluate cosmetic products on the market. …(V)oluntary submissions provide FDA with the best information available about cosmetic products and ingredients, their frequency of use, and businesses engaged in their manufacture and distribution (Federal Register, vol. 73, p. 76360, and vol. 69, p. 9339)." Information from the VCRP database is sometimes used by the Cosmetic Ingredient Review (CIR) panel in its safety assessments. When necessary to "address public safety concerns or provide information to support regulatory actions or guidance," the FDA will conduct its own research on cosmetic products and ingredients.
The Family Smoking Prevention and Tobacco Control Act of 2009 gives the FDA regulatory authority over the manufacture and marketing of tobacco products (cigarettes, cigarette tobacco, roll-your-own tobacco and smokeless tobacco). Among other details, the Act specifies that tobacco product manufacturers must provide the FDA with a list of ingredients for each product. It also authorizes the FDA to establish product standards, regulate ingredient levels, based on scientific research on health effects.
New tobacco product applications must include health and safety information specified by sections 907 and 910 of the Federal Food, Drug & Cosmetic Act, as amended by the Tobacco Control Act. These information requirements include, among other things, a detailed list of ingredients, components, and additives, and detailed description of the manufacturing process.
Though the FDA does not appear to have a specific policy on animal welfare or the 3Rs, it has stated (with regard to cosmetics, in particular) that it is "a strong advocate of methodologies for the refinement, reduction, and replacement of animal tests with alternative methodologies that do not employ the use of animals." To that end, the FDA participates in inter-agency and international efforts to increase the use of non-animal alternatives, has also undertaken a number of research and development initiatives that are germane to the 3Rs, and invites public commentary on relevant guidance.
The FDA is a member of the US Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM). In addition, informatics and computational safety analysis staff members in FDA’s Center for Drug Evaluation and Research have helped develop many of the in silico models now widely used within the agency. In 2010, the FDA joined a Memorandum of Understanding between the National Toxicology Program (NTP), NIH’s Chemical Genonomics Center (NCGC), and the Environmental Protection Agency (EPA), to collaborate on Tox21. Under this MOU, the agencies agree to pool their unique resources and capacities to advance the use of high throughput screening technologies and computational modeling, to more rapidly and effectively assess chemicals for potential toxicity. The FDA will share its extensive compilation of non-confidential, non-proprietary toxicological data acquired in product evaluations. The collaboration is expected to yield a reduction or replacement of animals in regulatory testing…in parallel with an increased ability to evaluate the large numbers of chemicals that currently lack adequate toxicological evaluation."
In 2015, the FDA and EPA announced a Memorandum of Understanding to share data on pesticides and toxic substances. The MOU "establishes a process of disclosure and sharing of their respective databases that will facilitate the decisions of each agency related to food safety, veterinary medications, and cosmetics." The agreement has the potential to greatly reduce duplication or unnecessary additional in vivo testing.
The Tissue Chip for Drug Screening Initiative is a collaboration between the FDA, NIH’s National Center for Advancing Translational Sciences (NCATS), the Defense Advanced Research Projects Agency (DARPA), and a number of academic research partners to develop 3-dimensional microphysiological tissue- and organ-chip systems. The chip systems are intended to be linked into a human-on-a-chip and used to safety-test pharmaceuticals, vaccines, or other biologic agents, and to test the effects of chemical and radiation exposures.
Inviting public comment on alternatives
In 2014, the agency invited public input on its widely consulted "Redbook" (Toxicological Principles for the Safety Assessment of Food Ingredients), asking for "ideas and opinions on what should be included, changed, or even removed" from the current edition. A transcript from the public meeting is available; among the proposals advanced, some constituents called for greater encouragement and acceptance of alternative methods. An extension of the invitation further encouraged suggestions for "(n)ew assays, test methods, and endpoints that could be useful for safety assessment, with justifications for why and how these proposed new methods should be considered."
The FDA introduced a database for searching all FDA Guidance Documents: http://www.fda.gov/RegulatoryInformation/Guidances/ucm2005656.htm
FDA created an electronic records submission application to facilitate voluntary reporting of product ingredients, certain new product applications, and after-market reporting (such as adverse events) for most products in its purview: http://www.fda.gov/ForIndustry/FDAeSubmitter/default.htm
Marilyn Matevia, PhD, AltTox Web Manager