Target Health Blog

Using Animals for Medical Research

April 1, 2019

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Quiz
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The mouse is a typical testing species.
Photo credit: by Linda Bartlett (Photographer) - This image was released by the National Cancer Institute, an agency part of the National Institutes of Health, with the ID 1963 (image) (next)., Public Domain,
https://commons.wikimedia.org/w/index.php?curid=24032505

In December 1903 Mark Twain, who opposed vivisection, published a short story, A Dog's Tale, in Harper's, written from the point of view of a dog whose puppy is experimented on and killed. The inspiration for this story may have been the Brown Dog Scandal roiling Great Britain, at that time. Writers and artists on both sides of the Atlantic, were opposed to using animals for medical 1) ___. In addition to Mark Twain, other writers were Thomas Hardy, Virginia Woolf and the Bloomsbury Group, among many others.

Debate about the ethical use of animals in research dates at least as far back as 1822 when the British Parliament enacted the first law for animal protection preventing cruelty to cattle. This was followed by the Cruelty to Animals Act of 1835 and 1849, which criminalized ill-treating, over-driving, and torturing 2) ___. In 1876, under pressure from the National Anti-Vivisection Society, the Cruelty to Animals Act was amended to include regulations governing the use of animals in research. This new act stipulated that 1) experiments must be proven absolutely necessary for instruction, or to save or prolong human life; 2) animals must be properly anesthetized; and 3) animals must be killed as soon as the experiment is over. Today, these three principles are central to the laws and guidelines governing the use of animals and research. In the U.S., the Animal Welfare Act of 1970 (see also Laboratory Animal Welfare Act) set standards for animal use and care in research. This law is enforced by APHIS's Animal Care program.

In academic settings in which NIH funding is used for animal research, institutions are governed by the NIH Office of Laboratory Animal Welfare (OLAW). At each site, OLAW guidelines and standards are upheld by a local review board called the Institutional Animal Care and Use Committee (IACUC). All laboratory experiments involving living animals are reviewed and approved by this committee. In addition to proving the potential for benefit to human health, minimization of pain and distress, and timely and humane euthanasia, experimenters must justify their protocols based on the principles of Replacement, Reduction and Refinement. Replacement refers to efforts to engage alternatives to animal use. This includes the use of computer models, non-living tissues and cells, and replacement of “higher-order“ animals (primates and mammals) with “lower“ 3) ___animals (e.g. cold-blooded animals, invertebrates, bacteria) wherever possible. Reduction refers to efforts to minimize number of animals used during the course of an experiment, as well as prevention of unnecessary replication of previous 4) ___. To satisfy this requirement, mathematical calculations of statistical power are employed to determine the minimum number of animals that can be used to get a statistically significant experimental result. Refinement refers to efforts to make experimental design as painless and efficient as possible in order to minimize the suffering of each animal subject.

In 1927, the Food, Drug, and Insecticide Administration, later known as the Food and Drug Administration (FDA), was formed. The Agency employed its first veterinarian, Dr. Henry Moskey, to evaluate vitamins and minerals in light of their claimed nutritional and treatment uses. A Veterinary Medical Branch was created in 1953 within the Bureau of Medicine, then part of the Department of Health, Education, and Welfare (DHEW).Recognizing the importance of animal health to the welfare of the country, the Secretary of DHEW established the Bureau of Veterinary Medicine (BVM) in 1965. At this time the major units within the Bureau were the Division of Veterinary Medical Review, Division of Veterinary New Drugs, and the Division of Veterinary Research. The number of units within BVM increased to five when the Secretary of DHEW approved a reorganization of BVM in 1970, which established two new divisions - Division of Compliance, and Division of Nutritional Sciences. Within six years, the burden of increased responsibility and an ever-growing workload necessitated another major reorganization of the Bureau. This reorganization, which went into effect in 1976, divided the activities of the Bureau into four principal areas: (1) Pre-clearance review of applications and petitions for drugs and feed additives; (2) Post-marketing surveillance and compliance activities; (3) Research; and (4) Administration. In 1984, the Bureau of Veterinary Medicine became the Center for Veterinary Medicine (CVM). Today, CVM is an internationally recognized public health organization with regulatory authority over food, food additives, drugs, and devices for animals.

The mission statement for FDA's Center for Veterinary Medicine (CVM) reads: “Protecting Human and Animal Health.“ To achieve this broad mission, CVM:

1.              Makes sure an animal 5) ___ is safe and effective before approving it. The center approves animal drugs for companion (pet) animals, such as dogs, cats, and horses; and for food-producing animals, such as cattle, pigs, and chickens. If the drug is for a food-producing animal, before approving it, the center also makes sure that food products made from treated animals - meat, milk, and eggs - are safe for people to eat;

2.              Monitors the safety and effectiveness of animal drugs on the market;

3.              Makes sure food for animals?which includes animal feed, pet food, and pet treats is safe, made under sanitary conditions, and properly labeled;

4.              Makes sure a food additive for use in food for animals is safe and effective before approving it;

5.              Conducts research that helps FDA ensure the safety of animal drugs, food for animals, and food products made from animals; and

6.              Helps make more animal drugs legally available for minor species, such as fish, hamsters, and parrots; and for minor (infrequent and limited) uses in a major species, such as cattle, turkeys, and dog

A new animal drug is defined, in part, as any drug intended for use in animals other than man, including any drug intended for use in animal feed but not including the animal feed, the composition of which is such that the drug is not generally recognized as safe and effective for the use under the conditions prescribed, recommended, or suggest in the labeling of the drug (21 U.S.C. 321(v)). As mandated by the Federal Food, Drug, and Cosmetic Act (the act), a new animal drug may not be sold into interstate commerce unless it is the subject of an approved new animal drug application (NADA), abbreviated NADA (ANADA), or there is a conditional approval (CNADA) in effect pursuant to 21 U.S.C. 360ccc or there is an index listing in effect pursuant to 21 USC 360ccc-1 (21 U.S.C. 331(a) and 360b(a)). Under section 512(j) of the act, unapproved investigational new animal drugs may be exempt from the approval requirements of the act. An investigational new animal drug may be shipped in interstate commerce for use by experts, qualified by scientific training and experience, to investigate their safety and effectiveness, if the requirements for the exemption set forth in 21 CFR part 511 are met.

There are three different types of new animal drug applications.

1.              NADAs and supplements - An NADA is used to seek approval of a new animal drug and includes any subsequent supplemental applications made to an approval.

2.              ANADAs and supplements - An ANADA is used to seek approval for a generic new animal drug and includes any subsequent supplements to an approved ANADA. A generic new animal drug is a copy of an approved new animal drug for which patents or other periods of exclusivity are near expiration.

3.              CNADAs - Applications for conditional approval allow a drug sponsor to legally market a new animal drug intended for a minor use or a minor species after proving it is safe under 21 U.S.C.““360b(d), but before collecting all the necessary effectiveness data. The drug sponsor can keep the product on the market for up to five years, while collecting effectiveness data required by 21 U.S.C. 360b(d), if FDA approves the sponsor's annual renewal requests.

Guidance for Industry related to New Animal Drug Applications

The Federal Food, Drug, and Cosmetic Act (the Act) defines medical device as "an 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, or [which is] intended to affect the structure or any function of the body of man or other animals." Further, a device "does not achieve its primary intended purposes through chemical action within or on the body of man or other animals, and is not dependent upon being metabolized for the achievement of its primary intended purposes." Examples of devices include such things as needles, syringes, surgical instruments, prosthetic devices, X-ray equipment, certain diagnostic test kits, and dental appliances. Pre-market Approval is Not Required: The FDA does not require submission of a 510(k), PMA, or any pre-market approval for 6) ___ used in veterinary medicine. Firms that manufacture radiation emitting devices need to register their products under the radiological health regulations, administered by the Center for Devices Radiological Health (CDRH). Device manufacturers who exclusively manufacture or distribute veterinary devices are not required to register their establishments and list veterinary devices and are exempt from post-marketing reporting. The agency that does have regulatory oversight over veterinary devices and can take appropriate regulatory action if a veterinary device is misbranded or adulterated, is the 7) ___. It is the responsibility of the manufacturer and/or distributor of these articles to assure that these animal devices are safe, effective, and properly labeled.

FDA recommends that manufacturers and/or distributors of veterinary medical devices request a review of their product labeling and promotional literature to ensure that it complies with the Act. This includes devices marketed in another country and offered for importation into the U.S. The FDA encourages veterinarians and animal owners to report adverse drug experiences and product defects associated with animal devices to FDA. In the United States, animal testing on vertebrates is primarily regulated by the Animal Welfare Act of 1966 (AWA), and the Animal Welfare Regulations which is enforced by the Animal Care division of the Animal and Plant Health Inspection Service (APHIS) of the United States Department of Agriculture (USDA). The AWA contains provisions to ensure that individuals of covered species used in research receive a certain standard of care and treatment, provided that the standard of care and treatment does not interfere with "the design, outlines, or guidelines of actual research or experimentation."

Currently, AWA only protects mammals. In 2002, the Farm Security Act of 2002, the fifth amendment to the AWA, specifically excluded purpose-bred birds, rats, and mice (as opposed to wild-captured mice, rats, and birds) from regulations. Even though most animals used in research are mice, rats, and fish, over a million other research animals per year are covered by the Animal Welfare Act and Animal Welfare Regulations. The AWA requires each institution using covered species to maintain an Institutional Animal Care and Use Committee (IACUC), which is responsible for local compliance with the Act. In addition, the IACUC reviews and approves each animal use protocol, which is a written description the researchers submit describing all procedures to be done with laboratory animals. Researchers must consult with a 8) ___ for each procedure that may cause more than momentary pain or distress to the animals. In addition, a written justification for these procedures, as well as documentation of a search for alternatives to these procedures, must be included with the protocol. The IACUC must review and approve these protocols at least annually. The IACUC also inspects all the animal facilities, including satellite facilities, every 6 months. As a part of this semi-annual inspection the committee also reviews the entire animal care and use program, and submits a "semi-annual report" to the Institutional Official. The Guide (enforced by OLAW) also has requirements for IACUC responsibilities and program reviews. Animal care and use in research in the United States are largely controlled by Institutional Animal Care and Use Committees.

During a 2002 House of Lords select committee inquiry into animal testing in the UK, witnesses stated that the UK has the tightest regulatory system in the 9) ___, and is the only country to require a cost-benefit assessment of every license application. There are 29 qualified inspectors covering 230 establishments, which are visited on average 11-12 times a year in both announced and unannounced inspections. As a result of the transposition of Directive 2010/63/EU, changes were made to the way research is reviewed and approved in the UK. All licensed establishments must have an Animal Welfare and Ethical Review Body (commonly referred to as AWERBs) which considers and monitors project applications for the site. The assessment of severity has also changed under the amendments to the Animals (Scientific Procedures) Act (1986). Working examples of severity bands are provided by European Commission Expert Working Group. The assessment of severity must also be conducted retrospectively, which results in severity being assigned on the basis of the actual suffering experienced by the animals, rather than what is presumed during study design. This in turn leads to more accurate prospective assignment of severity bands. The German Animal Welfare Act, 1972, is designed to enforce the utilitarian principle that there must be good reason for one to cause an animal harm and identifies that it is the responsibility of human beings to protect the lives and well-being of their fellow creatures. The Animal Welfare Act is supplemented by the Animal Protection Laboratory Animal Regulations, 2013, and the European Directive 2010/63/EU. All animal research facilities must be inspected at least every three years, with facilities conducting primate research being inspected at least once per 10) ___.

ANSWERS: 1) research; 2) animals; 3) order; 4) experiments; 5) drug; 6) devices; 7) FDA; 8) veterinarian; 9) world; 10) year

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