Using animals to learn more about life in general and humans in particular dates back to ancient times. In the first century BCE, researchers dissected the optic nerve in living animals, vivisected a pig while it was swallowing colored water in order to evaluate the action, and observed intact beating hearts
]. Animal experimentation continued with Galen in the first century CE but modern animal use in research and testing dates to Claude Bernard in 19th
The notion that testing chemicals on animals could be predictive of human responses and therefore should be legally mandated dates back to the 1930s, when the sulfa drugs were being introduced for infections. Sulfa drugs were some of the first drugs that were shown to be effective against certain bacterial infections, but they were difficult to dissolve in solution. This was a problem, as children usually require a liquid version of a medication because they will not swallow pills. In 1937, one sulfa drug was dissolved in ethylene glycol and subsequently administered to children and adults. The ethylene glycol, which is well-known today as an ingredient in anti-freeze, killed one hundred and seven people. This incident led directly to the enactment of the US Federal Food, Drug and Cosmetic Act
of 1938 to mandate some animal testing
The Nuremberg Code came out of a trial in post-war Germany in December of 1946, the second of the Nuremberg trials. The first tried 24 Nazis, including Hermann Göring and Rudolf Hess, at the International Military Tribunal for crimes against humanity. This first trial lasted eight months with ultimately seven of the 24 defendants being executed. Some were sentenced in absentia, some were acquitted, some committed suicide or could not be tried for medical reasons, and others were incarcerated
As the first trial progressed it became obvious that more people were responsible than merely the 24 under scrutiny, so a total of 12 more trials were held
]. These trials were held before US military tribunals, with the sole trier of fact being the United States. Thus the second trial was formally designated United States of America v. Karl Brandt et al.
, colloquially referred to as the “Doctors’ Trial” or the “Medical Case.” Four judges presided over the eight-month case, hearing 85 witnesses, and viewing 1,471 documents and 11,538 pages of transcript
]. Twenty out of 23 defendants were physicians. All had been singled out as being responsible for the execution of humans they deemed “unworthy of life” and for experiments conducted on concentration camp prisoners. Experiments contained in the indictments included those pertaining to treatments for persons who had been severely chilled, the effects of various poisons and vaccines, and testing for pharmaceutical treatments for phosphorus burns from incendiary bombs. All of the experiments were performed on unconsenting humans who were inmates of concentration camps
]. The defendants were charged with and tried for conspiracy to commit war crimes against humanity, war crimes, and crimes against humanity. The tribunal did not convict on the first charge; 15 of the defendants were convicted on counts two and three. Ten of the 23 defendants were further charged with, and found guilty of, membership in a criminal organization (the SS)
]. The Nuremberg Code also came out of these proceedings, comprising ten ethical ideals that strive to lay the groundwork for ensuring that human rights are respected in human experimentation.
The American Medical Association appointed an advisor to the prosecutor for US v. Brandt
, Dr Andrew C Ivy
]. Ivy was a scientist himself and had conducted research similar to what was being discussed at the trial, such as the effects of altitude on pilots
]. Ivy was also a staunch opponent of those seeking to remove animals from laboratories during the 1930s and 1940s. He was a co-founder of the National Society for Medical Research, an organization that campaigned in favor of animal experiments, and served as its secretary-treasurer for years. It was Ivy who wrote the manuscript the prosecutors used to evaluate the scientific aspects of the charges
]. This manuscript included:
"The experiment to be performed must be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease under study that the anticipated results will justify the performance of the experiment. . . . The experiment must be conducted . . . on the basis of the results of previous adequate animal experimentation, there is no a priori reason to believe that death or disabling injury will occur, except in such experiments as those on Yellow Fever where the experimenters serve as subjects along with non-scientific personnel."
The American Medical Association quickly adopted Ivy’s rules and this was presented at Nuremberg in such a way as to make it appear that the rules were well established in the US (
] also see
]). Ivy’s wording would appear almost verbatim in the ultimate Nuremberg Code. The Declaration of Helsinki, authored by the World Medical Association, was a medical adaption of the Nuremberg Code and came out in 1964. It has been revised six times since then. The Declaration of Helsinki
] came to supersede the Nuremberg Code as the normative ethical guidance for medical researchers
]. The Declaration of Helsinki represents an improvement over the Nuremberg Code in the sense that it balances the concerns of individuals against the benefits to the society
Both the Nuremberg Code and the Declaration of Helsinki indicate that animal-based research should be conducted before human experimentation, the former more unequivocally than the latter. Principle 3 of the Nuremberg Code states:
"The experiment should be so designed and based on the results of animal experimentation
and a knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance of the experiment
]. (Emphasis added.)"
This principle is predicated on the assumption that the animal experimentation will have predictive value for the efficacy of the ultimate experimentation on humans. Ironically, experiments were also conducted on animals in Nazi Germany despite the commonly held position that they were not
]. The following is from a document presented at the Doctor’s Trial (USA v. Karl Brandt, et al.
) at Nuremberg and is titled “The Blood Picture of the White Mouse in Experimental Infections and Chemotherapy” (spelling per the original document).
"In former works 1) we have reported on the application of hematolytic technique to prove the functional condition of the mesenchyma in artificially infected animals and chemotherapeut treatment. The differential blood picture in normal mice as we as in mice infected with recurring spirochetes and nagana trypanosomes treated with salvarsan and solganol was only briefly discussed and publication at a later date was promised. . . . To cause hyperemia the tails of the mice was dipped for a short while into water of 40oC, were severed and a drop . . ."
Principle 12 of the Declaration of Helsinki advises that medical research on humans must be based on animal experimentation as appropriate. Again, the assumption is that animal experimentation will have predictive value for human research or experimentation, thus protecting human rights. As we will see, the opposite is the case: reliance on animal-based research in conducting human experimentation is antithetical to a respect for human rights.
Neither the Nuremberg Code nor the Declaration of Helsinki is legally binding or legally enforceable in its own right. (However, see
]). They are ethical guidelines
. Both documents and the principles enshrined in them will be persuasive authority to any domestic court, and indeed an argument can be made that many if not most of the principles are customary law (i.e. international law, binding on all states, that is derived from the customary behaviour of states, indicating a consensus that the behaviour is obligatory). Requiring consent in experiments, for example, may be considered a principle of customary international law, and states may have recourse at the International Court of Justice if this principle is violated. However, international codes and declarations gain tangible lawful force for individuals when they are adopted into domestic laws. The USA Protection of Human Subjects
] reads as follows:
§46.118 Applications and proposals lacking definite plans for involvement of human subjects.
Certain types of applications for grants, cooperative agreements, or contracts are submitted to departments or agencies with the knowledge that subjects may be involved within the period of support, but definite plans would not normally be set forth in the application or proposal. These include activities such as institutional type grants when selection of specific projects is the institution's responsibility; research training grants in which the activities involving subjects remain to be selected; and projects in which human subjects' involvement will depend upon completion of instruments, prior animal studies, or purification of compounds.
§46.204 Research involving pregnant women or fetuses.
Pregnant women or fetuses may be involved in research if all of the following conditions are met:
(a) Where scientifically appropriate, preclinical studies, including studies on pregnant animals, and clinical studies, including studies on nonpregnant women, have been conducted and provide data for assessing potential risks to pregnant women and fetuses . . .(Emphasis added.)
In Canada, s. 30 of the Food and Drugs Act
] provides that the Governor in Council may make regulations for carrying the purposes and provisions of the Act into effect. The consequent Food and Drugs Regulations
] reference animal-based research in at least three separate provisions. Provision C.08.002.01 provides that a manufacturer of a new drug may file an extraordinary use new drug submission if the new drug is intended for:
(i) emergency use in situations where persons have been exposed to a chemical, biological, radiological or nuclear substance and action is required to treat, mitigate or prevent a life-threatening or other serious disease, disorder or abnormal physical state, or its symptoms, that results, or is likely to result, from that exposure, or
(ii) preventative use in persons who are at risk of exposure to a chemical, biological, radiological or nuclear substance that is potentially lethal or permanently disabling; and
However, s. C.08.002.01(2)(iv) requires that the submission for extraordinary use new drugs contains:
(iv) detailed reports of studies, in an animal species that is expected to react with a response that is predictive for humans, establishing the safety of the new drug, and providing substantial evidence of its effect, when used for the purpose and under the conditions of use recommended,
(v) information confirming that the end point of animal studies is clearly related to the desired benefit in humans,
(vi) information demonstrating that there is a sufficient understanding of the pharmacokinetics and pharmacodynamics of the new drug in animals and in humans to enable inferences to be drawn in respect of humans so as to allow for the selection of an effective dose in humans, . . .
Other provisions in the Regulations suggest an assumption that animal-based research has predictive value for humans, although interestingly, none—other than the foregoing—require the results of animal-based research. Rather, it is indicated that when animal-based research exists its results should be included in applications for drug authorization. In other words, with the exception of extraordinary use drugs, animal-based research does not appear to be mandated under the Regulations.
For example, provision C.05.005(e) provides that an application to sell or import a drug for a clinical trial involving human subjects shall contain an investigator’s brochure containing a variety of information, including
(ii) the pharmacological aspects of the drug, including its metabolites in all animal species tested,
(iii) the pharmacokinetics of the drug and the drug metabolism, including the biological transformation of the drug in all animal species tested,
(iv) any toxicological effects in any animal species tested under a single dose study, a repeated dose study or a special study in respect of the drug,
(v) any results of carcinogenicity studies in any animal species tested in respect of the drug, . . . [Emphasis added.]
Only when animal species have been tested should that information be included in the application. If the pharmacological aspects, pharmacokinetics, toxicological aspects, and carcinogenicity of the drug can be demonstrated using non-animal models, this is sufficient.
Regulations are law that is not enacted by the legislature, but rather is created by those to whom authority has been delegated under the governing act. They can be amended by the delegated authority. The Food and Drugs Act
allows the Governor in Council, whose decision-making is, in practice, undertaken by cabinet, to make regulations for that act. Moreover, all federal regulation-making in Canada is governed by the Statutory Instruments Act
]. Section 19.1(1) of the SIA
provides that a legislative committee may revoke all or part of any regulations. The development, implementation, evaluation, and review of regulations are further governed by the Cabinet Directive on Streamlining Regulation
. Among other things, this policy document requires the federal government to protect and advance the public interest in health, to make decisions based on evidence and the best available science, and to be efficient and effective by demonstrating tangible results for humans. If animal-based research does not advance the public interest, is not scientifically valid, and/or does not demonstrate tangible results for humans, then it cannot be required under federal regulations such as the Food and Drug Regulations
In 2009, animal testing to fulfill regulatory requirements, category PAU 3, accounted for 66% (96,211 animals) of Canadian experiments known to “cause pain near, at, or above the pain tolerance threshold of unanesthetized, conscious animals”
Similarly, the US Food and Drug regulations stipulate that results from animal-based research should be included in applications if it has been conducted (e.g. s. 314.50), but the plain meaning of the text is that it is not mandated. For example, Part 314, Subpart I of the Food and Drug Regulations set out standards for the “approval of new drugs when human efficacy studies are not ethical or feasible.” In such circumstances, the FDA will accept “adequate and well-controlled animal studies when the results of those animal studies establish that the drug product is reasonably likely to produce clinical benefit in humans.” The presumption underlying these regulations is that animal studies have predictive value for humans. The FDA does not require proof of efficacy in animal models while they do in practice mandate toxicity testing in animals. This should be interpreted in light of the fact that what the FDA requires differs from what the FDA accepts and in some cases this is a distinction without a difference. If efficacy has not been demonstrated in an animal model, the investigational new drug approval process can be far more complicated and difficult. In addition, there is variability in the approval process.
Nevertheless, the US Food and Drug Administration (FDA) states that it requires animal testing on a rodent and nonrodent species in order to determine toxicity in humans, the dose to administer to humans taking a new drug for the first time, in order to establish a margin of safety, and for monitoring purposes during clinical trials