Laboratory animals in nonclinical studies

Two questions decide how animal work is set up. Which species answers the scientific question, and which rules apply to the work once the species is chosen. In the United States the second question has a more complicated answer than it appears, because the main federal animal welfare statute does not cover the species most used in nonclinical pharmacology.

This article covers species selection, then the United States regulatory framework: which statute covers what, what an institutional review committee is required to do, and how third-party accreditation differs from regulatory compliance.

Choosing a species

Species selection is a scientific decision made before the study is designed, and for biologic products it is often the constraining one, because a biologic may only be pharmacologically active in a species whose target it recognizes. The purpose of choosing carefully is to generate data that inform the human dose and identify what to monitor. Animal data do not predict what will happen in patients, and choosing a species well does not make them do so.

What the choice is based on

The comparison that matters is between the species and the human on the specific axis the study depends on: whether the target is present and similar, whether the compound is metabolized by comparable routes, and whether the physiology or pathophysiology of interest is reproduced. Conventions have grown up around particular species and disease areas, with rats commonly used in bone, inflammation and metabolic work and mice in oncology and genetic disease, though these are conventions rather than rules and the choice should follow from the mechanism. Exposure data from the chosen species are what the starting dose in humans is derived from.

Practical factors also weigh on the decision. Availability of the strain, lead time from the supplier, the housing the facility can provide, and how the species tolerates the procedures the study requires all affect whether a design is feasible. These are worth raising early with the laboratory, because a species that is scientifically preferable but unavailable on the required schedule is not a viable choice.

The US regulatory framework

In the United States two separate frameworks apply, and which one governs a given study depends on the species and on the funding. The Animal Welfare Act, implemented by the Department of Agriculture, requires research facilities to register and subjects them to inspection.^[S7] Separately, research supported by Public Health Service funds is governed by the PHS Policy, under which an institution files an Animal Welfare Assurance with the Office of Laboratory Animal Welfare.^[S6] The principal reference standard for how animals are housed and cared for is the Guide for the Care and Use of Laboratory Animals, produced with support from the health, agriculture and accreditation bodies.^[S5]

The three Rs, and where they appear in US regulation

The three Rs are used in the United States as a description of good practice, and the term is standard. No provision of the federal regulations reviewed for this article carries that name, but the underlying requirement appears in the rules governing protocol review, described after the list below.

• {'items': ['Replacement: using methods that do not involve animals where they answer the same question.', 'Reduction: obtaining the required information from fewer animals, which is a study design and statistics question as much as an ethical one.', 'Refinement: modifying procedures to reduce pain and distress.']}

Review by an institutional animal care and use committee is not a common practice in the United States; it is a requirement. The regulations direct the chief executive of a research facility to appoint such a committee, and specify its minimum composition, which must include a veterinarian and a member who is not affiliated with the institution.^[S2] Among the findings the committee must make before approving a protocol is that the principal investigator has considered alternatives to procedures that may cause more than momentary or slight pain or distress.^[S3] That requirement is the regulatory expression of replacement and refinement. For a sponsor, the practical point is scheduling: committee review takes time, and it happens before the study can start.

Accreditation is not regulation

Many laboratories state that they are accredited by AAALAC International, and the organization is explicit about what that means: it states that it is not a regulatory body and does not make or enforce regulations.^[S4] Accreditation is a voluntary evaluation of an institution animal care and use programme against external standards, principally the Guide, and accredited organizations are re-evaluated every three years.^[S4][S5] It is useful information, because it means an outside body has reviewed the programme. It is not a substitute for registration where registration is required, it is not an assurance filed with the health authorities, and it says nothing about whether a particular study was conducted under the good laboratory practice regulation, which applies study by study.