By Debbi Miller Gutierrez
The subjects of pre-clinical trials for medical device or biotechnology testing must be as equivalent to the target group as possible or the generalizability of the research findings will not be considered valid. In many cases, using humans as research subjects is not feasible. In these instances, animal models are more appropriate. Choosing the suitable animal model requires an understanding, not only of species-specific anatomy and physiology, its relationship to humans, and the requisite regulatory documentation, but also the ethics of making such a choice. Good Laboratory Practice (GLP) is also an essential aspect of using animal models in research.
Choosing an Animal Model
The choice of an appropriate animal model for a pre-clinical trial depends on a complex matrix of characteristics pertaining to the device or drug being tested, the characteristics of the animal being considered and applicable regulatory requirements.
The medical device or biotechnology being tested will often immediately filter out certain animal models. For example, the size of the medical device may determine which species of animal can be used. Testing the efficacy and safety of pacemakers intended for human use requires an animal model large enough to house the device, so small animals such as mice or rats will not be useful, even if their cardiovascular systems were analogous to humans. In the case of pharmaceutical products, a disease or non-disease study will determine which animal model is appropriate.
Another important aspect of choosing an animal model is its analogous relationship to humans. Similarity depends on which part of the body is being selected for. For example, rabbits, cats, and pigs are usually selected for ophthalmological research, while ferrets and beagles are more suitable for urogenital research. Even within a discipline some animals are more appropriate than others, often depending on the specific anatomical area being studied. For example, while goats and pigs may both be options as animal models in orthopedic medical device testing, goats are more suitable for studies concerning the meniscus or ACL, while pigs are more appropriate for osteoporosis.
The cost and care of the animal model is also an important factor. Housing, feeding, and caring for sheep or horses will be much more expensive than providing the same care for ferrets or guinea pigs. The availability of a facility that can handle a specific animal model may determine choice as well.
When using animal models, several regulatory agencies come into play. The FDA and USDA are involved in all cases, but the National Institutes of Health and the Department of Defense may also be included, depending on the circumstances. Each of these agencies has its own specific regulatory expectations. Some practices may fall under “guidelines” while others may be requirements.
For example, in pharmaceutical testing the FDA requires both a non-rodent and a rodent animal model to determine how a product is absorbed and excreted from the blood, among other physiological processes. The DoD requires the use of alternative testing methods when doing so would yield results as reliable as an animal model, but if an animal model is chosen, a DoD veterinarian must inspect the testing facility before a study can proceed. Knowing which agency and which regulations within an agency is applicable to the proposed animal model is essential to a successful path to the marketplace for both medical devices and biotechnological products.
When using animal models in pre-clinical research, a great deal of documentation is generated before, during, and after the trials. One of the first items to be produced is the Justification Form, which provides the FDA with a Context of Use statement. This form includes such information as the reason for choosing a specific animal model, demographic information for the animals involved (age, gender, health overview, system of inclusion or exclusion of potential subjects), a description of the medical device or drug being tested and the protocol of how it will be presented or implemented, and the relationship between the animal model and humans. This report should also include a literature review summarizing the natural history of the animal, as well as how it will be cared for during the study.
A Protocol Form, prepared jointly by the study sponsor and the research facility includes operational information, such as who will carry out the study from start to finish, delineating each researcher, consultant, or supervisor, his or her qualifications, experience, role, and responsibilities. An in-depth description of the test article (or challenge agent in drug trials, according to the FDA) and a detailed explanation of the experimental design should also be included. Clinical care and data analysis procedures and methods are an essential addition to this document. The Protocol Form must be reviewed and updated on a regular and consistent basis throughout the study and notifications issued to all parties if modifications are made.
Good Laboratory Practice (GLP)
GLP is essential throughout the process of medical device or biotechnology testing. Adhering to good practices assures the reliability and validity of the research results. Ongoing documentation, review, and modification if needed are only some of the practices involved in meeting GLP guidelines. Testing using animal models adds another layer to GLP oversight and facilitation, especially when multiple agencies are involved. Although the FDA does recognize the challenges of certain animal model situations, it still requires the documentation of any limitations of GLP in these situations. Hiring a knowledgeable and effective GLP coordinator is extremely important to a successful outcome.
Choosing, or even determining whether to choose, an animal model is complicated. It requires a team of experts: physicians, engineers, veterinarians, documentarians, regulatory and GLP specialists, as well as marketing professionals. Some universities or non-profit organizations can assist with the pre-planning, selection, and testing phases, but for a comprehensive and professional approach, contract research organizations may be the best option. Their sole focus is on taking a product to market, and CROs have specific and extensive knowledge in the diverse factors that contribute to animal model selection, husbandry, and testing through scientifically rigorous, effective regulatory and responsibly ethical methods.