Species Selection

The basic question that helps to address this is “what is your test article type?”.  For small molecules, invariably there will be two species needed; a rodent and a non-rodent, while for a biopharmaceutical it could be either one species or two species. While there is public pressure to minimize the use of species that are considered more sentient, such as non-human primates, or that have special value to humans, such as dogs or cats, the justification for species selection is a scientific one.  Use of an inappropriate species that does not provide the proper data on the test article for humans does not meet the purpose of these safety studies which is to ensure the safety of the volunteers/patients that will participate in the clinical trials.  Furthermore, this could result in the FDA placing your program on clinical hold.

For small molecules, the standard means to determine the nonclinical species is through the use of in vitro metabolic profiling. Liver microsomes from a full spectrum of species (mouse, rat, dog, minipig, non-human primate, and human) are incubated with the test material and a profile of metabolic products is obtained. The profile from human is compared to the profile of the other species, and the rodent and non-rodent species that best covers the human metabolic profile are those used for the nonclinical studies. For most small molecules, history has shown this to be the rat and dog; however, it is not uncommon for one of these “standard” species to have a profile different than human and, therefore, the mouse or non-human primate (NHP), or other species, may need to be considered.

For biopharmaceuticals, regulatory agencies require the nonclinical studies to be conducted in the “most relevant” species, with relevance being based on the pharmacology of the test material in the nonclinical species. Species selection for biopharmaceuticals is supported through the use of in vitro and/or in vivo assays that demonstrate the ability of the drug to elicit a pharmacological effect in a particular species. Most biopharmaceuticals are designed to be specific for humans; therefore, they may not exert a pharmacological effect in lower order species such as the mouse, rat, or dog. In these cases, it is possible that the NHP may be the only species used in the nonclinical studies.

Study Design

Efforts to reduce the time and cost needed for overall drug development has led to increased complexity in nonclinical study designs to maximize the amount of data from the studies being conducted.  Addition of nonstandard behavioral, pharmacological, or physiological assessments as well as biomarkers for efficacy/toxicity, or other customized endpoints to standard safety study designs is becoming commonplace.  Caution should be exercised when considering the inclusion of additional items to a study design as this can create situations where collection of one type of data may interfere with another type of data due to added stress to the animals.

Another aspect to keep in mind is that many of the biomarkers require blood, plasma, and/or serum and there are limits to how much blood can be drawn from the animals. It is important to consult with the CRO on the timing and frequency of these additional assessments to understand the risk of confounding the data or creating adverse effects due to study procedures that could mask or enhance test article effects.

When designing your study, bear in mind that data generated by evaluations such as ECGs and blood pressure can be heavily influenced by the animals being stimulated by the amount of activity in the room at the time.  An option to consider is to reorder the evaluations so that some may fall on the second day, or have them occur in a room removed from the high level of activity that coincides with the first day activities.  It reduces the chance for errors, reduces the stress on the animals, and increases the quality of the data.

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