Improving the Utility and Translation of Animal Models for Nervous System Disorders Workshop Summary (2013) / Chapter Skim
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2 Evaluation of Current Animal Models
2 Evaluation of Current Animal Models
Pages 9-20
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From page 9... ...
Mark Tricklebank followed with a discussion about validation of animal models for drug discovery and how translation of preclinical research can be enhanced through skillful study design, planning, and proper statistical analysis; these points were echoed by other speakers and many participants throughout the workshop. Next, Katrina Kelner described three forms of publication bias that can impact the success of animal models: (1)
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When a new drug target is discovered and validated, lead candidate molecules are then identified and optimized. Preclinical testing evaluates the pharmacology and toxicology of the lead compound in animal models and Phase I clinical studies establish safety and dosing in humans.
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Animal models have long had an important role in the drug development process. As outlined by Paul, current expectations are that animal models can help researchers to • Better understand the fundamental pathology and pathogenesis of a disease.
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. Once a therapeutic target is selected, advances in in vitro screening technologies have made identification of potential drug molecules relatively easy.
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• The preclinical data accurately conveys the drug responses in a very specific, genetically circumscribed population of animals maintained in highly controlled environments, but this does not necessarily hold true in the heterogeneous human clinical population. • The measurements taken have, at best, only face validity for the variables that the experimenter would like to measure, and they need to be quantified in relation to the disease of interest.
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14 ANIMAL MODELS FOR NERVOUS SYSTEM DISORDERS BOX 2-1 Types of Validity Relative to Neuroscience Animal Models Construct validity: Ideally mimicking the molecular and/or structural basis of the disease Convergent validity: Evidenced by high correlation among perfor mance patterns across cognitive tasks designed to measure the same neurocognitive process Criterion validity: The ability of performance in one task to predict per formance on another, more ecologically valid test Discriminant validity: Evidenced by low correlation among outcomes across tasks designed to measure distinct neurocognitive constructs Face validity: Degree of similarity to disease-specific symptoms Predictive validity: Based on currently available therapy SOURCE: Tricklebank presentation (March 28, 2012)
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Improving animal models might occur through the use of clinically relevant pharmacological, environmental, neurodevelopmental, and genetic methods to perturb or impair normal function. In discussion, Sharon Rosenzweig-Lipson of IVS Pharma Consulting added that in addition to establishing the validity of an animal model, it is important to understand how decisions are made based on the model.
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3 Multiple laboratories within the consortium are using this touchscreen assay under standardized experimental conditions to compare the rate of task acquisition and response to drugs administered during task acquisition or posttraining. Tricklebank noted that convergent approaches combining behavior and physiology are critical for the preclinical validation of drug targets.
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Kelner supported the idea of a site that could publish negative results following review for rigorous experimental design and analysis. A participant from the National Institutes of Health (NIH)
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In addition, she said, funding agencies can require high-quality output from their funded scientists. Cultural Assumptions About What Good Science Is The third type of publication bias Kelner described results from cultural assumptions about what constitutes "good science." A common assumption is that the best science increases fundamental knowledge, not practical application.
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A participant added that if the mouse models for polygenic psychiatric disorders are really as poor as people think, perhaps it is time to ask under what circumstances it would be both worthwhile and ethical to go straight into human clinical trials after establishing safety.
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