Animal models are integral to the success of drug discovery and development. They play a crucial role at every stage—from target validation to safety assessment—and directly influence the success of IND (Investigational New Drug) and NDA (New Drug Application) submissions. The right model can dramatically improve the likelihood of clinical success by accurately predicting human responses.
This guide provides an overview of how to select the appropriate animal model at each stage of the drug development process, what factors to consider, and why specific models are more effective in certain applications.
How to Select Animal Models Across Different Stages of Drug Discovery
Early Discovery: Target Validation Models
Preclinical Development: Pharmacology and Efficacy Models
Safety Assessment: Toxicology and Regulatory Requirements
Specialized Models for Novel Therapies
Immuno-Oncology: Humanized Mouse Models
Gene & Nucleic Acid Therapie
CNS Drugs: Behavioral Models
Five Common Pitfalls in Animal Model Selection (and How to Avoid Them)
Why can species differences in target expression lead to model failure?
Why do some animal models fail to reflect the complexity of human diseases?
How do researchers overlook ADME species differences, and why is this problematic?
Why is balancing animal welfare with long study durations challenging?
What happens when researchers select models without considering clinical endpoints?
How to Select Animal Models Across Different Stages of Drug Discovery
1. Early Discovery: Target Validation Models
In early drug discovery, scientists need to verify whether a biological target is relevant to a disease. Genetically engineered mouse models—such as transgenic, knockout, or knock-in strains—help show how a target works in disease mechanisms.
Why They Matter:
- Provide insight into target biology
- Support proof-of-concept studies
- Help identify biomarkers
2. Preclinical Development: Pharmacology and Efficacy Models
During preclinical development, researchers evaluate how a drug candidate behaves in the body and whether it works. Choosing relevant pharmacology models is critical at this stage.
Disease-Induced Models:
Scientists use these in preclinical studies to replicate specific disease conditions under controlled settings.
Spontaneous or Genetic Models:
These can better mimic natural disease progression, offering useful insights for long-term or human trial-facing work.
Tips for Selecting the Right Model:
- Match the model to human disease biology
- Use endpoints that translate to human outcomes
- Plan for study duration and repeated measures
3. Safety Assessment: Toxicology and Regulatory Requirements
Before human testing, preclinical studies must show a drug is safe. Global regulatory agencies usually require safety data from both rodent and non-rodent toxicology testing animal species.
Key Considerations:
- ADME species difference
- Organ-specific toxicities
- Relevance to human metabolism and potential toxic effects
Choosing appropriate species for IND-enabling studies ensures reliable and meaningful safety data.
Specialized Models for Novel Therapies
New drug types often need more human-relevant models.
1. Immuno-Oncology: Humanized Mouse Models
Drugs like monoclonal antibodies or CAR-T therapies require models that replicate human immune responses.
Humanized mouse models for immuno-oncology allow pharmaceutical company researchers to study immunotherapies in a more human-like setting.
Why Use Them:
- Predict human immune system responses
- Improve translation to human clinical trials
2. Gene & Nucleic Acid Therapies
Gene therapies (e.g., AAV, mRNA) need models that support delivery, expression, and distribution of genetic material.
Selection Depends On:
- Human receptor compatibility
- Tissue-specific targeting
- Longitudinal tracking systems
3. CNS Drugs: Behavioral Models
Central nervous system disorders require models that replicate complex behaviors.
Behavioral tests help gauge drug impact but need careful standardization to reduce variability.
Five Common Pitfalls in Animal Model Selection (and How to Avoid Them)
Q1: Why can species differences in target expression lead to model failure?
Many biological targets—such as receptors, enzymes, and cytokines—show different expression levels or functional activities across species. A drug may bind strongly to a human receptor but show reduced or altered binding in rodents. This mismatch leads to misleading efficacy or safety conclusions.
How to Avoid It:
- Use humanized mouse models expressing human target genes.
- Perform cross-species expression and homology analysis before selecting a model.
- Validate target engagement in multiple species when possible.
Q2: Why do some animal models fail to reflect the complexity of human diseases?
Induced or simplified disease models may capture only one aspect of pathology, missing critical features such as immune involvement, tumor heterogeneity, or chronic progression seen in humans. This creates a translational gap between preclinical and clinical outcomes.
How to Avoid It:
- Combine complementary models (e.g., induced + spontaneous + PDX).
- Choose models with pathophysiological relevance to human disease.
- Incorporate biomarkers and imaging to validate disease progression.
Q3: How do researchers overlook ADME species differences, and why is this problematic?
Differences in absorption, distribution, metabolism, and excretion (ADME) can dramatically impact drug exposure and toxicity. For example, a compound metabolized safely in rodents may generate toxic metabolites in humans.
How to Avoid It:
- Conduct early cross-species ADME profiling.
- Select tox species with metabolic pathways similar to humans.
- Use in vitro human systems (hepatocytes, microsomes) to complement in vivo results.
Q4: Why is balancing animal welfare with long study durations challenging?
Chronic studies, oncology models, or repeated-dose designs may cause stress or discomfort to animals if not optimized. Ethical compliance with the 3R principles (Replacement, Reduction, Refinement) requires minimizing animal burden while preserving scientific integrity.
How to Avoid It:
- Apply refinement techniques (analgesia, improved housing, stress reduction).
- Use advanced imaging and non-invasive biomarkers to reduce animal numbers.
- Work with CROs that maintain high welfare standards and regulatory compliance.
Q5: What happens when researchers select models without considering clinical endpoints?
If the in vivo endpoints do not align with the intended clinical outcomes—such as using tumor volume instead of immune activation markers for immunotherapy—the results may not predict human responses, leading to ineffective clinical translation.
How to Avoid It:
- Ensure preclinical endpoints mirror clinical endpoints whenever possible.
- Incorporate PK/PD modeling to bridge animal data with human dosing strategies.
- Engage scientific experts early to optimize model–endpoint alignment.
HuaTeng's Perspective:
We specialize in offering strategies that prioritize both scientific validity and animal welfare, guiding clients through complex regulatory and ethical considerations.
Conclusion: The Importance of Choosing the Right Model for Drug Development Success
Choosing the correct animal model for drug discovery, preclinical development, and pharmacology studies can significantly impact the success of a drug program. With the growing diversity of therapeutic approaches, the right model is not just a scientific decision—it's a strategic one.
If you're unsure which animal model to choose, need guidance on designing IND-enabling studies, or want tips on accelerating clinical development, our expert scientists at HuaTeng are here to help.
Contact us today to receive a customized model-selection plan tailored to your specific drug targets and research pipeline.
