Safety Pharmacology Core Battery and Supplemental Studies
In the design and execution of safety pharmacology and toxicology studies, vast experience in stand-alone and integrated repeat-dose designs is necessary. Our safety pharmacologists are fluent in the latest technology and assessments, including the use of implanted and jacketed external telemetry (JET) for the collection of continuous electrocardiographic and hemodynamic data in large animals.
Our standard safety pharmacology studies incorporate the core battery of testing required for small molecule drugs, including the CNS FOB/Irwin screen, evaluation of respiratory function, and cardiovascular assessment including the in vitro hERG assay (to identify potential risk of QT interval prolongation).
Any or all of these assessments may be incorporated into toxicology to evaluate safety following repeated dosing or potential long-term effects. Additionally, these study designs offer a cost-effective means of addressing regulatory expectations while actively fostering the 3Rs.
ICH S7A & S7B Guidelines
Our comprehensive, global and harmonized safety pharmacology studies program complies with International Conference on Harmonization (ICH) Guidelines (S7A, S7B) and provides the expert interpretations needed to advance your program successfully.
Our global safety pharmacology team has incorporated the newly released recommendations from ICH E14/S7B Q&As for inclusion of non-clinical data within the clinical risk assessment into daily practices. Our safety pharmacologists that lead and conducted cardiovascular in vitro QTc assays are participating in the global cross-industry working groups resulting in several best practice manuscripts.
Charles River scientists interact with the industry, academic institutions, and regulatory agencies innovating the assays and tools needed to further the translation of preclinical data to clinical outcomes. Our integrated in vitro safety pharmacology and in vivo expertise provides a comprehensive approach for de-risking compounds across organ systems aiding in effective decision-making in early preclinical development.
The core battery of safety pharmacology GLP studies should be included in small molecule IND-enabling programs to assess the acute and potentially life-threatening risks of novel pharmaceuticals for human use.
- Cardiovascular System
Blood pressure, heart rate, electrocardiograms (ECGs), ventricular and pulmonary pressure, and echocardiography - Respiratory System
Respiratory rate, hemoglobin oxygen saturation, and tidal and minute volumes - Central Nervous System (CNS)
Functional observation battery (FOB), modified Irwin screen, body temperature, and large animal neurological evaluations - In Vitro Electrophysiology
Complete cardiac ion channel assessments (e.g., Na+, Ca++, K+, or hERG)
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Supplemental Studies
Second-tier studies can be used to develop a greater understanding of mechanistic effects on vital functions and evaluate potential adverse effects on other organ systems, such as renal and gastrointestinal systems.
- Tier II Assessments
- Cardiovascular system, cardiac output/arterial flow, vascular/peripheral resistance, and central nervous system (CNS) and respiratory system assessments
- Respiratory
- Lung resistance and plethysmography
- CNS
- Quantitative motor performance, CNS electrophysiology (EEG), and higher order neurofunctional endpoints
- Renal/Urinary
- Renal function and general clinical chemistry
- Gastrointestinal
- Motility and function
- In Vitro Electrophysiology
- Comprehensive In Vitro Proarrhythmia Assay (CiPA) battery including drug effects on multiple human cardiac currents using appropriate voltage protocols, in silico reconstruction of the human cardiac action potential, and in vitro effects in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs)
- Chemical or electrical, cultured, and/or dissociated neurons through various extracellular or intracellular electrophysiological configurations
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Frequently Asked Questions (FAQs) About Safety Pharmacology
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What is the role of the safety pharmacology core battery program?
The role of a safety pharmacology core battery program is to determine the potential undesirable pharmacodynamic effects of a drug on the central nervous, cardiovascular, and respiratory systems, in relation to exposures in the therapeutic range and above.
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When do I need supplemental studies for my safety pharmacology evaluation?
When compound and scientific considerations necessitate supplemental testing, you can rely on our vast experience in drug liability evaluation and our successful track record at lifting clinical holds. We can also help leverage your toxicology studies with the addition of innovative safety pharmacology data acquisition solutions which take advantage of integrated experimental designs.
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What should be the next step if an adverse safety finding is reported from one of the safety pharmacology core battery studies?
Charles River safety pharmacologists work together across scales (single cell through whole animal) to evaluate the integrated responses across the organ systems of interest. Recommendations could be made to determine risk, identification of premonitory signals for clinical translation, and/or for further preclinical evaluation to identify effected pathways or mechanisms of action for the adverse response.
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What is a safety pharmacology study?
Safety pharmacology studies investigate potential undesirable pharmacodynamic effects of a drug on physiological functions in relation to exposure in the therapeutic range and above. These are required for small molecule modalities by the FDA.
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What are the objectives of safety pharmacology studies?
Safety pharmacology studies are intended to identify undesirable pharmacodynamic properties of a substance that may have relevance to human safety, evaluate adverse pharmacodynamic and/or pathophysiological effects of a substance observed in toxicology and/or clinical studies, and to investigate the mechanism of the adverse pharmacodynamic effects observed.
Charles River offers a full suite of studies to evaluate in vitro and in vivo safety to meet the ICH guidance as well as mechanistic studies to de-risk compounds.
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What changed with the release of the ICH E14/S7B Q&As to the cardiovascular safety pharmacology study?
In Vitro: Many changes were recommended in the Q&As for consistency in conduct and reporting of the hERG assay, including recording temperature near physiologic (35-37° C), recording quality, primary endpoints (IC50, Hill coefficient, etc.), confirmation analysis, and positive control(s).
In Vivo: Beyond conducting studies in same species in toxicology studies, conscious large animals, and Latin square cross over design, the additions to the in vivo cardiovascular studies under ICH S7B Q&As are to report study sensitivity, least significant difference (LSD), to detect a change in measured endpoints, primarily QTc. Additionally, a recommendation to conduct concentration QTc analysis which would provide a visualization of the relationship between QTc and concentration or exposure of the test compound. A laboratory should report their historical assay sensitivity, minimal detectable difference (MDD), or include a positive control report to detect changes in QTc.