Progression of a new pharmaceutical/drug from the laboratory to clinical trials requires it to have both a recognised health benefit and an acceptably-low risk of inducing adverse effects. By identifying undesirable effects and their underlying mechanisms, safety pharmacology studies are an essential component of the drug development process. Here, we’ll review the importance of safety pharmacology testing in human pharmaceuticals.
What is the aim of safety pharmacology testing?
While toxicology assessments are principally concerned with defining a maximum tolerated dose, safety pharmacology studies examine undesirable pharmacodynamic effects in the therapeutic range and above, and aim to detect rare serious events. The challenge in safety pharmacology is identifying the likelihood of such events [1].
Do I need to perform safety pharmacology testing of my pharmaceutical?
Safety pharmacology testing is generally required for regulatory approval of human pharmaceuticals. It may not be required, for example, for some locally applied drugs, cytotoxic drugs for treatment of end-stage cancer and biotechnology-derived products [2].
In addition to the obvious benefit of precluding risk to the health of patients and clinical trial participants, safety pharmacology testing can help companies to avoid wasting resources on the further development of unsafe drugs past the early preclinical stage. To reduce costs further, developers can consider combining safety pharmacology studies with traditional toxicology studies, which has the added advantage of increased sensitivity/statistical power (based on the relatively large number of animals typically used in toxicology studies) and a reduction in the overall number of animals used for safety evaluations [1].
Bibra scientists can help to determine whether safety pharmacology studies are necessary for your product and if toxicology studies can be used to meet and/or supplement safety pharmacology requirements. Our team is skilled in searching the published literature and are experienced in identifying potential risks and/or adverse events.
Which safety pharmacology endpoints should I consider assessing?
ICH guideline S7A [2] provides recommendations for safety pharmacology studies. It applies to “new chemical entities” and “biotechnology-derived products for human use”, as well as to marketed pharmaceuticals in some situations, for example when adverse clinical events, a new patient population or a new route of administration raises new concerns.
In general, “core battery” tests on the central nervous, cardiovascular and respiratory systems are essential under ICH S7A, with follow-up and supplemental safety pharmacology tests being recommended where appropriate.
Core battery testing
The core battery of safety pharmacology testing, which should ordinarily be conducted in compliance with GLP, is focused on the vital functions of the body, with ICH S7A recommending the following assessments:
- Central nervous system: Motor activity, behavioural changes, coordination, sensory/motor reflex responses, body temperature
- Cardiovascular system: Blood pressure, heart rate, electrocardiogram
- Respiratory system: Respiratory rate, other measures of respiratory function (e.g., tidal volume or haemoglobin oxygen saturation)
Follow-up and supplemental testing
Follow-up studies on the core battery systems and/or supplemental studies of other organ systems may be required under the following conditions and should be conducted in compliance with GLP to the greatest extent feasible:
- Adverse effects are suspected based on the pharmacological properties or chemical class of the test substance
- Concerns are identified by the core battery tests, clinical trials, pharmacovigilance, experimental in vitro or in vivo studies, or literature reports
Supplemental studies may include analyses of the renal/urinary system, autonomic nervous system, gastrointestinal system and other organs. ICH S7A provides examples of follow-up and supplemental studies, although the list is not considered to be comprehensive or prescriptive.
Complementary to the S7A guideline, ICH S7B [3, 4] focuses specifically on assessment of the effects of pharmaceuticals on ventricular repolarisation and proarrhythmic risk, which may be required if such a risk is identified for your product.
What other factors should I consider when deciding which safety pharmacology endpoints to assess?
ICH S7A states that the following factors should be considered when planning which safety pharmacology endpoints to assess:
- Effects related to the therapeutic class of the substance (e.g., proarrhythmia is a common feature of antiarrhythmic agents)
- Adverse effects associated with the chemical/therapeutic class, but independent of the primary pharmacodynamic effects (e.g., QT prolongation [a problem with the heartbeat] is a rare event associated with almost all antidepressants and antipsychotics)
- Ligand binding or enzyme assay data suggesting a potential for adverse effects
- Results from other studies or human use that warrant further investigation
The intended use of the pharmaceutical can also impact the choice of safety pharmacology tests. The regulatory bar for acceptance of a new drug will likely depend on a risk/benefit assessment; for example, a treatment for a disease with a poor prognosis (such as liver or pancreatic cancer) may be allowed to enter phase 1 clinical trials with minimal preclinical safety pharmacology testing. In this case, a developer may be able to carry out fewer but more focused safety pharmacology tests.
What else do I need to consider when planning safety pharmacology studies?
According to ICH S7A, several other factors should be considered when designing safety pharmacology studies:
- Type of test system – in vivo, ex vivo, in vitro
- Sample size/controls
- Route of administration – clinical route should be used when feasible
- Dose levels – sufficient to define a dose-response relationship; including doses similar to or greater than those used in humans
- Duration of study – generally single-dose, although repeated-dose can be considered
- Studies on metabolites, isomers or finished products – if they contribute to pharmacological activity
When should I perform safety pharmacology testing?
ICH S7A guidance recommends that safety pharmacology testing is performed for pharmaceuticals as follows:
- Prior to first administration in humans
- During clinical development (to clarify observed or suspected adverse effects)
- Before regulatory approval (follow-up and supplemental studies as needed)
Summary
It’s clear to see the importance of safety pharmacology testing in drug development. ICH S7A and S7B provide useful guidance on the safety pharmacology assessment of human pharmaceuticals. Seeking professional advice when planning and evaluating such assessments will maximise the time and cost efficiency of the drug development process.
Bibra experts can help you to evaluate safety pharmacology data alongside toxicology endpoints, to ensure that all necessary regulatory criteria are met. Get in touch with us today to see how we can support your safety pharmacology testing.
References
[1] Pugsley MK, Authier S, Curtis M (2008). Principles of safety pharmacology. British Journal of Pharmacology 154(7):1382-99. DOI: 10.1038/bjp.2008.280. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2492105/
[2] ICH Guideline S7A (2001). International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Safety Pharmacology Studies for Human Pharmaceuticals. June 2001. CPMP/ICH/539/00. https://www.ema.europa.eu/documents/scientific-guideline/ich-s-7-safety-pharmacology-studies-human-pharmaceuticals-step-5_en.pdf
[3] ICH Guideline S7B (2005). International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Non-clinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals. November 2005. CPMP/ICH/423/02. https://www.ema.europa.eu/documents/scientific-guideline/ich-s-7-b-nonclinical-evaluation-potential-delayed-ventricular-repolarization-qt-interval_en.pdf
[4] ICH guideline E14/S7B (2022). Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential - questions and answers. March 2022. EMA/CHMP/ICH/415588/2020. https://www.ema.europa.eu/documents/scientific-guideline/ich-guideline-e14/s7b-clinical-nonclinical-evaluation-qt/qtc-interval-prolongation-proarrhythmic-potential-questions-answers-step-5_en.pdf