- INTRODUCTION
1.1 Objectives of the Guideline
This guideline was developed to prevent needless use of animals and other resources while protecting patients receiving marketed products and clinical trial participants from potential negative effects of drugs.
A definition, broad guidelines, and suggestions for safety pharmacology research are given in this guideline.
- Background
For many years, pharmacology studies have been carried out all over the world as part of the non-clinical evaluation of drugs intended for human consumption. However, there are no globally recognised criteria, goals, or guidelines for the planning and execution of safety pharmacology research.
The ICH topics “Timing of Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals (M3)” and “Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (S6)” introduced the term “safety pharmacology studies” as research that ought to be carried out to support the use of therapeutics in humans. Future debate will address the specifics of the safety pharmacology studies, such as their definition and objectives.
- Scope of the Guideline
In general, new chemical entities and human-use products developed from biotechnology are covered by this rule. When appropriate, this recommendation can be applied to pharmaceutical products that are currently on the market (e.g., when adverse clinical events, a new patient population, or a novel route of administration raises issues not previously addressed).
- General Principle
When choosing and carrying out safety pharmacology research, it is crucial to use a logical approach. The particular characteristics and intended applications of the pharmaceuticals will determine which research should be carried out and how they are designed.
It is important to utilise scientifically valid methodologies, and it is desirable to adopt internationally recognised methods that are applicable to pharmaceuticals. Furthermore, it is recommended that new technology and approaches be used in compliance with strong scientific standards.
While some safety pharmacology endpoints should be assessed in particular safety pharmacology studies, others can be included in the design of toxicological, kinetic, clinical, etc. research. Adverse effects of a substance may not be apparent from observations and measurements used to identify toxicity in traditional animal toxicity studies, even though they may be detected at exposures that fall within the therapeutic range in properly conducted safety pharmacology investigations.
- Definition of Safety Pharmacology
Primary pharmacodynamic, secondary pharmacodynamic, and safety pharmacology studies are the three types of pharmacology research. Studies that examine the possible adverse pharmacodynamic effects of a substance on physiological functions in connection to exposure in the therapeutic range and above are referred to as safety pharmacology studies for the purposes of this publication.
Along with the results of safety pharmacology investigations, information on the substance’s primary and secondary pharmacodynamic qualities should occasionally be considered when evaluating the substance’s safety for possible detrimental effects in people.
- GUIDELINE
2.1 Objectives of Studies
Safety pharmacology studies aim to: 1) identify a substance’s unwanted pharmacodynamic properties, that may be relevant to human safety;
2) to assess a substance’s pathophysiological and/or adverse pharmacodynamic effects seen in toxicology and/or clinical research; and 3) to look into the mechanism underlying any observed or suspected bad pharmacodynamic effects. To achieve these goals, the investigative strategy should be precisely defined.
2.2 General Considerations in Selection and Design of Safety Pharmacology Studies
Studies should be chosen and planned appropriately because pharmacological effects differ based on the particular characteristics of each test drug. The following elements should be considered (the list is not all-inclusive):
1) Adverse effects associated with the test substance’s therapeutic class, as the mechanism of action may indicate particular adverse effects (proarrhythmia is a common feature of antiarrhythmic agents, for example);
2) Adverse effects associated with members of the chemical or therapeutic class, but independent of the primary pharmacodynamic effects (e.g., anti-psychotics and QT prolongation);
3) Data from ligand binding or enzyme assays indicating a possibility of negative consequences;
4) Findings from earlier safety pharmacology studies, secondary pharmacodynamic studies, toxicological investigations, or human use that call for additional research to determine and describe the findings’ relevance to possible negative consequences in humans.
A more general approach to safety pharmacology investigations can be used in situations where there may not always be enough information (such as comparative metabolism) to logically choose or design the studies in accordance with the previously mentioned points during early development.
A hierarchy of organ systems can be developed according to their importance with respect to life-supporting functions. Vital organs or systems, the functions of which are acutely critical for life, such as the cardiovascular, respiratory and central nervous systems, are considered to be the most important ones to assess in safety pharmacology studies. Other organ systems, such as the renal or gastrointestinal system, the functions of which can be transiently disrupted by adverse pharmacodynamic effects without causing irreversible harm, are of less immediate investigative concern. Safety pharmacology evaluation of effects on these other systems may be of particular importance when considering factors such as the likely clinical trial or patient population (e.g. gastrointestinal tract in Crohn’s disease, renal function in primary renal hypertension, immune system in immunocompromised patients.).
2.3 Test Systems
2.3.1 General Considerations on Test Systems
Consideration should be given to the selection of relevant animal models or other test systems so that scientifically valid information can be derived. Selection factors can include the pharmacodynamic responsiveness of the model, pharmacokinetic profile, species, strain, gender and age of the experimental animals, the susceptibility, sensitivity, and reproducibility of the test system and available background data on the substance. Data from humans (e.g., in vitro metabolism), when available, should also be considered in the test system selection. The time points for the measurements should be based on pharmacodynamic and pharmacokinetic considerations. Justification should be provided for the selection of the particular animal model or test system.
2.3.2 Use of In Vivo and In Vitro Studies
Test systems include ex vivo and in vitro preparations, as well as animal models. Isolated organs and tissues, cell cultures, cellular fragments, subcellular organelles, receptors, ion channels, transporters, and enzymes are just a few examples of ex vivo and in vitro systems. Supportive studies can make advantage of in vitro systems (e.g., to get a profile of the substance’s activity or to explore the mechanism of effects reported in vivo).
It is best to employ unanesthetized animals for in vivo research. Preferable to data from restrained or unconditioned animals are those from unrestrained animals that may be chronically instrumented for telemetry, other appropriate instrumentation techniques for conscious animals, or animals conditioned to the laboratory environment. Avoiding discomfort or agony is a top priority while using unanesthetized animals.
2.3.3 Experimental Design
2.3.3.1 Sample Size and Use of Controls
The groups should be large enough to enable significant scientific interpretation of the produced data. Therefore, there should be a sufficient number of animals or isolated preparations to show or rule out the existence of a physiologically meaningful effect of the test substance. The magnitude of the biological impact that is concerning to humans should be considered. The experimental design should incorporate suitable positive and negative control groups. Positive controls might not be required in well-characterized in vivo test settings. It should be reasonable to exclude controls from research.
2.3.3.2 Route of Administration
When possible, the anticipated clinical route of administration should be utilised.
When such information is available, exposure to the parent material and its principal metabolites should be comparable to or higher than that attained in people, regardless of the mode of administration. If the test substance is intended for clinical use by more than one route of administration (e.g., oral and parenteral), or if significant qualitative and quantitative differences in systemic or local exposure have been observed or are predicted, it may be appropriate to assess effects by multiple routes.
Reference: https://database.ich.org/sites/default/files/S7A_Guideline.pdf
– Dr Subramanian S Iyer
