Safety Pharmacology Studies for Human Pharmaceuticals
This guidance was developed to help protect clinical trial participants and patients receiving marketed products from potential adverse effects of pharmaceuticals, while avoiding unnecessary use of animals and other resources.
This guidance provides a definition, general principles, and recommendations for safety pharmacology studies.
Pharmacology studies have been performed worldwide for many years as part of the nonclinical evaluation of pharmaceuticals for human use. There have been, however, no internationally accepted definitions, objectives or recommendations on the design and conduct of safety pharmacology studies. (Note 1)
The term safety pharmacology studies first appeared in ICH M3 Timing of Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals and S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals as studies that should be conducted to support use of therapeutics in humans (1, 2). Details of the safety pharmacology studies, including their definition and objectives, were left for future discussion.
A. Scope of the Guidance (1.3)
This guidance generally applies to new chemical entities and biotechnology-derived products for human use. This guidance can be applied to marketed pharmaceuticals when appropriate (e.g., when adverse clinical events, a new patient population, or a new route of administration raises concerns not previously addressed).
B. General Principle (1.4)
It is important to adopt a rational approach when selecting and conducting safety pharmacology studies. The specific studies that should be conducted and their design will vary based on the individual properties and intended uses of the pharmaceuticals. Scientifically valid methods should be used, and when there are internationally recognized methods that are applicable to pharmaceuticals, these methods are preferable. Moreover, the use of new technologies and methodologies in accordance with sound scientific principles is encouraged.
Some safety pharmacology endpoints can be incorporated in the design of toxicology, kinetic, and clinical studies, while in other cases these endpoints should be evaluated in specific safety pharmacology studies. Although adverse effects of a substance may be detectable at exposures that fall within the therapeutic range in appropriately designed safety pharmacology studies, such effects may not be evident from observations and measurements used to detect toxicity in conventional animal toxicity studies.
C. Definition of Safety Pharmacology (1.5)
Pharmacology studies can be divided into three categories: primary pharmacodynamic, secondary pharmacodynamic, and safety pharmacology studies.
For the purpose of this document, safety pharmacology studies are defined as those studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above.
In some cases, information on the primary and secondary pharmacodynamic properties of the substance contributes to the safety evaluation for potential adverse effects in humans and should be considered along with the findings of safety pharmacology studies.
II. GUIDANCE (2)
A. Objectives of Studies (2.1)
The objectives of safety pharmacology studies are (1) to identify undesirable pharmacodynamic properties of a substance that may have relevance to its human safety, (2) to evaluate adverse pharmacodynamic and/or pathophysiological effects of a substance observed in toxicology and/or clinical studies, and (3) to investigate the mechanism of the adverse pharmacodynamic effects observed and/or suspected. The investigational plan to meet these objectives should be clearly identified and delineated.
B. General Considerations in Selection and Design of Safety Pharmacology Studies (2.2)
1. ICH M3 Timing of Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals (FDA, 1997).
2. ICH S6 Preclinical Safety Evaluation of Biotechnology-derived Pharmaceuticals (FDA, 1997).
3. Mattsson, J. L., P. J. Spencer, and R. R. Albee, "A Performance Standard for Clinical and Functional Observational Battery Examinations of Rats," Journal of the American College of Toxicology, 15: 239 (1996).
4. Irwin, S., "Comprehensive Observational Assessment: 1a. A Systematic, Quantitative Procedure for Assessing the Behavioural and Physiologic State of the Mouse," Psychopharmacologia (Berlin), 13:222-257 (1968).
5. Haggerty, G. C., "Strategies for and Experience with Neurotoxicity Testing of New Pharmaceuticals," Journal of the American College of Toxicology, 10:677-687 (1991).
6. Murphy, D. J., "Safety Pharmacology of the Respiratory System: Techniques and
Study Design," Drug Development Research, 32: 237-246 (1994).
Please list, in general terms, the principles of safety pharmacology studies in humans.
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