Safety Pharmacology Studies for Human Pharmaceuticals

Safety Pharmacology Studies for Human Pharmaceuticals

physiological functions in relation to exposure in the therapeutic range and above. (See Note 2 for definitions of primary pharmacodynamic and secondary pharmacodynamic studies.) In some cases, information on the primary and secondary pharmacodynamic properties of the substance may contribute to the safety evaluation for potential adverse effect(s) in humans and should be considered along with the findings of safety pharmacology studies. 2. GUIDELINE 2.1 Objectives of Studies 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. 2.2 General Considerations in Selection and Design of Safety Pharmacology Studies Since pharmacological effects vary depending on the specific properties of each test substance, the studies should be selected and designed accordingly. The following factors should be considered (the list is not comprehensive): 1) Effects related to the therapeutic class of the test substance, since the mechanism of action may suggest specific adverse effects (e.g., proarrhythmia is a common feature of antiarrhythmic agents); 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) Ligand binding or enzyme assay data suggesting a potential for adverse effects; 4) Results from previous safety pharmacology studies, from secondary pharmacodynamic studies, from toxicology studies, or from human use that warrant further investigation to establish and characterize the relevance of these findings to potential adverse effects in humans. During early development, sufficient information (e.g., comparative metabolism) may not always be available to rationally select or design the studies in accordance with the points stated above; in such circumstances, a more general approach in safety pharmacology investigations can be applied. 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.).