Safety pharmacology, a discipline unrecognized until the last few years, is now the subject of Japanese, American, European and ICH draft guidelines. The aim of these guidelines, either of a general nature or targeted at one particular organ, is to define the necessary pharmacology studies as well as the conditions in which these studies must be performed to ensure the safe use of new molecules when they are administered to man. This presentation attempts to give a comparative analysis of these documents and to place them in the context of future international harmonization.

Europe↗

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[Regulatory status of safety pharmacology. Implications].

Safety Pharmacology is now specified by various European and international guidelines. The ICHS7A text, which has now been implemented, requires all new compounds to be tested before any administration in humans. The compound should be evaluated under GLPs for its potential effects on so-called vital functions (cardio-vascular, respiratory and central nervous system). Also, the potential risk for QT prolongation and Torsades de Pointes should be appropriately assessed using in vitro and in vivo models (CPMP/986/96 and draft ICHS7B) before the initiation of Phase I. Various other European or international guidelines relate to more specific evaluations: abuse liability, anti-osteoporotic compounds, etc. Safety Pharmacology should also, as other studies required for regulatory submission, be conform to the electronic records and signature constraints (CFR23 part 11 for the USA) and to the format of the Common Technical Document (ICHM4). To address all these requirements, the pharmaceutical industry should now be creating specially assigned Safety Pharmacology teams.

Drug Evaluation↗

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The size distribution of thyroid follicles in single thyroid glands, a peculiar problem of particle size distribution in stereology.

Follicle sections vary in size according to their inclination mainly in hypertrophied thyroids. Sagittal sections elicit a shift to small classes, while transversal sections, to large classes. There is no mathematical transformation able to convert data obtained by sections into "true" sizes of follicles, as may be achieved by isolation. All papers emphasizing only section diameters and inferring about follicle size must be cautiously interpreted, and even discarded, if they tend to establish differences in follicle size solely on that basis. Follicle isolation is necessary if we need to establish follicle size and shape. Although proportions are almost stable for rats of the same age and weight, the proportions of follicle size may vary, as dependent on age and other internal and external conditions. The situation is most complicated by colloid accumulation; but despite these impedimenta, TSH secretion enlarges the follicles, a situation hitherto not well established. Cell enlargement is consequently followed by follicle enlargement, despite colloid resorption.

Animals↗

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