Origin and Evolution of Safety Pharmacology 1321 Regulatory Requirements

Prior to 1990, regulatory guidance on non-clinical organ function testing was limited. The U.S. and European regulations provided only general references to the evaluation of drug effects on organ system functions.11-13 Organ function assessments included within investigational new drug applications (INDs) and registrations (NDAs) were inconsistent and often viewed as unimportant.14,15 However, in Japan, the Ministry of Heath and Welfare (MHW), now referred to as the Ministry of Health, Labor, and Welfare, had promulgated comprehensive guidance for organ function testing as early as in 1975 (see Table 13.5). These guidances described which organ systems would be evaluated as a first-tier evaluation (List A studies) and made specific recommendations regarding study designs (including description of models, criteria for dose selection, and which endpoints would be included in the investigation). These guidances also described a second tier of studies (List B) to be conducted based on the significant findings in List A investigations (Table 13.5).16 Because the Japanese guidance were the most comprehensive of their time, they became the de facto foundation for organ function testing throughout the pharmaceutical industry.2,17,18 The organ function studies included in Lists A and B were intertwined with studies whose aim was to catalog additional pharmacological functions and activities (i.e., secondary pharmacology) in addition to the primary pharmacological function/activity. Kinter et al.12 distinguished two subgroups of objectives embedded in the Japanese studies as safety and pharmacological profiling. This concept was enlarged upon the International Conference on Harmonization (ICH) safety pharmacology. Expert Working Group (EWG) to define three categories of pharmacology studies: primary and secondary pharmacodynamic studies, and safety pharmacology studies (see Section 13.318,19 and Table 13.5). During the same period, European, U.S., and Japanese regulatory agencies prepared positions on general pharmacology/safety pharmacology in the form of guidance and concept papers.18-21 Any complacency surrounding safety pharmacology was shattered in 1996 with the appearance of the first draft of a "Points to Consider" document on QT prolongation by the European Medicines Agency's Committee for Proprietary Medicinal Products (CPMP) and issued as an official document the following year.22 One of the more controversial aspects of this document was the recommendation to incorporate screening of all noncardiac drugs for effects on cardiac action potential in vitro. The opposition to this document from the pharmaceutical industry arose partly because this recommendation wrong-footed the industry. The positive impact of the CPMP document was that it resuscitated safety pharmacology as a rigorous scientific discipline. In 1998, the MHW and the Japanese Pharmaceutical Manufacturers' Association proposed to the ICH Steering Committee the adoption of an initiative on safety pharmacology. This proposal was accepted and given the designation of Topic S7.

The origin of the term safety pharmacology is obscure. It first appeared in the draft guidances of the ICH M3 and S6 (see Table 13.5).2324 ICH S6 stated that "...the aim of the

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