ABSTRACT
Among the earliest regulatory references to experimental paradigms consistent with that which we understand today as safety pharmacology investigations are those contained within Japanese regulatory history.1-3 This history, with contribution from other established regional regulatory authorities, has contributed signi˜cantly to the development of internationally recognized harmonized guidelines, ICH S7A, “Safety Pharmacology Studies for Human Pharmaceuticals,”4 and ICH S7B “Guidance on Safety Pharmacology Studies for Assessing the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals.”5 Based on expert input, these guidance documents have articulated formal recommendations for design, execution, and interpretive elements of safety pharmacology investigations in core and ancillary functions,6,7 including a discussion of techniques considered appropriate for determining the potential for a drug to produce alterations in patterns of cardiac conduction, especially as it relates to ventricular repolarization status. The development and promulgation of such internationally harmonized guidance documents
Introduction ............................................................................................................................................................................... 721 Safety Pharmacology Harmonized Guidelines ......................................................................................................................... 721 Sample Study Designs.............................................................................................................................................................. 722
Cardiovascular Function Studies.......................................................................................................................................... 722 Respiratory Function Studies............................................................................................................................................... 726 Combined Cardiorespiratory Safety Evaluations ................................................................................................................. 728 Central Nervous System Evaluations ................................................................................................................................... 732 Integrated Functional Safety and Toxicology Study Designs.............................................................................................. 734
Study Implementation............................................................................................................................................................... 736 Compound Characteristics................................................................................................................................................... 737 Prerequisite Data .................................................................................................................................................................. 737 Test System and Dose Selection .......................................................................................................................................... 738 Environmental Controls and Assay Sensitivity.................................................................................................................... 738
Historical Control Data for Core Safety Pharmacology Assays............................................................................................... 740 Conclusion................................................................................................................................................................................ 755 References ................................................................................................................................................................................. 755
stances surrounding unrecognized (cardiovascular) risks accompanying industry practice prior to their inception.8-12 While the issuance of regulatory guidance has not resulted in, nor reasonably may be expected to lead to the complete mitigation of risk, recommendations within these guidance documents have been put forth with the goal of enhancing, to the extent possible, the reliability and predictive validity of preclinical models used for the purpose of characterizing functional safety concerns. While speci˜c in some respects (e.g., recommendations on GLP status of different kinds of safety pharmacology studies, essential end points for characterization in core study designs), these guidance documents are notably, and it might be argued, necessarily more generic in the other sections relating to the speci˜cs of model selection and study design (e.g., species of choice, numbers of subjects and test conditions, etc.). This circumstance has been acknowledged in terms of facilitating an understanding of the goals of testing without unduly dictating application of a particular approach without appropriate consideration of the unique circumstances intrinsic to each development program. Accordingly, in the sections to follow, it should be realized that presentation of a “typical” study design or evaluative technique is done so only with the goal of serving as a point of reference for instructional purposes, and is not intended to be applicable to every situation.
