Drug Safety Assessment

Development of pharmaceuticals and their approval for marketing authorization is the result of multidisciplinary cooperation. Animal and in vitro experiments, the analysis of data, and their extrapolation to humans constitute a prerequisite for the development of effective, safe, and high-quality pharmaceuticals. The enormous complexity of activities bears the risk that individual researchers deviate from the traditional or recommended path. This is the reason why the International Conference/Council on Harmonization (ICH) was set up: to create guidelines to reduce possible redundancies or discrepancies during research and development and to allow for the submission and streamlined assessment of data to be reviewed by competent regulatory authorities. The objective of ICH is to create relative uniformity leading to acceptability for strategies in drug development and market authorization. Guidelines hereby serve to optimize and facilitate development of harmonized desirable standards to optimize research and regulations, and to accelerate their implementation. The aim of this chapter is to summarize the complex procedures needed to create guidelines and to support their use. The main focus here is on the guidances for nonclinical safety (e.g., pharmacology, kinetics, and toxicology, and interaction with other areas). In addition, a brief tour will be made addressing the guidelines on quality and efficacy. ICH represents the highest level of international recommendations for research and development (R&D). Twelve sets of nonclinical guidelines have been issued covering the legal responsibilities of sponsors and regulatory authorities (carcinogenicity, genotoxicity, kinetics, repeat dose toxicity, reproductive toxicity, biotechnology-derived compounds, safety pharmacology, immunotoxicology, anticancer pharmaceuticals, photosafety, pediatric safety, and biodistribution for gene therapy). In addition, multidisciplinary guidelines have been included (especially M3 for generalized strategic development advice and M4, the common technical dossier with detailed references to data formats). Issues arising with pharmaceutical compounds are complex and manifold, and guidelines cannot cover all problems. Therefore, a common quest for new solutions is constantly being carried out by regulatory agencies via scientific advice procedures. For drug developers, the high-level information, once adopted by ICH, should be supported by regional guidelines as may become necessary and by study designs described by OECD. All three authors have been long-term ICH EU topic leaders and have, from the beginning, supported the ICH initiative (originally started by the “six-pack” from the USA, EU, and Japanese regulators and pharmaceutical industries), which has become a global movement under the umbrella of the WHO.