ICH guidelines: inception, revision, and implications for drug development.

Since the inception of the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) in 1990, six-party Expert Working Groups (EWG) have developed and revised numerous guidelines on preclinical safety evaluation (Table 1). The six parties to ICH represent the regulatory bodies and pharmaceutical manufacturing organizations in the three regions: Europe, Japan, and the United States, where the majority of new medicines are developed. The development of ICH guidelines is a stepwise process. In step 1, the EWG prepares a ‘‘final harmonized draft.’’ Step 2 entails forwarding the draft to the Steering Committee for signature, which signifies acceptance for consultation. Step 3 is a process of consultation and discussion with regulatory organizations within the three regions and usually takes about 6 months or longer. Under step 3, the step 2 guideline is also released for public comments. Step 4 generates the Experts Document as a result of the consultation and is then submitted to the Steering Committee. Step 4 is reached when the Steering Committee endorses the adoption of the guideline by the regulatory bodies of the three regions. In the final step (step 5), the guidelines are incorporated into national or regional internal procedures, and the process is completed. The experience gained over the past decades, combined with the refined approaches for the generation of new drugs, has led to the recent ICH initiatives for developing new guidelines and revisiting some of the existing guidelines. The purpose of these initiatives is to optimize the scientific and technical aspects of the drug development process, ultimately accelerating the development of safe and effective medicines, while reducing animal use. The major ICH initiatives (bold in Table 1) include a new guideline, ICH S9, for preclinical evaluation of anticancer pharmaceuticals, an addendum to ICH S6 regarding preclinical safety evaluation of biologics, revision of ICH M3 which addresses the timing of preclinical studies in relation to various stages of clinical development, and a proposed new guideline on genotoxicity testing (ICH S2) that replaces and combines the ICH S2A and S2B. In this paper, we present the rationale behind these initiatives at ICH and some interpretation of the revised and new guidelines. We also provide commentary and perspective on the potential impact these new guidelines may have on preclinical safety evaluation programs.