Statistical concepts in the planning and evaluation of drug safety from clinical trials in drug development: issues of international harmonization.

The assessment of the safety of new drugs during pre-marketing clinical studies is an important and integral part of the drug development and regulatory evaluation process. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a project that brings together the regulatory decision-makers of Europe, Japan and the United States of America and the experts from the pharmaceutical industry in the three regions to seek ways to eliminate redundant and duplicative technical requirements among the developed countries for registering new medicinal substances and products. The ICH is developing guidelines or position papers to achieve the goal of harmonizing technical standards in three broad areas, namely, drug efficacy, safety and quality. Within the area of drug safety, this paper will discuss three of the safety topics because of their relevant statistical framework, and because these topics have not, to date, received any attention by the statistical community. The three issues under consideration by the International Conference on Harmonization (ICH), are: 1. Dose-response information to support drug registration (especially dose/toxicity relationships). 2. Studies in support of special populations; Geriatrics, A Draft Guideline. 3. ICH Draft Guideline 3 on 'The extent of population exposure required to assess clinical safety for drugs intended for long-term-treatment of non-life-threatening conditions'. The ICH special population guideline concerning studies in geriatric patients is closely related to a recent Food and Drug Administration 'Guideline for the study and evaluation of gender differences in the clinical evaluation of drugs', which is another example of a 'subgroup' for whom specific interest exists to evaluate drug safety and efficacy.