The Implications of Current Methodological Issues for International Guidance

Abstract

We describe a number of methodological issues that have arisen in recent years with respect to the clinical trial work included in marketing applications for new medicinal products. The issues are then used as a vehicle to discuss the relevant guidance provided in the ICH E9 guideline entitled “Statistical Principles for Clinical Trials.” We explore whether there are apparent deficiencies in current guidance and whether there is potential new subject matter to cover. The aspects of clinical trial methodology addressed in this way include interim analysis, statistical analysis plans, the analysis population, missing data, multiplicity of end-points, subgroup analysis, and prespecification. We conclude that the ICH E9 guideline is still fully relevant as it stands, but that more might usefully have been said on some topics. In addition, some new methodological challenges have emerged since it was written. Consensus agreement should be sought on a number of new topics and, if achieved, the appropriate place to record the agreement should be identified, either in new guidance documents or in an updated ICH E9.