The U.S. Food and Drug Administration (FDA) has issued a draft guidance that proposes the agency adopt, and in some cases, expand, an International Council for Harmonization (ICH) addendum to a 1998 clinical trials statistics guideline focused on the use of sensitivity analyses and targets for trial estimation and measurement.
The new draft guidance, “E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials,” clarifies and extends the original ICH E9 guideline, providing a framework for choosing specific statistical methods for clinical trials.
Among other topics, E9(R1) addresses randomization in trials. “It remains undisputed that randomization is a cornerstone of controlled clinical trials and that analysis should aim at exploiting the advantages of randomization to the greatest extent possible,” ICH says. “However, the question remains whether understanding the effect of a treatment policy always targets the treatment effect of greatest relevance to regulatory and clinical decision making.”
The addendum advocates new ways to consider other treatment effects, and provides points to consider for the design and analysis of trials to give estimates of effects that are reliable for informing decision making. It also recommends sponsors demonstrate their rationale for any uncollected data when analyses of trial results are conducted.
When conducting a sensitivity analysis, the FDA recommends avoiding a bevy of simultaneous changes to a study. Instead, it wants trial practitioners to investigate any impact one change at a time. The addendum includes suggested examples and strategies.
The draft harmonized text was endorsed by the ICH in July, and was accepted by the European Medicines Agency in August.
Author: Michael Causey