Practical risk management for adaptive integrated early phase clinical trials

Background: Risk management is an essential element of integrated, adaptive early phase protocols. Toxicities are major factors determining whether a study continues or is suspended, thus any rules regarding toxicities will significantly define study structure and progression. The revision to the European Medicines Agency's first-in-human and early phase clinical trials guideline mandates the use of unambiguous rules for severe and serious adverse reactions (AR). Methodology for designing rules for healthy volunteer and patient trials in investigational or marketed medicinal products are presented. Methods: Template rules were developed using standard NCI CTCAE terminology and a systematic, objective and consistent process. Severity, seriousness, frequency and reversibility of ARs were considered. These rules control decisions related to individual trial participants, dosing regimens and to dose escalation and/or progression to successive trial parts. Trial specific adaptations were made based on properties of the Investigational Medicinal Products (IMP), non-IMP, Reference Safety Information (RSI) and the degree of uncertainty about potential ARs. Results: Template toxicity rules were successfully applied to early phase adaptive integrated trials, with recent examples of trial specific adaptations. Templates covered decision making at five levels: at the level of the individual participant; within the group or cohort level; between cohorts; the study arm and at the whole study level. All case studies received regulatory authorisation and were performed in the UK. Figure 1 shows the principle of how template rules were applied in an integrated trial. Conclusions: Based on standardised input factors, rule-based algorithms were established to minimise risk and ensure efficient study progression. This template demonstrates how systematic, objective and consistent risk management of large integrated trials can be simple yet robust, facilitate effective decision making and ensure participant safety.