Abstract
Information on the safety profiles of medications that is critical for making decisions in clinical toxicology initially relies on the profile of adverse reactions determined during clinical development. Adverse reactions can be heuristically classified into types A (Augmented pharmacologic effect), B (bizarre or idiosyncratic effects), C (Chronic effects), D (Delayed effects), E (End-of-treatment effects), F (Failure of therapy) or G (Genetic reactions) and of these categories type A reactions can be expected to be of greatest interest during acute overdose. Causality assessments of individual adverse events during clinical trials are often unreliable, as evidenced by cases where an adverse reaction is assessed as being “related” to study drug but on unblinding the subject is found to have been on placebo. The determination of what adverse reactions can be expected depends on careful review of aggregate clinical trial data comparing the adverse events and clinical testing abnormalities for the investigational compound to placebo and active comparators. The Bradford-Hill criteria, the recommendations of CIOMS VI on evaluating clinical safety data and the FDA’s internal guidance for its reviewers on performing Clinical Safety Reviews are useful guides when evaluating clinical trial safety data. The interpretation of clinical trial safety data, selection of safety issues for future monitoring in Risk Management Plans and considerations for selecting information for the Warnings & Precautions and other Adverse Reactions sections of Package Inserts will be presented and discussed.
