EU regulators prefer to receive all individual SUSAR reports from sponsors (judged by sponsor and/or investigator) – concerned about missing important signals. Note, Reference Safety Information (RSI) listed in the Investigator’s Brochure, which forms the basis for the expectedness assessment of all “suspected” SARs that occur in clinical trials, requires aggregate assessments based on SPONSOR causality determination.
In 2017, the Clinical Trial Facilitation Group (CTFG), issued the RSI Q&A. Although aggregate safety analysis is described on a high level as a requirement for determination of expected serious events, it is not a specific discussion topic in the CTFG guidance. No consideration regarding methodologies or processes is made.
The FDA’s IND safety reporting guidance documents, while not as focused on the RSI, are more comprehensive with regard to aggregate assessment. Few events can be judged to be drug-related based on one or a small number of occurrences. In particular, reporting decisions for anticipated events in the study population would require an aggregate analysis. Notably, in ICH E2A, a clinically important increase in the rate of an expected serious ADR is subject to expedited reporting. This would also require an aggregate assessment. How to make aggregate safety assessments in ongoing studies (especially without unblinding study personnel) has not been described in ICH guidance.
The FDA has revised and clarified IND safety reporting requirements to improve the overall quality of safety monitoring and reporting of human drug and biological products, strengthening the agency’s ability to review critical safety information. Additionally, the FDA has revised the definitions and reporting standards to be as consistent as possible with international definitions and standards, in an effort to harmonize safety reporting internationally.
To meet the spirit of the final rule, sponsors have responded by developing processes and tools to evaluate, assess, and act on accumulating safety information during development on an ongoing basis. Now that sponsors and the FDA have aligned with solutions for the final rule, other regulatory agencies – who have had the same concerns as sponsors – will hopefully be realigning about safety reporting. The goal for safety is to identify, understand, and manage risks so that we can deliver effective medicines to the right patients.