US and EU regulators have been strengthening requirements for aggregate safety assessments throughout clinical development. For example, Reference Safety Information in the IB should be restricted to serious adverse reactions (multiple occurrences) where, after a thorough assessment by the sponsor, reasonable evidence of a causal relationship between the event and the investigational product exists. However, EU regulators still prefer to receive all individual SUSAR reports from sponsors, based on investigator as well as sponsor causality assessments.
The FDA, in contrast, has placed responsibility squarely on sponsors to send a safety report only after they have judged there to be a reasonable possibility that the study drug caused the events. Few events can be judged to be drug-related based on one or a small number of occurrences and reporting of all SAEs could obscure important safety information. The FDA expects sponsors to implement processes resulting in a substantial reduction in the number of safety reports without meaningful information.
Jacqueline Corrigan-Curay (Principal Deputy Center Director of CDER) explained the spirit of FDA’s IND safety reporting final rule as follows (2018 ASA Biopharm Stat Workshop):
The important thing is to have a thoughtful process; a system in place to look for clinically important imbalances, applying the best clinical and quantitative judgment, while maintaining trial integrity.
Sponsors have agreed with the spirit of the final rule – from the beginning – but have had concerns about how to determine the threshold for different events and the impact that repeated unblinding would have on trial integrity (Same concerns as EU regulators?). In response, they have developed processes and tools to evaluate, assess, and act on accumulating safety information during development – leveraging scientific expertise and medical judgment of multidisciplinary safety management teams.
FDA recognizes that causality assessments based on aggregate safety data review can be difficult and require medical judgment. Per the 2021 Draft Guidance: “FDA will focus on the sponsor’s process and reasoning underlying the sponsor’s decision … regarding whether SAEs evaluated by analyses of aggregate data meets IND safety reporting criteria.”
Applying a single approach to safety reporting from clinical trials is currently a challenge (Not possible?) due to varying regional requirements. As a result, investigators and regulators in different countries may receive diverse SUSAR data as trials progress. Now that some sponsors have demonstrated alignment with the FDA – regarding the reporting of events requiring aggregate assessment – can regional regulatory authorities regain alignment?