EU and US regulators have been strengthening requirements for aggregate safety assessments throughout development. However, emphasis has been different, with the EU more focused on postmarketing surveillance and the US more focused on premarketing clinical trials. Currently, 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 event. Few events can be judged to be drug-related based on one or a small number of occurrences. A reporting decision for an anticipated event in the study population requires an aggregate analysis. And so, the FDA expects a substantial reduction in the number of reports containing non-meaningful safety information.
Consequently, it can be challenging (Not possible?) to apply a single global approach to report handling.
Note, according to ICH E2A: Clinical Safety Data Management (1995), a clinically important increase in the rate of an expected serious ADR is subject to expedited reporting. This requires an aggregate analysis; however, how to make aggregate safety assessments in ongoing studies (especially without unblinding study personnel) has not been described in ICH guidance.
Sponsors and the FDA have been working together to improve approaches for assessing the accumulating safety data, with more cross-functional teams for planning and coordinating program-level safety assessments and more guidance on aggregate safety assessments.
FDA recognizes that these assessments can be difficult and require clinical judgment. It is important for the sponsor to document reasoning. Per the 2021 Draft Guidance: “FDA will focus on the sponsor’s process and reasoning underlying the sponsor’s decision.
To meet the spirit of the IND Safety Reporting final rule, sponsors have developed processes and tools to evaluate, assess, and act on accumulating safety information throughout development (including the ASAP process) – leveraging scientific expertise and medical judgment of multidisciplinary safety management teams – supplementing medical safety reviews of individual cases and medical monitoring of individual studies.
Bob Temple (Senior Advisor in CDER’s Office of New Drugs) said that when the agency issued its draft guidance in 2015, it didn’t say how to implement it, but left it to the companies to develop the actual process:
It’s really been quite gratifying to see how people have reacted to it. It has stopped us from getting crap, and helped people identify the things that really matter.
Consequently, it can be challenging to apply a single global approach to report handling.