Interdisciplinary Safety Evaluation for Learning and Decision-Making.

The FDA IND safety reporting Final Rule (21CFR 312.32) applies to all human drugs and biological products being studied under an Investigational New Drug (IND). A sponsor must file an IND safety report for any serious unexpected suspected adverse reaction (SUSAR) of a medicinal product being investigated. Some events may be obviously drug-related (e.g., agranulocytosis, anaphylactic reaction, drug-induced hepatic injury, Stevens-Johnson Syndrome). For serious adverse events that are not interpretable as individual occurrences, additional processes and procedures need to be employed for identifying and assessing risks in the accumulating safety data. The approaches shared in this manuscript apply principally to safety reporting of events that are anticipated to occur in the patient population-regardless of study participation. For these events, the study sponsor should periodically review the data in the aggregate and make a judgment as to whether there is a reasonable possibility of an event having been caused by the study drug rather than the underlying condition of the patient or a concomitant therapy. Factors cited for consideration are the size and consistency of the difference in event frequency between the test and control groups, supportive preclinical findings, evidence of a dose response relationship, plausible mechanism of action, known class effect and occurrence of other related adverse events. Examples are provided that demonstrate the flexibility sponsors have in meeting the spirit of the Final Rule; some combination and variation of methods from the examples could be employed. The important thing, as expressed by Jacqueline Corrigan-Curay (Director of the Office of Medical Policy, Center for Drug Evaluation and Research, FDA), 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 (Ball et al. in Interdisciplinary aggregate assessments for IND safety reporting: a dialogue among colleagues from industry, Academia and the FDA. ASA biopharmaceutical section regulatory-industry statistics workshop, 2018).