Is patient exposure preapproval and postapproval a determinant of the timing and frequency of occurrence of safety issues?

BACKGROUND: The amount of drug exposure, pre and post approval, is considered to be a direct determinant of knowledge about the safety of a drug. A larger pre-approval exposed population is supposed to reduce the risk of unanticipated safety issues post-approval. The amount of use in the postapproval population is also expected to influence the occurrence and timing of safety issues. We investigated how the amount of pre and post approval exposure influences the detection of post-approval safety issues.

METHODS: A cohort of innovative drugs approved in Europe was followed for the period of 2012-2016. The main outcome of interest was a new safety issue in the period. Post-approval exposure was collected at 6 month intervals, and pre-approval exposure was collected at the moment of authorisation. Other characteristics collected for the included drugs were anatomical therapeutical chemical (ATC) class, biological status, orphan status and type of approval. We used Cox proportional hazards regression to investigate the association between exposure and the hazard of having a first safety issue.

RESULTS: The pre-approval exposure was not associated with the risk of safety issues after adjusting for ATC class, biological status, and treatment duration. Higher post-approval exposure was associated with more new safety issues identified (HR = 2.44 (95% CI = 1.12-5.31)) for drugs with more than 1,000 patient-years of cumulative exposure compared to drugs with less than 1,000 patient years of exposure.

CONCLUSION: Our results suggest that postapproval exposure influences the detection of safety issues.