A Novel Approach to Visualize Risk Minimization Effectiveness: Peeping at the 2012 UK Proton Pump Inhibitor Label Change Using a Rapid Cycle Analysis Tool.

INTRODUCTION: Evaluation of risk minimization (RM) actions is an emerging area of regulatory science, often without tools to rapidly and systematically assess their effectiveness.

PURPOSE: The aim of this study was to evaluate whether chronographs, typically used for rapid signal detection in observational longitudinal databases, could be used to visualize RM effectiveness. We evaluated the UK Medicines and Healthcare products Regulatory Agency (MHRA) 2012 proton-pump inhibitors (PPIs) class-wide label change that warned of increased risk of bone fracture, advocated to limit duration of use, and recommended to treat those at risk for osteoporosis according to clinical guidelines.

METHODS: The cohort consisted of adults aged 18 years and above prescribed one of the five PPIs available in the UK The Health Improvement Network (THIN) database through September 2015. Four chronographs were compared using drug episodes that started before (PRE) and after (POST) the 20 April 2012 MHRA warning; fracture and osteoporosis were evaluated separately. Chronographs show a measure of observed/expected events, the Information Component (IC) and 95% credibility interval (CI), calculated at monthly time intervals relative to the start date of a prescription, and summed to estimate IC over a 3-year period; IC > 0 indicates observed > expected events. We hypothesized that chronographs may assess RM effectiveness if stratified by PRE/POST an RM intervention such as a label change.

RESULTS: There were 1,588,973 and 664,601 PPI users in the PRE and POST periods, respectively. We observed a 4.6% reduction in the proportion of long-term PPI episodes and a 4.1% reduction in the overall proportion of the THIN population using PPIs. Compared with the PRE chronographs, when both visually comparing and when examining the summed ICs for fracture in the POST period, a significant reduction was observed overall (IC = 0.024 [95% CI 0.015 to 0.33] PRE vs - 0.141 [95% CI - 0.162 to - 0.120] POST), suggesting less observed events than expected, and prior to PPI start, suggestive of strong channeling (IC = - 0.027 [95% CI - 0.037 to - 0.017] PRE vs - 0.291 [95% CI - 0.308 to - 0.274] POST). Results were qualitatively similar for osteoporosis.

CONCLUSIONS: This pilot demonstrated a novel application of a visual, rapid analysis technique to assess RM effectiveness, and supported a hypothesis that prescribers altered some behaviors after the MHRA label change, such as channeling patients at risk of fracture or osteoporosis away from PPI use and potentially reducing fracture outcomes. Limitations include lack of confounding control and outcomes defined only by diagnosis code. Results demonstrate the potential to use large healthcare databases with chronographs to rapidly assess RM effectiveness, similar to signal detection in pharmacovigilance, and may help design more comprehensive RM evaluation studies.