(309) Comparison of Post-Marketing Drug Safety Surveillance Research Required by Regulators of the United States and Europe Through the Case of Dapagliflozin

Publication Number: 983

Background: Identifying associations between drugs and potential adverse events (AEs) using a well-planned research design is important in post-marketing studies. It is needed to review the safety surveillance conducted according to AEs in the United States (US) and Europe, where post-marketing studies are actively conducted, to identify the type of research.

Objectives: We compared the safety surveillance process in the US and Europe for dapagliflozin, which was recently approved and widely used, to review the study design required at approval and post-approval.

Methods: We investigated European Medicines Agency (EMA) and US Food and Drug Administration (FDA) websites to find safety surveillance information of dapagliflozin since it was approved (Europe: Sep 11, 2012; the US: Jan 8, 2014). Post-marketing requirements, risk assessment, and safety communications from FDA and assessment reports, and a document of procedural steps authorization from EMA were investigated for comparison. Our study included clinical trials and observational studies about AEs.

Results: There was a difference in approval dates between the US and Europe because the US determined that additional data was necessary for approval due to safety concerns. Upon the approval of dapagliflozin in Europe, 3 clinical trials for urinary tract infection (UTI), clinical consequences of increased hematocrit, and bone fracture, 4 observational studies for UTI, renal impairment, liver injury, and cancer were submitted as initial risk management plans. And the US required 2 clinical trials for bladder cancer and major adverse cardiovascular events (MACE) and an observational study for hepatic abnormalities as post-marketing studies in the second review. One of the clinical trials evaluates diverse AEs of dapagliflozin including MACE, clinical consequences of increased hematocrit, liver toxicity, and cancer. After approval for dapagliflozin, diabetic ketoacidosis (DKA) was newly added to the label in both US and Europe. The first FDA safety communication was released in May 2015 and added to warnings based on FDA Adverse Event Reporting System. Europe requested EMA to review DKA in June 2015 due to the FDA’s safety communication and search in Eudravigilance. As a result, EMA added DKA in safety concerns and imposed a mandatory pharmacovigilance activity.

Conclusions: We identified that the US and Europe have used different types of studies in post-marketing surveillance even with the same drug. By comparing safety surveillance processes for diverse drugs such as dapagliflozin, proper post-marketing study can be identified for drugs.