A recent study published in PLOS ONE compares the post-marketing safety issues associated with dapagliflozin as identified by the European Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA), and the Korean Ministry of Food and Drug Safety (MFDS). The study highlights the importance of robust post-marketing surveillance (PMS) systems to monitor rare or unexpected adverse events (AEs) that may not be apparent during pre-market clinical trials.
The research team, led by Dr. Park S, analyzed safety concerns listed in the European Union Risk Management Plan (EU-RMP), adverse events noted in the Warnings and Precautions (WPs) section of the FDA drug label, and use-result surveillance results detailed in the Korean MFDS drug label. They also utilized data from the Korean Adverse Event Reporting System (KAERS) to detect safety signals.
Methodology
The study involved a comprehensive review of regulatory documents and adverse event databases. Researchers manually matched and compared safety issues identified by the EMA and FDA with those recognized in Korea. For safety issues unique to Korea, KAERS signals were compared with results from use-result surveillance. The analysis included 17 EMA/FDA safety issues, 38 KAERS signals, and 231 results from use-result surveillance.
Key Findings
The study revealed a significant concordance (71%) between the safety issues identified by the EMA/FDA and those in Korea. However, the researchers noted that Korean safety issues had limitations in capturing long-term outcomes and laboratory results. Some safety issues initially recognized in the EU-RMP and FDA drug labels were no longer found in the latest documents.
Among the 17 safety issues identified by the EMA/FDA, six—cardiovascular disorder, fasciitis necrotizing (genital)/genital infection, hypovolaemia, liver injury, pancreatitis, and urinary tract infection—were confirmed in both KAERS signals and use-result surveillance results. Diabetic ketoacidosis (DKA) was identified solely in KAERS signals, while breast cancer, fracture, hypersensitivity, kidney dysfunction/renal failure acute, and toe amputation were exclusively documented in the use-result surveillance results.
Implications for Post-Marketing Surveillance
The study underscores the need for enhanced PMS in Korea. The authors recommend establishing more specific laws and regulations and developing detailed guidelines that utilize a variety of real-world data and research methodologies to continuously assess causality throughout the product lifecycle.
"To enhance the activation of PMS research utilizing real-world data (RWD), it is essential to establish more specific laws and regulations, develop detailed guidelines, and foster better cooperation among all stakeholders involved," the authors stated.
Future Directions
The MFDS is currently phasing out the re-examination system and integrating it with the Risk Management Plan (RMP) system. This shift aims to create a comprehensive safety management strategy covering the entire lifecycle of pharmaceuticals. The MFDS is also amending regulations to allow the use of big data from healthcare information in post-market drug safety surveillance.
Limitations
The authors acknowledge several limitations, including the manual matching of safety issues, potential overlaps between use-result surveillance results and KAERS data, and the lack of causal relationships implied by the signals detected. They recommend further pharmacoepidemiological studies using population-based databases to explore potential associations between new safety information and dapagliflozin.
Conclusion
While alignment between the EMA/FDA and Korean safety issues was substantial, the study highlights the importance of continuous monitoring and adaptation of PMS systems to ensure patient safety. The findings emphasize the need for robust, data-driven approaches to identify and manage potential risks associated with pharmaceutical products.
