Benjamin Djulbegovic1, Paul Glasziou2, Farina A Klocksieben3, Tea Reljic3, Magali VanDenBergh4, Rahul Mhaskar3, John P A Ioannidis5, Iain Chalmers6. 1. Department of Supportive Care Medicine, City of Hope, 1500 East Duarte Rd, Duarte, CA, USA; Department of Hematology, City of Hope, 1500 East Duarte Rd, Duarte, CA, USA. Electronic address: bdjulbegovic@coh.org. 2. Bond University, 14 University Dr, Gold Coast, Queensland, Australia. 3. Program for Comparative Effectiveness Research, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL, USA. 4. H. Lee Moffitt Cancer Center & Research Institute, 12902 USF Magnolia Drive, Tampa, FL, USA. 5. Stanford Prevention Research Center, Department of Medicine, and Department of Health Research and Policy, Stanford University School of Medicine; Department of Statistics, Stanford University School of Humanities and Sciences; and Meta-Research Innovation Center at Stanford, 450 Serra Mall, Stanford, CA, USA. 6. James Lind Initiative, Summertown Pavilion, Middle Way, Oxford OX2 7LG, UK.
Abstract
OBJECTIVES: The aim of this study was to evaluate how often the European Medicines Agency (EMA) has authorized drugs based on nonrandomized studies and whether there is an association between treatment effects and EMA preference for further testing in randomized clinical trials (RCTs). STUDY DESIGN AND SETTING: We reviewed all initial marketing authorizations in the EMA database on human medicines between 1995 and 2015 and included authorizations granted without randomized data. We extracted data on treatment effects and EMA preference for further testing in RCTs. RESULTS: Of 723 drugs, 51 were authorized based on nonrandomized data. These 51 drugs were licensed for 71 indications. In the 51 drug-indication pairs with no preference for further RCT testing, effect estimates were large [odds ratio (OR): 12.0 (95% confidence interval {CI}: 8.1-17.9)] compared to effect estimates in the 20 drug-indication pairs for which future RCTs were preferred [OR: 4.3 (95% CI 2.8-6.6)], with a significant difference between effects (P = 0.0005). CONCLUSION: Nonrandomized data were used for 7% of EMA drug approvals. Larger effect sizes were associated with greater likelihood of approval based on nonrandomized data alone. We did not find a clear treatment effect threshold for drug approval without RCT evidence.
OBJECTIVES: The aim of this study was to evaluate how often the European Medicines Agency (EMA) has authorized drugs based on nonrandomized studies and whether there is an association between treatment effects and EMA preference for further testing in randomized clinical trials (RCTs). STUDY DESIGN AND SETTING: We reviewed all initial marketing authorizations in the EMA database on human medicines between 1995 and 2015 and included authorizations granted without randomized data. We extracted data on treatment effects and EMA preference for further testing in RCTs. RESULTS: Of 723 drugs, 51 were authorized based on nonrandomized data. These 51 drugs were licensed for 71 indications. In the 51 drug-indication pairs with no preference for further RCT testing, effect estimates were large [odds ratio (OR): 12.0 (95% confidence interval {CI}: 8.1-17.9)] compared to effect estimates in the 20 drug-indication pairs for which future RCTs were preferred [OR: 4.3 (95% CI 2.8-6.6)], with a significant difference between effects (P = 0.0005). CONCLUSION: Nonrandomized data were used for 7% of EMA drug approvals. Larger effect sizes were associated with greater likelihood of approval based on nonrandomized data alone. We did not find a clear treatment effect threshold for drug approval without RCT evidence.
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