Larger effect sizes in nonrandomized studies are associated with higher rates of EMA licensing approval

Benjamin Djulbegovic, Paul Glasziou, Farina A Klocksieben, Tea Reljic, Magali VanDenBergh, Rahul Mhaskar, John P A Ioannidis, Iain Chalmers

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Abstract

OBJECTIVES: Evaluate how often the European Medicines Agency (EMA) has authorized drugs based on non-randomized studies and whether there is an association between treatment effects and EMA preference for further testing in 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 non-randomized 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 [OR 12.0 (95% CI: 8.1 to 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 to 6.6)], with a significant difference between effects (p=0.0005).

CONCLUSIONS: Non-randomized data were used for 7% of EMA drug approvals. Larger effect sizes were associated with greater likelihood of approval based on non-randomized data alone. We did not find a clear treatment effect threshold for drug approval without RCT evidence.

Original languageEnglish
Pages (from-to)24-32
Number of pages9
JournalJournal of Clinical Epidemiology
Volume98
Early online date9 Feb 2018
DOIs
Publication statusPublished - Jun 2018

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Licensure
Drug Approval
Pharmaceutical Preparations
Marketing
Databases

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Djulbegovic, Benjamin ; Glasziou, Paul ; Klocksieben, Farina A ; Reljic, Tea ; VanDenBergh, Magali ; Mhaskar, Rahul ; Ioannidis, John P A ; Chalmers, Iain. / Larger effect sizes in nonrandomized studies are associated with higher rates of EMA licensing approval. In: Journal of Clinical Epidemiology. 2018 ; Vol. 98. pp. 24-32.
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title = "Larger effect sizes in nonrandomized studies are associated with higher rates of EMA licensing approval",
abstract = "OBJECTIVES: Evaluate how often the European Medicines Agency (EMA) has authorized drugs based on non-randomized studies and whether there is an association between treatment effects and EMA preference for further testing in 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 non-randomized 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 [OR 12.0 (95{\%} CI: 8.1 to 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 to 6.6)], with a significant difference between effects (p=0.0005).CONCLUSIONS: Non-randomized data were used for 7{\%} of EMA drug approvals. Larger effect sizes were associated with greater likelihood of approval based on non-randomized data alone. We did not find a clear treatment effect threshold for drug approval without RCT evidence.",
author = "Benjamin Djulbegovic and Paul Glasziou and Klocksieben, {Farina A} and Tea Reljic and Magali VanDenBergh and Rahul Mhaskar and Ioannidis, {John P A} and Iain Chalmers",
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Djulbegovic, B, Glasziou, P, Klocksieben, FA, Reljic, T, VanDenBergh, M, Mhaskar, R, Ioannidis, JPA & Chalmers, I 2018, 'Larger effect sizes in nonrandomized studies are associated with higher rates of EMA licensing approval' Journal of Clinical Epidemiology, vol. 98, pp. 24-32. https://doi.org/10.1016/j.jclinepi.2018.01.011

Larger effect sizes in nonrandomized studies are associated with higher rates of EMA licensing approval. / Djulbegovic, Benjamin; Glasziou, Paul; Klocksieben, Farina A; Reljic, Tea; VanDenBergh, Magali; Mhaskar, Rahul; Ioannidis, John P A; Chalmers, Iain.

In: Journal of Clinical Epidemiology, Vol. 98, 06.2018, p. 24-32.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Larger effect sizes in nonrandomized studies are associated with higher rates of EMA licensing approval

AU - Djulbegovic, Benjamin

AU - Glasziou, Paul

AU - Klocksieben, Farina A

AU - Reljic, Tea

AU - VanDenBergh, Magali

AU - Mhaskar, Rahul

AU - Ioannidis, John P A

AU - Chalmers, Iain

N1 - Copyright © 2018 Elsevier Inc. All rights reserved.

PY - 2018/6

Y1 - 2018/6

N2 - OBJECTIVES: Evaluate how often the European Medicines Agency (EMA) has authorized drugs based on non-randomized studies and whether there is an association between treatment effects and EMA preference for further testing in 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 non-randomized 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 [OR 12.0 (95% CI: 8.1 to 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 to 6.6)], with a significant difference between effects (p=0.0005).CONCLUSIONS: Non-randomized data were used for 7% of EMA drug approvals. Larger effect sizes were associated with greater likelihood of approval based on non-randomized data alone. We did not find a clear treatment effect threshold for drug approval without RCT evidence.

AB - OBJECTIVES: Evaluate how often the European Medicines Agency (EMA) has authorized drugs based on non-randomized studies and whether there is an association between treatment effects and EMA preference for further testing in 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 non-randomized 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 [OR 12.0 (95% CI: 8.1 to 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 to 6.6)], with a significant difference between effects (p=0.0005).CONCLUSIONS: Non-randomized data were used for 7% of EMA drug approvals. Larger effect sizes were associated with greater likelihood of approval based on non-randomized data alone. We did not find a clear treatment effect threshold for drug approval without RCT evidence.

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U2 - 10.1016/j.jclinepi.2018.01.011

DO - 10.1016/j.jclinepi.2018.01.011

M3 - Article

VL - 98

SP - 24

EP - 32

JO - Journal of Chronic Diseases

JF - Journal of Chronic Diseases

SN - 0895-4356

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