Analytical Methods for Comparing Uncontrolled Trials with External Controls from Real-World Data: a Systematic Literature Review and Comparison to European Regulatory and Health Technology Assessment Practice

Milou A Hogervorst, Kanaka V Soman, Helga Gardarsdottir, Wim G Goettsch, Lourens T Bloem

Research output: Contribution to journalReview articlepeer-review

Abstract

OBJECTIVES: This study aimed to provide an overview of analytical methods in scientific literature for comparing uncontrolled medicine trials with external controls from individual patient data real-world data (IPD-RWD) and to compare these methods with recommendations made in guidelines from European regulatory and health technology assessment (HTA) organizations and with their evaluations described in assessment reports.

METHODS: A systematic literature review (until March 1, 2023) in PubMed and Connected Papers was performed to identify analytical methods for comparing uncontrolled trials with external controls from IPD-RWD. These methods were compared descriptively with methods recommended in method guidelines and encountered in assessment reports of the European Medicines Agency (2015-2020) and 4 European HTA organizations (2015-2023).

RESULTS: Thirty-four identified scientific articles described analytical methods for comparing uncontrolled trial data with IPD-RWD-based external controls. The various methods covered controlling for confounding and/or dependent censoring, correction for missing data, and analytical comparative modeling methods. Seven guidelines also focused on research design, RWD quality, and transparency aspects, and 4 of those recommended analytical methods for comparisons with IPD-RWD. The methods discussed in regulatory (n = 15) and HTA (n = 35) assessment reports were often based on aggregate data and lacked transparency owing to the few details provided.

CONCLUSIONS: Literature and guidelines suggest a methodological approach to comparing uncontrolled trials with external controls from IPD-RWD similar to target trial emulation, using state-of-the-art methods. External controls supporting regulatory and HTA decision making were rarely in line with this approach. Twelve recommendations are proposed to improve the quality and acceptability of these methods.

Original languageEnglish
Pages (from-to)161-174
Number of pages14
JournalValue in Health
Volume28
Issue number1
Early online date4 Sept 2024
DOIs
Publication statusPublished - Jan 2025

Bibliographical note

Copyright © 2024. Published by Elsevier Inc.

Funding

Funding/Support: This work was commissioned and funded by the GetReal Institute (Utrecht, The Netherlands).

FundersFunder number
GetReal Institute

    Keywords

    • external controls
    • health technology assessment
    • indirect treatment comparisons
    • individual patient data
    • marketing authorization
    • real-world data

    Fingerprint

    Dive into the research topics of 'Analytical Methods for Comparing Uncontrolled Trials with External Controls from Real-World Data: a Systematic Literature Review and Comparison to European Regulatory and Health Technology Assessment Practice'. Together they form a unique fingerprint.

    Cite this