Jennings, A.C., Rutherford, M.J., Latimer, N.R. orcid.org/0000-0001-5304-5585 et al. (2 more authors) (2024) Perils of randomised controlled trial survival extrapolation assuming treatment effect waning: why the distinction between marginal and conditional estimates matters. Value in Health, 27 (3). pp. 347-355. ISSN 1098-3015
Abstract
OBJECTIVES:
A long-term, constant, protective treatment effect is a strong assumption when extrapolating survival beyond clinical trial follow-up, hence sensitivity to treatment effect waning is commonly assessed for economic evaluations. Forcing a HR (hazard ratio) to 1 does not necessarily estimate loss of individual-level treatment effect accurately due to HR selection bias. A simulation study was designed to explore the behaviour of marginal HRs under a waning conditional (individual-level) treatment effect and demonstrate bias in forcing a marginal HR to 1 when the estimand is 'survival difference with individual-level waning'.
METHODS:
Data were simulated under 4 parameter combinations (varying prognostic strength of heterogeneity and treatment effect). Time varying marginal HRs were estimated in scenarios where the true conditional HR attenuated to 1. ΔRMSTs (restricted mean survival time difference), estimated having constrained the marginal HR to 1, were compared to true values to assess bias induced by marginal constraints.
RESULTS:
Under loss of conditional treatment effect, the marginal HR took a value >1 due to covariate imbalances. Constraining this value to 1 lead to ΔRMST bias of up to 0.8 years (57% increase). Inflation of effect size estimates also increased with the magnitude of initial protective treatment effect.
CONCLUSIONS:
Important differences exist between survival extrapolations assuming marginal versus conditional treatment effect waning. When a marginal HR is constrained to 1 to assess efficacy under individual-level treatment effect waning, the survival benefits associated with the new treatment will be over-estimated and incremental cost-effectiveness ratios will be under-estimated.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2023 International Society for Pharmacoeconomics and Outcomes Research, Inc. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | conditional estimates; marginal estimates; randomised controlled trials |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 19 Jan 2024 10:04 |
Last Modified: | 27 Feb 2024 10:34 |
Status: | Published |
Publisher: | Elsevier BV |
Refereed: | Yes |
Identification Number: | 10.1016/j.jval.2023.12.008 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:208002 |