Informative censoring of surrogate end-point data in phase 3 oncology trials.
Bias inclinical trials
Informative censoring
Kaplan–Meier curve
Randomized oncology trials
Survival analysis
Journal
European journal of cancer (Oxford, England : 1990)
ISSN: 1879-0852
Titre abrégé: Eur J Cancer
Pays: England
ID NLM: 9005373
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
04
03
2021
revised:
25
04
2021
accepted:
30
04
2021
pubmed:
30
6
2021
medline:
15
12
2021
entrez:
29
6
2021
Statut:
ppublish
Résumé
Kaplan-Meier (K-M) analysis, the cornerstone of cancer clinical trial interpretation, assumes that censored patients are no more or less likely to experience an event than those followed. We sought to investigate the patterns of censoring in surrogate end-points of oncology randomised controlled trials (RCTs) and examine the relationship between censoring in practice-changing treatments that failed to demonstrate survival gain. In this cross-sectional study of phase III RCTs published in the New England Journal of Medicine, Lancet, and JAMA, between 2010 and 2020, K-M curves of surrogate end-points with statistical significance were extracted. The reverse K-M method (i.e., events and censoring are flipped) was used to examine differential censoring using the analogous reverse hazard ratio and restricted mean survival time. Sensitivity analysis was performed by partially restoring the balance in censoring between study arms. Of the 73 eligible studies with significant surrogates, 33 (45%) reported significant overall survival benefit (concordant trials), and 40 (55%) did not (discordant trials). The proportion of studies with significant differential censoring in surrogates was 43% (17/40) and 51% (17/33) in discordant and concordant trials, respectively. Trials with a significant censoring imbalance in the experimental arm occurred only in discordant trials (15% vs 0%, odds ratio [OR] = 12.62, P = 0.033), compared to excessive censoring in the control arm which occurred more in concordant trials (28% vs 52%; OR = 0.36, P = 0.036). Although censoring imbalance occurred in both groups, after sensitivity analysis, 50% of the discordant trials lost their statistical significance, compared to 15% of concordant trials (OR = 5.6, P = 0.0018). Censoring imbalance between study arms of RCTs suggests a potential systemic bias and raises uncertainty regarding the validity of the results. Informative censoring may explain the inconsistency between therapies that seem to improve disease outcomes without concomitant survival benefit and should trigger further investigation.
Sections du résumé
BACKGROUND
Kaplan-Meier (K-M) analysis, the cornerstone of cancer clinical trial interpretation, assumes that censored patients are no more or less likely to experience an event than those followed. We sought to investigate the patterns of censoring in surrogate end-points of oncology randomised controlled trials (RCTs) and examine the relationship between censoring in practice-changing treatments that failed to demonstrate survival gain.
METHODS
In this cross-sectional study of phase III RCTs published in the New England Journal of Medicine, Lancet, and JAMA, between 2010 and 2020, K-M curves of surrogate end-points with statistical significance were extracted. The reverse K-M method (i.e., events and censoring are flipped) was used to examine differential censoring using the analogous reverse hazard ratio and restricted mean survival time. Sensitivity analysis was performed by partially restoring the balance in censoring between study arms.
RESULTS
Of the 73 eligible studies with significant surrogates, 33 (45%) reported significant overall survival benefit (concordant trials), and 40 (55%) did not (discordant trials). The proportion of studies with significant differential censoring in surrogates was 43% (17/40) and 51% (17/33) in discordant and concordant trials, respectively. Trials with a significant censoring imbalance in the experimental arm occurred only in discordant trials (15% vs 0%, odds ratio [OR] = 12.62, P = 0.033), compared to excessive censoring in the control arm which occurred more in concordant trials (28% vs 52%; OR = 0.36, P = 0.036). Although censoring imbalance occurred in both groups, after sensitivity analysis, 50% of the discordant trials lost their statistical significance, compared to 15% of concordant trials (OR = 5.6, P = 0.0018).
CONCLUSION
Censoring imbalance between study arms of RCTs suggests a potential systemic bias and raises uncertainty regarding the validity of the results. Informative censoring may explain the inconsistency between therapies that seem to improve disease outcomes without concomitant survival benefit and should trigger further investigation.
Identifiants
pubmed: 34186504
pii: S0959-8049(21)00316-6
doi: 10.1016/j.ejca.2021.04.044
pii:
doi:
Substances chimiques
Biomarkers
0
Types de publication
Clinical Trial, Phase III
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
190-202Informations de copyright
Copyright © 2021 Elsevier Ltd. All rights reserved.