- •The assumption of uninformative censoring does not hold in many randomised trials.
- •The reverse Kaplan–Meier and reverse hazard ratio are useful for censoring analysis.
- •Excessive treatment arm censoring is specific to positive trials with no survival gain.
- •Fifty percent of trials with imbalanced censoring lose significance after restoring the balance.
- •Informative censoring explains inconsistencies in trials with discordant outcomes.
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.
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- Nonparametric estimation from incomplete observations.J Am Stat Assoc. 1958; 53: 457-481
- Informative censoring—a neglected cause of bias in oncology trials.Nat Rev Clin Oncol. 2020; 17: 327-328
- Immunotherapy with programmed cell death 1 vs programmed cell death ligand 1 inhibitors in patients with cancer.JAMA Oncol. 2020; 6: 1114-1115https://doi.org/10.1001/jamaoncol.2020.0628
- Hazards of hazard ratios-deviations from model assumptions in immunotherapy.N Engl J Med. 2018; 378: 1158-1159
- Pembrolizumab in microsatellite-instability–high advanced colorectal cancer.N Engl J Med. 2020; 383: 2207-2218
- Abiraterone for prostate cancer not previously treated with hormone therapy.N Engl J Med. 2017; 377: 338-351
- Analysis of progression-free survival in oncology trials: some common statistical issues.Pharmaceut Stat: The Journal of Applied Statistics in the Pharmaceutical Industry. 2007; 6: 99-113
- General right censoring and its impact on the analysis of survival data.Biometrics. 1979; : 139-156
- Recovery of information and adjustment for dependent censoring using surrogate markers.AIDS epidemiology, Springer1992: 297-331
- Estimation of treatment effect adjusting for dependent censoring using the IPCW method: an application to a large primary prevention study for coronary events (MEGA study).Clin Trials. 2007; 4: 318-328
- Nonignorable censoring in randomized clinical trials.Clin Trials. 2005; 2: 488-496
- Impact of informative censoring on the Kaplan-Meier estimate of progression-free survival in phase II clinical trials.J Clin Oncol. 2014; 32: 3068
- Censored patients in Kaplan–Meier plots of cancer drugs: an empirical analysis of data sharing.Eur J Canc. 2020; 141: 152-161
- Surrogate endpoints in oncology: when are they acceptable for regulatory and clinical decisions, and are they currently overused?.BMC Med. 2017; 15: 134
- Strength of validation for surrogate end points used in the US Food and Drug Administration's approval of oncology drugs.Elsevier, 2016: 713-725
- Cancer drugs approved on the basis of a surrogate end point and subsequent overall survival: an analysis of 5 years of US Food and Drug Administration approvals.JAMA Intern Med. 2015; 175: 1992-1994
- Blinded independent central review of progression-free survival in phase III clinical trials: important design element or unnecessary expense?.J Clin Oncol. 2008; 26: 3791
- Missing data and censoring in the analysis of progression-free survival in oncology clinical trials.J Biopharm Stat. 2013; 23: 951-970
- Issues in using progression-free survival when evaluating oncology products.J Clin Oncol. 2009; 27: 2874
- The clinical viewpoint: definitions, limitations of RECIST, practical considerations of measurement.AACR, 2013
- Review of survival analyses published in cancer journals.Br J Canc. 1995; 72: 511-518
- Quantification of the completeness of follow-up.Lancet. 2002; 359: 1309-1310
- A note on quantifying follow-up in studies of failure time.Contr Clin Trials. 1996; 17: 343-346
- Median follow-up in clinical trials.J Clin Oncol. 1991; 9: 191-192
- New methods for estimating follow-up rates in cohort studies.BMC Med Res Methodol. 2017; 17: 155
- BEST (Biomarkers, endpoints, and other tools) resource [Internet].2016
- The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies.Int J Surg. 2014; 12: 1495-1499
- WebPlotDigitizer.Austin, Texas, USA2017
- A critique of the fragility index.Lancet Oncol. 2019; 20e551
- Parameterization of a disease progression simulation model for sequentially treated metastatic human epidermal growth factor receptor 2 positive breast cancer patients.Curr Med Res Opin. 2016; 32: 991-996
- Evaluation of 1-year vs shorter durations of adjuvant trastuzumab among patients with early breast cancer: an individual participant data and trial-level meta-analysis.JAMA Network Open. 2020; 3 (e2011777–e2011777)
- Influence of glioblastoma contact with the lateral ventricle on survival: a meta-analysis.J. Neuro-oncol. 2017; 131: 125-133
- Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves.BMC Med Res Methodol. 2012; 12: 1-13
- Interpretability of cancer clinical trial results using restricted mean survival time as an alternative to the hazard ratio.JAMA Oncol. 2017; 3: 1692-1696
- The use of restricted mean survival time to estimate the treatment effect in randomized clinical trials when the proportional hazards assumption is in doubt.Stat Med. 2011; 30: 2409-2421
- Small sample confidence intervals for the odds ratio.Commun Stat Simulat Comput. 2004; 33: 1095-1113
- The R package survsim for the simulation of simple and complex survival data.J Stat Software. 2014; 59: 1-20
- Survival-inferred fragility index of phase 3 clinical trials evaluating immune checkpoint inhibitors.JAMA Network Open. 2020; 3 (e2017675–e2017675)
- Research outcomes and recommendations for the assessment of progression in cancer clinical trials from a PhRMA working group.Eur J Canc. 2011; 47: 1763-1771
- Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Oncol. 2016; 17: 367-377
- Blinding and patient-reported outcome completion rates in US Food and Drug Administration cancer trial submissions, 2007–2017. JNCI.J Natl Cancer Inst. 2019; 111: 459-464
- The cohort multiple randomized controlled trial design: a valid and efficient alternative to pragmatic trials?.Int J Epidemiol. 2017; 46: 96-102
- Analysis of control arm quality in randomized clinical trials leading to anticancer drug approval by the US Food and drug Administration.JAMA Oncol. 2019; 5: 887-892https://doi.org/10.1001/jamaoncol.2019.0167
- Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial.Lancet. 2011; 378: 1931-1939
- Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin's lymphoma.N Engl J Med. 2018; 378: 331-344
- Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.N Engl J Med. 2019; 381: 317-327
- Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study.Lancet. 2016; 387: 968-977
- Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma.N Engl J Med. 2016; 374: 1621-1634
- Olaparib for BRCA mutant pancreas cancer: should the POLO trial change clinical practice?.Cancer, 2020
- Oral anticancer drugs: how limited dosing options and dose reductions may affect outcomes in comparative trials and efficacy in patients.J Clin Oncol. 2014; 32: 1620
- Brentuximab vedotin for frontline Hodgkin lymphoma: how much will a successful trial cost patients and payers?.Eur J Canc. 2018; 104: 252-253
- Impact of informative censoring on the treatment effect estimate of disability worsening in multiple sclerosis clinical trials.Mult Scler Relat Disord. 2020; 39: 101865
Published online: June 26, 2021
Accepted: April 30, 2021
Received in revised form: April 25, 2021
Received: March 4, 2021
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