Journal Article
. 2018 Jun;37(22).
doi: 10.1002/sim.7831.

Point estimation following two-stage adaptive threshold enrichment clinical trials

Peter K Kimani 1 Susan Todd 2 Lindsay A Renfro 3 Nigel Stallard 1 
  • PMID: 29855066
  •     29 References
  •     2 citations


Recently, several study designs incorporating treatment effect assessment in biomarker-based subpopulations have been proposed. Most statistical methodologies for such designs focus on the control of type I error rate and power. In this paper, we have developed point estimators for clinical trials that use the two-stage adaptive enrichment threshold design. The design consists of two stages, where in stage 1, patients are recruited in the full population. Stage 1 outcome data are then used to perform interim analysis to decide whether the trial continues to stage 2 with the full population or a subpopulation. The subpopulation is defined based on one of the candidate threshold values of a numerical predictive biomarker. To estimate treatment effect in the selected subpopulation, we have derived unbiased estimators, shrinkage estimators, and estimators that estimate bias and subtract it from the naive estimate. We have recommended one of the unbiased estimators. However, since none of the estimators dominated in all simulation scenarios based on both bias and mean squared error, an alternative strategy would be to use a hybrid estimator where the estimator used depends on the subpopulation selected. This would require a simulation study of plausible scenarios before the trial.

Keywords: biomarker; multistage; personalized medicine; subgroup or subpopulation selection; targeted therapy.

Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.
Tony S Mok, Yi-Long Wu, +16 authors, Masahiro Fukuoka.
N Engl J Med, 2009 Aug 21; 361(10). PMID: 19692680
Highly Cited.
Estimation after subpopulation selection in adaptive seamless trials.
Peter K Kimani, Susan Todd, Nigel Stallard.
Stat Med, 2015 Apr 24; 34(18). PMID: 25903293    Free PMC article.
Selection and bias--two hostile brothers.
Peter Bauer, Franz Koenig, Werner Brannath, Martin Posch.
Stat Med, 2009 Oct 22; 29(1). PMID: 19844944
Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design.
A John Rush, Maurizio Fava, +18 authors, STAR*D Investigators Group.
Control Clin Trials, 2004 Apr 06; 25(1). PMID: 15061154
Highly Cited.
Adaptive randomized phase II design for biomarker threshold selection and independent evaluation.
Lindsay A Renfro, Christina M Coughlin, Axel M Grothey, Daniel J Sargent.
Chin Clin Oncol, 2015 Apr 07; 3(1). PMID: 25842081
Unbiased estimation of selected treatment means in two-stage trials.
Jack Bowden, Ekkehard Glimm.
Biom J, 2008 Jul 30; 50(4). PMID: 18663760
A Randomized, Double-Blind, Placebo-Controlled Phase II Study of the Efficacy and Safety of Monotherapy Ontuxizumab (MORAb-004) Plus Best Supportive Care in Patients with Chemorefractory Metastatic Colorectal Cancer.
Axel Grothey, Jonathan R Strosberg, +12 authors, Luis Alberto Diaz.
Clin Cancer Res, 2017 Nov 01; 24(2). PMID: 29084918
A threshold sample-enrichment approach in a clinical trial with heterogeneous subpopulations.
Aiyi Liu, Chunling Liu, +2 authors, Vivian W Yuan.
Clin Trials, 2010 Aug 06; 7(5). PMID: 20685769    Free PMC article.
Shrinkage estimation in two-stage adaptive designs with midtrial treatment selection.
Máximo Carreras, Werner Brannath.
Stat Med, 2012 Jun 30; 32(10). PMID: 22744936
Accounting for selection and correlation in the analysis of two-stage genome-wide association studies.
David S Robertson, A Toby Prevost, Jack Bowden.
Biostatistics, 2016 Mar 20; 17(4). PMID: 26993061    Free PMC article.
Point estimation in adaptive enrichment designs.
Kevin Kunzmann, Laura Benner, Meinhard Kieser.
Stat Med, 2017 Aug 08; 36(25). PMID: 28783881
Estimation in multi-arm two-stage trials with treatment selection and time-to-event endpoint.
Matthias Brückner, Andrew Titman, Thomas Jaki.
Stat Med, 2017 Jun 15; 36(20). PMID: 28612371    Free PMC article.
Statistical design for a confirmatory trial with a continuous predictive biomarker: A case study.
Adarsh Joshi, Jenny Zhang, Liang Fang.
Contemp Clin Trials, 2017 May 20; 63. PMID: 28522422
Conditionally unbiased estimation in phase II/III clinical trials with early stopping for futility.
Peter K Kimani, Susan Todd, Nigel Stallard.
Stat Med, 2013 Feb 16; 32(17). PMID: 23413228    Free PMC article.
Biomarkers predicting treatment outcome in depression: what is clinically significant?
Rudolf Uher, Katherine E Tansey, Karim Malki, Roy H Perlis.
Pharmacogenomics, 2012 Jan 20; 13(2). PMID: 22256872    Free PMC article.
Point estimation following two-stage adaptive threshold enrichment clinical trials.
Peter K Kimani, Susan Todd, Lindsay A Renfro, Nigel Stallard.
Stat Med, 2018 Jun 02; 37(22). PMID: 29855066    Free PMC article.
Clinical outcomes and biomarker profiles of elderly pretreated NSCLC patients from the BATTLE trial.
Anne S Tsao, Suyu Liu, +10 authors, Waun Ki Hong.
J Thorac Oncol, 2012 Oct 13; 7(11). PMID: 23059780    Free PMC article.
Adaptive designs for clinical trials assessing biomarker-guided treatment strategies.
J Wason, A Marshall, +2 authors, N Stallard.
Br J Cancer, 2014 Mar 29; 110(8). PMID: 24667651    Free PMC article.
Biomarker: Predictive or Prognostic?
Karla V Ballman.
J Clin Oncol, 2015 Sep 24; 33(33). PMID: 26392104
Highly Cited. Review.
Using Bayesian modeling in frequentist adaptive enrichment designs.
Noah Simon, Richard Simon.
Biostatistics, 2017 May 19; 19(1). PMID: 28520893    Free PMC article.
Optimizing Trial Designs for Targeted Therapies.
Thomas Ondra, Sebastian Jobjörnsson, +4 authors, Martin Posch.
PLoS One, 2016 Sep 30; 11(9). PMID: 27684573    Free PMC article.
Adaptive enrichment designs for clinical trials.
Noah Simon, Richard Simon.
Biostatistics, 2013 Mar 26; 14(4). PMID: 23525452    Free PMC article.
An adaptive design for updating the threshold value of a continuous biomarker.
Amy V Spencer, Chris Harbron, +2 authors, Ian Peers.
Stat Med, 2016 Nov 04; 35(27). PMID: 27417407    Free PMC article.
Biomarker-Guided Adaptive Trial Designs in Phase II and Phase III: A Methodological Review.
Miranta Antoniou, Andrea L Jorgensen, Ruwanthi Kolamunnage-Dona.
PLoS One, 2016 Feb 26; 11(2). PMID: 26910238    Free PMC article.
Unbiased estimation in seamless phase II/III trials with unequal treatment effect variances and hypothesis-driven selection rules.
David S Robertson, A Toby Prevost, Jack Bowden.
Stat Med, 2016 Apr 23; 35(22). PMID: 27103068    Free PMC article.
Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials.
Hai T Tran, Yuan Liu, +9 authors, John V Heymach.
Lancet Oncol, 2012 Jul 05; 13(8). PMID: 22759480
Highly Cited.
Estimation of treatment effect in two-stage confirmatory oncology trials of personalized medicines.
Wen Li, Cong Chen, Xiaoyun Li, Robert A Beckman.
Stat Med, 2017 Mar 18; 36(12). PMID: 28303586
Biomarker-adaptive threshold design: a procedure for evaluating treatment with possible biomarker-defined subset effect.
Wenyu Jiang, Boris Freidlin, Richard Simon.
J Natl Cancer Inst, 2007 Jun 29; 99(13). PMID: 17596577
Differential efficacy of escitalopram and nortriptyline on dimensional measures of depression.
Rudolf Uher, Wolfgang Maier, +19 authors, Peter McGuffin.
Br J Psychiatry, 2009 Mar 03; 194(3). PMID: 19252156
Point estimation following two-stage adaptive threshold enrichment clinical trials.
Peter K Kimani, Susan Todd, Lindsay A Renfro, Nigel Stallard.
Stat Med, 2018 Jun 02; 37(22). PMID: 29855066    Free PMC article.
Point and interval estimation in two-stage adaptive designs with time to event data and biomarker-driven subpopulation selection.
Peter K Kimani, Susan Todd, +4 authors, Nigel Stallard.
Stat Med, 2020 May 05; 39(19). PMID: 32363603    Free PMC article.