Journal Article
. 2009 Jul;27(24).
doi: 10.1200/JCO.2009.22.3701.

Clinical trial designs for predictive biomarker validation: theoretical considerations and practical challenges

Sumithra J Mandrekar 1 Daniel J Sargent  
  • PMID: 19597023
  •     41 References
  •     116 citations


Purpose: Biomarkers can add substantial value to current medical practice by providing an integrated approach to prediction using the genetic makeup of the tumor and the genotype of the patient to guide patient-specific treatment selection. We discuss and evaluate various clinical trial designs for the validation of biomarker-guided therapy.

Methods: Designs for predictive marker validation are broadly classified as retrospective (ie, using data from previously well-conducted randomized controlled trials [RCTs]) versus prospective (enrichment, unselected, hybrid, or adaptive analysis). We discuss the salient features of each design in the context of real trials.

Results: Well-designed retrospective analysis from well-conducted prospective RCTs can bring forward effective treatments to marker-defined subgroups of patients in a timely manner (eg, KRAS and colorectal cancer). Enrichment designs are appropriate when preliminary evidence suggest that patients with or without that marker profile do not benefit from the treatments in question; however, this may sometimes leave questions unanswered (eg, trastuzumab and breast cancer). An unselected design is optimal where preliminary evidence regarding treatment benefit and assay reproducibility is uncertain (eg, epidermal growth factor receptor and lung cancer). Hybrid designs are appropriate when preliminary evidence demonstrate the efficacy of certain treatments for a marker-defined subgroup, making it unethical to randomly assign patients with that marker status to other treatments (eg, multigene assay and breast cancer). Adaptive analysis designs allow for prespecified marker-defined subgroup analyses of data from an RCT.

Conclusion: The implementation of these design strategies will lead to a more rapid clinical validation of biomarker-guided therapy.

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Jai N Patel, Jennifer L Ersek, Edward S Kim.
Transl Lung Cancer Res, 2015 Dec 03; 4(5). PMID: 26629419    Free PMC article.
Clinical trial designs incorporating predictive biomarkers.
Lindsay A Renfro, Himel Mallick, +2 authors, Sumithra J Mandrekar.
Cancer Treat Rev, 2016 Feb 02; 43. PMID: 26827695    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.
Optimal marker-strategy clinical trial design to detect predictive markers for targeted therapy.
Yong Zang, Suyu Liu, Ying Yuan.
Biostatistics, 2016 Mar 10; 17(3). PMID: 26951724    Free PMC article.
Precision oncology: A new era of cancer clinical trials.
Lindsay A Renfro, Ming-Wen An, Sumithra J Mandrekar.
Cancer Lett, 2016 Mar 19; 387. PMID: 26987624    Free PMC article.
Bayesian Two-stage Biomarker-based Adaptive Design for Targeted Therapy Development.
Xuemin Gu, Nan Chen, +4 authors, J Jack Lee.
Stat Biosci, 2016 Sep 13; 8(1). PMID: 27617040    Free PMC article.
Optimal sequential enrichment designs for phase II clinical trials.
Yong Zang, Ying Yuan.
Stat Med, 2016 Sep 20; 36(1). PMID: 27640874    Free PMC article.
Strategies for power calculations in predictive biomarker studies in survival data.
Dung-Tsa Chen, Po-Yu Huang, +4 authors, Jhanelle E Gray.
Oncotarget, 2016 Sep 24; 7(49). PMID: 27661007    Free PMC article.
Future perspectives in melanoma research : Meeting report from the "Melanoma Bridge". Napoli, December 1st-4th 2015.
Paolo A Ascierto, Sanjiv Agarwala, +33 authors, Magdalena Thurin.
J Transl Med, 2016 Nov 17; 14(1). PMID: 27846884    Free PMC article.
Validation of biomarkers to predict response to immunotherapy in cancer: Volume II - clinical validation and regulatory considerations.
Kevin K Dobbin, Alessandra Cesano, +10 authors, Magdalena Thurin.
J Immunother Cancer, 2016 Nov 29; 4. PMID: 27891226    Free PMC article.
Biomarker-Guided Non-Adaptive Trial Designs in Phase II and Phase III: A Methodological Review.
Miranta Antoniou, Ruwanthi Kolamunnage-Dona, Andrea L Jorgensen.
J Pers Med, 2017 Jan 27; 7(1). PMID: 28125057    Free PMC article.
Precision medicine needs randomized clinical trials.
Everardo D Saad, Xavier Paoletti, Tomasz Burzykowski, Marc Buyse.
Nat Rev Clin Oncol, 2017 Feb 09; 14(5). PMID: 28169302
Integrating Pharmacoproteomics into Early-Phase Clinical Development: State-of-the-Art, Challenges, and Recommendations.
Savita Nandal, Tal Burt.
Int J Mol Sci, 2017 Feb 22; 18(2). PMID: 28218733    Free PMC article.
Phase II cancer clinical trials for biomarker-guided treatments.
Sin-Ho Jung.
J Biopharm Stat, 2017 Sep 14; 28(2). PMID: 28902567    Free PMC article.
On Enrichment Strategies for Biomarker Stratified Clinical Trials.
Xiaofei Wang, Jingzhu Zhou, Ting Wang, Stephen L George.
J Biopharm Stat, 2017 Sep 22; 28(2). PMID: 28933670    Free PMC article.
Relative efficiency of precision medicine designs for clinical trials with predictive biomarkers.
Weichung Joe Shih, Yong Lin.
Stat Med, 2017 Dec 06; 37(5). PMID: 29205435    Free PMC article.
Considerations for biomarker-targeted intervention strategies for tuberculosis disease prevention.
Andrew Fiore-Gartland, Lindsay N Carpp, +8 authors, Mark Hatherill.
Tuberculosis (Edinb), 2018 Mar 22; 109. PMID: 29559122    Free PMC article.
Roadmap for optimizing the clinical utility of emotional stress paradigms in human neuroimaging research.
Timothy J McDermott, Namik Kirlic, Robin L Aupperle.
Neurobiol Stress, 2018 Jun 12; 8. PMID: 29888309    Free PMC article.
Auxiliary variable-enriched biomarker-stratified design.
Ting Wang, Xiaofei Wang, +2 authors, Stephen L George.
Stat Med, 2018 Sep 18; 37(30). PMID: 30221368    Free PMC article.
Prospective Biomarker Study in Advanced RAS Wild-Type Colorectal Cancer: POSIBA Trial (GEMCAD 10-02).
Xabier García-Albéniz, Vicente Alonso, +17 authors, Joan Maurel.
Oncologist, 2019 Jun 27; 24(11). PMID: 31235483    Free PMC article.
A comparison of subgroup identification methods in clinical drug development: Simulation study and regulatory considerations.
Cynthia Huber, Norbert Benda, Tim Friede.
Pharm Stat, 2019 Jul 05; 18(5). PMID: 31270933    Free PMC article.
Paclitaxel Response Can Be Predicted With Interpretable Multi-Variate Classifiers Exploiting DNA-Methylation and miRNA Data.
Alexandra Bomane, Anthony Gonçalves, Pedro J Ballester.
Front Genet, 2019 Nov 12; 10. PMID: 31708973    Free PMC article.
Phase II Feasibility and Biomarker Study of Neoadjuvant Trastuzumab and Pertuzumab With Chemoradiotherapy for Resectable Human Epidermal Growth Factor Receptor 2-Positive Esophageal Adenocarcinoma: TRAP Study.
Charlotte I Stroes, Sandor Schokker, +22 authors, Hanneke W M van Laarhoven.
J Clin Oncol, 2019 Dec 07; 38(5). PMID: 31809243    Free PMC article.
Evaluation of heart failure biomarker tests: a survey of statistical considerations.
Arkendra De, Kristen Meier, +4 authors, Gene Pennello.
J Cardiovasc Transl Res, 2013 May 15; 6(4). PMID: 23670231
Considerations for the successful co-development of targeted cancer therapies and companion diagnostics.
Jane Fridlyand, Richard M Simon, +7 authors, Howard I Scher.
Nat Rev Drug Discov, 2013 Sep 07; 12(10). PMID: 24008432
An alternative method to analyse the biomarker-strategy design.
Cornelia Ursula Kunz, Thomas Jaki, Nigel Stallard.
Stat Med, 2018 Sep 28; 37(30). PMID: 30260533    Free PMC article.
Keeping phase III tuberculosis trials relevant: Adapting to a rapidly changing landscape.
Patrick P J Phillips, Carole D Mitnick, +3 authors, Andrew J Nunn.
PLoS Med, 2019 Mar 23; 16(3). PMID: 30901331    Free PMC article.
Xenograft-based, platform-independent gene signatures to predict response to alkylating chemotherapy, radiation, and combination therapy for glioblastoma.
Shuang G Zhao, Menggang Yu, +9 authors, Daniel R Wahl.
Neuro Oncol, 2019 May 24; 21(9). PMID: 31121035    Free PMC article.
Designing precision medicine trials to yield a greater population impact.
Ying-Qi Zhao, Michael L LeBlanc.
Biometrics, 2019 Oct 11; 76(2). PMID: 31598964    Free PMC article.
Precision Medicine and the Role of Biomarkers of Radiotherapy Response in Breast Cancer.
James Meehan, Mark Gray, +8 authors, Arran K Turnbull.
Front Oncol, 2020 May 12; 10. PMID: 32391281    Free PMC article.
Principles of Good Clinical Trial Design.
Ming-Wen An, Quyen Duong, Jennifer Le-Rademacher, Sumithra J Mandrekar.
J Thorac Oncol, 2020 May 18; 15(8). PMID: 32417343    Free PMC article.
Biomarkers for Aging Identified in Cross-sectional Studies Tend to Be Non-causative.
Paul G Nelson, Daniel E L Promislow, Joanna Masel.
J Gerontol A Biol Sci Med Sci, 2019 Jul 30; 75(3). PMID: 31353411    Free PMC article.
Biomarker-Driven Oncology Clinical Trials: Key Design Elements, Types, Features, and Practical Considerations.
Chen Hu, James J Dignam.
JCO Precis Oncol, 2020 Sep 15; 3. PMID: 32923854    Free PMC article.
Comparison of Clopidogrel and Ticlopidine/Ginkgo Biloba in Patients With Clopidogrel Resistance and Carotid Stenting.
Jong-Won Chung, Suk Jae Kim, +8 authors, Oh Young Bang.
Front Neurol, 2019 Feb 15; 10. PMID: 30761076    Free PMC article.
Placebo effects in a multiple sclerosis spasticity enriched clinical trial with the oromucosal cannabinoid spray (THC/CBD): dimension and possible causes.
Vincenzo Di Marzo, Diego Centonze.
CNS Neurosci Ther, 2014 Dec 06; 21(3). PMID: 25475413    Free PMC article.
Is It Possible to Personalize the Diagnosis and Treatment of Breast Cancer during Pregnancy?
Petra Tesarova, David Pavlista, Antonin Parizek.
J Pers Med, 2021 Jan 01; 11(1). PMID: 33379383    Free PMC article.
Statistical Considerations for Subgroup Analyses.
Xiaofei Wang, Steven Piantadosi, Jennifer Le-Rademacher, Sumithra J Mandrekar.
J Thorac Oncol, 2020 Dec 30; 16(3). PMID: 33373692    Free PMC article.
The Epithelial-Mesenchymal Transcription Factor Slug Predicts Survival Benefit of Up-Front Surgery in Head and Neck Cancer.
Herbert Riechelmann, Teresa Bernadette Steinbichler, +5 authors, Jozsef Dudas.
Cancers (Basel), 2021 Mar 07; 13(4). PMID: 33673269    Free PMC article.
Design and analysis of biomarker-integrated clinical trials with adaptive threshold detection and flexible patient enrichment.
Ting Wang, Xiaofei Wang, Stephen L George, Haibo Zhou.
J Biopharm Stat, 2020 Nov 12; 30(6). PMID: 33175640    Free PMC article.