Journal Article
. 2010 Apr;7(1).
doi: 10.2217/pme.09.49.

Clinical trial designs for evaluating the medical utility of prognostic and predictive biomarkers in oncology

Richard Simon 1 
Affiliations
  • PMID: 20383292
  •     36 References
  •     50 citations

Abstract

Physicians need improved tools for selecting treatments for individual patients. Many diagnostic entities hat were traditionally viewed as individual diseases are heterogeneous in their molecular pathogenesis and treatment responsiveness. This results in the treatment of many patients with ineffective drugs, incursion of substantial medical costs for the treatment of patients who do not benefit and the conducting of large clinical trials to identify small, average treatment benefits for heterogeneous groups of patients. In oncology, new genomic technologies provide powerful tools for the selection of patients who require systemic treatment and are most (or least) likely to benefit from a molecularly targeted therapeutic. In the large amount of literature on biomarkers, there is considerable uncertainty and confusion regarding the specifics involved in the development and evaluation of prognostic and predictive biomarker diagnostics. There is a lack of appreciation that the development of drugs with companion diagnostics increases the complexity of clinical development. Adapting to the fundamental importance of tumor heterogeneity and achieving the benefits of personalized oncology for patients and healthcare costs will require paradigm changes for clinical and statistical investigators in academia, industry and regulatory agencies. In this review, I attempt to address some of these issues and provide guidance on the design of clinical trials for evaluating the clinical utility and robustness of prognostic and predictive biomarkers.

Use of genomic signatures in therapeutics development in oncology and other diseases.
R Simon, S-J Wang.
Pharmacogenomics J, 2006 Jan 18; 6(3). PMID: 16415922
A method for testing a prespecified subgroup in clinical trials.
Yang Song, George Y H Chi.
Stat Med, 2007 Feb 03; 26(19). PMID: 17266164
Development and clinical utility of a 21-gene recurrence score prognostic assay in patients with early breast cancer treated with tamoxifen.
Soonmyung Paik.
Oncologist, 2007 Jul 03; 12(6). PMID: 17602054
When is a genomic classifier ready for prime time?
Richard Simon.
Nat Clin Pract Oncol, 2005 Nov 03; 1(1). PMID: 16264774
Review.
Validation of analytic methods for biomarkers used in drug development.
Cindy H Chau, Olivier Rixe, Howard McLeod, William D Figg.
Clin Cancer Res, 2008 Oct 03; 14(19). PMID: 18829475    Free PMC article.
Review.
Prediction error estimation: a comparison of resampling methods.
Annette M Molinaro, Richard Simon, Ruth M Pfeiffer.
Bioinformatics, 2005 May 21; 21(15). PMID: 15905277
Highly Cited.
Uses and abuses of tumor markers in the diagnosis, monitoring, and treatment of primary and metastatic breast cancer.
N Lynn Henry, Daniel F Hayes.
Oncologist, 2006 Jun 24; 11(6). PMID: 16794234
Review.
The use of genomics in clinical trial design.
Richard Simon.
Clin Cancer Res, 2008 Oct 03; 14(19). PMID: 18829477
Review.
Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.
Rafael G Amado, Michael Wolf, +9 authors, David D Chang.
J Clin Oncol, 2008 Mar 05; 26(10). PMID: 18316791
Highly Cited.
American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer.
Antonio C Wolff, M Elizabeth H Hammond, +22 authors, College of American Pathologists.
J Clin Oncol, 2006 Dec 13; 25(1). PMID: 17159189
Highly Cited.
Pivotal evaluation of the accuracy of a biomarker used for classification or prediction: standards for study design.
Margaret S Pepe, Ziding Feng, +2 authors, John D Potter.
J Natl Cancer Inst, 2008 Oct 09; 100(20). PMID: 18840817    Free PMC article.
Highly Cited.
Randomized phase III clinical trial designs for targeted agents.
Antje Hoering, Mike Leblanc, John J Crowley.
Clin Cancer Res, 2008 Jul 17; 14(14). PMID: 18628448    Free PMC article.
Use of archived specimens in evaluation of prognostic and predictive biomarkers.
Richard M Simon, Soonmyung Paik, Daniel F Hayes.
J Natl Cancer Inst, 2009 Oct 10; 101(21). PMID: 19815849    Free PMC article.
Highly Cited.
Approaches to evaluation of treatment effect in randomized clinical trials with genomic subset.
Sue-Jane Wang, Robert T O'Neill, H M James Hung.
Pharm Stat, 2007 Aug 11; 6(3). PMID: 17688238
Development of the 21-gene assay and its application in clinical practice and clinical trials.
Joseph A Sparano, Soonmyung Paik.
J Clin Oncol, 2008 Feb 09; 26(5). PMID: 18258979
Highly Cited. Review.
Limitations of the odds ratio in gauging the performance of a diagnostic, prognostic, or screening marker.
Margaret Sullivan Pepe, Holly Janes, +2 authors, Polly Newcomb.
Am J Epidemiol, 2004 Apr 24; 159(9). PMID: 15105181
Highly Cited. Review.
K-ras mutations and benefit from cetuximab in advanced colorectal cancer.
Christos S Karapetis, Shirin Khambata-Ford, +13 authors, John R Zalcberg.
N Engl J Med, 2008 Oct 24; 359(17). PMID: 18946061
Highly Cited.
HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials.
Alessandra Gennari, Maria Pia Sormani, +4 authors, Paolo Bruzzi.
J Natl Cancer Inst, 2007 Dec 27; 100(1). PMID: 18159072
Clinical trial designs for predictive biomarker validation: one size does not fit all.
Sumithra J Mandrekar, Daniel J Sargent.
J Biopharm Stat, 2009 Apr 23; 19(3). PMID: 19384694    Free PMC article.
Adaptive signature design: an adaptive clinical trial design for generating and prospectively testing a gene expression signature for sensitive patients.
Boris Freidlin, Richard Simon.
Clin Cancer Res, 2005 Nov 10; 11(21). PMID: 16278411
On the efficiency of targeted clinical trials.
A Maitournam, R Simon.
Stat Med, 2004 Nov 20; 24(3). PMID: 15551403
Statistical aspects of prognostic factor studies in oncology.
R Simon, D G Altman.
Br J Cancer, 1994 Jun 01; 69(6). PMID: 8198989    Free PMC article.
Highly Cited. Review.
A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
Soonmyung Paik, Steven Shak, +12 authors, Norman Wolmark.
N Engl J Med, 2004 Dec 14; 351(27). PMID: 15591335
Highly Cited.
HER2 and response to paclitaxel in node-positive breast cancer.
Daniel F Hayes, Ann D Thor, +14 authors, Cancer and Leukemia Group B (CALGB) Investigators.
N Engl J Med, 2007 Oct 12; 357(15). PMID: 17928597
Highly Cited.
Designs and adaptive analysis plans for pivotal clinical trials of therapeutics and companion diagnostics.
Richard Simon.
Expert Opin Med Diagn, 2008 Jun 01; 2(6). PMID: 23495781
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.
Perspectives and challenges of clinical pharmacogenomics in cancer.
Lajos Pusztai.
Pharmacogenomics, 2004 Jun 24; 5(5). PMID: 15212580
The cancer biomarker problem.
Charles L Sawyers.
Nature, 2008 Apr 04; 452(7187). PMID: 18385728
Highly Cited. Review.
Critical review of published microarray studies for cancer outcome and guidelines on statistical analysis and reporting.
Alain Dupuy, Richard M Simon.
J Natl Cancer Inst, 2007 Jan 18; 99(2). PMID: 17227998
Highly Cited. Review.
Prognostic and predictive factors revisited.
Daniel F Hayes.
Breast, 2005 Oct 22; 14(6). PMID: 16239111
Review.
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
Evaluating the efficiency of targeted designs for randomized clinical trials.
Richard Simon, Aboubakar Maitournam.
Clin Cancer Res, 2004 Oct 27; 10(20). PMID: 15501951
Gene signature evaluation as a prognostic tool: challenges in the design of the MINDACT trial.
Jan Bogaerts, Fatima Cardoso, +12 authors, TRANSBIG consortium.
Nat Clin Pract Oncol, 2006 Oct 05; 3(10). PMID: 17019432
Review.
Time-dependent ROC curves for censored survival data and a diagnostic marker.
P J Heagerty, T Lumley, M S Pepe.
Biometrics, 2000 Jul 06; 56(2). PMID: 10877287
Highly Cited.
Clinical trial designs for prospective validation of biomarkers.
Sumithra J Mandrekar, Axel Grothey, Matthew P Goetz, Daniel J Sargent.
Am J Pharmacogenomics, 2005 Oct 04; 5(5). PMID: 16196501
Pitfalls in the use of DNA microarray data for diagnostic and prognostic classification.
Richard Simon, Michael D Radmacher, Kevin Dobbin, Lisa M McShane.
J Natl Cancer Inst, 2003 Jan 02; 95(1). PMID: 12509396
Highly Cited. Review.
What should physicians look for in evaluating prognostic gene-expression signatures?
Jyothi Subramanian, Richard Simon.
Nat Rev Clin Oncol, 2010 Apr 28; 7(6). PMID: 20421890
Review.
Ovarian tumor marker HE4 is differently expressed during the phases of the menstrual cycle in healthy young women.
Emanuela Anastasi, Teresa Granato, +6 authors, Cecilia Midulla.
Tumour Biol, 2010 May 22; 31(5). PMID: 20490961
Personalized medicine and oncology practice guidelines: a case study of contemporary biomarkers in colorectal cancer.
Robin K Kelley, Stephanie L Van Bebber, Kathryn A Phillips, Alan P Venook.
J Natl Compr Canc Netw, 2011 Jan 15; 9(1). PMID: 21233242    Free PMC article.
Review.
Deep sequencing of gastric carcinoma reveals somatic mutations relevant to personalized medicine.
Joanna D Holbrook, Joel S Parker, +5 authors, Rakesh Kumar.
J Transl Med, 2011 Jul 26; 9. PMID: 21781349    Free PMC article.
Biomarker use in colorectal cancer therapy.
Robin K Kelley, Grace Wang, Alan P Venook.
J Natl Compr Canc Netw, 2011 Nov 08; 9(11). PMID: 22056657    Free PMC article.
Review.
Clinical trial designs for testing biomarker-based personalized therapies.
Tze Leung Lai, Philip W Lavori, Mei-Chiung I Shih, Branimir I Sikic.
Clin Trials, 2012 Mar 09; 9(2). PMID: 22397801    Free PMC article.
Comparison of CATs, CURB-65 and PMEWS as triage tools in pandemic influenza admissions to UK hospitals: case control analysis using retrospective data.
Puja R Myles, Jonathan S Nguyen-Van-Tam, +9 authors, Malcolm G Semple.
PLoS One, 2012 Apr 18; 7(4). PMID: 22509303    Free PMC article.
Promise and pitfalls of quantitative imaging in oncology clinical trials.
Brenda F Kurland, Elizabeth R Gerstner, +10 authors, Frank S Lieberman.
Magn Reson Imaging, 2012 Aug 18; 30(9). PMID: 22898682    Free PMC article.
Review.
Moving from correlative science to predictive oncology.
Richard Simon.
EPMA J, 2010 Sep 01; 1(3). PMID: 23199082    Free PMC article.
NCI-RTOG translational program strategic guidelines for the early-stage development of radiosensitizers.
Yaacov Richard Lawrence, Bhadrasain Vikram, +9 authors, Adam P Dicker.
J Natl Cancer Inst, 2012 Dec 13; 105(1). PMID: 23231975    Free PMC article.
Genomic biomarkers for personalized medicine: development and validation in clinical studies.
Shigeyuki Matsui.
Comput Math Methods Med, 2013 May 22; 2013. PMID: 23690882    Free PMC article.
Review.
Transparency of reporting in molecular diagnostics.
Stephen Bustin.
Int J Mol Sci, 2013 Aug 02; 14(8). PMID: 23903047    Free PMC article.
Strategies for dealing with missing data in clinical trials: from design to analysis.
James D Dziura, Lori A Post, +2 authors, Peter Peduzzi.
Yale J Biol Med, 2013 Sep 24; 86(3). PMID: 24058309    Free PMC article.
Review.
Multicenter trials using ¹⁸F-fluorodeoxyglucose (FDG) PET to predict chemotherapy response: effects of differential measurement error and bias on power calculations for unselected and enrichment designs.
Brenda F Kurland, Robert K Doot, +2 authors, Paul E Kinahan.
Clin Trials, 2013 Oct 31; 10(6). PMID: 24169628    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.
Identifying the survival subtypes of glioblastoma by quantitative volumetric analysis of MRI.
Zhe Zhang, Haihui Jiang, +7 authors, Song Lin.
J Neurooncol, 2014 May 16; 119(1). PMID: 24828264
Companion diagnostics for targeted cancer drugs - clinical and regulatory aspects.
Dana Olsen, Jan Trøst Jørgensen.
Front Oncol, 2014 Jun 07; 4. PMID: 24904822    Free PMC article.
Review.
Evaluation of a chemoresponse assay as a predictive marker in the treatment of recurrent ovarian cancer: further analysis of a prospective study.
C Tian, D J Sargent, +4 authors, R L Coleman.
Br J Cancer, 2014 Jul 09; 111(5). PMID: 25003664    Free PMC article.
Vaccination with autologous dendritic cells loaded with autologous tumor lysate or homogenate combined with immunomodulating radiotherapy and/or preleukapheresis IFN-α in patients with metastatic melanoma: a randomised "proof-of-principle" phase II study.
Francesco de Rosa, Laura Ridolfi, +15 authors, Massimo Guidoboni.
J Transl Med, 2014 Jul 24; 12. PMID: 25053129    Free PMC article.
Treatment of Metastatic Breast Cancer in a Real-World Scenario: Is Progression-Free Survival With First Line Predictive of Benefit From Second and Later Lines?
Marta Bonotto, Lorenzo Gerratana, +4 authors, Fabio Puglisi.
Oncologist, 2015 May 29; 20(7). PMID: 26018662    Free PMC article.
Innovative Clinical Trial Designs: Toward a 21st-Century Health Care System.
Tze L Lai, Philip W Lavori.
Stat Biosci, 2011 Dec 01; 3(2). PMID: 26140056    Free PMC article.
Statistical Methods for Establishing Personalized Treatment Rules in Oncology.
Junsheng Ma, Brian P Hobbs, Francesco C Stingo.
Biomed Res Int, 2015 Oct 09; 2015. PMID: 26446492    Free PMC article.
Review.
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.
Review.
Minimal Residual Disease Evaluation in Childhood Acute Lymphoblastic Leukemia: A Clinical Evidence Review.
Health Quality Ontario.
Ont Health Technol Assess Ser, 2016 Apr 22; 16(7). PMID: 27099643    Free PMC article.
Review.
Evolution of Chemosensitivity and Resistance Assays as Predictors of Clinical Outcomes in Epithelial Ovarian Cancer Patients.
Bradley J Monk, Thomas J Herzog, Krishnansu S Tewari.
Curr Pharm Des, 2016 Oct 30; 22(30). PMID: 27145761    Free PMC article.
Review.
Combining Prognostic and Predictive Enrichment Strategies to Identify Children With Septic Shock Responsive to Corticosteroids.
Hector R Wong, Sarah J Atkinson, +16 authors, Christopher J Lindsell.
Crit Care Med, 2016 Jun 09; 44(10). PMID: 27270179    Free PMC article.
An Enrichment Strategy For Sepsis Clinical Trials.
Hector R Wong, Christopher J Lindsell.
Shock, 2016 Jul 28; 46(6). PMID: 27454383    Free PMC article.
Comparing diagnostic tests on benefit-risk.
Gene Pennello, Norberto Pantoja-Galicia, Scott Evans.
J Biopharm Stat, 2016 Aug 23; 26(6). PMID: 27548805    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.
Subgroup-Based Adaptive (SUBA) Designs for Multi-Arm Biomarker Trials.
Yanxun Xu, Lorenzo Trippa, Peter Müller, Yuan Ji.
Stat Biosci, 2016 Sep 13; 8(1). PMID: 27617041    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.
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.
Review.
Beyond Correlations, Sensitivities, and Specificities: Case Examples of the Evaluation of Advanced Imaging in Oncology Clinical Trials and Cancer Treatment.
Frank I Lin, Erich P Huang, Lalitha K Shankar.
Acad Radiol, 2017 Apr 16; 24(8). PMID: 28410912    Free PMC article.
Review.
Beyond Correlations, Sensitivities, and Specificities: A Roadmap for Demonstrating Utility of Advanced Imaging in Oncology Treatment and Clinical Trial Design.
Erich P Huang, Frank I Lin, Lalitha K Shankar.
Acad Radiol, 2017 May 01; 24(8). PMID: 28456570    Free PMC article.
Review.
[Molecular biomarkers and prognostic factors for prostate cancer].
A Kretschmer, Y Tolkach, J Ellinger, G Kristiansen.
Urologe A, 2017 Jun 03; 56(7). PMID: 28573413
Review.
Exploitation of Gene Expression and Cancer Biomarkers in Paving the Path to Era of Personalized Medicine.
Hala Fawzy Mohamed Kamel, Hiba Saeed A Bagader Al-Amodi.
Genomics Proteomics Bioinformatics, 2017 Aug 17; 15(4). PMID: 28813639    Free PMC article.
Review.
Patient-derived xenografts effectively capture responses to oncology therapy in a heterogeneous cohort of patients with solid tumors.
E Izumchenko, K Paz, +21 authors, D Sidransky.
Ann Oncol, 2017 Sep 26; 28(10). PMID: 28945830    Free PMC article.
Highly Cited.
Evaluating Molecular Biomarkers for the Early Detection of Lung Cancer: When Is a Biomarker Ready for Clinical Use? An Official American Thoracic Society Policy Statement.
Peter J Mazzone, Catherine Rufatto Sears, +9 authors, ATS Assembly on Thoracic Oncology.
Am J Respir Crit Care Med, 2017 Sep 30; 196(7). PMID: 28960111    Free PMC article.
Future of Evidence Synthesis in Precision Oncology: Between Systematic Reviews and Biocuration.
Simina M Boca, Orestis A Panagiotou, +2 authors, Subha Madhavan.
JCO Precis Oncol, 2018 Jan 01; 2. PMID: 31930186    Free PMC article.
Development of a long non-coding RNA signature for prediction of response to neoadjuvant chemoradiotherapy in locally advanced rectal adenocarcinoma.
Lorenzo Ferrando, Gabriella Cirmena, +11 authors, Gabriele Zoppoli.
PLoS One, 2020 Feb 06; 15(2). PMID: 32023246    Free PMC article.
Implementing personalized cancer genomics in clinical trials.
Richard Simon, Sameek Roychowdhury.
Nat Rev Drug Discov, 2013 May 01; 12(5). PMID: 23629504
Highly Cited. Review.
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
Review.
Generating and evaluating evidence of the clinical utility of molecular diagnostic tests in oncology.
Patricia Deverka, Donna A Messner, +10 authors, Sean R Tunis.
Genet Med, 2015 Dec 04; 18(8). PMID: 26633547
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.
The major effects of health-related quality of life on 5-year survival prediction among lung cancer survivors: applications of machine learning.
Jin-Ah Sim, Young Ae Kim, +5 authors, Young Ho Yun.
Sci Rep, 2020 Jul 03; 10(1). PMID: 32612283    Free PMC article.
Bayesian personalized treatment selection strategies that integrate predictive with prognostic determinants.
Junsheng Ma, Francesco C Stingo, Brian P Hobbs.
Biom J, 2019 Feb 21; 61(4). PMID: 30786040    Free PMC article.
Inflammatory and Fibrogenic Factors in Proliferative Vitreoretinopathy Development.
Rishika Chaudhary, Robert A H Scott, +3 authors, Richard J Blanch.
Transl Vis Sci Technol, 2020 Aug 04; 9(3). PMID: 32742753    Free PMC article.
Review.
Adaptive Signature Design- review of the biomarker guided adaptive phase -III controlled design.
Arinjita Bhattacharyya, Shesh N Rai.
Contemp Clin Trials Commun, 2019 Jul 11; 15. PMID: 31289760    Free PMC article.
Review.
SP-D Serum Levels Reveal Distinct Epithelial Damage in Direct Human ARDS.
Konrad Peukert, Benjamin Seeliger, +10 authors, Christian Bode.
J Clin Med, 2021 Mar 07; 10(4). PMID: 33673270    Free PMC article.
Patient-derived organoids as a predictive biomarker for treatment response in cancer patients.
G Emerens Wensink, Sjoerd G Elias, +4 authors, Jeanine M L Roodhart.
NPJ Precis Oncol, 2021 Apr 14; 5(1). PMID: 33846504
Review.