Journal Article
. 2010 Jan;102(3).
doi: 10.1093/jnci/djp477.

Randomized clinical trials with biomarkers: design issues

Boris Freidlin 1 Lisa M McShane  Edward L Korn  
  • PMID: 20075367
  •     22 References
  •     111 citations


Clinical biomarker tests that aid in making treatment decisions will play an important role in achieving personalized medicine for cancer patients. Definitive evaluation of the clinical utility of these biomarkers requires conducting large randomized clinical trials (RCTs). Efficient RCT design is therefore crucial for timely introduction of these medical advances into clinical practice, and a variety of designs have been proposed for this purpose. To guide design and interpretation of RCTs evaluating biomarkers, we present an in-depth comparison of advantages and disadvantages of the commonly used designs. Key aspects of the discussion include efficiency comparisons and special interim monitoring issues that arise because of the complexity of these RCTs. Important ongoing and completed trials are used as examples. We conclude that, in most settings, randomized biomarker-stratified designs (ie, designs that use the biomarker to guide analysis but not treatment assignment) should be used to obtain a rigorous assessment of biomarker clinical utility.

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BMJ Open, 2018 Dec 14; 8(12). PMID: 30523133    Free PMC article.
Biostatistical and Logistical Considerations in the Development of Basket and Umbrella Clinical Trials.
Laura M Yee, Lisa M McShane, +2 authors, Edward L Korn.
Cancer J, 2019 Jul 25; 25(4). PMID: 31335389    Free PMC article.
Phase III Precision Medicine Clinical Trial Designs That Integrate Treatment and Biomarker Evaluation.
Mei-Yin C Polley, Edward L Korn, Boris Freidlin.
JCO Precis Oncol, 2020 Sep 15; 3. PMID: 32923845    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.
Hypoxia-activated prodrugs and (lack of) clinical progress: The need for hypoxia-based biomarker patient selection in phase III clinical trials.
Linda Spiegelberg, Ruud Houben, +8 authors, Ludwig J Dubois.
Clin Transl Radiat Oncol, 2019 Feb 09; 15. PMID: 30734002    Free PMC article.
Value-based and benefit-based strategies in deciding to bring a test into use should be distinguished.
Werner Vach.
Diagn Progn Res, 2017 Feb 08; 1. PMID: 31093536    Free PMC article.
Mitigating the risk of radiation-induced cancers: limitations and paradigms in drug development.
Stephen S Yoo, Timothy J Jorgensen, +9 authors, C Norman Coleman.
J Radiol Prot, 2014 Apr 15; 34(2). PMID: 24727460    Free PMC article.
Clinical and research applications of a brain tumor tissue bank in the age of precision medicine.
James Snyder, Laila M Poisson, +6 authors, Tobias Walbert.
Per Med, 2019 Mar 01; 16(2). PMID: 30816054    Free PMC article.
Moving Molecular Profiling to Routine Clinical Practice: A Way Forward?
Boris Freidlin, Carmen J Allegra, Edward L Korn.
J Natl Cancer Inst, 2019 Dec 24; 112(8). PMID: 31868907    Free PMC article.
Essential statistical principles of clinical trials of pain treatments.
Robert H Dworkin, Scott R Evans, Omar Mbowe, Michael P McDermott.
Pain Rep, 2021 Feb 02; 6(1). PMID: 33521483    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.