. 2016 Feb;11(2).
doi: 10.1371/journal.pone.0149803.

Biomarker-Guided Adaptive Trial Designs in Phase II and Phase III: A Methodological Review

Miranta Antoniou 1 Andrea L Jorgensen 1 Ruwanthi Kolamunnage-Dona 1 
  • PMID: 26910238
  •     123 References
  •     23 citations


Background: Personalized medicine is a growing area of research which aims to tailor the treatment given to a patient according to one or more personal characteristics. These characteristics can be demographic such as age or gender, or biological such as a genetic or other biomarker. Prior to utilizing a patient's biomarker information in clinical practice, robust testing in terms of analytical validity, clinical validity and clinical utility is necessary. A number of clinical trial designs have been proposed for testing a biomarker's clinical utility, including Phase II and Phase III clinical trials which aim to test the effectiveness of a biomarker-guided approach to treatment; these designs can be broadly classified into adaptive and non-adaptive. While adaptive designs allow planned modifications based on accumulating information during a trial, non-adaptive designs are typically simpler but less flexible.

Methods And Findings: We have undertaken a comprehensive review of biomarker-guided adaptive trial designs proposed in the past decade. We have identified eight distinct biomarker-guided adaptive designs and nine variations from 107 studies. Substantial variability has been observed in terms of how trial designs are described and particularly in the terminology used by different authors. We have graphically displayed the current biomarker-guided adaptive trial designs and summarised the characteristics of each design.

Conclusions: Our in-depth overview provides future researchers with clarity in definition, methodology and terminology for biomarker-guided adaptive trial designs.

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Br J Clin Pharmacol, 2019 Mar 09; 85(7). PMID: 30849187    Free PMC article.
Design of experiments for a confirmatory trial of precision medicine.
Kim May Lee, James Wason.
J Stat Plan Inference, 2019 Apr 23; 199. PMID: 31007363    Free PMC article.
The adaptive designs CONSORT extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design.
Munyaradzi Dimairo, Philip Pallmann, +17 authors, ACE Consensus Group.
Trials, 2020 Jun 18; 21(1). PMID: 32546273    Free PMC article.
The Adaptive designs CONSORT Extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design.
Munyaradzi Dimairo, Philip Pallmann, +17 authors, ACE Consensus Group.
BMJ, 2020 Jun 20; 369. PMID: 32554564    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.
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.
Effects of biomarker diagnostic accuracy on biomarker-guided phase 2 trials.
Jay Jh Park, Ofir Harari, +2 authors, Kristian Thorlund.
Contemp Clin Trials Commun, 2019 Jul 12; 15. PMID: 31294127    Free PMC article.
Adding flexibility to clinical trial designs: an example-based guide to the practical use of adaptive designs.
Thomas Burnett, Pavel Mozgunov, +3 authors, Thomas Jaki.
BMC Med, 2020 Nov 20; 18(1). PMID: 33208155    Free PMC article.
Transforming clinical trials in rheumatology: towards patient-centric precision medicine.
Costantino Pitzalis, Ernest H S Choy, Maya H Buch.
Nat Rev Rheumatol, 2020 Sep 06; 16(10). PMID: 32887976
Statistical consideration when adding new arms to ongoing clinical trials: the potentials and the caveats.
Kim May Lee, Louise C Brown, +2 authors, James Wason.
Trials, 2021 Mar 12; 22(1). PMID: 33691748    Free PMC article.