Journal Article
. 2020 Nov;18(1).
doi: 10.1186/s12916-020-01808-2.

Adding flexibility to clinical trial designs: an example-based guide to the practical use of adaptive designs

Thomas Burnett 1 Pavel Mozgunov 2 Philip Pallmann 3 Sofia S Villar 4 Graham M Wheeler 5 Thomas Jaki 2 
  • PMID: 33208155
  •     152 References
  •     1 citations


Adaptive designs for clinical trials permit alterations to a study in response to accumulating data in order to make trials more flexible, ethical, and efficient. These benefits are achieved while preserving the integrity and validity of the trial, through the pre-specification and proper adjustment for the possible alterations during the course of the trial. Despite much research in the statistical literature highlighting the potential advantages of adaptive designs over traditional fixed designs, the uptake of such methods in clinical research has been slow. One major reason for this is that different adaptations to trial designs, as well as their advantages and limitations, remain unfamiliar to large parts of the clinical community. The aim of this paper is to clarify where adaptive designs can be used to address specific questions of scientific interest; we introduce the main features of adaptive designs and commonly used terminology, highlighting their utility and pitfalls, and illustrate their use through case studies of adaptive trials ranging from early-phase dose escalation to confirmatory phase III studies.

Keywords: Efficient methods; Enrichment designs; Innovative trials; Multi-arm multi-stage platform trials; Novel designs.

Adaptive designs for dual-agent phase I dose-escalation studies.
Jennifer A Harrington, Graham M Wheeler, +2 authors, Duncan I Jodrell.
Nat Rev Clin Oncol, 2013 Mar 20; 10(5). PMID: 23507740
Confirmatory adaptive designs with Bayesian decision tools for a targeted therapy in oncology.
Werner Brannath, Emmanuel Zuber, +4 authors, Amy Racine-Poon.
Stat Med, 2009 Mar 07; 28(10). PMID: 19266565
A Practical Guide to Data Monitoring Committees in Adaptive Trials.
Matilde Sanchez-Kam, Paul Gallo, +5 authors, Thomas Laage.
Ther Innov Regul Sci, 2014 May 01; 48(3). PMID: 30235541
TAILoR (TelmisArtan and InsuLin Resistance in Human Immunodeficiency Virus [HIV]): An Adaptive-design, Dose-ranging Phase IIb Randomized Trial of Telmisartan for the Reduction of Insulin Resistance in HIV-positive Individuals on Combination Antiretroviral Therapy.
Sudeep Pushpakom, Ruwanthi Kolamunnage-Dona, +9 authors, TAILoR Study Group.
Clin Infect Dis, 2019 Aug 20; 70(10). PMID: 31425580    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.
Adaptive randomized study of idarubicin and cytarabine versus troxacitabine and cytarabine versus troxacitabine and idarubicin in untreated patients 50 years or older with adverse karyotype acute myeloid leukemia.
Francis J Giles, Hagop M Kantarjian, +10 authors, Elihu H Estey.
J Clin Oncol, 2003 May 02; 21(9). PMID: 12721247
Statistical and ethical issues in the design and conduct of phase I and II clinical trials of new anticancer agents.
M J Ratain, R Mick, R L Schilsky, M Siegler.
J Natl Cancer Inst, 1993 Oct 20; 85(20). PMID: 8411243
Twenty-five years of confirmatory adaptive designs: opportunities and pitfalls.
Peter Bauer, Frank Bretz, +2 authors, Gernot Wassmer.
Stat Med, 2015 Mar 18; 35(3). PMID: 25778935    Free PMC article.
The bivariate continual reassessment method. extending the CRM to phase I trials of two competing outcomes.
Thomas M Braun.
Control Clin Trials, 2002 Jun 12; 23(3). PMID: 12057877
Dose escalation methods in phase I cancer clinical trials.
Christophe Le Tourneau, J Jack Lee, Lillian L Siu.
J Natl Cancer Inst, 2009 May 14; 101(10). PMID: 19436029    Free PMC article.
Highly Cited. Review.
Sample size recalculation in internal pilot study designs: a review.
Tim Friede, Meinhard Kieser.
Biom J, 2006 Sep 16; 48(4). PMID: 16972704
Statistical controversies in clinical research: requiem for the 3 + 3 design for phase I trials.
X Paoletti, M Ezzalfani, C Le Tourneau.
Ann Oncol, 2015 Jun 20; 26(9). PMID: 26088197    Free PMC article.
When is a seamless study desirable? Case studies from different pharmaceutical sponsors.
Robert L Cuffe, David Lawrence, Andrew Stone, Marc Vandemeulebroecke.
Pharm Stat, 2014 Jun 04; 13(4). PMID: 24891148
Optimal designs for estimating the most successful dose.
Sarah Zohar, John O'Quigley.
Stat Med, 2006 Sep 14; 25(24). PMID: 16969893
A review of methods for futility stopping based on conditional power.
John M Lachin.
Stat Med, 2005 Sep 01; 24(18). PMID: 16134130
Sequential continual reassessment method for two-dimensional dose finding.
Ying Yuan, Guosheng Yin.
Stat Med, 2008 Jul 12; 27(27). PMID: 18618901
A comprehensive comparison of the continual reassessment method to the standard 3 + 3 dose escalation scheme in Phase I dose-finding studies.
Alexia Iasonos, Andrew S Wilton, +2 authors, David R Spriggs.
Clin Trials, 2008 Oct 02; 5(5). PMID: 18827039    Free PMC article.
Dose-finding design for multi-drug combinations.
Nolan A Wages, Mark R Conaway, John O'Quigley.
Clin Trials, 2011 Jun 10; 8(4). PMID: 21652689    Free PMC article.
Can response-adaptive randomization increase participation in acute stroke trials?
Jason S Tehranisa, William J Meurer.
Stroke, 2014 Jun 12; 45(7). PMID: 24916909    Free PMC article.
Drop-the-losers design: normal case.
Allan R Sampson, Michael W Sill.
Biom J, 2005 Aug 02; 47(3). PMID: 16053251
Statistical controversies in clinical research: early-phase adaptive design for combination immunotherapies.
N A Wages, C L Slingluff, G R Petroni.
Ann Oncol, 2016 Dec 25; 28(4). PMID: 28011450    Free PMC article.
Translation of innovative designs into phase I trials.
André Rogatko, David Schoeneck, +3 authors, Alan Porter.
J Clin Oncol, 2007 Nov 01; 25(31). PMID: 17971597
On the independence of data monitoring committee in adaptive design clinical trials.
Shein-Chung Chow, Ralph Corey, Min Lin.
J Biopharm Stat, 2012 Jun 02; 22(4). PMID: 22651119
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.
An overview of the optimal planning, design, and conduct of phase I studies of new therapeutics.
Patricia M LoRusso, Scott A Boerner, Lesley Seymour.
Clin Cancer Res, 2010 Mar 11; 16(6). PMID: 20215546
Experimental designs for phase I and phase I/II dose-finding studies.
J O'Quigley, S Zohar.
Br J Cancer, 2006 Jan 26; 94(5). PMID: 16434987    Free PMC article.
Improving Probabilities of Correct Interim Decision in Population Enrichment Designs.
Heiko Götte, Margarita Donica, Giacomo Mordenti.
J Biopharm Stat, 2014 Jun 11; 25(5). PMID: 24914474
Bayesian decision procedures for dose-escalation based on evidence of undesirable events and therapeutic benefit.
John Whitehead, Yinghui Zhou, +3 authors, Joanna Leadbetter.
Stat Med, 2005 Dec 13; 25(1). PMID: 16342336
AplusB: A Web Application for Investigating A + B Designs for Phase I Cancer Clinical Trials.
Graham M Wheeler, Michael J Sweeting, Adrian P Mander.
PLoS One, 2016 Jul 13; 11(7). PMID: 27403961    Free PMC article.
Confirmatory seamless phase II/III clinical trials with hypotheses selection at interim: opportunities and limitations.
Christopher Jenniso, Bruce W Turnbull.
Biom J, 2006 Sep 16; 48(4). PMID: 16972717
Bayesian adaptive dose-escalation procedures for binary and continuous responses utilizing a gain function.
Wai Yin Yeung, John Whitehead, +3 authors, Thomas Jaki.
Pharm Stat, 2015 Sep 10; 14(6). PMID: 26353113
Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols.
Jay J H Park, Ellie Siden, +6 authors, Edward J Mills.
Trials, 2019 Sep 20; 20(1). PMID: 31533793    Free PMC article.
Systematic Review.
Dose Transition Pathways: The Missing Link Between Complex Dose-Finding Designs and Simple Decision-Making.
Christina Yap, Lucinda J Billingham, +2 authors, John O'Quigley.
Clin Cancer Res, 2017 Jul 25; 23(24). PMID: 28733440
Adaptive designs undertaken in clinical research: a review of registered clinical trials.
Isabella Hatfield, Annabel Allison, +2 authors, Munyaradzi Dimairo.
Trials, 2016 Mar 20; 17(1). PMID: 26993469    Free PMC article.
Design of a placebo-controlled clinical trial of long-acting diltiazem and aspirin versus aspirin alone in patients receiving thrombolysis with a first acute myocardial infarction. Incomplete Infarction Trial of European Research Collaborators Evaluating Prognosis Post-Thrombolysis (diltiazem) (INTERCEPT) Research Group.
W E Boden, R Scheldewaert, +5 authors, I R Starkey.
Am J Cardiol, 1995 Jun 01; 75(16). PMID: 7762497
Combining multiple comparisons and modeling techniques in dose-response studies.
F Bretz, J C Pinheiro, M Branson.
Biometrics, 2005 Sep 02; 61(3). PMID: 16135025
Incorporating lower grade toxicity information into dose finding designs.
Alexia Iasonos, Sarah Zohar, John O'Quigley.
Clin Trials, 2011 Aug 13; 8(4). PMID: 21835856    Free PMC article.
A model-based approach in the estimation of the maximum tolerated dose in phase I cancer clinical trials.
Weili He, Jun Liu, Bruce Binkowitz, Hui Quan.
Stat Med, 2005 Jul 19; 25(12). PMID: 16025542
Paradigms for adaptive statistical information designs: practical experiences and strategies.
Sue-Jane Wang, H M James Hung, Robert O'Neill.
Stat Med, 2012 Aug 29; 31(25). PMID: 22927234
Bayesian adaptive dose-escalation designs for simultaneously estimating the optimal and maximum safe dose based on safety and efficacy.
Wai Yin Yeung, Bruno Reigner, +4 authors, Thomas Jaki.
Pharm Stat, 2017 Jul 12; 16(6). PMID: 28691311
Statistical consideration of adaptive methods in clinical development.
Shein-Chung Chow, Mark Chang, Annpey Pong.
J Biopharm Stat, 2005 Jul 19; 15(4). PMID: 16022164
A comparison of stochastic programming methods for portfolio level decision-making.
Emily Graham, Thomas Jaki, Chris Harbron.
J Biopharm Stat, 2019 Dec 12; 30(3). PMID: 31825729
Final Results of the RHAPSODY Trial: A Multi-Center, Phase 2 Trial Using a Continual Reassessment Method to Determine the Safety and Tolerability of 3K3A-APC, A Recombinant Variant of Human Activated Protein C, in Combination with Tissue Plasminogen Activator, Mechanical Thrombectomy or both in Moderate to Severe Acute Ischemic Stroke.
Patrick Lyden, Kent E Pryor, +29 authors, NeuroNEXT Clinical Trials Network NN104 Investigators.
Ann Neurol, 2018 Nov 20; 85(1). PMID: 30450637    Free PMC article.
Highly Cited.
Generalizing the TITE-CRM to adapt for early- and late-onset toxicities.
Thomas M Braun.
Stat Med, 2005 Oct 12; 25(12). PMID: 16217853
A two-stage design for choosing among several experimental treatments and a control in clinical trials.
P F Thall, R Simon, S S Ellenberg.
Biometrics, 1989 Jun 01; 45(2). PMID: 2765637
Using Randomization Tests to Preserve Type I Error With Response-Adaptive and Covariate-Adaptive Randomization.
Richard Simon, Noah Robin Simon.
Stat Probab Lett, 2011 Jul 20; 81(7). PMID: 21769160    Free PMC article.
Unbiased estimation for response adaptive clinical trials.
Jack Bowden, Lorenzo Trippa.
Stat Methods Med Res, 2015 Aug 13; 26(5). PMID: 26265771    Free PMC article.
Continual reassessment method: a likelihood approach.
J O'Quigley, L Z Shen.
Biometrics, 1996 Jun 01; 52(2). PMID: 8672707
An information theoretic phase I-II design for molecularly targeted agents that does not require an assumption of monotonicity.
Pavel Mozgunov, Thomas Jaki.
J R Stat Soc Ser C Appl Stat, 2019 Apr 23; 68(2). PMID: 31007292    Free PMC article.
Two-dimensional dose finding in discrete dose space.
Kai Wang, Anastasia Ivanova.
Biometrics, 2005 Mar 02; 61(1). PMID: 15737096
A multi-stage drop-the-losers design for multi-arm clinical trials.
James Wason, Nigel Stallard, Jack Bowden, Christopher Jennison.
Stat Methods Med Res, 2014 Sep 18; 26(1). PMID: 25228636    Free PMC article.
Competing designs for drug combination in phase I dose-finding clinical trials.
M-K Riviere, F Dubois, S Zohar.
Stat Med, 2014 Jan 28; 34(1). PMID: 24464821
Principles of dose finding studies in cancer: a comparison of trial designs.
Thomas Jaki, Sally Clive, Christopher J Weir.
Cancer Chemother Pharmacol, 2013 Jan 10; 71(5). PMID: 23299793    Free PMC article.
A framework for prospectively defining progression rules for internal pilot studies monitoring recruitment.
Lisa V Hampson, Paula R Williamson, Martin J Wilby, Thomas Jaki.
Stat Methods Med Res, 2017 Jun 08; 27(12). PMID: 28589752
A curve-free method for phase I clinical trials.
M Gasparini, J Eisele.
Biometrics, 2000 Jul 06; 56(2). PMID: 10877324
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.
Adaptive clinical trials: the promise and the caution.
Donald A Berry.
J Clin Oncol, 2010 Dec 22; 29(6). PMID: 21172875
Treatment allocation by minimisation.
Douglas G Altman, J Martin Bland.
BMJ, 2005 Apr 09; 330(7495). PMID: 15817555    Free PMC article.
Highly Cited. Review.
Toxicity-dependent feasibility bounds for the escalation with overdose control approach in phase I cancer trials.
Graham M Wheeler, Michael J Sweeting, Adrian P Mander.
Stat Med, 2017 Mar 16; 36(16). PMID: 28295513    Free PMC article.
Incoherent dose-escalation in phase I trials using the escalation with overdose control approach.
Graham M Wheeler.
Stat Pap (Berl), 2018 Jun 08; 59(2). PMID: 29875549    Free PMC article.
Dose-finding studies, MCP-Mod, model selection, and model averaging: Two applications in the real world.
Dominique Verrier, Sïndou Sivapregassam, Anne-Catherine Solente.
Clin Trials, 2014 May 30; 11(4). PMID: 24872360
Designing and evaluating dose-escalation studies made easy: The MoDEsT web app.
Philip Pallmann, Fang Wan, +5 authors, Thomas Jaki.
Clin Trials, 2019 Dec 21; 17(2). PMID: 31856600    Free PMC article.
Phase I dose-escalating study of docetaxel in combination with 5-day continuous infusion of 5-fluorouracil in patients with advanced gastric cancer.
Se Hoon Park, Soo-Mee Bang, +4 authors, Min Chung.
BMC Cancer, 2005 Jul 27; 5. PMID: 16042786    Free PMC article.
Bayesian adaptive bandit-based designs using the Gittins index for multi-armed trials with normally distributed endpoints.
Adam L Smith, Sofía S Villar.
J Appl Stat, 2018 Mar 20; 45(6). PMID: 29551849    Free PMC article.
Bayesian optimal designs for Phase I clinical trials.
Linda M Haines, Inna Perevozskaya, William F Rosenberger.
Biometrics, 2003 Nov 07; 59(3). PMID: 14601760
Thirty years of phase I radiochemotherapy trials: Latest development.
Romain Rivoirard, Alexis Vallard, +8 authors, Nicolas Magne.
Eur J Cancer, 2016 Feb 29; 58. PMID: 26922167
Model-based dose finding under model uncertainty using general parametric models.
José Pinheiro, Björn Bornkamp, Ekkehard Glimm, Frank Bretz.
Stat Med, 2013 Dec 05; 33(10). PMID: 24302486
Familywise error control in multi-armed response-adaptive trials.
D S Robertson, J M S Wason.
Biometrics, 2019 Feb 05; 75(3). PMID: 30714095    Free PMC article.
Resist the Temptation of Response-Adaptive Randomization.
Michael Proschan, Scott Evans.
Clin Infect Dis, 2020 Mar 31; 71(11). PMID: 32222766    Free PMC article.
Statistical properties of the traditional algorithm-based designs for phase I cancer clinical trials.
Y Lin, W J Shih.
Biostatistics, 2003 Aug 23; 2(2). PMID: 12933550
Cancer phase I clinical trials: efficient dose escalation with overdose control.
J Babb, A Rogatko, S Zacks.
Stat Med, 1998 Jun 10; 17(10). PMID: 9618772
Highly Cited.
Rendering the 3 + 3 Design to Rest: More Efficient Approaches to Oncology Dose-Finding Trials in the Era of Targeted Therapy.
Lei Nie, Eric H Rubin, +5 authors, Dinesh P de Alwis.
Clin Cancer Res, 2016 Jun 03; 22(11). PMID: 27250933
Combining different phases in the development of medical treatments within a single trial.
P Bauer, M Kieser.
Stat Med, 1999 Jul 17; 18(14). PMID: 10407255
A comparison of Bayesian adaptive randomization and multi-stage designs for multi-arm clinical trials.
James M S Wason, Lorenzo Trippa.
Stat Med, 2014 Jan 15; 33(13). PMID: 24421053
Sample size re-estimation in clinical trials.
Michael A Proschan.
Biom J, 2009 Apr 10; 51(2). PMID: 19358221
The use of unequal randomisation ratios in clinical trials: a review.
J C Dumville, S Hahn, J N V Miles, D J Torgerson.
Contemp Clin Trials, 2005 Oct 21; 27(1). PMID: 16236557
Dose-finding clinical trial design for ordinal toxicity grades using the continuation ratio model: an extension of the continual reassessment method.
Emily M Van Meter, Elizabeth Garrett-Mayer, Dipankar Bandyopadhyay.
Clin Trials, 2012 May 02; 9(3). PMID: 22547420    Free PMC article.
Response-adaptive clinical trials: case studies in the medical literature.
Andrew P Grieve.
Pharm Stat, 2016 Oct 13; 16(1). PMID: 27730735
A product of independent beta probabilities dose escalation design for dual-agent phase I trials.
Adrian P Mander, Michael J Sweeting.
Stat Med, 2015 Jan 30; 34(8). PMID: 25630638    Free PMC article.
A web tool for designing and conducting phase I trials using the continual reassessment method.
Nolan A Wages, Gina R Petroni.
BMC Cancer, 2018 Feb 07; 18(1). PMID: 29402249    Free PMC article.
Dose-finding designs for HIV studies.
J O'Quigley, M D Hughes, T Fenton.
Biometrics, 2002 Jan 05; 57(4). PMID: 11764240
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
Adaptive increase in sample size when interim results are promising: a practical guide with examples.
Cyrus R Mehta, Stuart J Pocock.
Stat Med, 2011 Nov 23; 30(28). PMID: 22105690
Continual reassessment methods in phase I trials of the combination of two drugs in oncology.
A Kramar, A Lebecq, E Candalh.
Stat Med, 1999 Jul 17; 18(14). PMID: 10407256
How to design a dose-finding study using the continual reassessment method.
Graham M Wheeler, Adrian P Mander, +9 authors, Simon J Bond.
BMC Med Res Methodol, 2019 Jan 20; 19(1). PMID: 30658575    Free PMC article.
Speeding up the evaluation of new agents in cancer.
Mahesh K B Parmar, Friederike M-S Barthel, +9 authors, Patrick Royston.
J Natl Cancer Inst, 2008 Aug 30; 100(17). PMID: 18728279    Free PMC article.
Learning health systems, clinical equipoise and the ethics of response adaptive randomisation.
Alex John London.
J Med Ethics, 2017 Nov 28; 44(6). PMID: 29175968
Uptake of novel statistical methods for early-phase clinical studies in the UK public sector.
Thomas Jaki.
Clin Trials, 2013 Feb 05; 10(2). PMID: 23378484
Outcome--adaptive randomization: is it useful?
Edward L Korn, Boris Freidlin.
J Clin Oncol, 2010 Dec 22; 29(6). PMID: 21172882    Free PMC article.
Adaptive assignment versus balanced randomization in clinical trials: a decision analysis.
D A Berry, S G Eick.
Stat Med, 1995 Feb 15; 14(3). PMID: 7724909
Improving safety of the continual reassessment method via a modified allocation rule.
Pavel Mozgunov, Thomas Jaki.
Stat Med, 2019 Dec 21; 39(7). PMID: 31859399    Free PMC article.
Sequential designs for phase III clinical trials incorporating treatment selection.
Nigel Stallard, Susan Todd.
Stat Med, 2003 Feb 15; 22(5). PMID: 12587100
Optimized adaptive enrichment designs.
Thomas Ondra, Sebastian Jobjörnsson, +4 authors, Martin Posch.
Stat Methods Med Res, 2017 Dec 20; 28(7). PMID: 29254436    Free PMC article.
Continual reassessment method vs. traditional empirically based design: modifications motivated by Phase I trials in pediatric oncology by the Pediatric Brain Tumor Consortium.
Arzu Onar, Mehmet Kocak, James M Boyett.
J Biopharm Stat, 2009 Apr 23; 19(3). PMID: 19384687    Free PMC article.
Comparison of methods for control allocation in multiple arm studies using response adaptive randomization.
Kert Viele, Kristine Broglio, Anna McGlothlin, Benjamin R Saville.
Clin Trials, 2019 Oct 22; 17(1). PMID: 31630567
Sequential designs for phase I clinical trials with late-onset toxicities.
Y K Cheung, R Chappell.
Biometrics, 2000 Dec 29; 56(4). PMID: 11129476
Highly Cited.
Bayesian adaptive design for targeted therapy development in lung cancer--a step toward personalized medicine.
Xian Zhou, Suyu Liu, +2 authors, J Jack Lee.
Clin Trials, 2008 Jun 19; 5(3). PMID: 18559407    Free PMC article.
Not too big, not too small: a goldilocks approach to sample size selection.
Kristine R Broglio, Jason T Connor, Scott M Berry.
J Biopharm Stat, 2014 Apr 05; 24(3). PMID: 24697532
When to keep it simple - adaptive designs are not always useful.
James M S Wason, Peter Brocklehurst, Christina Yap.
BMC Med, 2019 Aug 03; 17(1). PMID: 31370839    Free PMC article.
Telmisartan and Insulin Resistance in HIV (TAILoR): protocol for a dose-ranging phase II randomised open-labelled trial of telmisartan as a strategy for the reduction of insulin resistance in HIV-positive individuals on combination antiretroviral therapy.
Sudeep P Pushpakom, Claire Taylor, +9 authors, Munir Pirmohamed.
BMJ Open, 2015 Oct 18; 5(10). PMID: 26474943    Free PMC article.
Adaptive platform trials: definition, design, conduct and reporting considerations.
Adaptive Platform Trials Coalition.
Nat Rev Drug Discov, 2019 Aug 30; 18(10). PMID: 31462747
Maximum type 1 error rate inflation in multiarmed clinical trials with adaptive interim sample size modifications.
Alexandra C Graf, Peter Bauer, Ekkehard Glimm, Franz Koenig.
Biom J, 2014 Apr 23; 56(4). PMID: 24753160    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.
A simulation-based comparison of the traditional method, Rolling-6 design and a frequentist version of the continual reassessment method with special attention to trial duration in pediatric Phase I oncology trials.
Arzu Onar-Thomas, Zang Xiong.
Contemp Clin Trials, 2010 Mar 20; 31(3). PMID: 20298812    Free PMC article.
The BATTLE trial: personalizing therapy for lung cancer.
Edward S Kim, Roy S Herbst, +21 authors, Waun K Hong.
Cancer Discov, 2012 May 16; 1(1). PMID: 22586319    Free PMC article.
Highly Cited.
A Bayesian dose-finding design for drug combination clinical trials based on the logistic model.
Marie-Karelle Riviere, Ying Yuan, Frédéric Dubois, Sarah Zohar.
Pharm Stat, 2014 May 16; 13(4). PMID: 24828456
A Phase I Dose Escalation Study Demonstrates Quercetin Safety and Explores Potential for Bioflavonoid Antivirals in Patients with Chronic Hepatitis C.
Nu T Lu, Catherine M Crespi, +11 authors, Samuel W French.
Phytother Res, 2015 Dec 02; 30(1). PMID: 26621580    Free PMC article.
Identifying the most successful dose (MSD) in dose-finding studies in cancer.
Sarah Zohar, John O'Quigley.
Pharm Stat, 2006 Nov 04; 5(3). PMID: 17080752
Confirmatory seamless phase II/III clinical trials with hypotheses selection at interim: applications and practical considerations.
Heinz Schmidli, Frank Bretz, Amy Racine, Willi Maurer.
Biom J, 2006 Sep 16; 48(4). PMID: 16972715
Sample size re-estimation: recent developments and practical considerations.
A L Gould.
Stat Med, 2001 Aug 28; 20(17-18). PMID: 11523073
Escalation with overdose control for phase I drug-combination trials.
Yun Shi, Guosheng Yin.
Stat Med, 2013 May 01; 32(25). PMID: 23630103
A trivariate continual reassessment method for phase I/II trials of toxicity, efficacy, and surrogate efficacy.
Wei Zhong, Joseph S Koopmeiners, Bradley P Carlin.
Stat Med, 2012 Jul 19; 31(29). PMID: 22807126    Free PMC article.
Design and analysis of phase I clinical trials.
B E Storer.
Biometrics, 1989 Sep 01; 45(3). PMID: 2790129
Highly Cited.
Adaptive designs in clinical trials: why use them, and how to run and report them.
Philip Pallmann, Alun W Bedding, +13 authors, Thomas Jaki.
BMC Med, 2018 Mar 02; 16(1). PMID: 29490655    Free PMC article.
Highly Cited.
The method of minimization for allocation to clinical trials. a review.
Neil W Scott, Gladys C McPherson, Craig R Ramsay, Marion K Campbell.
Control Clin Trials, 2002 Dec 31; 23(6). PMID: 12505244
Highly Cited. Review.
An adaptive phase I design for identifying a biologically optimal dose for dual agent drug combinations.
Sumithra J Mandrekar, Yue Cui, Daniel J Sargent.
Stat Med, 2006 Oct 04; 26(11). PMID: 17016867
Dose finding with drug combinations in cancer phase I clinical trials using conditional escalation with overdose control.
Mourad Tighiouart, Steven Piantadosi, André Rogatko.
Stat Med, 2014 May 16; 33(22). PMID: 24825779    Free PMC article.
Development process of a consensus-driven CONSORT extension for randomised trials using an adaptive design.
Munyaradzi Dimairo, Elizabeth Coates, +16 authors, Douglas G Altman.
BMC Med, 2018 Nov 18; 16(1). PMID: 30442137    Free PMC article.
Simple procedures for blinded sample size adjustment that do not affect the type I error rate.
Meinhard Kieser, Tim Friede.
Stat Med, 2003 Dec 04; 22(23). PMID: 14652861
Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial.
S J Pocock, R Simon.
Biometrics, 1975 Mar 01; 31(1). PMID: 1100130
Highly Cited.
An efficient basket trial design.
Kristen M Cunanan, Alexia Iasonos, +2 authors, Mithat Gönen.
Stat Med, 2017 Jan 18; 36(10). PMID: 28098411    Free PMC article.
A practical Bayesian design to identify the maximum tolerated dose contour for drug combination trials.
Liangcai Zhang, Ying Yuan.
Stat Med, 2016 Nov 04; 35(27). PMID: 27580928    Free PMC article.
EarLy Elimination of Fatty Acids iN hypertriglyceridemia-induced acuTe pancreatitis (ELEFANT trial): Protocol of an open-label, multicenter, adaptive randomized clinical trial.
Noémi Zádori, Noémi Gede, +15 authors, Péter Hegyi.
Pancreatology, 2020 Jan 22; 20(3). PMID: 31959416
Group sequential trials revisited: simple implementation using SAS.
John Whitehead.
Stat Methods Med Res, 2010 Sep 30; 20(6). PMID: 20876163
Escalation with overdose control using time to toxicity for cancer phase I clinical trials.
Mourad Tighiouart, Yuan Liu, André Rogatko.
PLoS One, 2014 Mar 26; 9(3). PMID: 24663812    Free PMC article.
A multiple testing procedure for clinical trials.
P C O'Brien, T R Fleming.
Biometrics, 1979 Sep 01; 35(3). PMID: 497341
Highly Cited.
Missing steps in a staircase: a qualitative study of the perspectives of key stakeholders on the use of adaptive designs in confirmatory trials.
Munyaradzi Dimairo, Jonathan Boote, +2 authors, Susan Todd.
Trials, 2015 Sep 30; 16. PMID: 26416387    Free PMC article.
Continual reassessment method with multiple toxicity constraints.
Shing M Lee, Bin Cheng, Ying Kuen Cheung.
Biostatistics, 2010 Sep 30; 12(2). PMID: 20876664    Free PMC article.
Familywise error control in multi-armed response-adaptive two-stage designs.
Georg Gutjahr, Martin Posch, Werner Brannath.
J Biopharm Stat, 2011 Apr 26; 21(4). PMID: 21516571
Diltiazem in acute myocardial infarction treated with thrombolytic agents: a randomised placebo-controlled trial. Incomplete Infarction Trial of European Research Collaborators Evaluating Prognosis post-Thrombolysis (INTERCEPT)
W E Boden, W H van Gilst, +10 authors, K M Fox.
Lancet, 2000 Jun 01; 355(9217). PMID: 10832825
Efficiency of new dose escalation designs in dose-finding phase I trials of molecularly targeted agents.
Christophe Le Tourneau, Hui K Gan, Albiruni R A Razak, Xavier Paoletti.
PLoS One, 2012 Dec 20; 7(12). PMID: 23251419    Free PMC article.
Comparison of multi-arm multi-stage design and adaptive randomization in platform clinical trials.
Jianchang Lin, Veronica Bunn.
Contemp Clin Trials, 2017 Jan 17; 54. PMID: 28089763
Phase I Study of Ceritinib (LDK378) in Japanese Patients with Advanced, Anaplastic Lymphoma Kinase-Rearranged Non-Small-Cell Lung Cancer or Other Tumors.
Makoto Nishio, Haruyasu Murakami, +9 authors, Takashi Seto.
J Thorac Oncol, 2015 May 29; 10(7). PMID: 26020125    Free PMC article.
Response-adaptive designs for binary responses: How to offer patient benefit while being robust to time trends?
Sofía S Villar, Jack Bowden, James Wason.
Pharm Stat, 2017 Dec 22; 17(2). PMID: 29266692    Free PMC article.
Follow up after sample size re-estimation in a breast cancer randomized trial for disease-free survival.
Erinn M Hade, Gregory S Young, Richard R Love.
Trials, 2019 Aug 25; 20(1). PMID: 31443726    Free PMC article.
The Impact of Early-Phase Trial Design in the Drug Development Process.
Mark R Conaway, Gina R Petroni.
Clin Cancer Res, 2018 Oct 18; 25(2). PMID: 30327310    Free PMC article.
Bayesian Optimal Interval Design: A Simple and Well-Performing Design for Phase I Oncology Trials.
Ying Yuan, Kenneth R Hess, Susan G Hilsenbeck, Mark R Gilbert.
Clin Cancer Res, 2016 Jul 14; 22(17). PMID: 27407096    Free PMC article.
Bayesian adaptive clinical trials: a dream for statisticians only?
Sylvie Chevret.
Stat Med, 2011 Sep 10; 31(11-12). PMID: 21905067
Continual reassessment method: a practical design for phase 1 clinical trials in cancer.
J O'Quigley, M Pepe, L Fisher.
Biometrics, 1990 Mar 01; 46(1). PMID: 2350571
Highly Cited.
Patient specific dosing in a cancer phase I clinical trial.
J S Babb, A Rogatko.
Stat Med, 2001 Jul 06; 20(14). PMID: 11439422
Covariate-adjusted response-adaptive designs for binary response.
W F Rosenberger, A N Vidyashankar, D K Agarwal.
J Biopharm Stat, 2002 May 23; 11(4). PMID: 12018777
Cross-sector surveys assessing perceptions of key stakeholders towards barriers, concerns and facilitators to the appropriate use of adaptive designs in confirmatory trials.
Munyaradzi Dimairo, Steven A Julious, +2 authors, Jonathan Boote.
Trials, 2015 Dec 25; 16. PMID: 26700741    Free PMC article.
Dose-finding with two agents in Phase I oncology trials.
Peter F Thall, Randall E Millikan, Peter Mueller, Sang-Joon Lee.
Biometrics, 2003 Nov 07; 59(3). PMID: 14601749
Adaptive clinical trials: a partial remedy for the therapeutic misconception?
William J Meurer, Roger J Lewis, Donald A Berry.
JAMA, 2012 Jun 14; 307(22). PMID: 22692168
Group sequential enrichment design incorporating subgroup selection.
Baldur P Magnusson, Bruce W Turnbull.
Stat Med, 2013 Jan 15; 32(16). PMID: 23315698
Internal pilot studies II: comparison of various procedures.
D M Zucker, J T Wittes, O Schabenberger, E Brittain.
Stat Med, 1999 Dec 28; 18(24). PMID: 10611621
Minimization: a new method of assigning patients to treatment and control groups.
D R Taves.
Clin Pharmacol Ther, 1974 May 01; 15(5). PMID: 4597226
Highly Cited.
Using the continual reassessment method: lessons learned from an EORTC phase I dose finding study.
Xavier Paoletti, Benoît Baron, +4 authors, Richard Sylvester.
Eur J Cancer, 2006 Jun 03; 42(10). PMID: 16740385
Confirmatory seamless phase II/III clinical trials with hypotheses selection at interim: general concepts.
Frank Bretz, Heinz Schmidli, +2 authors, Willi Maurer.
Biom J, 2006 Sep 16; 48(4). PMID: 16972714
Individualized patient dosing in phase I clinical trials: the role of escalation with overdose control in PNU-214936.
Jonathan D Cheng, James S Babb, +9 authors, André Rogatko.
J Clin Oncol, 2004 Feb 18; 22(4). PMID: 14966084
An adaptive population enrichment phase III trial of TRC105 and pazopanib versus pazopanib alone in patients with advanced angiosarcoma (TAPPAS trial).
C R Mehta, L Liu, C Theuer.
Ann Oncol, 2018 Oct 26; 30(1). PMID: 30357394    Free PMC article.
Two-sample continual reassessment method.
J O'Quigley, L Z Shen, A Gamst.
J Biopharm Stat, 1999 Mar 26; 9(1). PMID: 10091908
CrossTORC and WNTegration in Disease: Focus on Lymphangioleiomyomatosis.
Jilly Frances Evans, Kseniya Obraztsova, Susan M Lin, Vera P Krymskaya.
Int J Mol Sci, 2021 Mar 07; 22(5). PMID: 33668092    Free PMC article.