Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Medicine
Published in: BMC Medicine 1/2018

Open Access 01-12-2018 | Correspondence

Adaptive designs in clinical trials: why use them, and how to run and report them

Authors: Philip Pallmann, Alun W. Bedding, Babak Choodari-Oskooei, Munyaradzi Dimairo, Laura Flight, Lisa V. Hampson, Jane Holmes, Adrian P. Mander, Lang’o Odondi, Matthew R. Sydes, Sofía S. Villar, James M. S. Wason, Christopher J. Weir, Graham M. Wheeler, Christina Yap, Thomas Jaki

Published in: BMC Medicine | Issue 1/2018

Login to get access

Abstract

Adaptive designs can make clinical trials more flexible by utilising results accumulating in the trial to modify the trial’s course in accordance with pre-specified rules. Trials with an adaptive design are often more efficient, informative and ethical than trials with a traditional fixed design since they often make better use of resources such as time and money, and might require fewer participants. Adaptive designs can be applied across all phases of clinical research, from early-phase dose escalation to confirmatory trials. The pace of the uptake of adaptive designs in clinical research, however, has remained well behind that of the statistical literature introducing new methods and highlighting their potential advantages. We speculate that one factor contributing to this is that the full range of adaptations available to trial designs, as well as their goals, advantages and limitations, remains unfamiliar to many parts of the clinical community. Additionally, the term adaptive design has been misleadingly used as an all-encompassing label to refer to certain methods that could be deemed controversial or that have been inadequately implemented.
We believe that even if the planning and analysis of a trial is undertaken by an expert statistician, it is essential that the investigators understand the implications of using an adaptive design, for example, what the practical challenges are, what can (and cannot) be inferred from the results of such a trial, and how to report and communicate the results. This tutorial paper provides guidance on key aspects of adaptive designs that are relevant to clinical triallists. We explain the basic rationale behind adaptive designs, clarify ambiguous terminology and summarise the utility and pitfalls of adaptive designs. We discuss practical aspects around funding, ethical approval, treatment supply and communication with stakeholders and trial participants. Our focus, however, is on the interpretation and reporting of results from adaptive design trials, which we consider vital for anyone involved in medical research. We emphasise the general principles of transparency and reproducibility and suggest how best to put them into practice.
Literature
1.
Friedman FL, Furberg CD, DeMets DL. Fundamentals of clinical trials, 4th ed. New York: Springer; 2010.CrossRef
2.
Shih WJ. Plan to be flexible: a commentary on adaptive designs. Biometrical J. 2006; 48:656–9.CrossRef
3.
4.
Campbell G. Similarities and differences of Bayesian designs and adaptive designs for medical devices: a regulatory view. Stat Biopharm Res. 2013; 5:356–68.CrossRef
5.
Chow SC, Chang M. Adaptive design methods in clinical trials, 2nd ed. Boca Raton: Chapman & Hall/CRC; 2012.
6.
Morgan CC. Sample size re-estimation in group-sequential response-adaptive clinical trials. Stat Med. 2003; 22:3843–57.PubMedCrossRef
7.
Parmar MKB, Barthel FMS, Sydes M, Langley R, Kaplan R, Eisenhauer E, et al.Speeding up the evaluation of new agents in cancer. J Natl Cancer Inst. 2008; 100:1204–14.PubMedPubMedCentralCrossRef
8.
Zohar S, Chevret S. Recent developments in adaptive designs for phase I/II dose-finding studies. J Biopharm Stat. 2007; 17:1071–83.PubMedCrossRef
9.
Sverdlov O, Wong WK. Novel statistical designs for phase I/II and phase II clinical trials with dose-finding objectives. Ther Innov Regul Sci. 2014; 48:601–12.CrossRef
10.
Maca J, Bhattacharya S, Dragalin V, Gallo P, Krams M. Adaptive seamless phase II/III designs—background, operational aspects, and examples. Drug Inf J. 2006; 40:463–73.CrossRef
11.
12.
Chow SC, Chang M, Pong A. Statistical consideration of adaptive methods in clinical development. J Biopharm Stat. 2005; 15:575–91.PubMedCrossRef
13.
Fleming TR, Sharples K, McCall J, Moore A, Rodgers A, Stewart R. Maintaining confidentiality of interim data to enhance trial integrity and credibility. Clin Trials. 2008; 5:157–67.PubMedPubMedCentralCrossRef
14.
Bauer P, Koenig F, Brannath W, Posch M. Selection and bias—two hostile brothers. Stat Med. 2010; 29:1–13.PubMed
15.
Posch M, Maurer W, Bretz F. Type I error rate control in adaptive designs for confirmatory clinical trials with treatment selection at interim. Pharm Stat. 2011; 10:96–104.PubMedCrossRef
16.
Graf AC, Bauer P. Maximum inflation of the type 1 error rate when sample size and allocation rate are adapted in a pre-planned interim look. Stat Med. 2011; 30:1637–47.PubMedPubMedCentralCrossRef
17.
Graf AC, Bauer P, Glimm E, Koenig F. Maximum type 1 error rate inflation in multiarmed clinical trials with adaptive interim sample size modifications. Biometrical J. 2014; 56:614–30.CrossRef
18.
Magirr D, Jaki T, Posch M, Klinglmueller F. Simultaneous confidence intervals that are compatible with closed testing in adaptive designs. Biometrika. 2013; 100:985–96.PubMedPubMedCentralCrossRef
19.
Kimani PK, Todd S, Stallard N. A comparison of methods for constructing confidence intervals after phase II/III clinical trials. Biometrical J. 2014; 56:107–28.CrossRef
20.
Lorch U, Berelowitz K, Ozen C, Naseem A, Akuffo E, Taubel J. The practical application of adaptive study design in early phase clinical trials: a retrospective analysis of time savings. Eur J Clin Pharmacol. 2012; 68:543–51.PubMedCrossRef
21.
Bauer P, Bretz F, Dragalin V, König F, Wassmer G. Twenty-five years of confirmatory adaptive designs: opportunities and pitfalls. Stat Med. 2016; 35:325–47.PubMedCrossRef
22.
23.
Chevret S. Bayesian adaptive clinical trials: a dream for statisticians only?Stat Med. 2012; 31:1002–13.PubMedCrossRef
24.
Jaki T. Uptake of novel statistical methods for early-phase clinical studies in the UK public sector. Clin Trials. 2013; 10:344–6.PubMedCrossRef
25.
Morgan CC, Huyck S, Jenkins M, Chen L, Bedding A, Coffey CS, et al.Adaptive design: results of 2012 survey on perception and use. Ther Innov Regul Sci. 2014; 48:473–81.CrossRef
26.
Dimairo M, Boote J, Julious SA, Nicholl JP, Todd S. Missing steps in a staircase: a qualitative study of the perspectives of key stakeholders on the use of adaptive designs in confirmatory trials. Trials. 2015; 16:430.PubMedPubMedCentralCrossRef
27.
Dimairo M, Julious SA, Todd S, Nicholl JP, Boote J. Cross-sector surveys assessing perceptions of key stakeholders towards barriers, concerns and facilitators to the appropriate use of adaptive designs in confirmatory trials. Trials. 2015; 16:585.PubMedPubMedCentralCrossRef
28.
Hatfield I, Allison A, Flight L, Julious SA, Dimairo M. Adaptive designs undertaken in clinical research: a review of registered clinical trials. Trials. 2016; 17:150.PubMedPubMedCentralCrossRef
29.
Meurer WJ, Legocki L, Mawocha S, Frederiksen SM, Guetterman TC, Barsan W, et al.Attitudes and opinions regarding confirmatory adaptive clinical trials: a mixed methods analysis from the Adaptive Designs Accelerating Promising Trials into Treatments (ADAPT-IT) project. Trials. 2016; 17:373.PubMedPubMedCentralCrossRef
30.
Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, et al.Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. J Am Med Assoc. 2004; 291:309–16.CrossRef
31.
Pushpakom SP, Taylor C, Kolamunnage-Dona R, Spowart C, Vora J, García-Fiñana M, et al. 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. BMJ Open. 2015; 5:e009566.PubMedPubMedCentralCrossRef
32.
Magirr D, Jaki T, Whitehead J. A generalized Dunnett test for multi-arm multi-stage clinical studies with treatment selection. Biometrika. 2012; 99:494–501.CrossRef
33.
Giles FJ, Kantarjian HM, Cortes JE, Garcia-Manero G, Verstovsek S, Faderl S, et al.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. J Clin Oncol. 2003; 21:1722–7.PubMedCrossRef
34.
Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are promising: a practical guide with examples. Stat Med. 2011; 30:3267–84.PubMedCrossRef
35.
Jennison C, Turnbull BW. Adaptive sample size modification in clinical trials: start small then ask for more?Stat Med. 2015; 34:3793–810.PubMedCrossRef
36.
Bowden J, Brannath W, Glimm E. Empirical Bayes estimation of the selected treatment mean for two-stage drop-the-loser trials: a meta-analytic approach. Stat Med. 2014; 33:388–400.PubMedPubMedCentralCrossRef
37.
Mason AJ, Gonzalez-Maffe J, Quinn K, Doyle N, Legg K, Norsworthy P, et al.Developing a Bayesian adaptive design for a phase I clinical trial: a case study for a novel HIV treatment. Stat Med. 2017; 36:754–71.PubMedCrossRef
38.
39.
40.
41.
42.
43.
Gaydos B, Koch A, Miller F, Posch M, Vandemeulebroecke M, Wang SJ. Perspective on adaptive designs: 4 years European Medicines Agency reflection paper, 1 year draft US FDA guidance—where are we now?Clin Investig. 2012; 2:235–40.CrossRef
44.
Elsäßer A, Regnstrom J, Vetter T, Koenig F, Hemmings RJ, Greco M, et al.Adaptive clinical trial designs for European marketing authorization: a survey of scientific advice letters from the European Medicines Agency. Trials. 2014; 15:383.PubMedPubMedCentralCrossRef
45.
DeMets DL, Fleming TR. The independent statistician for data monitoring committees. Stat Med. 2004; 23:1513–17.PubMedCrossRef
46.
47.
Grant AM, Altman DG, Babiker AG, Campbell MK, Clemens F, Darbyshire JH, et al.A proposed charter for clinical trial data monitoring committees: helping them to do their job well. Lancet. 2005; 365:711–22.CrossRef
48.
Antonijevic Z, Gallo P, Chuang-Stein C, Dragalin V, Loewy J, Menon S, et al.Views on emerging issues pertaining to data monitoring committees for adaptive trials. Ther Innov Regul Sci. 2013; 47:495–502.CrossRef
49.
Sanchez-Kam M, Gallo P, Loewy J, Menon S, Antonijevic Z, Christensen J, et al.A practical guide to data monitoring committees in adaptive trials. Ther Innov Regul Sci. 2014; 48:316–26.CrossRef
50.
DeMets DL, Ellenberg SS. Data monitoring committees—expect the unexpected. N Engl J Med. 2016; 375:1365–71.PubMedCrossRef
51.
Calis KA, Archdeacon P, Bain R, DeMets D, Donohue M, Elzarrad MK, et al.Recommendations for data monitoring committees from the Clinical Trials Transformation Initiative. Clin Trials. 2017; 14:342–8.PubMedPubMedCentralCrossRef
52.
Conroy EJ, Harman NL, Lane JA, Lewis SC, Murray G, Norrie J, et al.Trial steering committees in randomised controlled trials: a survey of registered clinical trials units to establish current practice and experiences. Clin Trials. 2015; 12:664–76.PubMedCrossRef
53.
Harman NL, Conroy EJ, Lewis SC, Murray G, Norrie J, Sydes MR, et al.Exploring the role and function of trial steering committees: results of an expert panel meeting. Trials. 2015; 16:597.PubMedPubMedCentralCrossRef
54.
Daykin A, Selman LE, Cramer H, McCann S, Shorter GW, Sydes MR, et al.What are the roles and valued attributes of a trial steering committee? Ethnographic study of eight clinical trials facing challenges. Trials. 2016; 17:307.PubMedPubMedCentralCrossRef
55.
He W, Gallo P, Miller E, Jemiai Y, Maca J, Koury K, et al.Addressing challenges and opportunities of ‘less well-understood’ adaptive designs. Ther Innov Regul Sci. 2017; 51:60–8.CrossRef
56.
Zhu L, Ni L, Yao B. Group sequential methods and software applications. Am Stat. 2011; 65:127–35.CrossRef
57.
Tymofyeyev Y. A review of available software and capabilities for adaptive designs In: He W, Pinheiro J, Kuznetsova OM, editors. Practical considerations for adaptive trial design and implementation. New York: Springer: 2014. p. 139–55.
58.
Gallo P, Chuang-Stein C, Dragalin V, Gaydos B, Krams M, Pinheiro J. Adaptive designs in clinical drug development—an executive summary of the PhRMA Working Group. J Biopharm Stat. 2006; 16:275–83.PubMedCrossRef
59.
Quinlan J, Krams M. Implementing adaptive designs: logistical and operational considerations. Drug Inf J. 2006; 40:437–44.CrossRef
60.
61.
Bretz F, Koenig F, Brannath W, Glimm E, Posch M. Adaptive designs for confirmatory clinical trials. Stat Med. 2009; 28:1181–217.PubMedCrossRef
62.
Quinlan J, Gaydos B, Maca J, Krams M. Barriers and opportunities for implementation of adaptive designs in pharmaceutical product development. Clin Trials. 2010; 7:167–73.PubMedCrossRef
63.
He W, Kuznetsova OM, Harmer M, Leahy C, Anderson K, Dossin N, et al.Practical considerations and strategies for executing adaptive clinical trials. Ther Innov Regul Sci. 2012; 46:160–74.
64.
He W, Pinheiro J, Kuznetsova OM. Practical considerations for adaptive trial design and implementation. New York: Springer; 2014.
65.
Curtin F, Heritier S. The role of adaptive trial designs in drug development. Expert Rev Clin Pharmacol. 2017; 10:727–36.PubMedCrossRef
66.
Petroni GR, Wages NA, Paux G, Dubois F. Implementation of adaptive methods in early-phase clinical trials. Stat Med. 2017; 36:215–24.PubMedCrossRef
67.
Sydes MR, Parmar MKB, James ND, Clarke NW, Dearnaley DP, Mason MD, et al.Issues in applying multi-arm multi-stage methodology to a clinical trial in prostate cancer: the MRC STAMPEDE trial. Trials. 2009; 10:39.PubMedPubMedCentralCrossRef
68.
Spencer K, Colvin K, Braunecker B, Brackman M, Ripley J, Hines P, et al.Operational challenges and solutions with implementation of an adaptive seamless phase 2/3 study. J Diabetes Sci Technol. 2012; 6:1296–304.PubMedPubMedCentralCrossRef
69.
Miller E, Gallo P, He W, Kammerman LA, Koury K, Maca J, et al.DIA’s Adaptive Design Scientific Working Group (ADSWG): best practices case studies for ‘less well-understood’ adaptive designs. Ther Innov Regul Sci. 2017; 51:77–88.CrossRef
70.
Schäfer H, Timmesfeld N, Müller HH. An overview of statistical approaches for adaptive designs and design modifications. Biom J. 2006; 48:507–20.PubMedCrossRef
71.
Wassmer G, Brannath W. Group sequential and confirmatory adaptive designs in clinical trials. Heidelberg: Springer; 2016.CrossRef
72.
Ellenberg SS, DeMets DL, Fleming TR. Bias and trials stopped early for benefit. J Am Med Assoc. 2010; 304:158.CrossRef
73.
Jennison C, Turnbull BW. Analysis following a sequential test. In: Group sequential methods with applications to clinical trials. Boca Raton: Chapman & Hall/CRC: 2000. p. 171–87.
74.
Emerson SS, Fleming TR. Parameter estimation following group sequential hypothesis testing. Biometrika. 1990; 77:875–92.CrossRef
75.
Liu A, Hall WJ. Unbiased estimation following a group sequential test. Biometrika. 1999; 86:71–8.CrossRef
76.
Bowden J, Glimm E. Unbiased estimation of selected treatment means in two-stage trials. Biometrical J. 2008; 50:515–27.CrossRef
77.
Bowden J, Glimm E. Conditionally unbiased and near unbiased estimation of the selected treatment mean for multistage drop-the-losers trials. Biometrical J. 2014; 56:332–49.CrossRef
78.
Whitehead J. On the bias of maximum likelihood estimation following a sequential test. Biometrika. 1986; 73:573–81.CrossRef
79.
Jovic G, Whitehead J. An exact method for analysis following a two-stage phase II cancer clinical trial. Stat Med. 2010; 29:3118–25.PubMedCrossRef
80.
Carreras M, Brannath W. Shrinkage estimation in two-stage adaptive designs with midtrial treatment selection. Stat Med. 2013; 32:1677–90.PubMedCrossRef
81.
Brueckner M, Titman A, Jaki T. Estimation in multi-arm two-stage trials with treatment selection and time-to-event endpoint. Stat Med. 2017; 36:3137–53.CrossRef
82.
83.
Choodari-Oskooei B, Parmar MK, Royston P, Bowden J. Impact of lack-of-benefit stopping rules on treatment effect estimates of two-arm multi-stage (TAMS) trials with time to event outcome. Trials. 2013; 14:23.PubMedPubMedCentralCrossRef
84.
Efron B, Tibshirani RJ. An introduction to the bootstrap. Boca Raton: Chapman & Hall/CRC; 1993.CrossRef
85.
Gao P, Liu L, Mehta C. Exact inference for adaptive group sequential designs. Stat Med. 2013; 32:3991–4005.PubMedCrossRef
86.
87.
Jennison C, Turnbull BW. Interim analyses: the repeated confidence interval approach. J R Stat Soc Series B Stat Methodol. 1989; 51:305–61.
88.
Proschan MA, Hunsberger SA. Designed extension of studies based on conditional power. Biometrics. 1995; 51:1315–24.PubMedCrossRef
89.
Kieser M, Friede T. Simple procedures for blinded sample size adjustment that do not affect the type I error rate. Stat Med. 2003; 22:3571–81.PubMedCrossRef
90.
żebrowska M, Posch M, Magirr D. Maximum type I error rate inflation from sample size reassessment when investigators are blind to treatment labels. Stat Med. 2016; 35:1972–84.PubMedCrossRef
91.
Bratton DJ, Parmar MKB, Phillips PPJ, Choodari-Oskooei B. Type I error rates of multi-arm multi-stage clinical trials: strong control and impact of intermediate outcomes. Trials. 2016; 17:309.PubMedPubMedCentralCrossRef
92.
Glimm E, Maurer W, Bretz F. Hierarchical testing of multiple endpoints in group-sequential trials. Stat Med. 2010; 29:219–28.PubMed
93.
Ye Y, Li A, Liu L, Yao B. A group sequential Holm procedure with multiple primary endpoints. Stat Med. 2013; 32:1112–24.PubMedCrossRef
94.
Maurer W, Branson M, Posch M. Adaptive designs and confirmatory hypothesis testing In: Dmitrienko A, Tamhane AC, Bretz F, editors. Multiple testing problems in pharmaceutical statistics. Boca Raton: Chapman & Hall/CRC: 2010.
95.
Posch M, Koenig F, Branson M, Brannath W, Dunger-Baldauf C, Bauer P. Testing and estimation in flexible group sequential designs with adaptive treatment selection. Stat Med. 2005; 24:3697–714.PubMedCrossRef
96.
97.
Wang SJ, Hung HMJ, O’Neill R. Regulatory perspectives on multiplicity in adaptive design clinical trials throughout a drug development program. J Biopharm Stat. 2011; 21:846–59.PubMedCrossRef
98.
99.
100.
Berry SM, Carlin BP, Lee JJ, Müller P. Bayesian adaptive methods for clinical trials. Boca Raton: Chapman & Hall/CRC; 2010.CrossRef
101.
Chevret S. Statistical methods for dose-finding experiments. Chichester: Wiley; 2006.CrossRef
102.
Cheung YK. Dose finding by the continual reassessment method. Boca Raton: Chapman & Hall/CRC; 2011.CrossRef
103.
104.
Jansen JO, Pallmann P, MacLennan G, Campbell MK. Bayesian clinical trial designs: another option for trauma trials?J Trauma Acute Care Surg. 2017; 83:736–41.PubMedCrossRef
105.
Kimani PK, Glimm E, Maurer W, Hutton JL, Stallard N. Practical guidelines for adaptive seamless phase II/III clinical trials that use Bayesian methods. Stat Med. 2012; 31:2068–85.PubMedCrossRef
106.
Liu S, Lee JJ. An overview of the design and conduct of the BATTLE trials. Chin Clin Oncol. 2015; 4:33.PubMed
107.
Cheng Y, Shen Y. Bayesian adaptive designs for clinical trials. Biometrika. 2005; 92:633–46.CrossRef
108.
Lewis RJ, Lipsky AM, Berry DA. Bayesian decision-theoretic group sequential clinical trial design based on a quadratic loss function: a frequentist evaluation. Clin Trials. 2007; 4:5–14.PubMedCrossRef
109.
Ventz S, Trippa L. Bayesian designs and the control of frequentist characteristics: a practical solution. Biometrics. 2015; 71:218–26.PubMedCrossRef
110.
Emerson SS, Kittelson JM, Gillen DL. Frequentist evaluation of group sequential clinical trial designs. Stat Med. 2007; 26:5047–80.PubMedCrossRef
111.
Emerson SS, Kittelson JM, Gillen DL. Bayesian evaluation of group sequential clinical trial designs. Stat Med. 2007; 26:1431–49.PubMedCrossRef
112.
Gsponer T, Gerber F, Bornkamp B, Ohlssen D, Vandemeulebroecke M, Schmidli H. A practical guide to Bayesian group sequential designs. Pharm Stat. 2014; 13:71–80.PubMedCrossRef
113.
Stallard N, Whitehead J, Cleall S. Decision-making in a phase II clinical trial: a new approach combining Bayesian and frequentist concepts. Pharm Stat. 2005; 4:119–28.CrossRef
114.
Dong G, Shih WJ, Moore D, Quan H, Marcella S. A Bayesian-frequentist two-stage single-arm phase II clinical trial design. Stat Med. 2012; 31:2055–67.PubMedCrossRef
115.
Hartley AM. Adaptive blinded sample size adjustment for comparing two normal means—a mostly Bayesian approach. Pharm Stat. 2012; 11:230–40.PubMedCrossRef
116.
Gallo P. Confidentiality and trial integrity issues for adaptive designs. Drug Inf J. 2006; 40:445–50.CrossRef
117.
118.
Chow SC, Corey R, Lin M. On the independence of data monitoring committee in adaptive design clinical trials. J Biopharm Stat. 2012; 22:853–67.PubMedCrossRef
119.
Friede T, Henderson R. Exploring changes in treatment effects across design stages in adaptive trials. Pharm Stat. 2009; 8:62–72.PubMedCrossRef
120.
Gallo P, Chuang-Stein C. What should be the role of homogeneity testing in adaptive trials?Pharm Stat. 2009; 8:1–4.PubMedCrossRef
121.
Gonnermann A, Framke T, Großhennig A, Koch A. No solution yet for combining two independent studies in the presence of heterogeneity. Stat Med. 2015; 34:2476–80.PubMedPubMedCentralCrossRef
122.
Parker RA. Testing for qualitative interactions between stages in an adaptive study. Stat Med. 2010; 29:210–18.PubMedCrossRef
123.
Wang SJ, Brannath W, Brückner M, Hung HMJ, Koch A. Unblinded adaptive statistical information design based on clinical endpoint or biomarker. Stat Biopharm Res. 2013; 5:293–310.CrossRef
124.
125.
126.
Bauer P, Einfalt J. Application of adaptive designs—a review. Biometrical J. 2006; 48:493–506.CrossRef
127.
128.
Lorch U, O’Kane M, Taubel J. Three steps to writing adaptive study protocols in the early phase clinical development of new medicines. BMC Med Res Methodol. 2014; 14:84.PubMedPubMedCentralCrossRef
129.
Stevely A, Dimairo M, Todd S, Julious SA, Nicholl J, Hind D, et al.An investigation of the shortcomings of the CONSORT 2010 statement for the reporting of group sequential randomised controlled trials: a methodological systematic review. PLoS One. 2015; 10:e0141104.PubMedPubMedCentralCrossRef
130.
131.
Nie L, Rubin EH, Mehrotra N, Pinheiro J, Fernandes LL, Roy A, et al.Rendering the 3 + 3 design to rest: more efficient approaches to oncology dose-finding trials in the era of targeted therapy. Clin Cancer Res. 2016; 22:2623–9.PubMedCrossRef
132.
133.
Cuffe RL, Lawrence D, Stone A, Vandemeulebroecke M. When is a seamless study desirable? Case studies from different pharmaceutical sponsors. Pharm Stat. 2014; 13:229–37.PubMedCrossRef
134.
Jaki T. Multi-arm clinical trials with treatment selection: what can be gained and at what price?Clin Investig. 2015; 5:393–9.CrossRef
135.
Coffey CS, Kairalla JA. Adaptive clinical trials: progress and challenges. Drugs R D. 2008; 9:229–42.PubMedCrossRef
136.
Cole M, Stocken D, Yap C. A pragmatic approach to the design and calibration of a Bayesian CRM dose finding trial. Trials. 2015;16 Suppl2:P210.
137.
Yap C, Billingham LJ, Cheung YK, Craddock C, O’Quigley J. Dose transition pathways: the missing link between complex dose-finding designs and simple decision making. Clin Cancer Res. 2017; 23:7440–7.PubMedCrossRef
138.
Yap C, Craddock C, Collins G, Khan J, Siddique S, Billingham L. Implementation of adaptive dose-finding designs in two early phase haematological trials: clinical, operational, and methodological challenges. Trials. 2013;14 Suppl 1:O75.
139.
Fisher AJ, Yonan N, Mascaro J, Marczin N, Tsui S, Simon A, et al. A study of donor ex-vivo lung perfusion in UK lung transplantation (DEVELOP-UK). J Heart Lung Transplant. 2016;35 Suppl 4:S80.
140.
Sydes MR, Parmar MKB, Mason MD, Clarke NW, Amos C, Anderson J, et al.Flexible trial design in practice—stopping arms for lack-of-benefit and adding research arms mid-trial in STAMPEDE: a multi-arm multi-stage randomized controlled trial. Trials. 2012; 13:168.PubMedPubMedCentralCrossRef
141.
Gaunt P, Mehanna H, Yap C. The design of a multi-arm multi-stage (MAMS) phase III randomised controlled trial comparing alternative regimens for escalating (COMPARE) treatment of intermediate and high-risk oropharyngeal cancer with reflections on the complications of introducing a new experimental arm. Trials. 2015;16 Suppl 2:O16.
142.
Gerety EL, Lawrence EM, Wason J, Yan H, Hilborne S, Buscombe J, et al.Prospective study evaluating the relative sensitivity of 18F-NaF PET/CT for detecting skeletal metastases from renal cell carcinoma in comparison to multidetector CT and 99mTc-MDP bone scintigraphy, using an adaptive trial design. Ann Oncol. 2015; 26:2113–8.PubMedPubMedCentralCrossRef
143.
Ho TW, Pearlman E, Lewis D, Hämäläinen M, Connor K, Michelson D, et al.Efficacy and tolerability of rizatriptan in pediatric migraineurs: results from a randomized, double-blind, placebo-controlled trial using a novel adaptive enrichment design. Cephalalgia. 2012; 32:750–65.PubMedCrossRef
144.
Wang SJ, Hung HMJ. Adaptive enrichment with subpopulation selection at interim: methodologies, applications and design considerations. Contemp Clin Trials. 2013; 36:673–81.PubMedCrossRef
145.
Kaplan R, Maughan T, Crook A, Fisher D, Wilson R, Brown L, et al.Evaluating many treatments and biomarkers in oncology: a new design. J Clin Oncol. 2013; 31:4562–8.PubMedPubMedCentralCrossRef
146.
Waldron-Lynch F, Kareclas P, Irons K, Walker NM, Mander A, Wicker LS, et al. Rationale and study design of the adaptive study of IL-2 dose on regulatory T cells in type 1 diabetes (DILT1D): a non-randomised, open label, adaptive dose finding trial. BMJ Open. 2014; 4:e005559.PubMedPubMedCentralCrossRef
147.
Biankin AV, Piantadosi S, Hollingsworth SJ. Patient-centric trials for therapeutic development in precision oncology. Nature. 2015; 526:361–70.PubMedCrossRef
148.
Antoniou M, Jorgensen AL, Kolamunnage-Dona R. Biomarker-guided adaptive trial designs in phase II and phase III: a methodological review. PLoS One. 2016; 11:e0149803.PubMedPubMedCentralCrossRef
149.
Warner P, Weir CJ, Hansen CH, Douglas A, Madhra M, Hillier SG, et al. Low-dose dexamethasone as a treatment for women with heavy menstrual bleeding: protocol for response-adaptive randomised placebo-controlled dose-finding parallel group trial (DexFEM). BMJ Open. 2015; 5:e006837.PubMedPubMedCentralCrossRef
150.
Fardipour P, Littman G, Burns DD, Dragalin V, Padmanabhan SK, Parke T, et al.Planning and executing response-adaptive learn-phase clinical trials: 2. case studies. Drug Inf J. 2009; 43:725–34.CrossRef
151.
Grieve AP. Response-adaptive clinical trials: case studies in the medical literature. Pharm Stat. 2017; 16:64–86.PubMedCrossRef
152.
Whitehead J, Thygesen H, Jaki T, Davies S, Halford S, Turner H, et al.A novel phase I/IIa design for early phase oncology studies and its application in the evaluation of MK-0752 in pancreatic cancer. Stat Med. 2012; 31:1931–43.PubMedCrossRef
153.
Khan J, Yap C, Clark R, Fenwick N, Marin D. Practical implementation of an adaptive phase I/II design in chronic myeloid leukaemia: evaluating both efficacy and toxicity using the EffTox design. Trials. 2013;14 Suppl 1:P20.
154.
Brock K, Billingham L, Copland M, Siddique S, Sirovica M, Yap C. Implementing the EffTox dose-finding design in the Matchpoint trial. BMC Med Res Methodol. 2017; 17:112.PubMedPubMedCentralCrossRef
Metadata
Title
Adaptive designs in clinical trials: why use them, and how to run and report them
Authors
Philip Pallmann
Alun W. Bedding
Babak Choodari-Oskooei
Munyaradzi Dimairo
Laura Flight
Lisa V. Hampson
Jane Holmes
Adrian P. Mander
Lang’o Odondi
Matthew R. Sydes
Sofía S. Villar
James M. S. Wason
Christopher J. Weir
Graham M. Wheeler
Christina Yap
Thomas Jaki
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2018
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-018-1017-7

Other articles of this Issue 1/2018

BMC Medicine 1/2018 Go to the issue

Correction

Correction to: Outcomes of notifications to health practitioner boards: a retrospective cohort study

Research article

Human antibodies activate complement against Plasmodium falciparum sporozoites, and are associated with protection against malaria in children

Research article

Practice variation in the use of tests in UK primary care: a retrospective analysis of 16 million tests performed over 3.3 million patient years in 2015/16

Research article

Differences in the health transition patterns of migrants and non-migrants aged 50 and older in southern and western Europe (2004–2015)

Research article

Optimising first- and second-line treatment strategies for untreated major depressive disorder — the SUN☺D study: a pragmatic, multi-centre, assessor-blinded randomised controlled trial

Research article

Geographic variation in sexual behavior can explain geospatial heterogeneity in the severity of the HIV epidemic in Malawi