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How to Use and Interpret the Results of a Platform TrialUsers’ Guide to the Medical Literature

Educational Objective
To understand the design and interpretation of platform trials.
1 Credit CME
Abstract

Platform trials are a type of randomized clinical trial that allow simultaneous comparison of multiple intervention groups against a single control group that serves as a common control based on a prespecified interim analysis plan. The platform trial design enables introduction of new interventions after the trial is initiated to evaluate multiple interventions in an ongoing manner using a single overarching protocol called a master (or core) protocol. When multiple treatment candidates are available, rapid scientific therapeutic discoveries may be made. Platform trials have important potential advantages in creating an efficient trial infrastructure that can help address critical clinical questions as the evidence evolves. Platform trials have recently been used in investigations of evolving therapies for patients with COVID-19. The purpose of this Users’ Guide to the Medical Literature is to describe fundamental concepts of platform trials and master protocols and review issues in the conduct and interpretation of these studies. This Users’ Guide is intended to help clinicians and readers understand articles reporting on interventions evaluated using platform trial designs.

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Article Information

Corresponding Author: Edward J. Mills, PhD, 802-777 W Broadway, Vancouver, BC V5Z 1J5, Canada (millsej@mcmaster.ca).

Correction: This article was corrected for a missing author affiliation on January 20, 2022.

Accepted for Publication: November 30, 2021.

Author Contributions: Dr Mills had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Drafting of the manuscript: Park, Mills.

Critical revision of the manuscript for important intellectual content: All authors.

Administrative, technical, or material support: Park.

Supervision: Murthy, Mills.

Conflict of Interest Disclosures: Dr Park reported being a former employee of Cytel and receiving grants from the Bill and Melinda Gates Foundation for the TOGETHER trial. Dr Detry reported being an employee of Berry Consultants LLC, a statistical consulting company that collaborates on numerous platform trials (this work was independent of any of the consulting projects and received no funding). Dr Murthy reported being an investigator for the REMAP-CAP trial, receiving grants from the Canadian Institutes of Health Research, and receiving salary support from the Health Research Foundation and Innovative Medicines Canada. Dr Mills reported being an employee of Cytel and being co–principal investigator of the TOGETHER trial. No other disclosures were reported.

References
1.
Angus  DC , Derde  L , Al-Beidh  F ,  et al; Writing Committee for the REMAP-CAP Investigators.  Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial.   JAMA. 2020;324(13):1317-1329. doi:10.1001/jama.2020.17022PubMedGoogle Scholar
2.
Angus  DC , Berry  S , Lewis  RJ ,  et al.  The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-Acquired Pneumonia) study: rationale and design.   Ann Am Thorac Soc. 2020;17(7):879-891. doi:10.1513/AnnalsATS.202003-192SDPubMedGoogle ScholarCrossref
3.
Woodcock  J , LaVange  LM .  Master protocols to study multiple therapies, multiple diseases, or both.   N Engl J Med. 2017;377(1):62-70. doi:10.1056/NEJMra1510062PubMedGoogle ScholarCrossref
4.
Berry  SM , Connor  JT , Lewis  RJ .  The platform trial: an efficient strategy for evaluating multiple treatments.   JAMA. 2015;313(16):1619-1620. doi:10.1001/jama.2015.2316PubMedGoogle ScholarCrossref
5.
Angus  DC , Alexander  BM , Berry  S ,  et al; Adaptive Platform Trials Coalition.  Adaptive platform trials: definition, design, conduct and reporting considerations.   Nat Rev Drug Discov. 2019;18(10):797-807. doi:10.1038/s41573-019-0034-3PubMedGoogle Scholar
6.
Park  JJH , Harari  O , Dron  L , Lester  RT , Thorlund  K , Mills  EJ .  An overview of platform trials with a checklist for clinical readers.   J Clin Epidemiol. 2020;125:1-8. doi:10.1016/j.jclinepi.2020.04.025PubMedGoogle ScholarCrossref
7.
Park  JJH , Siden  E , Zoratti  MJ ,  et al.  Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols.   Trials. 2019;20(1):572. doi:10.1186/s13063-019-3664-1PubMedGoogle ScholarCrossref
8.
Sterne  JAC , Murthy  S , Diaz  JV ,  et al; WHO REACT Working Group.  Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis.   JAMA. 2020;324(13):1330-1341. doi:10.1001/jama.2020.17023PubMedGoogle Scholar
9.
Dean  NE , Gsell  PS , Brookmeyer  R ,  et al.  Creating a framework for conducting randomized clinical trials during disease outbreaks.   N Engl J Med. 2020;382(14):1366-1369. doi:10.1056/NEJMsb1905390PubMedGoogle ScholarCrossref
10.
Detry  MA , Lewis  RJ , Broglio  KR , Connor  JT , Berry  SM , Berry  DA . Standards for the Design, Conduct, and Evaluation of Adaptive Randomized Clinical Trials. Patient-Centered Outcomes Research Institute guidance report. Revised March 15, 2012. Accessed December 2, 2021. https://www.pcori.org/assets/Standards-for-the-Design-Conduct-and-Evaluation-of-Adaptive-Randomized-Clinical-Trials.pdf
11.
Bauer  P , Bretz  F , Dragalin  V , König  F , Wassmer  G .  Twenty-five years of confirmatory adaptive designs: opportunities and pitfalls.   Stat Med. 2016;35(3):325-347. doi:10.1002/sim.6472PubMedGoogle ScholarCrossref
12.
Bhatt  DL , Mehta  C .  Adaptive designs for clinical trials.   N Engl J Med. 2016;375(1):65-74. doi:10.1056/NEJMra1510061PubMedGoogle ScholarCrossref
13.
Park  JJH , Hsu  G , Siden  EG , Thorlund  K , Mills  EJ .  An overview of precision oncology basket and umbrella trials for clinicians.   CA Cancer J Clin. 2020;70(2):125-137. doi:10.3322/caac.21600PubMedGoogle ScholarCrossref
14.
Siden  EG , Park  JJ , Zoratti  MJ ,  et al.  Reporting of master protocols towards a standardized approach: a systematic review.   Contemp Clin Trials Commun. 2019;15:100406. doi:10.1016/j.conctc.2019.100406PubMedGoogle Scholar
15.
Schiavone  F , Bathia  R , Letchemanan  K ,  et al; Past and Present Members of the STAMPEDE and FOCUS4 Trial Management Group.  This is a platform alteration: a trial management perspective on the operational aspects of adaptive and platform and umbrella protocols.   Trials. 2019;20(1):264. doi:10.1186/s13063-019-3216-8PubMedGoogle ScholarCrossref
16.
REMAP-CAP. Current protocol documents. Accessed September 27, 2021. https://www.remapcap.org/protocol-documents
17.
Sydes  MR , Parmar  MKB , Mason  MD ,  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. doi:10.1186/1745-6215-13-168PubMedGoogle ScholarCrossref
18.
Barker  AD , Sigman  CC , Kelloff  GJ , Hylton  NM , Berry  DA , Esserman  LJ .  I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy.   Clin Pharmacol Ther. 2009;86(1):97-100. doi:10.1038/clpt.2009.68PubMedGoogle ScholarCrossref
19.
Saville  BR , Berry  SM .  Efficiencies of platform clinical trials: a vision of the future.   Clin Trials. 2016;13(3):358-366. doi:10.1177/1740774515626362PubMedGoogle ScholarCrossref
20.
Parmar  MK , Carpenter  J , Sydes  MR .  More multiarm randomised trials of superiority are needed.   Lancet. 2014;384(9940):283-284. doi:10.1016/S0140-6736(14)61122-3PubMedGoogle ScholarCrossref
21.
Reis  G , Moreira Silva  EADS , Medeiros Silva  DC ,  et al; TOGETHER Investigators.  Effect of early treatment with hydroxychloroquine or lopinavir and ritonavir on risk of hospitalization among patients with COVID-19: the TOGETHER randomized clinical trial.   JAMA Netw Open. 2021;4(4):e216468. doi:10.1001/jamanetworkopen.2021.6468PubMedGoogle Scholar
22.
Saville  BR , Connor  JT , Ayers  GD , Alvarez  J .  The utility of bayesian predictive probabilities for interim monitoring of clinical trials.   Clin Trials. 2014;11(4):485-493. doi:10.1177/1740774514531352PubMedGoogle ScholarCrossref
23.
Hummel  J , Wang  S , Kirkpatrick  J .  Using simulation to optimize adaptive trial designs: applications in learning and confirmatory phase trials.   Clin Investig (Lond). 2015;5(4):401-413. doi:10.4155/cli.15.14Google ScholarCrossref
24.
Viele  K , McGlothlin  A , Broglio  K .  Interpretation of clinical trials that stopped early.   JAMA. 2016;315(15):1646-1647. doi:10.1001/jama.2016.2628PubMedGoogle ScholarCrossref
25.
Mayer  C , Perevozskaya  I , Leonov  S ,  et al.  Simulation practices for adaptive trial designs in drug and device development.   Stat Biopharm Res. 2019;11(4):325-335. doi:10.1080/19466315.2018.1560359Google ScholarCrossref
26.
Thorlund  K , Haggstrom  J , Park  JJ , Mills  EJ .  Key design considerations for adaptive clinical trials: a primer for clinicians.   BMJ. 2018;360:k698. doi:10.1136/bmj.k698PubMedGoogle Scholar
27.
Park  JJ , Thorlund  K , Mills  EJ .  Critical concepts in adaptive clinical trials.   Clin Epidemiol. 2018;10:343-351. doi:10.2147/CLEP.S156708PubMedGoogle ScholarCrossref
28.
Biswas  A , Bhattacharya  R .  Response-adaptive designs for continuous treatment responses in phase III clinical trials: a review.   Stat Methods Med Res. 2016;25(1):81-100. doi:10.1177/0962280212441424PubMedGoogle ScholarCrossref
29.
Viele  K , Broglio  K , McGlothlin  A , Saville  BR .  Comparison of methods for control allocation in multiple arm studies using response adaptive randomization.   Clin Trials. 2020;17(1):52-60. doi:10.1177/1740774519877836PubMedGoogle ScholarCrossref
30.
US Food and Drug Administration. Adaptive Designs for Clinical Trials of Drugs and Biologics Guidance for Industry. US Food and Drug Administration; 2019.
31.
Lewis  RJ , Angus  DC .  Time for clinicians to embrace their inner bayesian? reanalysis of results of a clinical trial of extracorporeal membrane oxygenation.   JAMA. 2018;320(21):2208-2210. doi:10.1001/jama.2018.16916PubMedGoogle ScholarCrossref
32.
McGlothlin  AE , Viele  K .  Bayesian hierarchical models.   JAMA. 2018;320(22):2365-2366. doi:10.1001/jama.2018.17977PubMedGoogle ScholarCrossref
33.
Quintana  M , Viele  K , Lewis  RJ .  Bayesian analysis: using prior information to interpret the results of clinical trials.   JAMA. 2017;318(16):1605-1606. doi:10.1001/jama.2017.15574PubMedGoogle ScholarCrossref
34.
Greenland  S , Senn  SJ , Rothman  KJ ,  et al.  Statistical tests, P values, confidence intervals, and power: a guide to misinterpretations.   Eur J Epidemiol. 2016;31(4):337-350. doi:10.1007/s10654-016-0149-3PubMedGoogle ScholarCrossref
35.
Committee for Proprietary Medicinal Products. ICH Topic E 10: Choice of Control Group in Clinical Trials. European Medicines Agency; 2001:30.
36.
Thorlund  K , Dron  L , Park  JJH , Mills  EJ .  Synthetic and external controls in clinical trials—a primer for researchers.   Clin Epidemiol. 2020;12:457-467. doi:10.2147/CLEP.S242097PubMedGoogle ScholarCrossref
37.
Lee  KM , Wason  J .  Including non-concurrent control patients in the analysis of platform trials: is it worth it?   BMC Med Res Methodol. 2020;20(1):165. doi:10.1186/s12874-020-01043-6PubMedGoogle ScholarCrossref
38.
Yu  LM , Bafadhel  M , Dorward  J ,  et al; PRINCIPLE Trial Collaborative Group.  Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.   Lancet. 2021;398(10303):843-855. doi:10.1016/S0140-6736(21)01744-XPubMedGoogle ScholarCrossref
39.
Berry  SM , Reese  CS , Larkey  PD .  Bridging different eras in sports.   J Am Stat Assoc. 1999;94(447):661-676. doi:10.1080/01621459.1999.10474163Google ScholarCrossref
40.
Viele  K , Berry  S , Neuenschwander  B ,  et al.  Use of historical control data for assessing treatment effects in clinical trials.   Pharm Stat. 2014;13(1):41-54. doi:10.1002/pst.1589PubMedGoogle ScholarCrossref
41.
Dron  L , Golchi  S , Hsu  G , Thorlund  K .  Minimizing control group allocation in randomized trials using dynamic borrowing of external control data—an application to second line therapy for non-small cell lung cancer.   Contemp Clin Trials Commun. 2019;16:100446. doi:10.1016/j.conctc.2019.100446PubMedGoogle Scholar
42.
He  W , Kuznetsova  OM , Harmer  M ,  et al.  Practical considerations and strategies for executing adaptive clinical trials.   Ther Innov Regul Sci. 2012;46(2):160-174. doi:10.1177/0092861512436580Google Scholar
43.
Sterne  JAC , Savović  J , Page  MJ ,  et al.  RoB 2: a revised tool for assessing risk of bias in randomised trials.   BMJ. 2019;366:l4898. doi:10.1136/bmj.l4898PubMedGoogle Scholar
44.
Dimairo  M , Pallmann  P , Wason  J ,  et al; ACE Consensus Group.  The Adaptive Designs CONSORT Extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design.   BMJ. 2020;369:m115. doi:10.1136/bmj.m115PubMedGoogle Scholar
45.
Dimairo  M , Pallmann  P , Wason  J ,  et al; ACE Consensus Group.  The Adaptive Designs CONSORT Extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design.   Trials. 2020;21(1):528. doi:10.1186/s13063-020-04334-xPubMedGoogle ScholarCrossref
46.
Orkin  AM , Gill  PJ , Ghersi  D ,  et al; CONSERVE Group.  Guidelines for reporting trial protocols and completed trials modified due to the COVID-19 pandemic and other extenuating circumstances: the CONSERVE 2021 statement.   JAMA. 2021;326(3):257-265. doi:10.1001/jama.2021.9941PubMedGoogle ScholarCrossref
47.
Guyatt  G , Rennie  D , Meade  MO , Cook  DJ . Users’ Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice. 3rd ed. McGraw-Hill Education; 2015. https://jamaevidence.mhmedical.com/book.aspx?bookID=847
48.
Horby  P , Lim  WS , Emberson  JR ,  et al; RECOVERY Collaborative Group.  Dexamethasone in hospitalized patients with Covid-19.   N Engl J Med. 2021;384(8):693-704. doi:10.1056/NEJMoa2021436PubMedGoogle Scholar
49.
James  ND , Spears  MR , Clarke  NW ,  et al; STAMPEDE Investigators.  Failure-free survival and radiotherapy in patients with newly diagnosed nonmetastatic prostate cancer: data from patients in the control arm of the STAMPEDE trial.   JAMA Oncol. 2016;2(3):348-357. doi:10.1001/jamaoncol.2015.4350PubMedGoogle ScholarCrossref
50.
Sydes  MR , Spears  MR , Mason  MD ,  et al; STAMPEDE Investigators.  Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.   Ann Oncol. 2018;29(5):1235-1248. doi:10.1093/annonc/mdy072PubMedGoogle ScholarCrossref
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