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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

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.

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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
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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
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
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REMAP-CAP. Current protocol documents. Accessed September 27, 2021. https://www.remapcap.org/protocol-documents
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
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
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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
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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
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
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
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
Park  JJ , Thorlund  K , Mills  EJ .  Critical concepts in adaptive clinical trials.   Clin Epidemiol. 2018;10:343-351. doi:10.2147/CLEP.S156708PubMedGoogle ScholarCrossref
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
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
US Food and Drug Administration. Adaptive Designs for Clinical Trials of Drugs and Biologics Guidance for Industry. US Food and Drug Administration; 2019.
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
McGlothlin  AE , Viele  K .  Bayesian hierarchical models.   JAMA. 2018;320(22):2365-2366. doi:10.1001/jama.2018.17977PubMedGoogle ScholarCrossref
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
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Committee for Proprietary Medicinal Products. ICH Topic E 10: Choice of Control Group in Clinical Trials. European Medicines Agency; 2001:30.
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
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
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
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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
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