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JAMA | Users' Guides to the Medical Literature

How to Use and Interpret the Results of a Platform Trial

Users’ Guide to the Medical Literature
Jay J. H. Park, PhD; Michelle A. Detry, PhD; Srinivas Murthy, MD, CM, MHSc; Gordon Guyatt, MD, MSc; Edward J. Mills, PhD

Multimedia
Platform trials are a type of randomized clinical trial that allow simultaneous comparison of CME Quiz at
multiple intervention groups against a single control group that serves as a common control jamacmelookup.com
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 Author Affiliations: Author
interpretation of these studies. This Users’ Guide is intended to help clinicians and readers affiliations are listed at the end of this
article.
understand articles reporting on interventions evaluated using platform trial designs.
Corresponding Author: Edward J.
Mills, PhD, 802-777 W Broadway,
JAMA. 2022;327(1):67-74. doi:10.1001/jama.2021.22507 Vancouver, BC V5Z 1J5, Canada
(millsej@mcmaster.ca).

structure wherein interventions can be added and discontinued at

Clinical Scenario
A hospitalist physician is evaluating a 60-year-old patient with
severe COVID-19 who was admitted to the intensive care unit (ICU)
and is receiving high-flow oxygen via nasal cannula. A resident phy-
sician on the ICU team is considering administration of intravenous
hydrocortisone to the patient. The hospitalist physician is
requested to assess the evidence regarding that decision. The phy-
sician is aware of a platform trial, the Randomized, Embedded,
Multifactorial Adaptive Platform Trial for Community-Acquired
Pneumonia (REMAP-CAP), that investigated hydrocortisone vs no
hydrocortisone for patients with severe COVID-19.1 REMAP-CAP is
an ongoing, international, multicenter platform trial that aims to
determine best treatment strategies for patients with severe pneu-
monia in pandemic and nonpandemic settings.2 This trial is investi-
gating multiple interventions including corticosteroids.
The article reporting the corticosteroid findings of the
REMAP-CAP trial presented results on organ support–free days,
in-hospital mortality, and other clinical outcomes of 2 hydrocorti-
sone regimens vs no hydrocortisone.1 To assess this article, and in
particular to determine what inferences can be drawn from plat-
form trials compared with conventional randomized clinical trials
(RCTs), the physician uses the framework in the Users’ Guide to
Platform Trials (Box 1).
Fundamental Principles of Platform Trials
Platform trials are RCTs that allow for multiple interventions to be
simultaneously evaluated and new interventions to be added after
the trial is initiated (Figure).3-5 The platform provides a single infra-
different times after their clinical questions are answered through
comparisons against a control group, sometimes shared across
interventions.3-5 The control group and the standard care provided
can be updated during platform trials as interventions are shown to
be effective or ineffective over time.5
In the setting of multiple competing but unestablished treat-
ments with new treatments on the horizon, as occurred during the
COVID-19 pandemic, platform trials have important potential
advantages compared with traditional, fixed approaches to clinical
trial research. In many conventional RCTs, data are analyzed when
the last participant has finished their trial follow-up. These RCTs
typically have a fixed sample size and a defined end and usually
address only 1 intervention vs a comparator (ie, 2-group RCTs). In
contrast, platform trials are typically designed with the intention of
continuing for a longer duration to enable multiple interventions to
be evaluated at different times. Platform trials also include pre-
specified interim statistical analyses that allow for adaptive actions
(eg, stopping an intervention early for futility or expected success).
Although multigroup and factorial RCTs can evaluate multiple inter-
ventions with a broader scope than 2-group RCTs, these trials are
limited to the interventions determined at the beginning of the
trial. With a focus on identifying treatments for a medical condition
instead of evaluating specific interventions, platform trials are able
to evaluate multiple interventions to determine if any reach desired
levels of efficacy compared with standard care, and they can
quickly add or discontinue an intervention according to emerging
internal or external evidence.6
Platform trials are becoming more common in medical
research, but their utility may be limited if clinicians and other read-
ers are unfamiliar with their underlying concepts and their
interpretation.1,7,8 The purpose of this Users’ Guide to the Medical

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 Clinical Review & Education Users' Guides to the Medical Literature
Box 1. Questions Addressing Risk of Bias in Platform Trials
• Were prespecified plans for interim and statistical analyses
used in the trial? Were the prespecified plans applied equally to
all interventions?a
• Did the investigators include nonconcurrent randomized
participants or limit statistical comparisons to concurrently
randomized patients?a
• Did the investigators minimize risk of bias from information flow
within and outside the specific platform?
• Did the investigators follow reporting guidelines in published
reports of the trials?
a
Addresses risk of bias specifically for platform trials.
Literature is to provide guidance on how to interpret the results
from platform trials (Box 1) and to describe the fundamental con-
cepts of platform trials (see Box 2 for relevant definitions).
The Master Protocol
A master protocol is a set of documents with standardized operat-
ing procedures compiled for the goal of increasing trial quality
and efficiency.3 Three types of clinical trials that may be conducted
under the master protocol framework include basket trials,
umbrella trials, and platform trials.3,7,13 In basket trials, a targeted
therapy is evaluated for multiple diseases with a common risk
factor, such as a molecular alteration, or risk factors that that may
help predict whether patients will respond to the given therapy.
Umbrella trials evaluate multiple targeted therapies in a single dis-
ease that is stratified into multiple substudies based on different
molecular or other predictive risk factors.3,13,14 Both of these trial
types can be platform trials in nature if they are designed to have
a common control group and enable the addition of new inter-
ventions during the trial. A key element of these trials is use of
a master protocol.5
In platform trials, the master protocol may be structured in a
modular format with all common generic elements of the trial,
including documented standardized operating procedures that are
implemented for clinical trial evaluation. A modular-structured
master protocol may include intervention appendixes specific to
each intervention that outline protocol elements specific to the
intervention and that differ from the master protocol as well as
other nonintervention appendixes outlining design details (eg, an
adaptive-design report including details on the prespecified adap-
tation and the simulated trial operating characteristics).5 The addi-
tion of new interventions can be expedited because the master
protocol is not updated every time a new intervention is added or
discontinued; instead, an intervention-specific appendix is added.
Administrative requirements such as institutional ethical review
may be expedited as the trial design for the new intervention is
typically identical to the design that was first approved, and new
interventions may be indicated in an amendment to the trial proto-
col rather than requiring a complete new review.15
The master protocol will often include details regarding
mechanisms for adding new interventions. The master protocol
and other documents of platform trials are often available as
supplementary materials of publications and on trial websites (see,
for example the protocol documents of the REMAP-CAP platform
trial16). The protocol may also prespecify the communication plans
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How to Use and Interpret the Results of a Platform Trial
for the dissemination of trial results after an intervention in the trial
is completed and the responsibilities of a committee (eg, trial steer-
ing committee) that may hold the ultimate decision for approving
the reporting of results.
In platform trials, interventions, regardless of when they are
added to the trial, are evaluated using prespecified adaptive deci-
sion rules outlined in the protocol documents.5 Once the master pro-
tocol is finalized, new interventions follow the master protocol pre-
specified plans for interim analyses and decision rules unless
deviations from the master protocol are prespecified in the inter-
vention-specific appendix. The goal is to have few deviations from
the master protocol, yet allow for flexibility, if required, due to an
evolving clinical field during the ongoing platform trial.
When a new intervention is available, several scientific and
practical considerations may guide the decisions regarding its
inclusion in the trial, including a sound rationale, support by a
robust biological hypothesis, positive evidence of potential effi-
cacy, adequate safety profile, ease of administration, and low
cost.17,18 These scientific merits may be reviewed by an indepen-
dent working group that consists of members from industry, aca-
demia, patient advocacy groups, and others with technical exper-
tise, clinical expertise, or both and who are not directly involved
in the platform trial. An independent working group can screen
and prioritize candidate interventions to be added to the platform
trial in instances for which many interventions could be simulta-
neously evaluated.
Shared Infrastructure and Control Groups
for Ongoing Evaluation
In many platform trials, a large trial network can be established across
multiple trial centers using standardized operating procedures out-
lined in the protocol.3,14 Coordinated screening mechanisms with
centralized trial systems are implemented to streamline and im-
prove the quality of many trial processes and logistics.3 The com-
mon database(s) and randomization system across the shared in-
frastructure may allow for more seamless integration of the new
interventions being added into the trial. These features combined
with centralized analytics may improve standardization of clinical
evaluation and reporting of different interventions being evalu-
ated in the platform over time.
A platform trial can evaluate multiple different interventions
against standardized common control groups. To address each of
these interventions separately in an RCT would require multiple
separate teams creating separate protocols, recruiting participating
centers, establishing a methods center, obtaining ethics approval,
and addressing all the challenges that arise as the trial proceeds.
Conducting multiple trials independently could result in inefficien-
cies. Within a platform trial, this entire process is done only once,
creating a large trial network across multiple centers or sites using
standardized operating procedures outlined in the master protocol,
with central coordination, for all interventions and the control
group.3,14 In creating coordinated screening mechanisms with cen-
tralized randomization, study monitoring, and common database
(s), the platform trial achieves efficiency and may also enhance
quality.3 For example, the REMAP-CAP platform trial has evaluated
multiple interventions within multiple therapeutic areas (referred
to as domains by the REMAP Investigators), including antiviral
agents, corticosteroids, and immunoglobulins.2
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 How to Use and Interpret the Results of a Platform Trial
Figure. Illustrative Example of a Platform Trial Schema
Placebo (common control)
Treatment 1
S TA RT O F P L AT F O R M T R I A L
Treatment 2
Treatment 3
Treatment 4
Treatment 5
Treatment 6
Treatment 7
Common Control Group
Different platform trials vary in design and objectives, but they all
plan on patients being randomized to an intervention or a simi-
larly defined control group against which each intervention can
be evaluated. 7,14 When at a single point in time, patients are
randomized to more than 1 intervention or a common control
group, platform trials can improve efficiency by reducing the
number of patients needed in the control group compared with
the numbers of participants that would be needed in multiple
independent RCTs.4,19
Such sample size savings represent an efficiency that could al-
low testing more interventions than in multiple, separate interven-
tion trials. The efficiencies could result in lower costs relative to mul-
tiple individual trials that address the same questions, addressing
more interventions with the same cost, or some combination.20
When effective interventions are identified in a platform trial, the
control and standard care can be updated in the platform, allowing
research to continue toward investigating additional improvement
in the new standard care.
In multifactorial platform trials such as REMAP-CAP, in which
multiple interventions from multiple intervention groupings
within a common clinical mode were simultaneously evaluated,
there are instances for which patients may only be eligible for a sub-
set of the intervention groups.1,2 In such case, it is important that
only control group patients who were also eligible for the same in-
terventions are used for statistical estimates of treatment effects to
obtain a valid estimate of the comparative effectiveness. In placebo-
controlled platform trials, multiple placebos may be required in
the control group.21
The Users’ Guides for Platform Trials
Were Prespecified Plans for Interim and Statistical Analyses
Used in the Trial?
Well-planned platform trials will use statistical analyses with pre-
specified adaptations (ie, modification of key trial characteristics
such as sample size and allocation ratios) and decision rules.
Interim analyses will generally be used to allow for early stopping
for futility or efficacy as prespecified adaptations. The decision for
early stopping for futility may be made when the intervention dem-
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The platform initially starts as a
3-group randomized clinical trial with
placebo as a common control, and
new treatments are introduced into
the platform over time. Green circles
indicate start of random assignment
of participants to a new intervention,
and red circles indicate stopping of
assignment and/or testing of that
intervention.
onstrates little to no chance of demonstrating desired clinical ben-
efits even if more participants are randomized to that intervention
group.22 With early stopping for greater efficacy, an intervention
can be declared as effective before the maximum recruitment tar-
get is reached for that intervention. Similar to other clinical trials
that allow early stopping at a prespecified interim analysis, plat-
form trials require prespecification of interim analysis plans and
characterization of operating characteristics such as the type I error
rate. Because the accuracy of treatment effect estimates in trials
that are stopped early for efficacy can be a concern when the
sample size is small, efficacy and statistical superiority thresholds
for early stopping are generally chosen to be more conservative for
interim analyses than for the final analysis of trials that continue to
completion.23,24 Simulations are generally used to plan for interim
analyses in platform trials.25,26
Response-adaptive randomization is a potential design feature
in multi-intervention platform trials in which allocation ratios can
be adapted, based on prespecified rules, at each interim analyses
over the course of the trial.27,28 The allocation ratio among the
intervention groups is adapted to favor the interventions with
more favorable interim results, while keeping the allocation ratio to
the control group fixed.27,28 In platform trials and other multigroup
trials, response-adaptive randomization could minimize the num-
ber of participants being treated with a less effective treatment
and allow effective treatments to more quickly complete the trial
because they receive more patients and improve the probability of
selecting the best treatment group given that allocation is
adequately maintained in the control group.29 The optimal alloca-
tion ratio of intervention to control groups should be determined
using simulations.29
Because each platform trial will have different goals and there-
fore design features, there are no default interim analyses plans
that are best for all platform trials, and the simulations should be
conducted before starting the trial to determine the best design for
each platform trial.30 The process of simulating virtual patients in
virtual trial designs are used to inform, revise, and determine the
final statistical design, including the interim analysis plans and deci-
sion rules. Many of the design features, such as early stopping and
response-adaptive randomization, can affect the performance
characteristics (eg, type I error rate, statistical power, expected
sample size) of a given platform trial. Therefore, it is important to
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 Clinical Review & Education Users' Guides to the Medical Literature
Box 2. Glossary of Terms Used in Platform Trials
Platform trial: A type of randomized clinical trial design in which
multiple interventions can be evaluated simultaneously against
a common control group with flexibilities of allowing new
interventions to be added and the control group to be updated
throughout the trial.5 Platform trials use a master protocol (also
called a core protocol9) to streamline and improve the quality of
many of the trial processes and logistics.3 These trials typically
compare multiple interventions against a common control group
using prespecified interim analysis plans for statistical efficiencies.
Master protocol: Generally refers to an overarching protocol
designed to evaluate multiple interventional hypotheses.3,7 The
master protocol document often contains standardized operating
procedures that are supplemented with intervention-specific
appendixes, a statistical analysis plan (SAP) appendix, a simulation
appendix, and other protocol-related appendixes in a modular
structured format.5 The details on the prespecified modifications
and decision rules that will be applied to all interventions are
included in the SAP and simulation appendixes.
Fixed sample trial design: Conventional clinical trial design in
which the clinical trial data are assessed for efficacy after the last
participants have finished clinical follow-up. Clinical trials with fixed
sample trial designs are designed with a fixed maximum sample size,
a fixed number of interventions, and a defined end to the trial.4
Adaptive trial design: In an adaptive trial design, key trial
characteristics (eg, randomization proportions, sample size,
treatment groups) evolve in response to information accruing
within the trial according to prespecified rules.10-12 Adaptive trial
designs use interim analyses according to prespecified schedules
that allow key trial characteristics to evolve over time.
Simulation study: Used to investigate behavior of methods when
applied to synthetic data sets generated with known characteristics.
In clinical trial design planning, simulations can be used to investigate
operating characteristics of different trial designs. For instance, trial data
generatedwithandwithoutatreatmenteffectcanbeusedtoassesshow
often a given trial design correctly or incorrectly rejects the null
hypothesis to estimate its statistical power and type I error rate.
Interim analysis: A randomized clinical trial statistical analysis of
clinical efficacy data that occurs before the last participant has finished
clinicalfollow-up.Interimanalysesmayleadtoearlystoppingforstatistical
superiority when there is a sufficiently robust effect that exceeds pre-
specified statistical thresholds. Interim analyses may also lead to early
stopping for futility when data analysis suggests there is little chance of
achievingadesiredmagnitudeoftreatmenteffect.Thetermstrialupdate
or adaptive analysis may also be used instead of interim analysis.
Response-adaptive randomization: A type of adaptive trial design
in which allocation ratios are adapted based on interim results so
more patients are randomized to treatments with favorable
interim results than those with less favorable results. This design is
often included in platform trials.
Concurrent control group participants: A concurrent control
group includes participants who were randomized to the
control group during the same time period as the participants
in a particular intervention treatment group.
Nonconcurrent control group participants: A nonconcurrent
control group includes participants who were enrolled and
randomized to the control group before the period of time in
which participants in the intervention group(s) are enrolled into
the trial. There may be other types of nonconcurrent control
groups whereby the patients in the control group are enrolled
after a given experimental group has finished clinical evaluation.
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How to Use and Interpret the Results of a Platform Trial
evaluate different design features during the planning stage.23,26
Given the long-term or ongoing nature of platform trials, it may also
be beneficial to conduct additional simulations when more data
become available that may either validate or contradict the
assumptions that were made during the planning stage.5
As the investigators reported, the REMAP-CAP platform trial had
a prespecified statistical analysis plan for the COVID-19 corticoste-
roid interventions that was prepared by a blinded steering commit-
tee, posted online before data lock and conduct of the final analy-
ses, and included as a supplement with the published artricle.1 Use
of a bayesian adaptive design and final analyses were planned using
simulations. For their specific bayesian design, simulations showed
an estimated power of 90% of determining whether either of 2 hy-
drocortisone groups would be statistically superior to the control of
no corticosteroid with a sample size of 500 patients and an odds ra-
tio of 1.75 compared with the control, or at a sample size of 1000
patients if the odds ratio was 1.50.1
Platform trials like REMAP-CAP that are designed under the
framework of bayesian statistics may allow for more intuitive
interpretations.31-33 Traditionally used frequentist statistical mea-
sures such as 95% CIs are often misinterpreted as 95% chance of
the study estimate intervals containing the true effect size.34 The
REMAP-CAP investigators used 95% credible intervals (CrIs), which
are bayesian equivalent measures for CIs.34 Bayesian statistical analy-
sis also allows for estimation of probability of a certain intervention
being statistically superior to standard care, which also may be more
intuitive to understand and apply in clinical practice.31
Did the Investigators Include Nonconcurrent Randomized
Participants or Limit Statistical Comparisons
to Concurrently Randomized Patients?
In conventional RCTs, enrollment for all groups including the con-
trol group will start at the same time, with randomization used to
allocate patients into different groups, and statistical comparisons
are made with data from the concurrently randomized control
group.35 In platform trials, investigational groups enter and finish the
trial at different times. For new interventions that are added into the
platform later, there will be a set of previously randomized partici-
pants in the control group (ie, nonconcurrent control participants)
(Box 2). Although the control group participants have not been ran-
domized at the same time as each intervention group participant in
the platform trial, they were enrolled under the same inclusion and
exclusion criteria and had end-point information collected in a con-
sistent manner. Because diseases may change over time, as in
COVID-19 waves, it is not possible to be as confident of prognostic
balance—the goal of randomization—as when patients are random-
ized concurrently to intervention and control groups.
In the REMAP-CAP platform trial, the primary outcome analy-
sis was conducted for all randomized patients who met criteria for
severe COVID-19 criteria as of June 17, 2020, not only those who were
randomized within the corticosteroid intervention group of the over-
all platform trial. Because REMAP-CAP is investigating multiple thera-
peutic intervention groups with sites not necessarily participating
in all intervention groups, some patients were eligible but were not
randomized to receive a corticosteroid intervention.1 These pa-
tients were included in the analysis that used a bayesian hierarchi-
cal model. The model included covariate terms for each patient’s eli-
gibility, resulting in the corticosteroid treatment effect being
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 How to Use and Interpret the Results of a Platform Trial
estimated using only the data from patients who were randomized
concurrently to 1 of the corticosteroid regimen groups or the con-
trol group. The patients enrolled to other therapeutic areas (eg, an-
tiviral agents or immunoglobulins) contributed to estimate the prog-
nostic factors (ie, location, age, sex, and time period) on the
outcomes of interest.1 In a preplanned sensitivity analysis, the in-
vestigators repeated the analysis limited to patients randomized to
the hydrocortisone and no-hydrocortisone groups, without includ-
ing patients randomized to other interventions.1 This second analy-
sis evaluated the consistency of the adjusted results in the primary
analysis using all control group participants with results using only
concurrently randomized patients.
Sharing control information and using the nonconcurrent con-
trol group data are qualitatively different than supplementing a trial
with historical or observational control group data or external clini-
cal trial data because the participants met the same trial enroll-
ment criteria and data were measured and collected in a consistent
environment.36 While temporal variability may exist in platform trials,
because patients are randomized and followed up with the same
standardized operating procedures outlined in the master proto-
col, nonconcurrent control group data collected earlier in the plat-
form trial may have minimal temporal variability compared with con-
current control group data. Using the nonconcurrent control group
data can increase statistical power, and statistical adjustments for
temporal variability and other confounders can minimize the ef-
fect of prognostic imbalance. However, incorporating the noncon-
current control group data may not ensure prognostic balance in the
same way that randomization does.37 It is crucial that platform trial
authors report their results differentiating comparisons based on
concurrently randomized patients from comparisons based on those
who are not.38
When assessing a report of a platform trial that used noncon-
current control group data, it is important to compare the results of
the analysis incorporating nonconcurrent control group data with
the analysis limited to concurrent control group data for any incon-
sistency. It is also important to consider the statistical methods that
were applied to incorporate nonconcurrent and concurrent con-
trol group data. Nonconcurrent control group data may be ac-
counted for by modeling possible temporal variations in the con-
trol population.5,39 Statistical methods, such as dynamic borrowing
methods, use data-driven approaches to determine the amount of
information borrowing based on degree of consistency between the
nonconcurrent and concurrent data.36,38,40,41 These methods bor-
row the nonconcurrent data the most when it is consistent with the
concurrent data and borrow less when the data are inconsistent.40
Did the Investigators Minimize Risk of Bias From Information
Flow Within and Outside the Specific Platform?
During the conduct of clinical trials, some information about treat-
ment effects and other information about the trial (eg, baseline con-
trol event rate) is known to the unblinded data and safety monitor-
ing board (DSMB) and the unblinded statistical analysis committee
(SAC) who conduct the prespecified interim analyses. This informa-
tion needs to be tightly controlled among the limited unblinded
groups because reduced generalizability and bias can occur when
information from an ongoing trial causes changes to the partici-
pant pool, investigator behavior, and other aspects of the trial.10 Simi-
lar to other nonplatform adaptive clinical trials, interim analyses can
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Users' Guides to the Medical Literature Clinical Review & Education
reveal some information about the performance of the experimen-
tal intervention. Knowledge of the trial adaptations, such as re-
sponse-adaptive randomization, that have occurred can reveal some
information regarding the observed treatment effect, so steps to
mitigate operational biases in adaptive clinical trials will likely in-
clude a strict communication and information flow structure from
individuals who will conduct the unblinded analyses and review the
unblinded data (eg, DSMB and SAC members).42
The number of study personnel with access to unblinded data
or knowledge of implemented adaptations should be limited, com-
munication among such personnel and investigators and others
involved in the trial should be limited, and this information should
be reported in publications of trial results. The REMAP-CAP investi-
gators reported that the trial was overseen by an international trial
steering committee that was blinded to treatment assignment and
outcomes and an unblinded DSMB, that the prespecified statistical
analysis plan was prepared by a blinded steering committee, and
that the prespecified statistical analyses were conducted by the
SAC, who communicated with the DSMB. They also reported that
because the primary analysis included information about assign-
ment to other ongoing therapeutic areas, the unblinded SAC per-
formed the primary analysis and did not share treatment effect
information for ongoing interventions.1
Given the ongoing nature of platform trials, the potential for in-
formation leakage needs to be minimized whenever possible. Sev-
eral important considerations need to be made when reporting plat-
form trial results that use data from ongoing interventions being
evaluated in the platform via conference presentations or peer re-
view publications. For instance, it is not always clear how results from
a platform trial should be reported for a given intervention if that
intervention is found to be more effective than the control for spe-
cific prespecified patient groups or parameters (such as defined by
a given biomarker subtype), when the same intervention is still being
evaluated in other remaining groups. In some platform trials, scien-
tific communication of results may be delayed until the interven-
tion is no longer active for clinical evaluation to preserve scientific
integrity. For example, the master protocol for REMAP-CAP indi-
cates that all manuscripts and abstracts resulting from the data col-
lected during the trial are prepared by the relevant trial subcommit-
tees (referred to as domain-specific working groups in REMAP) and
approved for dissemination by the international trial steering com-
mittee. The central group determines the amount of information that
can be publicly shared while preserving the scientific integrity of the
platform. The publication of interim or definite results by indi-
vidual investigators without review and approval from the interna-
tional trial steering committee is not permitted.2
Did the Investigators Follow Reporting Guidelines
in Published Reports of the Trials?
Reporting standard guidelines and risk-of-bias assessment tools
for conventional RCTs apply to platform trials. Important potential
bias source categories such as randomization process, deviation
from intended interventions, missing outcome data, measure-
ment of outcomes, and selective reporting that are included in
the Cochrane risk-of-bias assessment tool are important to con-
sider.43 A recently developed extension of the Consolidated Stan-
dards of Reporting Trials (CONSORT) for adaptive trials has out-
lined several important reporting considerations that may be
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 Clinical Review & Education Users' Guides to the Medical Literature
helpful to the users and readers of platform trials.44,45 In cases of
extenuating circumstances that lead to important modifications to
platform trials, readers can use the CONSORT and SPIRIT (Standard
Protocol Items: Recommendations for Interventional Trials) Exten-
sion for RCTs Revised in Extenuating Circumstances (CONSERVE)
2021 statement as a framework to evaluate the effect of modifica-
tions that the trial investigators have made.46 Similar to when read-
ing other clinical trial publications, readers of platform trial publica-
tions can also apply the existing Users’ Guides and risk-of-bias
assessment tools.43-45,47
What Are the Results?
The relevant results of a platform trial focus on (1) the difference in
the clinical effectiveness measured by the primary outcome be-
tween experimental treatment group and control group; (2) the harm
outcomes that should favor the experimental intervention group
over the control group; and (3) whether the new experimental
therapy allocated to the intervention group provides clinically mean-
ingful differential benefit over that provided to the control group.
A given platform trial may have several publications, such as to out-
line the trial design and report results of experimental interven-
tions separately. Each publication may be specific to the compara-
tive effectiveness of a single intervention vs the control, and
comparisons between interventions may not directly be provided.
If the publication is specific to a single intervention, there can be over-
lap of control group patients appearing in different publications that
report results of different interventions. In a single platform trial pub-
lication, the number of participants randomized to other trial inter-
ventions or recruited before or after the given intervention was ac-
tive for recruitment should be provided in the CONSORT flow
diagram but provided in a general concealed nature if it is from in-
terventions still actively participating in the platform.1,48-50
The corticosteroid therapeutic area of REMAP-CAP included
403 adult patients with severe COVID-19 who were enrolled and
randomly assigned to a 7-day, fixed-dose intravenous course of 50
mg or 100 mg of hydrocortisone every 6 hours (n = 143), a shock-
dependent intravenous course of 50 mg of hydrocortisone every 6
hours (n = 152), or no hydrocortisone (n = 108) between March 9
and June 17, 2020. 1 The prespecified statistical analysis plan
defined respiratory and cardiovascular organ support–free days up
to day 21 as the primary outcome and included other secondary
outcomes such as in-hospital mortality.1,16 The prespecified statisti-
cal thresholds in the analysis plan were not met for either of the 2
hydrocortisone regimens evaluated in REMAP-CAP, and the enroll-
ment to the hydrocortisone groups was halted on June 17, 2020,
following the announced results of mortality benefits of dexameth-
asone in patients with COVID-19 receiving either invasive mechani-
cal ventilation or supplemental oxygen in the RECOVERY trial.1,48
The REMAP-CAP investigators made the decision to halt the
intervention groups due to external factors, not based on internal
trial results, because investigators or other study personnel did
not have access to unblinded data at the time of their decision,
highlighting adequate control of information within the trial.1
ARTICLE INFORMATION Author Affiliations: Division of Experimental
Accepted for Publication: November 30, 2021. Medicine, Department of Medicine, University of
British Columbia, Vancouver, Canada (Park); Berry
Consultants LLC, Austin, Texas (Detry); Department
72 JAMA January 4, 2022 Volume 327, Number 1 (Reprinted)
© 2022 American Medical Association. All rights reserved.
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How to Use and Interpret the Results of a Platform Trial
However, after stopping randomization to the intervention groups,
when the prespecified corticosteroid group final analyses were per-
formed, the investigators observed that in comparison with the
no-hydrocortisone group, fixed-dose hydrocortisone showed a
93% probability of being statistically superior, with an odds ratio of
1.43 (95% CrI, 0.91-2.27) for the primary end point of organ
support–free days, whereas the shock-dependent hydrocortisone
regimen showed an 80% probability of being statistically superior
to no hydrocortisone, with an odds ratio of 1.22 (95% CrI,
0.76-1.94).1 All statistical comparisons were limited to concurrently
enrolled patients.1
The findings of the REMAP-CAP trial1 were published simulta-
neously in JAMA on September 2, 2021, with the World Health
Organization (WHO) Rapid Evidence Appraisal for COVID-19 Thera-
pies (REACT) Working Group’s meta-analysis that explored the
association between systematic corticosteroids and mortality
among critically ill patients with COVID-19.8 This meta-analysis
included mortality data from 1703 patients in 7 RCTs including
those in the REMAP-CAP trial.8 The WHO REACT meta-analysis
found that lower 28-day mortality was associated with corticoste-
roid treatment compared with usual care or placebo. The associa-
tion between corticosteroids and lower mortality was similar for
hydrocortisone and dexamethasone, suggesting a possible class
effect that was not specific to any particular corticosteroid. The
results provided moderate-quality evidence of a substantial mortal-
ity reduction associated with corticosteroids in severely and criti-
cally ill patients with COVID-19, establishing the drug as a core
aspect of management of these patients.8
Clinical Scenario Resolution
For the 60-year-old patient with COVID-19 who was admitted to
the ICU and was receiving high-flow oxygen via nasal cannula, the
hospitalist physician considered the evidence from the REMAP-
CAP platform trial by applying the principles outlined in this article
while considering the totality of evidence from the WHO REACT
meta-analysis that examined steroid use across critically ill patients
with COVID-19.1,8 Based on these findings, the care team decided
to administer corticosteroids because they understood there was
a high likelihood of benefit to reduce organ support and mortality
with fixed-dose hydrocortisone and dexamethasone.
Conclusions
Platform trials represent a potentially useful approach for medical
research. In addition to meeting conventional risk-of-bias criteria,
prespecification of statistical analysis plans, and adequate control
of information flow, the risk of bias in a given platform trial can be
minimized. Platform trials, with their ongoing and intervention-
agnostic nature, may contribute research findings more efficiently
and potentially be more patient centered.
of Pediatrics, Faculty of Medicine, University of
British Columbia, Vancouver, Canada (Murthy);
Department of Health Research Methods,
Evidence, and Impact, McMaster University,
jama.com
 How to Use and Interpret the Results of a Platform Trial
Hamilton, Ontario, Canada (Guyatt, Mills); Cytel Inc,
Vancouver, British Columbia, Canada (Mills).
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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