BACKGROUND: Today's clinical research faces challenges such as a lack of clinical equipoise between treatment arms, reluctance in randomizing for multiple treatments simultaneously, inability to address interactions and increasingly restricted resources. Furthermore, many trials are biased by extensive exclusion criteria, relatively small sample size and less appropriate outcome measures. FINDINGS: We propose a 'Multiplex' trial design that preserves clinical equipoise with a continuous and factorial trial design that will also result in more efficient use of resources. This multiplex design accommodates subtrials with appropriate choice of treatment arms within each subtrial. Clinical equipoise should increase consent rates while the factorial design is the best way to identify interactions. CONCLUSION: The multiplex design may evolve naturally from today's research limitations and challenges, while principal objections seem absent. However this new design poses important infrastructural, organisational and psychological challenges that need in depth consideration

Keus, Frederik

Nijsten, Maarten W

van der Horst, Iwan C C

BMC Research Notes

English

PubMed

University of Groningen

More ethical and more efficient clinical research:multiplex trial design

BACKGROUND: Today's clinical research faces challenges such as a lack of clinical equipoise between treatment arms, reluctance in randomizing for multiple treatments simultaneously, inability to address interactions and increasingly restricted resources. Furthermore, many trials are biased by extensive exclusion criteria, relatively small sample size and less appropriate outcome measures.FINDINGS: We propose a 'Multiplex' trial design that preserves clinical equipoise with a continuous and factorial trial design that will also result in more efficient use of resources. This multiplex design accommodates subtrials with appropriate choice of treatment arms within each subtrial. Clinical equipoise should increase consent rates while the factorial design is the best way to identify interactions.CONCLUSION: The multiplex design may evolve naturally from today's research limitations and challenges, while principal objections seem absent. However this new design poses important infrastructural, organisational and psychological challenges that need in depth consideration.</p

Proceedings - University of Groningen

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More ethical and more efficient clinical research: multiplex trial design

Frederik Keus

Iwan CC van der Horst

Maarten W Nijsten

Springer - Publisher Connector

Keus et al. BMC Research Notes 2014, 7:530
http://www.biomedcentral.com/1756-0500/7/530SHORT REPORT Open AccessMore ethical and more efficient clinical research:
multiplex trial design
Frederik Keus*, Iwan CC van der Horst and Maarten W NijstenAbstract
Background: Today’s clinical research faces challenges such as a lack of clinical equipoise between treatment arms,
reluctance in randomizing for multiple treatments simultaneously, inability to address interactions and increasingly
restricted resources. Furthermore, many trials are biased by extensive exclusion criteria, relatively small sample size
and less appropriate outcome measures.
Findings: We propose a ‘Multiplex’ trial design that preserves clinical equipoise with a continuous and factorial trial
design that will also result in more efficient use of resources. This multiplex design accommodates subtrials with
appropriate choice of treatment arms within each subtrial. Clinical equipoise should increase consent rates while
the factorial design is the best way to identify interactions.
Conclusion: The multiplex design may evolve naturally from today’s research limitations and challenges, while
principal objections seem absent. However this new design poses important infrastructural, organisational and
psychological challenges that need in depth consideration.
Keywords: Trial design, Clinical equipoise, Factorial design, Simultaneous randomization, Interaction, BiasBackground
Randomised clinical trials (RCT) should provide high-
level evidence. However RCT’s often exhibit several im-
portant limitations: (A) Clinical equipoise is frequently not
present for the interventions that are compared [1]. (B)
Patients are often not allowed to participate in multiple
trials for mainly non-methodological reasons. (C) The
costs to initiate, conduct and successfully conclude trials
are high. (D) Trials may only include small proportions of
the relevant patients leading to results with low external
validity. (E) Frequently, trialists choose surrogate or inter-
mediate outcomes [2,3]. (F) And unrealistic, small sample
sizes may be based on inappropriate optimism regarding
the expected effect size [3]. All these factors can increase
bias and can thus lead to unreliable conclusions [4].
Multiplex trial design may offer benefits including a more
ethical and more efficient clinical research methodology.
Findings
We hypothesize that a novel design, called multiplex,
will allow a more ethical and more efficient framework* Correspondence: f.keus@umcg.nl
Department of Critical Care, University of Groningen, University Medical
Center Groningen, Groningen, the Netherlands
© 2014 Keus et al.; licensee BioMed Central Lt
Commons Attribution License (http://creativec
reproduction in any medium, provided the or
Dedication waiver (http://creativecommons.or
unless otherwise stated.for conducting clinical studies. The principle of multi-
plexing [5] is widely used in many technical areas.
Briefly, it denotes the combination of multiple signals
into a single combined continuous signal that later can
be decomposed into its individual signals (Figure 1).
Clinical trial design could evolve into a similar approach
(Figure 2).
The proposed multiplex trial has several key design ele-
ments, including a combination of the continuous and fac-
torial approaches (Table 1). Patients are enrolled within a
permanent trial structure and at any time point several
subtrials will be conducted to address different hypoth-
eses. The multiplex principle includes a factorial design to
simultaneously run various subtrials for the same patient
category [6,7]. The number of clinical comparisons that
are studied will vary over time, depending on the subtrials
that are running at any time point. For all subtrials a rele-
vant outcome according to Grading of Recommendations
Assessment Development and Evaluation (GRADE) [2] is
used. For example in critical care many interventions could
be assessed for the agreed-upon outcome, i.e. hospital mor-
tality. Enforcing clinical equipoise between the interven-
tions within each subtrial, and their various combinationsd. This is an Open Access article distributed under the terms of the Creative
ommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
iginal work is properly credited. The Creative Commons Public Domain
g/publicdomain/zero/1.0/) applies to the data made available in this article,
Figure 1 Multiplex communication principle. In communications technology and in other fields multiplexing is used to combine multiple
independent packages of information into a continuous single signal that after transmission can be decomposed into the original
information packages.
Keus et al. BMC Research Notes 2014, 7:530 Page 2 of 5
http://www.biomedcentral.com/1756-0500/7/530justifies that patients are simultaneously included in mul-
tiple subtrials. Such a design will result in increased effi-
ciency as patients are randomised for multiple subtrials
simultaneously and because of the continuous nature. It
may demonstrate robust detection of interactions, in-
creased patient consent by respecting equipoise and in-
creased generalisability of results by using fewer exclusion
criteria (Table 1).
Key elements of multiplex design
(A) The condition of clinical equipoise is often not met by
the interventions that are compared [8], for example be-
cause of an inappropriate control arm [9]. Freedman [1]
proposed that ‘clinical equipoise’ should be based on
present or imminent controversy in the clinical commu-
nity over which treatment would be the preferred treat-
ment. Thus this requirement is satisfied if there is genuine
uncertainty within the expert medical community - not
necessarily on the part of the individual investigator -
about the preferred treatment [1]. For example, clinicians
could be evenly divided whether epinephrine or norepin-
ephrine would be optimal for a specific condition.
Despite strong debates, the universal nature of this
ethical bedrock of trials cannot be ignored [8,10]. Re-
specting clinical equipoise may well result in smaller ex-
pected differences in outcome. Consequently, the sample
size estimation would be larger to adequately address
the question of the subtrial.
(B) Patients do usually not participate in more than one
trial. Competitive motives, more than scientific or patients’
interests, may explain this phenomenon. A patient who
participates in several subtrials at the same time will con-
tribute to several clinical questions in parallel and thus the
costs per subtrial will decrease. In real life, patients who
receive N different simultaneous treatments are thus sub-
jected to a multitude, i.e. N · (N-1) of potential interactions.
Interactions may remain undetected after approval and
market launch [11,12]. If possible, interactions ought to beidentified during a trial, rather than many years after intro-
duction of drugs or interventions into clinical practice. In
case that a certain combination of treatments from differ-
ent subtrials is known a priori to be undesired, such a par-
ticular combination could be excluded in the multiplex
design.
(C) Currently the planning, initiation, conduct, conclu-
sion and analysis of individual trials are associated with
large costs. In contrast, the multiplex organisational and
logistical structure - because of its permanent nature -
does not need to be rebuilt once it has been established.
Conducting randomisation superimposed on an existing
registry was demonstrated to result in an important re-
duction in costs [13].
(D) Regarding inclusion criteria, many trials only in-
clude a small proportion of all eligible patients, when re-
ported. Extensive use of exclusion criteria creates trial
results applicable only for selected cases. Trials need to
produce results which can be generalized to clinical
practice by adopting wide inclusion criteria, and limited
exclusion criteria [14]. Included patients need to repre-
sent the large majority of eligible patients. The multiplex
trial design adopts wide inclusion criteria and as few ex-
clusion criteria as possible. Within this framework, sub-
group analyses may eventually reveal hypotheses for
more or less favourable effects in specific patient groups.
(E) Concerning outcome, less important measures
such as continuous outcomes and surrogate outcomes
are frequently used, something mainly based on doc-
tors’ or hospital’s interests (e.g. costs or hospital stay).
GRADE emphasizes that outcome measures need to be
ranked from to the perspective of the patient [2]. The
multiplex trial design was conceived according to this
principle: simple and robust outcomes such as mortal-
ity and (severe) adverse events that are most relevant
to patients.
(F) Unfortunately, many trial sizes are too small to de-
tect relevant statistical differences. Unwarranted optimism
su
rv
iv
al
time
2000 4000
1 1000
1200 1600
1800 2000
00230022
…..
clinical
equipoise
single continuous trial with 
subtrials
subtrials 
third trial
vs.
fourth trial
vs.
vs.
vs.
first trial
second trial
Conventional
design
outcomes interactions
Multiplex
design
…..
Figure 2 Conventional versus multiplex trial design. In most conventional randomized controlled trials, the effect of only one intervention is
examined. Multiple questions are typically addressed in a serial manner. Thus in the first trial patients 1-1000 are studied to compare red and
brown treatments, in the second trial patients 1200 -1600 (green vs. dark green) the third trial patients 1800-2000 (yellow vs. orange) and in the
fourth trial patients 2200-3200 (light blue vs. dark blue). The different numbers of included patients result from different power requirements.
The gaps in included patients are related with logistical issues. Within the multiplex trial concept as many questions as possible are addressed
simultaneously, provided clinical equipoise exists between all treatments (and their combinations) that are examined. For example the three
different subtrials may examine the two interventions for blood pressure, pain and fever respectively in patient 2000 through 4000. Although the
subtrials use more patients and thus have greater power, a lower overall number of patients is required, underscoring the efficiency of factorial
trial design. The continuous nature of the multiplex design also reduces “down-time” (as indicated by the breaks between the four convential
trials). Interactions between treatments can only reliably be detected with a factorial design, although the needed sample size to do so requires
advanced analysis.
Keus et al. BMC Research Notes 2014, 7:530 Page 3 of 5
http://www.biomedcentral.com/1756-0500/7/530concerning intervention effects or the use of inappropriate
surrogate outcomes are sometimes employed to justify
small sample sizes. This may lead to false positive or false
negative conclusions. There is considerable evidence that
the majority of trials are underpowered, so definitive con-
clusions cannot be drawn for many clinical questions [15].
Usually far more randomised patients are needed before
clinical questions can reliably be answered, and even more
so when truly equivalent interventions are compared since
differences will be smaller. Multiplex trial design therefore
must entail large(r) sample sizes [16].
Discussion
The combination of a continuous and factorial trial with
clinical equipoise between all interventions, requires thateach subtrial should be designed with low risks of bias
and sufficiently large sample sizes based on realistic
intervention effects focusing on outcome measures ac-
cording to GRADE [2,4,15,17].
Key elements of the multiplex design interact: both
equipoise and choosing relevant outcomes inevitably
lead to larger sample sizes as hypothesized differences
in intervention effects will be smaller. This effect, how-
ever, will be offset by higher efficiency due to simultan-
eous randomisation of patients in multiple subtrials. A
critical multiplex advantage is that only factorial studies
can detect interactions [7,18]. Since equipoise and qual-
ity are central principles of the proposed multiplex de-
sign, we believe that patient’s confidence and consent
will increase.
Table 1 Key elements, requirements and additional benefits of multiplex trial design
Key elements
A Clinical equipoise between treatment arms
B Factorial design allows simultaneous participation in multiple subtrials
C Continuous design so subtrials are embedded in a permanent infrastructure
D Broad inclusion criteria
E Relevant and robust outcome measures according to GRADE
F Large sample sizes
Requirements
Treatment arms reflect current practice (A)
Increased involvement of patients (B)
Streamlined consent procedure for multiple subtrials (B)
Multiple principal investigators must closely collaborate (B)
Mutual acceptance of multiple sponsors (B)
Extensive involvement of institutional review board (A,B,C)
Integration with existing outcome registries (C,E,F)
Advanced ICT infrastructure (B,C)
Benefits
Patients More confidence in clinical research (A,B,E)
Scientific Detection of interactions (B)
Results with low risks of bias (A,D,E,F)
Results with low risks of random error (A,D,E,F)
Higher external validity (C,D,F)
Societal More answers to relevant clinical questions (B,C,D,E,F)
More efficient use of resources (B,C,D)
Summary of the components of the multiplex concept (A through F) and the various requirements as well as further benefits that we foresee that are related with
these components.
Keus et al. BMC Research Notes 2014, 7:530 Page 4 of 5
http://www.biomedcentral.com/1756-0500/7/530Organisational issues as well as the willingness of in-
vestigators to cooperate must be addressed if multiplex
is to succeed. Informed consent for multiple subtrials
must be condensed into a single transparent informed
consent procedure. Attitudes toward intellectual and
material ownership of trials need to change fundamen-
tally. Funding of multiplex trial units may originate from
sponsors such as health service providers, drug and de-
vice industries, as well as clinical investigators. Although
sponsors will have to relinquish part of their control of
trials [19], in return the required resources would be
borne by multiple sponsors. Ownership of trials as well
as which subtrials are prioritized should be reconsidered
as well as who will manage a multiplex institute. We be-
lieve that many registries (e.g. for cardiology or critical
care) that currently record outcome on a nation-wide
basis might provide part of the infrastructure for con-
ducting multiplex trials. Modern information technology
and web-based applications may offer solutions for data
registration as well as transparency towards patients.
Large sample sizes inevitably demand a multi-centre ap-
proach and probably the organisational structure willexpand beyond national boundaries, creating additional
legal challenges. Although these and other yet unthought-
of issues must all be addressed before we can embark
upon such a complex enterprise, we firmly believe that the
multiplex trial design is a natural direction trial design
must evolve into.Conclusion
We believe that the multiplex design is compatible with
basic ethical principles and that it is a natural methodo-
logical direction that trial design should evolve into. Ob-
viously, considerable psychological, organizational and
regulatory hurdles have to be overcome before multiplex
trial design becomes reality.Competing interests
The authors declare that they have no competing interests.Authors’ contributions
All three authors contributed to this debate paper. All authors read and
approved the final manuscript.
Keus et al. BMC Research Notes 2014, 7:530 Page 5 of 5
http://www.biomedcentral.com/1756-0500/7/530Acknowledgements
We wish to thank Christian Gluud, Karim Mahmoud, Wim Sluiter and Felix
Zijlstra for their comments.
Received: 10 February 2014 Accepted: 30 July 2014
Published: 14 August 2014
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More ethical and more efficient clinical research:multiplex trial design

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