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The ethical challenges raised in the design and conduct of pragmatic trials: An interview study with key stakeholders

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Background: There is a concern that the apparent effectiveness of interventions tested in clinical trials may not be an accurate reflection of their actual effectiveness in usual practice. Pragmatic randomized controlled trials (RCTs) are designed with the intent of addressing this discrepancy. While pragmatic RCTs may increase the relevance of research findings to practice they may also raise new ethical concerns (even while reducing others). To explore this question, we interviewed key stakeholders with the aim of identifying potential ethical challenges in the design and conduct of pragmatic RCTs with a view to developing future guidance on these issues. Methods: Interviews were conducted with clinical investigators, methodologists, patient partners, ethicists, and other knowledge users (e.g., regulators). Interviews covered experiences with pragmatic RCTs, ethical issues relevant to pragmatic RCTs, and perspectives on the appropriate oversight of pragmatic RCTs. Interviews were coded inductively by two coders. Interim and final analyses were presented to the broader team for comment and discussion before the analytic framework was finalized. Results: We conducted 45 interviews between April and September 2018. Interviewees represented a range of disciplines and jurisdictions as well as varying content expertise. Issues of importance in pragmatic RCTs were (1) identification of relevant risks from trial participation and determination of what constitutes minimal risk; (2) determining when alterations to traditional informed consent approaches are appropriate; (3) the distinction between research, quality improvement, and practice; (4) the potential for broader populations to be affected by the trial and what protections they might be owed; (5) the broader range of trial stakeholders in pragmatic RCTs, and determining their roles and responsibilities; and (6) determining what constitutes "usual care" and implications for trial reporting. Conclusions: Our findings suggest both the need to discuss familiar ethical topics in new ways and that there are new ethical issues in pragmatic RCTs that need greater attention. Addressing the highlighted issues and developing guidance will require multidisciplinary input, including patient and community members, within a broader and more comprehensive analysis that extends beyond consent and attends to the identified considerations relating to risk and stakeholder roles and responsibilities.
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R E S E A R C H Open Access
The ethical challenges raised in the design
and conduct of pragmatic trials: an
interview study with key stakeholders
Stuart G. Nicholls
1*
, Kelly Carroll
1
, Merrick Zwarenstein
2
, Jamie C. Brehaut
1,3
, Charles Weijer
4
, Spencer P. Hey
5
,
Cory E. Goldstein
4
, Ian D. Graham
1,3
, Jeremy M. Grimshaw
1,3,6
, Joanne E. McKenzie
7
, Dean A. Fergusson
1,3,6
,
Monica Taljaard
1,3
, on behalf of the Ethics of Pragmatic Trials project
Abstract
Background: There is a concern that the apparent effectiveness of interventions tested in clinical trials may not be
an accurate reflection of their actual effectiveness in usual practice. Pragmatic randomized controlled trials (RCTs)
are designed with the intent of addressing this discrepancy. While pragmatic RCTs may increase the relevance of
research findings to practice they may also raise new ethical concerns (even while reducing others). To explore this
question, we interviewed key stakeholders with the aim of identifying potential ethical challenges in the design and
conduct of pragmatic RCTs with a view to developing future guidance on these issues.
Methods: Interviews were conducted with clinical investigators, methodologists, patient partners, ethicists, and
other knowledge users (e.g., regulators). Interviews covered experiences with pragmatic RCTs, ethical issues relevant
to pragmatic RCTs, and perspectives on the appropriate oversight of pragmatic RCTs. Interviews were coded
inductively by two coders. Interim and final analyses were presented to the broader team for comment and
discussion before the analytic framework was finalized.
Results: We conducted 45 interviews between April and September 2018. Interviewees represented a range of
disciplines and jurisdictions as well as varying content expertise. Issues of importance in pragmatic RCTs were (1)
identification of relevant risks from trial participation and determination of what constitutes minimal risk; (2)
determining when alterations to traditional informed consent approaches are appropriate; (3) the distinction
between research, quality improvement, and practice; (4) the potential for broader populations to be affected by
the trial and what protections they might be owed; (5) the broader range of trial stakeholders in pragmatic RCTs,
and determining their roles and responsibilities; and (6) determining what constitutes usual careand implications
for trial reporting.
Conclusions: Our findings suggest both the need to discuss familiar ethical topics in new ways and that there are
new ethical issues in pragmatic RCTs that need greater attention. Addressing the highlighted issues and developing
guidance will require multidisciplinary input, including patient and community members, within a broader and
more comprehensive analysis that extends beyond consent and attends to the identified considerations relating to
risk and stakeholder roles and responsibilities.
Keywords: Pragmatic trial, Randomized controlled trial, Comparative effectiveness, Research ethics, Informed
consent, Benefit-harm analysis, Vulnerable participants, Qualitative, Interviews
© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
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the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
* Correspondence: snicholls@ohri.ca
1
Clinical Epidemiology Program-Ottawa Hospital Research Institute (OHRI),
Ottawa, ON, Canada
Full list of author information is available at the end of the article
Nicholls et al. Trials (2019) 20:765
https://doi.org/10.1186/s13063-019-3899-x
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Introduction
The randomized controlled trial (RCT) is a commonly
used experimental research design for generating robust
evidence on benefits and harms of health interventions.
RCTs are a major research endeavour; a 2010 Institute
of Medicine report estimated that there were almost 11,
000 ongoing interventional trials, with anticipated enrol-
ment of 2.8 million people [1]. Studies have suggested as
many as 75 trials are published on a daily basis [2].
However, RCTs are not homogenous and vary in their
intent and design features [3]. Explanatory RCTs aim to
generate an understanding of the mechanism of action
for the intervention. Accordingly, their design should
focus on tightly controlling aspects of delivery and the
study environment. Pragmatic RCTs, on the other hand,
are intended to have their results directly inform clinical
or health policy decisions and should thus mimic as
closely as possible the users, settings and circumstances
in which it is thought the interventions under evaluation
will be used [4].
Much work over the last 1015 years has sought to ar-
ticulate the elements of trial design upon which trials
may be more explanatory or pragmatic [58]. Specific-
ally, work to develop the PRagmatic - Explanatory Con-
tinuum Indicator Summary 2 (PRECIS-2) tool identified
trials as existing upon a multiaxial continuum, and pro-
posed nine design features upon which trials could be
more explanatory or more pragmatic. For example, trial
designs that reflect a more pragmatic approach may take
place in settings similar to the usual-care settings (as op-
posed to research facilities), may deploy the intervention
using resources or organisational support as would be
available in usual care, or may allow for flexibility in the
delivery of the intervention at the healthcare profes-
sionalsdiscretion as may be the case in usual care (see
Additional file 1: Table S1 for a full list of the PRECIS-2
domains and descriptions). In addition to study designs
that use patient randomization, pragmatic trials may also
utilize emerging trial designs. Indeed, in the context of
health systems or health policy trials, cluster RCT de-
signs - such as the cluster cross-over design [9], and the
stepped-wedge cluster design [9,10] - are being used to
not only evaluate system-level interventions but also
individual-level interventions adopted at scale.
Interest in pragmatic RCTs has increased substantially
in recent years, most notably since the turn of the cen-
tury [11,12]. The increased interest in pragmatic RCTs
is likely due to the needs of decision-makers at policy
and clinical levels for more rapid, affordable, relevant,
applicable research on clinical, policy and service deliv-
ery choices, conducted within usual-care health systems,
and the needs of research funders to demonstrate the
contribution of research tax dollars to health improve-
ments. Further, there is a concern that the apparent
effectiveness of interventions tested in explanatory RCTs
may not be an accurate reflection of their actual effect-
iveness in usual practice and, therefore, more pragmatic
RCTs are needed to address this discrepancy and im-
prove the ability of decision-makers to successfully select
treatment and care options from among competing al-
ternatives [13].
While pragmatic RCTs may increase the relevance of
research findings to practice they may also raise new
ethical concerns, even while reducing others. Attempts
to more closely align research encounters with usual
care blur the boundary between research and clinical
care, which raises opportunities to streamline consent
approaches, but may also generate concerns about un-
derstanding. Similarly, attempts to recruit study partici-
pants that better reflect the background clinical
population may address concerns about the routine ex-
clusion of certain patient groups from clinical trials,
while at the same time raising concerns about how pa-
tients considered vulnerable ought to be protected [14].
While there is a growing body of empirical research
exploring ethical challenges generated by pragmatic
RCTs (e.g. [1520]), few studies draw on actual experi-
ences of investigators, participants, and other stake-
holders in the design or conduct of pragmatic RCTs.
Moreover, this literature is dominated by studies arising
from the USA and may not reflect concerns raised by
stakeholders in other jurisdictions where healthcare sys-
tems and research regulations differ. Further, this litera-
ture has focussed to a great extent on a limited number
of topics, such as questions of when written consent ap-
proaches may be modified [16,17,19,21], while exclud-
ing broader ethical challenges pertaining to other facets
of pragmatic RCT designs. There is a need to identify is-
sues drawn from the experiences of teams conducting
pragmatic RCTs that reflect their varied attitudes to the
underlying concepts of pragmatism, as well as their ex-
periences with widely varied interventions and contexts
using different pragmatic RCT designs.
As part of a larger research programme to develop
ethical guidance for the design and conduct of pragmatic
RCTs [20,22], we interviewed key stakeholders with the
aim of identifying potential ethical challenges that prag-
matic RCTs pose.
Methods
We conducted semi-structured interviews with key
stakeholders in the design and conduct of pragmatic
RCTs including clinician investigators, methodologists,
patient partners within study teams, members of re-
search ethics committees, and knowledge users (e.g. reg-
ulators, policy makers). Individuals were eligible for
interview if they were involved in the development or
implementation of a specific pragmatic RCT, had
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published works addressing the ethical challenges in
pragmatic RCTs, had been engaged in work on the
methodological development of pragmatic RCTs, or had
been engaged in the governance or oversight of prag-
matic RCTs.
Identification and recruitment of participants
Interviewees were purposively sampled based on their
role and jurisdiction (to capture different experiences
with trials conducted under different governance struc-
tures, such as varying ethics guidelines and regulations).
In addition, interviewees were sampled to include those
with experience of a range of study designs (such as
cluster RCTs or RCTs in which health administrative
data are used for outcome ascertainment), and different
interventions (including drugs, devices, surgical, and be-
havioural trials), with the aim of generating a broad
range of perspectives on ethical considerations that re-
flect the heterogeneity in pragmatic RCT designs. Poten-
tial interviewees were identified through the study
teams investigator networks, a search of published prag-
matic RCTs (including review of two existing reviews of
pragmatic RCTs [23,24]), and searches of research fund-
ing programme websites from which self-labelled prag-
matic RCTs were identified.
Initial contact and subsequent follow up with potential
interviewees were made via email by the study team, ex-
cept for patient partners or community members of trial
teams who were approached through the principal inves-
tigator(s) for the identified studies. In this case, the prin-
cipal or nominated investigator was asked to either
provide the contact information of the patient partners
or community members involved in their trial, or to for-
ward a study invitation and consent form on behalf of
our team and to which patient partners or community
members could choose to respond. In all cases, if the
identified individual indicated a willingness to partici-
pate, a date and time for the interview was arranged. On
the agreed date, the consent form was reviewed, and
consent obtained to proceed with the interview. Recruit-
ment continued until no new or relevant data were iden-
tified, and no new categories were being generated from
the data [25].
Data collection
Interviews were conducted by one researcher (SGN) with
training and experience in qualitative methods and re-
search ethics. In addition, a subset of interviews was con-
ducted in tandem with a second member of the research
team who also had extensive training in qualitative re-
search approaches (KC). Interviews were conducted in
person, by telephone, or by web-conferencing depending
on the location and preference of the interviewee. Inter-
view guides were developed and pilot tested with
members of the study team. The full guide comprised of
three main sections: (1) experiences with pragmatic RCTs;
(2) perceptions of ethical issues relevant to pragmatic
RCTs (structured around the PRECIS-2 domains [5]); and
(3) perspectives on oversight and regulation of pragmatic
RCTs (see interview guides in Additional file 1:Ma-
terial S1 and Additional file 2:MaterialS2).The
study was reviewed and approved by the Ottawa
Health Sciences Research Ethics Board (reference
20170435-01H) and all individuals provided informed
consent to participate in the study.
Interviews were audio-recorded with consent, and
transcribed verbatim by a professional transcription ser-
vice. De-identified transcripts were made available to in-
terviewees for additional comments, apart from one
participant who died between the conduct of the inter-
view and completion of transcription. Additional com-
ments were received from three participants and were
incorporated into the final version of the transcript. In
one instance a participant did not wish to be audio-
recorded and so, with their consent, written notes were
taken instead. Finalized versions of transcripts or field
notes were imported into qualitative data analysis soft-
ware (NVivo 11 [26]) for analysis.
Analysis
Given the present goal of identifying a range of issues, as
opposed to developing an underlying theory, the exam-
ination of the transcripts was analyzed thematically [27,
28]. Transcripts were coded and labelled inductively,
with no prior coding scheme. A strength of the thematic
analysis approach is its flexibility insofar as it is theoret-
ically or epistemologically agnostic, allowing it to be
used independently of a world view.
Interviews were coded by two researchers (SGN and
KC). Each researcher independently coded the same
transcripts and met to discuss differences in coding and
reach consensus on the major themes. Due to the high
degree of consistency in the coding of an initial cohort
of texts (n= 11), (i.e., the same text segments coded in
the same or similar ways) the process was revised such
that one researcher (SG) coded the remainder of tran-
scripts, which were then reviewed by the second coder
(KC) and discussed to reach consensus. Interim and final
analyses were presented to the broader team for discus-
sion before the framework was finalized. The study is re-
ported consistent with the Standards for Reporting
Qualitative Research (SRQR) reporting guideline [29].
Results
Forty-five interviews were conducted between April
2018 and September 2018. Mean interview length was
58 minutes (range 26103 minutes). Interviewees ranged
in terms of their experience; patient partners or
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community members tended to have been involved in a
single trial, while clinical investigators and methodolo-
gists had generally been involved in multiple trials. Ethi-
cists and knowledge users, while not directly involved in
the design or conduct of trials, often had exposure to
multiple trials. Participants also varied in the types of tri-
als to which they had been exposed. These included a
range of clinical areas, such as cardiac research, critical
care, obstetrics and gynaecology, surgery, and public
health. Participants also varied with respect to experi-
ences with different types of trial design, such as cluster
RCTs or stepped-wedge designs, and trials that varied
with respect to the degree to which they were self-
identified as being more or less pragmatic on PRECIS-2
domains. As such, while the interviews used selected ex-
amples, comments and overall discussion drew on a
breadth of experiences. An overview of participant
demographics is presented in Table 1.
In this analysis we focus on the substantive areas
where interviewees identified ethical issues that were of
particular relevance to pragmatic RCTs (as opposed to
issues that were relevant to all RCTs). We identified six
major themes with ethical implications: (1) identification
of relevant risks from trial participation and determin-
ation of what constitutes minimal risk; (2) determining
when alterations to traditional informed consent ap-
proaches are appropriate; (3) the distinction between re-
search, quality improvement, and practice; (4) the
potential for broader populations to be affected by the
trial and what protections they might be owed; (5) the
broader range of trial stakeholders in pragmatic RCTs,
and determining their roles and responsibilities; and (6)
determining what constitutes usual careand implica-
tions for trial reporting. Some specific issues were raised
by particular stakeholder groups or in relation to par-
ticular aspects of design, and these are reported within
the broader themes. We discuss each theme subse-
quently, and exemplar quotes for all themes are provided
in Table 2.
Identification of relevant risks from trial participation and
determination of what constitutes minimal risk
Risk was a recurring theme. It was raised in relation to
the types of risks that should be deemed relevant (for ex-
ample, in determining eligibility criteria or for disclosure
in consent procedures) and how these differed from
usual clinical care, how risks should be incorporated and
traded off within benefit-harm analyses, when studies
should be considered to meet the designation of min-
imal risk, and implications of risk designation on the
regulations that need to be followed.
With respect to eligibility, interviewees discussed the
risks to participants and which risks should be consid-
ered relevant to setting eligibility criteria. Interviewees
commented on the benefits of pragmatic RCTS and
drew distinctions between those patients who may be at
higher risk of adverse outcomes irrespective of the inter-
vention at hand and those that may be at a higher risk
because of the intervention (see Quote 1.1). This was
noted due to the perception that pragmatic trials of min-
imal risk interventions can be employed in populations
that are of poor health. This was particularly relevant in
relation to broader considerations of potential benefits
and harms to participants in a trial, and how this was
managed within governance processes such as ethics re-
view or other regulatory reviews. For example, inter-
viewees raised the point that risk assessments may be
more complicated in pragmatic RCTs with a more
heterogenous population in which risks may accrue dif-
ferently to different sub-populations. Specific reference
was also made to the risks of trial interventions or com-
parators when these were claimed to be usual care or
standard care. Some participants suggested that when
the intervention(s) or comparator(s) was described as
usual care, it should be considered to be low or minimal
risk.
Others suggested that head-to-head trials of two usual
care interventions did not necessarily mean that there
was no risk to trial participation and rather it depended
on whether participating created a change in the partici-
pants welfare (Quote 1.2). This fed back into broader
questions of what should be considered a risk and the
comfort with conducting RCTs in contexts where pa-
tients had a poor prognosis.
Table 1 Participant demographics (N= 45)
Item Number Percent
Country
USA 16 36%
Canada 10 22%
UK 10 22%
Australia 6 13%
France 1 2%
Other 2 4%
Expertise
Clinical investigator 10 22%
Methodologist 6 13%
Ethicist or lawyer 7 16%
Knowledge user (e.g., regulator) 6 13%
Patient partner or community member 16 36%
Sex
Female 22 49%
Experience with research in low-resource settings (N= 29)
Yes 8 28%
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Table 2 Exemplar quotes for identified themes
Theme Example quotes
1. Identification of relevant risks from trial participation and
determination of what constitutes minimal risk
1.1 [A] nother issue would be around things like adverse events. [] [T]hats another
thing about pragmatic trials, relatively low risk [] but youre putting it [the
intervention] into a high-risk situation. [] [Y] our intervention is actually very low risk,
but its a question of what do you do then about your adverse events? And I do know
examples where none of the ones Ive been involved in but examples where
regulators have said youve got to collect all your adverse events which could be really,
really expensive.TE010, Methodologist, UK
1.2 I think the, the biggest issue is why something is a risk. I would say its a why
question. Its sort of like saying [] both of these are standard treatments, for example,
if youre comparing standard treatments. And if you went to one doctor this would be
an accepted treatment. You go to another doctor this is an accepted treatment its all
kind of haphazard out in the real world anyway so all were doing is randomizing so
wheres the risks? Right.[]Soits, its more of a question of conceptualizing how
people are affected because of the pragmatic trial #1, and #2 because of that is there
any change in their welfare prospect thats directly attributable to the research? I think
thats the question thats difficult to answer and not sufficiently explored.TE018, Ethicist,
USA
1.3 And then theres the issue of should we be going to treat some of them as minimal
risk which, at least in the US context, opens up the possibility of doing an expedited
review of a clinical trial.TE014, Ethicist, USA
1.4 So, so here [in Australia] its reasonably clear. Here its absolute risk, so our system
defines risk not in terms of the likelihood or probability of the risk but instead purely in
terms of the magnitude.TE024, Ethicist, Australia
2. Determining when alternative consent practices
are appropriate
2.1 [T] he trial that were running now, we focused the argument of consent for
basically giving consent to follow your data, to have access to your PHI [Personal Health
Information] and not actually for the intervention because again, you were going to get
one of these two interventions regardless. [] So, we focused our argument on that
and we havent had any problems with the IRB side of that but what I found interesting
was again the consent forms still 9 pages. [] I find that kind of stuff really takes away
from the patient receiving informed consent. They just end up with a huge stack of
paper.TE005, Clinical investigator, USA
2.2 [T] raditional people tend to argue about whether you need to include the detailed
long consent in written form versus a more abbreviated consent. The more
adventuresome people argue about whether you need consent at all if its really
answering a question about two modes of practice both of which are used commonly
and are in play where theres no particular reason to pick one over the other.TE006,
Knowledge user, USA
2.3 I think one of the problems that doesnt afflict investigator-initiated pragmatic
studies that does afflict a commercially sponsored trial is the lack of a financial incentive
for investigators to recruit patients. [T] his is where a pragmatic trial is beneficial if
youre doing a large trial with limited data collection, youre not paying investigators a
lot of money so they can generate a huge surplus then that that to me is a good thing.
TE025, Clinical investigator, Australia
2.4 I wonder if that [consent to data, not intervention] might not be the right way to
think about this kind of trial [pragmatic trials]. So, its not that youre necessarily
consenting to whichever treatment practice is the opted-for treatment practice, I mean
if both treatments are standard treatment that might be given in this case. Instead what
youre giving access to is your information and the results of that, how youre feeling
about it and all those kinds of things. I just think that might be a way of thinking about
how you could do a consent process for this.TE024, Ethicist, Australia
2.5 And then theres the issue of should we be going to treat some of them as minimal
risk which, at least in the US context, opens up the possibility of doing an expedited
review of a clinical trial which is pretty uncommon otherwise and opens up the
possibility of a waiver or modification of informed consent on US regs.TE014, Ethicist,
USA,
2.6 [Y] es, we still quite often face problems with consent. So especially in emergency
departments if were needing to invoke or trying to invoke emergency consent we still
get a lot of kickback about whether we need to go out for a proxy consent at that
point in time or whether we must go and find family members who can consent. So
there are layers of people who can consent on their behalf. And, you know, very often
our argument has been that you need to include these people for whom this is
potentially at that stage lifesaving, then we cant wait. So there is still a lot of discussion
around that and a lot of work needs to go into the crafting of the writing of the
rationale for why we want to go ahead without consent.TE008, Methodologist, UK
2.7 And the concerning issues really revolve around the ability to waive consent if the
intervention is time critical..TE023, Clinical investigator, Australia
2.8 I can easily see scandals occurring. But people really have to realize that, if a
particular clinic or a research program screws up, they could say wow that was a
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Table 2 Exemplar quotes for identified themes (Continued)
Theme Example quotes
problem with that researcher and so forth. If you do a pragmatic trial where the entire
practice infrastructure of a healthcare system is involved and which endorses what
happened [waiver of consent], then from a patient subjects perspective theyre think
this entire healthcare system conspired against me. [laugh] That could happen, you
know, if something happened. So I think that I think its a big issue.TE018, Ethicist, USA
2.9 But my worry about all this kind of stuff where youre doing stuff without getting
consent and, and so on is that is that youll get these cases where we get used to a
practice... Ethics committees become quite comfortable with it. Its standard practice and
then somebody says something to someone and somebody goes hey Im in a research
trial? What? I thought I was getting standard care? And if thats not handled really, really
carefully and it becomes a big media story it hurts recruitment for research. It hurts
funding for research and so on.TE024, Ethicist, Australia
2.10 I think that the, the legal challenges, the ethical challenges, the consent challenges
are often under played, you know. Its recognized but you have the situation where
youll have researchers having sort of this internal consensus [] and its almost like
they think that well we [will] resolve this issue without understanding that theres this
legal framework outside, these legal norms outside, that you actually have to satisfy.
That researchers or even research policy people cant do it with a workshop [laugh] and
you cant do it with a consensus meeting. Those things are not going to resolve this
issue, because the norms that determine how youre supposed to proceed are actually
designed or actually exist within liberal democracies, [] all its going to take is one
controversy and the whole thing is gonna unravel. And we saw that with Henrietta
Lacks in the United States. We saw that with the Texas blood spot situation where they
destroyed was it 6, 7, 8 million samples as a result of a couple of families complaining.
So, this matters, right you cant forge ahead on wishful thinking and a consensus of
researchers. On the contrary youve got to resolve it more broadly.TE021, Lawyer,
Canada
3. The distinction between research, quality improvement,
and practice
3.1 However, there are huge regulations around anything that you label clinical trial. So,
I can go off and behave in the most bizarre fashion as an independent clinician [], I
get there will be peer review etc. but basically, I can do what I want. If I want to include
people in a clinical trial I have to go through all manner of checks and balances which
is fair enough when youre studying experimental treatments. But when youre doing
more clinical effectiveness trials I think its possibly an ethical issue that these things are
putting enormous barriers in the way of actually doing the research that needs to be
done.TE025, Clinical investigator, Australia
3.2 [] theres this sort of double standard betweenpeople are only interested in
research ethics and not practice ethics. And, you know, doctors do unethical things all
the time [S] omeone once said in the New England Medical Journal: if I want to give
half my patients a new treatment I have to get ethics committee approval. If I want to
give all my patients a new treatment I dont.TE001, Methodologist, UK
3.3 Im quite sceptical about the kind of general case of oh we need a completely new
system;oh we need to completely change everythingand so on. Im more happy
with the kind of approach that places like Australia take where they just say its all
researchTE024, Ethicist, Australia
3.4 [T] he first thing is what kind of ethical framework [should be used with pragmatic
trials]? Is it a research ethical framework? Is it a systems or healthcare improvement
framework or is it both? [] So thats for me the biggest question and the most
important and the one that this project really needs to sort out clearly.TE002, Clinical
Investigator, Canada
3.5 Its true of any trial [that discussion happens between patients in and outside the
trial] [] so the notion of the kind of often hard line like you cant talk about this
[research outside the trial]; [this distinction], makes no sense on the recruiting side from
my perspective. [].LM002, Patient partner, USA
4. The potential for broader populations to be affected by
the trial and establishing what protections they might
be owed
4.1 I sometimes get the sense that, if youre doing a trial on women with post-partum
haemorrhage, people think its a vulnerable group weve got to be extra vigilant, but
actually what they do is by making it harder to enrol these women in clinical trials or
making it longer (the assessment process), they actually disadvantage them instead of
doing anything good for them.TE001, Clinical Investigator, UK
4.2 [W] here everybody is potentially involved, how do we make sure from a language
barrier standpoint or an economic standpoint that people arent excluded because
theyre not asking the right questions or they dont understand the material. So I think
the medical things [exclusion criteria] made perfect sense to me and I think we dealt
with it more on an inclusion side than an exclusion side.LM006, Patient partner, USA
4.3 The one issue is, how do we trade off, or do we need to trade off, or even, do we
need to think about the ethics of those in the trial, those in the control group versus
those in the intervention group and those outside the trials who might one day be
eligible for these things. [] I think it might be an idea to think about that question
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Table 2 Exemplar quotes for identified themes (Continued)
Theme Example quotes
against a number of different groups: patients offered the intervention, patients
receiving the intervention, patients in the control group, patients who might one day
benefit from the information from this trial.TE002, Clinical investigator, Canada
5. The broader range of trial stakeholders in pragmatic
RCTs, and determining their roles and responsibilities
5.1 I guess thinking more expansively, more recently there has been a lot of suggestion
or proposals to increase the efficiency of trials by doing registry-based randomized trials,
which is again an extension of the same practice [...] And whos the guardian of that
data and who should make these approaches and who should allow potentially a trial
to sit overly on that dataset. So guardianship issues, permission issues, consent issues,
approach issues, privacy issues.TE008, Methodologist, UK
5.2 [] there have been trials that have kind of got both the scientific regulator and
the payers points built in [] But the objectives I think are quite different. I mean the
regulator is looking purely at efficacy and safety so the regulators coming to it from the
more explanatory end. And the payer is looking at quality of life or qualities or
effectiveness. Thats whats coming into it in the more pragmatic end.TE015, Knowledge
user, UK
5.3 The most interesting IRB ethics thing that Ive been involved in over the last couple
of trials is essentially this off label use [] the FDA or Health Canada they dont
necessarily want to review every single clinical study being done in the country, yet the
rules are that if its off label they need to. And, at least in the US, the FDA has written
very clear guidance documents that basically say the best people to understand
whether this off-label use increases the risk to the patients are actually the practitioners
and the local IRB. But the local IRBs still dont want to take on all the liability per se so
then they still make you go through the FDA. And that again has been very frustrating
because that really is the pragmatic side, right?TE005, Clinical investigator, USA
5.4 The one thing that I am very clear on and my PPI group were very clear on was
that we were not the medical side of the trial. We were the public trial and we took
advice from the professors etc. as to what things like the placebo should be.LM007,
Community member, UK
6. Determining what constitutes usual careand
implications for trial reporting
6.1 [] obviously its one of those things [usual care] where theres no agreement and
I think the most you can do is explain what you mean every time for a given situation. I
mean the standard of care is actually more often used in the legal setting in terms of, if
you did something wrong. If youre accused of malpractice, you could say no, this was
standard practice. This has been the standard within the community of physicians and
for this kind of disorder and so forth. And then there might be instances where an
intervention might not be used very often, in fact rarely used for purely practical or
accidental historical reasons, but no one would think that that was substandard if you
used it, right?TE018, Ethicist, USA
6.2 usual care is how patients are treated in routine practice if you can profile usually
from EHR data sources. So, for example, a patient with diabetes in a given healthcare
system, how frequently are they seeing their primary care doctor and their
endocrinologist on a yearly basis? What proportion of them are on insulin or other
diabetes agents? And how does that conform to recommended practice guidelines? So
guidelines define some of that but your local care pattern is going to differ a little bit
from the guideline. But you can define that and it will differ by region and
environment.TE007, Clinical investigator, USA
6.3 I think that [usual care] fits in nicely with the whole pragmatic/explanatory thing. So
on the pragmatic side my interpretation would be usual care is at the individual
practitioner level []And on the explanatory side usual care will be some national,
regional standard that everybody can agree on and then therefore you can standardize
usual care to sort of a standard of care.TE005, Clinical investigator, USA
6.4 Well usual cares not a single thing. Usual cares whatever that patient would have
got in contact with whatever clinician they happened to be in contact with in whatever
clinic they happened to be in. And so, the problem with usual care which explanatory
trialists really struggle with and, and so they should and so should we as more
pragmatic trialists, is the care that the control group gets in a usual care trial is going to
be pretty variedTE002, Clinical Investigator, Canada
6.5 I think others have argued well once you get consent from someone youre
obligated in the usual care arm to give them the standard of care which is almost
always higher than the usual care that people actually get. I dont subscribe to that, but
I also think there are many trials in which to answer the scientific question and, and the
pragmatic question you actually do need to give standard of care.TE006, Knowledge
user, USA
6.6 [] are you compromising standard of care by having them [specific patient
groups] in the study? Meaning that if you withhold standard of care therapies or
treatments as part of a patients participation in the study, thats not ethical. The study
should actually look at things on top of that or in comparison to it, but withholding it is
not proper.TE007, Clinical investigator, USA
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A key aspect to the discussion of risk was how risks
were managed within the oversight of pragmatic RCTs,
such as ethics review processes or regulatory require-
ments. An aspect of the discussion relating to risks of
usual care interventions was whether this opened oppor-
tunities for different types of review process (see Quote
1.3). On this point, it was noted that different jurisdic-
tions may apply different standards to determine the re-
view requirements with some jurisdictions applying
assessments of relative risk of participation in the RCT
(i.e., additional risks to participants generated by the re-
search study) while others may employ assessments of
absolute risk (i.e., risk of an outcome that is based purely
on the likelihood of the outcome irrespective of that in-
cremental differences between research and care), which
may lead to different process requirements (Quote 1.4).
The importance of risk determinations, and in particular,
a determination that a trial poses minimal risk to partici-
pants, for governance decisions was emphasised. It was
noted that, in some cases, a designation of minimal risk
could serve as a necessary condition for expedited or
delegated review of research protocols, or waiver of con-
sent. However, this again was subject to jurisdictional
variation with respect to the types of studies that could
be considered under an expedited review process, even if
deemed to be minimal risk.
Determining when alternative consent practices are
appropriate
Interviewees discussed a variety of alternative consent
processes, ranging from verbal discussion and acknow-
ledgement, to deferred consent, proxy consent, opt out
approaches (with and without notification), and waiver
of consent. While interviewees raised many concerns
that are already well-documented within the broader
clinical trials literature (such as perceptions that ethics
review committees spend substantial time reviewing and
commenting on consent forms at the expense of consid-
eration for other aspects of study design), three
particular consent-related issues were emphasized with
respect to pragmatic RCTs, namely: (1) the potential for
consent to be simplified or modified from standard writ-
ten consent practices and the circumstances where this
may be legitimate; (2) the separation of consent to trial
interventions and consent to data collection, and; (3) the
acceptable instances where consent can be waived
completely.
There was much discussion of (and consternation at)
existing consent approaches, and a desire to simplify
these (Quotes 2.12.2). For example, an integrated con-
sent approach in which clinicians approach participants
for consent to the RCT within the clinical encounter
was discussed as an alternate approach. While recruit-
ment of trial participants by their treating clinician is
not a unique issue in pragmatic RCTs, it was flagged as
potentially being more pronounced in pragmatic RCTs
due to the closer integration of research and clinical
care. This was raised as a consideration due to the per-
ception that, as several interviewees commented, prag-
matic RCTs were less likely to have commercial
investment and so may have lower budgets that limit in-
frastructure to support recruitment. While some inter-
viewees raised concerns about the potential for patients
to feel a pressure to participate when recruited by their
treating physician, some saw the lack of financial sup-
port for recruitment as ethically advantageous. This was
based on the perception that the limited resources pre-
vent physicians from being remunerated based on the
number of people they recruit, thus removing the poten-
tial financial incentive to over recruit or recruit margin-
ally eligible or unsuitable participants (Quote 2.3).
While alternative approaches to traditional written in-
formed consent were discussed, participants varied in
their enthusiasm for adapting or altering consent ap-
proaches. Rather than seeking alternate approaches that
sought to capture a single consent for all aspects of the
study (i.e. that covered enrollment, interventions, and
data collection), some argued it may be appropriate to
Table 2 Exemplar quotes for identified themes (Continued)
Theme Example quotes
6.7 the major concern, of course, is that routine practice is changing all the time. Well
we hope it is, I mean, there is all this money going in for infrastructure and for []
capacity building on a routine basis. Its much harder, then, to think of a pragmatic trial
that will exactly mirror routine practice that is itself flexible. So rather than the
intervention being flexible its[] whether the intervention evaluated in a pragmatic
trial is [] going to map on to the intervention as it appears in routine practice [and] to
how relevant the data will be.TE020, Ethicist, UK
6.8 The other part of pragmatic trial is that the intervention could be less described or
some part of the intervention could be different from one physician to another in
pragmatic trials. You could either explain very well all the different components of your
intervention or you could decide in your pragmatic trials that some of the components
of the interventions are to the discretion of the physician [] Even if it is stuff like that
it must be at least reported in the paper and its not always reported.TE016, Clinical
Investigator, France
RCT randomized controlled trial
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consider to what the trial participants should consent.
For example, one interviewee provided an analogy to
education research arguing that when an intervention is
consistent with accepted standards and is unavoidable,
then it may be more appropriate to disentangle consent
to the intervention and consent to data collection
(Quote 2.4). In this case, consent would be sought only
for data collection in the study, as opposed to the expos-
ure to the intervention that could not be avoided with-
out extensive means.
A particular aspect of discussion was the circum-
stances under which one could consider a waiver of con-
sent, thus avoiding consent entirely. When waiver of
consent was raised, participants discussed the criterion
of impracticability, as well as the aforementioned criter-
ion of minimal risk (Quote 2.5), and under what circum-
stances these could arise. When considering
impracticability, discussion revolved around the urgency
of the intervention, the population being studied, re-
sources required (both financial and human), or setting-
related characteristics that may make it impracticable to
get individual consent (Quotes 2.62.7).
A note of caution, however, was raised on the use of
waivers of consent. Several respondents emphasized the
potential fall-out of failing to manage the use of waivers
appropriately. Particular caution, almost exclusively
raised by the ethicist and legal stakeholder participants,
referred to the need for consent approaches to be con-
sistent with legal norms and requirements, but also how
negative media coverage of studies using a waiver of
consent may serve to erode public trust and have a
harmful impact on research through reduced recruit-
ment or funding (Quotes 2.82.10). In making these
points, respondents described historic research ethics
cases (such as organ retention at Alder Hey Childrens
Hospital in the UK and at Greenlane Hospital in New
Zealand [30,31]).
The distinction between research, quality improvement,
and practice
Frustration was expressed at the lack of agreed criteria
for demarcating clinical practice, quality improvement,
and research. While the lack of clarity regarding the dis-
tinction was commented on by all stakeholder groups,
the context in which the comments arose differed be-
tween the patient partners and community members,
and other groups such as the clinical investigators and
methodologists. The clinical investigators and methodol-
ogists tended to discuss the distinction in the context of
the research ethics and regulatory requirements (Quotes
3.1 and 3.2); with the perception that the distinction be-
tween research and practice was ill-defined, and that cri-
teria such as intent to publish were inappropriate. Other
interviewees argued that when the interventions under
investigation are used in routine clinical practice, there
may be negligible difference between the research and
practice; referred to by one participant as patients re-
ceiving randomizedcare rather than random(i.e., ar-
bitrary) care. Thus, a common claim was that flawed
criteria were being used to make the distinction between
activities that needed regulatory oversight and those that
did not and that this was resulting in an unnecessary ad-
ministrative burden for research when in fact the pa-
tients situation was perceived to be no different than
what it would be in usual care, without the research.
Others suggested that there may be some criteriasuch
as generalizability of the resultsthat may be relevant to
distinguish research from practice (Quote 3.3). However,
perceptions of appropriate regulatory perspectives var-
ied, with some respondents arguing for the development
of new health systems ethics frameworks, while others
argued that existing frameworks were likely sufficient,
but greater exposure to pragmatic RCTs is needed
(Quote 3.4).
By contrast, patient partners and community members
reflected on their real-life experiences of patient care
and participation in research, and how the boundaries
between research and practice were blurred or non-
existent for them. Specifically, they noted how patients
transition between research and care with an informa-
tion flow between the two or how information about tri-
als is exchanged informally between patients in their
clinical care (Quote 3.5). As such, interviewees proble-
matized the idea of a clear line between the research and
clinical aspects of care.
The potential for broader populations to be affected by
the trial and establishing what protections they might be
owed
Interviewees discussed how pragmatic RCTs may in-
clude a broader range of patients than explanatory trials
that might only have included a subset of a clinical
population, and that this raised challenges of identifying
the extent to which particular groups or individuals may
be affected by the trial and the protections owed to
them. Others discussed how pragmatic RCTs of health
systems or health policy trials may have an impact on in-
dividuals not traditionally considered to be research par-
ticipants and raised questions on how responsible
parties should respond. This was not just in relation to
who may be affected in a material sense, but also those
who may expect to have legitimate claims of those con-
ducting the trial.
One particular area of concern was equity and justice
in relation to the participants who were recruited within
trials. Interviewees raised concerns about groups, such
as pregnant women, children, and those patients with
co-morbidities, being excluded from explanatory trials
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and how pragmatic RCTs may be beneficial in this
regardbecausetheyweremoreinclusiveoftherange
of patients who would be seen in usual practice
(Quote 4.1). Several patient partners and community
members also pointed out the potential for inequal-
ities within trials and how there may be systemic
barriers to participation, such as limited literacy
levels or home commitments, even when participants
met inclusion criteria (Quote 4.2). The exclusion of
participants based on elements not associated with
eligibility criteria was viewed as a potential threat for
pragmatic RCTs when compared to explanatory
RCTs. However, it was also noted that in some juris-
dictions, such as France, certain patient characteris-
tics, such as ethnicity, cannot be collected, which
may preclude consideration of certain equity issues
within the trial.
Interviewees also reflected on whether and to what
extent pragmatic RCTs should have a broader consid-
eration with respect to the range of individuals or
groups affected by the trial, in terms of those affected
during the conduct of the trial, but also subsequently
affected by the results. One example given was how
members of the public who provide cardiopulmonary
resuscitation may be affected by research on out-of-
hospital resuscitation but have limited contact with a
study. In this instance, the interviewee raised the
question of what those members of the public were
owed in terms of research protections or follow up.
Other examples included whether the impact of an
intervention on family members who may support
frail or cognitively impaired participants should be
captured within studies. Others raised the question of
whether there is a need to consider ethical obligations
to the background populations from which trial par-
ticipants are drawn in pragmatic RCTs or even to fu-
ture generations of patients. The question was then
raised as to what rights or protections these groups
areowed(Quote4.3).Similarly,thequestionaroseas
to how we should consider stakeholders groups who
occupy multiple roles. For example, healthcare staff
may be the target of an intervention while simultan-
eously having to collect data from patients and fam-
ilies or provide feedback on an intervention and so
may be considered participants, but also part of the
trial intervention. As such, issues were threefold:
which individuals fall within the bounds of those
owed protections within the context of the trial? On
what basis are these boundaries drawn? And what are
the identified individuals or groups owed in terms of
protections or rights relative to the trial; that is, can
we establish differential protections or responses to
these individuals depending on the extent to which
they are affected by the trial?
The broader range of trial stakeholders in pragmatic
RCTs, and determining their roles and responsibilities
Interviewees noted that pragmatic RCTs employ a range
of designs or design features, such as comparative effect-
iveness research on interventions routinely offered in
usual-care settings, and may evaluate a wider range of
interventions, such as policies, than traditional explana-
tory trials, which often focus on new drug treatments or
technologies. Because of this broad range of designs,
contexts, and interventionsincluding complex inter-
ventionsparticipants indicated that pragmatic RCTs
potentially engage a broader range of stakeholders in
their design or conduct.
While interviewees identified commonly cited groups,
such as trial steering committees, data safety and moni-
toring boards, clinicians, and researchers as stakeholders
with important roles and responsibilities, they also iden-
tified other groups. These included healthcare adminis-
trators, health maintenance organizations, clinical
research regulators (such as Health Canada or the Food
and Drug Administration), and stakeholder advisory
committees that include a broader range of perspectives
such as patient partners. This broader range of stake-
holders potentially engaged within a trial predicated
further ethical considerations in terms of not only ne-
gotiating who had ethical responsibilities as part of
the trial, but also how the identified responsibilities
were divided between the different stakeholders. For
example, when a trial accesses registry or health ad-
ministrative data, how does one determine who the
relevant stakeholders are and what they are respon-
sible for? (Quote 5.1).
As an example, it was observed that some trials may
attempt to satisfy multiple stakeholders (such as payers
and regulators) in an effort to be more efficient, yet the
differing perspectives and needs of these stakeholders
also had the potential to raise tensions within the trial,
for example in terms of the design choices that may bet-
ter satisfy one stakeholder than another (Quote 5.2).
One participant noted how a trial in which regulated
drugs were used off labelled to the regulator and re-
search ethics committee trying to ascribe responsibility
to the other, suggesting that the division of responsi-
bilities between multiple stakeholders may be con-
tested (Quote 5.3). Others noted how within a trial
team there would be areas for each stakeholder that
were deemed to be legitimately within their scope for
comment and others that were outside their scope.
For example, several patient partners and community
members made reference to identifying and raising is-
sues of inequality within the trial as part of their per-
ceived role within the trial team, but indicated
methodological aspects of study design may be out-
side their remit or expertise (Quote 5.4).
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As such, interviewees raised the identification of stake-
holders who have roles to play in the design and conduct
of pragmatic RCTs as a necessary prerequisite to then
determining what responsibilities, including their duties
to trial participants, those stakeholders have, but that
these stakeholders may extend beyond clinical investiga-
tors and their teams.
Determining what constitutes usual careand
implications for trial reporting
Interviewees demonstrated varied interpretations of the
term usual caresometimes using the term interchange-
ably with routine careor with standard of care. Some
pointed to specific differences in terminology. For ex-
ample, in a medical-legal context, the term standard
practicemay be used to describe acceptable practice as
opposed to a more epidemiological use where usual
caretended to be used to describe the care most fre-
quently used for a particular clinical condition (see
Quote 6.1).
As previously mentioned, interviewees had different
views about how usual care should be defined, which in-
fluenced perceptions of what evidence would be neces-
sary or sufficient to demonstrate a practice as usual care.
Descriptions included consistency with local practice or
consistency across study sites, while others argued that
local variation, national practice variation, and practices
laid down in guidelines could all be determining factors
as to what constituted usual care (Quotes 6.26.4).
Other dimensions of discussion included how usual
careas a description of practicewas differentiated
from standard of care or practice standards defined as
an expected level of care to be received. One example of
this was concern about potential liability for adverse
events when evaluating practices that differed from prac-
tice standards, such as those laid down by a Ministry or
College. Others suggested that offering substandard care
within a trial (either in the intervention or comparator
arms) was unethical, even if it was consistent with usual
care (Quotes 6.5 and 6.6).
Some interviewees further problematized the notion of
usual care as a discrete and static comparator. For ex-
ample, some suggested that in quickly developing spe-
cialties, or in low-resource settings, rapidly evolving
practice would make it difficult to impose a single prior
standard (even at individual study sites) as usual care
(Quote 6.7). This latter point was especially emphasized
in the context of reporting trial interventions. It was
noted that when trials make claims to be applying inter-
ventions or comparators that represent usual care, this
required clear reporting to understand what exactly con-
stituted that care. For some, the reporting of interven-
tions labelled as usual care in pragmatic RCTs was
viewed as suboptimal (Quote 6.8).
A final aspect raised by interviewees was holding usual
care as a standard when usual care was not necessarily
based on evidence. Several interviewees argued that a ra-
tionale for pragmatic comparative effectiveness RCTs of
existing practices was, in fact, that practices had devel-
oped based on expert opinion and not necessarily be-
cause of evidence of benefit. As such, explicitly
examining those care standards was key.
Despite the definitional differences, variation in usual-
care practice was important for consideration of equi-
poise. For example, several participants discussed how
variation in usual practice regarding the use of treatment
options would be indicative of uncertainty with respect
to which was best and so would demonstrate community
equipoise and justification for a trial.
Discussion
In the present study we interviewed a range of stake-
holders to explore their perspectives on ethical issues
raised by pragmatic RCTs. The substantive areas of dis-
cussion were highly consistent with topics in the clinical
trials literature, including risk [3234], consent [35,36],
the governance of research activities [24,37,38], the se-
lection of study participants [39], the roles and responsi-
bilities of different stakeholders [4042], and the
publication and reporting transparency of trials [4346],
but also indicated that the available literature on ethics
in pragmatic RCTs is relatively narrow in its focus. Our
findings suggest that not only do we need to discuss fa-
miliar topics (such as appropriate consent approaches
and participant protections) in new ways, but also that
there are new questions (such as the different roles and
responsibilities of a broader range of stakeholders in
pragmatic RCTs) that need to be addressed.
These findings must be considered within the limita-
tions of the study. First, interviews were conducted in
English only. Consequently, issues pertaining to language
or that may be specific to jurisdictions where English is
not commonly spoken may be underrepresented. To try
and mitigate this to a degree we interviewed respondents
from a broad range of jurisdictions, including jurisdic-
tions where the primary language is not English, and
who had experience in a range of contexts. Second, pa-
tient partners and community members of study teams
were recruited via the principal investigator of the iden-
tified study due to lack of a prior sampling frame. This
may have introduced selection bias for a more posi-
tive outlook on pragmatic RCTs. Finally, participants
were not provided a single definition of what consti-
tuted a pragmatic RCT. As such, definitions of prag-
matic RCTs may have differed, yet the similarity of
issues raised across participants suggests that any
variation in definition had little influence on the key
ethical issues they identified.
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Central to much of the discussion was risk. This ac-
cords well with work by Kim and colleagues [34,36], for
example, who have not only questioned whether usual
care interventions may be considered more than min-
imal risk, but also note the important role that risk as-
sessment has for research ethics committees in their
evaluation of the potential benefits and harms of re-
search. While Chen and Kim [34] propose a framework
for the analysis of risks, controversies on the nature of
risks and the extent to which risks must be disclosed
[4751] illustrate that there is still disagreement on the
relevant risks to be considered within trials, how these
should be conceptualized, and how these are conveyed
to trial participants. The development of guidance and
best practices will not only need to engage with those
stakeholders who review and oversee the conduct of
pragmatic RCTs, such as research ethics review commit-
tees, but will necessitate discussions between researchers
and the patient community with respect to understand-
ing what are important risks for consideration and how
these can be conveyed in an appropriate manner.
Despite the prominence of consent as a topic of dis-
cussion (e.g. [5256]), an aspect raised here, but which
is largely missing within the literature on pragmatic
RCTs, was the need to engage with the broader legal
norms that cover consent and the potential negative im-
pact on public trust and the social licence for research
[57] should alterations and waiver of consent be the sub-
ject of negative media coverage or legal challenges. This
was identified by a 2014 report to the UK National
Health Service, and which indicated that there may be
important differences between types of trial with respect
to additional consent needs and that guidance was re-
quired to balance legal requirements while minimizing
burdens to the patient and the person seeking consent
[58]. We suggest that such guidance remains necessary.
While there has been some discussion on the protec-
tions owed to directand indirectparticipants of re-
search [53] this debate has tended to focus on those
proximally affected by a trial. The emphasis from inter-
viewees in the present study was that there is a need for
broader debate with respect to the individuals or groups
affected by trials, and that this should also consider
those more distal to the trial. A particular concern relat-
ing to trial participants was justice and equity. This em-
phasis on justice aligns well to the importance placed on
including participants in pragmatic RCTs that reflect
typical clinical populations [59], but also concerns
expressed within previous studies of trial recruitment
that found patients may be excluded by clinical re-
searchers for practical reasons such as ability to travel or
level of education rather than clinically relevant eligibil-
ity criteria [60]. Recent work by Johnson et al. indicates
that the degree of pragmatism of an RCT may be
perceived to change over time between design and im-
plementation [61]. While such changes may reflect prac-
tical constraints or changes that need to be made,
vigilance should be maintained with regard to equity
considerations if changes affect the trial population.
Moreover, the attention to equity conveyed here may
also reflect a growing appreciation that justice require-
ments have not received sufficient attention within the
research ethics literature, as emphasized by recent revi-
sions to the Council for International Organizations of
Medical Sciences (CIOMS) guidelines, which explicitly
raise the topic of social justice in research [6265].
The potential for different individuals or groups to be
affected by a pragmatic RCT in different ways and to dif-
ferent extents raises the possibility that one should con-
sider whether there are differing responsibilities to those
affected by an RCT. Recent work has explored whether
it would be ethically permissible to offer different finan-
cial payments to individuals enrolled within a trial if this
addressed inequalities in the burdens imposed by trial
participation [66] but, to date, the question of whether
different obligations are owed to individuals differently
affected by pragmatic RCTs has largely not been
addressed.
While guidance, such as the Ottawa Statement on the
Ethical Design and Conduct of Cluster Randomized Tri-
als [67], identifies gatekeepers as serving an important
role in cluster randomized trials, interviewees identified
a broader set of individuals (such as healthcare adminis-
trators) who may feature in the development of prag-
matic RCTs. How the roles and responsibilities of
different stakeholders should be partitioned has received
little attention in the literature on pragmatic RCTs. Con-
sistent with the range of stakeholders identified in the
present study, Faden et al. [40] identify healthcare ad-
ministrators, payers, and purchasers as having important
moral obligations in the context of learning activities,
yet how these individuals should share responsibilities
remains unclear. Whicher et al. [42] have proposed an
ethical framework that outlines the roles of gatekeepers
at different research stages, but this framework re-
quires extension to specify to whom the stakeholders
have responsibility within each of the identified re-
search stages.
A final area of discussion was the concept of usual (or
standard) care, a topic that has been a key point of dis-
cussion within recent trial controversies [47,48,50,68].
As per Zwarenstein et al. [69], we do not wish to pre-
scribe a specific definition of usual care. Rather we note
that it is the responsibility of the trial team to determine
and appropriately describe what usual care constitutes.
However, consistent with the CONSORT extension for
pragmatic trials [43] and the Template for intervention
description an replication (TIDieR) guidelines [70],
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describing control interventions or co-interventions as
usual careis not sufficient and they should be de-
scribed in the same level of detail as the intervention
arm. Notwithstanding the presence of these reporting
guidelines, there is a paucity of research evaluating the
extent to which the reporting of pragmatic RCTs meet
recommendations.
Conclusions
Based on this analysis we propose a set of questions that
require further attention within the trial ethics literature
(see Table 3). We believe that future work addressing
these questions will contribute to ethically and empiric-
ally informed guidance and may greatly enhance the de-
sign and conduct of pragmatic RCTs.
Table 3 Key ethical questions for future evaluation
Key feature of pragmatic trials Explanation Ethical questions to be addressed
A key feature of pragmatic RCTs is that they
often involve minimal modification of the
clinical setting or organization and evaluate
interventions commonly used in practice
Pragmatic trials may include elements of
clinical practice, quality improvement, and
research and these may have different
implications for regulation or oversight
What are the ethically important distinctions
between research, clinical practice and quality
improvement in pragmatic trials? What criteria
should be used to determine the type of
oversight and regulation necessary for a
pragmatic RCTs? How should these activities
be regulated and on what basis would
regulatory oversight differ?
Pragmatic RCTs seek to minimize the
discrepancy between the trial and usual
clinical care, which may include approaches to
patient consent
Pragmatic RCTs may seek to recruit
participants using altered consent approaches
compared to standard written consent for
research.
When are alterations and waivers of traditional
informed consent appropriate in pragmatic
RCTs? Does the general requirement for larger
sample sizes and emphasis on external validity
in pragmatic RCTs constitute a sufficient
justification for waivers or alterations of
consent (or may it raise concerns)?
It can be difficult to determine which risks
and benefits need to be disclosed to
participants in the informed consent process
when risks may be no more than usual care
What risks and benefits should be disclosed to
participants in pragmatic RCTs of usual care
interventions?
A key feature of pragmatic RCTs is that they
seek to generate evidence applicable to a
(the) wider population
There may be different actors (both within
and outside of the trial in question) whose
interests are affected by pragmatic RCTs in
morally relevant ways
Who are the individuals or groups affected by
the trial (and how do we determine who have
legitimate claims on those conducting the
trial)?
Systemic barriers to trial participation may
exist even when individuals are eligible
What are the responsibilities of identified
stakeholders with respect to equity of access
to pragmatic RCTs for those who are eligible?
How should these responsibilities be
determined?
A key feature of pragmatic RCTs is that they
often include policy-relevant or health
systems-relevant questions
There may be stakeholders who may
influence the conduct or outcomes in
pragmatic RCTs; they may have different
responsibilities
Who are the stakeholders who have roles or
responsibilities in relation to the trial (and how
do we determine the individuals or groups
who have roles)? What are their duties or
responsibilities within the trial?
A key feature of pragmatic RCTs is that they
may include a broader patient population
with a broader range of risks/benefits and
often assess interventions commonly used in
practice (or already approved) that may be
low risk
Due to inclusion of heterogeneous
populations, pragmatic RCTs may include risks
and benefits of differing magnitude which
may accrue to different individuals or groups
How should we identify relevant risks and
benefits to individuals or groups within a
pragmatic RCT? How should these risks and
benefits be evaluated?
Pragmatic RCTs may not be exposing
participants to treatments of unproven
effectiveness; the use of existing treatments
may have more well-characterized risk and
benefit profiles
a
.
What criteria should be used to classify a
pragmatic RCT as minimal risk?
External validity is key to pragmatic RCTs; in
addition, they often include a comparator arm
of usual carethat is heterogenous
It can be difficult to determine what
constitutes usual care and what meets legal
definitions of accepted medical practice in
pragmatic RCTs
What evidence is required to substantiate a
claim that an intervention or comparator is
usual care and if this would constitute
minimal risk? Are two standardized arms
within a usual care range actually usual care?
Interpretation of a pragmatic RCT requires that
the trial context (including the nature and
variation within the intervention and
comparator) is reported well
What are the essential elements of pragmatic
RCTs that must be reported? How well are
pragmatic RCTs reported, especially in relation
to the constitution of usual care arms?
RCT randomized controlled trial
a
This may not be the case for complex interventions, which may add further difficulty for risk assessment and evaluation for risk/benefit ratios
Nicholls et al. Trials (2019) 20:765 Page 13 of 16
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
We suggest that, despite existing guidance on min-
imal risk and consent approaches [71], there is a need
for further work to develop practically applicable
frameworks for risk assessment in pragmatic RCTs
and on the disclosure of risks to potential participants
especially where claims to routine, standard, or
usual care are made. We propose that notions of
usual care require greater conceptual exploration with
respect to the identification of relevant risks and con-
duct of benefit-harm analyses, as well as practical
guidance on how researchers and regulators should
describe and interpret interventions or comparators
described as usual care.
Furthermore, guidance with respect to when and how
alternate consent approaches may be employed remains
necessary. In particular, we suggest there is a need for
greater discussion of the circumstances under which
waivers of consent may appropriately be employed and
the risks and benefits that need to be disclosed to partici-
pants, particularly in the context of pragmatic RCTs with
a usual-care arm, which may change over time.
Finally, the roles and responsibilities of key stake-
holders and the rights and protections owed to different
populations who may be affected by a pragmatic RCT
require further elaboration and guidance as to how these
may differ from those in more explanatory RCTs. Here,
special consideration should be given to justice and
equity concerns, given the potentially heterogenous pop-
ulations within pragmatic RCTs.
Supplementary information
Supplementary information accompanies this paper at https://doi.org/10.
1186/s13063-019-3899-x.
Additional file 1. PRECIS-2 Framework
Additional file 2. Trial expert interview guide.
Additional file 3. Patient partner and community member interview guide.
Additional file 4. List of investigators for the CIHR Ethics of Pragmatic
Trials project.
Abbreviation
RCT: Randomized controlled trial
Acknowledgements
We would like to thank the trial investigators who facilitated study
recruitment of patient partners and community members, and all
interviewees who agreed to take part. For a complete list of the full
investigative team see Additional File 4.
Authorscontributions
MT, CW, JMG, and DAF conceived the project idea and co-led the funding
application. SGN, KC, MT, MZ, SPH, JCB, CEG, DAF, IDG, JM, and CW devel-
oped the interview guide. SGN and KC conducted the interviews and ana-
lysis. SGN wrote the initial draft of the manuscript with input from MT and
KC. SGN, MT, KC, CW, DAF, MZ, SPH, IDG, JCB, JM, CEG, and JMG all contrib-
uted critical revisions and approved the final manuscript.
Funding
This work is supported by the Canadian Institutes of Health Research
through the Project Grant competition (competitive, peer-reviewed), award
number PJT-153045. JMG holds a Canada Research Chair in Health Know-
ledge Transfer and Uptake. CW holds a Canada Research Chair in Bioethics.
IDG is a recipient of a Canadian Institutes of Health Research Foundation
Grant (FDN# 143237).
Availability of data and materials
The datasets generated and/or analyzed during the current study are not
publicly available due potential identifiability.
Ethics approval and consent to participate
The study was reviewed and approved by the Ottawa Health Sciences
Research Ethics Board (reference 20170435-01H) and all individuals provided
informed consent to participate in the study.
Consent for publication
All authors have approved the manuscript for publication.
Competing interests
CW receives consulting income from Eli Lilly and Company Canada. MZ has
received reimbursement for conducting training in pragmatic trial design
from National Cancer Institute, NIH; and Karolinska Institute, Stockholm,
Sweden. The remaining authors declare that they have no competing
interests.
Author details
1
Clinical Epidemiology Program-Ottawa Hospital Research Institute (OHRI),
Ottawa, ON, Canada.
2
Centre for Studies in Family Medicine, Schulich School
of Medicine and Dentistry, Western University, London, ON, Canada.
3
School
of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada.
4
Rotman Institute of Philosophy, Western University, London, ON, Canada.
5
Center for Bioethics, Harvard Medical School and Program on Regulation,
Therapeutics, and Law at Brigham and Womens Hospital, Boston, MA, USA.
6
Department of Medicine University of Ottawa, Ottawa Hospital Research
Institute (OHRI), ON, Ottawa, Canada.
7
School of Public Health and Preventive
Medicine, Monash University, Melbourne, Victoria, Australia.
Received: 25 June 2019 Accepted: 8 November 2019
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... III. A pragmatic study design, almost solely present among the later RCTs in our review, also potentially has ethical issues related to its ICs [13] as we will further discuss under a separate subheading. ...
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Background It was our impression that safety outcome trials were getting more frequent, raising ethical issues mainly related to patient autonomy. We and others had also proposed this autonomy would be best served if wording of the informed consents would be in the public domain. Methods Initially two observers and an arbiter tabulated the main aims of randomized controlled trials (RCTs) published in 1990–1991 vs. 2019–2020 as efficacy, safety, or undecided in four mainline medical journals, from the websites. A pragmatic design as well as other salient features was also tabulated. After noting too many trials were categorized as undecided, two additional independent observers and the arbiter did a reassessment. Results In our reassessment of 889 RCTs, 309 in earlier and 580 in the later time period, 828 (93%) were categorized as efficacy and 47 (5%) as a safety trial. We were undecided in 14 (2%) trials. The proportion of safety outcome trials between the two time periods were similar [14/309 (5%) vs. 33/580 (6%)] while RCTs of any category conducted in the critical care settings notably increased in time [12/309 (4%) vs. 52/580 (9%) OR 2.4; 1.3–4.6]. Death was a primary outcome measure in 0/14 among the earlier and 16/33 (49%) among the later safety outcome trials. Stroke in 9 and myocardial infarction in 8 safety outcome trials were additional primary outcome measures in the same group. There were 2 pragmatic trials in the earlier and 93 in the later period. Conclusion Although we did not observe a differential increase among the safety outcome trials of all categories, those in critical care settings had significantly increased in time. So did the safety outcome trials with primary outcome measures like death, myocardial infarction, and stroke as well as randomized controlled trials with a pragmatic design. These raise the issue of autonomy related to how clearly the sought-after safety through designing empirical studies primarily to quantitate harm had been worded to the trial participants in plain language. We maintain this issue cannot be adequately addressed unless the informed consent forms, especially for safety outcome trials, are in the public domain.
... Despite the evolving international debate on the role of consent for pragmatic trials and the need to review current consenting requirements when the risk for participants is considered to be low [27], in Australia ethics committees currently rarely delineate between traditional and pragmatic RCTs in this regard. Based on some responses from interviewers and increasing articles calling for international consensus and reform around this space [27][28][29][30][31], consent for pragmatic trials is an evolving matter and hopefully one that lands on a pragmatic consenting solution which is risk assessment based. Overall current ethics requirements were not identified as onerous or overly prohibitive but responses did highlight the opportunity to pursue a more simplified review pathway commensurate to the RRCT risk profile. ...
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Background Traditional randomised controlled trials (RCTs) are the gold standard for evaluating the effectiveness of interventions in clinical research. Traditional RCTs however are complex, expensive and have low external validity. Registry-based randomised controlled trials (RRCTs) are an emerging alternative approach that integrates the internal validity of a traditional RCT with the external validity of a clinical registry by recruiting more real-world patients and leveraging an existing registry platform for data collection. As RRCTs are a novel research design, there is limited understanding of the RRCT landscape in Australia. This qualitative study aims to explore the RRCT landscape in Australia including current capacity and capabilities, and to identify challenges and opportunities for conducting RRCTs. Methods We conducted 30 semi-structured interviews with 18 clinician researchers, 6 research program managers and 6 research governance officers. Interviews were audio-recorded and transcribed verbatim. We analysed the data using thematic analysis. Results We identified four overarching themes: (1) understanding of the RRCT methodology concept and knowledge of Australian clinical registries and RRCT landscape; (2) enablers and barriers in the uptake and conduct of RRCTs; (3) ethics and governance requirements impacting the conduct of RRCTs and (4) recommendations for the promotion, support and implementation of RRCTs. Understanding of and ability to define an RRCT varied considerably amongst participants, as did their appreciation of the role the registry should play in supporting these trials. Lack of ongoing funding to support both registries and RRCTs, along with low awareness and minimal education around this methodology, were identified as the predominant barriers to the uptake of RRCTs in Australia. The simplicity of RRCTs, specifically their pragmatic nature and lower costs, was identified as one of their best attributes. There was consensus that inadequate funding, onerous research governance requirements and poor awareness of this methodology were currently prohibitive in enticing clinicians and researchers to conduct RRCTs. Recommendations to improve the uptake of RRCTs included establishing a sustainable funding model for both registries and RRCTs, harmonising governance requirements across jurisdictions and increasing awareness of RRCTs through education initiatives. Conclusions RRCTs in Australia are an evolving methodology with slow but steady uptake across a number of clinical disciplines. Whilst RRCTs are increasingly identified as a beneficial alternative methodology to evaluate and improve current standards of care, several barriers to effective RRCT implementation were identified. Creating greater awareness of the benefits of RRCTs across a number of stakeholders to help secure ongoing funding and addressing both registry and RRCT governance challenges are two essential steps in enhancing the uptake of RRCTs in Australia and internationally.
... It has been reported that researchers may have difficulty identifying what 'usual care' is when obtaining informed consent. (3) Determining the sample size is critical to the study design and should be done during study development. This is important if the researchers wish to make inferences about the study results. ...
... A qualitative study asked key stakeholders about the challenges raised by pragmatic trials [25]. It was noted that the difference between research, quality improvement, and practice is sometimes unclear. ...
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Background: There are few data on patient and public involvement (PPI) in pragmatic trials. We aimed to describe the prevalence and nature of PPI within pragmatic trials, describe variation in prevalence of PPI by trial characteristics and compare prevalence of PPI reported by trial authors to that reported in trial publications. Methods: We applied a search filter to identify pragmatic trials published from 2014 to 2019 in MEDLINE. We invited the corresponding authors of pragmatic trials to participate in an online survey about their specific trial. Results: Of 3163 authors invited, 2585 invitations were delivered, 710 (27.5%) reported on 710 unique trials and completed the survey; 334 (47.0%) conducted PPI. Among those who conducted PPI, for many the aim was to increase the research relevance (86.3%) or quality (76.5%). Most PPI partners were engaged at protocol development stages (79.1%) and contributed to the co-design of interventions (70.9%) or recruitment or retention strategies (60.5%). Patient and public involvement was more common among trials involving children, trials conducted in the United Kingdom, cluster randomized trials, those explicitly labelled as "pragmatic" in the study manuscript, and more recent trials. Less than one-quarter of trials (22.8%) that reported PPI in the survey also reported PPI in the trial manuscript. Interpretation: Nearly half of trialists in this survey reported conducting PPI and listed several benefits of doing so, but researchers who did not conduct PPI often cited a lack of requirement for it. Patient and public involvement appears to be significantly underreported in trial publications. Consistent and standardized reporting is needed to promote transparency about PPI methods, outcomes, challenges and benefits.
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Background Randomized controlled trial (RCT) trial designs exist on an explanatory-pragmatic spectrum, depending on the degree to which a study aims to address a question of efficacy or effectiveness. As conceptualized by Schwartz and Lellouch in 1967, an explanatory approach to trial design emphasizes hypothesis testing about the mechanisms of action of treatments under ideal conditions (efficacy), whereas a pragmatic approach emphasizes testing effectiveness of two or more available treatments in real-world conditions. Interest in, and the number of, pragmatic trials has grown substantially in recent years, with increased recognition by funders and stakeholders worldwide of the need for credible evidence to inform clinical decision-making. This increase has been accompanied by the onset of learning healthcare systems, as well as an increasing focus on patient-oriented research. However, pragmatic trials have ethical challenges that have not yet been identified or adequately characterized. The present study aims to explore the views of key stakeholders with respect to ethical issues raised by the design and conduct of pragmatic trials. It is embedded within a large, four-year project that seeks to develop guidance for the ethical design and conduct of pragmatic trials. As a first step, this study will address important gaps in the current empirical literature with respect to identifying a comprehensive range of ethical issues arising from the design and conduct of pragmatic trials. By opening up a broad range of topics for consideration within our parallel ethical analysis, we will extend the current debate, which has largely emphasized issues of consent, to the range of ethical considerations that may flow from specific design choices. Methods Semi-structured interviews with key stakeholders (e.g. trialists, methodologists, lay members of study teams, bioethicists, and research ethics committee members), across multiple jurisdictions, identified based on their known experience and/or expertise with pragmatic trials. Discussion We expect that the study outputs will be of interest to a wide range of knowledge users including trialists, ethicists, research ethics committees, journal editors, regulators, healthcare policymakers, research funders and patient groups. All publications will adhere to the Tri-Agency Open Access Policy on Publications. Electronic supplementary material The online version of this article (10.1186/s12910-018-0332-z) contains supplementary material, which is available to authorized users.
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Background: There is a widely recognized need for more pragmatic trials that evaluate interventions in real-world settings to inform decision-making by patients, providers, and health system leaders. Increasing availability of electronic health records, centralized research ethics review, and novel trial designs, combined with support and resources from governments worldwide for patient-centered research, have created an unprecedented opportunity to advance the conduct of pragmatic trials, which can ultimately improve patient health and health system outcomes. Such trials raise ethical issues that have not yet been fully addressed, with existing literature concentrating on regulations in specific jurisdictions rather than arguments grounded in ethical principles. Proposed solutions (e.g. using different regulations in "learning healthcare systems") are speculative with no guarantee of improvement over existing oversight procedures. Most importantly, the literature does not reflect a broad vision of protecting the core liberty and welfare interests of research participants. Novel ethical guidance is required. We have assembled a team of ethicists, trialists, methodologists, social scientists, knowledge users, and community members with the goal of developing guidance for the ethical design and conduct of pragmatic trials. Methods: Our project will combine empirical and conceptual work and a consensus development process. Empirical work will: (1) identify a comprehensive list of ethical issues through interviews with a small group of key informants (e.g. trialists, ethicists, chairs of research ethics committees); (2) document current practices by reviewing a random sample of pragmatic trials and surveying authors; (3) elicit views of chairs of research ethics committees through surveys in Canada, UK, USA, France, and Australia; and (4) elicit views and experiences of community members and health system leaders through focus groups and surveys. Conceptual work will consist of an ethical analysis of identified issues and the development of new ethical solutions, outlining principles, policy options, and rationales. The consensus development process will involve an independent expert panel to develop a final guidance document. Discussion: Planned output includes manuscripts, educational materials, and tailored guidance documents to inform and support researchers, research ethics committees, journal editors, regulators, and funders in the ethical design and conduct of pragmatic trials.
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Background: Pragmatic randomized controlled trials (RCTs) are designed to evaluate the effectiveness of interventions in real-world clinical conditions. However, these studies raise ethical issues for researchers and regulators. Our objective is to identify a list of key ethical issues in pragmatic RCTs and highlight gaps in the ethics literature. Methods: We conducted a scoping review of articles addressing ethical aspects of pragmatic RCTs. After applying the search strategy and eligibility criteria, 36 articles were included and reviewed using content analysis. Results: Our review identified four major themes: 1) the research-practice distinction; 2) the need for consent; 3) elements that must be disclosed in the consent process; and 4) appropriate oversight by research ethics committees. 1) Most authors reject the need for a research-practice distinction in pragmatic RCTs. They argue that the distinction rests on the presumptions that research participation offers patients less benefit and greater risk than clinical practice, but neither is true in the case of pragmatic RCTs. 2) Most authors further conclude that pragmatic RCTs may proceed without informed consent or with simplified consent procedures when risks are low and consent is infeasible. 3) Authors who endorse the need for consent assert that information need only be disclosed when research participation poses incremental risks compared to clinical practice. Authors disagree as to whether randomization must be disclosed. 4) Finally, all authors view regulatory oversight as burdensome and a practical impediment to the conduct of pragmatic RCTs, and argue that oversight procedures ought to be streamlined when risks to participants are low. Conclusion: The current ethical discussion is framed by the assumption that the function of research oversight is to protect participants from risk. As pragmatic RCTs commonly involve usual care interventions, the risks may be minimal. This leads many to reject the research-practice distinction and question the need for informed consent. But the function of oversight should be understood broadly as protecting the liberty and welfare interest of participants and promoting public trust in research. This understanding, we suggest, will focus discussion on questions about appropriate ethical review for pragmatic RCTs.
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Introduction: Learning health care systems (LHS) hold the promise of improving medical care by systematically and continuously integrating the delivery of medical services with clinical research. One important type of integration would involve embedding trials that compare interventions that are already commonly in use (as "accepted" or "standard of care") into the clinical setting-trials that could cost-effectively improve care. But the traditional requirement of informed consent for clinical trials stands in tension with the conduct of such trials. Method: Narrative analysis. Results: Although some have suggested that the idea of LHS makes the distinction between research and ordinary clinical care obsolete, the distinction remains ethically relevant even when it comes to randomized clinical trials (RCTs) that compare standard-of-care interventions. This paper presents an ethical framework for analyzing standard-of-care RCTs in resolving the tension between such trials and traditional requirements of research ethics. Conclusion: It is important not to treat all standard-of-care RCTs as a monolithic category of special ethical status. Close attention to ethical issues in specific standard-of-care RCTs is crucial if the LHS movement is to avoid ethical lapses that could be counterproductive to its long term vision.
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Background: Effectiveness of interventions in pragmatic trials may not translate directly into population impact, because of limited uptake by clinicians and/or the public. Uptake of an intervention is influenced by a number of factors. Methods: We propose a method for calculating population impact of clinical interventions that accounts for the intervention uptake. We suggest that population impact may be estimated by multiplying the two key components: (1) the effectiveness of the intervention in pragmatic trials (trial effect); and, (2) its uptake in clinical practice. We argue that participation rates in trials may be a valid proxy for uptake in clinical practice and, in combination with trial effectiveness estimates, be used to rank interventions by their likely population impact. We illustrate the method using the example of four interventions to decrease antibiotic prescription for acute respiratory infections in primary care: delayed prescribing, procalcitonin test, C-Reactive Protein, shared decision making. Results: In order to estimate uptake of interventions from trial data we need detailed reporting on the recruitment processes used for clinician participation in the trials. In the antibiotic prescribing example, between 75 and 91% of the population would still be prescribed or consume antibiotics because effective interventions were not taken up. Of the four interventions considered, we found that delayed prescribing would have the highest population impact and shared decision making the lowest. Conclusion: Estimates of uptake and population impact of an intervention may be possible from pragmatic RCTs, provided the recruitment processes for these trials are adequately reported (which currently few of them are). Further validation of this method using empirical data on intervention uptake in the real world would support use of this method to decide on public funding of interventions.
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Results: Embedded pragmatic clinical trials (PCTs) are set in routine health care, have broad eligibility criteria, and use routinely collected electronic data. Many consider them a breakthrough innovation in clinical research and a necessary step in clinical trial development. To identify barriers and success factors, we reviewed published embedded PCTs and interviewed 30 researchers and clinical leaders in 7 US delivery systems. Literature: We searched PubMed, the Cochrane library, and clinicaltrials.gov for studies reporting embedded PCTs. We identified 108 embedded PCTs published in the last 10 years. The included studies had a median of 5540 randomized patients, addressed a variety of diseases, and practice settings covering a broad range of interventions. Eighty-one used cluster randomization. The median cost per patient was $97 in the 64 trials for which it was possible to obtain cost data. Interviews: Delivery systems required research studies to align with operational priorities, existing information technology capabilities, and standard quality improvement procedures. Barriers that were identified included research governance, requirements for processes that were incompatible with clinical operations, and unrecoverable costs. Conclusions: Embedding PCTs in delivery systems can provide generalizable knowledge that is directly applicable to practice settings at much lower cost than conventional trials. Successful embedding trials require accommodating delivery systems' needs and priorities.
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Recognising that offers of payment to research participants can serve various purposes—reimbursement, compensation and incentive—helps uncover differences between participants, which can justify differential payment of participants within the same study. Participants with different study-related expenses will need different amounts of reimbursement to be restored to their preparticipation financial baseline. Differential compensation can be acceptable when some research participants commit more time or assume greater burdens than others, or if inter-site differences affect the value of compensation. Finally, it may be permissible to offer differential incentive payments if necessary to advance the goals of a study. We encourage investigators and Institutional Review Boards to think about whether to offer payment, in what amounts and for what purpose, and also to consider whether differential payment can help promote the scientific and ethical goals of clinical research.
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Waivers of informed consent for research participation are permitted in the United States under the Common Rule, the Health Insurance Portability and Accountability Act regulations, and the FDA's Exception from Informed Consent (EFIC) rule for emergency research. We assess the novel question regarding what legal right researchers have to carry out research procedures on or about another person, be it experimental medical intervention, psychological or social manipulation, or invasion of privacy, without the permission of their subjects. Our analysis frames waivers of consent as a species of presumed consent, and we address the underlying empirical question of whether it is reasonable to believe that subjects from whom no consent is sought would in fact agree, if asked. A scoping review of what is known about participation and refusal rates in US-based research suggests that a large minority, on average, do not agree to take part in research. Refusal rates vary widely. This suggests that, while researchers may assert the social utility of their studies are high enough to justify waivers, there is reason to suspect that many who would be enrolled under a waiver of consent would not want to be enrolled. We conclude that waivers should be rare, and that IRBs and researchers must explicitly address study acceptability in the community at large and the target population of their proposed research.
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The SUPPORT trial highlights ethical challenges raised by comparative effectiveness randomized controlled trials (ceRCTs) involving one or more usual care interventions. Debate about the SUPPORT trial has focused on whether study interventions posed "reasonably foreseeable risks" to enrolled infants and, thereby, reflects a preoccupation with U.S. regulations. As ceRCTs are conducted globally, our analysis of the SUPPORT trial is grounded in internationally accepted ethical principles. We argue that the central ethical issue raised by the SUPPORT trial is the following: should the SUPPORT trial interventions be conceptualized as practice, or research? The answer to this question has important implications for "downstream" ethical requirements-including whether the usual care interventions in ceRCTs require research ethics committee review, undergo harm-benefit analysis, and are included in informed consent documents-and it is antecedent to the development of ethical guidance for ceRCTs.