Data sharing among data monitoring committees and responsibilities to patients and science
Data sharing among data monitoring committees and responsibilities to patients and science
Iain Chalmers 0
Douglas G Altman 2
Hazel McHaffie 1
Nancy Owens 4
Richard WI Cooke 3
0 James Lind Initiative , Summertown Pavilion, Middle Way, Oxford OX2 7LG , UK
1 Institute of Medical Ethics , Gloucestershire , UK
2 Centre for Statistics in Medicine, University of Oxford, Wolfson College Annexe , Linton Road, Oxford OX2 6UD , UK
3 Department of Neonatal Medicine, Liverpool Women's Hospital , Crown Street, Liverpool L8 7SS , UK
4 , PO Box 5080, Braddon ACT 2612 , Australia
Over the past three decades it has become increasingly recognized that systematic assessment of as high a proportion as possible of relevant research evidence is needed to protect the best interests of patients and the public. For example, this principle is manifested in clinical guidelines and, increasingly, in the design and monitoring of new research. For scientific and ethical reasons, those responsible for monitoring the progress of ongoing clinical trials may need to seek unpublished and interim data to protect the interests of actual or potential participants in research. The challenge facing data monitoring committees has received relatively little attention, however. In this paper we review some of the commentaries on the issue and the few accounts of actual data monitoring committee experiences. We then present details of our own recent experience as members of the data monitoring committee for the BOOST-2 trial; one of five concurrent trials assessing the level of arterial oxygen which should be targeted in the care of very premature neonates. We conclude that efficient protection both of the interests of actual or potential participants in research and of science requires that data monitoring committees have access to all relevant research, including unpublished and interim data.
Taking account of all relevant evidence when planning
Science is cumulative, and scientists should accumulate
scientifically. Failure to observe this principle in clinical
research has resulted in substantial avoidable suffering
and death, and unnecessary waste of research resources
. Applying this principle in practice means that
clinical trials should be designed in the light of systematic
reviews of relevant existing data .
The need for statistically more reliable clinical research
findings became widely recognized in the late 1970s and
1980s, mainly among researchers assessing treatments for
heart disease and cancer. This was manifested in the
emergence both of systematic reviews using meta-analysis and
of very large trials. In addition, trialists formed international
groups to conduct collaborative analyses based on
individual patient data derived from their separate but similar
trials. In the 1990s, some trialists took this principle a step
further by pioneering prospective meta-analyses: when
similar but administratively separate trials were being
conducted more or less concurrently, they agreed in
advance which common core data should be collected by
every team, and which collaborative analyses would be
done on completion of data collection using pooled
Taking account of all relevant evidence when monitoring
It is increasingly widely accepted that all relevant
evidence (published and unpublished) should be taken into
account when estimating treatment effects from
completed trials. Likewise, there is a consensus that data
monitoring committees (DMCs) for ongoing clinical
trials should take account of evidence from any relevant
new publications or conference presentations .
Indeed, if harmful effects are suspected, relevant evidence
may include research on the same intervention but given
for different health problems.
This principle has been codified in the DMC charter
proposed by the DAMOCLES Group [6,7]. That group
considered the issue of sharing information among
DMCs of similar concurrent trials. They noted that the
issues are complex but observed that there are merits in
the committee chairs making contact and agreeing to
consult each other if their committee is faced by, or has
decided to make, a decision that would change that
trials protocol (including an early end to recruitment) .
In the case of the NeOProM Collaboration, discussed
below, the DMC charter for the UK trial specified that
the DMC's judgments should be based not only on the
accumulating data from the UK trial, but also on any
other relevant data. Accordingly, when one of the trials
(the US trial) in the NeOProM Collaboration reported a
difference in mortality of marginal statistical significance
, the other four DMCs responsible for the related
ongoing trials commissioned new analyses based on
interim data from their respective studies. None of these
analyses were judged to provide any grounds for
discontinuing recruitment. Nevertheless, this reassurance was
insufficient to prevent some centers deciding to cease
recruitment. A similar series of analyses occurred in
relation to two controlled trials of ganciclovir for the
prevention of cytomegalovirus disease in HIV/AIDS
Taking account of all relevant evidence - unpublished as
well as published - when monitoring clinical trials
For scientific and ethical reasons, those monitoring the
progress of any ongoing trial should base their
judgments on analyses of as high a proportion as possible of
the relevant data. This implies going beyond relevant
evidence already in the public domain to unpublished
and interim data.
More than a decade ago it was recognized that sharing
data confidentially among DMCs could improve the
chances that trials would be completed successfully .
This was indeed the case in respect of the decisions
taken by a DMC responsible for two related controlled
trials of radiotherapy. Taking account of interim analyses
from both studies led to a recommendation that
recruitment should continue and, importantly, this led to a
different conclusion from the research than would
otherwise have happened .
Sharing unpublished interim data among DMCs
responsible for separate but similar trials can also lead to
decisions to discontinue or to continue recruitment. For
example, after DMCs monitoring three similar trials
comparing different policies for managing cerebral
infarcts had shared all of the accumulated data from the
three trials, it was decided that recruitment to all three
trials should cease . By contrast, prompted by a
worrying trend in one of two trials of combination
antiretroviral therapy in HIV/AIDS, the two DMCs agreed
to share key outcome data on the basis of strict
confidentiality, and the resulting analysis provided the
reassurance needed to allow continued recruitment .
Although it is not uncommon that there are other
similar concurrent trials, most DMCs regard the
particular trial that they have been appointed to monitor as an
island unto itself , and they are usually disinclined to
share interim results. The issue of divulging such interim
data to other DMCs faced with similar ethical and
scientific challenges rarely arises. There are, however,
rare examples of DMCs conceptualizing their
responsibilities to patients and science as requiring them to
taking account of all relevant evidence - unpublished
as well as published. Should a DMC take that view,
however, they may well encounter major procedural
and other impediments.
A relevant case study: five concurrent trials of oxygen
supplementation in preterm infants
Our experience involved a planned prospective
metaanalysis of studies recruiting concurrently to address a
longstanding uncertainty about what level of arterial
oxygen saturation should be targeted when
prematurelyborn infants require supplementary oxygen . Evidence
from controlled trials had shown that if the oxygen levels
are relatively high there is an increased risk of the infant
developing the blinding condition retinopathy of
prematurity. On the other hand, observational data had
suggested that keeping levels of arterial oxygen relatively low
might result in increased mortality, and neurological
handicap among long term survivors.
During the past decade, five similar trials - in the
USA, New Zealand, Canada, Australia and the UK
were organized more or less concurrently to investigate
this therapeutic dilemma. Although they were separately
organized and funded, all of them compared different
oxygen tension targeting strategies intended to minimize
both mortality and serious morbidity. It was recognized
at the outset that none of the five trials, individually,
would have the statistical power to provide a reliable
estimate of survival without serious morbidity 18 to 24
months after birth. Indeed, two of these trials were only
funded on the understanding that the data from several
similar trials would be combined. Consequently the
researchers responsible for the trials formed the Neonatal
Oxygenation Prospective Meta-analysis (NeOProM)
Collaboration, which agreed that, on completion, data
from all the trials would contribute to a collaborative
Partial success in applying a good principle in practice
As members of the DMC for the UK trial contributing
to the NeOProM Collaboration, we believe it is
important to describe our experience of endeavoring to apply
this good principle in practice. Our DMC charter stated
that we had the right to share confidential information if
we deemed this to be necessary. Furthermore, the
NeOProM Collaborations protocol recognized the
importance of communication among the DMCs for the
related oxygen trials, and stated that its management
committee would consider any requests from DMCs to
share data, should the need arise . Accordingly,
because data from the other four trials were of obvious
relevance to our responsibility, the chair of our DMC
wrote to the DMC chairs of the other trials in 2006,
expressing the hope that we can help each other fulfil our
respective commitments to the babies being treated in
these trials (Emails sent 11 and 15 July 2006).
No response was received from the other DMC chairs
for several years; but consideration of the proposal
became urgent when, more than three years later, in 2009,
the management group of the US trial sent results, in
advance of publication , to those associated with the
trials that were still recruiting. Although the US trial
results did not have sufficient follow-up to report on the
primary outcome (long term survival without major
disability), they showed a marginally statistically significant
(P < 0.04) higher level of mortality when lower levels of
oxygen were targeted.
This information prompted the Canadian DMC chair
to contact the UK DMC chair to ask for UK reactions to
these results (Email received 10 December 2009). After
each of the DMCs responsible for monitoring the trials
that were still recruiting had independently considered
the US results and the data from their own country,
none found any grounds for possible discontinuation of
These separate analyses of the individual oxygen trials
were insufficient to quell concern among many
clinicians, however. These prompted the principal
investigator of the UK trial to write to the UK DMC chair (letter
received 17 June 2010) to say that British clinicians
wanted to know whether the aggregated evidence to
date is such that a final analysis of the full UK trial
sample or the pooled data from all of the trials is strongly
expected to show a significant difference in mortality
The UK DMC chair responded (Email sent 23 June
2010) by reiterating his view that it was in the interests
of babies and their parents that we (the DMCs) should
base our judgments on ALL the currently available data.
His response was copied to the Canadian and
Australasian DMC chairs. The Canadian DMC chair responded
positively, saying that his committee would be
comfortable with a pooled meta-analysis of key outcomes (Email
received 23 June 2010), and suggesting that this analysis
should be conducted by the statisticians of the relevant
trials. He also made clear that the results of this analysis
should be provided confidentially, and only to the DMCs of
the respective trials for their consideration. As a result,
proposed standard tabulations taking account of the analyses
envisaged in the NeOProM Collaborations protocol, were
drafted and circulated (on 5 August 2010).
The encouraging signs of willingness among the
DMCs responsible for ongoing trials to collaborate in
pooled analyses were short lived, however. Following a
meeting with the principal investigator of the Canadian
trial, the chair of the Canadian DMC first informed the
other two DMC chairs that the Canadian view was now
that the collaborative analysis should not be conducted
by the three trial statisticians working together, as he
had suggested previously, but instead only by the
Canadian DMC statistician (Email received 4 August 2010).
The Canadian trial steering committee (TSC) issued a
memorandum conveying that decision, but then sent
another that concluded with its view that:
At this time, the risk of premature disclosure of
mortality data from ongoing NeOProM trials considerably
outweighs any potential benefits of any interim pooled
analysis. Therefore, we will no longer authorize the
release of interim COT [Canadian Oxygen Trial] data for
the purpose of such a pooled analysis (memorandum
dated 23 November 2010 received 24 November 2010).
Given that the Canadian trialists had meanwhile
ceased recruitment (because they had enrolled their
target sample size), the conduct of their trial could not be
influenced by shared access to all the relevant data
available. However, their decision not to share their data had
major consequences for the two DMCs (UK and
Australasian) that remained responsible for
monitoring their ongoing trials. These DMCs would have
been able to make more informed judgments about
stopping or extending recruitment had they had
access to data from the Canadian trial in addition to
data from the ongoing trials for which they were
responsible in their own countries.
The significance of the Canadian action was
highlighted still further by the fact that, part way through the
trial, there had been changes in the equipment used to
monitor the interventions in the oxygen trials .
Based on interim analyses, there was a distinct
possibility that extended recruitment (and so extra funding)
would be needed to obtain sufficient evidence relevant
to the modified equipment, which had been distributed
worldwide to replace that used at the start of the trials.
Decisions to stop or extend recruitment in the two
ongoing trials would have been better informed had the
DMCs had access to the relevant data from all the
relevant trials. As it was, the two DMCs were able to benefit
from access to each others interim data and a combined
collaborative analysis of these, together with the
published results of the US trial . Using conservative
statistical assumptions, the combined analysis suggested
strongly that targeting arterial oxygen to remain within
the higher range was associated with a convincing, and
statistically highly significant, increased survival. Each of
the two DMCs decided independently to forward these
pooled analyses promptly to their respective TSCs. The
TSCs decided independently of each other to cease
recruitment to their respective trials; and they
subsequently reported this decision and the collaborative
analyses which had led to their decisions in a letter
published in the New England Journal of Medicine .
A decade ago, Dixon and Lagakos  noted that it is
expected that DMCs will base their recommendations
on all available relevant information, even if they must
go to some extra trouble to get it. Given the evidence
that DMC decisions based on analyses of all relevant
evidence, unpublished as well as published, can be very
important for patients and science, any arguments against
sharing interim data confidentially among DMCs that
are monitoring related trials need to be very persuasive,
on both ethical and scientific grounds. Dixon and
Lagakos noted that there are fewer concerns about
making available to the DMCs of other ongoing trials the
results of trials that have completed recruitment but
remain unpublished .
Despite arguments against confidential data sharing
among DMCs , our experience leads us to believe
that, in the circumstances in which we found ourselves,
the ethical and scientific arguments in favor of sharing
data outweighed those against sharing. It is in the
interests of patients, participants in clinical research and
science that judgments about the initiation, analysis and
reporting of clinical research should be informed by as
high a proportion as possible of the relevant data. This
principle has become increasingly accepted over recent
years. What has been less widely considered is that
judgments during a trial should also ideally be informed by
analyses of all relevant interim research data [19,20].
This may be achieved by DMCs sharing confidential
interim data, although this practice appears very rare.
Occasionally it may result from planned publication of
interim data .
The example we have described of partial success in
applying this principle in practice raises questions about
how chief investigators should view their responsibilities
to patients, clinicians and science. Although frontline
clinicians involved in the neonatal oxygen trials had
requested collaborative analyses of all the relevant interim
data, and despite agreement in principle among all the
DMCs that these analyses would be undertaken and
shared in confidence, this proposal was vetoed by the
steering committee of a trial that had completed
recruitment. We believe that this decision by the Canadian
TSC was not in the interests of patients or science, quite
apart from making the onerous responsibility of the
DMCs for ongoing trials more burdensome than it
needed to have been. This judgment reflects the fact that
pre-trial selection of target sample sizes inevitably
involves guesswork that interim analyses may show to
have been incorrect, to which the appropriate scientific
response is sample size reestimation .
A DMCs responsibility for the integrity of a trial is a
serious one. Decisions to provide trial steering
committees with unblinded analyses of accumulated data, let
alone make recommendations about whether a trial
should continue, are not to be taken lightly. The
availability of interim data from concurrent trials would
make the task of DMCs easier. Few authors seem to
have considered this issue, even those who have focused
on adverse events [23,24]. In that context, Shah et al.
wrote: DSMBs [Data Safety and Monitoring Boards]
and sponsors have an ethical obligation to disclose
information to protect the safety of participants in
other trials .
A major overarching ethical responsibility of DMCs is
to do what is best for current and future patients. We
believe that judgments should be informed by as high a
proportion as possible of the relevant evidence -
published and unpublished. Although this principle has been
stated previously, it remains far from accepted, so
further discussion and debate is needed to identify any
circumstances in which data sharing among DMCs would
operate against the interests of patients first and science
second. Consideration should be given to (i) who should
have the authority to approve and to veto confidential
sharing of interim data among DMCs; and (ii) how
much weight to give to data from a DMCs particular
trial and data from other similar trials (especially if they
have begun at different times), and whether to combine
data formally using meta-analysis.
Professor Martin Dennis (Email to IC, 25 February
2013) has kindly provided us with an example of the
arrangements that have been agreed among the chief
investigators of three concurrent trials (in the UK,
Australasia and Sweden) to establish whether giving
fluoxetine for six months after acute stroke
improves recovery (FOCUS, ISRCTN83290762; AFFINITY,
ACTRN1261000774921; EFFECTS, not yet registered). The
three trials have virtually the same protocol, although
methods of follow-up and secondary data items have had
to take account of different national settings. The
arrangements they have agreed for data sharing provide an
exemplar of how ethical and scientific responsibilities can be
addressed. The chief investigators of each trial are members
of the TSC of the other trials. Each trial has its own DMC
but the charters are very similar. Consideration was given
to routine review by a common DMC of all available data
from the three trials combined, but this was judged to be
impractical because of the different database systems being
used. The compromise decision has been that, where
stipulated by the charters, the chairs of the three respective
DMCs will communicate and share information which
might alter the decision making of the others. The chief
investigators have also written into their protocols (which will
be published) that there will be a pre-specified individual
patient meta-analysis using the data from all three trials.
We suggest that, when trials are being planned, the
possibility of sharing information should be discussed with
those responsible for any other, similar planned or
ongoing trials, as the chief investigators of the three trials
of fluoxetine after stroke have done. Similar good
practice was exemplified by the investigators of the three
trials of surgery for malignant infarction of the middle
cerebral artery, to which we referred earlier in this paper
. They reported that:
a collaborative protocol for a pooled analysis of
individual patient data from the three trials was planned
before the interruption of the first two trials. The
principal aim of this pooled analysis was to obtain sufficient
data to reliably estimate the effects of early
decompressive surgery as soon as possible so as to avoid
unnecessary (and unethical) continuation of
randomisation in the individual trials .
It is clearly scientifically and ethically desirable not
only to discuss the possibility of data sharing, but also to
lay down, as far as possible, how and when this should
happen. Shah and colleagues proposed that sponsors
and DSMBs routinely work together in advance to
develop a plan for disclosing relevant information .
We agree. If the academic community wishes to be seen
to be putting the interests of patients and science above
individual agendas, concerns and benefits, the issue of
sharing interim analyses needs to be given more
attention than it has received in the past. One of the
challenges in taking this matter further is that
perspectives are required from both ethics and science.
We are grateful to colleagues in Australasia and New Zealand for agreeing to
share interim data on the ongoing trials for which they and we were
responsible. We are also grateful to two reviewers - Rustam al Shahi Salman
and Ricardo Fernandes - for helpful suggestions for improving our paper.
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