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Compliance of clinical trial registries with the World Health Organization minimum data set: A survey

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Since September 2005 the International Committee of Medical Journal Editors has required that trials be registered in accordance with the World Health Organization (WHO) minimum dataset, in order to be considered for publication. The objective is to evaluate registries' and individual trial records' compliance with the 2006 version of the WHO minimum data set. A retrospective evaluation of 21 online clinical trial registries (international, national, specialty, pharmaceutical industry and local) from April 2005 to February 2007 and a cross-sectional evaluation of a stratified random sample of 610 trial records from the 21 registries. Among 11 registries that provided guidelines for registration, the median compliance with the WHO criteria were 14 out of 20 items (range 6 to 20). In the period April 2005-February 2007, six registries increased their compliance by six data items, on average. None of the local registry websites published guidelines on the trial data items required for registration. Slightly more than half (330/610; 54.1%, 95% CI 50.1% - 58.1%) of trial records completed the contact details criteria while 29.7% (181/610, 95% CI 26.1% - 33.5%) completed the key clinical and methodological data fields. While the launch of the WHO minimum data set seemed to positively influence registries with better standardisation of approaches, individual registry entries are largely incomplete. Initiatives to ensure quality assurance of registries and trial data should be encouraged. Peer reviewers and editors should scrutinise clinical trial registration records to ensure consistency with WHO's core content requirements when considering trial-related publications.
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Trials
Open Access
Methodology
Compliance of clinical trial registries with the World Health
Organization minimum data set: a survey
Lorenzo P Moja*1, Ivan Moschetti1, Munira Nurbhai2, Anna Compagnoni1,
Alessandro Liberati1,3, Jeremy M Grimshaw2,4, An-Wen Chan5,6,
Kay Dickersin7, Karmela Krleza-Jeric6, David Moher8, Ida Sim9 and
Jimmy Volmink10
Address: 1Italian Cochrane Centre, Mario Negri Institute for Pharmacological Research, Milan, Italy, 2Clinical Epidemiology Program, Ottawa
Health Research Institute, Canada, 3Università degli Studi di Modena e Reggio Emilia, Modena, Italy, 4Institute of Population Health, University
of Ottawa, Canada, 5Department of Medicine, University of Toronto, Canada, 6Randomised Controlled Trials Unit, Canadian Institutes of Health
Research, Ottawa, Canada, 7Johns Hopkins Bloomberg School of Public Health, Baltimore, USA, 8Chalmers Research Group, Children's Hospital
of Eastern Ontario Research Institute; Department of Epidemiology & Community Medicine, Faculty of Medicine, University of Ottawa, Canada,
9Department of Medicine, University of California, San Francisco, USA, and World Health Organization, Geneva, Switzerland and 10Faculty of
Health Sciences, University of Stellenbosch, Cape Town and South African Cochrane Centre, Medical Research Council, South Africa
Email: Lorenzo P Moja* - moja@marionegri.it; Ivan Moschetti - moschetti@marionegri.it; Munira Nurbhai - mnurbhai@ohri.ca;
Anna Compagnoni - anna.compagnoni@tin.it; Alessandro Liberati - alesslib@mailbase.it; Jeremy M Grimshaw - jgrimshaw@ohri.ca; An-
Wen Chan - anwen.chan@utoronto.ca; Kay Dickersin - kdickers@jhsph.edu; Karmela Krleza-Jeric - Karmela.Krleza-Jeric@cihr-irsc.gc.ca;
David Moher - davidmoher@gmail.com; Ida Sim - sim@medicine.ucsf.edu; Jimmy Volmink - jvolmink@cormack.uct.ac.za
* Corresponding author
Abstract
Background: Since September 2005 the International Committee of Medical Journal Editors has required
that trials be registered in accordance with the World Health Organization (WHO) minimum dataset, in
order to be considered for publication. The objective is to evaluate registries' and individual trial records'
compliance with the 2006 version of the WHO minimum data set.
Methods: A retrospective evaluation of 21 online clinical trial registries (international, national, specialty,
pharmaceutical industry and local) from April 2005 to February 2007 and a cross-sectional evaluation of a
stratified random sample of 610 trial records from the 21 registries.
Results: Among 11 registries that provided guidelines for registration, the median compliance with the
WHO criteria were 14 out of 20 items (range 6 to 20). In the period April 2005–February 2007, six
registries increased their compliance by six data items, on average. None of the local registry websites
published guidelines on the trial data items required for registration. Slightly more than half (330/610;
54.1%, 95% CI 50.1% – 58.1%) of trial records completed the contact details criteria while 29.7% (181/610,
95% CI 26.1% – 33.5%) completed the key clinical and methodological data fields.
Conclusion: While the launch of the WHO minimum data set seemed to positively influence registries
with better standardisation of approaches, individual registry entries are largely incomplete. Initiatives to
ensure quality assurance of registries and trial data should be encouraged. Peer reviewers and editors
should scrutinise clinical trial registration records to ensure consistency with WHO's core content
requirements when considering trial-related publications.
Published: 22 July 2009
Trials 2009, 10:56 doi:10.1186/1745-6215-10-56
Received: 26 November 2008
Accepted: 22 July 2009
This article is available from: http://www.trialsjournal.com/content/10/1/56
© 2009 Moja et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Trials 2009, 10:56 http://www.trialsjournal.com/content/10/1/56
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Background
Registering clinical trials is a topical issue for the health
research community.[1] More than 30 years ago, the first
trials registry was initiated as a way to keep track of all tri-
als initiated and to make possible retrieval of information
about unpublished trials.[2] In the interim, several trials
registries have emerged, for many different purposes,
including recruiting patients to trials.[3]
To those performing systematic reviews, trials registries
provide an essential tool to assess completeness of the
information about all initiated trials addressing a given
research question, regardless of a trial's ultimate publica-
tion status. But to judge a trial's eligibility for inclusion in
a systematic review, the review team needs access to key
protocol information. A "minimum dataset" was initially
proposed in 1993[4] and has been updated since then.[5]
Despite a proliferation of small, specialized registries and
interest in a more comprehensive approach, there is cur-
rently no single worldwide registry that contains all ongo-
ing trials and is considered the acknowledged repository
of trial data. Coordinated efforts to assure global trial reg-
istration have lagged until recently, when a series of events
caught the attention of the broader medical community.
In 2004 the International Committee of Medical Journal
Editors (ICMJE), responding to reporting failures related
to harms from anti-depressants [6], strongly encouraged
the registration of trials. They issued a policy requiring tri-
als commencing participant enrollment after September
2005 to be registered in order to be considered for publi-
cation within their journals.[7] The ICMJE does not man-
date registration in any particular registry as long as it is
electronically searchable, freely accessible to the public,
open to all registrants, and managed by a non-profit
organization. However, the ICMJE requires that trials reg-
istration adhere to the 20-item minimum dataset defined
by the World Health Organization (WHO).[5] The World
Association of Medical Editors supported the ICMJE cam-
paign to register all clinical trials at their inception.[8] The
objective of this descriptive study is to evaluate whether
trial registries and individual trial records within the
selected trial registries complied with the WHO minimum
data set drafted in April 2005[5], issued in February
2006[9].
Methods
We defined a trial registry as a database of planned, ongo-
ing or completed trials, published or unpublished, con-
taining details of the trial's objectives, patient population,
sample size, and tested interventions.[4] This definition is
in agreement with the definition by the WHO.[10] An
official entry in the registry for a single trial is referred to
as a trial record.
Registry Compliance
In April 2005, we selected a convenience sample of 21 tri-
als registries for this study. These registries included inter-
national, national, disease specific, pharmaceutical industry,
and local registries. Details of the registries are presented in
Additional File 1. The registries were chosen because they
were widely known (except for the local registries),
online, active, freely accessible, and in English. To select
local registries we randomly sampled 10 institutions out
of 184 entities referring to limited geographic area (e.g.
UCSF University of California at San Francisco) and listed
in the 'hospitals and clinical research centres' subset of Tri-
alsCentral.[11]
For each registry in our sample, two reviewers independ-
ently abstracted whether key protocol items were present.
We defined key protocol items as the 20-item WHO min-
imum dataset drafted in April 2005 [5] and the subse-
quent version updated in February 2006 [9], and their
definitions for the appraisal checklist (Table 1). We
assessed how many of the WHO criteria were available for
registrants to complete ('registry compliance with WHO cri-
teria'). Two members of the team independently (LPM,
MN) continued to monitor trial registries' websites from
April 2005 to February 2007, collecting information
included on data fields, amendments and additions and
any mention of the ICMJE or WHO initiatives about reg-
istration. Disagreements were resolved by discussion
between the two study authors. We used a cohort design
to evaluate trial registry compliance over a prolonged
timeframe (number of WHO items included in each reg-
istry between April 2005 and February 2007).
Record Compliance
From each of the 21 selected registries we randomly sam-
pled a convenience preset number of trial records, to reach
a planned total of 600 records (final sample of 610 single
trial records). Samples varied according to registry storage.
No restrictions were placed on trial status, design or med-
ical area, although some registries had adopted inclusion
criteria. The trial record data collection was completed
between April and August 2005.
We assessed how commonly the WHO criteria were actu-
ally completed in single trial records ('record compliance').
When necessary, specific items were operationalized: for
example, the WHO criteria 'contact details' was divided
into 'name of contact person' and 'address', 'telephone',
'fax' or 'e-mail'. Key clinical and methodological details
were defined as the presence of condition, intervention,
study type, at least one outcome and key inclusion and
exclusion criteria. Although different registries and guide-
lines define the minimum data items with varying levels
of quality and detail, our operational definitions for con-
sidering an item "compliant" were inclusive. For example,
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Table 1: WHO minimal dataset: version issued in April 2005 (used as checklist in this study) [5] and revised version issued in February-
March 2006[9]
Item 2005 Revised Item 2006 Abridged Definition/Explanation*
1 Unique trial number Primary Registry and Trial Identification number Name of Primary Registry, and the unique ID number
assigned by the Primary Registry to this trial.
2 Trial registration date Date of Registration in Primary Registry Date when trial was officially registered in the
Primary Registry.
3 Secondary IDs Secondary identification number(s) Other identifying numbers and issuing authorities
besides the Primary Registry, if any.
4 Funding source(s) Source(s) of Monetary or Material Support Major source(s) of monetary or material support for
the trial (e.g., funding agency, foundation, company).
5 Primary sponsor Primary Sponsor The individual, organization, group or other legal
person taking responsibility for securing the
arrangements to initiate and/or manage a trial
(including arrangements to ensure that the trial design
meets appropriate standards and to ensure
appropriate conduct and reporting).
6 Secondary sponsor(s) Secondary Sponsor(s) Additional individuals, organizations or other legal
persons, if any, that have agreed with the primary
sponsor to take on responsibilities of sponsorship.
7 Responsible contact person Contact for Public Queries Email address, telephone number, or postal address
of the contact who will respond to general queries,
including information about current recruitment
status
8 Research contact person Contact for Scientific Queries Email address, telephone number, or postal address,
and affiliation of the person to contact for scientific
queries about the trial.
9 Title of the study (brief title) Public Title Title intended for the lay public in easily understood
language.
10 Official scientific title of the study Scientific Title Scientific title of the trial as it appears in the protocol
submitted for funding and ethical review. Include trial
acronym if available.
11 Research ethics review Eliminated
Countries of Recruitment The countries from which participants will be, are
intended to be, or have been recruited.
12 Condition Health Condition(s) or Problem(s) Studied Primary health condition(s) or problem(s) studied
(e.g., depression, breast cancer, medication error).
13 Intervention(s) Intervention(s) Enter the specific name of the intervention(s) and the
comparator/control(s) being studied. Use the
International Non-Proprietary Name if possible. If the
intervention consists of several separate treatments,
list them all. For each intervention, describe other
intervention details as applicable (dose, duration,
mode of administration, etc).
14 Key inclusion and exclusion criteria Key Inclusion and exclusion criteria Inclusion and exclusion criteria for participant
selection, including age and sex.
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an intervention item that reports "subjects will be
assigned into either cyclophosphamide (0.5 to 1 g/m2) or
methylprednisolone (1 g/m2) infusion; both treatments
will be administered every four weeks during one year"
would have been considered completed in the trial record
for the purpose of this study, whereas an intervention
reported as "adjuvant treatment" without other details
would have been considered incomplete (See Additional
file 2 for the operational definitions we adopted). Dupli-
cate data extraction was undertaken for the first 50 trial
records and inter-rater reliability was assessed with k sta-
tistic (0.80–1 k statistic values for the majority of fields).
Subsequent data extraction was undertaken by a single
rater. We calculated 95% confidence intervals using bino-
mial approximation.
The evaluation of the 610 individual trial records was
done at a single point in time (April-August 2005) and
thus is a cross-sectional study.
Results are presented as percentage compliance with
WHO items. The percentages are expressed with 95% con-
fidence intervals in parentheses. Percentage of registry not
compliant items for 2005 and 2006 were calculated as
independent data and the difference between the two per-
centages were evaluated by Chi-Square test.
Results
Registry Compliance
Table 2 lists registries and compliance by item with the
WHO minimum data set. None of the local registry web-
sites published definitions of the trial information (sub-
mission fields) required for registration or mentioned the
recent initiatives of the ICMJE or WHO; two local regis-
tries did not include any trial records.
During the period April 2005 to February 2007, six regis-
tries increased their compliance with WHO criteria by 6
data items, on average, ameliorating their compliance
from 10 to 16 items. Two international (ClinicalTrials.gov
and ISRCTN) and one national registry (ACTR) modified
their content submission fields to become fully compliant
with WHO standards during our data collection period.
Two pharmaceutical industry registries (Novartis and
ClinicalStudyResults) that completely lacked registration
criteria and definitions in April 2005 modified their struc-
ture, increasing the number of items offered to 6 and 14
respectively. The Roche registry rose from 9 to 16 items.
The RehabTrials.org registry stopped being accessible in
2006. In the subgroup of registries providing guidelines
for registration (11 registries), by February 2007, median
compliance with the WHO criteria was 14 out of 20 items
(range 6 to 20). From 2005 to 2006 the number of registry
not compliant items decreased significantly from 46.4%
(39.6–53.2) to 30.0% (24.0–36.5) (p = 0.0039).
15 Study type Study Type A single arm trial is one in which all participants are
given the same intervention. A trial is "randomized" if
participants are assigned to intervention groups using
a method based on chance.
16 Anticipated trial start date Date of First Enrollment Anticipated or actual date of enrollment of the first
participant.
17 Target sample size Target Sample Size Number of participants that this trial plans to enroll.
18 Recruitment status Recruitment Status Recruitment status of this trial (e.g., pending, active,
temporary halt, closed).
19 Primary outcome Primary Outcome(s) Outcomes are events, variables, or experiences that
are measured because it is believed that they may be
influenced by the intervention. The Primary Outcome
should be the outcome used in sample size
calculations, or the main outcome(s) used to
determine the effects of the intervention(s). Enter the
names of all primary outcomes in the trial as well as
the pre-specified timepoint(s) of primary interest.
20 Key secondary outcomes Key Secondary Outcomes Secondary outcomes are events, variables, or
experiences that are of secondary interest or that are
measured at timepoints of secondary interest.
* From the final version released in February 2006
Table 1: WHO minimal dataset: version issued in April 2005 (used as checklist in this study) [5] and revised version issued in February-
March 2006[9] (Continued)
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Table 2: Types of trial registries and compliance with WHO criteria at the end of data collection period (February 2007).
Registries
International National Specialty Pharma Local Total out of 11
registries
(excluding locals)
Criteria requested ISCRTN CT ACTR UK NRR PDQ STD RTR GSK N CSR
Details not presented by
registries
x
Details available
Unique trial number x x x x x x x xx 9
Trial registration date x xxx4
Secondary Ids x xxxx x6
Funding source(s) x x x x x x x x xx 10
Primary sponsor x xxxx xx x8
Secondary sponsor(s) x xxx X x6
Responsible contact
person
xxx PNR x5
Research contact person x x x x x x x x8
Title of the study
(brief title)
xxx xx x xx 8
Official scientific title of
the study
xxx xxxxxx x10
Research ethics review* xPNRxMC PNR 4
Countries of recruitment
(replaced ethics review,
May 2006)*
xxxxx x6
Condition x x x x x x x x xx 10
Intervention(s) x x x x x x x xx 9
Key inclusion and
exclusion criteria
xxx xx xx x8
Study type x x x x x x x x8
Anticipated trial start date x xxxxx xxx9
Target sample size x xxxxxx7
Recruitment status xxx xxxx 7
Primary outcome x xxxxx xxx9
Key secondary outcomes x xxx x xx7
Total out of 20 criteria20 20 20 13 16 14 5 16 10 6 14
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Record Compliance
Table 3 lists the percentages of compliant records relative
to registries. The final sample of 610 trial records covered
different years (range: 1981 to 2005). However the major-
ity of trials were recently registered (<1999 n = 77 (13%
out of 610); 2004–2000 n = 246 (40% out of 610); 2005
n = 156 (26% out of 610)). In 131 records the registration
date was not available. Overall, 330 trial records, 54.1%
(50.1% – 58.1), completed the contact details criteria.
Trial records in national registries adhered more often
with this requirement (compliance 99%) while those in
drug company registries never reported it (Figure 1). 181
records, 29.7% (26.1 – 33.5), provided complete infor-
mation about key aspects of trial design (target condition,
intervention, study type, at least one outcome and key
inclusion and exclusion criteria; Figure 2). Among these
five key methodological data fields compliance varied
across items from 40.5% (36.6 – 44.5) for primary out-
come measures to 75.2% (71.6 – 78.6) for target condi-
tion. 'Research ethics review' (6.9% (5.0% – 9.2)),
'responsible contact person' (8.2% (6.1 – 10.7)) and 'sec-
ondary outcomes' (21.6% (18.4% – 25.1)) had lower
compliance rates.
Discussion
Summary of key findings
As of February 2007, the compliance of information in
trial registries is unsatisfactory despite the emerging con-
sensus that the availability of such information is ethically
and scientifically essential.[12] We found that in August
2005, only 54% of trial records provided adequate contact
information and less than 30% contained the complete
information necessary to provide a general picture of trial
objectives, such as outcome measures and details of the
intervention. The launch of the WHO minimum dataset
and its enforcement by the ICMJE seemed to positively
influence registries: 6 out of 11 increased their compliance
by the time of the ICMJE requirement. Some of the WHO
criteria seemed to be easily adopted by registries, while
others were less so: compliance was variable among regis-
tries and there were inconsistencies between registry-
offered fields and record compliance (i.e., many registries
Mentions WHO 2005/
2006
x x x x -x-- ---
Mentions ICJME 2004/
2005
x x x x -------
X = items present when data collection begun; X = items added during study period; Total criteria considering the field 'Countries of recruitment'.
MC = only for multi-centre trials; PNR = provided not reported.
Abbreviation: ISRCTN, Current Controlled Trials; CT, ClinicalTrials.gov; ACTR, Australian Clinical Trials Registry; UK NRR, UK National
Research Register; PDQ, US National Cancer Institute; STD, Stroke Trials Directory; RT, Rehabilitation Trials (access to web site withdrawn in
2006); R, Roche; GSK, GlaxoSmithKline; N, Novartis; CSR, ClinicalStudyResults.
Table 2: Types of trial registries and compliance with WHO criteria at the end of data collection period (February 2007). (Continued)
Contact detailsFigure 1
Contact details. Percentage (95% confidence interval) of trial records reporting minimum contact details (defined as the
presence of name of contact person and one additional item: address, telephone, fax or e-mail) by type of registry.
0
20
40
60
80
100
International
(n=200)
National (n=100) Specialty (n=99) Pharma (n=121) Local (n=90)
Type of registry
% Completion (95% CI)
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failed to offer all 20 WHO data items for completion, and
registrants failed to comply with many of the data items
that were offered).
Strengths and weaknesses
Our assessment was limited to a sample of 21 registries to
reflect different types of registries.[13] Our sample of
records can be criticised in some respects. Although we
chose the registries to reflect diversity based upon a priori
defined important information (e.g., target health profes-
sionals or patients, profit or no-profit aims, etc), and with-
out prior knowledge of what we would find, the selection
was largely of registries published in English. We consid-
ered including registries from Spain and Italy which have
country-wide mandatory trial registration [14,15] but
their registries did not meet our inclusion criteria of being
in the public domain. In Italy only funding agencies and
ethics committees have unrestricted access. In Spain the
online version of their national registry is still under con-
struction. It is possible that these registries differ from oth-
ers in terms of the amount and quality of information
collected and this may limit the generalisability of this
study. Our results for a sample of trials registries in 2005–
2007 are a snapshot from what has become a rapidly
evolving field. For example, in 2005–2007 the WHO for-
mally established the International Clinical Trials Registry
Platform (ICTRP) to standardise the scope and content of
trial registration.[16] The WHO finalized the criteria to
build a global network of qualified registries, adopting a
hierarchical structure (primary and partner registries) and
creating a web site that enables users to search a central
database that contains the trial registration data sets pro-
vided by primary registries.[17] Triggered by the ICMJE
and WHO initiatives, trial registration has become very
active. Thus, ClinicalTrials.gov increased from a routine
weekly registration of 30 new trials to 220 new trials [18]
and changed its registration requirements http://prs
info.clinicaltrials.gov.[19] ISRCTN's trial records
expanded from 2 705 to 6 449, and transferred its owner-
ship to a not-for-profit organization to comply with the
ICMJE requirement that registries be non-profit adopting
a new URL http://isrctn.org.[20] Since 2007, ISRCTN has
required an administrative charge (£132) to registry new
trials, while ClinicalTrials.gov maintains a free of charge
policy. The Australian Clinical Trials Registry (ACTR) was
established in April 2005 by merging old registries into a
new highly standardised version incorporating the com-
plete WHO minimum dataset.[21] At the time of our
study, the Lilly website only linked to its records in Clini-
calTrials.gov but has since launched its own registry with
information about recruiting and non-recruiting trials,
while also providing identification numbers.[22]
Another element of change is related to our assessment
tool: we used the draft April 2005 WHO minimum dataset
to assess the trials registered in our study, although the
finalised version released in February 2006 was somewhat
different (research ethics review item was removed and
Countries of recruitment was added).[9] The draft and final
dataset versions are shown in Table 1 (definitions/expla-
nations are from the final version). Neither version of the
WHO dataset was available for use as a benchmark by reg-
istries and registrants before April 2005. Our findings
highlight the variation in registry and record compliance
Clinical and methodological detailsFigure 2
Clinical and methodological details. Percentage (95% confidence interval) of trial records reporting clinical and methodo-
logical details (defined as the presence of condition, intervention, study type, at least one outcome and key inclusion and exclu-
sion criteria) by type of registry.
0
20
40
60
80
100
International
(n=200)
National (n=100) Specialty (n=99) Pharma (n=121) Loc al (n=90)
Type of registry
% Complet ion ( 95% CI)
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Table 3: Percentage of compliance of trial records according to WHO criteria by trial registry.
Registries (number of records)
International National Specialty Pharma
Criteria requested ISCRTN
(n = 100)
CT
(n = 100)
ACTR (n = 50) UK NRR
(n = 50)
PDQ
(n = 33)
STD
(n = 33)
RT
(n = 33)
R
(n = 8)
GSK
(n = 72)
N
(n = 4)
CSR
(n = 37)
Local
(n = 90)
Total, %
(95% CI)
Unique trial number 100 100 100 100 0 0 0 100 100 100 97.3 90 82.1
(78.9 to 85.1)
Trial registration date 100 100 100 100 100 100 100 100 100 0 0 0 78.5
(75.0 to 81.7)
Secondary Ids 100 91 16 4 100 0 0 0 0 0 0 0 38.4
(34.5 to 42.4)
Funding source(s) 100 100 96 76 66.7 69.7 90 100 100 100 100 27.8 83.1
(79.9 to 86.0)
Primary sponsor 100 100 90 92 66.7 69.7 90.9 100 31.9 100 100 27.8 75.9
(72.3 to 79.2)
Secondary sponsor
(s)
14 10 38 0 0 6.1 6.1 0 0 0 0 0 7.7
(5.7 to 10.1)
Responsible contact person 0 0 100 0 0 0 0 0 0 0 0 0 8.2
(6.1 to 10.7)
Research contact person 95 20 100 98 93.9 63.6 30.3 0 0 0 0 60 54.1
(50.1 to 58.1)
Title of the study (brief title) 98 18 66 0 0 60.6 0 0 0 0 0 12.2 29.5
(25.9 to 33.3)
Official scientific title of the study 83 95 100 94 97 69.7 84.9 100 100 0 89.2 82.2 89.3
(86.6 to 91.7)
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Research ethics review 1 0 78 0 3 0 3 0 0 0 0 0 6.9
(5.0 to 9.2)
Condition 70 85 92 66 97 100 84.9 100 95.8 100 83.8 22.2 75.2
(71.6 to 78.6)
Intervention(s) 56 68 74 24 75.8 97 42.4 0 100 0 64.9 17.8 58.4
(54.3 to 62.3)
Key inclusion and exclusion criteria 23 97 100 44 18.2 87.9 0 100 97.2 50 64.9 28.9 58.5
(54.5 to 62.5)
Study type 43 74 98 58 9.1 97 33.3 0 94.4 0 64.9 45.6 61.3
(57.3 to 65.2)
Anticipated trial start date 8 65 100 100 0 39.4 3 0 100 0 64.9 0 46.4
(42.4 to 50.4)
Target sample size 40 83 100 24 72.7 100 39.4 0 80.6 0 64.9 0 55.2
(51.2 to 59.2)
Recruitment status 3 99 100 100 93.9 100 12.1 100 0 0 54.1 7.8 50.0
(46.0 to 54.0)
Primary outcome 7 48 100 34 0 100 18.2 0 83.3 0 64.9 2.2 40.5
(36.6 to 44.5)
Key secondary outcomes 6 10 58 6 6.1 54.6 3 0 61.1 0 48.7 1.1 21.6
(18.4 to 25.1)
Note: In CT, PDQ and STD 'Funding source(s)' and 'Primary sponsor' are not distinct. By default contact person without specification has been refereed to Research contact person.
Abbreviation: ISRCTN, Current Controlled Trials; CT, ClinicalTrials.gov; ACTR, Australian Clinical Trials Registry; UK NRR, UK National Research Register; PDQ, US National Cancer Institute; STD,
Stroke Trials Directory; RT, Rehabilitation Trials; R, Roche; GSK, GlaxoSmithKline; N, Novartis; CSR, ClinicalStudyResults.
Table 3: Percentage of compliance of trial records according to WHO criteria by trial registry. (Continued)
Trials 2009, 10:56 http://www.trialsjournal.com/content/10/1/56
Page 10 of 12
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with the 2005 WHO criteria up to February 2007. It
should be also stressed that registry and record compli-
ance are not independent since registrants can only pro-
vide the information requested, and therefore the
variation in registry compliance will constrain record
compliance. As with previous studies, we could not evalu-
ate the actual proportion of trials registered among all tri-
als conducted over the time period examined: this could
be achieved only assessing the number of trials launched
at the source point (e.g., funding agencies, industry, ethics
committees, regulators) and it is out of the scope of the
present work.
Our study in context
Our results partially overlap with the results reported by
Zarin et al. who surveyed record completion on Clinical-
Trials.gov between May and October 2005.[23] Zarin
assessed completeness of Intervention name (compliance
rates at 100% and 90% for non-industry and industry
records, respectively) and Primary outcome (compliance
rate available only for industry records, 76%). We found
lower compliance for Intervention name (68%), though
this difference could be because we examined registries
over a different time interval. As Zarin et al. showed, many
records changed their completion of registration around
the time of ICJME deadline: it is possible that investigators
were motivated to update the recent records over the older
ones or that registries' editors started to scrutinise trial
records with more stringent policies.[18] If true, this could
also explain the lower compliance rate we found for Pri-
mary outcome compared to Zarin et al. Completion rate
also depends on the operational definition adopted by
assessors. The definition used by Zarin et al. is less strin-
gent compared to the one we adopted.
An interesting result of our study is that industry registries
appear to satisfy WHO minimal dataset in terms of meth-
odological details more completely than non-industry
registries. This result seems to contrast with the pharma-
ceutical industry's concern over the disclosure of the five
methodological items.[24] This finding could be due to
trials listed on company registries are for 'approved drugs'
and the information is no longer considered to be com-
mercially sensitive. Another possibility is that the different
drug companies, while having a common overall posi-
tion, ultimately adopt heterogeneous policies on disclos-
ing their data items. Pharmaceutical company registries
did not include details in their registries for a contact per-
sons for each trial, although they did include an e-mail
address for additional information about trials. This was
not considered as meeting the WHO criterion, however, as
accountability appeared too vague if a contact name was
not provided. These results have been confirmed by
another study which analysed the proportion of trial
records listing complete contact information of Canadian
investigators in a sample of records in ISRCTN and Clini-
calTrials.gov and found largely incomplete contact infor-
mation in industry funded trials.[25]
Conclusion
Implications for systematic reviewers
As part of their broad search to identify potentially eligible
data systematic reviewers should include trial registries for
ongoing trials, particularly in situations where there is
great uncertainty about the efficacy of an intervention and
it is possible that new trial data may influence the sum-
mary judgment of the review. Our findings revealed that
registries often do not contain meaningful information on
many key methodological data fields and thus at this time
cannot be used reliably as referent information sources to
describe included studies in systematic reviews. Details of
research contact persons, when present, can be used to
address questions about methodological aspects of a trial
or unpublished data.
Implications for trial registration
In the move towards global trial registration, there is room
for better standardisation of approaches and better report-
ing of registration data items. This effort is in keeping with
other global efforts to improve the reporting of ran-
domised trials, such as the CONSORT Statement.[26] The
WHO is developing criteria for internationally acceptable
trial registries, and has established a working group of trial
registries to develop better approaches to data entry vali-
dation and other aspects of quality assurance.[27] Given
the variability in registry compliance and record com-
pleteness, editors and peer reviewers of medical journals
should scrutinise trial registration records to ensure con-
sistency with WHO's minimum dataset when considering
trial-related publications and should report the trial iden-
tification numbers, including those assigned by WHO.
Implications for research
As registries adopt the WHO minimum dataset, there is a
need to assess the evolution of registries and records over
time, and whether the 20 WHO criteria are sufficient to
judge the scientific conduct of trials or should be
expanded. Further research is also needed to determine
whether early trial registration increases informed patient
recruitment and improves quality and completeness of
subsequent publications: the impetus for clinical trial reg-
istration stems from the added value of including all clin-
ical trials, not just published ones, within systematic
reviews.[6] As such, there is a need to prospectively mon-
itor protocol amendments and the accessibility of unpub-
lished clinical trial data. Including primary outcome
information within a registry will also enable us to evalu-
ate whether the disturbingly high frequency of outcome
reporting bias declines.[28,29] Following from these
ideas, trial registries will be most useful if they increase the
Trials 2009, 10:56 http://www.trialsjournal.com/content/10/1/56
Page 11 of 12
(page number not for citation purposes)
accessibility of evidence, including data on adverse events.
In other words, the real test for trial registries is whether
they facilitate making the results of unpublished trials,
and unpublished results of published trials, available to
the public. whether through trial registries or dedicated
results repositories or databases.[30] The United States
FDA Amendments Act 2007 (U.S. Public Law 110-85),
which is the world's first legislative requirement for the
public reporting of trial results, is an important step in this
direction. Simply registering trials is not going to solve the
problem, but it is a necessary first step to enable identifi-
cation of all trials and the subsequent tracking of their
results.
Clinical trial registration was advocated more than thirty
years ago[2], and important progress has recently been
made. We have a scientific, ethical and moral obligation
to clinical trial participants to ensure that clinical trial reg-
istries are created with and adhere to the highest possible
standards.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
LM, AL and JMG conceived the study concept. LM, IM,
MN, AL, JMG and AWC conceived the study protocol. LM,
IM and MN were involved in the acquisition of data. LM,
IM, MN and AC were involved in the analysis of data. LM,
IM, MN, AL and JMG were involved in drafting of the
manuscript. All authors were involved in the interpreta-
tion and critical revision of the manuscript for important
intellectual content.
Additional material
Acknowledgements
We thank Bushra Chaudry, research assistant, Clinical Epidemiology Pro-
gram, Ottawa Health Research Institute, for helping us extracting trial
records' information. We are grateful to Drummond Rennie for his valua-
ble comments. Funding/Support: Jeremy Grimshaw holds a Canada
Research Chair in Health Knowledge Transfer and Uptake. David Moher
holds a University of Ottawa Research Chair.
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Additional file 1
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Additional file 2
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study.
Click here for file
[http://www.biomedcentral.com/content/supplementary/1745-
6215-10-56-S2.doc]
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... With such discrepancies, many existing studies have strived to investigate trends and factors influencing oncology trials in the initial era of the pandemic to plan future directions. Previously, Lamont et al. and Unger et al. also reported on new oncology trial commencement after the COVID-19 pandemic, but analyzing different data over a short period of time with discrepant outcomes might require more supportive evidence showing the impact of COVID-19 on the commencement of oncology trials [11,16]. As one of the first studies to investigate the trends and factors associated with the number of new oncology trials influenced by the COVID-19 outbreak followed by comparing the pre-and postpandemic era, the current study provides more comprehensive outcomes with trial information recorded during longer periods of time and affected factors to promote oncology trials during this medical crisis. ...
... In addition, an increase in the number of new oncology trials was also observed in the postpandemic era according to the 1-year comparison. Although a natural increase in the number of trials as the year went on could explain the number of new oncology trials during the postpandemic era, previous studies supported the finding that a natural increase in trial initiation did not occur [16,23]. Furthermore, in terms of the current outcomes, the number of new cancer trials varied among countries. ...
... To sustain clinical trials, a stable funding source should be supported [28]; however, most resources have been directed to combat the COVID-19 crisis [29]. The current study findings indicate that funding for oncology trials by industries might be associated with the increased launch of new cancer trials during the pandemic [16], which explains their ongoing efforts to support and conduct oncology trials, as the industry hopes to proactively overcome the COVID lockdown situation [23]. Furthermore, although governments only included NIH or U.S. federal agencies, compared to the prepandemic era, in the postpandemic period, the number of cancer studies funded by the government increased. ...
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This study aimed to assess the trend in oncology trial commencements registered on ClinicalTrials.gov and to evaluate the contributing factors by comparing the trends in the pre- and post-COVID-19 pandemic era. The ClinicalTrials.gov database was searched to identify oncology study trials starting from 1 January 2018 to 28 February 2021. Data on the variables of start/complete date, phase, status, funding source, center, country and study type were extracted. According to the time point of the COVID-19 pandemic declaration by the World Health Organization (WHO), March 2020, we analyzed the extracted data, including interrupted time series (ITS) analysis and multivariable regression analysis. We identified 18,561 new oncology trials during the study period. A total of 5678 oncology trials in the prepandemic period and 6134 in the postpandemic period were included in the comparative analysis. The year 2020 had the most newly launched trials (32.3%), and the majority of trials were planned to be conducted for longer than two years (70.3%). The results of ITS show the trend in the commencement of oncology trials was significantly increased after the pandemic declaration (coefficient = 27.99; 95% CI = 19.27 to 36.71). Drug intervention trials were the largest contributor to the increased trial number compared to different interventions, such as trials of devices or procedures (OR = 1.14; 95% CI = 1.03 to 1.26, OR = 1.09; 95% CI = 0.91 to 1.29, and OR = 1.12; 95% CI = 0.96 to 1.31, respectively), whereas the United Kingdom was the highest contributor to the number of decreased trials (OR = 0.67; 95% CI = 0.51 to 0.89 p = 0.01) in the postpandemic era. The interruption in oncology trial initiation was diminished shortly after the COVID-19 pandemic declaration, which was influenced by several factors, such as interventions or national responses. Based on the current outcomes, appropriate strategies for developing oncology trials can be planned to mitigate the impact of future crises on oncology trials.
... Accordingly, there have been calls for (i) a comparison of such registries, to help develop suitable standards [25], and (ii) ways to improve the accessibility and content of the PR+ [27]. However, several years ago it was shown that there had been non-compliance with the WHO minimal dataset [28], and non-optimal website functionality and user experience [10,11,29]. Since across-the-board improvements have not taken place, this issue needs to be reiterated. ...
... 1. Accessibility. One of the principal reasons for the existence of clinical trial registries is to provide the public with information, and to thereby increase trust in the trial enterprise [28]. Therefore, we first examined the accessibility of information in the PR+. ...
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Background It is an ethical and scientific obligation to register each clinical trial, and report its results, accurately, comprehensively and on time. The WHO recognizes 17 public registries as Primary Registries, and has also introduced a set of minimal standards in the International Standards for Clinical Trial Registries (ISCTR) that primary registries need to implement. These standards are categorized into nine sections—Content, Quality and Validity, Accessibility, Unambiguous Identification, Technical Capacity, Administration and Governance, the Trial Registration Data Set (TRDS), Partner registries and Data Interchange Standards. This study compared the WHO’s primary registries, and the US’s ClinicalTrials.gov, to examine the implementation of ISCTR, with the aim of defining features of an interim ideal registry. Methods and findings The websites of the 18 registries were evaluated for 14 features that map to one or more of the nine sections of ISCTR, and assigned scores for their variations of these features. The assessed features include the nature of the content; the number and nature of fields to conduct a search; data download formats; the nature of the audit trail; the health condition category; the documentation available on a registry website; etc. The registries received scores for their particular variation of a given feature based on a scoring rationale devised for each individual feature analysed. Overall, the registries received between 27% and 80% of the maximum score of 94. The results from our analysis were used to define a set of features of an interim ideal registry. Conclusions To the best of our knowledge, this is the first study to quantify the widely divergent quality of the primary registries’ compliance with the ISCTR. Even with this limited assessment, it is clear that some of the registries have much work to do, although even a few improvements would significantly improve them.
... Results references may also be entered manually in selected registries, with varying degrees of structure. 2,15,16 ClinicalTrials.gov, for example, provides fields for digital object identifier (DOI) and PubMed identifier (PubMed ID), whereas the German Clinical Trials Registry (DRKS) offers an unstructured free-text field. ...
... 32 As DRKS does not provide an application programming interface, we built a webscraper to capture the necessary fields. 33 We queried the PubMed Entrez Programming Utilities application programming interface on 15 August 2021 for all trial results PubMed IDs. 34,35 From the PubMed Extensible Markup Language (XML), we extracted bibliometric information, including the publication abstract and secondary identifier (or databank) metadata. ...
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Background/Aims Informed clinical guidance and health policy relies on clinicians, policymakers, and guideline developers finding comprehensive clinical evidence and linking registrations and publications of the same clinical trial. To support the finding and linking of trial evidence, the World Health Organization, the International Committee of Medical Journal Editors, and the Consolidated Standards of Reporting Trials ask researchers to provide the trial registration number in their publication and a reference to the publication in the registration. This practice costs researchers minimal effort and makes evidence synthesis more thorough and efficient. Nevertheless, trial evidence appears inadequately linked, and the extent of trial links in Germany remains unquantified. This cross-sectional study aims to evaluate links between registrations and publications across clinical trials conducted by German university medical centers and registered in ClinicalTrials.gov or the German Clinical Trials Registry. Secondary aims are to develop an automated pipeline that can be applied to other cohorts of trial registrations and publications, and to provide stakeholders, from trialists to registries, with guidance to improve trial links. Methods We used automated strategies to download and extract data from trial registries, PubMed, and results publications for a cohort of registered, published trials conducted across German university medical centers and completed between 2009 and 2017. We implemented regular expressions to detect and classify publication identifiers in registrations, and trial registration numbers in publication metadata, abstracts, and full-texts. Results In breach of long-standing guidelines, 75% (1,418) of trials failed to reference trial registration numbers in both the abstract and full-text of the journal article in which the results were published. Furthermore, 50% (946) of trial registrations did not contain links to their results publications. Seventeen percent (327) of trials had no links, so that associating registration and publication required manual searching and screening. Overall, trials in ClinicalTrials.gov were better linked than those in the German Clinical Trials Registry; PubMed and registry infrastructures appear to drive this difference. Trial registration numbers were more likely to be transferred to PubMed metadata from abstracts for ClinicalTrials.gov trials than for German Clinical Trials Registry trials. Most (78%, 662/849) ClinicalTrials.gov registrations with a publication link were automatically indexed from PubMed metadata, which is not possible in the German Clinical Trials Registry. Conclusions German university medical centers have not comprehensively linked trial registrations and publications, despite established recommendations. This shortcoming threatens the quality of evidence synthesis and medical practice, and burdens researchers with manually searching and linking trial data. Researchers could easily improve this by copy-and-pasting references between their trial registrations and publications. Other stakeholders could build on this practice, for example, PubMed could capture additional trial registration numbers using automated strategies (like those developed in this study), and the German Clinical Trials Registry could automatically index publications from PubMed.
... Despite the value of data collected during the compassionate use of conventional drugs is mostly considered as limited [52], non-trial preapproval use might provide important information on outcomes and AEs related to this unique class of therapeutics, mostly intended for patient populations that may be small, and whose effects in most cases cannot be reversed [53]. Other steps required to improve the transparency of HGE trials are more demanding, since the WHO ICTRP platform gathers trial registration data sets provided by different primary registries, still not completely complying with the WHO TRDS [54]. However, in 2021 WHO launched recommendations on the governance of HGE on a global scale, including also their trial registration, for which the "traditional" international standards should be particularly adapted [42]. ...
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... Several studies have analyzed ClinicalTrials.gov records for missing fields required by the Food and Drug Administration Amendments Act of 2007, which governs US trial registries, and the World Health Organization (WHO) minimum data set, which provides guidelines for registries internationally [43][44][45][46] found that information about the principal investigators of trials in ClinicalTrials.gov are inconsistent both within multiple occurrences in the same record and across records. ...
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Metadata that are structured using principled schemas and that use terms from ontologies are essential to making biomedical data findable and reusable for downstream analyses. The largest source of metadata that describes the experimental protocol, funding, and scientific leadership of clinical studies is ClinicalTrials.gov. We evaluated whether values in 302,091 trial records adhere to expected data types and use terms from biomedical ontologies, whether records contain fields required by government regulations, and whether structured elements could replace free-text elements. Contact information, outcome measures, and study design are frequently missing or underspecified. Important fields for search, such as condition and intervention, are not restricted to ontologies, and almost half of the conditions are not denoted by MeSH terms, as recommended. Eligibility criteria are stored as semi-structured free text. Enforcing the presence of all required elements, requiring values for certain fields to be drawn from ontologies, and creating a structured eligibility criteria element would improve the reusability of data from ClinicalTrials.gov in systematic reviews, metanalyses, and matching of eligible patients to trials.
... This trial was registered with clinicaltrials.gov (NCT03084549) on 14 April 2017 and includes all items from the World Health Organization (WHO) Trial Registration Data Set (supplementary attachment) [44]. ...
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Background: Perineal pain due to episiotomy is commonly reported and can be severe enough to disturb the mother-infant dyad during the postpartum period. Its incidence at day 7 postpartum varies from 63% to 74%. Recent studies have investigated the analgesic efficacy of perineal infiltration of ropivacaine after episiotomy but have only focused on the immediate postpartum period (at 24 and 48 h after birth). Large, adequately powered, multicenter, randomized controlled trials are required to evaluate the impact of ropivacaine infiltration on perineal pain and mid- and long-term quality of life before the widespread use of ropivacaine to prevent perineal pain after episiotomy can be recommended. Methods/design: The ROPISIO study is a two-center, randomized, double-blind, placebo-controlled trial being conducted in La Roche sur Yon and Nantes, France. It will involve 272 women with vaginal singleton delivery and mediolateral episiotomy at term (≥ 37 weeks). Perineal infiltration (ropivacaine 75 mg or placebo) will be administrated just after vaginal birth and before episiotomy repair. The primary outcome will be the analgesic efficacy at day 7 postpartum (midterm), defined by the Numeric Pain Rating Scale (NPRS) strictly superior to 3/10 on the perineal repair area. Secondary outcomes will be the analgesic efficacy (NPRS) and the impact of pain on daily behavior, on the quality of life (36-item Short Form Health Survey), on the occurrence of symptoms of postpartum depression (Edinburgh Postnatal Depression Scale), and on sexual health (Female Sexual Function Index) at 3 and 6 months (long-term) using validated online questionnaires. This study will have 90% power to show approximately 30% relative risk reduction in the incidence of perineal pain at day 7, from 70.0% to 50.0%. Discussion: Ropivacaine is a promising candidate drug, inexpensive, and easy to administer, and it would be suitable to include in the routine management of deliveries in labor ward. This study will investigate if perineal ropivacaine infiltration just after birth can reduce mid- and long-term postpartum pain and increase quality of life in women with mediolateral episiotomy. Trial registration: ClinicalTrials.gov, NCT03084549. Registered on 14 April 2017.
... This trial is registered with clinicaltrials.gov (NCT03084549 on April 14, 2017) and include all items from the World Health Organization (WHO) Trial Registration Data Set (supplementary attachment) [45]. ...
Preprint
Full-text available
Background Perineal pain due to episiotomy is commonly reported and can be severe enough to disturb the mother-infant dyad during the postpartum period. Its incidence at day 7 postpartum varies from 63% to 74%. Recent studies have already investigated the analgesic efficacy of perineal infiltration of ropivacaine after episiotomy, but have only focused on the immediate postpartum period (at 24 and 48 hours after birth). Large, adequately powered, multicenter, randomized controlled trials are required to evaluate the impact of ropivacaine infiltration on perineal pain and mid- and long-term quality of life before the widespread use of ropivacaine to prevent perineal pain after episiotomy can be recommended. Methods The ROPISIO study is a two-center, randomized, double-blind, placebo-controlled trial in La Roche sur Yon and Nantes, France. It will involve 272 women with vaginal singleton delivery and mediolateral episiotomy at term (≥ 37 weeks). Perineal infiltration (ropivacaine 75mg or placebo) will be administrated just after vaginal birth and before episiotomy repair. The primary outcome will be the analgesic efficacy at day 7 postpartum (mid-term), defined by the numerical rating scale of pain (ENS NRS) strictly superior to 3/10 on the perineal repair area. Secondary outcomes will be the analgesic efficacy (ENS NRS), the impact of pain on daily behavior, on the quality of life (36-Item Short Form Health Survey), on the occurrence of symptoms of postpartum depression (Edinburgh Postnatal Depression Scale) and on sexuality (Female Sexual Function Index) at 3 and 6 months (long-term) using validated online questionnaires. This study will have 90% power to show approximately 30% relative risk reduction in the incidence of perineal pain at day 7, from 70.0% to 50.0%. Discussion Ropivacaine is a promising candidate drug, inexpensive, easy to administer, and would be suitable to include in the routine management of deliveries in labor ward. This study will investigate if perineal ropivacaine infiltration just after birth can reduce mid- and long-term postpartum pain and increase quality of life in women with mediolateral episiotomy.
... Only valid ORCID numbers should be accepted by the system and the database should not permit the registration of a trial unless the name of a PI-in these standardized formats-has been entered. Other researchers have also noted the absence of proper information in the name field [26,27] and clearly the situation has not improved much over time. If, as stated several years ago [26], it is important that the scientific leadership of a trial be named, then those names must be accurate. ...
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Background: Despite evidence of selective outcome reporting across multiple disciplines, this has not yet been assessed in trials studying the effects of exercise in people with cancer. Therefore, the purpose of our study was to explore prospectively registered randomised controlled trials (RCTs) in exercise oncology for evidence of selective outcome reporting. Methods: Eligible trials were RCTs that 1) investigated the effects of at least partially supervised exercise interventions in people with cancer; 2) were preregistered (i.e. registered before the first patient was recruited) on a clinical trials registry; and 3) reported results in a peer-reviewed published manuscript. We searched the PubMed database from the year of inception to September 2020 to identify eligible exercise oncology RCTs clinical trial registries. Eligible trial registrations and linked published manuscripts were compared to identify the proportion of sufficiently preregistered outcomes reported correctly in the manuscripts, and cases of outcome omission, switching, and silently introduction of non- novel outcomes. Results: We identified 31 eligible RCTs and 46 that were ineligible due to retrospective registration. Of the 405 total prespecified outcomes across the 31 eligible trials, only 6.2% were preregistered complete methodological detail. Only 16% (n=148/929) of outcomes reported in published results manuscripts were linked with sufficiently preregistered outcomes without outcome switching. We found 85 total cases of outcome switching. A high proportion (41%) of preregistered outcomes were omitted from the published results manuscripts, and many published outcomes (n=394; 42.4%) were novel outcomes that had been silently introduced (median, min-max=10, 0-50 per trial). We found no examples of preregistered efficacy outcomes that were measured, assessed, and analysed as planned. Conclusions: We found evidence suggestive of widespread selective outcome reporting and non-reporting bias (omitted preregistered outcomes, outcome switching, and silently introduced novel outcomes). The existence of such reporting discrepancies has implications for the integrity and credibility of RCTs in exercise oncology.
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That it is not possible to find information about all initiated clinical trials is of international concern. This is a particular worry because scientists tend to publish their positive findings more often than their negative findings (publication bias). A comprehensive register of initiated clinical trials, with each trial assigned a unique identifier, would inform reviewers, physicians, and others (eg, consumers) about which trials had been started and directly address the problem of publication bias. Patients and their clinicians could also know which trials are open for enrollment, thus speeding medical advances. Individuals who participate in clinical trials typically provide consent in the belief that they are contributing to medical knowledge. But if the knowledge gained is never reported, the trust between patients and investigators and that between patients and research ethics review boards are both damaged. Ethical issues are of particular concern if industry is gaining financially from public involvement in trials, but refusing to reciprocate by making information from industry-sponsored trials generally available. All stakeholders-investigators, research organizations and institutions, journal editors, lawmakers, consumers, and others-must act now, together and in their own domains, to ensure comprehensive registration of clinical trials.
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Selective reporting of outcomes within published studies based on the nature or direction of their results has been widely suspected, but direct evidence of such bias is currently limited to case reports. To study empirically the extent and nature of outcome reporting bias in a cohort of randomized trials. Cohort study using protocols and published reports of randomized trials approved by the Scientific-Ethical Committees for Copenhagen and Frederiksberg, Denmark, in 1994-1995. The number and characteristics of reported and unreported trial outcomes were recorded from protocols, journal articles, and a survey of trialists. An outcome was considered incompletely reported if insufficient data were presented in the published articles for meta-analysis. Odds ratios relating the completeness of outcome reporting to statistical significance were calculated for each trial and then pooled to provide an overall estimate of bias. Protocols and published articles were also compared to identify discrepancies in primary outcomes. Completeness of reporting of efficacy and harm outcomes and of statistically significant vs nonsignificant outcomes; consistency between primary outcomes defined in the most recent protocols and those defined in published articles. One hundred two trials with 122 published journal articles and 3736 outcomes were identified. Overall, 50% of efficacy and 65% of harm outcomes per trial were incompletely reported. Statistically significant outcomes had a higher odds of being fully reported compared with nonsignificant outcomes for both efficacy (pooled odds ratio, 2.4; 95% confidence interval [CI], 1.4-4.0) and harm (pooled odds ratio, 4.7; 95% CI, 1.8-12.0) data. In comparing published articles with protocols, 62% of trials had at least 1 primary outcome that was changed, introduced, or omitted. Eighty-six percent of survey responders (42/49) denied the existence of unreported outcomes despite clear evidence to the contrary. The reporting of trial outcomes is not only frequently incomplete but also biased and inconsistent with protocols. Published articles, as well as reviews that incorporate them, may therefore be unreliable and overestimate the benefits of an intervention. To ensure transparency, planned trials should be registered and protocols should be made publicly available prior to trial completion.
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In a recent article in JAMA on the registration of clinical trials,1 Dickersin and I pointed out that, 30 years after the idea of registering trials had been proposed, 18 years after registration of trials at inception had been shown to eliminate publication bias, and despite the presence of numerous trial registers large and small, Manheimer and Anderson2 were correct in stating that "No comprehensive system for tracking, organizing, and disseminating information about ongoing clinical trials currently exists." We described a profound confusion about even the most basic data from, or existence of, clinical trials. Only half of the million or so trials conducted over the past 56 years are likely to have been reported,1 and of those reported, a substantial proportion did not appear in MEDLINE.
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To comprehend the results of a randomized, controlled trial (RCT), readers must understand its design, conduct, analysis, and interpretation. That goal can be achieved only through complete transparency from authors. Despite several decades of educational efforts, the reporting of RCTs needs improvement. Investigators and editors developed the original CONSORT (Consolidated Standards of Reporting Trials) statement to help authors improve reporting by using a checklist and flow diagram. The revised CONSORT statement presented in this paper incorporates new evidence and addresses some criticisms of the original statement. The checklist items pertain to the content of the Title, Abstract, Introduction, Methods, Results, and Discussion. The revised checklist includes 22 items selected because empirical evidence indicates that not reporting the information is associated with biased estimates of treatment effect or because the information is essential to judge the reliability or relevance of the findings. We intended the flow diagram to depict the passage of participants through an RCT. The revised flow diagram depicts information from four stages of a trial (enrollment, intervention allocation, follow-up, and analysis). The diagram explicitly includes the number of participants, for each intervention group, that are included in the primary data analysis. Inclusion of these numbers allows the reader to judge whether the authors have performed an intention-to-treat analysis. In sum, the CONSORT statement is intended to improve the reporting of an RCT, enabling readers to understand a trial's conduct and to assess the validity of its results.
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To comprehend the results of a randomized, controlled trial (RCT), readers must understand its design, conduct, analysis, and interpretation. That goal can be achieved only through complete transparency from authors. Despite several decades of educational efforts, the reporting of RCTs needs improvement. Investigators and editors developed the original CONSORT (Consolidated Standards of Reporting Trials) statement to help authors improve reporting by using a checklist and flow diagram. The revised CONSORT statement presented in this paper incorporates new evidence and addresses some criticisms of the original statement. The checklist items pertain to the content of the Title, Abstract, Introduction, Methods, Results, and Discussion. The revised checklist includes 22 items selected because empirical evidence indicates that not reporting the information is associated with biased estimates of treatment effect or because the information is essential to judge the reliability or relevance of the findings. We intended the flow diagram to depict the passage of participants through an RCT. The revised flow diagram depicts information from four stages of trial (enrollment, intervention allocation, follow-up, and analysis). The diagram explicitly includes the number of participants, for each intervention group, that are included in the primary data analysis. Inclusion of these numbers allows the reader to judge whether the authors have performed an intention-to-treat analysis. In sum, the CONSORT statement is intended to improve the reporting of an RCT, enabling readers to understand a trial's conduct and to assess the validity of its results.
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Questions concerning the safety of selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression in children led us to compare and contrast published and unpublished data on the risks and benefits of these drugs. We did a meta-analysis of data from randomised controlled trials that evaluated an SSRI versus placebo in participants aged 5-18 years and that were published in a peer-reviewed journal or were unpublished and included in a review by the Committee on Safety of Medicines. The following outcomes were included: remission, response to treatment, depressive symptom scores, serious adverse events, suicide-related behaviours, and discontinuation of treatment because of adverse events. Data for two published trials suggest that fluoxetine has a favourable risk-benefit profile, and unpublished data lend support to this finding. Published results from one trial of paroxetine and two trials of sertraline suggest equivocal or weak positive risk-benefit profiles. However, in both cases, addition of unpublished data indicates that risks outweigh benefits. Data from unpublished trials of citalopram and venlafaxine show unfavourable risk-benefit profiles. Published data suggest a favourable risk-benefit profile for some SSRIs; however, addition of unpublished data indicates that risks could outweigh benefits of these drugs (except fluoxetine) to treat depression in children and young people. Clinical guideline development and clinical decisions about treatment are largely dependent on an evidence base published in peer-reviewed journals. Non-publication of trials, for whatever reason, or the omission of important data from published trials, can lead to erroneous recommendations for treatment. Greater openness and transparency with respect to all intervention studies is needed.