NAOSITE: Nagasaki University's Academic Output SITE
Title
Improved participants understanding of research information in real
settings using the SIDCER informed consent form: a randomizedcontrolled informed consent study nested with eight clinical trials
Author(s)
Koonrungsesomboon, Nut
Citation
Nagasaki University (長崎大学), 博士(医学) (2017-03-21)
Issue Date
2017-03-21
URL
http://hdl.handle.net/10069/37978
Right
© Springer-Verlag Berlin Heidelberg 2016
The final publication is available at link.springer.com
This document is downloaded at: 2020-05-26T00:04:52Z
http://naosite.lb.nagasaki-u.ac.jp
TITLE PAGE
Title:
Improved Participants’ Understanding of Research Information in Real Settings Using the SIDCER Informed
Consent Form: A Randomized-Controlled Informed Consent Study Nested with Eight Clinical Trials
Concise title:
Improved Participants’ Understanding in Eight Clinical Trials
Authors:
Nut Koonrungsesomboon1,2, Thipaporn Tharavanij3, Kittichet Phiphatpatthamaamphan3, Ratha-korn Vilaichone3,
Sudsayam Manuwong4, Parichat Curry4, Sith Siramolpiwat3, Thanachai Punchaipornpon3, Supakit Kanitnate5,
Nattapol Tammachote5, Rodsarin Yamprasert6, Waipoj Chanvimalueng7, Rujirat Kaewkumpai6, Soiphet
Netanong6, Peerapong Kitipawong3, Paskorn Sritipsukho8,9, Juntra Karbwang1,*
1
Department of Clinical Product Development, Institute of Tropical Medicine, Nagasaki University, 1-12-4
Sakamoto, Nagasaki 852-8523, Japan
2
Leading Program, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki
852-8523, Japan
3
Department of Medicine, Faculty of Medicine, Thammasat University, Pathum Thani 12121, Thailand
4
Department of Anesthesiology, Faculty of Medicine, Thammasat University, Pathum Thani 12121, Thailand
5
Department of Orthopedics, Faculty of Medicine, Thammasat University, Pathum Thani 12121, Thailand
6
Center of Excellence in Applied Thai Traditional Medicine Research, Thammasat University, Pathum Thani
1
12121, Thailand
7
Department of Otolaryngology, Faculty of Medicine, Thammasat University, Pathum Thani 12121, Thailand
8
Department of Pediatrics, Faculty of Medicine, Thammasat University, Pathum Thani 12121, Thailand
9
Center of Excellence in Applied Epidemiology, Thammasat University, Pathum Thani 12121, Thailand
*Corresponding author: Juntra Karbwang, M.D., Ph.D.
1-12-4 Sakamoto, Nagasaki 852-8523, Japan
Tel: +81-95-819-7558
Fax: +81-95-819-7846
Email address: karbwangj@nagasaki-u.ac.jp
Trial registration:
Name of the clinical trial registry: Chinese Clinical Trial Registry
Registration number: ChiCTR-TRC-14004817.
Acknowledgments:
This study was supported by a grant from Faculty of Medicine, Thammasat University, and partially supported
by TDR, the Special Programme for Research and Training in Tropical Diseases, co-sponsored by UNICEF,
UNDP, the World Bank, and WHO through the Forum for Ethical Review Committees in the Asian and Western
Pacific region (FERCAP). Dr. Nut Koonrungsesomboon is a recipient of a scholarship from the Program for
Nurturing Global Leaders in Tropical and Emerging Communicable Diseases, Graduate School of Biomedical
Sciences, Nagasaki University.
We thank Ms. Tasaneeya Chantravekin and Ms. Vanida Jansom for their
2
assistance on the data collection process. We are thankful to Ms. Chotimanee Kaewserm and her colleagues
for their assistance in reviewing the SIDCER ICFs from laypersons’ perspectives. We would like to express
our gratitude to Prof. Kenji Hirayama for his valuable comments and advice. Thanks are extended to Ms.
Junjira Laothavorn for her assistance in editing the manuscript.
3
Abstract
Purpose: This study aimed to test the applicability and effectiveness of the principles and informed consent
form (ICF) template proposed by the Strategic Initiative for Developing Capacity in Ethical Review (SIDCER)
across multiple clinical trials involving Thai research participants with various conditions.
Methods: A single-center, randomized-controlled study nested with eight clinical trials was conducted at
Thammasat University Hospital, Thailand. A total of 258 participants from any of the eight clinical trials were
enrolled and randomly assigned to read either the SIDCER ICF (n = 130) or the conventional ICF (n = 128) of
the respective trial.
Their understanding of necessary information was assessed using the post-test
questionnaire; they were allowed to consult a given ICF while completing the questionnaire. The primary
endpoint was the proportion of the participants who had the post-test score of ≥80%, and the secondary endpoint
was the total score of the post-test.
Results: The proportion of the participants in the SIDCER ICF group who achieved the primary endpoint was
significantly higher than that of the conventional ICF group (60.8 vs. 41.4%, p = 0.002). The total score of the
post-test was also significantly higher among the participants who read the SIDCER ICF than those who read
the conventional ICF (83.3 vs. 76.0%, p < 0.001).
Conclusions: The present study demonstrated that the SIDCER ICF was applicable and effective to improve
Thai research participants’ understanding of research information in diverse clinical trials. Using the SIDCER
ICF methodology, clinical researchers can improve the quality of ICFs for their trials.
4
Keywords: Informed consent; Consent forms; Comprehension; Understanding; Clinical trials; Clinical studies.
5
Introduction
Several clinical trials have faced with the challenge of a limited, suboptimal understanding of
necessary trial-related information among research subjects [1-4]. Some subjects may enter a trial unaware of
foreseeable risks and of the fact that they are taking part in research [5, 6].
They may unintentionally violate
the study protocol due to insufficient understanding, affecting the validity and reliability of results obtained [7].
A written informed consent form (ICF) is mandatory and essential in most clinical studies as it is a
primary vehicle for disclosure of research information and documentation of subjects’ consent according to
international ethical guidelines and regulations [8-10]. Therefore, it should contain adequate and relevant
information for the subjects’ decision making in a concise and simple language [11]. However, the observation
of the current practice shows that the ICFs used in contemporary clinical trials have been lengthened over time
[12, 13], and many of them are complicated, poorly organized, incomprehensible, incomplete, or even
misinformed [14-17]. A recent systematic review and meta-analysis on informed consent demonstrates no
increased proportion of research subjects who have an optimal understanding of trial information over 30 years
[18].
In an attempt to address concerns on the quality of ICFs, the Strategic Initiative for Developing
Capacity in Ethical Review (SIDCER) – an international network, launched by World Health Organization – has
recently proposed principles and a guideline for the development of an enhanced ICF, named “SIDCER ICF”
[19].
The first validation was performed in Thai volunteers where the SIDCER ICF methodology was applied
to a clinical pharmacokinetics drug-drug interaction study involving healthy subjects [20].
6
The results
demonstrated that the SIDCER ICF improved the participants’ understanding, when compared to the
conventional ICF [20]. Further investigations in different types of research studies and settings are required to
confirm its applicability and effectiveness.
This study aimed to test the applicability and effectiveness of the SIDCER ICF methodology across
multiple clinical trials involving Thai populations with diverse conditions in actual informed consent processes.
We hypothesized that the SIDCER ICF would be superior to the conventional ICF in obtaining the participants’
optimal understanding of trial information.
7
Methods
This study (hereafter referred as “ICF study”) was a single-center, open-label, randomized-controlled
study of the two different ICF interventions (1:1), i.e., the SIDCER ICF and the conventional ICF, using a
post-test questionnaire as an assessment tool. The ICF study was conducted at Thammasat University Hospital,
Pathum Thani, Thailand. The ICF study protocols and all related documents were approved by the Human
Ethics Committee of Thammasat University. The ICF study was registered in the WHO registry network as
ChiCTR-TRC-14004817.
Recruitment of collaborating studies
Clinical trials that were planned to be conducted at Thammasat University Hospital during May 2014
to April 2016 were assessed for study eligibility based on predefined criteria: (1) a study with an intervention(s)
involving human subjects aged >18 years old that its protocol had been approved by the Human Ethics
Committee of Thammasat University; (2) a study with the planned number of subjects involved of at least 10
individuals at Thammasat University Hospital; (3) a study not involving patients with a psychological,
neurological or visual disorder; (4) a study having a written ICF approved; and (5) a study that the investigators
(hereafter referred as “collaborating investigators”) agreed to collaborate and involve in the ICF study.
Clinical trials that met all the above criteria were recruited and are hereafter referred as “collaborating studies.”
The ICF study investigators provided the collaborating investigators with administrative assistance during the
process of protocol amendments required to embed the ICF study into a collaborating study (see below). The
8
collaborating investigators could initiate patient enrollment for their trial using the approved conventional ICF
without the delay as a result of protocol modification and resubmission of the amendments to the research ethics
committee for approval (Fig. 1).
Protocol amendments of collaborating studies
The protocols of collaborating studies were undergone an amendment for the informed consent
process: (1) the use of any of the two ICF interventions (see below) by random assignment and (2) the process
of the subjects’ understanding assessment using the post-test questionnaire (see below).
The amended
informed consent process provided an option for all prospective subjects of collaborating studies to make a
voluntary decision whether to participate in the ICF study. Eligible subjects of collaborating studies who chose
not to participate in the ICF study would undergo the conventional process of informed consent using the
conventional ICF and needed not to perform the post-test questionnaire.
The amended protocols were then
submitted to the Human Ethics Committee of Thammasat University for review and approval.
ICF interventions: the SIDCER ICF and the conventional ICF
An original ICF (in Thai) of each collaborating study which had been approved by the Human Ethics
Committee of Thammasat University prior to the ICF study recruitment was considered as a conventional ICF
and used as a control in this ICF study.
9
A SIDCER ICF (in Thai) of each collaborating study was developed following the SIDCER ICF
methodology extensively described elsewhere [19]. In brief, the protocol of each collaborating study was
reviewed and the essential information was selected and synthesized; then, information as is relevant to the
study participants’ decision making on whether to participate in the collaborating study was included in the
SIDCER ICF template (available from: http://ijme.in/pdf/appendix-1.pdf?v=1) in a narrative and illustrative
manner, where appropriate. The SIDCER ICF of each collaborating study was reviewed by the respective
collaborating investigator(s) to ensure the accuracy of the information presented and by independent laypersons
to improve the readability and understandability of the SIDCER ICF. It was submitted together with the
respective amended protocol to the Human Ethics Committee of Thammasat University for review and
approval.
Assessment tool: the post-test questionnaire
The post-test questionnaire (in Thai) used in previous studies [20, 21] was modified to include study
specific information of each collaborating study. The questionnaire consisted of 25 short case scenarios or less,
based on the nature of each collaborating study. One scenario addressed one required element of the ICF
content using a common practical situation relevant to the study, and a question with three possible answers was
structured in a way that the participants would have had to apply their understanding of the information given to
the scenario. Each of these ICF mandatory elements per regulatory was necessary for the individuals’ rational
decision of whether participation in the trial was consistent with their interests and preferences.
10
The
questionnaire of each collaborating study was reviewed and corrected by the respective collaborating
investigator(s) and independent laypersons.
It was then submitted to the Human Ethics Committee of
Thammasat University for review and approval.
Study endpoints
The primary endpoint was the proportion of the participants who had the post-test score of ≥80%.
The secondary endpoints were the total score of the post-test, the score of each category of the elements required,
and the time spent for reading a given ICF and completing the post-test questionnaire.
Sample size determination
The number of 250 subjects was required to detect the 20% difference between two independent
proportions of the primary endpoint (p1 = 0.8 and p2 = 0.6) with the precision and confidence level of 95% (α =
0.05), 80% power (1 - β = 0.8), and the allocation ratio of 1, using a continuity correction with an estimate of
20% for missing data.
The estimated sample size was calculated using G*power 3.1.9.2 for Windows.
Study procedure
Prospective patients who were invited to take part in each collaborating study or their representatives,
when necessary, were invited to participate in the ICF study. Individuals who declined to participate in the ICF
study or cannot read and write Thai were excluded. The ICF study was carried out in an anonymous manner
11
using a subject number given, and none of identifiable or health-related information was collected. Informed
consent was obtained verbally from all individual participants prior to their participation in the ICF study.
The two main processes of this ICF study included (1) the process of reading a given ICF and (2) the
process of doing the post-test questionnaire.
In each collaborating study, the prospective subjects or their
representatives, when necessary, were enrolled sequentially and randomly assigned to read either the SIDCER
ICF or the conventional ICF, using a predetermined computer-generated randomization list.
Eligible
individuals could read a given ICF and ask any inquiry until their satisfaction; then, the post-test questionnaire
was distributed. They were allowed to keep and read the ICF while completing the questionnaire. The time
spent on the two processes was recorded. After the post-test, the participants were corrected any inaccurate
understanding of the trial information prior to their decision to participate in a respective parent clinical study.
Data analysis
A correct or incorrect answer of each question in the post-test questionnaire was counted as a score of
1 or 0, respectively.
For each collaborating study, the total score of the post-test and the score of each category
of the ICF elements required were calculated and converted into a percentage. Data from all collaborating
studies were assembled, and the predefined endpoints of this ICF study were then analyzed.
The chi-squared test or the Fisher exact test, where appropriate, was applied for the comparison of
nominal data between the two groups. The Wilcoxon rank sum test was used for the comparison of interval
data between the two groups as none of the data was normally distributed. The endpoints were adjusted by
12
calculating a percentage of the score from only the questions of which description of the corresponding elements
were available in both ICF interventions of a collaborating study.
This “adjusted endpoints” aimed to
determine the effectiveness of the linguistics and presentational means used in the two different ICFs, exclusive
of the lack of certain information in the conventional ICF.
The chi-squared test and the Kruskal-Wallis test
were applied to check for differences of nominal data and interval data, respectively, among collaborating
studies. Subgroup analyses were performed by applying the chi-squared test or the Fisher exact test, where
appropriate, to determine the impact of gender (male and female) generation (generation Y, individuals whose
age was up to 34 years at an enrollment date; generation X, individuals whose age was between 35 and 51 years;
and baby boomers, individuals whose age was over 52 years) and educational level (level 1, high school or
lower; level 2, bachelor degree or equivalent; and level 3, master/doctoral degree or equivalent) on the primary
endpoint.
The multivariate analysis was performed to identify any associations between demographic
variables and the primary outcome.
A statistical significance was set at α = 0.05 for all tests. Statistical analysis was performed using
standard statistical software (SPSS version 22.0). Figures were generated using GraphPad Prism version 5.0 or
Microsoft PowerPoint 2007.
13
Fig. 1 Appproach for stu
tudy recruitmeent
(1) The IICF study inveestigators approached an appproved cliniccal study proto
ocol and assesssed for study eligibility.
(2) If eliigible, the IC
CF study inveestigators preepared a protocol amendm
ment and relat
ated materials (i.e., the
SIDCER
R ICF and thee post-test queestionnaire) ffor the recruitted study. After
A
reviewedd and corrected by the
collaboraating investiggator(s), the amended prootocol and materials
m
weree submitted tto the researrch ethics
committeee (EC) for appproval. (3) The
T collaboraating investigaators enrolled prospective ppatients using any of the
two ICF interventionss (the SIDCE
ER ICF or thee conventionaal ICF) by raandom assignm
nment, followeed by the
understannding assessm
ment using thee post-test quuestionnaire. During the period
p
of prottocol modificcation and
resubmisssion for ethiccal approval, the collaboraating investigators could enroll prospecctive patients using the
approvedd conventionall ICF.
14
Results
Eight clinical trials met the ICF study recruitment criteria and were coded as study 1 to study 8.
features
of eight
collaborating
studies
are
given
in
Table 1:
All
were
The
investigator-initiated,
randomized-controlled trials. The median page length of the SIDCER ICFs was significantly shorter than that
of the conventional ICFs (4 pages vs. 7.5 pages, p = 0.001; 1,502 words vs. 2,542 words, p = 0.012).
Of 286 individuals who were invited to participate in any of the eight collaborating studies during the
ICF study period, a total of 258 participants (aged 50.5 ± 15.2 years) were enrolled into this ICF study.
One
hundred and thirty participants were randomly assigned to the SIDCER ICF group, while the others to the
conventional ICF group (Fig. 2). Their demographic data are shown in Table 2: 61.2% were female, 53.9%
were under the baby boomers generation, and 52.7% had educational level 1.
In the SIDCER ICF group, 60.8% of the participants (79/130) achieved the primary endpoint,
compared to 41.4% (53/128) in the conventional ICF group (RR = 1.468, 95% CI = 1.145-1.881, p = 0.002) (Fig.
3). There was also a significantly higher proportion of the participants in the SIDCER ICF group who
achieved the adjusted primary endpoint, when compared to that of the conventional ICF group (64.6 vs. 50.8%,
RR = 1.272, 95% CI = 1.029-1.574, p = 0.024). In the SIDCER ICF group, there was no statistically
significant difference among eight collaborating studies for the proportions of the participants who achieved the
primary endpoint (χ2(7) = 6.672, p = 0.464), while a significant difference was seen in the conventional ICF
group (χ2(7) = 35.311, p < 0.001).
Subgroup analyses on the primary endpoint demonstrated that male participants, the participants
15
under the baby boomers generation, and the participants who had educational level 1 statistically significantly
favored the SIDCER ICF (Fig. 3). The post hoc analyses demonstrated a power of test (1-β) of 23.9, 5.2, 9.5,
12.5, and 4.1% in female participants, the participants under the generation Y and the generation X, and the
participants who had educational level 2 and level 3, respectively.
The multivariate analysis demonstrated that
education and age were significantly associated with the primary endpoint (OR = 4.42, 95%CI = 2.62-7.47, p <
0.001; OR = 0.97, 95%CI = 0.95-0.99, p = 0.001, respectively).
The assessment of the secondary endpoints showed that the total score of the post-test and the score
of scientific aspects in the SIDCER ICF group were significantly higher than those of the conventional ICF
group (83.3 vs. 76.0%, p < 0.001; and 87.5 vs. 75.0%, p < 0.001, respectively), whereas there was no statistical
difference between the two groups for the scores of the other aspects and the time spent (Table 3).
The
adjusted total score of the post-test in the SIDCER ICF group was also significantly higher than that of the
conventional ICF group (86.0 vs. 80.5%, p = 0.002).
The SIDCER ICF group had no statistically significant
difference among eight collaborating studies for the total score (χ2(7) = 6.766, p = 0.454), whereas a significant
difference was noted in the conventional ICF group (χ2(7) = 41.643, p < 0.001).
Comparative proportions of the participants who correctly answered each item in the post-test
questionnaire between the two groups showed significant differences in seven (out of 25) items (Fig. 4). The
SIDCER ICF was superior to the conventional ICF in improving the participants’ understanding on the
following elements: the foreseeable risks (p = 0.046), the purpose of the study (p = 0.029), trial treatment (i.e.,
randomization and the use of placebo, if applicable) (p = 0.012), identification of any experimental procedures
16
(p = 0.047), who can access the data (p = 0.025), the duration of the subject’s participation (p = 0.006), and the
number of subjects required (p < 0.001).
17
Table 1 Characteristics of the collaborating studies
Study
1
Condition
Age
of the patients
(years)
Dyslipidemia
35-65
Study design
Double-blind,
randomized,
Intervention under
Clinical
investigation
phase
Herbal drug vs.
SIDCER ICF
Conventional
ICF
Pages
Words
Pages
Words
II
4
1657
8
2940
II
4
1654
8
2353
IV
5
1442
5
1554
n/a
5
1436
5
1500
II
4
1558
8
2731
III
4
1434
5
2273
IV
4
1589
9
3477
II
4
1446
7
2930
Simvastatin
controlled
2
Dyslipidemia
18-70
Double-blind,
randomized,
Herbal drug vs.
Simvastatin
controlled
3
Osteoarthritis
50-85
of the knee
Double-blind,
Anti-inflammatory
randomized,
agent vs. Placebo
controlled
4
Osteoarthritis
50-85
of the knee
Double-blind,
One surgical
randomized,
intervention vs.
controlled
another surgical
intervention
5
Allergic
20-60
rhinitis
Double-blind,
randomized,
Herbal drug vs.
Loratadine
controlled
6
Hepatocellular
18-65
carcinoma
Double-blind,
Hepatoprotective
randomized,
agent vs. Placebo
controlled
7
Dyspepsia
18-70
Open-label,
Modified standard
randomized,
triple therapy
controlled
regimen vs.
sequential therapy
regimen
8
Elective
surgery
18-80
Double-blind,
Herbal drug vs.
randomized,
Placebo
controlled
n/a, not applicable
18
Fig. 2 Floow diagram of
o the collaborating studies
Two hunndred and fiftyy-eight particiipants from eiight collaboraating studies were
w
enrolledd: 130 were asssigned to
the SIDC
CER ICF (S-IC
CF) group, wh
hile 128 to thee conventionall ICF (C-ICF) group.
19
Table 2 Demographic data of the participants (n = 258)
SIDCER ICF
Conventional ICF
(n = 130)
(n = 128)
Sex
Male
49
(37.7%)
51
(39.8%)
Female
81
(62.3%)
77
(60.2%)
Generation Y
23
(17.7%)
25
(19.5%)
Generation X
38
(29.2%)
33
(25.8%)
Baby Boomers
69
(53.1%)
70
(54.7%)
Level 1
73
(56.2%)
63
(49.2%)
Level 2
54
(41.5%)
59
(46.1%)
Level 3
3
(2.3%)
6
(4.7%)
Generation
Education
Data represent the number of participants. Generation was divided into three subgroups: (1) Generation Y
includes participants whose age was up to 34 years at an enrollment date, (2) generation X includes participants
whose age was between 35 and 51 years, and (3) baby boomers includes participants whose age was over 52
years.
Education was divided into three levels: Level 1 represents high school level or lower, level 2 represents
bachelor degree or equivalent, and level 3 represents master/doctoral degree or equivalent.
20
Fig. 3 Comparisons of the primary endpoint between the two groups
Data represent the proportion of the participants whose post-test score was satisfied according to the 80%
passing level. Relative risk is the ratio derived from the proportion of the SIDCER ICF group divided by that
of the conventional ICF group (asterisk).
21
Table 3 Comparisons of the secondary endpoints between the two groups
SIDCER ICF
Conventional ICF
(n = 130)
(n = 128)
P value
Total score (%)
83.3
(75.0-91.7)
76.0
(66.7-87.5)
<0.001
General aspects (%)
60.0
(60.0-80.0)
60.0
(60.0-80.0)
0.380
Rights aspects (%)
100.0
(100.0-100.0)
100.0
(75.0-100.0)
0.481
Scientific aspects (%)
87.5
(75.0-100.0)
75.0
(62.5-87.5)
<0.001
Ethical aspects (%)
75.0
(62.5-87.5)
75.0
(62.5-87.5)
0.410
Time (min)
30.0
(20.0-50.0)
30.0
(20.0-40.0)
0.959
Data represent the median (interquartile, Q1-Q3) of the total score of the post-test, the score in each category of
the ICF elements, and the time spent for reading a given ICF and completing the post-test questionnaire.
entries indicate statistical significance (p value < 0.05).
22
Bold
Fig. 4 Comparisons of the participants’ understanding of each ICF element between the two groups
Data represent the proportion of the participants who correctly answered each item in the post-test questionnaire.
Relative risk is the ratio derived from the proportion of the SIDCER ICF group divided by that of the
conventional ICF group (asterisk).
23
Discussion
The present ICF study nested with eight clinical trials validated the applicability of the SIDCER ICF
methodology in the development of enhanced ICFs for various clinical trials. Significant improvement of the
participants’ understanding indicates the effectiveness of the SIDCER ICF in the real informed consent process
among Thai populations with diverse conditions.
This is supported by (1) a significantly higher proportion of
the participants who achieved the satisfactory level of understanding at 80% and a higher median score of the
post-test in the SIDCER ICF group, when compared to the conventional ICF group, and (2) no statistically
significant difference of these two main values in the SIDCER ICF group among eight collaborating studies.
Not only was the necessary information provided complete, the linguistics and presentational means used in the
SIDCER ICF also contributed to the superiority of the SIDCER ICF over the conventional ICF regarding the
participants’ understanding, as demonstrated by the adjusted endpoints.
Given that the present study was designed to test the applicability and effectiveness of the SIDCER
ICF methodology in actual clinical trials, it rises above the limitation of the previous simulation study in a mock
population [20] and provides stronger evidence to support the value of the SIDCER ICF methodology in
enhancing subjects’ understanding of trial-related information in various clinical research.
This study
addresses a common pitfall consistently raised by two systematic reviews on informed consent interventions that
enhanced ICFs are commonly effective in a fictitious situation, while a few studies demonstrate the superiority
of enhanced ICFs in a realistic setting [22, 23].
The success of collaboration with eight clinical trials at Thammasat University Hospital made the
24
validation of the SIDCER ICF methodology in real settings possible. This was partly attributable to an
innovative approach of the present study proposal for study recruitment.
Literature notes that trial
investigators may be reluctant to team up with the ICF study investigators if collaborations are too burdensome
or defer their trial initiation [24, 25].
Our approach reduced administrative burden of collaborating
investigators and did not delay their trial enrollment (Fig. 1). We demonstrated that embedding an informed
consent study into many clinical trials is feasible.
The present study demonstrated that the SIDCER ICF could do better particularly in scientific aspects
of the clinical studies. Five out of seven items in which the results significantly favored the SIDCER ICF
belonged to scientific aspects (Fig. 4), including randomization and the use of placebo which is a difficult
concept for laypersons to understand [18, 26].
This indicates that the SIDCER ICF provided clearer
information that helped the participants understand and interpret scientific matters of the collaborating studies
more accurately, when compared to the conventional ICF.
The SIDCER ICF methodology was proven suitable and effective to research participants with
advanced age or low educational level.
This is supported by the significantly improved understanding of the
participants under the baby boomers generation and those with educational level 1 using the SIDCER ICF. In
clinical research, investigators and research ethics committees may take note of or be aware of a limited
understanding of research subjects with advanced age or low educational level as the evidence suggests [18, 22,
27]. Therefore, the application of the SIDCER ICF methodology could be helpful to address this concern and
could ensure or increase the validity of consent obtained from those groups of populations. However, the
25
superiority of the SIDCER ICF over the conventional ICF in other subgroups requires further investigations
because the results of the present study remained inconclusive, as demonstrated by the post hoc analysis for a
power of test.
Although the SIDCER ICF was proven superior to the conventional ICF, there is still room for
improvement of the SIDCER ICF development. It may be worthwhile to consider using more graphic displays
to increase visualization or simplification of some difficult aspects of the study (e.g., a pictograph format for
depicting foreseeable risks) [28] or utilizing techniques for improving processability (e.g., larger font for a study
involving a geriatric population) [29]. A dialog and discussion between investigators, or qualified persons
designated by the investigators, and prospective subjects are still indispensible, while consideration of other
modes of information delivery (e.g., multimedia) during an informed consent process may be warranted in some
cases [30, 31].
It should be noted that the inherent weakness of an ICF study nested with several clinical trials is the
variation of the conventional ICFs’ quality used as a control in different collaborating studies. This could
result in diverse effectiveness values in a comparative group, as demonstrated by multiple comparisons of the
endpoints in the conventional ICF group of this study.
Reducing or limiting a number of clinical trials
involved may decrease the heterogeneity of the effectiveness values in a control group among collaborating
studies. However, study recruitment strategies may require modifications and target only large clinical trials in
order to achieve the adequate number of subjects required for testing hypotheses of an informed consent study in
a real setting. Future studies on comparative informed consent interventions should take into account the study
26
recruitment strategies and an appropriate number of collaborating studies involved.
27
Conclusions
The SIDCER ICF improved the understanding of the participants in this study nested in the actual
informed consent processes of eight clinical trials conducted at Thammasat University Hospital.
This
demonstrates the applicability and effectiveness of the SIDCER ICF principles and template for enhancing the
quality of ICFs and improving the subjects’ understanding in real research settings. Further studies to assess its
applicability and effectiveness in different languages and settings and in other groups of populations (e.g.,
vulnerable populations) are warranted.
28
Acknowledgments
This study was supported by a grant from Faculty of Medicine, Thammasat University, and partially
supported by TDR, the Special Programme for Research and Training in Tropical Diseases, co-sponsored by
UNICEF, UNDP, the World Bank, and WHO through the Forum for Ethical Review Committees in the Asian
and Western Pacific region (FERCAP). Dr. Nut Koonrungsesomboon is a recipient of a scholarship from the
Program for Nurturing Global Leaders in Tropical and Emerging Communicable Diseases, Graduate School of
Biomedical Sciences, Nagasaki University. We thank Ms. Tasaneeya Chantravekin and Ms. Vanida Jansom for
their assistance on the data collection process.
We are thankful to Ms. Chotimanee Kaewserm and her
colleagues for their assistance in reviewing the SIDCER ICFs from laypersons’ perspectives. We would like to
express our gratitude to Prof. Kenji Hirayama for his valuable comments and advice. Thanks are extended to
Ms. Junjira Laothavorn for her assistance in editing the manuscript.
Authors’ contributions
NK designed the study, developed the ICF study protocol and related materials, analyzed the data,
interpreted the results, and prepared a drafted manuscript. TT designed the study, developed the ICF study
protocol and related materials, conducted and collaborated the study, collected the data, and provided comments
for manuscript improvement.
KP, RV, SM, PC, SS, TP, SK, NT, RY, WC, RK, SN, and PK provided the
collaborating study protocols and the conventional ICFs, reviewed the materials, conducted the study, and
collected the data.
PS reviewed the ICF study protocol and related materials, and collaborated the study. JK
29
designed the study, developed the ICF study protocol and related materials, analyzed the data, interpreted the
results, and finalized the manuscript.
Compliance with ethical standards
All procedures performed in this study were in accordance with the ethical standards of the
institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable
ethical standards.
Conflict of interest
The authors declare that they have no conflict of interest.
30
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