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Beneficial Microbes, 2022; 13(03): 195-204 Wageningen Academic
Publishers
ISSN 1876-2883 print, ISSN 1876-2891 online, DOI 10.3920/BM2021.0124 195
1. Introduction
Randomised controlled trials (RCTs) offer an unique
opportunity to detect important safety signals under
controlled circumstances in an early stage. To report on
safety, a three-step approach is commonly used. First,
safety data is used in order to create an overview of the
frequency of adverse events (AEs), which are defined as:
‘any untoward medical occurrence in a patient or clinical
trial subject administered a medicinal product and which
does not necessarily has a causal relationship with this
treatment’. Secondly, the severity of the identified AEs are
determined. Events with a high severity are called serious
adverse events (SAEs). A SAE is defined as any untoward
medical occurrence that at any dose results in death, a
life-threatening adverse event, inpatient hospitalisation
or prolongation of existing hospitalisation, a persistent or
significant incapacity or substantial disruption of the ability
conduct normal life functions, or a congenital anomaly/
birth defect. Lastly, the likelihood of causality of the AEs
in relation to the study product is assessed. AEs with a
suspected relationship to the study product are called
Inadequate safety reporting in the publications of randomised clinical trials in irritable
bowel syndrome: drug versus probiotic interventions
A.M. van der Geest
1*
, I. Schukking
1
, R.J.M. Brummer
2
, H. Pieterse
3
, M. van den Nieuwboer
4
, L.H.M. van de
Burgwal1 and O.F.A. Larsen1
1
Vrije Universiteit Amsterdam, Athena Institute, De Boelelaan 1085, 1081 HV Amsterdam, the Netherlands;
2
Nutrition-Gut-
Brain Interactions Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, Örebro University,
Fakultetsgatan 1, 70182 Örebro, Sweden; 3University of Ghent, Heymans Institute of Pharmacology, C. Heymanslaan 10,
9000 Ghent, Belgium; 4Stichting Darmgezondheid, Oversteek 35, 6717 ZS Ede, the Netherlands; a.m.vander.geest@vu.nl
Received: 8 September 2021 / Accepted: 27 February 2022
© 2022 Wageningen Academic Publishers
REVIEW ARTICLE
Abstract
Randomised controlled clinical trials (RCTs) offer a unique opportunity to obtain controlled efficacy and safety
data to support clinical decisions. However, most RCT reporting has a stronger focus on efficacy rather than safety.
This study aimed to identify the safety profile of both probiotic and drug interventions in irritable bowel syndrome
(IBS). In connection to this paper, an accompanying paper was published in which a meta-analysis was conducted
to evaluate the efficacy of probiotic interventions compared to that of drug interventions in IBS. Together, these two
studies provide a first assessment regarding the feasibility to determine a burden to benefit ratio for both probiotic
and drug interventions in IBS. RCTs including participants (>18 years old) with IBS and comparing probiotic or drugs
interventions with control groups were identified by a systematic search of MEDLINE (January 2015 – Jan 2021).
Reported safety profiles in drug studies were completer and more detailed as compared with studies on probiotics.
Several inconsistencies in safety reporting were identified between and within drug and probiotic studies, such as:
didn’t report on safety; only reported adverse reactions (ARs) or adverse events (AEs) with a certain severity; didn’t
report the total number of AEs; didn’t split in the control- or experimental arm; didn’t specify AEs; and used different
thresholds for ‘common’ AEs. Hence, it is difficult to compare safety data from drug and probiotic RCTs across and
between different studies. On the current approaches to safety reporting, we could not establish an unambiguous
safety profile for neither probiotic and drug interventions in IBS. These shortcomings hamper a critical comparison
of the burden to benefit ratio for IBS intervention.
Keywords: adverse events, burden to benefit ratio, safety profile
OPEN ACCESS
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196 Beneficial Microbes 13(03)
Van der Geest et al.
adverse reactions (ARs) (EMA, 1995). Safety reporting
is not only of tremendous importance for the safety and
well-being of participants in RCTs, but it also provides
an evidentiary basis to contribute to regulatory approvals
of safe and effective therapies. In practice, however,
RCT reporting is mainly focused on the assessment of
the efficacy outcomes whereas historically, the reporting
of safety information has not been top priority in food
(supplement) studies, such as probiotics (Ioannidis and
Lau, 2002). Therefore, medical decisions for certain types
of therapeutics are directed by efficacy data rather than by
weighing the benefits against risks.
In response to the article of Ioannidis and Lau (2002), many
medical journals and editorial groups have endorsed the
Consolidated Standards of Reporting Trials statement
(CONSORT) (Ioannidis et al., 2004). The CONSORT
Statement offers a standard way for authors to prepare
reports of trial findings, facilitating their complete and
transparent reporting, and aiding their critical appraisal
and interpretation. Hence, this tandem publication aimed
to determine both efficacy (Van der Geest et al., 2022) and
safety (this article) of RCTs, contributing to an assessment of
a burden to benefit ratio to substantiate medical decisions.
This article will determine safety profiles by analysing the
AEs reported in RCTs.
As a test case, we have chosen to investigate the safety of
therapies directed to irritable bowel syndrome (IBS), since
it is one of the few indications for which both probiotic and
drug therapies are applied. In addition, IBS is a common
chronic gastrointestinal disorder which approximately
affects between ~3.8% (using Rome IV criteria) and 9.2%
(using Rome III criteria) people globally, with lifetime
prevalence rates (Oka et al., 2020). Common symptoms
are abdominal pain, bloating, gas related to frequency or
form of bowel movements (Lacy et al., 2016). Furthermore,
IBS does not only affect the patients’ quality of life but
also infers considerable costs, both in terms of healthcare
delivery as well as with respect to society and economy
(Black and Ford, 2020). Various drug and non-drug
therapies are recommended to find symptomatic relief
and improve quality of life (Cangemi and Lacy, 2019).
Health professionals are more often recommending
non-drug therapies due to, amongst others, perspective
of sustained treatment, fear of antibiotic resistance, the
increasing demand of consumers for natural substitutes to
drugs, and the emergence of scientific and clinical evidence
showing the efficacy of alternatives such as probiotics (Reid
et al., 2003). The safety of alternatives such as probiotics
in comparison to drug remedies is, however, questioned
despite various articles demonstrate the opposite (Larsen
et al., 2017; Van den Nieuwboer et al., 2014, 2015a,b).
To support clinical decisions by health professionals, a
comparison between the safety profiles of probiotic and
drug therapies for the treatment of IBS should be accessible.
To our knowledge, no studies have compared the safety
of probiotic and drug interventions in patients. To this
end, we first determined the efficacy of probiotic and
drug interventions by conducting a meta-analysis, which
is presented in a separate article. The present article will
determine the safety profile of both probiotic and drug
interventions. By using this information, a burden to benefit
ratio might reveal the potential differences regarding
efficacy and safety of the two interventions in IBS patients.
2. Materials and methods
Search strategy and eligibility criteria
Our search strategy and eligibility criteria are in line with a
meta-analysis conducted by Ford and colleagues (Ford et al.,
2018). A systematic search of the literature was conducted
in MEDLINE (January 2015 – January 2021) to identify
studies relevant for examining the efficacy of probiotics
and drugs on IBS. Studies on IBS were identified with the
following search syntax: (‘IBS*’ [title/abstract] OR ‘irritable
bowel syndrome:’ [title/abstract]] OR ‘spastic colon’ [title/
abstract]) NOT review’ [title/abstract]). The following
search restriction were applied: participants aged >18
and year of publication between 2015-2021. Abstracts of
the papers identified by the initial search were evaluated
for appropriateness to the study question. All potentially
relevant papers were evaluated in detail by two reviewers
who assessed all identified articles independently, according
to the prospectively defined eligibility criteria (Table 1). The
eligibility criteria of the search were RCTs with placebo
or no therapy and examining the effect of probiotic or
drug interventions with both a treatment- and follow-up
period of at least seven days in adult patients aged >18
years with IBS. The diagnosis of IBS should be based on
Table 1. Eligibility criteria.
Randomised controlled trials.
Diagnosis of IBS based on either a clinician’s opinion, or complying to
specific diagnostic criteria.1
Minimum treatment duration of seven days.
Minimum follow-up duration of seven days.
Dichotomous assessment of response to therapy in terms of effect
on persistence of IBS symptoms following therapy, or continuous
data in the form of effect on IBS symptom scores such as global IBs
symptoms scores, abdominal pain and bloating at study end.2
1 Manning, Kruis score, Rome I, II, III or IV.
2 Preferably patient-reported, but if this was not available then as
assessed by a physician or questionnaire data.
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Inadequate safety reporting in probiotic RCTs for IBS
Beneficial Microbes 13(03) 197
either a physician’s opinion or symptom-based diagnostic
criteria. After inclusion, additional records were identified
by checking references in selected articles (snowballing).
Outcome assessment
The primary outcomes assessed were the safety profiles
of both experimental- and control groups of probiotic
and drug trials. Secondary outcomes assessed were the
reporting differences between probiotic and drug trials.
3. Results
Figure 1 shows the flow of information through the different
phases of our systematic review. The search strategy
generated a total of 269 records, of which 46 full-text articles
were assessed for eligibility. 14 Studies were excluded from
the meta-analysis as they did not meet the inclusion criteria
(Table 1), leaving 32 eligible articles. Out of the 32 articles,
14 reported probiotic interventions and 18 reported drug
interventions. Supplementary Tables S2 and S3 show the
characteristics of all studies included in this meta-analysis
(arranged alphabetically by first author’s last name).
Safety reporting criteria among probiotic and drug RCTs
To make a reliable comparison regarding the safety profile of
probiotics and drugs, there are two criteria the articles must
comply with: (1) there has to be reported on safety; and (2)
there has to be reported on all AEs without specifications as
severity or relation to the study product. When comparing
all AEs, the subjective nature of classifying AEs into groups
based on severity or suspected relation to the study product,
will be avoided.
Probiotics
For each article included through database searching,
articles on probiotics were checked not only for the term
‘safety’ but also for terms related to safety (e.g. adverse
events, side effects). Two out of 13 articles on probiotics
did not use any term related to safety. From the 11 probiotic
studies that did report on safety, different types of AEs
were reported: some studies reported only on AEs with a
certain severity (e.g. moderate, or severe), or only SAE or
only reported on AEs with a possible relationship to the
study product, AR, or studies reported on AEs without a
further specification as severity or a relationship to the
Full-text articles assessed
for eligibility
(n=46)
Full-text articles excluded
because they met exclusion
criteria
(n=15)
Studies included in
quantitative synthesis
Probiotics n=13
Drugs n=18
Records identified through database
searching
(n=260)
Additional records identified
through other sources
(n=9)
Records excluded (title and
abstract confirmed not
appropriate
(n=223)
Studies included in
qualitative synthesis
(n=269)
Figure 1. Flow diagram of assessment of studies identified in the systematic review and meta-analysis.
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Van der Geest et al.
198 Beneficial Microbes 13(03)
study product. Studies that did not reported on all AEs
without further specification as severity or a relationship
to the study product were excluded for further analysis.
The 6 articles that did report on AEs without specifying
on a certain type of AE such as SAE or AR were further
analysed in order to make a reliable comparison regarding
the safety profile of probiotics.
Drugs
Each article on drugs used the term ‘safety’ or a term related
to safety. From the 18 studies on drugs that reported on
safety, one study was excluded for further analysis since
the author only reported on ARs. 16 drugs articles that
did report on AEs without specifying on a certain type of
AE were further analysed to make a reliable comparison
regarding the safety profile of drugs. In conclusion, 6 out
of 13 articles on probiotics and 16 out of 18 articles on
drugs were included for further analysis on the incidence
rate of AEs.
Incidence rate of adverse events for both probiotic and
drugs interventions
To establish safety profiles, the incidence rate of AEs for
both the control- and experimental groups were assessed
by dividing the total number of AEs for each study by the
number of participants involved and the study duration
in days, resulting in an average number of all reported
AEs per person per day. Detailed information on all data
points in Figure 2 can be found Supplementary Table S1.
Interestingly, the mean AEs per person per day in both
the control- and experimental arm of the drug group is
higher compared to the experimental and control arm of
the probiotic group, despite similar inclusion criteria. This
observation can possibly be explained by the variation in
IBS types. As different types of IBS show differences in
prevalence and severity of complaints. As the control and
experimental groups include patients with different types
of IBS, the observed differences in number of AEs between
the groups van be explained by this variation. Another
possibility for this difference may be inadequate safety
reporting, resulting in differences in registration of AEs.
To rule out this possibility, we will first assess the details
of the provided safety information.
The level of detail of provided safety information
The level of detail of the provided safety information was
assessed by looking into three safety parameters: (1) studies
reported on the total number of AEs; (2) the number of AEs
in the study were split per arm (control- and experimental
group); and (3) the studies specified the type of AEs.
Probiotics
After the assessment of the type of safety reporting (see
previous section), 6 studies on probiotics were found
eligible for further investigation. These 6 studies were first
assessed whether they reported on the total number of
0
0.005
0.01
0.015
0.02
0.025
0.03
0.035
Probiotics - experimental
Probiotics - control
Drugs - experimental
Drugs - control
OUTLIER More than 3/2
times of upperquartile
MAXIMUM Greatest value,
excluding outliers
UPPER QUARTILE 25% of
data greater than this value
OUTLIER Less than 3/2
times of lower quartile
LOWER QUARTILE 25%
of data less than this value
MEDIAN 50% of data
greater than this value;
middle of dataset
MINIMUM Least value,
excluding outliers
Figure 2. Adverse events (AEs) per person per day differ between drugs and probiotics control groups: minimum (0, 0.0015;
respectively probiotic and drug), maximum (0.0074, 0.0325; respectively probiotic and drug) and median (0.009, 0.005; respectively
probiotic and drug).
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Inadequate safety reporting in probiotic RCTs for IBS
Beneficial Microbes 13(03) 199
AEs (Figure3). A total of 4 studies did report on the total
number of AEs. Of the 4 studies that did report on the total
number of AEs, 3 studies also split the number of AEs per
arm. However, of these 3 studies, only one study specified
the type of AEs. No further assessment was possible due
to the number of articles on probiotics that fulfilled all
assessment criteria (n=1).
Drugs
After the assessment of the type of safety reporting, 16
studies on drugs were assessed if they reported on the
total number of AEs (Figure 4). A total of 15 studies did
report on the total number of AEs. The 15 studies that
reported on all AEs also split the number of AEs per arm
and specified the type of AEs. The remaining 15 articles
Articles that comply with safety reporting criteriaThe level of detail of provided safety information
Studies included because they
reported on all AEs without
specification as severity or relation
to the study product
(n=6)
Probiotic RCT articles included
through database
searching (n=13)
Studies included because they
report on safety
(n=11)
Studies that reported on the total
number of AEs were assessed on
in depth reporting
(n=4)
Studies that split the number of
AEs per arm
(n=3)
Studies that did specify the
type of AEs
(n=1)
Studies excluded because:
They only reported on AR
(n=4)
They only reported on SAE
(n=1)
Studies excluded because they
did not report on safety
(n=2)
Studies excluded because no AEs
were reported during
intervention which made
in-depth reporting assessment
impossible
(n=2)
Studies excluded because they
did not split AEs per arm
(n=1)
Studies that did not specify the
type of AEs
(n=2)
Figure 3. After analysis of thirteen probiotic articles, only one article complied with the safety parameters (did split adverse events
(AEs) per arm, and did specify the type of AEs).
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Van der Geest et al.
200 Beneficial Microbes 13(03)
Articles that comply with safety reporting criteria
Studies included because they
reported on all AEs without
specification as severity or relation
to the study product
(n=16)
Studies excluded because:
They only reported on AR
(n=2)
Drugs RCT included through
database searching
(n=18)
Studies included because they
report on safety
(n=18)
Studies that reported on the total
number of AEs were assessed on in
depth reporting
(n=15)
Studies excluded because no AEs were
reported during intervention which
made in-depth reporting assessment
impossible
(n=1)
Studies that split the number
of AEs per arm
(n=15)
The level of detail of provided safety information
Studies that did specify the type
of AEs
(n=15)
Remaining studies specified
most common as:
Specified all AEs (n=0)
>1% (n=2)
>2% (n=9)
>3% (n=2)
Unclear (n=2)
Figure 4. After analysis all drugs articles complied with the safety parameters (did split adverse events (AEs) per arm, and did
specify the type of AEs). However, due to variety in specification of AEs in ‘most common’, only 9 out of 18 drugs articles are
usable for comparison, when most common is specified as >2%.
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Inadequate safety reporting in probiotic RCTs for IBS
Beneficial Microbes 13(03) 201
on drugs chose different ways to specify ‘most common’
AEs. Five variations were identified while analysing the
articles: (1) they specified all AEs; (2) they reported only
‘most common’ AEs, specified as ≥1%; (3) they reported
only ‘most common’ AEs, specified as ≥2%; (4) they reported
only ‘most common’ AEs, specified as ≥3%; (5) it remains
unclear how and if they specified AEs; respectively, n=0,
n=2, n=9, n=2, and n=2.
Challenges of the current approaches to safety reporting
Complete reporting of safety data in a standardised way is
crucial to compare outcomes across several RCTs. However,
our attempt to assess the safety profile of both drug and
probiotic RCTs was hampered by inadequate reported
safety data. We outlined several challenges concerning the
comparability of the probiotic and drug RCT:
•
Not mentioning anything about safety or only used
generic or vague statements, such as ‘the drug was
generally well tolerated’.
• Failing to provide separate data for each study arm.
• Failing to provide total number for all AEs.
•
Only report on an AE with a specific severity or
seriousness.
•
Providing total numbers for all AEs for each study arm,
without separate data for each type of AE.
•
Reporting only the AEs observed at a certain frequency
or rate threshold (for example, 1% or 3% of participants).
Despite all the efforts made over the years, still a lot of
overlap between the poor reporting practices for Harms-
Related Data identified in 2004 and the poor reporting
practices identified in our study were found, indicating little
improvement in safety reporting over time (Ioannidis et
al., 2004). In conclusion, no comparison is possible across
and between the reported AEs in probiotic versus drug
studies, due to tremendous variation in safety reporting
and probiotic and drug trials being not compliant with the
section ‘harms’ of the CONSORT statement. In addition,
none of the publications of the selected probiotic and
drug trials refer to a clinical study report where the safety
profile might be reported as indicated by the CONSORT
statement. As a result, based on the current approaches to
safety reporting we could not establish a safety profile of
probiotic and drug interventions.
4. Discussion
In this article, we attempted to assess the safety profile of
both probiotic and drug interventions for IBS. This study
showed an inconsistent reporting of safety data in the
individual RCT, indicating selective filtering of all collected
safety data. Due to the varieties in safety reporting, safety
data cannot be critically evaluated and used for secondary
analysis within and between probiotic- and drug studies.
Figure 5: After analysis of 4 probiotic articles, only 1 article complied with all safety parameters (did split AEs per arm, and
did specify the type of AEs).
Although several individual studies evaluated the safety
profile of orally consumed probiotics as safe, earlier research
also stated that about half of the health care professionals
(HCPs) (slightly) disagrees that the usage of probiotics is
safe, indicating a need for clarity of safety data (Larsen et
al., 2017; Van den Nieuwboer et al., 2014, 2015a,b; Van
der Geest et al., 2020). Although the collection of safety
information is a prerequisite for adequate reporting on RCT,
our results showed that still 14% of probiotic trials did not
report on safety at all (Figure 2). This might explain the
lack of knowledge concerning safety in relation to probiotic
consumption.
To date, probiotics are found in three types: (1)
food supplements; (2) dietary supplements; and (3)
pharmaceuticals (Žuntar et al., 2020). In addition,
probiotics, if assigned to the category food- or dietary
supplements, are not subject to the same strict safety and
effectiveness requirements for trials as drugs are, which
might explain the major difference between articles on
probiotics, that rarely report on safety, and articles on
drugs, that regularly report on safety. However, consistent
safety reporting could contribute to more efficient use
of probiotics in practice due to improved scientific and
medical evidence. Adopting the drug standards would
be the first step in fulfilling the need of consistent safety
reporting. This might also lead to a higher level of credibility
of safety data and foster a better comparison of probiotic
and drug safety outcomes.
In this study we explored inconsistent safety reporting as a
cause of variation in the safety data. Apart from identified
variation in safety reporting, differences in study design
and –characteristics also might have contributed to the
inconsistencies found in the safety data across and among
RCTs. An example of differences in study characteristics
is the variation among the severity of the symptoms of
participants at baseline (i.e. at the start of the intervention).
High severity of symptoms or a high baseline value of
complaints might affect the amount and/or severity of
reported AEs. In addition, confounding factors could have
affected safety results. A notable confounding factor are
mental (co-)morbidities, such as depression. IBS is called a
gut-brain disorder because symptoms do not solely relate
to aberrations in the functioning of the gastrointestinal
tract, but symptoms related to anxiety and depression
are also highly prevalent in IBS patients (Moloney et al.,
2016). The occurrence of AEs may be affected by variety
among the included patients with higher (co-)morbidity
such as depression. Proactive screening or laboratory tests
of potential participants could minimise variety in study
characteristics. Furthermore, differences in study design,
such as data collection methods as passive collection (for
example spontaneously reported by patients); or prompted
collection (for example questionnaires or diaries); could
also have contributed to the inconsistencies found in
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Van der Geest et al.
202 Beneficial Microbes 13(03)
reported AEs. This has important implications for the
occurrence of AEs reported with passive collection resulting
in fewer reported AEs. In addition, in some study design
authors are not transparent concerning the method of
collection reported (Phillips et al., 2019). In addition, the
more frequent assessment might result in more reported
AEs as well.
Future research
Earlier research recognised the need to optimise the quality
of safety reporting for other indications such as arthritis,
hypertension, sinusitis, and HIV (Ioannidis and Lau, 2002),
and a collective effort was made to standardise reporting
methods. Although guidelines, as those of the CONSORT
statement on the structure and content of safety reports,
should be helpful, in practice these guidelines are either not
used at all or not used correctly. Therefore, collective effort
is needed on the adoption of safety reporting guidelines
by researchers. Future research should identify barriers
researchers stumble across when they (should) report on
safety in order to contribute to safety data being considered
a major endpoint of nutritional RCTs upfront. Following
these recommendations will maximise the potential success
of safety data being used to perform secondary analyses or
meta-analyses with higher accuracy and compatibility of
the outcomes among various combined studies. This will
eventually lead to increased knowledge of both safety and
efficacy of interventions which can be used by HCP to make
informed decisions on whether to recommend a treatment.
In conclusion, recent attempts to enhance safety reporting
appear to be insufficient. This article advocates a drug
approach to safety reporting of nutrition interventions
like probiotics in order to avoid ambiguity about the
methodology underlying the establishment of the efficacy
and safety results. More transparency of the study design
and study characteristics and consistent presentation of
safety data is warranted. Lastly, researchers involved in
RCTs are recommended to use an international ethical
and scientific quality standard for designing, recording
and reporting trials, such as Good Clinical Practice (GCP)
guidelines.
Supplementary material
Supplementary material can be found online at https://doi.
org/10.3920/BM2021.0124.
Table S1. Detailed information on all data points of the
boxplot shown in Figure 2.
Table S2. Characteristics of all probiotic studies of irritable
bowel syndrome included in this meta-analysis.
Table S3. Characteristics of all drugs studies of irritable
bowel syndrome included in this meta-analysis.
Conflict of interest
This work was not financially supported. O.F.A. Larsen is
also Senior Manager Science at Yakult Nederland B.V., H.
Pieterse is also owner of Profess Medical Consultancy B.V.,
M. van den Nieuwboer is also consultant at FFUND BV and
at BIMINI Biotech BV., R.J.M Brummer is also a member of
the Scientific Advisory Board of Chr Hansen A/S., L.H.M.
van de Burgwal is consultant for several commercial parties
in the field of probiotics and life sciences; none of her
advising practices are related to, or in conflict with the
content of this research.
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