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Guy Peryer, Su Golder, Daniela R Junqueira, Sunita Vohra, Yoon Kong Loke; on behalf of the
Cochrane Adverse Effects Methods Group
Key Points:
• To achieve a balanced perspective, all reviews should try to consider adverse aspects of
interventions.
• There are major challenges in specifying relevant outcomes and study designs for
systematic reviews evaluating adverse effects. This is due to high diversity in the number
and type of possible adverse effects, as well as variation in their definition, methods of
ascertainment, incidence and time-course.
• Review authors should pre-specify their approach to reviewing studies of adverse effects
within the review protocol. The approach may be confirmatory (focused on particular
adverse effects of interest), exploratory (opportunistic capture of any adverse effects
that happen to be reported), or a hybrid (combination of both).
• Depending on the approach used and outcomes of interest to the review, identification
of relevant adverse effects data may require a bespoke search process that includes a
wider selection of sources than that required to identify data on beneficial outcomes.
• Because adverse effects data are often handled with less rigour than the primary
beneficial outcomes of a study, review authors must recognize the possibility of poor
case definition, inadequate monitoring and incomplete reporting when synthesizing
data.
Cite this chapter as: Peryer G, Golder S, Junqueira D, Vohra S, Loke YK. Chapter 19: Adverse
effects. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA
(editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated
February 2022). Cochrane, 2022. Available from www.training.cochrane.org/handbook.
This chapter addresses special issues about adverse effects in Cochrane Reviews. It focuses
on methodological differences when assessing adverse effects compared with other
outcomes.
Although prospective collection of adverse event data is desirable, many adverse effects
cannot be pre-specified because they are not yet known or suspected to be associated with
an intervention. Thus, spontaneous report monitoring may occur, which involves
recording all adverse events (pre-defined or not) throughout the duration of the study. Both
participants and researchers recognizing any adverse event can file a report at any time.
This may uncover new or unexpected adverse effects not previously associated with the
intervention. For regulated products (e.g. drugs, biologics, vaccines), spontaneously
reported adverse events are usually coded, grouped and categorized following established
dictionaries for analysis and presentation.
Whichever monitoring method is used to collect information about adverse events, study
investigators may combine adverse events into global or composite measures, which are
Copyright © 2022 The Cochrane Collaboration
often reported as total number of serious adverse events, or number of withdrawals due to
adverse events, or total number of adverse events in an anatomic or organ system (e.g.
gastrointestinal, cardiovascular). However, these composite measures do not give
information on what exactly the events were, and so it is usually necessary to drill down for
details of distinct or individual adverse events, such as nausea or rash.
Ideally, the definition and ascertainment of adverse events should be as uniform as possible
across the included studies in the review. The lack of systematic monitoring or follow-up,
coupled with divergent methods of seeking, verifying and classifying adverse events, can
introduce heterogeneity in effect estimates among studies. Review authors will therefore
need to pay close attention to outcome definition and method of monitoring when
interpreting or comparing frequencies, rates and risk estimates for adverse effects.
effects, review authors may decide to conduct a separate review of only the adverse effects
of an intervention (see Box 19.2.a). Whichever strategy is taken, review authors will need to
decide whether to focus only on a pre-specified set of adverse events (a ‘confirmatory’
approach), or analyse data on adverse events identified during the conduct of the review
(an ‘exploratory’ approach). In practice, some review authors will use a hybrid of these two
approaches. Consideration will also be needed of whether the same sources of evidence will
be used to look at beneficial and adverse effects, or whether additional types of evidence
will be sought to examine the adverse effects. Finally, the specific selection and definition
of adverse effects will need to be considered. In this section we tackle these key
considerations for formulating a review to look at adverse effects.
For an intervention that is given for a variety of diseases or conditions, yet whose adverse
effect profile might be expected to be similar in different populations and settings, it may
be reasonable to examine adverse effects regardless of the condition for which the
intervention was delivered. This can be achieved in a stand-alone Cochrane Review
focusing only on adverse effects.
For example, aspirin is used for many conditions, such as in patients after a stroke, with
peripheral vascular disease, and with coronary artery disease. The main effects of aspirin
on outcomes relevant to these different conditions would typically be addressed in
separate Cochrane Reviews. However, the mechanism of harm and susceptibility to
adverse effects (such as bleeding into the brain or gut) are sufficiently similar across the
different disease groups that an independent review might address them together.
Indeed, if trials exist on combined populations, such a question would be difficult to
address in any other way.
When adopting the confirmatory approach, review authors should aim to pre-specify
adverse effects that are anticipated or already recognized to be associated with the
intervention, and assumed to be measured regularly and consistently in studies. Selection
of adverse effects of interest can be based on biological, physiological or psychological
plausibility. For example, in a review of a surgical intervention it is plausible to pre-specify
‘wound infection’ as an adverse outcome of interest. Similarly, a systematic review of drug
therapy that affects platelets or clotting would be justified in pre-specifying bleeding as an
adverse outcome of interest. In some cases, it may be reasonable to select adverse effects
for review based on previously established observation or association, although the
plausible mechanism of effect has not yet been established.
The exploratory approach can identify unanticipated and rare adverse effects of an
intervention. This may inform which outcomes are investigated in future reviews of pre-
specified adverse events that use the confirmatory approach. In addition, the exploratory
approach may provide data on possible associations between an intervention and a list of
observed adverse events, which can be used to generate new signals to add to existing
safety profiles.
A limitation of the exploratory approach is that the specific adverse effects reported may
have been selectively analysed and reported because of the nature of the findings (e.g.
based on statistical significance rather than clinical importance). Also, post-hoc or arbitrary
analytic decisions regarding data extraction and analysis are often required when review
authors encounter long lists of adverse events. Processes for selection and synthesis of such
data need consideration in the review protocol, even if the outcomes of interest are not fully
specified.
Regardless of the approach adopted, review authors should be mindful of the potential for
problems related to definition and ascertainment of adverse events when reviews are based
solely on published data.
Copyright © 2022 The Cochrane Collaboration
Box 19.2.b Illustration of three approaches to reviewing the adverse effects of a particular
intervention: acupuncture
Exploratory approach: Review authors aim to synthesize data on all or any adverse
effects that are mentioned in the included studies.
19.2.2 Strategies for assessing beneficial and adverse effects in the same
review
When conducting a review of both beneficial and adverse effects of interventions, review
authors may:
1. use the same eligibility criteria to assess intended (beneficial) and unintended
(adverse) effects, in terms of types of studies, types of participant and types of
interventions; or
2. use different eligibility criteria for selecting studies that address unintended (adverse)
effects compared with studies that address intended (beneficial) effects.
Using the same eligibility criteria to gather data on both types of outcome makes the review
easier to conduct, not least because a single search can usually be undertaken if outcome
terms are not stipulated in the search string. It also may allow for a direct comparison
between beneficial and adverse effects, because the data are derived from the same types
of studies (although it will not necessarily be the case that exactly the same studies report
data on both beneficial and adverse effects). Two disadvantages of using the same eligibility
criteria are (i) that the types of studies that are most appropriate to address the beneficial
effects – typically randomized trials – may not be large enough or long enough to capture
important adverse effects; and (ii) that it may lead to omission of relevant data on adverse
effects if the adverse effects are also observed when the intervention is given for other
conditions (see also Box 19.2.a).
Thus, review authors may apply different eligibility criteria when attempting to identify
adverse effects data. The two main aspects of eligibility that may differ are the types of study
design and the types of participants. It is also possible that studies performed for a different
purpose may be eligible for the adverse effects component of the review.
• Different study designs: To address adverse effects it may be necessary to seek non-
randomized studies, because the effects are unlikely to be seen in randomized trials due
to their size, duration or restricted eligibility for participants: see Section 19.2.3.
Copyright © 2022 The Cochrane Collaboration
Spontaneous case reports or case series may assist in signalling rare and previously
unknown events. However, for most Cochrane Reviews, these data sources should be used
for scoping purposes only (particularly as they do not have denominator data to allow
estimation of risks or rates). These spontaneous reports may guide drafting of the protocol
when there is a need to choose relevant or important adverse effects as outcomes of
interest.
Composite adverse outcomes are often reported by trials. Common examples include ‘total
number of participants with adverse events’, or ‘numbers of withdrawals due to adverse
events’. Review authors should recognize major difficulties in interpreting composite
adverse outcomes that are potentially constructed from hundreds of diverse events,
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because an important signal of rare serious adverse events could be masked by common,
trivial adverse events. Also, review authors should hesitate to interpret data on withdrawals
as surrogate markers for safety or tolerability, for the following reasons.
• The attribution of reason(s) for discontinuation is complex and may be due to mild but
irritating side effects, toxicity, lack of efficacy, non-medical reasons, or a combination of
causes.
• The pressures on patients and investigators under trial conditions to reduce the number
of withdrawals and dropouts can result in rates that do not reflect the experience of
adverse events within the wider population.
• Unblinding of intervention assignment often precedes the decision to withdraw. This
can lead to an over-estimate of the intervention’s effect on patient withdrawal. For
example, symptoms of patients in the placebo arm are less likely to lead to
discontinuation. Conversely, patients in the active intervention group who complained
of symptoms suggesting adverse effects may have been more readily withdrawn.
of the primary clinical research databases. Performing a search in MEDLINE alone is not
recommended.
A case study reviewing adverse effects of thiazolidinedione use in patients diagnosed with
type 2 diabetes mellitus tested over 60 sources (Golder and Loke 2012).The results indicated
that the minimum combination of sources required to identify all relevant references
included 11 sources: the pharmaceutical company website, Science Citation Index, Embase,
BIOSIS Previews, British Library Direct, Medscape DrugInfo, American Hospital Formulary
Service (AHFS First), Thomson Reuters Integrity, Conference Papers Index, hand searching
and reference checking. In this specific example, just searching MEDLINE failed to retrieve
66% of relevant references. A search strategy conducted in MEDLINE, Embase and the
Cochrane Central Register of Controlled Trials (CENTRAL) failed to retrieve 57% of relevant
references. This example illustrates the breadth of sources needed to ensure identification
of relevant data. Authors will need to consider sources most relevant to their clinical
question; the list above is an illustration only.
Mandatory changes applied to trials regulated by the Food and Drug Administration (FDA)
regarding the submission of adverse events data to ClinicalTrials.gov, and the legislated
publication of clinical data by the European Medicines Agency (EMA), means that previous
accessibility limitations are steadily improving. Although accessibility is likely to continue
to improve, the logistics and feasibility of routinely using such data sources for adverse
effects reviews has yet to be established. Review authors should therefore report on the
number of unpublished studies identified and instances where data on adverse effects were
inaccessible.
A possible option for the larger databases is to use a broad search involving two
components at the same time: generic index terms combined with specific free-text
searches using the ‘OR’ Boolean function. Both specific and generic search techniques have
strengths and limitations, but the strengths are increased and limitations reduced when
they are combined. It is therefore advisable to combine index terms and free-text searching
(where possible) to increase search sensitivity and reduce the possibility of missing relevant
material. More details are provided in the online Technical Supplement to Chapter 4.
19.4.2 Recommended tools for assessing risk of bias in adverse effects data
Review authors should use the currently recommended risk-of-bias tools, the RoB 2 tool for
randomized trials (see Chapter 8), and the ROBINS-I tool for non-randomized studies (see
Chapter 25). Although these tools are most easily directed at outcomes that have been pre-
specified by the review team, they are suitable for any type of quantitative outcome
analysed in a review. Where adverse effects are extracted post hoc from included trials in an
exploratory approach, it may not be possible to list important co-interventions or
confounding variables in the review protocol, as would usually be expected for using the
ROBINS-I tool.
Particular issues in assessing risk of bias for adverse effects data include outcome definition
and methods of monitoring adverse effects. These warrant special attention when there are
significant concerns over bias towards the null stemming from poor definition,
ascertainment or reporting of harms. This is particularly important for new or unexpected
adverse events that have not been pre-specified as outcomes of interest in the trials, and
where monitoring and reporting may be potentially inadequate. Additional resources such
as the McHarm tool (Chou et al 2010) and the Agency for Healthcare Research and Quality
Copyright © 2022 The Cochrane Collaboration
(AHRQ) assessment tool (Chou et al 2007, Viswanathan and Berkman 2012) provide further
discussion of these issues.
There is evidence that Cochrane Reviews may suffer from reporting bias. Kicinski and
colleagues explored the potential impact of reporting bias on meta-analyses in Cochrane
Reviews published between 1990 and 2005 (Kicinski et al 2015). They applied hypothesized
mechanisms of reporting bias to 802 meta-analyses of efficacy and 304 meta-analyses of
safety that each combined at least 10 individual estimates. The results from their model
indicated that statistically significant results favouring treatment were more likely to be
included in meta-analyses of efficacy than non-significant results. In contrast, results
showing no evidence of adverse effect had greater probability of inclusion in a meta-
analysis of safety than statistically significant results of adverse effects. Reporting bias
therefore, may lead to the erroneous conclusion that an intervention is safe or relatively free
from adverse effects.
It is important to evaluate the consistency and similarity of case definitions and methods of
ascertainment for harms outcomes from the various included studies before comparing or
synthesizing adverse effects data across studies. An important source of potential
heterogeneity in effect estimates for adverse effects is variation in outcome definition and
measurement. Review authors should ask study authors to resolve any ambiguity by
providing additional data, or disaggregated data, which can be reanalysed more
consistently.
Important analytical challenges relating to imprecision of estimates and rare events are
covered in Chapter 10 (Section 10.4.4); see also Section 19.5.2 for particular challenges of
determining whether there were zero adverse events.
Grouping adverse effects together in a composite measure (e.g. total number of adverse
effects) can only give a broad impression, and may lead to genuine differences between the
Copyright © 2022 The Cochrane Collaboration
Review authors should include at least one adverse effect outcome in the ‘Summary of
findings’ table. If the review did not focus on detailed evaluation of any adverse effects, then
the review authors should make an explicit statement that harms were not assessed, rather
than say (or imply) the intervention appears to be safe.
If a serious adverse event of interest, such as heart failure, was not explicitly mentioned in
the text or the serious adverse effects tables, the question then arises as to whether it is
reasonable to interpret this as zero heart failure events. We generally recommend against
extracting data as ‘zero’ unless it is clearly listed as such in the study report. Even where
heart failure is explicitly reported as ‘zero’, we suggest that review authors carefully check
the methods section of the included study for details on the rigour of monitoring for the
adverse outcome (e.g. specific active surveillance for heart failure, versus reliance only on
spontaneous reports that are prone to under-reporting). Ambiguity frequently crops up in
the extraction and interpretation of absence of harms, so review authors should record how
they reached a decision of ‘zero events’.
19.7 References
Chou R, Fu R, Carson S, Saha S, Helfand M. Methodological shortcomings predicted lower
harm estimates in one of two sets of studies of clinical interventions. Journal of Clinical
Copyright © 2022 The Cochrane Collaboration
Chou R, Aronson N, Atkins D, Ismaila AS, Santaguida P, Smith DH, Whitlock E, Wilt TJ,
Moher D. AHRQ series paper 4: assessing harms when comparing medical interventions:
AHRQ and the effective health-care program. Journal of Clinical Epidemiology 2010; 63:
502-512.
Golder S, Loke YK. The contribution of different information sources for adverse effects
data. International Journal of Technology Assessment in Health Care 2012; 28: 133-137.
Golder S, Loke YK, Zorzela L. Some improvements are apparent in identifying adverse
effects in systematic reviews from 1994 to 2011. Journal of Clinical Epidemiology 2013; 66:
253-260.
Golder S, Loke YK, Wright K, Norman G. Reporting of adverse events in published and
unpublished studies of health care interventions: a systematic review. PLoS Medicine 2016;
13: e1002127.
Loke YK, Mattishent K. If nothing happens, is everything all right? Distinguishing genuine
reassurance from a false sense of security. CMAJ: Canadian Medical Association Journal
2015; 187: 15-16.
Saini P, Loke YK, Gamble C, Altman DG, Williamson PR, Kirkham JJ. Selective reporting bias
of harm outcomes within studies: findings from a cohort of systematic reviews. BMJ 2014;
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Schroll JB, Penninga EI, Gøtzsche PC. Assessment of Adverse Events in Protocols, Clinical
Study Reports, and Published Papers of Trials of Orlistat: A Document Analysis. PLoS
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Smith PG, Morrow RH, Ross DA. Outcome measures and case definition in: Field Trials of
Health Interventions: A Toolbox. Smith PG, Morrow RH, Ross DA, editors. Oxford (UK):
Oxford University Press; 2015.
Viswanathan M, Berkman ND. Development of the RTI item bank on risk of bias and
precision of observational studies. Journal of Clinical Epidemiology 2012; 65: 163-178.
Zorzela L, Loke YK, Ioannidis JP, Golder S, Santaguida P, Altman DG, Moher D, Vohra S,
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