Abstract
BackgroundAdverse events (AEs) in clinical trials may be reported in multiple sources. Different methods for reporting adverse events across trials or across sources for a single trial may produce inconsistent information about the adverse events associated with interventions.MethodsWe compared the methods authors use to decide which AEs to include in a particular source (i.e., “selection criteria”), including the number of different types of AEs reported (i.e., rather than the number of events). We compared sources (e.g., journal articles, clinical study reports (CSRs)) of trials for two drug-indications—gabapentin for neuropathic pain and quetiapine for bipolar depression. Electronic searches were completed in 2015. We identified selection criteria and assessed how criteria affected AE reporting.ResultsWe identified 21 gabapentin and 7 quetiapine trials. We found 6 gabapentin CSRs and 2 quetiapine CSRs, all written by drug manufacturers. All CSRs reported all AEs without applying selection criteria; by comparison, no other source reported all AEs, and 15/68 (22%) gabapentin sources and 19/48 (40%) quetiapine sources reported using selection criteria. Selection criteria greatly affected the number of AEs reported. For example, 67/316 (21%) AEs in one quetiapine trial met the criterion “occurring in ≥2% of participants in any treatment group,” while only 5/316 (2%) AEs met the criterion “occurring in ≥10% of quetiapine-treated patients and twice as frequent in the quetiapine group as the placebo group.”ConclusionsSelection criteria for reporting AEs vary across trials and across sources for individual trials. If investigators do not pre-specify selection criteria, they might “cherry-pick” AEs based on results. Even if investigators pre-specify selection criteria, selective reporting will produce biased meta-analyses and clinical practice guidelines. Data about all AEs identified in clinical trials should be publicly available; however, sharing data will not solve all the problems identified in this study.
Highlights
The U.S Food and Drug Administration (FDA) and other regulators may approve drugs and biologic agents for marketing when the results of randomized clinical trials indicate that their potential benefits outweigh their potential harms, which are often called “adverse events” (AEs)
Adverse event (AE) selection criteria in public and non-public sources We identified selection criteria only in public sources and in Clinical study report (CSR)-synopses
CSRs did not describe which selection criteria would be used to report AEs in other sources, such as journal articles; we found no scientific rationale or evidence that selection criteria used in other sources were prespecified [35]
Summary
The U.S Food and Drug Administration (FDA) and other regulators may approve drugs and biologic agents for marketing when the results of randomized clinical trials indicate that their potential benefits outweigh their potential harms, which are often called “adverse events” (AEs). AEs can be collected non-systematically when participants report them spontaneously to investigators or in response to open-ended questions such as “have you noticed any symptoms since your last examination?” (Table 1) [1,2,3,4]. Syntheses of clinical trial findings should include all available evidence; they are often based on AE information reported in public sources, such as journal articles (Table 1) [6]. Previously non-public sources are becoming available for some trials [8,9,10], including through data sharing services such as Vivli [11], Yale Open Data Access (YODA) [12, 13], and clinicalstudydatarequest.com, clinical study reports (CSRs) and individual patient datasets (IPD) remain unavailable for many trials. Different methods for reporting adverse events across trials or across sources for a single trial may produce inconsistent information about the adverse events associated with interventions
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