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Cited by 69Pharmacology and Obesity TreatmentPharmaceutical industry and healthcarePharmacovigilance and Adverse Drug Reactions

Assessment of Adverse Events in Protocols, Clinical Study Reports, and Published Papers of Trials of Orlistat: A Document Analysis

Open access
Schroll, Jeppe Bennekou, Penninga, Elisabeth I., Gøtzsche, Peter C.·2016·PLOS Medicine
DOI 10.1371/journal.pmed.1002101PMC PMC4987052
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Abstract

BACKGROUND: Little is known about how adverse events are summarised and reported in trials, as detailed information is usually considered confidential. We have acquired clinical study reports (CSRs) from the European Medicines Agency through the Freedom of Information Act. The CSRs describe the results of studies conducted as part of the application for marketing authorisation for the slimming pill orlistat. The purpose of this study was to study how adverse events were summarised and reported in study protocols, CSRs, and published papers of orlistat trials. METHODS AND FINDINGS: We received the CSRs from seven randomised placebo controlled orlistat trials (4,225 participants) submitted by Roche. The CSRs consisted of 8,716 pages and included protocols. Two researchers independently extracted data on adverse events from protocols and CSRs. Corresponding published papers were identified on PubMed and adverse event data were extracted from this source as well. All three sources were compared. Individual adverse events from one trial were summed and compared to the totals in the summary report. None of the protocols or CSRs contained instructions for investigators on how to question participants about adverse events. In CSRs, gastrointestinal adverse events were only coded if the participant reported that they were "bothersome," a condition that was not specified in the protocol for two of the trials. Serious adverse events were assessed for relationship to the drug by the sponsor, and all adverse events were coded by the sponsor using a glossary that could be updated by the sponsor. The criteria for withdrawal due to adverse events were in one case related to efficacy (high fasting glucose led to withdrawal), which meant that one trial had more withdrawals due to adverse events in the placebo group. Finally, only between 3% and 33% of the total number of investigator-reported adverse events from the trials were reported in the publications because of post hoc filters, though six of seven papers stated that "all adverse events were recorded." For one trial, we identified an additional 1,318 adverse events that were not listed or mentioned in the CSR itself but could be identified through manually counting individual adverse events reported in an appendix. We discovered that the majority of patients had multiple episodes of the same adverse event that were only counted once, though this was not described in the CSRs. We also discovered that participants treated with orlistat experienced twice as many days with adverse events as participants treated with placebo (22.7 d versus 14.9 d, p-value < 0.0001, Student's t test). Furthermore, compared with the placebo group, adverse events in the orlistat group were more severe. None of this was stated in the CSR or in the published paper. Our analysis was restricted to one drug tested in the mid-1990s; our results might therefore not be applicable for newer drugs. CONCLUSIONS: In the orlistat trials, we identified important disparities in the reporting of adverse events between protocols, clinical study reports, and published papers. Reports of these trials seemed to have systematically understated adverse events. Based on these findings, systematic reviews of drugs might be improved by including protocols and CSRs in addition to published articles.

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  • Substantial discrepancies have been observed between protocol specified plans for the data collection and reporting of harms and what is described in publications of completed trials.

    “Substantial discrepancies have been observed between protocol specified plans for the data collection and reporting of harms and what is described in publications of completed trials.282”

    From SPIRIT 2025 explanation and elaboration: updated guideline for protocols of randomised trials (2025) · cites this paper as [282]

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Authors
Schroll, J. B., Penninga, E. I., & Gøtzsche, P. C.
Affiliations
Rigshospitalet (DK)
Corresponding author
Schroll, Jeppe Bennekou
ORCID
Venue
PLOS Medicine
Publisher
Public Library of Science (PLoS)
Published
2016-08-16
Volume
13
Issue
8
Pages
e1002101
ISSN
  • 1549-1277 (ISSN-L)
  • 1549-1676
DOI
10.1371/journal.pmed.1002101
PMC
PMC4987052
OpenAlex
W2511112097
Cited by
69
References
37
Citations by year
2026: 2 · 2025: 9 · 2024: 3 · 2023: 7 · 2022: 4 · 2021: 10 · 2020: 7 · 2019: 8 · 2018: 9 · 2017: 6 · 2016: 4
FWCI
7.28
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
The Danish Council for Independent research (12-126864)
Topics
  • Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmaceutical industry and healthcare
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
Keywords
orlistat, adverse event reporting, clinical study reports, publication bias, serious adverse events, gastrointestinal adverse effects, trial withdrawal, obesity treatment, drug safety, European Medicines Agency, Roche, Freedom of Information Act
MeSH terms
Orlistat, Clinical Protocols, Humans, Lactones, Obesity, Periodicals as Topic, Bibliometrics, Randomized Controlled Trials as Topic, Treatment Outcome, Anti-Obesity Agents

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