title: Assessment of Adverse Events in Protocols, Clinical Study Reports, and Published Papers of Trials of Orlistat: A Document Analysis.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Jeppe Bennekou
authors.initials: JB
authors.lastname: Schroll
authors.affiliation: Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Elisabeth I
authors.initials: EI
authors.lastname: Penninga
authors.affiliation: Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Gøtzsche
mesh_terms: D019440:Anti-Obesity Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015706:Bibliometrics; D002985:Clinical Protocols; D006801:Humans; D007783:Lactones / Q000009:adverse effects* / Q000627:therapeutic use; D009765:Obesity / Q000188:drug therapy; D000077403:Orlistat; D010506:Periodicals as Topic / Q000592:standards / Q000706:statistics & numerical data; D016032:Randomized Controlled Trials as Topic / Q000592:standards / Q000706:statistics & numerical data; D016896:Treatment Outcome
chemical_list: D019440:Anti-Obesity Agents; D007783:Lactones; D000077403:Orlistat