March 8, 2017 Leave a comment
A new study comparing the protocols, clinical study reports (CSRs) and published papers on anti-obesity drug orlistat, has revealed a disparity in how adverse events were summarised and reported (Schroll et al, 2016).
Orlistat, which is manufactured by pharmaceutical company Roche, was approved by the European Medicines Agency (EMA) in 1998 but, along with other slimming drugs, has since encountered regulatory barriers. Nearly all slimming pills (but not orlistat) have been withdrawn from European markets because of harms.
Researchers at the Nordic Cochrane Centre in Copenhagen used a Freedom of Information Act request to the EMA to acquire the CSRs, which describe the results of studies conducted as part of the application for marketing authorisation of the drug.
Seven randomised placebo controlled orlistat trials were included in the application for marketing authorisation for the drug, and involved a total of 4,225 participants. Adverse events outlined in the CSRs were then compared by the researchers to each corresponding published trial paper identified on PubMed.
It was revealed that due to post hoc filters, only 3–33% of the total number of investigator-reported adverse events from the trials were outlined in the publications, though six of seven papers stated that ‘all adverse events were recorded.’
The investigators noted that none of the protocols to investigators for reporting harms 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. Events falling under the bracket of bothersome included ‘fatty/oily stool,’ ‘liquid stools’ (which term the protocol suggested to be used instead of diarrhoea), ‘increased defaecation,’ ‘stools soft,’ ‘decreased defaecation,’ and ‘pellets.’ Results sections in the core reports of the CSRs often stated that most of the adverse events were considered unrelated to the drug and that they were generally mild to moderate. The many gastrointestinal adverse events were explained as part of the pharmacological effect of orlistat. The researchers suggested that since gastrointestinal complaints are normal in healthy people, this type of censoring might have made it more difficult to detect gastrointestinal adverse events caused by orlistat.
Additionally, serious adverse events were assessed by the researchers 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.
The researchers also revealed that in one trial, both the number of adverse effects and the number of days with adverse effects in participants taking the drug were understated in the corresponding publication. While 1,318 adverse events were not listed or mentioned in the CSR itself, the researchers were able to identify them through manually counting individual adverse events reported in an appendix.
Overall, the analysis revealed that participants treated with orlistat had experienced almost twice as many days with adverse events as those treated with placebo (22.7 days versus 14.9 days). Additionally, it was noted that the adverse events that occurred in the orlistat group were more severe compared with the placebo group. However, none of this information was stated in the CSR or the corresponding published paper.
A statement issued by Roche said: ‘Since the 1990s, technology for analysing data has changed and society’s desire and expectations for access has increased and so our practices have evolved.
‘We understand and support calls for the pharmaceutical industry to be transparent about clinical trial results, this is why we expanded our policy in 2013 to better share data from clinical trials across Roche medicines.
‘Roche are now at the forefront of the data sharing movement and now release all clinical study reports, periodic safety reports and summary reports of clinical data for all licensed, terminated or discontinued medicines.’
Based on the characteristics of harms observed and reported in these trials, the researchers at the Nordic Cochrane Centre suggested that reports of harms include duration of adverse effects. They also suggested that systematic reviews of drugs might be improved by including protocols and CSRs in addition to published articles.
They highlight how even though publication bias is well covered in the medical literature, few studies have analysed clinical study reports. They argue that in the future this could be a very important source of information. Other studies have found that only a fraction of adverse events were reported in published papers compared to the CSRs. For example, a study carried out by the German government’s Institute for Quality and Efficiency in Health Care looked at the CSRs for treatments assessed over a 5-year period and found that CSRs contained more information on adverse events and treatment effects than was published in trial reports and journal articles (Wieseler et al, 2013).
As mentioned by Schroll et al (2016), their research emphasises the ‘need for detailed analysis plans for harms data.’
Schroll JB, Penninga EI, Gøtzsche PC (2016) Assessment of Adverse Events in Protocols, Clinical Study Reports, and Published Papers of Trials of Orlistat: A Document Analysis. PLoS Med 13(8): e1002101. doi: 10.1371/journal.pmed.1002101
Wieseler B, Wolfram N, McGauran N et al (2013) Completeness of reporting of patient-relevant clinical trial outcomes: comparison of unpublished clinical study reports with publicly available data. PLoS Med 10(10): e1001526. doi: 10.1371/journal.pmed.1001526
Taken from Nurse Prescribing, published 13 October 2016.