Benefits and harms in clinical trials of duloxetine for treatment of major depressive disorder: comparison of clinical study reports, trial registries, and publicationsBMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g3510 (Published 04 June 2014) Cite this as: BMJ 2014;348:g3510
- Emma Maund, PhD student1,
- Britta Tendal, postdoctoral researcher1,
- Asbjørn Hróbjartsson, senior researcher 1,
- Karsten Juhl Jørgensen, senior researcher1,
- Andreas Lundh, physician12,
- Jeppe Schroll, PhD student1,
- Peter C Gøtzsche, Professor1
- 1Nordic Cochrane Centre, Rigshospitalet Dept 7811, Copenhagen, Denmark
- 2Department of Infectious Diseases, Hvidovre University Hospital, Kettegårds Allé 30, 2650 Hvidovre, Denmark
- Correspondence to: E Maund
- Accepted 5 May 2014
Objective To determine, using research on duloxetine for major depressive disorder as an example, if there are inconsistencies between protocols, clinical study reports, and main publicly available sources (journal articles and trial registries), and within clinical study reports themselves, with respect to benefits and major harms.
Design Data on primary efficacy analysis and major harms extracted from each data source and compared.
Setting Nine randomised placebo controlled trials of duloxetine (total 2878 patients) submitted to the European Medicines Agency (EMA) for marketing approval for major depressive disorder.
Data sources Clinical study reports, including protocols as appendices (total 13 729 pages), were obtained from the EMA in May 2011. Journal articles were identified through relevant literature databases and contacting the manufacturer, Eli Lilly. Clinicaltrials.gov and the manufacturer’s online clinical trial registry were searched for trial results.
Results Clinical study reports fully described the primary efficacy analysis and major harms (deaths (including suicides), suicide attempts, serious adverse events, and discontinuations because of adverse events). There were minor inconsistencies in the population in the primary efficacy analysis between the protocol and clinical study report and within the clinical study report for one trial. Furthermore, we found contradictory information within the reports for seven serious adverse events and eight adverse events that led to discontinuation but with no apparent bias. In each trial, a median of 406 (range 177-645) and 166 (100-241) treatment emergent adverse events (adverse events that emerged or worsened after study drug was started) in the randomised phase were not reported in journal articles and Lilly trial registry reports, respectively. We also found publication bias in relation to beneficial effects.
Conclusion Clinical study reports contained extensive data on major harms that were unavailable in journal articles and in trial registry reports. There were inconsistencies between protocols and clinical study reports and within clinical study reports. Clinical study reports should be used as the data source for systematic reviews of drugs, but they should first be checked against protocols and within themselves for accuracy and consistency.
We thank Julie Borring, Kristine Rasmussen, Trine Gro Saida, and Louise Schow Jensen for assistance with data extraction; Eli Lilly Medical Information Department for their response to a request for a list of publications for the nine trials and providing the pdf of duloxetine Lilly trial registry reports; the EMA for providing the material and for responding to queries relating to the material; and Jesper Krogh for sharing material he obtained from the EMA.
Contributors: All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. EM, BT, and PCG contributed to the study concept and design. EM, BT, AH, KJ, AL, and JS contributed to the acquisition of data. All authors contributed to the analysis and interpretation of data, and drafts of manuscripts. All the authors critically reviewed the manuscript for publication. PCG provided administrative, technical, and material support, and was the study supervisor. PCG is guarantor.
Funding: This study is part of a PhD (EM) funded by Rigshospitalets Forskningsudvalg. The funding source had no role in the design and conduct of the study; data collection, management, analysis, and interpretation; preparation, review, and approval of the manuscript; or the decision to submit the paper for publication.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Ethical approval: Not required.
Transparency declaration: the manuscript’s guarantor affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.
Data sharing: The clinical study reports we used can be obtained from us.
This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/.