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The importance of transparency in clinical trials: a European progress report

Gene and Stuart discuss the impressive new  EU Trials Tracker that they argue,once again, starkly demonstrates the major problem of unreported clinical trials.

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Gene Matthews is a partner in the product liability team where he focuses on clinical trial injuries and medical device claims. Stuart Warmington is a solicitor in the same team.

It has long been known that the under-reporting of clinical trial outcomes has the potential to distort the true picture of how effective, or safe, medical treatments are. For example, in 2010, a group of researchers carried out a systematic review of the studies relating to Reboxetine (an anti-depressant medication) where they reviewed all published and – crucially – previously unpublished research. Where Reboxetine had initially been thought of as a safe and effective treatment, this full systematic review concluded that it was, “ineffective and potentially harmful”, and that the, “published evidence…has been substantially affected by publication bias, underlining the urgent need for mandatory publication of clinical trial data[1].

If you’d like to see the phenomenon in action, just try The Economist’s Clinical Trial Simulator where you can ‘play the system’, and see what effect supressing less favourable results has on perceived performance of your own fictional drug! In the real world, this raises profound ethical questions about the evidential basis on which doctors prescribe treatments, and the access that patients have to all the facts when they consent to receive them.

Recognising the problem, the European Medicines Agency introduced regulations in 2012 that required the results of all trials on the EU Clinical Trials Register to have their results posted to the Registry within 12 months of the completion of the study. The final deadline for compliance was 21 December 2016. A team from the EBM DataLab (including Ben Goldacre, who has done huge amounts of work to raise awareness of the issues surrounding clinical trials generally) has now completed an analysis of the extent to which these rules have been complied with.
 
The result is the EU Trials Tracker, and the findings are stark[2].
 
As of 13 September 2018, 49.9% of trials that were known to be due to have their results reported had failed to do. It is possible to breakdown the results into ‘sponsors’ (i.e. the companies or academic institutions etc. that fund clinical trials), and it can be seen that many of the worst performers are academic institutions. This is particularly disappointing when one considers their role in furthering scientific understanding.
 
When digging down into the detail, it is also clear that incorrect or incomplete data on the Register has prevented a complete analysis of compliance. 29.4% of trials listed as complete do not actually have their completion date recorded on the Register. This is significant because it means that the investigators from EBM DataLab could not calculate the due date (i.e. within 12 months of completion) for those trials and, by extension, whether they had failed to report in time. As a result, trials without completion dates have been excluded from the analysis and the investigators suggest that this could mean that they may have actually over-estimated compliance (at 51.1%!).
 
Some reassurance can be found in the fact that commercial sponsors (who have been accused over the years of having conflicts of interests when sponsoring clinical research) are, in fact, some of the most compliant sponsors. The investigators also suggest that poor compliance among the worst performers likely to be due, for example, to ineffective, “administrative procedures” – rather than a widespread intention to supress research.
 
That being said, as demonstrated by the Reboxetine case mentioned above, missing data – for whatever the reason – prevents doctors and patients from having access to the full facts. For this reason, the EU Trials Tracker is an important development and one that it is hoped encourages ever greater reporting compliance amongst the research community. At the end of the day, that can only benefit the people who actually end up using the treatments: the patients.

 
[1] Eyding et al. (2010), Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials. BMJ. 2010; 341: c4737.
[2] Further detail regarding methodology and findings of the EU Trials Tracker can be found in the accompanying report in the BMJ: Goldacre et al. (2018) Compliance with requirement to report results on the EU Clinical Trials Register: cohort study and web resource. BMJ 2018;362:k3218

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