Unpublished data from clinical trials, as well as inadequate reporting of data that are published, can undermine clinical decision-making, harm patients and waste public money invested in health systems, an editorial in the BMJ warns.
Not only that, but researchers or other involved parties who deliberately conceal results from clinical trials have breached their duty to study participants who consent to running the risks of clinical research in the belief that the knowledge generated will benefit others, the editorial says.
It calls for professional associations to take disciplinary action against clinical researchers who fail to disclose data. “This may achieve quicker results than legislation in individual countries, although this is also desirable,” write Richard Lehman, senior research fellow in the Department of Primary Care at the University of Oxford, UK and Elizabeth Loder, the BMJ’s clinical epidemiology editor.
The BMJ editorial accompanies a number of linked articles examining the extent, causes and consequences of unpublished data from clinical trials.
These articles, Lehman and Loder maintain, “confirm the fact that a large proportion of evidence from human trials is unreported, and much of what is reported is done so inadequately. We are not dealing here with trial design, hidden bias, or problems of data analysis—we are talking simply about the absence of the data”.
The articles also make clear that past failures to ensure proper regulation and registration of trials, coupled with “a current culture of haphazard publication and incomplete data disclosure”, have rendered “the proper analysis of the harms and benefits of common interventions almost impossible for systematic reviewers”, the authors contend.
An important first step towards remedying this situation, they suggest, would be retrospective disclosure of full individual participant data from clinical trials, as was the case with Medtronic’s recent agreement to release data on its recombinant human bone morphogenetic protein-2 (INFUSE Bone Graft) for independent analysis.
Future systems of research governance should insist on “nothing less” than the full trial protocol, final study report, raw dataset and any associated journal publications and regulatory submissions as a basis for systematic reviews, Lehman and Loder argue.
Ensuring this happens may require the global organisation of a suitable shared database for all raw data from human trials—“an obvious next step for the World Health Organization after its excellent work on the International Clinical Trials Registry Platform Search Portal”, they suggest.
Cuts both ways
Among the findings in the associated research articles were that incorporating unpublished evidence into existing meta-analyses of nine drugs approved by the US Food and Drug Administration in 2001 and 2002 produced identical estimates of drug efficacy in just three of 41 cases.In the remaining instances, report Beth Hart and colleagues, estimates of drug efficacy were evenly split between more (19/41) and less (19/41) effective.
“It is sometimes assumed that incorporation of missing data will reduce estimates of drug benefits, but this study shows that ‘publication bias’ can cut both ways,” Lehman and Loder comment.
Two further studies addressed the issue of timely dissemination of trial results.
A survey by Ross et al of US research conducted between 2005-2008 and primarily or partially funded by the National Institutes of Health showed that in less than half of the sample were the summary reports of trials registered with ClinicalTrials.gov published in a peer-reviewed, MEDLINE-indexed biomedical journal within 30 months of completion.
Moreover, one third of the trials remained unpublished 51 months after completion, the authors found.
As Lehman and Loder point out, The US Food and Drug Administration Amendments Act of 2007 made publication of a results summary on ClinicalTrials.gov within 12 months mandatory for all eligible trials in the US “initiated or ongoing as of September 2007”.
A review by Prayle et al looked at the extent to which this goal has been achieved, finding that only 22% of trials subject to mandatory reporting had results available within one year of completion.