the NHS, clinical trial conduct might seem an unlikely source of concern. But worries are increasingly being raised in the medical press and wider public media.
FEATURE
Rejected results: Addressing transparency in clinical trials
Do surgeons have a duty to make trial data publicly available? 204
JE Fitzgerald Specialist Registrar, General Surgery Royal Free Hospital NHS Trust SJ Chapman Academic Foundation Doctor, University of Leeds EM Harrison Senior Lecturer in General Surgery and Consultant Surgeon A Bhangu Specialist Registrar, Colorectal Surgery University of Birmingham DOI: 10.1308/147363515X14272809070889
FEATURE
A
mong the myriad problems faced by the NHS, clinical trial conduct might seem an unlikely source of concern. But worries are increasingly being raised in the medical press and wider public media. This newfound topicality has largely resulted from publicity surrounding the AllTrials campaign (www.alltrials.net), which was initiated by epidemiologist-turned-writer Ben Goldacre and highlighted the substantial number of unregistered or unpublished clinical trials.1 Such hidden studies and inaccessible results may be introducing bias across medical practice, weakening our evidence base, wasting resources, and potentially harming patients.2 So far, the adverse press surrounding this issue is confined to pharmaceutical companies, who are reticent to release data that are publicly defended as commercially sensitive.3 Readers could therefore be forgiven for thinking that this issue has little impact on surgical research, but evidence points to the contrary. Our recent British Medical Journal study of surgical trial discontinuation and non-publication revealed that approximately 1 in 5 surgical randomised trials were discontinued early (21%), 1 in 3 were unpublished (34%), and less than half of the investigators for these ‘lost’ trials were still contactable.4 Other studies across medicine indicate that non-publication rates may be as high as 50% in some areas.5,6,7,8 Our understanding of trial conduct stems mainly from the mandatory registration prior to journal publication requirement introduced by the International Committee of Medical Journal Editors (ICMJE) in 2005.9 This was supplemented by US legislation in 2007 that required clinical trials to post results on the clinicaltrials.gov registry within a year of completion. Despite these efforts, both have been widely ignored owing to inadequate or absent enforcement.10,11 The quality of registration of the trials that are reported in surgical journals is inferior to those in general medical journals, with a higher prevalence of selective outcome reporting.12 Problems with surgical trial
methodology reporting13 and wider issues across medicine – including wasted research due to inadequate methods,14 potentially misleading subgroup analyses,15 and publication bias driven by significant or positive trial results16 – mean that clinical trial conduct has considerable room for improvement. Within these concerns, inaccessible results arising from trial abandonment or non-disclosure pose a particular problem, given their potential for avoidable waste and patient harm. Two leading medical journals recently called on ‘researchers and editors to help restore invisible and abandoned trials’, such is the growing concern.17 The restoring of invisible and abandoned trials (RIAT) initiative encourages others to publish previously unreleased trial data
Non-publication rates may be as high at 50% when the original investigators or sponsors fail to do so.18 One of the first publications restored under this initiative was a surgical randomised controlled trial that investigated the survival advantage for carcinoembryonic antigen-prompted reoperation for recurrent colorectal cancer. It had remained unpublished for 20 years.19,20 How can future trial frameworks address these varied issues? Above all, surgeons have a professional and ethical duty to ensure trial results are made available, even if these do not ultimately result in an academic journal paper. The World Medical Association’s Declaration of Helsinki, setting out the ethical principles of research, states that: ‘Authors have a duty to make publicly available the results of their research on human subjects.’21 However, this can be difficult to deliver, given the conflicting time, funding, service, academic and personal commit-
ments that clinician researchers face every day. Against these demands, a problematic study may be too readily abandoned, or unremarkable results put aside with an intention to publish that is never realised. These conflicts should be acknowledged, and a pragmatic trials system built that means it is not just surgeons and their physician colleagues who bear responsibility for driving a cultural shift towards trial transparency. The cooperation of all stakeholders is required to encourage and enforce best practice within an improved regulatory framework. This may include ensuring that funding organisations make their support contingent on suitable data-sharing and publishing agreements, as current guidelines appear to be deficient.22 Ethics committees, Institutional Review Boards, and the academic and medical institutions hosting trials must also take a more vigorous role in monitoring conduct, completion, analysis and data sharing.23 Efforts must be made to ensure continued access to data, in case the study is later discontinued or abandoned.24 This could be achieved by nomination of ‘data controllers’, who act as independent repositories of trial data, at the point of trial registration. This might address the reported difficulties in communicating with the investigators of discontinued or abandoned trials, helping to share data from such studies with interested parties or, more widely, through pre-existing free online resources such as FigShare (http://figshare.com) or ResearchGate (www.researchgate.net). Online trial registries might need to move from passive protocol-hosting to more dynamic and interactive relationships with investigators. This includes tracking studies through their life-cycles and flagging those that discontinue, partially report, or appear to have been abandoned. Simple interventions, such as email reminders of investigators’ legal obligations, show significantly improved result-reporting.25 Patients are likely unaware of the extent of these problems and the resulting risks 205
Research
from futile trial participation. Their engagement in this process will also be vital in making sure a shift in research culture and reporting transparency. Finally, when trial results are submitted for publication, academic journals should take a more active role in ensuring that trial registration is complete, study reporting and analysis is appropriate, and access to original protocols and anonymised results is transparent. All this adds to an already-cumbersome trials process, so it is important that measures are implemented in a way that minimises any increase in the substantial administrative and financial burdens to investigators. Guidance from professional bodies, or even legislative changes to the regulatory framework, might be required. Investigators, funders, host institutions, and journals potentially all have some conflicted interests that may preclude effective self-policing. European clinical trials law is already moving to address this.26 A decade has now passed since journals first required trial registration prior to publication. Considerable research has enabled us to identify a number of problems in need of urgent attention. Inaccessible research and poor methodology distorts the evidence available for clinical decision-making, reduces research efficiency, restricts scarce funding, and could ultimately undermine public trust in medical science. Appropriately addressing this might prove to be one of the biggest challenges facing future clinical research in surgery, but one that urgently needs to be recognised.
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