Opinion piece
The forecast for future clinical trials and clinical
trialists - storms or sunshine?
Catharina JM Klijn1, Peter AG Sandercock DM2*
1. Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; and Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands
2.Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
*Corresponding author
Word count
Abstract 144
Main text 992
1 Table
13 references
.
Abstract
Randomised controlled trials are the most unbiased way to evaluate many types of healthcare interventions. Pharmaceutical and medical technology industries play an important role in developing and testing new interventions that have commercial potential. However, many interventions for the prevention, treatment and rehabilitation of stroke are either not drugs or devices or have no commercial potential. Like many other clinicians who are uncertain about the value of existing or new treatments,we are involved ininvestigator-led clinical trials to resolve treatmentuncertainties. There is common agreement that, investigator-led clinical trials are facing increasing difficultiesand that as a result clinicians may be deterred from pursuing clinical trials as a research career. In this article, we express our concerns for the future of such trials, balanced with the hope that systems to foster and sustain this important type of research in the future, can be developed.
Background
As clinicians with experience of leading investigator-led randomised controlled trials (RCTs) and supporting other clinician trialists undertake theirs,we worry about the future of such trials and about the prospects for the ‘next generation’ of clinicians who might lead them. Here, wegive a personal view on the outlook.
The sunshine and the storms
Investigator-ledstroke RCTs have had a huge impact on clinical practice. In the field of stroke it is striking how many of the advances in treatment and prevention have come from investigator-led RCTs funded by governments and non-industry sources (Table 1). While the continuing steady growth in the number of clinical trials in stroke appears reassuring at first sight, the steady stream of publicly1,2 and privately expressed concerns about the difficulties facing investigator-led RCTsand patient-focused clinical research3makes us worry that the future for investigator-led trials and the career prospects for the next generation of clinician trialists may not be so bright.
Storms: current issues
The changing clinical trial regulatory environmentmakes multinational academic clinical trials increasingly challenging2.The need to meet ever-increasing regulatory requirements increases costs, induces delays and increases ‘research waste’.4 The leaders of investigator-led trials also report difficulties unrelated to regulatory problems:they have experienced in many aspects of design, funding, recruitment,conduct and reporting of their trials1. Furthermore, even in wealthy countries obtaining funding for trials of interventions without commercial potential is very difficult.3In our view,the concern remains true that the research agenda in stroke is driven more by commercial intereststhanby health care need.5,6
Sunshine: new opportunities.
Appropriate synthesis of relevant pre-clinical and other biomedical data is increasingly recognised as a key step in improving the design of clinical trials and thus a means to reduce research waste6. The CAMARADESgroup has pioneered,and now provides, a supporting framework for the systematic review and meta-analysis ofpreclinical data ( Wider use of evidence-based methods for the design, conduct and analysis of trials promises to make trials more efficient, affordable and less wasteful7. Trial Forge ( is an initiative that aims to increase the evidence base for trial decision making and, in doing so, to improve trial efficiency. Trial Forge will not be a guideline or a checklist but a ‘go to’ website for research on randomised trials methods, with a linked programme of applied methodology research, coupled to an effective evidence-dissemination process. The ESO clinical trials working group is supporting this initiative with a view to encourage research into methods to improve recruitment in stroke trials.8 Rapid growth in the number of clinical trial units to support clinicians develop and undertake clinical trials may facilitate the conduct of investigator-driven trials, but provision is patchy and even if a clinician has access to a local Clinical Trial Unit, it may not have relevant expertise to conduct trials in stroke.To circumvent the manifest difficulties of conducting multinational trials2,4 several trialists have created a federation of single-nation trialsall addressing the same question, planning to create a unified individual patient data meta-analysis when all trials are completed (Table 1). This has been done very explicitly with the three current trials of fluoxetine to facilitate recovery after stroke: FOCUS (UK), EFFECTS(Nordic), AFFINITY (Australia).9The UK Stroke Research Network has had a huge positive impact on trial recruitment and contributed to the success of a number of investigator-led trials and we hope the UK Government will continue to support it. We welcome the plans for international collaboration betweenEuropean, North American and other trials networks discussed at the 2015 ESO conference.
Storm clouds and remaining gaps
The huge and growing global burden of stroke, especially in low- and middle-income countries, means that the limited research resources available should be directed at the highest health research priorities,which differ substantially between the wealthy and less wealthy parts of the world.10However, funding for basic and translational research is greater than for clinical research.3 Formal prioritisation programmes with extensive public engagement are powerful and help select the questions most relevant to our patients11and the wider priorities for global strokeresearch.12 Achieving consensus between clinicians and the publicand taking greater control of the research agenda3will help to ensure that clinical trials remain relevant and sustainable.10 A remaining major concern is the difficulties faced by young clinicians to complete their professional training as a physician, and at the same time acquire the clinical skills, methodological knowledge and practical research experience to enable them to lead their own trials.3 Formal clinical academic training programmes, geared to the needs of clinicians who aim for a career in patient-focused research, are clearly needed.3 Whilethe Masters programmes in clinical trials offered by our own and other universities are helpful, ‘hands-on’ experience is essential in learning the ‘how-to’ of clinical trials. Sackett has suggested ‘clinical clerkships’ in clinical trials as one solution,13 but these are not yet widely available.We emphasise that early-career trialists need continuing support to overcome barriers to funding, conduct and completion of their trials,3 especially through the ‘dark moments’ every trialist experiences at times of particular difficulty.
Conclusions
To follow our meteorological theme, our forecast is ‘sunshine and showers’for patient-focused clinical research and randomised trials. The aphorism ‘there is no such thing as bad weather, only bad gear’ suggests that, with the right tools and support, the next generationof clinical trialists and bedside researchers will be able to perform excellent research with huge impact on healthcare. We therefore hope that they will be given the priority and support they deserve and will not be ‘left out in the rain’.
Acknowledgements and funding
The idea for this paper arose in November 2014, at a meeting of the Brain Center Rudolf Magnus Utrecht and Edinburgh Neuroscience collaboration, when CK and PS presented a joint lecture entitled ‘The future climate for clinical trials and clinical trialists - storms or sunshine?’ The meeting was supported by a grant from the Brain CenterRudolf Magnus Utrecht.
Table 1 Investigator led trials which have had a clear impact on clinical practice
Stroke prevention
•BP lowering (MRC)
•Aspirin (Canadian TIA, UKTIA, Dutch TIA, SALT),
•Anticoagulants (EAFT, SPIRIT, ESPRIT, WARSS, SPAF, BAFTA)
•Surgery for stroke prevention (ECST, NASCET, VA, ACST)
•Endovascular therapy for carotid stenosis (CAVATAS, ICSS, CREST, EVA-3S, SPACE)*
•Cholesterol reduction (HPS)
Stroke treatment
•Aspirin for acute stroke (IST*, CAST*, ARTIS)
•Thrombolysis for acute stroke (NINDS, IST3*)
•Hemicraniectomy (HAMLET, DESTINY-1, DESTINY-2, DECIMAL)*
•Endovascular therapy (MRCLEAN, ESCAPE, THRILL, EXTEND-IA, REVASCAT)*
•Subarachnoid Haemorrhage (ISAT, STAR, MASH-1 & 2)
•Intracerebral Haemorrhage (INTERACT-2; STICH-1 and 2)
Stroke Care and rehabilitation
•Stroke Units & Stroke Units Trialists Collaboration
•Early basic stroke care (QASC)
•Early mobilisation policy (AVERT)
•Deep Vein Thrombosis prevention (CLOTS-1, CLOTS-2, CLOTS-3)
- Note: these trials pre-planned a collaborative individual patient data meta-analysis.
Reference List
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