The nuts and bolts of neuroscience trials
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In Context 1092 www.thelancet.com/neurology Vol 8 December 2009 Books The nuts and bolts of neuroscience trials Clinical trials are conceptually simple forms of research: take a group of individuals and randomly allocate them to one (or sometimes more) different exposures, one of which is usually a control, and follow them up to detect differences between the groups in one key, and several other important, outcomes. This procedure allows rejection of a null hypothesis regarding the likely effects of the intervention. Relevant to this endeavour is ensuring appropriate study design, funding, management, analyses, and publication of the results within a reasonable timeframe and budget, so that, ultimately, knowledge is advanced and health gains can be made for a reasonable return on the investment. However, those who are new to clinical trials are often daunted by the complexity of the ethical and regulatory requirements, the high infrastructure and direct costs, and the recurring problems of inadequate recruitment of patients and overly optimistic expectations for treatment effects. For clinical trials in the neurosciences, there are particular challenges that need to be addressed, particularly with regard to diagnosis: the nervous system has limited responses to injury or illness and the measurements of outcomes that are often needed to take into account both physical (disability) and mental domains are complex. Another problem is that neuroscientists and neurologists have not been as successful as other disciplines, such as cardiology and oncology, in forming networks to solve important clinical problems. Clinical Trials in the Neurosciences is a welcome addition to the scientific literature because this text provides a broad overview of an increasingly important area through a collection of topical chapters written by experienced, albeit predominantly US-based, researchers. After some brief introductory historical perspectives, the chapters are structured around several theme sections: Preclinical Trials, with reference to the STAIR (Stroke Therapy Academic Industry Roundtable) criteria for ischaemic stroke models and extrapolation of animal studies to man; Randomised Blinded Trials, discussing design, analysis, and endpoint assessment; Multicentred Trials, outlining organisation, recruitment, quality control, and budget; Special Populations and Genetic Studies, reviewing progressive neurological diseases, children, neurological emergencies, and gene therapy; Imaging, highlighting logistics and relevance of MRI, CT, and PET modality endpoints; and Training and Education, discussing funding opportunities and career training pathways. With 34 chapters condensed into just over 200 pages, the book clearly loses detail by providing only brief reviews of key aspects, and I was often left wanting more. Furthermore, the emphasis is on the conduct of clinical trials in the North American context. Even so, there were several chapters that stood out: Strategies for Recruiting and Retaining Minorities had some useful advice; Neurological Emergencies is an increasingly important direction of research given the short time window of opportunity to intervene in head injury, spinal cord compression, seizures, and stroke; and Behavioural/Neuropsychological Outcomes and Quality of life Endpoints contained useful advice for clinical practice as well as research. However, given an increasing reliance on international collaborative research, the fact that there was no reference to multicultural research collaboration or even the ethics of undertaking clinical trials in low-resource settings was surprising. With the considerable challenges that academics face in initiating clinical trials, inclusion of a chapter on developing a protocol would have been useful, rather than simply including an appendix that contained checklist requirements for a protocol, manual of operations, and a data safety and monitoring plan. This chapter could have outlined the use of systematic reviews and meta- analysis to both justify and quantify plausible potential treatment effects, and thus emphasise the importance of the CONSORT guidelines as a framework for a protocol and for publishing the results. Although the chapter Phase I/II— Design and Analysis contained some useful comments on type I and type II random statistical errors (I always forget which is which!) and the role of pilot studies in developing phase III trials, I was amazed that there was no discussion around the importance of confidence intervals rather than p values here or elsewhere in the book. Other problems that trouble clinicians are analysis of subgroups, dichotomous versus continuous endpoints, and non-inferiority versus equivalence design. Given the increasing regulatory and ethical complexities, high costs, and the lengthy timelines, clinical trials are increasingly being restricted to industry and large academic institutions, which is potentially detrimental to public health care. Although the testing of new drugs for regulatory purposes is important, the mechanical nature and business orientation of such work has the potential to stifle academic creativity and limit the testing of effectiveness (and cost- effectiveness) of health-care provision. This book will hopefully provide a useful guide to the inexperienced researcher who has caught the bug and wishes to pursue a career that, in part or as a whole, involves efforts to translate knowledge regarding neuronal injury and repair from the bench into new therapies for the prevention and treatment of neurological conditions at the bedside. Craig Anderson [email protected] Clinical Trials in the Neurosciences Edited by KM Woodbury-Harris, BM Coull Karger, 2009. Pp 214. $228. ISBN 978-3-8055-9023-5
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Transcript of The nuts and bolts of neuroscience trials
In Context
1092 www.thelancet.com/neurology Vol 8 December 2009
BooksThe nuts and bolts of neuroscience trialsClinical trials are conceptually simple forms of research: take a group of individuals and randomly allocate them to one (or sometimes more) diff erent exposures, one of which is usually a control, and follow them up to detect diff erences between the groups in one key, and several other important, outcomes. This procedure allows rejection of a null hypothesis regarding the likely eff ects of the intervention. Relevant to this endeavour is ensuring appropriate study design, funding, management, analyses, and publication of the results within a reasonable timeframe and budget, so that, ultimately, knowledge is advanced and health gains can be made for a reasonable return on the investment. However, those who are new to clinical trials are often daunted by the complexity of the ethical and regulatory requirements, the high infrastructure and direct costs, and the recurring problems of inadequate recruitment of patients and overly optimistic expectations for treatment eff ects.
For clinical trials in the neurosciences, there are particular challenges that need to be addressed, particularly with regard to diagnosis: the nervous system has limited responses to injury or illness and the measurements of outcomes that are often needed to take into account both physical (disability) and mental domains are complex. Another problem is that neuroscientists and neurologists have not been as successful as other disciplines, such as cardiology and oncology, in forming networks to solve important clinical problems.
Clinical Trials in the Neurosciences is a welcome addition to the scientifi c literature because this text provides a broad overview of an increasingly important area through a collection of topical chapters written by experienced, albeit predominantly US-based, researchers. After some brief introductory historical perspectives, the chapters are structured around several theme sections: Preclinical Trials, with reference to the STAIR (Stroke Therapy Academic Industry Roundtable) criteria for ischaemic stroke models and extrapolation of animal studies to man; Randomised Blinded Trials, discussing design, analysis, and endpoint assessment; Multicentred Trials, outlining organisation, recruitment, quality control, and budget; Special Populations and Genetic Studies, reviewing progressive neurological diseases, children, neurological emergencies, and gene therapy; Imaging, highlighting logistics and relevance of MRI, CT, and PET modality endpoints; and Training and Education, discussing funding opportunities and career training pathways.
With 34 chapters condensed into just over 200 pages, the book clearly loses detail by providing only brief reviews of key aspects, and I was often left wanting more. Furthermore, the emphasis is on the conduct of clinical trials in the North
American context. Even so, there were several chapters that stood out: Strategies for Recruiting and Retaining Minorities had some useful advice; Neurological Emergencies is an increasingly important direction of research given the short time window of opportunity to intervene in head injury, spinal cord compression, seizures, and stroke; and Behavioural/Neuropsychological Outcomes and Quality of life Endpoints contained useful advice for clinical practice as well as research. However, given an increasing reliance on international collaborative research, the fact that there was no reference to multicultural research collaboration or even the ethics of undertaking clinical trials in low-resource settings was surprising. With the considerable challenges that academics face in initiating clinical trials, inclusion of a chapter on developing a protocol would have been useful, rather than simply including an appendix that contained checklist requirements for a protocol, manual of operations, and a data safety and monitoring plan. This chapter could have outlined the use of systematic reviews and meta-analysis to both justify and quantify plausible potential treatment eff ects, and thus emphasise the importance of the CONSORT guidelines as a framework for a protocol and for publishing the results. Although the chapter Phase I/II—Design and Analysis contained some useful comments on type I and type II random statistical errors (I always forget which is which!) and the role of pilot studies in developing phase III trials, I was amazed that there was no discussion around the importance of confi dence intervals rather than p values here or elsewhere in the book. Other problems that trouble clinicians are analysis of subgroups, dichotomous versus continuous endpoints, and non-inferiority versus equivalence design.
Given the increasing regulatory and ethical complexities, high costs, and the lengthy timelines, clinical trials are increasingly being restricted to industry and large academic institutions, which is potentially detrimental to public health care. Although the testing of new drugs for regulatory purposes is important, the mechanical nature and business orientation of such work has the potential to stifl e academic creativity and limit the testing of eff ectiveness (and cost-eff ectiveness) of health-care provision.
This book will hopefully provide a useful guide to the inexperienced researcher who has caught the bug and wishes to pursue a career that, in part or as a whole, involves eff orts to translate knowledge regarding neuronal injury and repair from the bench into new therapies for the prevention and treatment of neurological conditions at the bedside.
Craig Anderson [email protected]
Clinical Trials in the Neurosciences
Edited by KM Woodbury-Harris, BM Coull
Karger, 2009. Pp 214. $228.ISBN 978-3-8055-9023-5
