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Chinese Clinical Oncology Sep 2015Treatment of brain tumors is increasingly informed by biomarkers. One use is to appropriately group tumors with similar genetic/genomic characteristics and to design... (Review)
Review
Treatment of brain tumors is increasingly informed by biomarkers. One use is to appropriately group tumors with similar genetic/genomic characteristics and to design trials separately for the individual groups. The biomarker's use is to predict patient response so that the most effective treatment can be selected for patients based on their tumor characteristics. Trial designs that recruit unselected patients are poorly suited for identifying treatments effective only in subsets of patients given the relatively small numbers of patients available for trials. Investigators are beginning to use different designs that better account for tumor heterogeneity. In this article, an overview of the role of biomarkers in brain tumor trials is presented in the context of existing clinical trials as well as trials that may be launched within the next several years.
Topics: Biomarkers, Tumor; Brain Neoplasms; Clinical Trials as Topic; History, 20th Century; History, 21st Century; Humans; Research Design
PubMed: 26408305
DOI: 10.3978/j.issn.2304-3865.2015.09.04 -
Clinical Cancer Research : An Official... Nov 2013A workshop entitled "Lessons Learned from Radiation Oncology Trials" was held on December 7-8, 2011, in Bethesda, MD, to present and discuss some of the recently... (Review)
Review
A workshop entitled "Lessons Learned from Radiation Oncology Trials" was held on December 7-8, 2011, in Bethesda, MD, to present and discuss some of the recently conducted radiation oncology clinical trials with a focus on those that failed to refute the null hypothesis. The objectives of this workshop were to summarize and examine the questions that these trials provoked, to assess the quality and limitations of the preclinical data that supported the hypotheses underlying these trials, and to consider possible solutions to these challenges for the design of future clinical trials. Several themes emerged from the discussions: (i) opportunities to learn from null-hypothesis trials through tissue and imaging studies; (ii) value of preclinical data supporting the design of combinatorial therapies; (iii) significance of validated biomarkers; (iv) necessity of quality assurance in radiotherapy delivery; (v) conduct of sufficiently powered studies to address the central hypotheses; and (vi) importance of publishing results of the trials regardless of the outcome. The fact that well-designed hypothesis-driven clinical trials produce null or negative results is expected given the limitations of trial design and complexities of cancer biology. It is important to understand the reasons underlying such null results, however, to effectively merge the technologic innovations with the rapidly evolving biology for maximal patient benefit through the design of future clinical trials.
Topics: Biomarkers, Tumor; Clinical Trials as Topic; Combined Modality Therapy; Humans; Neoplasms; Quality Assurance, Health Care; Treatment Failure
PubMed: 24043463
DOI: 10.1158/1078-0432.CCR-13-1116 -
Spinal Cord Sep 2019Traumatic spinal cord injury (SCI) leads to immediate neuronal and axonal damage at the focal injury site and triggers secondary pathologic series of events resulting... (Review)
Review
Traumatic spinal cord injury (SCI) leads to immediate neuronal and axonal damage at the focal injury site and triggers secondary pathologic series of events resulting in sensorimotor and autonomic dysfunction below the level of injury. Although there is no cure for SCI, neuroprotective and regenerative therapies show promising results at the preclinical stage. There is a pressing need to develop non-invasive outcome measures that can indicate whether a candidate therapeutic agent or a cocktail of therapeutic agents are positively altering the underlying disease processes. Recent conventional MRI studies have quantified spinal cord lesion characteristics and elucidated their relationship between severity of injury to clinical impairment and recovery. Next to the quantification of the primary cord damage, quantitative MRI measures of spinal cord (rostrocaudally to the lesion site) and brain integrity have demonstrated progressive and specific neurodegeneration of afferent and efferent neuronal pathways. MRI could therefore play a key role to ultimately uncover the relationship between clinical impairment/recovery and injury-induced neurodegenerative changes in the spinal cord and brain. Moreover, neuroimaging biomarkers hold promises to improve clinical trial design and efficiency through better patient stratification. The purpose of this narrative review is therefore to propose a guideline of clinically available MRI sequences and their derived neuroimaging biomarkers that have the potential to assess tissue damage at the macro- and microstructural level after SCI. In this piece, we make a recommendation for the use of key MRI sequences-both conventional and advanced-for clinical work-up and clinical trials.
Topics: Brain; Clinical Trials as Topic; Humans; Magnetic Resonance Imaging; Neuroimaging; Practice Guidelines as Topic; Spinal Cord Injuries
PubMed: 31267015
DOI: 10.1038/s41393-019-0309-x -
Clinical Trials (London, England) Oct 2021The COVID-19 pandemic has resulted in unprecedented challenges for healthcare systems worldwide. It has also stimulated research in a wide range of areas including rapid...
The COVID-19 pandemic has resulted in unprecedented challenges for healthcare systems worldwide. It has also stimulated research in a wide range of areas including rapid diagnostics, novel therapeutics, use of technology to track patients and vaccine development. Here, we describe our experience of rapidly setting up and delivering a novel COVID-19 vaccine trial, using clinical and research staff and facilities in three National Health Service Trusts in Cambridgeshire, United Kingdom. We encountered and overcame a number of challenges including differences in organisational structures, research facilities available, staff experience and skills, information technology and communications infrastructure, and research training and assessment procedures. We overcame these by setting up a project team that included key members from all three organisations that met at least daily by teleconference. This group together worked to identify the best practices and procedures and to harmonise and cascade these to the wider trial team. This enabled us to set up the trial within 25 days and to recruit and vaccinate the participants within a further 23 days. The lessons learned from our experiences could be used to inform the conduct of clinical trials during a future infectious disease pandemic or public health emergency.
Topics: COVID-19; COVID-19 Vaccines; Clinical Trials as Topic; Humans; Pandemics; State Medicine; United Kingdom
PubMed: 34154428
DOI: 10.1177/17407745211024764 -
Journal of the American College of... Jun 2009New and emerging therapies might provide benefit in patients with pulmonary arterial hypertension. Their efficacy and safety will be compared with existing combination... (Review)
Review
New and emerging therapies might provide benefit in patients with pulmonary arterial hypertension. Their efficacy and safety will be compared with existing combination therapies in randomized clinical trials. Appropriate end points for these trials need to be identified: these will include exercise testing, the composite end point of time to clinical worsening, and hemodynamic markers, including advanced imaging modalities and biomarkers. Quality-of-life questionnaires are useful and important secondary end points; pulmonary arterial hypertension-specific questionnaires are currently being developed. Advantages and disadvantages of various trial designs, including placebo-controlled monotherapy or add-on trials, noninferiority studies, and withdrawal trials are also discussed.
Topics: Clinical Trials as Topic; Endpoint Determination; Exercise Test; Hemodynamics; Humans; Hypertension, Pulmonary; Quality of Life; Randomized Controlled Trials as Topic; Research Design; Respiratory Function Tests; Treatment Outcome
PubMed: 19555863
DOI: 10.1016/j.jacc.2009.04.007 -
CNS Drugs Mar 2017Due to the heterogeneous nature of the disease, it is a challenge to capture disease activity of multiple sclerosis (MS) in a reliable and valid way. Therefore, it can... (Review)
Review
Due to the heterogeneous nature of the disease, it is a challenge to capture disease activity of multiple sclerosis (MS) in a reliable and valid way. Therefore, it can be difficult to assess the true efficacy of interventions in clinical trials. In phase III trials in MS, the traditionally used primary clinical outcome measures are the Expanded Disability Status Scale and the relapse rate. Secondary outcome measures in these trials are the number or volume of T2 hyperintense lesions and gadolinium-enhancing T1 lesions on magnetic resonance imaging (MRI) of the brain. These secondary outcome measures are often primary outcome measures in phase II trials in MS. Despite several limitations, the traditional clinical measures are still the mainstay for assessing treatment efficacy. Newer and potentially valuable outcome measures increasingly used or explored in MS trials are, clinically, the MS Functional Composite and patient-reported outcome measures, and on MRI, brain atrophy and the formation of persisting black holes. Several limitations of these measures have been addressed and further improvements will probably be proposed. Major improvements are the coverage of additional functional domains such as cognitive functioning and assessment of the ability to carry out activities of daily living. The development of multidimensional measures is promising because these measures have the potential to cover the full extent of MS activity and progression. In this review, we provide an overview of the historical background and recent developments of outcome measures in MS trials. We discuss the advantages and limitations of various measures, including newer assessments such as optical coherence tomography, biomarkers in body fluids and the concept of 'no evidence of disease activity'.
Topics: Biomarkers; Clinical Trials as Topic; Humans; Magnetic Resonance Imaging; Multiple Sclerosis; Tomography, Optical Coherence; Treatment Outcome
PubMed: 28185158
DOI: 10.1007/s40263-017-0412-5 -
Drug and Alcohol Dependence Jan 2016The development and approval of an efficacious pharmacotherapy for stimulant use disorders has been limited by the lack of a meaningful indicator of treatment success,... (Review)
Review
BACKGROUND
The development and approval of an efficacious pharmacotherapy for stimulant use disorders has been limited by the lack of a meaningful indicator of treatment success, other than sustained abstinence.
METHODS
In March, 2015, a meeting sponsored by Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) was convened to discuss the current state of the evidence regarding meaningful outcome measures in clinical trials for stimulant use disorders. Attendees included members of academia, funding and regulatory agencies, pharmaceutical companies, and healthcare organizations. The goal was to establish a research agenda for the development of a meaningful outcome measure that may be used as an endpoint in clinical trials for stimulant use disorders.
RESULTS AND CONCLUSIONS
Based on guidelines for the selection of clinical trial endpoints, the lessons learned from prior addiction clinical trials, and the process that led to identification of a meaningful indicator of treatment success for alcohol use disorders, several recommendations for future research were generated. These include a focus on the validation of patient reported outcome measures of functioning, the exploration of patterns of stimulant abstinence that may be associated with physical and/or psychosocial benefits, the role of urine testing for validating self-reported measures of stimulant abstinence, and the operational definitions for reduction-based measures in terms of frequency rather than quantity of stimulant use. These recommendations may be useful for secondary analyses of clinical trial data, and in the design of future clinical trials that may help establish a meaningful indicator of treatment success.
Topics: Amphetamine-Related Disorders; Central Nervous System Stimulants; Clinical Trials as Topic; Congresses as Topic; Humans; Practice Guidelines as Topic; Substance-Related Disorders; Treatment Outcome
PubMed: 26652899
DOI: 10.1016/j.drugalcdep.2015.11.004 -
Dialogues in Clinical Neuroscience 2011Clinical trials have been the main tool used by the health sciences community to test and evaluate interventions, Trials can fall into two broad categories: pragmatic... (Review)
Review
Clinical trials have been the main tool used by the health sciences community to test and evaluate interventions, Trials can fall into two broad categories: pragmatic and explanatory. Pragmatic trials are designed to evaluate the effectiveness of interventions in real-life routine practice conditions, whereas explanatory trials aim to test whether an intervention works under optimal situations. Pragmatic trials produce results that can be generalized and applied in routine practice settings. Since most results from exploratory trials fail to be broadly generalizable, the "pragmatic design" has gained momentum. This review describes the concept of pragmatism, and explains in particular that there is a continuum between pragmatic and explanatory trials, rather than a dichotomy. Special focus is put on the limitations of the pragmatic trials, while recognizing the importance for and impact of this design on medical practice.
Topics: Clinical Trials as Topic; Evidence-Based Medicine; Humans; Research Design; Treatment Outcome
PubMed: 21842619
DOI: 10.31887/DCNS.2011.13.2/npatsopoulos -
Research Synthesis Methods Mar 2016Quasi-randomization might expedite recruitment into trials in emergency care settings but may also introduce selection bias. (Review)
Review
BACKGROUND
Quasi-randomization might expedite recruitment into trials in emergency care settings but may also introduce selection bias.
METHODS
We searched the Cochrane Library and other databases for systematic reviews of interventions in emergency medicine or urgent care settings. We assessed selection bias (baseline imbalances) in prognostic indicators between treatment groups in trials using true randomization versus trials using quasi-randomization.
RESULTS
Seven reviews contained 16 trials that used true randomization and 11 that used quasi-randomization. Baseline group imbalance was identified in four trials using true randomization (25%) and in two quasi-randomized trials (18%). Of the four truly randomized trials with imbalance, three concealed treatment allocation adequately. Clinical heterogeneity and poor reporting limited the assessment of trial recruitment outcomes.
CONCLUSIONS
We did not find strong or consistent evidence that quasi-randomization is associated with selection bias more often than true randomization. High risk of bias judgements for quasi-randomized emergency studies should therefore not be assumed in systematic reviews. Clinical heterogeneity across trials within reviews, coupled with limited availability of relevant trial accrual data, meant it was not possible to adequately explore the possibility that true randomization might result in slower trial recruitment rates, or the recruitment of less representative populations.
Topics: Clinical Trials as Topic; Databases, Bibliographic; Emergency Medicine; Humans; Prognosis; Random Allocation; Risk; Selection Bias
PubMed: 26333419
DOI: 10.1002/jrsm.1163 -
The European Respiratory Journal Jul 2009There is enormous interest in the treatment of pulmonary arterial hypertension (PAH), so it is appropriate to consider the design of trials of new therapies and the... (Review)
Review
There is enormous interest in the treatment of pulmonary arterial hypertension (PAH), so it is appropriate to consider the design of trials of new therapies and the end-points to be measured when trying to decide whether or not a therapy is effective. In May 2003, the first meeting devoted solely to the discussion of end-points and trial design in PAH was held in Gleneagles, UK. At that time, most of the randomised controlled trials in PAH had used 6-min walking distance and/or resting haemodynamics as their primary end-points. The present article considers the progress that has been made since 2003. It deals with aspects of clinical trial design (such as noninferiority, superiority and withdrawal trials), considers end-points used in previous and current studies (such as 6-min walking distance, time to clinical worsening, haemodynamics, imaging and plasma brain natriuretic peptide), and considers what end-points might be used in the future. The second end-points meeting was held in Turnberry, UK, in June 2007. It had a similar format to the first meeting. Much of what is presented here is a summary of the workshops from that meeting. An attempt has been made to both summarise the current state of end-points and trial design and suggest new ways in which they could be improved. The present article forms one of a series being published in the European Respiratory Journal on pulmonary hypertension.
Topics: Clinical Trials as Topic; Echocardiography; Endpoint Determination; Exercise Test; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging; Quality of Life; Randomized Controlled Trials as Topic; Research Design; Respiratory Function Tests; Tomography, X-Ray Computed; Treatment Outcome
PubMed: 19567606
DOI: 10.1183/09031936.00107108