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Urologic Oncology Mar 2021Clinical trials are pillars of modern clinical evidence generation. However, the clinical trial enterprise can be inefficient, and trials often fail before their planned...
OBJECTIVES
Clinical trials are pillars of modern clinical evidence generation. However, the clinical trial enterprise can be inefficient, and trials often fail before their planned endpoint is reached. We sought to estimate how often urologic oncology trials fail, why trials fail, and associations with trial failure.
METHODS
We queried phase 2/3 urologic clinical trial data from ClinicalTrials.gov registered between 2007 and 2019, with status marked as active, completed, or terminated. We extracted relevant trial data, including anticipated and actual accrual, from trial records and ClinicalTrials.gov archives. We manually coded reasons given in the "why stopped" free text field for trial failure into categories (poor accrual, interim results, toxicity/adverse events, study agent unavailable, canceled by the sponsor, inadequate budget, logistics, trial no longer needed, principal investigator left, no reason given, or other). We considered trials terminated for safety or efficacy to be completed trials. Trials marked as terminated for other reasons were considered failed trials. We then estimated the rate of trial failure using competing risks methods. Finally, we assessed associations with trial failure using a Cox proportional hazards model.
RESULTS
A total of 1,869 urologic oncology trials were included. Of these, 225 (12.0%) failed, and 51 (2.7%) were terminated for "good" reasons (e.g., toxicity, efficacy). Of the 225 failed trials, 122 (54%) failed due to poor accrual. Failed trials had a lower anticipated accrual than successfully completed trials (55 vs. 63 patients, P<0.001). A total of 6,832 patients were actually accrued to failed trials. The 10-year estimated risk of trial failure was 17% (95% CI 15%-22%). Single center trials, phase 3 trials, drug trials, and trials with exclusively USA sites were more likely to fail.
CONCLUSION
We estimate that 17%, or roughly 1 in 6, of urologic oncology trials fail, most frequently for poor accrual. Further investigations are needed into systemic, trial, and site-specific factors that may impact accrual and successful trial completion.
Topics: Clinical Trials as Topic; Early Termination of Clinical Trials; Humans; Urologic Neoplasms
PubMed: 33257221
DOI: 10.1016/j.urolonc.2020.10.070 -
Ending Gender Inequality in Cardiovascular Clinical Trial Leadership: JACC Review Topic of the Week.Journal of the American College of... Jun 2021Women are under-represented as leaders of cardiovascular randomized controlled trials, representing 1 in 10 lead authors of cardiovascular trials published in... (Review)
Review
Women are under-represented as leaders of cardiovascular randomized controlled trials, representing 1 in 10 lead authors of cardiovascular trials published in high-impact journals. Although the proportion of cardiovascular specialists who are women has increased in recent years, the proportion of cardiovascular clinical trialists who are women has not. This gap, underpinned by systemic sexism, has not been adequately addressed. The benefits of diverse randomized controlled trial leadership extend to patients and professionals. In this position statement, we present strategies adopted by some organizations to end gender inequality in research leadership. We offer an actionable roadmap for early-career researchers, scientists, academic institutions, professional societies, trial sponsors, and journals to follow, with the goal of harnessing the strength of women and under-represented groups as research leaders and facilitating a just culture in the cardiovascular clinical trial enterprise.
Topics: Cardiology; Clinical Trials as Topic; Female; Humans; Leadership; Male; Periodicals as Topic; Physicians, Women; Sexism; United States
PubMed: 34112322
DOI: 10.1016/j.jacc.2021.04.038 -
Rheumatology (Oxford, England) Sep 2017This article discusses points to consider when undertaking a clinical trial to test therapy for skin ulcers in SSc. A validated definition of skin ulcers should be used... (Review)
Review
This article discusses points to consider when undertaking a clinical trial to test therapy for skin ulcers in SSc. A validated definition of skin ulcers should be used if available. Defining a uniform SSc patient population, including consideration of disease duration, history of digital ulcers and capillaroscopic patterns, is important. Excluding confounding factors such as infection, calcinosis and trauma should be strongly considered, or at least accounted for, in defining patients. Outcome measures such as time to healing, prevention of new ulcers, function, pain and objective measures such as US, laser Doppler and thermography can be considered as outcome measures, although their validation has not yet been achieved and efforts may be needed to validate them before use. Likewise, biomarkers should be considered or consideration should be given to storing serum, plasma or cells for possible future analysis. A pre-planned analysis is important and should include consideration of missing data.
Topics: Clinical Trials as Topic; Disease Management; Humans; Scleroderma, Systemic; Skin Ulcer
PubMed: 28992171
DOI: 10.1093/rheumatology/kex200 -
Journal of Cardiac Failure May 2018Heart failure (HF) is a major global health problem. Clinical trials test efficacy, effectiveness, and safety of novel and emerging therapies in HF. We sought to... (Review)
Review
BACKGROUND
Heart failure (HF) is a major global health problem. Clinical trials test efficacy, effectiveness, and safety of novel and emerging therapies in HF. We sought to determine the salient features of ongoing interventional clinical trials in HF.
METHODS AND RESULTS
We accessed the ClinicalTrials.gov registry of the National Institutes of Health (NIH) and the International Clinical Trials Registry Platform of the World Health Organization on January 1, 2017, and extracted pertinent information on current HF clinical trials for systematic review. Of 794 HF trials that met our inclusion criteria, almost one-half (49.1%) evaluated clinical end points and one-third (32.8%) examined imaging end points as primary outcomes. One-fourth (24.8%) were industry sponsored and one-third (35.6%) were university sponsored. The NIH and other United States federal agencies funded only 14 trials (1.8% of all trials; 10.7% of trials in the US). Among 536 HF trials with specified left ventricular ejection fraction status, 434 (81.0%) focused on HF with reduced ejection fraction (HFrEF) and only 102 (19.0%) trials targeted HF with preserved ejection fraction (HFpEF).
CONCLUSIONS
Ongoing HF trials are predominantly sponsored by nongovernmental funding agencies. Although HFpEF occurs as commonly as HFrEF in the community, the number of clinical trials targeting HFpEF is substantially lower compared with HFrEF.
Topics: Clinical Trials as Topic; Disease Management; Heart Failure; Humans; Registries; Stroke Volume; United States
PubMed: 29482028
DOI: 10.1016/j.cardfail.2018.02.006 -
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 -
Chinese Clinical Oncology Dec 2015The identification of new targets in cancer biology has changed the traditional approach to cancer diagnosis and treatment and therefore also to drug development. The... (Review)
Review
The identification of new targets in cancer biology has changed the traditional approach to cancer diagnosis and treatment and therefore also to drug development. The classical 'one size fits all' approach needed to be modified into a tailored approach that took into account the patient-to-patient variation. Innovative trials are warranted, based on the integration of new types of design and integrating the knowledge coming from new disciplines like bioinformatics, biostatistics, epidemiology and health economics. Several initiatives have started at national levels but also in large pan-European academic organizations [like the European Organization for Research and Treatment of Cancer (EORTC)] in the scope of generating a harmonized healthcare landscape across Europe.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Clinical Trials as Topic; Humans; Lung Neoplasms; Molecular Diagnostic Techniques; Molecular Targeted Therapy; Patient Selection; Precision Medicine; Predictive Value of Tests; Research Design
PubMed: 26730756
DOI: 10.3978/j.issn.2304-3865.2015.11.03 -
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 -
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 -
Stroke Jul 2015
Review
Topics: Animals; Cell- and Tissue-Based Therapy; Clinical Trials as Topic; Humans; Infusions, Intra-Arterial; Stroke
PubMed: 26045599
DOI: 10.1161/STROKEAHA.115.007149