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Rheumatology (Oxford, England) Sep 2017This article discusses points to consider when undertaking a clinical trial to test therapy for renal involvement in SSc, not including scleroderma renal crisis.... (Review)
Review
This article discusses points to consider when undertaking a clinical trial to test therapy for renal involvement in SSc, not including scleroderma renal crisis. Double-blind, randomized controlled trials vs placebo or standard background therapy should be strongly considered. Inclusion criteria should consider a pre-specified range of renal functions or stratification of renal function. Gender and age limitations are probably not necessary. Concomitant medications including vasodilators, immunosuppressants and endothelin receptor antagonists and confounding illnesses such as diabetes, kidney stones, hypertension and heart failure need to be considered. A measure of renal function should be strongly considered, while time to dialysis, mortality, prevention of scleroderma renal crisis and progression of renal disease can also be considered, although they remain to be validated. Detailed, pre-planned analysis should be strongly considered and should include accounting for missing data.
Topics: Clinical Trials as Topic; Disease Management; Humans; Kidney Diseases; Scleroderma, Systemic
PubMed: 28992172
DOI: 10.1093/rheumatology/kex201 -
Neurotherapeutics : the Journal of the... Apr 2015The last 2 decades have seen a surge in the number of amyotrophic lateral sclerosis (ALS) clinical trials with the hope of finding successful treatments. Clinical... (Review)
Review
The last 2 decades have seen a surge in the number of amyotrophic lateral sclerosis (ALS) clinical trials with the hope of finding successful treatments. Clinical trialists aim to repurpose existing drugs and test novel compounds to target potential ALS disease pathophysiology. Recent technological advancements have led to the discovery of new causative genetic agents and modes of delivering potential therapy, calling for increasingly sophisticated trial design. The standard ALS clinical trial design may be modified depending on study needs: type of therapy; route of therapy delivery; phase of therapy development; applicable subpopulation; market availability of therapy; and utility of telemedicine. Novel biomarkers of diagnostic, predictive, prognostic, and pharmacodynamic value are undergoing development and validation for use in clinical trials. Design modifications build on the traditional clinical trial design and may be employed in either the learning or confirming trial phase. Novel designs aim to minimize patient risk, study duration, and sample size, while improving efficiency and promoting statistical power to herald an exciting era for clinical research in ALS.
Topics: Amyotrophic Lateral Sclerosis; Biomedical Research; Clinical Trials as Topic; History, 20th Century; Humans
PubMed: 25700798
DOI: 10.1007/s13311-015-0341-2 -
The Oncologist Jun 2019Communication of clinical trial outcomes is important, but the results of many clinical trials are never published. If we do not publish the results of clinical trials,...
Communication of clinical trial outcomes is important, but the results of many clinical trials are never published. If we do not publish the results of clinical trials, the lessons learned from those trials will perish. The Oncologist offers a powerful solution through the Clinical Trial Results publishing platform, which uses an established template for authors to easily build a manuscript by simply providing the essential trial data. Through it, every patient's legacy of clinical trial enrollment can matter.
Topics: Clinical Trials as Topic; Humans; Information Dissemination; Medical Oncology; Neoplasms; Publishing; Treatment Outcome
PubMed: 31064889
DOI: 10.1634/theoncologist.2019-0319 -
Fertility and Sterility Oct 2014Clinical trials testing infertility treatments often do not report on the major outcomes of interest to patients and clinicians and the public (such as live birth) nor...
Clinical trials testing infertility treatments often do not report on the major outcomes of interest to patients and clinicians and the public (such as live birth) nor on the harms, including maternal risks during pregnancy and fetal anomalies. This is complicated by the multiple participants in infertility trials which may include a woman (mother), a man (father), and a third individual if successful, their offspring (child), who is also the desired outcome of treatment. The primary outcome of interest and many adverse events occur after cessation of infertility treatment and during pregnancy and the puerperium, which creates a unique burden of follow-up for clinical trial investigators and participants. In 2013, because of the inconsistencies in trial reporting and the unique aspects of infertility trials not adequately addressed by existing Consolidated Standards of Reporting Trials (CONSORT) statements, we convened a consensus conference in Harbin, China, with the aim of planning modifications to the CONSORT checklist to improve the quality of reporting of clinical trials testing infertility treatment. The consensus group recommended that the preferred primary outcome of all infertility trials is live birth (defined as any delivery of a live infant after ≥20 weeks' gestation) or cumulative live birth, defined as the live birth per women over a defined time period (or number of treatment cycles). In addition, harms to all participants should be systematically collected and reported, including during the intervention, any resulting pregnancy, and the neonatal period. Routine information should be collected and reported on both male and female participants in the trial. We propose to track the change in quality that these guidelines may produce in published trials testing infertility treatments. Our ultimate goal is to increase the transparency of benefits and risks of infertility treatments to provide better medical care to affected individuals and couples.
Topics: Checklist; Clinical Trials as Topic; Consensus; Endpoint Determination; Female; Humans; Infertility; Male; Patient Selection; Pregnancy; Pregnancy Outcome; Research Design; Risk Assessment; Risk Factors; Sample Size; Treatment Outcome
PubMed: 25225072
DOI: 10.1016/j.fertnstert.2014.08.002 -
Chinese Clinical Oncology Sep 2015High-throughput technologies enable the measurement of a large number of molecular characteristics from a small tissue specimen. High-dimensional molecular information... (Review)
Review
High-throughput technologies enable the measurement of a large number of molecular characteristics from a small tissue specimen. High-dimensional molecular information (referred to as omics data) offers the possibility of predicting the future outcome of a patient (prognosis) and predicting the likely response to a specific treatment (prediction). Embedded in the vast amount of data is the hope that there exists some signal that will enable practitioners to deliver therapy personalized to the molecular profile of a tumor, thereby improving health outcomes. The challenges are to determine that the omics assays are valid and reproducible in a clinical setting, to develop a valid and optimal omics-based test that algorithmically determines the optimal treatment regime, to evaluate that test in a powerful and unbiased manner, and finally to demonstrate clinical utility: that the test under study improves clinical outcome as compared to not using the test. We review the statistical considerations involved in each of these stages, specifically dealing with the challenges of high-dimensional, omics data.
Topics: Clinical Laboratory Techniques; Clinical Trials as Topic; Data Interpretation, Statistical; Genomics; High-Throughput Screening Assays; Humans; Models, Statistical; Neoplasms; Prognosis
PubMed: 26408296
DOI: 10.3978/j.issn.2304-3865.2015.01.02 -
Translational Stroke Research Oct 2016Standard imaging in acute stroke enables the exclusion of non-stroke structural CNS lesions and cerebral haemorrhage from clinical and pre-clinical ischaemic stroke... (Review)
Review
Standard imaging in acute stroke enables the exclusion of non-stroke structural CNS lesions and cerebral haemorrhage from clinical and pre-clinical ischaemic stroke trials. In this review, the potential benefit of imaging (e.g., angiography and penumbral imaging) as a translational tool for trial recruitment and the use of imaging endpoints are discussed for both clinical and pre-clinical stroke research. The addition of advanced imaging to identify a "responder" population leads to reduced sample size for any given effect size in phase 2 trials and is a potentially cost-efficient means of testing interventions. In pre-clinical studies, technical failures (failed or incomplete vessel occlusion, cerebral haemorrhage) can be excluded early and continuous multimodal imaging of the animal from stroke onset is feasible. Pre- and post-intervention repeat scans provide real time assessment of the intervention over the first 4-6 h. Negative aspects of advanced imaging in animal studies include increased time under general anaesthesia, and, as in clinical studies, a delay in starting the intervention. In clinical phase 3 trial designs, the negative aspects of advanced imaging in patient selection include higher exclusion rates, slower recruitment, overestimated effect size and longer acquisition times. Imaging may identify biological effects with smaller sample size and at earlier time points, compared to standard clinical assessments, and can be adjusted for baseline parameters. Mechanistic insights can be obtained. Pre-clinically, multimodal imaging can non-invasively generate data on a range of parameters, allowing the animal to be recovered for subsequent behavioural testing and/or the brain taken for further molecular or histological analysis.
Topics: Animals; Brain; Brain Ischemia; Clinical Trials as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Fibrinolytic Agents; Humans; Neuroimaging; Stroke
PubMed: 27543177
DOI: 10.1007/s12975-016-0487-1 -
Journal of Psychiatry & Neuroscience :... Jan 2021The goal of precision medicine (individually tailored treatments) is not being achieved for neurobehavioural conditions such as psychiatric disorders. Traditional... (Review)
Review
The goal of precision medicine (individually tailored treatments) is not being achieved for neurobehavioural conditions such as psychiatric disorders. Traditional randomized clinical trial methods are insufficient for advancing precision medicine because of the dynamic complexity of these conditions. We present a pragmatic solution: the precision clinical trial framework, encompassing methods for individually tailored treatments. This framework includes the following: (1) treatment-targeted enrichment, which involves measuring patients' response after a brief bout of an intervention, and then randomizing patients to a full course of treatment, using the acute response to predict long-term outcomes; (2) adaptive treatments, which involve adjusting treatment parameters during the trial to individually optimize the treatment; and (3) precise measurement, which involves measuring predictor and outcome variables with high accuracy and reliability using techniques such as ecological momentary assessment. This review summarizes precision clinical trials and provides a research agenda, including new biomarkers such as precision neuroimaging, transcranial magnetic stimulation-electroencephalogram digital phenotyping and advances in statistical and machine-learning models. Validation of these approaches - and then widespread incorporation of the precision clinical trial framework - could help achieve the vision of precision medicine for neurobehavioural conditions.
Topics: Clinical Trials as Topic; Humans; Mental Disorders; Nervous System Diseases; Outcome Assessment, Health Care; Precision Medicine; Research Design
PubMed: 33206039
DOI: 10.1503/jpn.200042 -
International Journal For Equity in... Mar 2018Clinical trials for identification of efficient and effective new diagnostic and treatment modalities are needed to address disproportionately high burden of... (Review)
Review
BACKGROUND
Clinical trials for identification of efficient and effective new diagnostic and treatment modalities are needed to address disproportionately high burden of communicable (e.g., HIV/AIDS, tuberculosis, and malaria) and non-communicable diseases (e.g., diabetes) in developing countries. However, gross under-representation in global clinical trial platforms contributes to sustained health inequity in these countries. We reviewed the literature on barriers facing clinical researchers in developing countries for conducting clinical trials in their countries.
METHODS
Literature indexed in PubMed, Embase, CINAHL and Web of Science, WHO Global Health Library were searched. Grey literature was also searched. Search key words included barriers, challenges, clinical trials and developing countries. Articles within the scope of this review were appraised by two reviewers.
RESULTS
Ten studies, which are reported in 15 papers, were included in this review. Following critical review we identified five unifying themes for barriers. Barriers for conducting clinical trials included lack of financial and human capacity, ethical and regulatory system obstacles, lack of research environment, operational barriers and competing demands.
CONCLUSION AND RECOMMENDATION
There were substantial barriers at system, organization and individual level. We propose that to address this problem, instituting a system for wider implementation of local investigator-initiated trials is warranted. These trials are more applicable to local populations because they build on local healthcare knowledge. They are more demand-led, influence policy and responsive to a country's needs because they are driven by a local or national agenda.
Topics: Attitude to Health; Clinical Trials as Topic; Communication Barriers; Developing Countries; Humans; Research Support as Topic
PubMed: 29566721
DOI: 10.1186/s12939-018-0748-6 -
Advances in Experimental Medicine and... 2019Biomarkers have a key role in Alzheimer's disease (AD) drug development. Biomarkers can assist in diagnosis, demonstrate target engagement, support disease modification,... (Review)
Review
Biomarkers have a key role in Alzheimer's disease (AD) drug development. Biomarkers can assist in diagnosis, demonstrate target engagement, support disease modification, and monitor for safety. The amyloid (A), tau (T), neurodegeneration (N) Research Framework emphasizes brain imaging and CSF measures relevant to disease diagnosis and staging and can be applied to drug development and clinical trials. Demonstration of target engagement in Phase 2 is critical before advancing a treatment candidate to Phase 3. Trials with biomarker outcomes are shorter and smaller than those required to show clinical benefit and are important to understanding the biological impact of an agent and inform go/no-go decisions. Companion diagnostics are required for safe and effective use of treatments and may emerge in AD drug development programs. Complementary biomarkers inform the use of therapies but are not mandatory for use. Biomarkers promise to de-risk AD drug development, attract sponsors to AD research, and accelerate getting new drugs to those with or at risk for AD.
Topics: Alzheimer Disease; Biomarkers; Clinical Trials as Topic; Drug Development; Humans; Neuroimaging
PubMed: 30747416
DOI: 10.1007/978-3-030-05542-4_2 -
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