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Journal of Clinical Epidemiology Dec 2023To inform clinical practice guidelines, randomized controlled trials (RCTs) of the management of pneumonia need to address the outcomes that are most important to...
OBJECTIVES
To inform clinical practice guidelines, randomized controlled trials (RCTs) of the management of pneumonia need to address the outcomes that are most important to patients and health professionals using consistent instruments, to enable results to be compared, contrasted, and combined as appropriate. This systematic review describes the outcomes reported in clinical trials of pneumonia management and the instruments used to measure these outcomes.
STUDY DESIGN AND SETTING
Based on a prospective protocol, we searched MEDLINE/PubMed, Cochrane CENTRAL and clinical trial registries for ongoing or completed clinical trials evaluating pneumonia management in adults in any clinical setting. We grouped reported outcomes thematically and classified them following the COMET Initiative's taxonomy. We describe instruments used for assessing each outcome.
RESULTS
We found 280 eligible RCTs of which 115 (41.1%) enrolled critically ill patients and 165 (58.9%) predominantly noncritically ill patients. We identified 43 distinct outcomes and 108 measurement instruments, excluding nonvalidated scores and questionnaires. Almost all trials reported clinical/physiological outcomes (97.5%). Safety (63.2%), mortality (56.4%), resource use (48.6%) and life impact (11.8%) outcomes were less frequently addressed. The most frequently reported outcomes were treatment success (60.7%), mortality (56.4%) and adverse events (41.1%). There was significant variation in the selection of measurement instruments, with approximately two-thirds used in less than 10 of the 280 RCTs. None of the patient-reported outcomes were used in 10 or more RCTs.
CONCLUSION
This review reveals significant variation in outcomes and measurement instruments reported in clinical trials of pneumonia management. Outcomes that are important to patients and health professionals are often omitted. Our findings support the need for a rigorous core outcome set, such as that being developed by the European Respiratory Society.
Topics: Adult; Humans; Pneumonia; Treatment Outcome; Clinical Trials as Topic
PubMed: 37898460
DOI: 10.1016/j.jclinepi.2023.10.011 -
Endocrinology, Diabetes & Metabolism Apr 2021Developing a novel therapeutic product for the treatment of type 2 diabetes (T2D) is a long, resource-intensive process. Novel biomarkers could potentially aid clinical...
Developing a novel therapeutic product for the treatment of type 2 diabetes (T2D) is a long, resource-intensive process. Novel biomarkers could potentially aid clinical trial design by shortening clinical trials or enabling better prediction of at-risk populations and/or disease progression. Novel clinical trial designs could lead to reduced costs of development and less burden to patients, due to shorter trial duration, and/or less burdensome assessments.
Topics: Biomarkers; Clinical Trials as Topic; Cohort Studies; Cost Savings; Cost of Illness; Diabetes Mellitus, Type 2; Disease Progression; Humans; Monitoring, Physiologic; Patient Reported Outcome Measures; Prediabetic State; Research Design; Time Factors
PubMed: 33855210
DOI: 10.1002/edm2.207 -
JACC. Heart Failure Mar 2021Heart failure with preserved ejection fraction (HFpEF) is an increasingly diagnosed condition whose failure to respond to new drugs effective in heart failure with... (Review)
Review
Heart failure with preserved ejection fraction (HFpEF) is an increasingly diagnosed condition whose failure to respond to new drugs effective in heart failure with reduced ejection fraction is of great concern. HFpEF is an incompletely understood and markedly heterogeneous syndrome, but cardiac amyloidosis is increasingly recognized as one of its various causes. The specific hemodynamic and pathophysiological features of cardiac amyloidosis result in poor tolerance of heart failure medications and in worse outcomes compared with other causes. Until recently, patients considered for HFpEF trials were not routinely screened for cardiac amyloidosis. This review examines how real-world patients with cardiac amyloidosis met inclusion criteria for 8 major HFpEF clinical trials, including the recent PARAGON (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) trial. This review discusses how the presence in the trial populations of a subset of patients with cardiac amyloidosis might contribute to explain the absence of efficacy of medications for HFpEF in trials so far. A multistep screening strategy is suggested in which patients with red flags for cardiac amyloidosis undergo both a light chain assay and technetium-labeled cardiac scintigraphy (technetium-labeled cardiac scintigraphy scan), which, when negative, rule out cardiac amyloidosis. Using this strategy would allow the testing of new medications for HFpEF in populations containing no patients with cardiac amyloidosis, thus potentially increasing the likelihood of showing therapeutic efficacy, and finally making some effective treatment available.
Topics: Amyloidosis; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Heart Failure; Humans; Prospective Studies; Stroke Volume
PubMed: 33549560
DOI: 10.1016/j.jchf.2020.12.005 -
Cancer Letters May 2020Fourier Transform Infrared Spectroscopy (FTIR) has been largely employed by scientific researchers to improve diagnosis and treatment of cancer, using various biofluids... (Review)
Review
Fourier Transform Infrared Spectroscopy (FTIR) has been largely employed by scientific researchers to improve diagnosis and treatment of cancer, using various biofluids and tissues. The technology has proved to be easy to use, rapid and cost-effective for analysis on human blood serum to discriminate between cancer versus healthy control samples. The high sensitivity and specificity achievable during samples classification aided by machine learning algorithms, offers an opportunity to transform cancer referral pathways, as it has been demonstrated in a unique and recent prospective clinical validation study on brain tumours. We herein highlight the importance of early detection in cancer research using FTIR, discussing the technique, the suitability of serum for analysis and previous studies, with special focus on pre-clinical factors and clinical translation requirements and development.
Topics: Algorithms; Blood Specimen Collection; Body Fluids; Brain Neoplasms; Clinical Trials as Topic; Humans; Machine Learning; Neoplasms; Sensitivity and Specificity; Spectroscopy, Fourier Transform Infrared
PubMed: 32112901
DOI: 10.1016/j.canlet.2020.02.020 -
Journal of the National Cancer Institute Mar 2020Historically, the gold standard for evaluation of cancer therapeutics, including medical devices, has been the randomized clinical trial. Although high-quality clinical... (Review)
Review
Historically, the gold standard for evaluation of cancer therapeutics, including medical devices, has been the randomized clinical trial. Although high-quality clinical data are essential for safe and judicious use of therapeutic oncology devices, class II devices require only preclinical data for US Food and Drug Administration approval and are often not rigorously evaluated prior to widespread uptake. Herein, we review master protocol design in medical oncology and its application to therapeutic oncology devices, using examples from radiation oncology. Unique challenges of clinical testing of radiation oncology devices (RODs) include patient and treatment heterogeneity, lack of funding for trials by industry and health-care payers, and operator dependence. To address these challenges, we propose the use of master protocols to optimize regulatory, financial, administrative, quality assurance, and statistical efficiency of trials evaluating RODs. These device-specific master protocols can be extrapolated to other devices and encompass multiple substudies with the same design, statistical considerations, logistics, and infrastructure. As a practical example, we outline our phase I and II master protocol trial of stereotactic magnetic resonance imaging-guided adaptive radiotherapy, which to the best of our knowledge is the first master protocol trial to test a ROD. Development of more efficient clinical trials is needed to promote thorough evaluation of therapeutic oncology devices, including RODs, in a resource-limited environment, allowing more practical and rapid identification of the most valuable advances in our field.
Topics: Clinical Trials as Topic; Equipment and Supplies; Humans; Magnetic Resonance Imaging; Neoplasms; Radiation Oncology; Radiotherapy, Image-Guided; Randomized Controlled Trials as Topic; Stereotaxic Techniques; United States; United States Food and Drug Administration
PubMed: 31504680
DOI: 10.1093/jnci/djz167 -
The Journal of Pain 2020The estimated probability of progressing from phase 3 analgesic clinical trials to regulatory approval is approximately 57%, suggesting that a considerable number of... (Review)
Review
The estimated probability of progressing from phase 3 analgesic clinical trials to regulatory approval is approximately 57%, suggesting that a considerable number of treatments with phase 2 trial results deemed sufficiently successful to progress to phase 3 do not yield positive phase 3 results. Deficiencies in the quality of clinical trial conduct could account for some of this failure. An Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting was convened to identify potential areas for improvement in trial conduct in order to improve assay sensitivity (ie, ability of trials to detect a true treatment effect). We present recommendations based on presentations and discussions at the meeting, literature reviews, and iterative revisions of this article. The recommendations relate to the following areas: 1) study design (ie, to promote feasibility), 2) site selection and staff training, 3) participant selection and training, 4) treatment adherence, 5) data collection, and 6) data and study monitoring. Implementation of these recommendations may improve the quality of clinical trial data and thus the validity and assay sensitivity of clinical trials. Future research regarding the effects of these strategies will help identify the most efficient use of resources for conducting high quality clinical trials. PERSPECTIVE: Every effort should be made to optimize the quality of clinical trial data. This manuscript discusses considerations to improve conduct of pain clinical trials based on research in multiple medical fields and the expert consensus of pain researchers and stakeholders from academia, regulatory agencies, and industry.
Topics: Chronic Pain; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Congresses as Topic; Consensus; Data Accuracy; Humans; Pain Measurement; Patient Selection
PubMed: 31843583
DOI: 10.1016/j.jpain.2019.12.003 -
BMJ Open Nov 2022Cerebral palsy (CP) is the most common childhood physical disability. Accurate diagnosis before 6 months is possible using predictive tools and decision-making skills....
Can web-based implementation interventions improve physician early diagnosis of cerebral palsy? Protocol for a 3-arm parallel superiority randomised controlled trial and cost-consequence analysis comparing adaptive and non-adaptive virtual patient instructional designs with control to evaluate...
INTRODUCTION
Cerebral palsy (CP) is the most common childhood physical disability. Accurate diagnosis before 6 months is possible using predictive tools and decision-making skills. Yet diagnosis is typically made at 12-24 months of age, hindering access to early interventions that improve functional outcomes. Change in practice is required for physicians in key diagnostic behaviours. This study aims to close the identified research-practice gap and increase accurate CP diagnosis before 6 months of age through tailored web-based implementation interventions. This trial will determine whether adaptive e-learning using virtual patients, targeting CP diagnostic behaviours and clinical decision-making skills, effectively changes physician behaviour and practice compared with non-adaptive e-learning instructional design or control.
METHODS AND ANALYSIS
This study is a 3-arm parallel superiority randomised controlled trial of two tailored e-learning interventions developed to expedite physician CP diagnosis. The trial will compare adaptive (arm 1) and non-adaptive (arm 2) instructional designs with waitlist control (arm 3) to evaluate change in physician behaviour, skills and diagnostic practice. A sample size of 275 paediatric physicians enables detection of small magnitude effects (0.2) of primary outcomes between intervention comparators with 90% power (α=0.05), allowing for 30% attrition. Barrier analysis, Delphi survey, Behaviour Change Wheel and learning theory frameworks guided the intervention designs. Adaptive and non-adaptive video and navigation sequences utilising virtual patients and clinical practice guideline content were developed, integrating formative key features assessment targeting clinical decision-making skills relative to CP diagnosis.Physician outcomes will be evaluated based on postintervention key feature examination scores plus preintervention/postintervention behavioural intentions and practice measures. Associations with CP population registers will evaluate real-world diagnostic patient outcomes. Intervention costs will be reported in a cost-consequence analysis from funders' and societal perspectives.
ETHICS AND DISSEMINATION
Ethics approved from The University of Sydney (Project number 2021/386). Results will be disseminated through peer-reviewed journals and scientific conferences.
TRIAL REGISTRATION NUMBER
Australian New Zealand Clinical Trials Registry: ACTRN 12622000184774.
Topics: Humans; Child; Cerebral Palsy; Australia; Early Diagnosis; Physicians; Internet; Randomized Controlled Trials as Topic
PubMed: 36410832
DOI: 10.1136/bmjopen-2022-063558 -
Clinical Pharmacology and Therapeutics Jan 2022Concerns regarding both the limited generalizability and the slow pace of traditional randomized trials have led to calls for greater use of real-world evidence in the... (Review)
Review
Concerns regarding both the limited generalizability and the slow pace of traditional randomized trials have led to calls for greater use of real-world evidence in the evaluation of new treatments or products. Real-world clinical trials or pragmatic trials often differ from traditional clinical trials in the use of open-label or nonblinded treatments delivered by real-world clinicians in community practice settings. Blinding and standardization of treatment may sometimes be necessary for internal validity, but they may also obscure or distort meaningful differences between treatments. When investigators consider whether blinding of clinicians, patients, or assessors is necessary, we suggest they consider several specific questions: Will clinicians, patients, and assessors have expectations or preferences regarding benefits or adverse effects? How might those expectations affect treatment uptake, treatment adherence, or assessment of outcomes? Will expectations differ in the settings where trial results will be applied? How would blinding of treatment reduce biases? How would blinding obscure true differences between treatments? How would procedures necessary for blinding reduce acceptability or increase risk of trial participation? When investigators consider how strictly treatments should be standardized, we suggest they consider several specific questions: How would treatment effectiveness or safety vary according to clinician experience or expertise? What level of experience or expertise is available in potential trial settings and settings where trial results would be applied? Is some level of standardization necessary for valid inference? Considering any special vulnerabilities of the study population, is some level of standardization necessary to assure participant safety?
Topics: Double-Blind Method; Humans; Pragmatic Clinical Trials as Topic; Reference Standards; Research Design; Treatment Outcome
PubMed: 33829639
DOI: 10.1002/cpt.2256 -
Anesthesia and Analgesia Sep 2019Despite over a half-century of recognizing fibrinolytic abnormalities after trauma, we remain in our infancy in understanding the underlying mechanisms causing these... (Review)
Review
Despite over a half-century of recognizing fibrinolytic abnormalities after trauma, we remain in our infancy in understanding the underlying mechanisms causing these changes, resulting in ineffective treatment strategies. With the increased utilization of viscoelastic hemostatic assays (VHAs) to measure fibrinolysis in trauma, more questions than answers are emerging. Although it seems certain that low fibrinolytic activity measured by VHA is common after injury and associated with increased mortality, we now recognize subphenotypes within this population and that specific cohorts arise depending on the specific time from injury when samples are collected. Future studies should focus on these subtleties and distinctions, as hypofibrinolysis, acute shutdown, and persistent shutdown appear to represent distinct, unique clinical phenotypes, with different pathophysiology, and warranting different treatment strategies.
Topics: Blood Coagulation Disorders; Clinical Trials as Topic; Fibrinolysis; Humans; Injury Severity Score; Thrombelastography; Wounds and Injuries
PubMed: 31425218
DOI: 10.1213/ANE.0000000000004234 -
ESMO Open Feb 2023During the European Society for Medical Oncology (ESMO) Congress 2022, outcome data of a great number of clinical trials were presented. For the attending medical... (Review)
Review
BACKGROUND
During the European Society for Medical Oncology (ESMO) Congress 2022, outcome data of a great number of clinical trials were presented. For the attending medical oncologist, it is important to structure these data in a way that facilitates a trade-off between treatment burden and benefit.
MATERIALS AND METHODS
To illustrate this, we carried out a narrative non-systematic review of 12 selected oral presentations with potential impact on future daily practice, focusing on trial methodology, possible study flaws, reported clinical benefit and implementability.
RESULTS
The selected presentations encompassed 10 phase III trials, 1 randomized phase II trial and 1 phase II trial. In 7 out of 12 trials, quality of life and/or patient-reported outcomes had been evaluated. None of the trials, which reported progression-free survival (PFS) data, provided information, which could exclude informative censoring bias. In none of the trials reporting overall survival (OS) data, potential flaws due to undesirable crossover and imbalance between study groups regarding post-progression treatments were addressed. For the 11 reviewed randomized trials, the ESMO-Magnitude of Clinical Benefit Scale (MCBS) grade achieved with the new intervention was calculated based on the presented data. The MCBS grade varied from 1 to 5.
CONCLUSIONS
Our review confirms the high-quality standard of current cancer research and the clinical relevance of the research questions answered. However, during presentation of PFS and/or OS data, factors known to affect PFS and OS analysis should be structurally addressed. In order to keep cancer care affordable and sustainable, it could be considered to include an ESMO-MCBS threshold in the drug appraisal process of regulatory authorities.
Topics: Humans; Clinical Trials, Phase II as Topic; Medical Oncology; Progression-Free Survival; Quality of Life; Randomized Controlled Trials as Topic; Survival Analysis; Neoplasms
PubMed: 36634532
DOI: 10.1016/j.esmoop.2022.100773