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Heart Failure Reviews May 2017Heart failure is a growing cardiovascular disease with significant epidemiological, clinical, and societal implications and represents a high unmet need. Strong efforts... (Review)
Review
Heart failure is a growing cardiovascular disease with significant epidemiological, clinical, and societal implications and represents a high unmet need. Strong efforts are currently underway by academic and industrial researchers to develop novel treatments for heart failure. Biomarkers play an important role in patient selection and monitoring in drug trials and in clinical management. The present review gives an overview of the role of available molecular, imaging, and device-derived digital biomarkers in heart failure drug development and highlights capabilities and limitations of biomarker use in this context.
Topics: Biomarkers; Clinical Trials as Topic; Consensus; Diagnostic Imaging; Disease Management; Heart Failure; Humans; Patient Selection
PubMed: 28332132
DOI: 10.1007/s10741-017-9608-5 -
Drug Metabolism and Pharmacokinetics 2009
Topics: Area Under Curve; Bayes Theorem; Clinical Laboratory Techniques; Clinical Trials as Topic; Humans; Pharmacokinetics; Sampling Studies
PubMed: 19571430
DOI: 10.2133/dmpk.24.199 -
Journal of Hepatology Feb 2018Non-alcoholic steatohepatitis is a disease without a single, specific, diagnostic marker, hence multiple indicators are required to measure therapeutic efficacy.... (Review)
Review
Non-alcoholic steatohepatitis is a disease without a single, specific, diagnostic marker, hence multiple indicators are required to measure therapeutic efficacy. Moreover, drug candidates for non-alcoholic steatohepatitis target many distinct mechanisms that are believed to promote hepatic injury. Therefore, a wide range of endpoints must be reached, sequentially, as required by the drug development process. Some of these endpoints validate the mechanism of action, others are used to anticipate histological efficacy. Histological endpoints are still considered the best predictors of clinical outcome, but they can only be reliably tested in larger, late phase trials. Herein, we will review the rationale and clinical data supporting the use of specific endpoints at different stages of therapeutic trials. We will also discuss the validity and limitations of current phase IIb histological endpoints, particularly a one stage reduction in fibrosis, for their ability to predict progression to cirrhosis, which is the ultimate outcome measure in therapeutic trials.
Topics: Clinical Trials as Topic; Disease Management; Disease Progression; Endpoint Determination; Humans; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Prognosis
PubMed: 29223369
DOI: 10.1016/j.jhep.2017.12.001 -
Trials Mar 2017Clinical research should ultimately improve patient care. For this to be possible, trials must evaluate outcomes that genuinely reflect real-world settings and concerns....
Clinical research should ultimately improve patient care. For this to be possible, trials must evaluate outcomes that genuinely reflect real-world settings and concerns. However, many trials continue to measure and report outcomes that fall short of this clear requirement. We highlight problems with trial outcomes that make evidence difficult or impossible to interpret and that undermine the translation of research into practice and policy. These complex issues include the use of surrogate, composite and subjective endpoints; a failure to take account of patients' perspectives when designing research outcomes; publication and other outcome reporting biases, including the under-reporting of adverse events; the reporting of relative measures at the expense of more informative absolute outcomes; misleading reporting; multiplicity of outcomes; and a lack of core outcome sets. Trial outcomes can be developed with patients in mind, however, and can be reported completely, transparently and competently. Clinicians, patients, researchers and those who pay for health services are entitled to demand reliable evidence demonstrating whether interventions improve patient-relevant clinical outcomes.
Topics: Bias; Clinical Trials as Topic; Data Interpretation, Statistical; Endpoint Determination; Humans; Patient Participation; Publication Bias; Research Design; Treatment Outcome
PubMed: 28288676
DOI: 10.1186/s13063-017-1870-2 -
Clinical Infectious Diseases : An... Jun 2000Bacille Calmette-Guérin (BCG) vaccines are widely used, even though estimates of efficacy have ranged from zero to 80%. BCG is a relatively safe vaccine, but it can... (Review)
Review
Bacille Calmette-Guérin (BCG) vaccines are widely used, even though estimates of efficacy have ranged from zero to 80%. BCG is a relatively safe vaccine, but it can cause disseminated infection, especially in immunocompromised hosts. Thus, the development of a more reliably efficacious and safer vaccine is important to the control of tuberculosis. The testing of any new vaccine in human populations presents a number of ethical challenges that must be addressed. These include (1) the appropriateness of conducting such trials in developing countries; (2) the use of a BCG-vaccinated population as the control group; (3) the provision of tuberculin skin-test screening and preventive therapy to study participants; (4) the involvement of various "communities" in the trial(s); (5) the structure and process of ethical review; (6) establishing an effective method of obtaining informed consent; and (7) the roles and responsibilities of researchers and others in ensuring that trial results are available to the study population after the trial ends.
Topics: BCG Vaccine; Bacterial Vaccines; Clinical Trials as Topic; Developing Countries; Ethics, Medical; Humans; Mycobacterium tuberculosis; Tuberculin Test; Tuberculosis, Pulmonary
PubMed: 10875798
DOI: 10.1086/313872 -
Statistics in Medicine Dec 2019As biomarker information from early-phase trials can be unreliable due to high variability, it is logical to take a prospective two-stage approach when designing a...
As biomarker information from early-phase trials can be unreliable due to high variability, it is logical to take a prospective two-stage approach when designing a late-phase confirmatory trial, ie, refining the target population at the first stage and performing the hypothesis testing at the second stage. The use of a reliable intermediate endpoint at the first stage can further improve the trial efficiency from both time and cost perspectives. Nevertheless, there are needs for expanding such two-stage confirmatory designs to more stages for monitoring efficacy on the refined population. There is limited literature on this matter, particularly for two popular designs with population selection midway, ie, the biomarker enrichment design and the basket design. In this manuscript, we focus on these two popular designs and discuss how to implement the interim efficacy analyses after population refinement while controlling type I error. Power and stopping probability are also explored for the two designs.
Topics: Adaptive Clinical Trials as Topic; Biomarkers; Biostatistics; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Endpoint Determination; Humans; Lung Neoplasms; Models, Statistical; Probability; Progression-Free Survival; Prospective Studies; Survival Analysis
PubMed: 31621949
DOI: 10.1002/sim.8371 -
Medwave Jun 2020Sequential analysis of clinical trials allows researchers a continuous monitoring of emerging data and greater security to avoid subjecting the trial participants to a... (Review)
Review
Sequential analysis of clinical trials allows researchers a continuous monitoring of emerging data and greater security to avoid subjecting the trial participants to a less effective therapy before the inferiority is evident, while controlling the overall error rate. Although it has been widely used since its development, sequential analysis is not problem-free. Among them main issues to be mentioned are the balance between safety and efficacy, overestimation of the effect size of interventions and conditional bias. In this review, we develop different aspects of this methodology and the impact of including early-stopped clinical trials in systematic reviews with meta-analysis.
Topics: Clinical Trials as Topic; Data Analysis; Early Termination of Clinical Trials; Humans; Meta-Analysis as Topic; Research Design; Systematic Reviews as Topic
PubMed: 32603319
DOI: 10.5867/medwave.2020.05.7930 -
Clinical Cancer Research : An Official... May 2021Washout periods and concomitant medication exclusions are common in cancer clinical trial protocols. These exclusion criteria are often applied inconsistently and...
PURPOSE
Washout periods and concomitant medication exclusions are common in cancer clinical trial protocols. These exclusion criteria are often applied inconsistently and without evidence to justify their use. The authors sought to determine how washout period and concomitant medication allowances can be broadened to speed trial enrollment and improve the generalizability of trial data to a larger oncology practice population without compromising the safety of trial participants.
EXPERIMENTAL DESIGN
A multistakeholder working group was convened to define problems associated with excessively long washout periods and exclusion of patients due to concomitant medications. The group performed a literature search and evaluated study data from the Pancreatic Cancer Action Network (PanCAN), Emory University School of Medicine (Atlanta, GA), and the FDA to understand recent approaches to these eligibility criteria. The group convened to develop consensus recommendations for broadened eligibility criteria.
RESULTS
The data analysis found that exclusion criteria based on washout periods and concomitant medications are frequently inconsistent and lack scientific rationale. Scientific rationale for appropriate eligibility criteria are presented in the article; for washout periods, rationale is presented by treatment type.
CONCLUSIONS
Arbitrary or blanket washout and concomitant medication exclusions should be eliminated. Where there is evidence to support them, clinically relevant washout periods and concomitant medication-related eligibility criteria may be included..
Topics: Biomedical Research; Clinical Decision-Making; Clinical Trials as Topic; Disease Management; Humans; Medical Oncology
PubMed: 33563635
DOI: 10.1158/1078-0432.CCR-20-3855 -
Journal of Biopharmaceutical Statistics 2014Growing interest in stratified medicine is leading to increasing importance of subgroup analyses in confirmatory clinical trials. Conventionally, confirmatory clinical... (Review)
Review
Growing interest in stratified medicine is leading to increasing importance of subgroup analyses in confirmatory clinical trials. Conventionally, confirmatory clinical trials either focus on a subgroup identified in advance or assess subgroup effects once the trial is completed. The focus of this article is methodology for adaptive clinical trials that both identify whether a treatment is particularly effective in a predefined subgroup, potentially enabling alteration of recruitment, and assess the effectiveness in the subgroup and/or whole population. Methods for such adaptive trials are described and compared, and the logistical and regulatory issues associated with such approaches are discussed.
Topics: Algorithms; Clinical Trials as Topic; Computer Simulation; Endpoint Determination; Humans; Neoplasms; Organization and Administration; Patient Selection; Research Design; Sample Size; Software; Treatment Outcome
PubMed: 24392984
DOI: 10.1080/10543406.2013.857238 -
Controlled Clinical Trials Jun 1984Concepts used in evaluating the results of diagnostic tests have been applied to clinical trials by several authors and each has reached the same conclusion: positive...
Concepts used in evaluating the results of diagnostic tests have been applied to clinical trials by several authors and each has reached the same conclusion: positive trials are more often falsely positive than would intuitively be expected. This conclusion is, however, based on assumptions that require close examination. First of all, it depends upon equating the power of a clinical trial with the sensitivity of a diagnostic test. Although it is possible to define circumstances in which the two are equivalent, decisions made on the basis of the results of clinical trials usually employ a broader definition of "true positive" than, it is shown, is implied by equating sensitivity with power. Secondly, it is assumed that one can speak meaningfully of the baseline "prevalence" of positive trials. The practical application of this concept can be shown to be extremely difficult. Thus, approaching clinical trials as if they were a type of diagnostic test is superficially appealing. However, this may result in misleading conclusions.
Topics: Clinical Trials as Topic; False Negative Reactions; False Positive Reactions; Humans; Random Allocation
PubMed: 6744884
DOI: 10.1016/0197-2456(84)90117-x