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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 -
Cancer Dec 2018To describe the international landscape of clinical trials in carbon-ion radiotherapy (CIRT), the authors reviewed the current status of 63 ongoing clinical trials... (Review)
Review
To describe the international landscape of clinical trials in carbon-ion radiotherapy (CIRT), the authors reviewed the current status of 63 ongoing clinical trials (median, 47 participants) involving CIRT identified from the US clinicaltrials.gov trial registry and the World Health Organization International Clinical Trials Platform Registry. The objectives were to evaluate the potential for these trials to define the role of this modality in the treatment of specific cancer types and identify the major challenges and opportunities to advance this technology. A significant body of literature suggested the potential for advantageous dose distributions and, in preclinical biologic studies, the enhanced effectiveness for CIRT compared with photons and protons. In addition, clinical evidence from phase I/II trials, although limited, indicated the potential for CIRT to improve cancer outcomes. However, current high-level phase III randomized clinical trial evidence does not exist. Although there has been an increase in the number of trials investigating CIRT since 2010, and the number of countries and sites offering CIRT is slowly growing, this progress has excluded other countries. Several recommendations are proposed to study this modality to accelerate progress in the field, including: 1) increasing the number of multinational randomized clinical trials, 2) leveraging the existing CIRT facilities to launch larger multinational trials directed at common cancers combined with high-level quality assurance; and 3) developing more compact and less expensive next-generation treatment systems integrated with radiobiologic research and preclinical testing.
Topics: Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Heavy Ion Radiotherapy; Humans; Multicenter Studies as Topic; Neoplasms; Progression-Free Survival; Randomized Controlled Trials as Topic; Registries; Sample Size; Treatment Outcome
PubMed: 30307603
DOI: 10.1002/cncr.31662 -
Translational Neurodegeneration May 2024The use of biomarker-led clinical trial designs has been transformative for investigating amyloid-targeting therapies for Alzheimer's disease (AD). The designs have... (Review)
Review
The use of biomarker-led clinical trial designs has been transformative for investigating amyloid-targeting therapies for Alzheimer's disease (AD). The designs have ensured the correct selection of patients on these trials, supported target engagement and have been used to support claims of disease modification and clinical efficacy. Ultimately, this has recently led to approval of disease-modifying, amyloid-targeting therapies for AD; something that should be noted for clinical trials investigating tau-targeting therapies for AD. There is a clear overlap of the purpose of biomarker use at each stage of clinical development between amyloid-targeting and tau-targeting clinical trials. However, there are differences within the potential context of use and interpretation for some biomarkers in particular measurements of amyloid and utility of soluble, phosphorylated tau biomarkers. Given the complexities of tau in health and disease, it is paramount that therapies target disease-relevant tau and, in parallel, appropriate assays of target engagement are developed. Tau positron emission tomography, fluid biomarkers reflecting tau pathology and downstream measures of neurodegeneration will be important both for participant recruitment and for monitoring disease-modification in tau-targeting clinical trials. Bespoke design of biomarker strategies and interpretations for different modalities and tau-based targets should also be considered.
Topics: Alzheimer Disease; Humans; tau Proteins; Biomarkers; Clinical Trials as Topic
PubMed: 38773569
DOI: 10.1186/s40035-024-00417-w -
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 -
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 -
Expert Review of Clinical Pharmacology 2015Major recent advances in the diagnosis, treatment, prevention and screening of cancer have led to improvements in survival and other outcomes for cancer patients. When...
Major recent advances in the diagnosis, treatment, prevention and screening of cancer have led to improvements in survival and other outcomes for cancer patients. When the 198 identified rare cancers are taken in aggregate, rare cancers account for 22% of all cancer diagnoses, higher than any single common cancer. Yet median survival for patients with rare cancer patients remains poor as clinical trial and treatment advancements trail those achieved for common cancer. Overcoming the challenges inherent in the study of rare diseases is critical to achieve improvements in outcomes for patients. Combining a redesign of clinical trial protocols with the new paradigm for the treatment of all cancers, may lead to improvements in survival benefits for rare cancers in line with those achieved in the treatment of more common types.
Topics: Clinical Trials as Topic; Humans; Neoplasms; Rare Diseases; Research Design; Survival Rate
PubMed: 26517109
DOI: 10.1586/17512433.2015.1088382 -
Nature Reviews. Neurology Apr 2016Each of the thousands of rare neurological diseases requires a widely distributed network of centres, investigators and patients, so as to foster multidisciplinary... (Review)
Review
Each of the thousands of rare neurological diseases requires a widely distributed network of centres, investigators and patients, so as to foster multidisciplinary investigations and involve sufficient numbers of patients in the discovery of disease pathogenesis and novel treatment. In this Review, we highlight the value of this collaborative approach in patient-oriented research into rare neurological channelopathies. Two networks, the Consortium for Clinical Investigations of Neurological Channelopathies (CINCH) and the Clinical Research Consortium for Studies of Cerebellar Ataxias (CRC-SCA), provide a link between patients with rare channelopathies and investigators who are studying disease pathogenesis and developing novel treatments. Interactions between patients, researchers and advocacy groups promote shared agendas that benefit patient education and recruitment, research collaboration and funding, and training and mentoring of junior investigators who are attracted to the study of the diseases that provide the focus for the two networks. Here, we discuss how linkage of national and international centres has enabled recruitment of study participants, provided opportunities for novel studies of pathogenesis, and facilitated successful clinical trials.
Topics: Biomedical Research; Channelopathies; Clinical Trials as Topic; Humans; Multicenter Studies as Topic; Patient Selection; Treatment Outcome
PubMed: 26943780
DOI: 10.1038/nrneurol.2016.18 -
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 -
Spinal Cord May 2018This is a focused review article. (Review)
Review
STUDY DESIGN
This is a focused review article.
OBJECTIVES
This review presents important features of clinical outcomes assessments (COAs) in human spinal cord injury research. Considerations for COAs by trial phase and International Classification of Functioning, Disability and Health are presented as well as strengths and recommendations for upper extremity COAs for research. Clinical trial tools and designs to address recruitment challenges are identified.
METHODS
The methods include a summary of topics discussed during a two-day workshop, conceptual discussion of upper extremity COAs and additional focused literature review.
RESULTS
COAs must be appropriate to trial phase and particularly in mid-late-phase trials, should reflect recovery vs. compensation, as well as being clinically meaningful. The impact and extent of upper vs. lower motoneuron disease should be considered, as this may affect how an individual may respond to a given therapeutic. For trials with broad inclusion criteria, the content of COAs should cover all severities and levels of SCI. Specific measures to assess upper extremity function as well as more comprehensive COAs are under development. In addition to appropriate use of COAs, methods to increase recruitment, such as adaptive trial designs and prognostic modeling to prospectively stratify heterogeneous populations into appropriate cohorts should be considered.
CONCLUSIONS
With an increasing number of clinical trials focusing on improving upper extremity function, it is essential to consider a range of factors when choosing a COA.
SPONSORS
Craig H. Neilsen Foundation, Spinal Cord Outcomes Partnership Endeavor.
Topics: Clinical Trials as Topic; Humans; Outcome Assessment, Health Care; Spinal Cord Injuries
PubMed: 29284795
DOI: 10.1038/s41393-017-0015-5 -
Investigative Ophthalmology & Visual... May 2017The purpose of this study was to investigate the use of imaging biomarkers in published clinical trials (CTs) in ophthalmology and its eventual changes during the past... (Review)
Review
PURPOSE
The purpose of this study was to investigate the use of imaging biomarkers in published clinical trials (CTs) in ophthalmology and its eventual changes during the past 10 years.
METHODS
We sampled from published CTs in the fields of cornea, retina, and glaucoma between 2005-2006 and 2015-2016. Data collected included year of publication, phase, subspecialty, location, compliance with Consolidated Standards for Reporting Trials, impact factor, presence and use of imaging biomarkers (diagnostic, prognostic and predictive; primary and secondary surrogate endpoints), and use of centralized reading centers.
RESULTS
We included 652 articles for analysis, equally distributed in three timeframes (2005-2006, 2010-2011, and 2015-2016), mainly reporting phase IV CTs and trials on procedures (42.2% and 35.4%, respectively). Imaging biomarkers were included in 46.3% of the analyzed CTs and their use significantly increased over time (P < 0.05). Optical coherence tomography was the most frequently used device (27.7%), whereas diagnostic biomarkers and secondary surrogate endpoints were the most frequent biomarker types (19.5% and 22.5%, respectively). Early-phase CTs showed an increase in the use of biomarkers for patient selection and stratification over time (P < 0.05), but not in the use of imaging surrogate endpoints (P = 0.90). Only 3 of 59 (5.1%) of phase III CTs included primary surrogate imaging endpoints, whereas secondary surrogate imaging endpoints were present in 50.8% of these trials (P < 0.001). Retinal CTs had the highest prevalence for each type of imaging biomarker (P < 0.001). Reading centers were used in 52 of 302 CTs (17.2%), with no significant time-related increase.
CONCLUSIONS
Imaging biomarkers are increasingly used in published CTs in ophthalmology. Additional efforts, including centralized reading centers, are needed to improve their validation and use, allowing a wider use of these tools as primary surrogate endpoints in phase III CTs.
Topics: Clinical Trials as Topic; Diagnostic Techniques, Ophthalmological; Endpoint Determination; Eye Diseases; Forecasting; Humans; Ophthalmology; Prognosis
PubMed: 28525561
DOI: 10.1167/iovs.17-21790