Publisher: Sage Publications   (Total: 1086 journals)

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Showing 1 - 200 of 1086 Journals sorted alphabetically
AADE in Practice     Hybrid Journal   (Followers: 6)
Abstracts in Anthropology     Full-text available via subscription   (Followers: 24)
Academic Pathology     Open Access   (Followers: 5)
Accounting History     Hybrid Journal   (Followers: 17, SJR: 0.527, CiteScore: 1)
Acta Radiologica     Hybrid Journal   (Followers: 2, SJR: 0.754, CiteScore: 2)
Acta Radiologica Open     Open Access   (Followers: 3)
Acta Sociologica     Hybrid Journal   (Followers: 37, SJR: 0.939, CiteScore: 2)
Action Research     Hybrid Journal   (Followers: 51, SJR: 0.308, CiteScore: 1)
Active Learning in Higher Education     Hybrid Journal   (Followers: 349, SJR: 1.397, CiteScore: 2)
Adaptive Behavior     Hybrid Journal   (Followers: 9, SJR: 0.288, CiteScore: 1)
Administration & Society     Hybrid Journal   (Followers: 14, SJR: 0.675, CiteScore: 1)
Adoption & Fostering     Hybrid Journal   (Followers: 23, SJR: 0.313, CiteScore: 0)
Adsorption Science & Technology     Open Access   (Followers: 8, SJR: 0.258, CiteScore: 1)
Adult Education Quarterly     Hybrid Journal   (Followers: 227, SJR: 0.566, CiteScore: 2)
Adult Learning     Hybrid Journal   (Followers: 43)
Advances in Dental Research     Hybrid Journal   (Followers: 8, SJR: 1.791, CiteScore: 4)
Advances in Developing Human Resources     Hybrid Journal   (Followers: 30, SJR: 0.614, CiteScore: 2)
Advances in Mechanical Engineering     Open Access   (Followers: 137, SJR: 0.272, CiteScore: 1)
Advances in Methods and Practices in Psychological Science     Full-text available via subscription   (Followers: 10)
Advances in Structural Engineering     Full-text available via subscription   (Followers: 46, SJR: 0.599, CiteScore: 1)
Advances in Tumor Virology     Open Access   (Followers: 3, SJR: 0.108, CiteScore: 0)
AERA Open     Open Access   (Followers: 10)
Affilia     Hybrid Journal   (Followers: 5, SJR: 0.496, CiteScore: 1)
Agrarian South : J. of Political Economy     Hybrid Journal   (Followers: 2)
Air, Soil & Water Research     Open Access   (Followers: 13, SJR: 0.214, CiteScore: 1)
Alexandria : The J. of National and Intl. Library and Information Issues     Full-text available via subscription   (Followers: 66)
Allergy & Rhinology     Open Access   (Followers: 4)
AlterNative : An Intl. J. of Indigenous Peoples     Full-text available via subscription   (Followers: 12, SJR: 0.194, CiteScore: 0)
Alternative Law J.     Hybrid Journal   (Followers: 10, SJR: 0.176, CiteScore: 0)
Alternatives : Global, Local, Political     Hybrid Journal   (Followers: 12, SJR: 0.351, CiteScore: 1)
American Behavioral Scientist     Hybrid Journal   (Followers: 23, SJR: 0.982, CiteScore: 2)
American Economist     Hybrid Journal   (Followers: 8)
American Educational Research J.     Hybrid Journal   (Followers: 220, SJR: 2.913, CiteScore: 3)
American J. of Alzheimer's Disease and Other Dementias     Hybrid Journal   (Followers: 18, SJR: 0.67, CiteScore: 2)
American J. of Cosmetic Surgery     Hybrid Journal   (Followers: 6)
American J. of Evaluation     Hybrid Journal   (Followers: 17, SJR: 0.646, CiteScore: 2)
American J. of Health Promotion     Hybrid Journal   (Followers: 34, SJR: 0.807, CiteScore: 1)
American J. of Hospice and Palliative Medicine     Hybrid Journal   (Followers: 43, SJR: 0.65, CiteScore: 1)
American J. of Law & Medicine     Full-text available via subscription   (Followers: 11, SJR: 0.204, CiteScore: 1)
American J. of Lifestyle Medicine     Hybrid Journal   (Followers: 6, SJR: 0.431, CiteScore: 1)
American J. of Medical Quality     Hybrid Journal   (Followers: 11, SJR: 0.777, CiteScore: 1)
American J. of Men's Health     Open Access   (Followers: 8, SJR: 0.595, CiteScore: 2)
American J. of Rhinology and Allergy     Hybrid Journal   (Followers: 9, SJR: 0.972, CiteScore: 2)
American J. of Sports Medicine     Hybrid Journal   (Followers: 207, SJR: 3.949, CiteScore: 6)
American Politics Research     Hybrid Journal   (Followers: 33, SJR: 1.313, CiteScore: 1)
American Review of Public Administration     Hybrid Journal   (Followers: 20, SJR: 2.062, CiteScore: 2)
American Sociological Review     Hybrid Journal   (Followers: 316, SJR: 6.333, CiteScore: 6)
American String Teacher     Full-text available via subscription   (Followers: 2)
Analytical Chemistry Insights     Open Access   (Followers: 25, SJR: 0.224, CiteScore: 1)
Angiology     Hybrid Journal   (Followers: 3, SJR: 0.849, CiteScore: 2)
Animation     Hybrid Journal   (Followers: 14, SJR: 0.197, CiteScore: 0)
Annals of Clinical Biochemistry     Hybrid Journal   (Followers: 10, SJR: 0.634, CiteScore: 1)
Annals of Otology, Rhinology & Laryngology     Hybrid Journal   (Followers: 17, SJR: 0.807, CiteScore: 1)
Annals of Pharmacotherapy     Hybrid Journal   (Followers: 54, SJR: 1.096, CiteScore: 2)
Annals of the American Academy of Political and Social Science     Hybrid Journal   (Followers: 46, SJR: 1.225, CiteScore: 3)
Annals of the ICRP     Hybrid Journal   (Followers: 4, SJR: 0.548, CiteScore: 1)
Anthropocene Review     Hybrid Journal   (Followers: 9, SJR: 3.341, CiteScore: 7)
Anthropological Theory     Hybrid Journal   (Followers: 42, SJR: 0.739, CiteScore: 1)
Antitrust Bulletin     Hybrid Journal   (Followers: 11)
Antiviral Chemistry and Chemotherapy     Open Access   (Followers: 2, SJR: 0.635, CiteScore: 2)
Antyajaa : Indian J. of Women and Social Change     Hybrid Journal  
Applied Biosafety     Hybrid Journal   (Followers: 1, SJR: 0.131, CiteScore: 0)
Applied Psychological Measurement     Hybrid Journal   (Followers: 23, SJR: 1.17, CiteScore: 1)
Applied Spectroscopy     Full-text available via subscription   (Followers: 26, SJR: 0.489, CiteScore: 2)
Armed Forces & Society     Hybrid Journal   (Followers: 21, SJR: 0.29, CiteScore: 1)
Arts and Humanities in Higher Education     Hybrid Journal   (Followers: 42, SJR: 0.305, CiteScore: 1)
Asia Pacific Media Educator     Hybrid Journal   (Followers: 1, SJR: 0.23, CiteScore: 0)
Asia-Pacific J. of Management Research and Innovation     Full-text available via subscription   (Followers: 3)
Asia-Pacific J. of Public Health     Hybrid Journal   (Followers: 11, SJR: 0.558, CiteScore: 1)
Asian and Pacific Migration J.     Full-text available via subscription   (Followers: 108, SJR: 0.324, CiteScore: 1)
Asian Cardiovascular and Thoracic Annals     Hybrid Journal   (Followers: 2, SJR: 0.305, CiteScore: 0)
Asian J. of Comparative Politics     Hybrid Journal   (Followers: 5)
Asian J. of Legal Education     Full-text available via subscription   (Followers: 4)
Asian J. of Management Cases     Hybrid Journal   (Followers: 6, SJR: 0.101, CiteScore: 0)
ASN Neuro     Open Access   (Followers: 2, SJR: 1.534, CiteScore: 3)
Assessment     Hybrid Journal   (Followers: 17, SJR: 1.519, CiteScore: 3)
Assessment for Effective Intervention     Hybrid Journal   (Followers: 16, SJR: 0.578, CiteScore: 1)
Australasian Psychiatry     Hybrid Journal   (Followers: 18, SJR: 0.433, CiteScore: 1)
Australian & New Zealand J. of Psychiatry     Hybrid Journal   (Followers: 29, SJR: 1.801, CiteScore: 2)
Australian and New Zealand J. of Criminology     Hybrid Journal   (Followers: 526, SJR: 0.612, CiteScore: 1)
Australian J. of Career Development     Hybrid Journal   (Followers: 4)
Australian J. of Education     Hybrid Journal   (Followers: 42, SJR: 0.403, CiteScore: 1)
Australian J. of Management     Hybrid Journal   (Followers: 13, SJR: 0.497, CiteScore: 1)
Autism     Hybrid Journal   (Followers: 328, SJR: 1.739, CiteScore: 4)
Autism & Developmental Language Impairments     Open Access   (Followers: 11)
Behavior Modification     Hybrid Journal   (Followers: 12, SJR: 0.877, CiteScore: 2)
Behavioral and Cognitive Neuroscience Reviews     Hybrid Journal   (Followers: 26)
Bible Translator     Hybrid Journal   (Followers: 13)
Biblical Theology Bulletin     Hybrid Journal   (Followers: 18, SJR: 0.184, CiteScore: 0)
Big Data & Society     Open Access   (Followers: 50)
Biochemistry Insights     Open Access   (Followers: 7)
Bioinformatics and Biology Insights     Open Access   (Followers: 12, SJR: 1.141, CiteScore: 2)
Biological Research for Nursing     Hybrid Journal   (Followers: 7, SJR: 0.685, CiteScore: 2)
Biomarker Insights     Open Access   (Followers: 1, SJR: 0.81, CiteScore: 2)
Biomarkers in Cancer     Open Access   (Followers: 10)
Biomedical Engineering and Computational Biology     Open Access   (Followers: 13)
Biomedical Informatics Insights     Open Access   (Followers: 8)
Bioscope: South Asian Screen Studies     Hybrid Journal   (Followers: 3, SJR: 0.235, CiteScore: 0)
BMS: Bulletin of Sociological Methodology/Bulletin de Méthodologie Sociologique     Hybrid Journal   (Followers: 4, SJR: 0.226, CiteScore: 0)
Body & Society     Hybrid Journal   (Followers: 27, SJR: 1.531, CiteScore: 3)
Bone and Tissue Regeneration Insights     Open Access   (Followers: 2)
Brain and Neuroscience Advances     Open Access  
Breast Cancer : Basic and Clinical Research     Open Access   (Followers: 11, SJR: 0.823, CiteScore: 2)
British J. of Music Therapy     Hybrid Journal   (Followers: 8)
British J. of Occupational Therapy     Hybrid Journal   (Followers: 203, SJR: 0.323, CiteScore: 1)
British J. of Pain     Hybrid Journal   (Followers: 26, SJR: 0.579, CiteScore: 2)
British J. of Politics and Intl. Relations     Hybrid Journal   (Followers: 32, SJR: 0.91, CiteScore: 2)
British J. of Visual Impairment     Hybrid Journal   (Followers: 13, SJR: 0.337, CiteScore: 1)
British J.ism Review     Hybrid Journal   (Followers: 18)
BRQ Business Review Quarterly     Open Access   (Followers: 1)
Building Acoustics     Hybrid Journal   (Followers: 4, SJR: 0.215, CiteScore: 1)
Building Services Engineering Research & Technology     Hybrid Journal   (Followers: 3, SJR: 0.583, CiteScore: 1)
Bulletin of Science, Technology & Society     Hybrid Journal   (Followers: 8)
Business & Society     Hybrid Journal   (Followers: 12)
Business and Professional Communication Quarterly     Hybrid Journal   (Followers: 8, SJR: 0.348, CiteScore: 1)
Business Information Review     Hybrid Journal   (Followers: 16, SJR: 0.279, CiteScore: 0)
Business Perspectives and Research     Hybrid Journal   (Followers: 3)
Cahiers Élisabéthains     Hybrid Journal   (Followers: 1, SJR: 0.111, CiteScore: 0)
Calcutta Statistical Association Bulletin     Full-text available via subscription   (Followers: 1)
California Management Review     Hybrid Journal   (Followers: 31, SJR: 2.209, CiteScore: 4)
Canadian J. of Kidney Health and Disease     Open Access   (Followers: 6, SJR: 1.007, CiteScore: 2)
Canadian J. of Nursing Research (CJNR)     Hybrid Journal   (Followers: 13)
Canadian J. of Occupational Therapy     Hybrid Journal   (Followers: 140, SJR: 0.626, CiteScore: 1)
Canadian J. of Psychiatry     Hybrid Journal   (Followers: 28, SJR: 1.769, CiteScore: 3)
Canadian J. of School Psychology     Hybrid Journal   (Followers: 11, SJR: 0.266, CiteScore: 1)
Canadian Pharmacists J. / Revue des Pharmaciens du Canada     Hybrid Journal   (Followers: 3, SJR: 0.536, CiteScore: 1)
Cancer Control     Open Access   (Followers: 1)
Cancer Growth and Metastasis     Open Access   (Followers: 1)
Cancer Informatics     Open Access   (Followers: 4, SJR: 0.64, CiteScore: 1)
Capital and Class     Hybrid Journal   (Followers: 7, SJR: 0.282, CiteScore: 1)
Cardiac Cath Lab Director     Full-text available via subscription  
Cardiovascular and Thoracic Open     Open Access  
Career Development and Transition for Exceptional Individuals     Hybrid Journal   (Followers: 9, SJR: 0.44, CiteScore: 1)
Cartilage     Hybrid Journal   (Followers: 5, SJR: 0.889, CiteScore: 3)
Cell and Tissue Transplantation and Therapy     Open Access   (Followers: 2)
Cell Transplantation     Open Access   (Followers: 4, SJR: 1.023, CiteScore: 3)
Cephalalgia     Hybrid Journal   (Followers: 7, SJR: 1.581, CiteScore: 3)
Child Language Teaching and Therapy     Hybrid Journal   (Followers: 35, SJR: 0.501, CiteScore: 1)
Child Maltreatment     Hybrid Journal   (Followers: 9, SJR: 1.22, CiteScore: 3)
Child Neurology Open     Open Access   (Followers: 6)
Childhood     Hybrid Journal   (Followers: 19, SJR: 0.894, CiteScore: 2)
Childhood Obesity and Nutrition     Open Access   (Followers: 11)
China Information     Hybrid Journal   (Followers: 7, SJR: 0.767, CiteScore: 2)
China Report     Hybrid Journal   (Followers: 10, SJR: 0.221, CiteScore: 0)
Chinese J. of Sociology     Full-text available via subscription   (Followers: 4)
Chronic Illness     Hybrid Journal   (Followers: 6, SJR: 0.672, CiteScore: 2)
Chronic Respiratory Disease     Hybrid Journal   (Followers: 9, SJR: 0.808, CiteScore: 2)
Chronic Stress     Open Access  
Citizenship, Social and Economics Education     Full-text available via subscription   (Followers: 6, SJR: 0.145, CiteScore: 0)
Cleft Palate-Craniofacial J.     Hybrid Journal   (Followers: 8, SJR: 0.757, CiteScore: 1)
Clin-Alert     Hybrid Journal   (Followers: 1)
Clinical and Applied Thrombosis/Hemostasis     Open Access   (Followers: 16, SJR: 0.49, CiteScore: 1)
Clinical and Translational Neuroscience     Open Access  
Clinical Case Studies     Hybrid Journal   (Followers: 3, SJR: 0.364, CiteScore: 1)
Clinical Child Psychology and Psychiatry     Hybrid Journal   (Followers: 45, SJR: 0.73, CiteScore: 2)
Clinical EEG and Neuroscience     Hybrid Journal   (Followers: 6, SJR: 0.552, CiteScore: 2)
Clinical Ethics     Hybrid Journal   (Followers: 10, SJR: 0.296, CiteScore: 1)
Clinical Medicine Insights : Arthritis and Musculoskeletal Disorders     Open Access   (Followers: 3, SJR: 0.537, CiteScore: 2)
Clinical Medicine Insights : Blood Disorders     Open Access   (SJR: 0.314, CiteScore: 2)
Clinical Medicine Insights : Cardiology     Open Access   (Followers: 6, SJR: 0.686, CiteScore: 2)
Clinical Medicine Insights : Case Reports     Open Access   (Followers: 1, SJR: 0.283, CiteScore: 1)
Clinical Medicine Insights : Circulatory, Respiratory and Pulmonary Medicine     Open Access   (Followers: 3, SJR: 0.425, CiteScore: 2)
Clinical Medicine Insights : Ear, Nose and Throat     Open Access   (Followers: 1)
Clinical Medicine Insights : Endocrinology and Diabetes     Open Access   (Followers: 33, SJR: 0.63, CiteScore: 2)
Clinical Medicine Insights : Oncology     Open Access   (Followers: 3, SJR: 1.129, CiteScore: 3)
Clinical Medicine Insights : Pediatrics     Open Access   (Followers: 3)
Clinical Medicine Insights : Psychiatry     Open Access   (Followers: 10)
Clinical Medicine Insights : Reproductive Health     Open Access   (Followers: 2, SJR: 0.776, CiteScore: 0)
Clinical Medicine Insights : Therapeutics     Open Access   (Followers: 1, SJR: 0.172, CiteScore: 0)
Clinical Medicine Insights : Trauma and Intensive Medicine     Open Access   (Followers: 4)
Clinical Medicine Insights : Urology     Open Access   (Followers: 2)
Clinical Medicine Insights : Women's Health     Open Access   (Followers: 4)
Clinical Nursing Research     Hybrid Journal   (Followers: 30, SJR: 0.471, CiteScore: 1)
Clinical Pathology     Open Access   (Followers: 3)
Clinical Pediatrics     Hybrid Journal   (Followers: 22, SJR: 0.487, CiteScore: 1)
Clinical Psychological Science     Hybrid Journal   (Followers: 11, SJR: 3.281, CiteScore: 5)
Clinical Rehabilitation     Hybrid Journal   (Followers: 75, SJR: 1.322, CiteScore: 3)
Clinical Risk     Hybrid Journal   (Followers: 5, SJR: 0.133, CiteScore: 0)
Clinical Trials     Hybrid Journal   (Followers: 21, SJR: 2.399, CiteScore: 2)
Clothing and Textiles Research J.     Hybrid Journal   (Followers: 25, SJR: 0.36, CiteScore: 1)
Common Law World Review     Full-text available via subscription   (Followers: 18)
Communication & Sport     Hybrid Journal   (Followers: 8, SJR: 0.385, CiteScore: 1)
Communication and the Public     Hybrid Journal   (Followers: 1)
Communication Disorders Quarterly     Hybrid Journal   (Followers: 17, SJR: 0.458, CiteScore: 1)
Communication Research     Hybrid Journal   (Followers: 20, SJR: 2.171, CiteScore: 3)
Community College Review     Hybrid Journal   (Followers: 9, SJR: 1.451, CiteScore: 1)
Comparative Political Studies     Hybrid Journal   (Followers: 248, SJR: 3.772, CiteScore: 3)
Compensation & Benefits Review     Hybrid Journal   (Followers: 8)
Competition & Change     Hybrid Journal   (Followers: 11, SJR: 0.843, CiteScore: 2)
Competition and Regulation in Network Industries     Full-text available via subscription   (Followers: 8, SJR: 0.143, CiteScore: 0)
Concurrent Engineering     Hybrid Journal   (Followers: 3, SJR: 0.642, CiteScore: 2)
Conflict Management and Peace Science     Hybrid Journal   (Followers: 38, SJR: 2.441, CiteScore: 1)
Contemporary Drug Problems     Full-text available via subscription   (Followers: 3, SJR: 0.609, CiteScore: 2)
Contemporary Education Dialogue     Hybrid Journal   (Followers: 5, SJR: 0.102, CiteScore: 0)
Contemporary Issues in Early Childhood     Full-text available via subscription   (Followers: 7, SJR: 0.766, CiteScore: 1)
Contemporary Review of the Middle East     Full-text available via subscription   (Followers: 12)
Contemporary Sociology : A J. of Reviews     Full-text available via subscription   (Followers: 34, SJR: 0.195, CiteScore: 0)
Contemporary Voice of Dalit     Full-text available via subscription   (Followers: 1)
Contexts     Hybrid Journal   (Followers: 6)
Contributions to Indian Sociology     Hybrid Journal   (Followers: 4, SJR: 0.376, CiteScore: 0)

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Similar Journals
Journal Cover
Clinical Trials
Journal Prestige (SJR): 2.399
Citation Impact (citeScore): 2
Number of Followers: 21  
Hybrid Journal Hybrid journal   * Containing 1 Open Access Open Access article(s) in this issue *
ISSN (Print) 1740-7745 - ISSN (Online) 1740-7753
Published by Sage Publications Homepage  [1086 journals]
  • 2019 Peer Reviewers
    • Pages: 113 - 114
      Abstract: Clinical Trials, Volume 17, Issue 1, Page 113-114, February 2020.

      Citation: Clinical Trials
      PubDate: 2020-01-29T05:41:13Z
      DOI: 10.1177/1740774520903571
      Issue No: Vol. 17, No. 1 (2020)
  • Commentary on Hsiue et al: Cost savings and data limitations of new cancer
           drug studies
    • Authors: Peter B Bach
      Abstract: Clinical Trials, Ahead of Print.

      Citation: Clinical Trials
      PubDate: 2020-02-19T09:28:42Z
      DOI: 10.1177/1740774520907668
  • The costs of cancer drugs
    • Authors: Colin B Begg
      Abstract: Clinical Trials, Ahead of Print.

      Citation: Clinical Trials
      PubDate: 2020-02-19T09:27:52Z
      DOI: 10.1177/1740774520907662
  • Designing clinical trials with (restricted) mean survival time endpoint:
           Practical considerations
    • Authors: Anne Eaton, Terry Therneau, Jennifer Le-Rademacher
      Abstract: Clinical Trials, Ahead of Print.
      Background/aims:The difference in mean survival time, which quantifies the treatment effect in terms most meaningful to patients and retains its interpretability regardless of the shape of the survival distribution or the proportionality of the treatment effect, is an alternative endpoint that could be used more often as the primary endpoint to design clinical trials. The underuse of this endpoint is due to investigators’ lack of familiarity with the test comparing the mean survival times and the lack of tools to facilitate trial design with this endpoint. The aim of this article is to provide investigators with insights and software to design trials with restricted mean survival time as the primary endpoint.Methods:A closed-form formula for the asymptotic power of the test of restricted mean survival time difference is presented. The effects of design parameters on power were evaluated for the mean survival time test and log-rank test. An R package which calculates the power or the sample size for user-specified parameter values and provides power plots for each design parameter is provided. The R package also calculates the probability that the restricted mean survival time is estimable for user-defined trial designs.Results:Under proportional hazards and late differences in survival, the power of the mean survival time test can approach that of the log-rank test if the restriction time is late. Under early differences, the power of the restricted mean survival time test is higher than that of the log-rank test. Duration of accrual and follow-up have little influence on the power of the restricted mean survival time test. The choice of restriction time, on the other hand, has a large impact on power. Because the power depends on the interplay among the design factors, plotting the relationship between each design parameter and power allows the users to select the designs most appropriate for their trial. When modification is necessary to ensure the difference in restricted mean survival time is estimable, the three available modifications all perform adequately in the scenarios studied.Conclusion:The restricted mean survival time is a survival endpoint that is meaningful to investigators and to patients and at the same time requires less restrictive assumptions. The biggest challenge with this endpoint is selection of the restriction time. We recommend selecting a restriction time that is clinically relevant to the disease and the clinical setting of the trial of interest. The practical considerations and the R package provided in this work are readily available tools that researchers can use to design trials with restricted mean survival time as the primary endpoint.
      Citation: Clinical Trials
      PubDate: 2020-02-17T09:02:53Z
      DOI: 10.1177/1740774520905563
  • Regulatory-grade clinical trial design using real-world data
    • Authors: Mark S Levenson
      Abstract: Clinical Trials, Ahead of Print.
      Real-world data and evidence provide the potential to address the effectiveness and safety of drugs. The U.S. Food & Drug Administration has initiated a program to evaluate the potential use of real-world evidence for regulatory uses. Whether a study is designed for regulatory purposes or for other purposes, existing regulation and guidance provide a reference for high-quality studies. Clarifying the study objectives and the role of real-world data in the study are important considerations. Robustness and transparency of the analysis allow for greater understanding and acceptance of the study results.
      Citation: Clinical Trials
      PubDate: 2020-02-17T08:58:08Z
      DOI: 10.1177/1740774520905576
  • A review of available software for adaptive clinical trial design
    • Authors: Michael John Grayling, Graham Mark Wheeler
      Abstract: Clinical Trials, Ahead of Print.
      Background/aims:The increasing cost of the drug development process has seen interest in the use of adaptive trial designs grow substantially. Accordingly, much research has been conducted to identify barriers to increasing the use of adaptive designs in practice. Several articles have argued that the availability of user-friendly software will be an important step in making adaptive designs easier to implement. Therefore, we present a review of the current state of software availability for adaptive trial design.Methods:We review articles from 31 journals published in 2013–2017 that relate to methodology for adaptive trials to assess how often code and software for implementing novel adaptive designs is made available at the time of publication. We contrast our findings against these journals’ policies on code distribution. We also search popular code repositories, such as Comprehensive R Archive Network and GitHub, to identify further existing user-contributed software for adaptive designs. From this, we are able to direct interested parties toward solutions for their problem of interest.Results:Only 30% of included articles made their code available in some form. In many instances, articles published in journals that had mandatory requirements on code provision still did not make code available. There are several areas in which available software is currently limited or saturated. In particular, many packages are available to address group sequential design, but comparatively little code is present in the public domain to determine biomarker-guided adaptive designs.Conclusions:There is much room for improvement in the provision of software alongside adaptive design publications. In addition, while progress has been made, well-established software for various types of trial adaptation remains sparsely available.
      Citation: Clinical Trials
      PubDate: 2020-02-17T08:57:13Z
      DOI: 10.1177/1740774520906398
  • Adding new experimental arms to randomised clinical trials: Impact on
           error rates
    • Authors: Babak Choodari-Oskooei, Daniel J Bratton, Melissa R Gannon, Angela M Meade, Matthew R Sydes, Mahesh KB Parmar
      Abstract: Clinical Trials, Ahead of Print.
      Background:Experimental treatments pass through various stages of development. If a treatment passes through early-phase experiments, the investigators may want to assess it in a late-phase randomised controlled trial. An efficient way to do this is adding it as a new research arm to an ongoing trial while the existing research arms continue, a so-called multi-arm platform trial. The familywise type I error rate is often a key quantity of interest in any multi-arm platform trial. We set out to clarify how it should be calculated when new arms are added to a trial some time after it has started.Methods:We show how the familywise type I error rate, any-pair and all-pairs powers can be calculated when a new arm is added to a platform trial. We extend the Dunnett probability and derive analytical formulae for the correlation between the test statistics of the existing pairwise comparison and that of the newly added arm. We also verify our analytical derivation via simulations.Results:Our results indicate that the familywise type I error rate depends on the shared control arm information (i.e. individuals in continuous and binary outcomes and primary outcome events in time-to-event outcomes) from the common control arm patients and the allocation ratio. The familywise type I error rate is driven more by the number of pairwise comparisons and the corresponding (pairwise) type I error rates than by the timing of the addition of the new arms. The familywise type I error rate can be estimated using Šidák’s correction if the correlation between the test statistics of pairwise comparisons is less than 0.30.Conclusions:The findings we present in this article can be used to design trials with pre-planned deferred arms or to add new pairwise comparisons within an ongoing platform trial where control of the pairwise error rate or familywise type I error rate (for a subset of pairwise comparisons) is required.
      Citation: Clinical Trials
      PubDate: 2020-02-17T08:55:49Z
      DOI: 10.1177/1740774520904346
  • Economic vulnerability and payment for research participation
    • Authors: Luke Gelinas, Sarah A White, Barbara E Bierer
      Abstract: Clinical Trials, Ahead of Print.
      There has been significant analysis of the ethical and regulatory issues involved with paying research participants, but less attention has been focused specifically on paying economically vulnerable individuals and the unique challenges it may present. This is important, as individuals of lower socio-economic standing are present in all disease groups and study populations. Moreover, clinical research is often conducted in economically under-developed locales, such as lower- or middle-income countries as well as impoverished locales of otherwise wealthy nations (such as, for example, rural Appalachia in the United States). Is it ethical to offer payment in such contexts' What are the ethical considerations relevant for determining payment rates and practices to individuals who are economically vulnerable' We offer an analysis of these issues, focusing on four unique areas of concern: (1) whether the risk of undue influence is greater for economically vulnerable individuals than for wealthier ones; (2) whether payment unacceptably raises the risk of ‘unjust influence’ or disproportionate representation of poor people in clinical research; (3) the positive reasons in favor of paying economically vulnerable people that stem from the ethical value of fairness; and (4) appropriate compensation rates for economically vulnerable populations. Our analysis supports the position that payment to economically vulnerable populations is ethically justified and indeed desirable when certain conditions are met.
      Citation: Clinical Trials
      PubDate: 2020-02-17T08:54:33Z
      DOI: 10.1177/1740774520905596
  • Compliance of French academic clinical trials with the Clinical Trial
           Facilitation and Coordination Group recommendations on contraception and
           pregnancy testing requirements
    • Authors: Sabrina Crepin, Anne Chiffoleau, Marylaure Gavard, Pascale Olivier-Abbal, Caroline Roussillon, Sophie Ruault, Charlotte Muller, Laure Peyro-Saint-Paul, Thavarak Ouk, Marie-Paule Franceschi, Catherine Mouchel, Sophie Duranton, Nadine Petitpain, Anne Coubret-Dumas
      Abstract: Clinical Trials, Ahead of Print.
      Background/AimsThe Clinical Trials Coordination and Facilitation Group has issued recommendations on contraception and pregnancy testing to help sponsors meet regulatory expectations and harmonize practices to limit embryofetal risks in clinical trials. Our objective was to assess the compliance of French academic clinical trials with these recommendations and to describe the mitigation measures required by sponsors in their trials.MethodsA cross-sectional study was performed on the French academic drug trials authorized by the national competent authority between January 2015 and June 2018. We included trials which tested systemic administration of drugs and enrolled men or women of childbearing potential.ResultsData from 97 trials included were compiled. One-third of the trials (23.8%–43.3%, 95% confidence interval) complied with the Clinical Trial Facilitation and Coordination Group recommendations. No improvement over time or according to embryofetotoxic status or drug duration exposure was found. Contraception was required in 56.7% of trials and was more often required in case of potentially embryofetotoxic drugs (68.5% vs 41.9%, p = 0.013) or exposure over 1 month (71.7% vs 43.8%, p = 0.006). Pregnancy testing at inclusion was required in 59.1% of trials and additional testing in 17.2%. Pregnancy testing at inclusion was more often required in trials with drug exposure above 1 month (67.4% vs 45.8%, p = 0.035).ConclusionFrench academic sponsors barely met the recommendations on contraception and pregnancy testing potentially leading to potential embryofetal risks in case of pregnancy. They need to implement these recommendations quickly.
      Citation: Clinical Trials
      PubDate: 2020-02-06T11:51:53Z
      DOI: 10.1177/1740774520903720
  • Information growth for sequential monitoring of clinical trials with a
           stepped wedge cluster randomized design and unknown intracluster
    • Authors: Siobhan P Brown, Abigail B Shoben
      Abstract: Clinical Trials, Ahead of Print.
      Background/aimsIn a stepped wedge study design, study clusters usually start with the baseline treatment and then cross over to the intervention at randomly determined times. Such designs are useful when the intervention must be delivered at the cluster level and are becoming increasingly common in practice. In these trials, if the outcome is death or serious morbidity, one may have an ethical imperative to monitor the trial and stop before maximum enrollment if the new therapy is proven to be beneficial. In addition, because formal monitoring allows for the stoppage of trials when a significant benefit for new therapy has been ruled out, their use can make a research program more efficient. However, use of the stepped wedge cluster randomized study design complicates the implementation of standard group sequential monitoring methods. Both the correlation of observations introduced by the clustered randomization and the timing of crossover from one treatment to the other impact the rate of information growth, an important component of an interim analysis.MethodsWe simulated cross-sectional stepped wedge study data in order to evaluate the impact of sequential monitoring on the Type I error and power when the true intracluster correlation is unknown. We studied the impact of varying intracluster correlations, treatment effects, methods of estimating the information growth, and boundary shapes.ResultsWhile misspecified information growth can impact both the Type I error and power of a study in some settings, we observed little inflation of the Type I error and only moderate reductions in power across a range of misspecified information growth patterns in our simulations.ConclusionTaking the study design into account and using either an estimate of the intracluster correlation from the ongoing study or other data in the same clusters should allow for easy implementation of group sequential methods in future stepped wedge designs.
      Citation: Clinical Trials
      PubDate: 2020-02-06T11:51:35Z
      DOI: 10.1177/1740774520901488
  • Discordant attitudes and beliefs about cancer clinical trial participation
           between physicians, research staff, and cancer patients
    • Authors: Grace C Hillyer, Melissa Beauchemin, Dawn L Hershman, Moshe Kelsen, Frances L Brogan, Rossy Sandoval, Karen M Schmitt, Andria Reyes, Mary Beth Terry, Andrew B Lassman, Gary K Schwartz
      Abstract: Clinical Trials, Ahead of Print.
      Background/AimsEssential to bringing innovative cancer treatments to patients is voluntary participation in clinical trials but approximately 8% of American cancer patients are enrolled onto a trial. We used a domain-oriented framework to assess barriers to cancer clinical trial enrollment.MethodsPhysicians (MD, DO, fellows, residents) and research staff (physician assistants, nurse practitioners, staff and research nurses, clinical assistants, and program coordinators) involved in clinical research at a comprehensive cancer center completed an online survey in 2017; adult cancer patients not currently enrolled in a trial were interviewed in 2018. To inform the construct of our physician/staff and patient surveys and to assess barriers to clinical trial enrollment, we first conducted in-depth interviews among 14 key informants representing medical, hematologic, gynecologic, neurologic, radiation oncology, as well as members of the clinical research team (one clinical research coordinator, one research nurse practitioner). Perceived structural, provider- and patient-level barriers to clinical trial enrollment were assessed. Differences in perceptions, attitudes, and beliefs toward clinical trial enrollment between (1) physicians and staff, (2) patients by ethnicity, and (3) physicians/staff and patients were examined.ResultsIn total, 120 physicians/staff involved in clinical research (39.2% physicians, 60.8% staff; 48.0% overall response rate) and 150 cancer patients completed surveys. Nearly three-quarters of physician/staff respondents reported difficulty in keeping track of the eligibility criteria for open studies but was more often cited by physicians than staff (84.4% vs 64.3%, p = 0.02). Physicians more often reported lack of time to present clinical trial information than did staff(p 
      Citation: Clinical Trials
      PubDate: 2020-02-03T12:07:45Z
      DOI: 10.1177/1740774520901514
  • Broadening community engagement in clinical research: Designing and
           assessing a pilot crowdsourcing project to obtain community feedback on an
           HIV clinical trial
    • Authors: Suzanne Day, Allison Mathews, Meredith Blumberg, Thi Vu, Stuart Rennie, Joseph D Tucker
      Abstract: Clinical Trials, Ahead of Print.
      Background/AimsCommunity engagement is widely acknowledged as an important step in clinical trials. One underexplored method for engagement in clinical trials is crowdsourcing. Crowdsourcing involves having community members attempt to solve a problem and then publicly sharing innovative solutions. We designed and conducted a pilot using a crowdsourcing approach to obtain community feedback on an HIV clinical trial, called the Acceptability of Combined Community Engagement Strategies Study. In this work, we describe and assess the Acceptability of Combined Community Engagement Strategies Study’s crowdsourcing activities in order to examine the opportunities of crowdsourcing as a clinical trial community engagement strategy.MethodsThe crowdsourcing engagement activities involved in the Acceptability of Combined Community Engagement Strategies Study were conducted in the context of a phase 1 HIV antibody trial ( identifier: NCT03803605). We designed a series of crowdsourcing activities to collect feedback on three aspects of this clinical trial: the informed consent process, the experience of participating in the trial, and fairness/reciprocity in HIV clinical trials. All crowdsourcing activities were open to members of the general public 18 years of age or older, and participation was solicited from the local community. A group discussion was held with representatives of the clinical trial team to obtain feedback on the utility of crowdsourcing as a community engagement strategy for informing future clinical trials.ResultsCrowdsourcing activities made use of innovative tools and a combination of in-person and online participation opportunities to engage community members in the clinical trial feedback process. Community feedback on informed consent was collected by transforming the clinical trial’s informed consent form into a series of interactive video modules, which were screened at an open public discussion. Feedback on the experience of trial participation involved designing three fictional vignettes which were then transformed into animated videos and screened at an open public discussion. Finally, feedback on fairness/reciprocity in HIV clinical trials was collected using a crowdsourcing idea contest with online and in-person submission opportunities. Our public discussion events were attended by 38 participants in total; our idea contest received 43 submissions (27 in-person, 16 online). Facebook and Twitter metrics demonstrated substantial engagement in the project. The clinical team found crowdsourcing primarily useful for enhancing informed consent and trial recruitment.ConclusionThere is sufficient lay community interest in open calls for feedback on the design and conduct of clinical trials, making crowdsourcing both a novel and feasible engagement strategy. Clinical trial researchers are encouraged to consider the opportunities of implementing crowdsourcing to inform trial processes from a community perspective.
      Citation: Clinical Trials
      PubDate: 2020-02-03T12:07:05Z
      DOI: 10.1177/1740774520902741
  • Role of health plan administrative claims data in participant recruitment
           for pragmatic clinical trials: An Aspirin Dosing: A Patient-centric Trial
           Assessing Benefits and Long-term Effectiveness (ADAPTABLE) example
    • Authors: Qian Shi, Sonali Shambhu, Amanda Marshall, Elaine Rose-Kennedy, Holly Robertson, Mark Paullin, William Schuyler Jones, Mark Cziraky, Kevin Haynes
      Abstract: Clinical Trials, Ahead of Print.
      Aim:The purpose of this study is to evaluate HealthCore/Anthem Research Network recruitment strategies, compare response and enrollment rates for different recruitment strategies, and describe demographic and clinical characteristics of responders and enrollees.Methods:HealthCore/Anthem Research Network, a part of the Health Plan Research Network of the Patient-Centered Clinical Data Research Network, used administrative claims data to identify eligible health plan members for potential participation in the Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-term Effectiveness study. We approached health plan members, identified with a validated Patient-Centered Clinical Data Research Network common data model computable phenotype, and their clinical providers during November 2017 to August 2018. Providers were offered the option to exclude their patients’ participation in Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-term Effectiveness prior to our direct patient (member) outreach. Member identification was in two phases: Phase 1: 1 January 2006 to 1 April 2017, and Phase 2: 1 January 2006 to 2 February 2018. Phase 1 consisted of two batches of mail and one phone call per patient. In Phase 2, which included two similar batches of patients, outreach was via either mail or brochure and one phone call.Results:Phase 1 and Phase 2 included 133,373 and 51,777 members, respectively. We engaged 28,593 providers in Phase 1, and 5077 in Phase 2. In Phase 1, 264,158 mixed email/mail messages were delivered to 133,373 members, followed by 90,481 phone calls from November 2017 to February 2018. In Phase 2, after simple randomization to letter or brochure, 51,777 members were sent email/mail or mailed brochure in three waves from May 2018 to July 2018. In this 9-week period, 51,623 communications were sent to 25,914 members in the email/mail group, and 50,160 brochures to 25,863 in the brochure group. Following email/mail or mailed brochure outreach, 16,624 and 16,580 calls were made to the groups, respectively. Overall, 1549 health plan members visited the study portal by 1 September 2018; 355 electronically signed the Informed Consent Form and enrolled. Mailed brochures drove more portal visits in Phase 2, but a lower percentage of responders enrolled. Recruitment was better in Phase 2—2.3 enrollees per 1000 outreach members versus 1.8 in Phase 1.Conclusion:This study showed the ability of a health plan within Patient-Centered Clinical Data Research Network to identify potential study participants with administrative claims, and use different outreach methods to facilitate recruitment and enrollment for pragmatic clinical trials.
      Citation: Clinical Trials
      PubDate: 2020-02-03T12:06:47Z
      DOI: 10.1177/1740774520902989
  • How do clinical research coordinators learn Good Clinical Practice' A
           mixed-methods study of factors that predict uptake of knowledge
    • Authors: Jessica T Mozersky, Alison L Antes, Kari Baldwin, Michelle Jenkerson, James M DuBois
      Abstract: Clinical Trials, Ahead of Print.
      Background:Good Clinical Practice is an international standard for the design and conduct of clinical trials to ensure ethical and scientific integrity. Recent National Institutes of Health policy mandates Good Clinical Practice training for all investigators and staff involved in National Institutes of Health–funded clinical trials, yet approaches to Good Clinical Practice training vary widely. There are limited data on Good Clinical Practice knowledge among the clinical trial workforce and no evidence regarding effective methods to learn Good Clinical Practice.Methods:We used an exploratory sequential mixed-methods design. We conducted 18 exploratory qualitative interviews with clinical research coordinators to help inform the development of the quantitative survey. We then administered a validated 32-item, multiple-choice test of Good Clinical Practice knowledge with a survey of work and training experiences to 625 clinical research coordinators at three academic medical centers in the United States. Variables that were significantly associated with Good Clinical Practice knowledge were entered into a multiple regression analysis to identify unique predictors of Good Clinical Practice knowledge. We controlled for verbal–numerical reasoning and learning orientation.Results:During qualitative interviews, clinical research coordinators reported that formal Good Clinical Practice training had value but they simultaneously emphasized the importance of experience, day-to-day practice, and observing colleagues and mentors as essential to supplement formal training. In our quantitative survey, five variables predicted a total of 22% of variance in Good Clinical Practice knowledge scores: years of experience as a clinical research coordinator, working on diverse types of trials, supporting industry-funded trials, being certified in clinical research coordination, and aggregated hours of online and face-to-face training (in that order).Conclusion:The duration and richness of experience as a clinical research coordinator were the strongest predictors of Good Clinical Practice knowledge, a finding consistent with our exploratory qualitative interview results. Our findings suggest that formal online and face-to-face training has a minimal influence on Good Clinical Practice knowledge. The type of training—whether online or face to face—does not make a significant difference in Good Clinical Practice knowledge scores. Much of the variance in Good Clinical Practice knowledge remains unexplained, calling for further research in this area.
      Citation: Clinical Trials
      PubDate: 2020-01-27T12:57:24Z
      DOI: 10.1177/1740774519893301
  • To attend, or not to attend: Examining caregiver intentions and study
           compliance in a pediatric, randomized controlled trial
    • Authors: Jacqueline A Sullivan, Anna M Wiese, Kelly M Boone, Joseph Rausch, Sarah A Keim
      Abstract: Clinical Trials, Ahead of Print.
      Background/AimsThe Intent to Attend is a brief questionnaire recommended by the National Research Council to address dropout concerns and improve prediction of missing data in clinical trials, although implementation has been very limited. As a formative study in pediatric research, the relationship between caregiver intentions and study compliance was investigated in a 180-day trial of dietary supplementation of preterm toddlers. Treatment effect estimation in the context of missing data was also explored.MethodsStudy compliance (i.e. study completion, supplement adherence, and diary completion) was tracked over three study visits. Baseline questionnaires asked caregivers about intentions concerning study completion via the Intent to Attend, screened for mental health symptoms (depression, trait anxiety), and captured family demographics. Simple and multiple logistic regression models were built to examine associations between caregiver intent and compliance outcomes. The Intent to Attend was also employed as an auxiliary variable to account for missing data within mixed models estimating the treatment effect on the primary outcomes.ResultsOf the 316 caregiver–child dyads included, 95% of caregivers with low intentions had a child complete the study, but only 87% of caregivers with high intentions had a child complete the study. Low intentions to complete the study were associated with a more than 60% lower odds of study non-completion, but the confidence interval included the null (odds ratio: 0.36; 95% confidence interval: 0.11, 1.20). No effect measure modification by caregiver mental health, child sex, or annual income was detected. Income was the only significant predictor of study non-completion; the lowest income group was almost four times more likely to be study non-completers compared with the highest income group, even after adjustment for child sex and caregiver mental health (adjusted odds ratio = 3.59, 95% confidence interval: 1.38, 9.31). When using Intent to Attend as an auxiliary variable, similar results were obtained when compared with the original treatment effect estimates on the primary outcomes.ConclusionContrary to prior adult studies, there is no clear relationship between caregiver intentions and study compliance. Findings elucidate the complexities of caregiver–child interactions during pediatric trial participation.
      Citation: Clinical Trials
      PubDate: 2020-01-27T12:56:20Z
      DOI: 10.1177/1740774519893307
  • Effect of telephone calls from a centralized coordinating center on
           participant retention in a randomized clinical trial
    • Authors: Adam R Glassman, Wesley T Beaulieu, Cynthia R Stockdale, Roy W Beck, Neil M Bressler, Leanne T Labriola, Michele Melia, Kristina Oliver, Jennifer K Sun
      Abstract: Clinical Trials, Ahead of Print.
      Background/Aims:In clinical trials, participant retention is critical to reduce bias and maintain statistical power for hypothesis testing. Within a multi-center clinical trial of diabetic retinopathy, we investigated whether regular phone calls to participants from the coordinating center improved long-term participant retention.Methods:Among 305 adults in the Diabetic Retinopathy Clinical Research Retina Network Protocol S randomized trial, 152 participants were randomly assigned to receive phone calls at baseline, 6 months, and annually through 3 years (annual contact group) while 153 participants were assigned to receive a phone call at baseline only (baseline contact group). All participants could be contacted if visits were missed. The main outcomes were visit completion, excluding deaths, at 2 years (the primary outcome time point) and at 5 years (the final time point).Results:At baseline, 77% (117 of 152) of participants in the annual contact group and 76% (116 of 153) in the baseline contact group were successfully contacted. Among participants in the annual contact group active at each annual visit (i.e. not dropped from the study or deceased), 85% (125 of 147), 79% (108 of 136), and 88% (110 of 125) were contacted successfully by telephone around the time of the 1-, 2-, and 3-year visits, respectively. In the annual and baseline contact groups, completion rates for the 2-year primary outcome visit were 88% (129 of 147) versus 87% (125 of 144), respectively, with a risk ratio of 1.01 (95% confidence interval: 0.93–1.10, p = .81). At 5 years, the final study visit, participant completion rates were 67% (96 of 144) versus 66% (88 of 133) with a risk ratio of 1.01 (95% confidence interval = 0.85–1.19, p = .93). At 2 years, the completion rate of participants successfully contacted at baseline was 89% (202 of 226) versus 80% (52 of 65) among those not contacted successfully (risk ratio = 1.12, 95% confidence interval = 0.98–1.27, p = .09); at 5 years, the completion percentages by baseline contact success were 69% (148 of 213) versus 56% (36 of 64; risk ratio = 1.24, 95% confidence interval = 0.98–1.56, p = .08).Conclusion:Regular phone calls from the coordinating center to participants during follow-up in this randomized clinical trial did not improve long-term participant retention.
      Citation: Clinical Trials
      PubDate: 2020-01-27T12:55:45Z
      DOI: 10.1177/1740774519894229
  • Trial marketing in the Pan-Canadian Early Detection of Lung Cancer Study
    • Authors: Janice L Rudkowski, Gregory R Pond, Alain Tremblay, Michael Johnston, Glen Goss, Garth Nicholas, Simon Martel, Rick Bhatia, Geoffrey Liu, Heidi Schmidt, Martin C Tammemagi, Sukhinder Atkar-Khattra, Ming-Sound Tsao, Stephen Lam, John R Goffin
      Abstract: Clinical Trials, Ahead of Print.
      Background:Recruitment to clinical trials is suboptimal, increasing costs, and delaying the potential implementation of clinical advances. Among other barriers, the lack of marketing experience among trialists may limit recruitment. In this observational study, in the context of the Pan-Canadian Early Detection of Lung Cancer Trial, we assessed the value of a motivational survey of study participants in planning a tailored advertising campaign and analysed the value of individual components of advertising in generating telephone calls to the study and recruited subjects.Methods:The Pan-Canadian Early Detection of Lung Cancer Trial was a single arm study assessing risk modelling for lung cancer screening by low-dose computed tomography scan and autofluorescence bronchoscopy. Individuals were recruited to eight sites across Canada without a central marketing plan. On contact with the study, individuals reported how they heard about the study according to a predefined list. One site, the Juravinski Cancer Centre, worked with a marketing expert to develop a survey to assess participant motivations, source of study awareness, and personal habits. The survey was used to develop a media campaign for recruitment. Media events were collected from all sites. The primary analysis assessed the number of telephone contacts and recruited subjects associated with various media factors. Individual print media characteristics were assessed for their effect on recruitment.Results:At all sites, 7059 individuals contacted the study, and 2537 were eligible and recruited. Among 52 individuals completing the Juravinski Cancer Centre survey, motivation included concern for personal risk of lung cancer (71%), followed by desire to contribute to a cure (67%), followed by personal knowledge of a person with lung cancer (50%). Most reported hearing of the study from the newspaper (58%) despite no print ad yet being distributed. With survey input, a newsprint campaign was executed. The number of media events varied by site (median: 13, range: 3–28). Among all recruits, 56.4% reported referral by newspaper followed by family/friend (14%). Telephone contacts and recruited subjects per event varied significantly by site, while unpaid media events appeared superior to paid events. Print media characteristics associated with increased telephone contacts and recruitment included use of a rational appeal (vs a mixed rational–emotional), less use of white space, and larger headline font.Conclusion:A survey of trial candidates provides useful information regarding personal motivation, media use, and lifestyle. Unpaid media events appear superior in generating recruitment, while print media may be superior to radio and television in selecting eligible recruits. The utility of individual print media characteristics appears to differ from the commercial advertising literature. Further research on marketing in clinical trials is encouraged to improve recruitment ( registration: NCT00751660,
      Citation: Clinical Trials
      PubDate: 2020-01-02T11:43:08Z
      DOI: 10.1177/1740774519895966
  • Using a Delphi survey to gain an international consensus on the challenges
           of conducting trials with adults with intellectual disabilities
    • Authors: Peter Mulhall, Laurence Taggart, Vivien Coates, Toni McAloon
      Abstract: Clinical Trials, Ahead of Print.
      Background/aimsPeople with intellectual disability experience higher rates of multi-morbidity and health inequalities, they are frequently prescribed medications and more likely to have an avoidable or premature death. There is a recognised lack of randomised controlled trials, and subsequently a lack of evidence base, for many of the interventions and treatments provided to people with intellectual disabilities. Very few disability-specific trials are conducted, and people with intellectual, and other cognitive, disabilities are routinely excluded from mainstream trials. There is an urgent need to facilitate more disability-specific trials or to encourage mainstream trialists to include people with disabilities in their studies. Obtaining a thorough understanding of the challenges inherent in these trials, and sharing this knowledge within the research community, may contribute significantly towards addressing this need. The aim of this study was to explore the practical and methodological challenges to conducting trials with adults with intellectual disabilities and to reach a consensus regarding which are the most important challenges for researchers for inclusion in a resource toolkit.MethodsA three-round modified Delphi survey was conducted with a panel of international trials researchers within the intellectual disability field. Items were assessed in terms of the consensus level and stability of responses.ResultsA total of 64 challenges and barriers were agreed upon, across all aspects of the trial pathway, from planning through to reporting. Some challenges and barriers had been noted in the literature previously, but many previously uncited barriers (both systemic and attitudinal) were identified.ConclusionThis is the first international survey exploring the experiences of researchers conducting randomised controlled trials with adults with intellectual disabilities. Many of the barriers and challenges reported can be overcome with creativity and some additional resources. Other challenges, including attitudes towards conducting trials with disabled populations, maybe harder to overcome. These findings have implications for conducting trials with other populations with cognitive or communication difficulties. Implications for disability researchers, funding bodies and ethical review panels are discussed.
      Citation: Clinical Trials
      PubDate: 2019-12-20T06:57:26Z
      DOI: 10.1177/1740774519887168
  • Adaptive dose-finding based on safety and feasibility in early-phase
           clinical trials of adoptive cell immunotherapy
    • Authors: Nolan A Wages, Camilo E Fadul
      Abstract: Clinical Trials, Ahead of Print.
      Background/aims:Dose feasibility is a challenge that may arise in the development of adoptive T cell therapies for cancer. In early-phase clinical trials, dose is quantified either by a fixed or per unit body weight number of cells infused. It may not be feasible, however, to administer a patient’s assigned dose due to an insufficient number of cells harvested or functional heterogeneity of the product. The study objective becomes to identify the maximum tolerated dose with high feasibility of being administered. This article describes a new dose-finding method that adaptively accounts for safety and feasibility endpoints in guiding dose allocation.Methods:We propose an adaptive dose-finding method that integrates accumulating feasibility and safety data to select doses for participant cohorts in early-phase trials examining adoptive cell immunotherapy. We sequentially model the probability of dose-limiting toxicity and the probability of feasibility using independent beta-binomial models. The probability model for toxicity borrows information across all dose levels using isotonic regression, allowing participants infused at a lower dose than his or her planned dose to contribute safety data to the dose-finding algorithm. We applied the proposed methodology in a single simulated trial and evaluated its operating characteristics through extensive simulation studies.Results:In simulations conducted for a phase I study of adoptive immunotherapy for newly diagnosed glioblastoma, the proposed method demonstrates the ability to identify accurately the feasible maximum tolerated doses and to treat participants at and around these doses. Over 10 hypothesized scenarios studied, the percentage of correctly selecting the true feasible and maximum tolerated dose ranged from 50% to 90% with sample sizes averaging between 21 and 24 participants. A comparison to the only known existing method accounting for safety and feasibility yields competitive performance.Conclusion:We have developed a new practical adaptive dose-finding method to assess feasibility in early-phase adoptive cell therapy trials. A design that incorporates feasibility, as a function of the quantity and quality of the product manufactured, in addition to safety will have an impact on the recommended phase II doses in studies that evaluate patient outcomes.
      Citation: Clinical Trials
      PubDate: 2019-12-20T06:55:44Z
      DOI: 10.1177/1740774519890145
  • Designing and evaluating dose-escalation studies made easy: The MoDEsT web

         This is an Open Access Article Open Access Article

    • Authors: Philip Pallmann, Fang Wan, Adrian P Mander, Graham M Wheeler, Christina Yap, Sally Clive, Lisa V Hampson, Thomas Jaki
      Abstract: Clinical Trials, Ahead of Print.
      Background/aims:Dose-escalation studies are essential in the early stages of developing novel treatments, when the aim is to find a safe dose for administration in humans. Despite their great importance, many dose-escalation studies use study designs based on heuristic algorithms with well-documented drawbacks. Bayesian decision procedures provide a design alternative that is conceptually simple and methodologically sound, but very rarely used in practice, at least in part due to their perceived statistical complexity. There are currently very few easily accessible software implementations that would facilitate their application.Methods:We have created MoDEsT, a free and easy-to-use web application for designing and conducting single-agent dose-escalation studies with a binary toxicity endpoint, where the objective is to estimate the maximum tolerated dose. MoDEsT uses a well-established Bayesian decision procedure based on logistic regression. The software has a user-friendly point-and-click interface, makes changes visible in real time, and automatically generates a range of graphs, tables, and reports. It is aimed at clinicians as well as statisticians with limited expertise in model-based dose-escalation designs, and does not require any statistical programming skills to evaluate the operating characteristics of, or implement, the Bayesian dose-escalation design.Results:MoDEsT comes in two parts: a ‘Design’ module to explore design options and simulate their operating characteristics, and a ‘Conduct’ module to guide the dose-finding process throughout the study. We illustrate the practical use of both modules with data from a real phase I study in terminal cancer.Conclusion:Enabling both methodologists and clinicians to understand and apply model-based study designs with ease is a key factor towards their routine use in early-phase studies. We hope that MoDEsT will enable incorporation of Bayesian decision procedures for dose escalation at the earliest stage of clinical trial design, thus increasing their use in early-phase trials.
      Citation: Clinical Trials
      PubDate: 2019-12-20T06:54:07Z
      DOI: 10.1177/1740774519890146
  • Non-inferiority designs comparing placebo to a proven therapy for
           childhood pneumonia in low-resource settings
    • Authors: Susanne May, Siobhan P Brown, Robert H Schmicker, Scott S. Emerson, Evangelyn Nkwopara, Amy Sarah Ginsburg
      Abstract: Clinical Trials, Ahead of Print.
      Background/aims:After a new treatment is recommended to be first-line treatment for a specific indication, outcome and population, it may be unethical to use placebo as a comparator in trials for that setting. Nevertheless, in specific circumstances, use of a placebo group might be warranted, for example, when it is believed that an active treatment may not be efficacious or cost-effective for a specific subpopulation. An example is antibiotic treatment for pneumonia, which may not be effective for many patients taking it due to the emergence of antibiotic-resistant strains or the high prevalence of viral and low prevalence of bacterial pneumonia.Methods:We explore the applicability of different design options in cases where the benefit of an established treatment is questioned, with particular emphasis on issues that arise in a low-resource setting. Using the example of a clinical trial comparing the effectiveness of placebo versus amoxicillin in treating children 2–59 months of age with fast breathing pneumonia in Lilongwe, Malawi, we discuss the pros and cons of superiority versus non-inferiority designs, an intent-to-treat versus as-treated analysis and the use and interpretation of one- versus two-sided confidence intervals.Results:We find that a non-inferiority design using an intent-to-treat analysis is the most appropriate design and analysis option. In addition, the presentation of one- versus two-sided confidence intervals can depend on the results but can maintain type I error.Conclusion:In the setting where the benefit of a previously established beneficial treatment is questioned, a non-inferiority design that includes placebo as the tested treatment option can be the most appropriate design option.
      Citation: Clinical Trials
      PubDate: 2019-12-09T07:07:07Z
      DOI: 10.1177/1740774519888460
  • Prevalence and significance of race and ethnicity subgroup analyses in
           Cochrane intervention reviews
    • Authors: Patrick Liu, Joseph S Ross, John PA Ioannidis, Sanket S Dhruva, Vasilis Vasiliou, Joshua D Wallach
      Abstract: Clinical Trials, Ahead of Print.

      Citation: Clinical Trials
      PubDate: 2019-11-11T07:19:23Z
      DOI: 10.1177/1740774519887148
  • A randomized evaluation of on-site monitoring nested in a multinational
           randomized trial
    • Authors: Nicole Wyman Engen, Kathy Huppler Hullsiek, Waldo H Belloso, Elizabeth Finley, Fleur Hudson, Eileen Denning, Catherine Carey, Mary Pearson, Jonathan Kagan
      First page: 3
      Abstract: Clinical Trials, Ahead of Print.
      Background:Evidence from prospectively designed studies to guide on-site monitoring practices for randomized trials is limited. A cluster randomized study, nested within the Strategic Timing of AntiRetroviral Treatment (START) trial, was conducted to evaluate on-site monitoring.Methods:Sites were randomized to either annual on-site monitoring or no on-site monitoring. All sites were centrally monitored, and local monitoring was carried out twice each year. Randomization was stratified by country and projected enrollment in START. The primary outcome was a participant-level composite outcome including components for eligibility errors, consent violations, use of antiretroviral treatment not recommended by protocol, late reporting of START primary and secondary clinical endpoints (defined as the event being reported more than 6 months from occurrence), and data alteration and fraud. Logistic regression fixed effect hierarchical models were used to compare on-site versus no on-site monitoring for the primary composite outcome and its components. Odds ratios and 95% confidence intervals comparing on-site monitoring versus no on-site monitoring are cited.Results:In total, 99 sites (2107 participants) were randomized to receive annual on-site monitoring and 97 sites (2264 participants) were randomized to be monitored only centrally and locally. The two monitoring groups were well balanced at entry. In the on-site monitoring group, 469 annual on-site monitoring visits were conducted, and 134 participants (6.4%) in 56 of 99 sites (57%) had a primary monitoring outcome. In the no on-site monitoring group, 85 participants (3.8%) in 34 of 97 sites (35%) had a primary monitoring outcome (odds ratio = 1.7; 95% confidence interval: 1.1–2.7; p = 0.03). Informed consent violations accounted for most outcomes in each group (56 vs 41 participants). The largest odds ratio was for eligibility violations (odds ratio = 12.2; 95% confidence interval: 1.8–85.2; p = 0.01). The number of participants with a late START primary endpoint was similar for each monitoring group (23 vs 16 participants). Late START grade 4 and unscheduled hospitalization events were found for 34 participants in the on-site monitoring group and 19 participants in the no on-site monitoring group (odds ratio = 2.0; 95% confidence interval: 1.1–3.7; p = 0.02). There were no cases of data alteration or fraud. Based on the travel budget for on-site monitoring and the hours spent conducting on-site monitoring, the estimated cost of on-site monitoring was over US$2 million.Conclusion:On-site monitoring led to the identification of more eligibility and consent violations and START clinical events being reported more than 6 months from occurrence as compared to no on-site monitoring. Considering the nature of the excess monitoring outcomes identified at sites receiving on-site monitoring, as well as the cost of on-site monitoring, the value to the START study was limited.
      Citation: Clinical Trials
      PubDate: 2019-10-24T12:50:11Z
      DOI: 10.1177/1740774519881616
  • Commentary on Engen et al: Risk-based, dynamic, process-oriented
           monitoring strategies and their burden
    • Authors: Marnie Bertolet, Maria Mori Brooks, Jeffrey L Carson
      First page: 15
      Abstract: Clinical Trials, Ahead of Print.

      Citation: Clinical Trials
      PubDate: 2019-10-24T12:50:31Z
      DOI: 10.1177/1740774519881617
  • Benefit, burden, and impact for a cohort of post-approval cancer
           combination trials
    • Authors: Benjamin Gregory Carlisle, Adélaïde Doussau, Jonathan Kimmelman
      First page: 18
      Abstract: Clinical Trials, Ahead of Print.
      Background:After approval, drug developers often pursue trials aimed at extending the uses of a new drug by combining it with other drugs. Little is known about the risk and benefits associated with such research.Methods:To establish a historic benchmark of risk and benefit, we searched Medline and Embase for clinical trials testing anti-cancer drugs in combination within 5 years of approval by the Food and Drug Administration of 12 anti-cancer “index” drugs first licensed 2005–2007 inclusive. Risk was assessed based on grade 3 or above drug-related adverse events; benefit was assessed based on efficacy outcomes and advancement of combinations into clinical practice guidelines or approval by the Food and Drug Administration.Results:We captured 323 published post-approval trials exploring combinations, including 266 unique combination–indication pairings and enrolling 29,835 patients. The pooled risk ratios for treatment-related grade 3–4 severe adverse events and deaths attributed to the study drugs for trials randomized between a combination arm and a comparator were 1.54 (1.33–1.79) and 1.51 (1.16–1.97), respectively. The pooled hazard ratios for overall survival and progression-free survival were 0.99 (0.92–1.05) and 0.85 (0.79–0.93), respectively. None of the combination–indication pairings launched after initial drug approval received approval by the Food and Drug Administration, and 13 pairings (4.9%) were recommended by the National Comprehensive Cancer Network within 5 years of the first trial within that pairing. The proportion of patients in our sample who participated in trials leading to an approval by the Food and Drug Administration or a National Comprehensive Cancer Network guideline recommendation was 12.7% with 5 years of follow-up, and 22.3% among pairings for which there were 8 years of follow-up.Conclusion:Patients were just as likely to benefit in the treatment arm as the control arm in terms of overall survival, but they were more likely to experience a treatment-related severe adverse event in post-approval trials of combination therapy.
      Citation: Clinical Trials
      PubDate: 2019-10-03T01:11:05Z
      DOI: 10.1177/1740774519873883
  • Recruitment of trial participants through electronic medical record
           patient portal messaging: A pilot study
    • Authors: Timothy B Plante, Kelly T Gleason, Hailey N Miller, Jeanne Charleston, Kristen McArthur, Cheryl Dennison Himmelfarb, Mariana Lazo, Daniel E Ford, Edgar R Miller, Lawrence J Appel, Stephen P Juraschek
      First page: 30
      Abstract: Clinical Trials, Ahead of Print.
      Background/aim:Cost-efficient methods are essential for successful participant recruitment in clinical trials. Patient portal messages are an emerging means of recruiting potentially eligible patients into trials. We assessed the response rate and complaint rate from direct-to-patient, targeted recruitment through patient portals of an electronic medical record for a clinical trial, and compared response rates by differences in message content.Methods:The Study to Understand Fall Reduction and Vitamin D in You (STURDY) trial is a National Institutes of Health–sponsored, community-based study of vitamin D supplementation for fall prevention in older adults conducted at Johns Hopkins. Potential participants were identified using the Epic electronic medical record at the Johns Hopkins Health System based on age (≥70 years), ZIP code (30-mile radius of study site), and prior activation of a patient portal account. We prepared a shorter message and a longer message. Both had basic information about study participation, but the longer message also contained information about the significance of the study and a personal invitation from the STURDY principal investigator. The Hopkins Institutional Review Board did not require prior consent from the patient or their providers. We calculated the response rate and tracked the number of complaints and requests for removal from future messages. We also determined response rate according to message content.Results:Of the 5.5 million individuals receiving care at the Johns Hopkins Health System, a sample of 6896 met our inclusion criteria and were sent one patient portal recruitment message between 6 April 2017 and 3 August 2017. Assessment of enrollment by this method ended on 1 December 2017. There were 116 patients who expressed interest in the study (response rate: 1.7%). Twelve (0.2%) recipients were randomized. There were two complaints (0.03%) and one request to unsubscribe from future recruitment messages (0.01%). Response rate was higher with the longer message than the shorter message (2.1% vs 1.2%; p = 0.005).Conclusion:Patient portal messages inviting seniors to participate in a randomized controlled trial resulted in a response rate similar to commercial email marketing and resulted in very few complaints or opt-out requests. Furthermore, a longer message with more content enhanced response rate. Recruitment through patient portals might be an effective strategy to enroll trial participants.
      Citation: Clinical Trials
      PubDate: 2019-10-04T06:33:02Z
      DOI: 10.1177/1740774519873657
  • Nonparticipation reasons in a randomized international trial of a new
           latent tuberculosis infection regimen
    • Authors: Kimberley N Chapman Hedges, Andrey S Borisov, Jussi J Saukkonen, Nigel A Scott, Emily J Hecker, Lorna Bozeman, Carol Dukes Hamilton, Amy Kerrigan, Patricia Bessler, Antonio Moreno-Martinez, Bert Arevalo, Stefan V Goldberg
      First page: 39
      Abstract: Clinical Trials, Ahead of Print.
      Background/aimsEfficient recruitment of eligible participants, optimizing time and sample size, is a crucial component in conducting a successful clinical trial. Inefficient participant recruitment can impede study progress, consume staff time and resources, and limit quality and generalizability or the power to assess outcomes. Recruitment for disease prevention trials poses additional challenges because patients are asymptomatic. We evaluated candidates for a disease prevention trial to determine reasons for nonparticipation and to identify factors that can be addressed to improve recruitment efficiency.MethodsDuring 2001–2009, the Tuberculosis Trials Consortium conducted Study 26 (PREVENT TB), a randomized clinical trial at 26 sites in four countries, among persons with latent tuberculosis infection at high risk for tuberculosis disease progression, comparing 3 months of directly observed once-weekly rifapentine plus isoniazid with 9 months of self-administered daily isoniazid. During March 2005–February 2008, non-identifying demographic information, risk factors for experiencing active tuberculosis disease, and reasons for not enrolling were collected from screened patients to facilitate interpretation of trial data, to meet Consolidated Standards of Reporting Trials standards, and to evaluate reasons for nonparticipation.ResultsOf the 7452 candidates screened in Brazil, Canada, Spain, and the United States, 3584 (48%) were not enrolled, because of ineligibility (41%), site decision (10%), or patient choice (49%). Among those who did not enroll by own choice, and for whom responses were recorded on whether they would accept treatment outside of the study (n = 1430), 68% reported that they planned to accept non-study latent tuberculosis infection treatment. Among 1305 patients with one or more reported reasons for nonparticipation, study staff recorded a total of 1886 individual reasons (reason count: median = 1/patient; range = 1–9) for why patients chose not to enroll, including grouped concerns about research (24% of 1886), work or school conflicts (20%), medication or health beliefs (16%), latent tuberculosis infection beliefs (11%), and patient lifestyle and family concerns (10%).ConclusionEducational efforts addressing clinical research concerns and beliefs about medication and health, as well as study protocols that accommodate patient-related concerns (e.g. work, school, and lifestyle) might increase willingness to enter clinical trials. Findings from this evaluation can support development of communication and education materials for clinical trial sites at the beginning of a trial to allow study staff to address potential participant concerns during study screening.
      Citation: Clinical Trials
      PubDate: 2019-11-06T09:57:44Z
      DOI: 10.1177/1740774519885380
  • Comparison of methods for control allocation in multiple arm studies using
           response adaptive randomization
    • Authors: Kert Viele, Kristine Broglio, Anna McGlothlin, Benjamin R. Saville
      First page: 52
      Abstract: Clinical Trials, Ahead of Print.
      Background/Aims:Response adaptive randomization has many polarizing properties in two-arm settings comparing control to a single treatment. The generalization of these features to the multiple arm setting has been less explored, and existing comparisons in the literature reach disparate conclusions. We investigate several generalizations of two-arm response adaptive randomization methods relating to control allocation in multiple arm trials, exploring how critiques of response adaptive randomization generalize to the multiple arm setting.Methods:We perform a simulation study to investigate multiple control allocation schemes within response adaptive randomization, comparing the designs on metrics such as power, arm selection, mean square error, and the treatment of patients within the trial.Results:The results indicate that the generalization of two-arm response adaptive randomization concerns is variable and depends on the form of control allocation employed. The concerns are amplified when control allocation may be reduced over the course of the trial but are mitigated in the methods considered when control allocation is maintained or increased during the trial. In our chosen example, we find minimal advantage to increasing, as opposed to maintaining, control allocation; however, this result reflects an extremely limited exploration of methods for increasing control allocation.Conclusion:Selection of control allocation in multiple arm response adaptive randomization has a large effect on the performance of the design. Some disparate comparisons of response adaptive randomization to alternative paradigms may be partially explained by these results. In future comparisons, control allocation for multiple arm response adaptive randomization should be chosen to keep in mind the appropriate match between control allocation in response adaptive randomization and the metric or metrics of interest.
      Citation: Clinical Trials
      PubDate: 2019-10-19T12:19:54Z
      DOI: 10.1177/1740774519877836
  • Comparison between protocols and publications for prognostic and
           predictive cancer biomarker studies
    • Authors: Adelaide Doussau, Esther Vinarov, Brianna Barsanti-Innes, Jonathan Kimmelman
      First page: 61
      Abstract: Clinical Trials, Ahead of Print.
      Background:Method prespecification in study protocols is important for controlling bias in reports. The primary goal of this study was to assess potential for discordance between study protocols and publications reporting predictive or prognostic cancer biomarker research. Secondary objectives included comparing characteristics of publications with accessible protocols compared to those without.Methods:Publications reporting predictive or prognostic cancer biomarker research were identified from 15 major journals, 2012–2015. Protocols were sought online or through repeated queries of corresponding authors. The following four items were extracted: (1) biomarkers, (2) biospecimen/assays, (3) sample size, (4) endpoints. We defined “explicit discordance” as the presence of major inconsistencies on these items.Results:Of 149 eligible publications, we obtained 19 eligible protocols online (13%). Out of a random sample of 103 publications where protocols were not available online, 12 protocols (12%) were furnished by corresponding authors; 8 (8% of authors) explicitly stated the absence of a protocol. Among 24 retrospective cohort studies, no protocol could be accessed. We found explicit discordance between publications and protocols for 18 studies (58%), in particular choice of biomarkers (36%), biospecimen/assays (6%), or endpoints (29%).Conclusion:Protocols are generally not accessible or not used for cancer biomarker studies. Publications were often explicitly discordant with protocols, particularly regarding biomarkers and endpoints. Our findings point to common unaddressed risk of bias in publications of major journals reporting the relationship between cancer biomarkers and clinical endpoints.
      Citation: Clinical Trials
      PubDate: 2019-10-05T10:04:52Z
      DOI: 10.1177/1740774519876912
  • Cluster randomised trials with different numbers of measurements at
           baseline and endline: Sample size and optimal allocation
    • Authors: Andrew J Copas, Richard Hooper
      First page: 69
      Abstract: Clinical Trials, Ahead of Print.
      Background/Aims:Published methods for sample size calculation for cluster randomised trials with baseline data are inflexible and primarily assume an equal amount of data collected at baseline and endline, that is, before and after the intervention has been implemented in some clusters. We extend these methods to any amount of baseline and endline data. We explain how to explore sample size for a trial if some baseline data from the trial clusters have already been collected as part of a separate study. Where such data aren’t available, we show how to choose the proportion of data collection devoted to the baseline within the trial, when a particular cluster size or range of cluster sizes is proposed.Methods:We provide a design effect given the cluster size and correlation parameters, assuming different participants are assessed at baseline and endline in the same clusters. We show how to produce plots to identify the impact of varying the amount of baseline data accounting for the inevitable uncertainty in the cluster autocorrelation. We illustrate the methodology using an example trial.Results:Baseline data provide more power, or allow a greater reduction in trial size, with greater values of the cluster size, intracluster correlation and cluster autocorrelation.Conclusion:Investigators should think carefully before collecting baseline data in a cluster randomised trial if this is at the expense of endline data. In some scenarios, this will increase the sample size required to achieve given power and precision.
      Citation: Clinical Trials
      PubDate: 2019-10-03T01:12:08Z
      DOI: 10.1177/1740774519873888
  • Closed testing of each group versus the others combined in a multiple
           group analysis
    • Authors: John M Lachin, Ionut Bebu
      First page: 77
      Abstract: Clinical Trials, Ahead of Print.
      Background:Many studies, such as a study of comparative effectiveness, entail a comparison of the beneficial and adverse effects of multiple K[math] 2 competing therapies. Often, the analysis consists of a comparison of the K groups using an omnibus (T2-like) test for any difference among the groups followed by pairwise comparisons with adjustments for multiple tests.Methods:We evaluate the properties of an analysis strategy in which each group is compared to the average of the others in hopes of establishing the overall superiority (or harm) of at least one of the therapies. Testing of one-versus-others can be accomplished for virtually any model using simple tests, and the type I error probability [math] can be controlled by conducting such tests under the closed testing principle. Testing using linear models, the family of generalized linear models, and Cox proportional hazards models is described with examples.Results:Since each tested hypothesis compares one treatment to the average of the others, the K-level null hypothesis in the tree of closed testing is equivalent to any of the (K−1)-level tests, thus reducing the number of tests required. This applies to linear, generalized linear, and Cox proportional hazards models. While the Bonferroni, Holm, and Hommel procedures preserve the desired level [math], all are conservative relative to closed one-versus-others testing and closed testing in general provides greater power.Conclusion:Testing each of the multiple treatments versus the average of the others is readily and efficiently conducted under the closed testing principle and may be especially useful in the assessment of studies of comparative effectiveness.
      Citation: Clinical Trials
      PubDate: 2019-10-24T12:49:08Z
      DOI: 10.1177/1740774519879932
  • Recommendations for improving clinical trial design to facilitate the
           study of youth-onset type 2 diabetes
    • Authors: Muhammad Yazid Jalaludin, Margarita Barrientos-Pérez, Mona Hafez, Jane Lynch, Naim Shehadeh, Serap Turan, Daniel Weghuber
      First page: 87
      Abstract: Clinical Trials, Ahead of Print.
      BackgroundThe prevalence of type 2 diabetes is increasing in youths and differs from adult-onset type 2 diabetes in its characteristics and progression. Currently, only two drugs are approved for youth-onset type 2 diabetes and many patients are not meeting glycemic targets. Clearly, there is an urgent need to complete clinical trials in youths with type 2 diabetes to increase the therapeutic choice for these patients. However, factors such as limited patient numbers, unwillingness of patients to participate in trials, failure to meet strict inclusion and exclusion criteria, and poor clinic attendance have limited the size and number of trials in this complicated patient demographic.RecommendationsThis is a narrative opinion piece on the design of clinical trials in youth-onset type 2 diabetes prepared by researchers who undertake this type of study in different countries. The review addresses possible ways to enhance trial designs in youth-onset type 2 diabetes to meet regulatory requirements, while minimizing the barriers to patients’ participation. The definition of adolescence, recruitment of sufficient patient numbers, increasing flexibility in selection criteria, improving convenience of trial visits, requirements of a control group, possible endpoints, and trial compliance are all considered. The authors recommend allowing extrapolation from adult data, using multiple interventional arms within future trials, broadening inclusion criteria, and focusing on endpoints beyond glucose control, among others, in order to improve the successful completion of more trials in this population.ConclusionsImprovements in trial design will enable better recruitment and retention and thereby more evidence for treatment outcomes for youth-onset type 2 diabetes.
      Citation: Clinical Trials
      PubDate: 2019-08-27T06:37:11Z
      DOI: 10.1177/1740774519870190
  • Availability of study protocols for randomized trials published in
           high-impact medical journals: A cross-sectional analysis
    • Authors: O’Mareen Spence, Kyungwan Hong, Richie Onwuchekwa Uba, Peter Doshi
      First page: 99
      Abstract: Clinical Trials, Ahead of Print.
      Background:To improve reporting transparency and research integrity, some journals have begun publishing study protocols and statistical analysis plans alongside trial publications. We sought to assess the overall availability and characteristics of protocols and statistical analysis plans of randomized clinical trials published in the top five (by impact factor) general medicine journals.Methods:All randomized clinical trials published in Annals of Internal Medicine, BMJ, JAMA, Lancet, and NEJM in 2016 were identified. For each randomized clinical trial, we searched for protocols and statistical analysis plans on journal websites (including supplementary material) and in the article, for example, a referenced publication or link to trial or institutional website. Characteristics of randomized clinical trials were extracted from the publication and clinical trial registry. A detailed assessment of protocols and statistical analysis plans was conducted in a 20% random sample of randomized clinical trials.Results:Protocols were available for 299 (82%) trials, ranging from 50% in BMJ to>95% in NEJM and JAMA. Statistical analysis plans were available for 182 (50%) trials and varied from
      Citation: Clinical Trials
      PubDate: 2019-08-27T06:37:31Z
      DOI: 10.1177/1740774519868310
  • A third trial oversight committee: Functions, benefits and issues
    • Authors: J Athene Lane, Carrol Gamble, William J Cragg, Doreen Tembo, Matthew R Sydes
      First page: 106
      Abstract: Clinical Trials, Ahead of Print.
      Background/aims:Clinical trial oversight is central to the safety of participants and production of robust data. The United Kingdom Medical Research Council originally set out an oversight structure comprising three committees in 1998. The first committee, led by the trial team, is hands-on with trial conduct/operations (‘Trial Management Group’) and essential. The second committee (Data Monitoring Committee), usually completely independent of the trial, reviews accumulating trial evidence and is used by most later phase trials. The Independent Data Monitoring Committee makes recommendations to the third oversight committee. The third committee, (‘Trial Steering Committee’), facilitates in-depth interactions of independent and non-independent trial members and gives broader oversight (blinded to comparative analysis). We investigated the roles and functioning of the third oversight committee with multiple research methods. We reflect upon these findings to standardise the committee’s remit and operation and to potentially increase its usage.Methods:We utilised findings from our recent published suite of research on the third oversight committee to inform guideline revision. In brief, we conducted a survey of 38 United Kingdom–registered Clinical Trials Units, reviewed a cohort of 264 published trials, observed 8 third oversight committee meetings and interviewed 52 trialists. We convened an expert panel to discuss third oversight committees. Subsequently, we interviewed nine patient/lay third committee members and eight committee Chairs.Results:In the survey, most Clinical Trials Units required a third committee for all their trials (27/38, 71%) with independent members (ranging from 1 to 6). In the survey and interviews, the independence of the third committee was valued to make unbiased consideration of Independent Data Monitoring Committee recommendations and to advise on trial progress, protocol changes and recruitment issues in conjunction with the trial leadership. The third committee also advised funders and sponsors about trial continuation and represented patients and the public by including lay members. Of the cohort of 264 published trials, 144 reported a ‘steering’ committee (55%), but the independence of these members was not described so these may have been internal Trial Management Groups. Around two thirds of papers (60%) reported having an Independent Data Monitoring Committee and 26.9% neither a steering nor an Independent Data Monitoring Committee. However, before revising the third committee charter (Terms of Reference), greater standardisation is needed around defining member independence, composition, primacy of decision-making, interactions with other committees and the lifespan.Conclusion:A third oversight committee has benefits for trial oversight and conduct, and a revised charter will facilitate greater standardisation and wider adoption.
      Citation: Clinical Trials
      PubDate: 2019-10-31T06:05:55Z
      DOI: 10.1177/1740774519881619
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