Publisher: Sage Publications   (Total: 1166 journals)

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Showing 1 - 200 of 1166 Journals sorted alphabetically
AADE in Practice     Hybrid Journal   (Followers: 6)
Abstracts in Anthropology     Full-text available via subscription   (Followers: 29)
Academic Pathology     Open Access   (Followers: 6)
Accounting History     Hybrid Journal   (Followers: 18, SJR: 0.527, CiteScore: 1)
Acta Radiologica     Hybrid Journal   (Followers: 1, SJR: 0.754, CiteScore: 2)
Acta Radiologica Open     Open Access   (Followers: 2)
Acta Sociologica     Hybrid Journal   (Followers: 39, SJR: 0.939, CiteScore: 2)
Action Research     Hybrid Journal   (Followers: 53, SJR: 0.308, CiteScore: 1)
Active Learning in Higher Education     Hybrid Journal   (Followers: 398, SJR: 1.397, CiteScore: 2)
Adaptive Behavior     Hybrid Journal   (Followers: 9, SJR: 0.288, CiteScore: 1)
Administration & Society     Hybrid Journal   (Followers: 18, SJR: 0.675, CiteScore: 1)
Adoption & Fostering     Hybrid Journal   (Followers: 25, SJR: 0.313, CiteScore: 0)
Adsorption Science & Technology     Open Access   (Followers: 9, SJR: 0.258, CiteScore: 1)
Adult Education Quarterly     Hybrid Journal   (Followers: 262, SJR: 0.566, CiteScore: 2)
Adult Learning     Hybrid Journal   (Followers: 51)
Advances in Dental Research     Hybrid Journal   (Followers: 11, SJR: 1.791, CiteScore: 4)
Advances in Developing Human Resources     Hybrid Journal   (Followers: 35, SJR: 0.614, CiteScore: 2)
Advances in Mechanical Engineering     Open Access   (Followers: 156, SJR: 0.272, CiteScore: 1)
Advances in Methods and Practices in Psychological Science     Full-text available via subscription   (Followers: 20)
Advances in Structural Engineering     Full-text available via subscription   (Followers: 51, SJR: 0.599, CiteScore: 1)
AERA Open     Open Access   (Followers: 14)
Affilia     Hybrid Journal   (Followers: 6, SJR: 0.496, CiteScore: 1)
Africa Spectrum     Open Access   (Followers: 17)
Agrarian South : J. of Political Economy     Hybrid Journal   (Followers: 3)
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: 68)
Allergy & Rhinology     Open Access   (Followers: 5)
AlterNative : An Intl. J. of Indigenous Peoples     Full-text available via subscription   (Followers: 39, SJR: 0.194, CiteScore: 0)
Alternative Law J.     Hybrid Journal   (Followers: 12, SJR: 0.176, CiteScore: 0)
Alternatives : Global, Local, Political     Hybrid Journal   (Followers: 12, SJR: 0.351, CiteScore: 1)
Alternatives to Laboratory Animals     Full-text available via subscription   (Followers: 11, SJR: 0.297, CiteScore: 1)
American Behavioral Scientist     Hybrid Journal   (Followers: 26, SJR: 0.982, CiteScore: 2)
American Economist     Hybrid Journal   (Followers: 7)
American Educational Research J.     Hybrid Journal   (Followers: 260, SJR: 2.913, CiteScore: 3)
American J. of Alzheimer's Disease and Other Dementias     Hybrid Journal   (Followers: 23, SJR: 0.67, CiteScore: 2)
American J. of Cosmetic Surgery     Hybrid Journal   (Followers: 9)
American J. of Evaluation     Hybrid Journal   (Followers: 18, SJR: 0.646, CiteScore: 2)
American J. of Health Promotion     Hybrid Journal   (Followers: 35, SJR: 0.807, CiteScore: 1)
American J. of Hospice and Palliative Medicine     Hybrid Journal   (Followers: 47, SJR: 0.65, CiteScore: 1)
American J. of Law & Medicine     Full-text available via subscription   (Followers: 12, SJR: 0.204, CiteScore: 1)
American J. of Lifestyle Medicine     Hybrid Journal   (Followers: 7, SJR: 0.431, CiteScore: 1)
American J. of Medical Quality     Hybrid Journal   (Followers: 13, SJR: 0.777, CiteScore: 1)
American J. of Men's Health     Open Access   (Followers: 9, SJR: 0.595, CiteScore: 2)
American J. of Rhinology and Allergy     Hybrid Journal   (Followers: 11, SJR: 0.972, CiteScore: 2)
American J. of Sports Medicine     Hybrid Journal   (Followers: 249, SJR: 3.949, CiteScore: 6)
American Politics Research     Hybrid Journal   (Followers: 36, SJR: 1.313, CiteScore: 1)
American Review of Public Administration     Hybrid Journal   (Followers: 28, SJR: 2.062, CiteScore: 2)
American Sociological Review     Hybrid Journal   (Followers: 358, SJR: 6.333, CiteScore: 6)
American String Teacher     Full-text available via subscription   (Followers: 3)
Analytical Chemistry Insights     Open Access   (Followers: 26, SJR: 0.224, CiteScore: 1)
Angiology     Hybrid Journal   (Followers: 5, SJR: 0.849, CiteScore: 2)
Animation     Hybrid Journal   (Followers: 15, 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: 20, SJR: 0.807, CiteScore: 1)
Annals of Pharmacotherapy     Hybrid Journal   (Followers: 59, SJR: 1.096, CiteScore: 2)
Annals of the American Academy of Political and Social Science     Hybrid Journal   (Followers: 51, SJR: 1.225, CiteScore: 3)
Annals of the ICRP     Hybrid Journal   (Followers: 4, SJR: 0.548, CiteScore: 1)
Anthropocene Review     Hybrid Journal   (Followers: 8, SJR: 3.341, CiteScore: 7)
Anthropological Theory     Hybrid Journal   (Followers: 48, SJR: 0.739, CiteScore: 1)
Antitrust Bulletin     Hybrid Journal   (Followers: 14)
Antiviral Chemistry and Chemotherapy     Open Access   (Followers: 2, SJR: 0.635, CiteScore: 2)
Antyajaa : Indian J. of Women and Social Change     Hybrid Journal   (Followers: 1)
Applied Biosafety     Hybrid Journal   (Followers: 1, SJR: 0.131, CiteScore: 0)
Applied Psychological Measurement     Hybrid Journal   (Followers: 21, SJR: 1.17, CiteScore: 1)
Applied Spectroscopy     Full-text available via subscription   (Followers: 27, SJR: 0.489, CiteScore: 2)
Armed Forces & Society     Hybrid Journal   (Followers: 25, SJR: 0.29, CiteScore: 1)
Arthaniti : J. of Economic Theory and Practice     Full-text available via subscription  
Arts and Humanities in Higher Education     Hybrid Journal   (Followers: 49, 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: 15, SJR: 0.558, CiteScore: 1)
Asia-Pacific J. of Rural Development     Hybrid Journal   (Followers: 2)
Asian and Pacific Migration J.     Full-text available via subscription   (Followers: 8, 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: 19, SJR: 1.519, CiteScore: 3)
Assessment for Effective Intervention     Hybrid Journal   (Followers: 15, SJR: 0.578, CiteScore: 1)
Australasian J. of Early Childhood     Hybrid Journal   (Followers: 7, SJR: 0.535, CiteScore: 1)
Australasian Psychiatry     Hybrid Journal   (Followers: 18, SJR: 0.433, CiteScore: 1)
Australian & New Zealand J. of Psychiatry     Hybrid Journal   (Followers: 30, SJR: 1.801, CiteScore: 2)
Australian and New Zealand J. of Criminology     Hybrid Journal   (Followers: 547, SJR: 0.612, CiteScore: 1)
Australian J. of Career Development     Hybrid Journal   (Followers: 5)
Australian J. of Education     Hybrid Journal   (Followers: 51, SJR: 0.403, CiteScore: 1)
Australian J. of Management     Hybrid Journal   (Followers: 13, SJR: 0.497, CiteScore: 1)
Autism     Hybrid Journal   (Followers: 358, SJR: 1.739, CiteScore: 4)
Autism & Developmental Language Impairments     Open Access   (Followers: 17)
Avian Biology Research     Hybrid Journal   (Followers: 6, SJR: 0.401, CiteScore: 1)
Behavior Modification     Hybrid Journal   (Followers: 14, SJR: 0.877, CiteScore: 2)
Behavioral and Cognitive Neuroscience Reviews     Hybrid Journal   (Followers: 27)
Behavioral Disorders     Hybrid Journal   (Followers: 2)
Beyond Behavior     Hybrid Journal   (Followers: 2)
Bible Translator     Hybrid Journal   (Followers: 13)
Biblical Theology Bulletin     Hybrid Journal   (Followers: 24, SJR: 0.184, CiteScore: 0)
Big Data & Society     Open Access   (Followers: 55)
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: 11)
Biomedical Engineering and Computational Biology     Open Access   (Followers: 14)
Biomedical Informatics Insights     Open Access   (Followers: 8)
Bioscope: South Asian Screen Studies     Hybrid Journal   (Followers: 4, 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: 29, SJR: 1.531, CiteScore: 3)
Bone and Tissue Regeneration Insights     Open Access   (Followers: 2)
Brain and Neuroscience Advances     Open Access  
Brain Science Advances     Open Access  
Breast Cancer : Basic and Clinical Research     Open Access   (Followers: 12, SJR: 0.823, CiteScore: 2)
British J. of Music Therapy     Hybrid Journal   (Followers: 9)
British J. of Occupational Therapy     Hybrid Journal   (Followers: 253, SJR: 0.323, CiteScore: 1)
British J. of Pain     Hybrid Journal   (Followers: 31, SJR: 0.579, CiteScore: 2)
British J. of Politics and Intl. Relations     Hybrid Journal   (Followers: 39, SJR: 0.91, CiteScore: 2)
British J. of Visual Impairment     Hybrid Journal   (Followers: 14, 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: 9)
Business & Society     Hybrid Journal   (Followers: 15)
Business and Professional Communication Quarterly     Hybrid Journal   (Followers: 9, SJR: 0.348, CiteScore: 1)
Business Information Review     Hybrid Journal   (Followers: 17, 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     Hybrid Journal   (Followers: 1)
California Management Review     Hybrid Journal   (Followers: 37, SJR: 2.209, CiteScore: 4)
Canadian Association of Radiologists J.     Full-text available via subscription   (Followers: 2, SJR: 0.463, CiteScore: 1)
Canadian J. of Kidney Health and Disease     Open Access   (Followers: 8, SJR: 1.007, CiteScore: 2)
Canadian J. of Nursing Research (CJNR)     Hybrid Journal   (Followers: 15)
Canadian J. of Occupational Therapy     Hybrid Journal   (Followers: 168, 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: 12, 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: 2)
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: 10, SJR: 0.282, CiteScore: 1)
Cardiac Cath Lab Director     Full-text available via subscription   (Followers: 1)
Cardiovascular and Thoracic Open     Open Access   (Followers: 1)
Career Development and Transition for Exceptional Individuals     Hybrid Journal   (Followers: 10, SJR: 0.44, CiteScore: 1)
Cartilage     Hybrid Journal   (Followers: 6, SJR: 0.889, CiteScore: 3)
Cell Transplantation     Open Access   (Followers: 5, SJR: 1.023, CiteScore: 3)
Cephalalgia     Hybrid Journal   (Followers: 8, SJR: 1.581, CiteScore: 3)
Cephalalgia Reports     Open Access   (Followers: 4)
Child Language Teaching and Therapy     Hybrid Journal   (Followers: 34, SJR: 0.501, CiteScore: 1)
Child Maltreatment     Hybrid Journal   (Followers: 11, 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: 12)
China Information     Hybrid Journal   (Followers: 9, SJR: 0.767, CiteScore: 2)
China Report     Hybrid Journal   (Followers: 11, SJR: 0.221, CiteScore: 0)
Chinese J. of Sociology     Full-text available via subscription   (Followers: 5)
Christian Education J. : Research on Educational Ministry     Hybrid Journal   (Followers: 1)
Chronic Illness     Hybrid Journal   (Followers: 6, SJR: 0.672, CiteScore: 2)
Chronic Respiratory Disease     Hybrid Journal   (Followers: 12, 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: 32, SJR: 0.49, CiteScore: 1)
Clinical and Translational Neuroscience     Open Access   (Followers: 1)
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: 8, SJR: 0.552, CiteScore: 2)
Clinical Ethics     Hybrid Journal   (Followers: 13, 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   (Followers: 1, SJR: 0.314, CiteScore: 2)
Clinical Medicine Insights : Cardiology     Open Access   (Followers: 8, 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: 4, SJR: 0.425, CiteScore: 2)
Clinical Medicine Insights : Ear, Nose and Throat     Open Access   (Followers: 2)
Clinical Medicine Insights : Endocrinology and Diabetes     Open Access   (Followers: 34, 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: 1, 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: 3)
Clinical Medicine Insights : Women's Health     Open Access   (Followers: 4)
Clinical Nursing Research     Hybrid Journal   (Followers: 34, SJR: 0.471, CiteScore: 1)
Clinical Pathology     Open Access   (Followers: 5)
Clinical Pediatrics     Hybrid Journal   (Followers: 25, SJR: 0.487, CiteScore: 1)
Clinical Psychological Science     Hybrid Journal   (Followers: 16, SJR: 3.281, CiteScore: 5)
Clinical Rehabilitation     Hybrid Journal   (Followers: 78, SJR: 1.322, CiteScore: 3)
Clinical Risk     Hybrid Journal   (Followers: 5, SJR: 0.133, CiteScore: 0)
Clinical Trials     Hybrid Journal   (Followers: 22, SJR: 2.399, CiteScore: 2)
Clothing and Textiles Research J.     Hybrid Journal   (Followers: 28, SJR: 0.36, CiteScore: 1)
Collections : A J. for Museum and Archives Professionals     Full-text available via subscription   (Followers: 3)
Common Law World Review     Full-text available via subscription   (Followers: 17)
Communication & Sport     Hybrid Journal   (Followers: 8, SJR: 0.385, CiteScore: 1)
Communication and the Public     Hybrid Journal   (Followers: 2)
Communication Disorders Quarterly     Hybrid Journal   (Followers: 15, SJR: 0.458, CiteScore: 1)
Communication Research     Hybrid Journal   (Followers: 24, SJR: 2.171, CiteScore: 3)
Community College Review     Hybrid Journal   (Followers: 8, SJR: 1.451, CiteScore: 1)
Comparative Political Studies     Hybrid Journal   (Followers: 293, SJR: 3.772, CiteScore: 3)
Compensation & Benefits Review     Hybrid Journal   (Followers: 8)
Competition & Change     Hybrid Journal   (Followers: 12, SJR: 0.843, CiteScore: 2)

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Similar Journals
Journal Cover
Clinical Trials
Journal Prestige (SJR): 2.399
Citation Impact (citeScore): 2
Number of Followers: 22  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1740-7745 - ISSN (Online) 1740-7753
Published by Sage Publications Homepage  [1166 journals]
  • The U.S. Food and Drug Administration’s Complex Innovative Trial Design
           Pilot Meeting Program: Progress to date

    • Free pre-print version: Loading...

      Authors: Dionne Price, John Scott
      Abstract: Clinical Trials, Ahead of Print.
      BackgroundThe Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research of the U.S. Food and Drug Administration have been leaders in advancing science to protect and promote public health by ensuring that safe and effective drugs and biological products are available to those who need them. Recently, new therapeutic discoveries, increased understanding of disease mechanisms, the need for innovation to optimally use resources, and global public health crises have led to an evolving drug development landscape. As a result, the U.S. Food and Drug Administration and medical product developers are faced with unique challenges and opportunities. The U.S. Food and Drug Administration is proactively meeting the challenges of this evolving landscape through various efforts, including the Complex Innovative Trial Design Pilot Meeting Program. Our focus, here, will be on the pilot meeting program.MethodsThe U.S. Food and Drug Administration has defined a process to facilitate the implementation of the Complex Innovative Trial Design Pilot Meeting Program. The process is transparent and outlines the steps and timeline for submission, review, and meetings.ResultsFive submitted meeting requests have been selected for participation in the Complex Innovative Trial Design Pilot Meeting Program.ConclusionThe pilot meeting program has been successful in further educating stakeholders on the potential uses of complex innovative designs in trials intended to provide substantial evidence of effectiveness. The selected submissions, thus far, have all utilized a Bayesian framework. The reasons for the use of Bayesian approaches may be due to the flexibility provided, the ability to incorporate multiple sources of evidence, and a desire to better understand the U.S. Food and Drug Administration perspective on such approaches. We are confident the pilot meeting program will have continued success and impact the collective goal of bringing safe and effective medical products to patients.
      Citation: Clinical Trials
      PubDate: 2021-10-16T11:26:30Z
      DOI: 10.1177/17407745211050580
       
  • Commentary on Price and Scott: Complex innovative trial design

    • Free pre-print version: Loading...

      Authors: Alexia Iasonos, John O’Quigley
      Abstract: Clinical Trials, Ahead of Print.

      Citation: Clinical Trials
      PubDate: 2021-10-13T06:25:40Z
      DOI: 10.1177/17407745211050601
       
  • Design and implementation of an international, multi-arm, multi-stage
           platform master protocol for trials of novel SARS-CoV-2 antiviral agents:
           Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3)

    • Free pre-print version: Loading...

      Authors: Daniel D Murray, Abdel G Babiker, Jason V Baker, Christina E Barkauskas, Samuel M Brown, Christina C Chang, Victoria J Davey, Annetine C Gelijns, Adit A Ginde, Birgit Grund, Elizabeth Higgs, Fleur Hudson, Virginia L Kan, H Clifford Lane, Thomas A Murray, Roger Paredes, Mahesh KB Parmar, Sarah Pett, Andrew N Phillips, Mark N Polizzotto, Cavan Reilly, Uriel Sandkovsky, Shweta Sharma, Marc Teitelbaum, B Taylor Thompson, Barnaby E Young, James D Neaton, Jens D Lundgren
      Abstract: Clinical Trials, Ahead of Print.
      Background/aimsSafe and effective therapies for COVID-19 are urgently needed. In order to meet this need, the Accelerating COVID-19 Therapeutic Interventions and Vaccines public–private partnership initiated the Therapeutics for Inpatients with COVID-19. Therapeutics for Inpatients with COVID-19 is a multi-arm, multi-stage platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of novel candidate antiviral therapeutic agents for adults hospitalized with COVID-19. Five agents have so far entered the protocol, with rapid answers already provided for three of these. Other agents are expected to enter the protocol throughout 2021. This protocol contains a number of key design and implementation features that, along with challenges faced by the protocol team, are presented and discussed.MethodsThree clinical trial networks, encompassing a global network of clinical sites, participated in the protocol development and implementation. Therapeutics for Inpatients with COVID-19 utilizes a multi-arm, multi-stage design with an agile and robust approach to futility and safety evaluation at 300 patients enrolled, with subsequent expansion to full sample size and an expanded target population if the agent shows an acceptable safety profile and evidence of efficacy. Rapid recruitment to multiple agents is enabled through the sharing of placebo, the confining of agent-specific information to protocol appendices, and modular consent forms. In collaboration with the Food and Drug Administration, a thorough safety data collection and Data and Safety Monitoring Board schedule was developed for the study of potential therapeutic agents with limited in-human data in hospitalized patients with COVID-19.ResultsAs of 8 August 2021, five agents have entered the Therapeutics for Inpatients with COVID-19 master protocol and a total of 1909 participants have been randomized to one of these agents or matching placebo. There were a number of challenges faced by the study team that needed to be overcome in order to successfully implement Therapeutics for Inpatients with COVID-19 across a global network of sites. These included ensuring drug supply and reliable recruitment allowing for changing infection rates across the global network of sites, the need to balance the collection of data and samples without overburdening clinical staff and obtaining regulatory approvals across a global network of sites.ConclusionThrough a robust multi-network partnership, the Therapeutics for Inpatients with COVID-19 protocol has been successfully used across a global network of sites for rapid generation of efficacy data on multiple novel antiviral agents. The protocol design and implementation features used in this protocol, and the approaches to address challenges, will have broader applicability. Mechanisms to facilitate improved communication and harmonization among country-specific regulatory bodies are required to achieve the full potential of this approach in dealing with a global outbreak.
      Citation: Clinical Trials
      PubDate: 2021-10-11T05:11:43Z
      DOI: 10.1177/17407745211049829
       
  • Clinical studies sponsored by digital health companies participating in
           the FDA’s Precertification Pilot Program: A cross-sectional analysis

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      Authors: Victoria L Bartlett, Sanket S Dhruva, Nilay D Shah, Joseph S Ross
      Abstract: Clinical Trials, Ahead of Print.

      Citation: Clinical Trials
      PubDate: 2021-10-11T05:09:28Z
      DOI: 10.1177/17407745211048493
       
  • Why restricted mean survival time methods are especially useful for
           non-inferiority trials

    • Free pre-print version: Loading...

      Authors: Matteo Quartagno, Tim P Morris, Ian R White
      Abstract: Clinical Trials, Ahead of Print.

      Citation: Clinical Trials
      PubDate: 2021-09-23T10:28:19Z
      DOI: 10.1177/17407745211045124
       
  • Reply to Quartagno et al.

    • Free pre-print version: Loading...

      Authors: Boris Freidlin, Chen Hu, Edward L Korn
      Abstract: Clinical Trials, Ahead of Print.

      Citation: Clinical Trials
      PubDate: 2021-09-15T02:33:56Z
      DOI: 10.1177/17407745211045123
       
  • Ethically designing research to inform multidimensional, rapidly evolving
           policy decisions: Lessons learned from the PROMISE HIV Perinatal
           Prevention Trial

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      Authors: Seema K Shah, Alex John London, Lynne Mofenson, James V Lavery, Grace John-Stewart, Patricia Flynn, Gerhard Theron, Shrikhant I Bangdiwala, Dhayendre Moodley, Lameck Chinula, Lee Fairlie, Tumalano Sekoto, Tebogo J Kakhu, Avy Violari, Sufia Dadabhai, Katie McCarthy, Mary Glenn Fowler
      Abstract: Clinical Trials, Ahead of Print.
      Research in rapidly evolving policy contexts can lead to the following ethical challenges for sponsors and researchers: the study’s standard of care can become different than what patients outside the study receive, there may be political or other pressure to move ahead with unproven interventions, and new findings or revised policies may decrease the relevance of ongoing studies. These ethical challenges are considerable, but not unprecedented. In this article, we review the case of a multinational, randomized, controlled perinatal HIV prevention trial, the “PROMISE” (Promoting Maternal Infant Survival Everywhere) study. PROMISE compared the relative efficacy and safety of interventions to prevent mother to child transmission of HIV. The sponsor engaged an independent international ethics panel to address controversy about the study’s standard of care and relevance as national and international guidelines changed. This ethics panel concluded that continuing the PROMISE trial as designed was ethically permissible because: (1) participants in all arms received interventions that were effective, and there was insufficient evidence about whether one intervention was more effective or safer than the other, and (2) data from PROMISE could be useful for a diverse range of stakeholders. In general, trials designed to inform rapidly evolving policy issues should develop mechanisms to revisit social value while recognizing that the value of research varies for diverse stakeholders with legitimate reasons to weigh evidence differently. We conclude by providing four reasons that trials may depart from the standard of care after a change in policy, while remaining ethically justifiable, and by suggesting how to improve existing trial oversight mechanisms to address evolving social value.
      Citation: Clinical Trials
      PubDate: 2021-09-15T02:33:19Z
      DOI: 10.1177/17407745211045734
       
  • Application of tetrad testing to the evaluation of blinding strategies for
           ancillary supplies used in controlled clinical trials

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      Authors: Sébastien Dasnoy, Maxime Fouache, Andy White
      Abstract: Clinical Trials, Ahead of Print.
      Background/Aims:Ensuring verum and placebo cannot be visually distinguished from each other is a critical aspect of blinded controlled clinical trials. Our objective was to propose a rational approach to the visual evaluation of placebo matching candidates.Methods:Verum and placebo samples were prepared in clear clinical ancillary supplies (intravenous bags, syringes and administration lines) covered at different levels using opaque sleeves. Triangle and tetrad tests, two sensory discriminative testing methods widely used in the food industry, were applied to assess visual differences between verum and placebo.Results:Triangle and tetrad test results allowed defining the level of opaque coverage required to ensure blinding for three biological drug molecules of therapeutic interest. While the limited number of panelists did not allow a statistically sound comparison of triangle and tetrad test methodologies, tetrad test has a theoretical higher power than triangle test, meaning fewer panelists are needed to reach the same statistical conclusion.Conclusion:Tetrad test offers a rational approach to define a blinding strategy for ancillary supplies used in a controlled clinical trial.
      Citation: Clinical Trials
      PubDate: 2021-09-09T06:15:06Z
      DOI: 10.1177/17407745211044119
       
  • Clinical trial site identification practices and the use of electronic
           health records in feasibility evaluations: An interview study in the
           Nordic countries

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      Authors: Niina Laaksonen, Mia Bengtström, Anna Axelin, Juuso Blomster, Mika Scheinin, Risto Huupponen
      Abstract: Clinical Trials, Ahead of Print.
      Introduction:Feasibility evaluations are performed to create the best possible starting point for the set-up and execution of a clinical trial, and to identify any obstacles for successful trial conduct. New digital technologies can provide various types of data for use in feasibility evaluations. There is a need to identify and compare such data sources for trial site identification and for evaluating the sites’ patient recruitment potential. Especially, information is needed on the use of electronic health records. We investigated how different data sources are used by pharmaceutical companies operating in the Nordic countries for identifying trial sites and for evaluating their potential to recruit trial participants.Methods:This was a semi-structured qualitative interview study with 21 participants from pharmaceutical companies and contract research organizations operating in Finland, Sweden, Denmark and Norway. Qualitative content analysis was applied.Results:For identifying countries and trial sites on a global level, the trial sponsors mostly used databases on previous trial performance. The use of electronic health record data was very limited. Sites’ and investigators’ visibility in various databases was seen as fundamental for their countries becoming selected into new clinical trials. For estimating the sites’ recruitment projections, most sites were seen to base their patient count estimates solely on their previous experience. Some sites had reviewed their electronic health record data, which was considered to increase the accuracy of their recruitment estimates and these sites’ attractivity. Along with dialogs with investigators, the sponsors used various data sources to validate the investigators’ estimates. Legislative obstacles were seen to hinder the use of electronic health record queries for estimation of patient counts.Conclusion:Visibility in the databases used by trial sponsors is crucial for the countries and sites to be identified. Site selection appears to be based on trust and relationships built from experience, but electronic data provide the support upon which the trust is based. Estimation of the number of potential trial participants is a complex and time-consuming process for both investigators and sponsors. Sponsors seem to favour sites who could support their patient count estimates with electronic health record data as they were quicker in providing the estimates and more reliable than sites with no electronic health record evidence. The patient count evaluation process could be simplified, accelerated and made more reliable with more systematic use of electronic health record evidence in the feasibility evaluation phase. This would increase the accuracy of the patient count estimates and, on its part, contribute to improved recruitment success.
      Citation: Clinical Trials
      PubDate: 2021-08-25T09:32:17Z
      DOI: 10.1177/17407745211038512
       
  • Characteristics of available studies and dissemination of research using
           major clinical data sharing platforms

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      Authors: Enrique Vazquez, Henri Gouraud, Florian Naudet, Cary P Gross, Harlan M Krumholz, Joseph S Ross, Joshua D Wallach
      Abstract: Clinical Trials, Ahead of Print.
      Background/Aims:Over the past decade, numerous data sharing platforms have been launched, providing access to de-identified individual patient-level data and supporting documentation. We evaluated the characteristics of prominent clinical data sharing platforms, including types of studies listed as available for request, data requests received, and rates of dissemination of research findings from data requests.Methods:We reviewed publicly available information listed on the websites of six prominent clinical data sharing platforms: Biological Specimen and Data Repository Information Coordinating Center, ClinicalStudyDataRequest.com, Project Data Sphere, Supporting Open Access to Researchers–Bristol Myers Squibb, Vivli, and the Yale Open Data Access Project. We recorded key platform characteristics, including listed studies and available supporting documentation, information on the number and status of data requests, and rates of dissemination of research findings from data requests (i.e. publications in a peer-reviewed journals, preprints, conference abstracts, or results reported on the platform’s website).Results:The number of clinical studies listed as available for request varied among five data sharing platforms: Biological Specimen and Data Repository Information Coordinating Center (n = 219), ClinicalStudyDataRequest.com (n = 2,897), Project Data Sphere (n = 154), Vivli (n = 5426), and the Yale Open Data Access Project (n = 395); Supporting Open Access to Researchers did not provide a list of Bristol Myers Squibb studies available for request. Individual patient-level data were nearly always reported as being available for request, as opposed to only Clinical Study Reports (Biological Specimen and Data Repository Information Coordinating Center = 211/219 (96.3%); ClinicalStudyDataRequest.com = 2884/2897 (99.6%); Project Data Sphere = 154/154 (100.0%); and the Yale Open Data Access Project = 355/395 (89.9%)); Vivli did not provide downloadable study metadata. Of 1201 data requests listed on ClinicalStudyDataRequest.com, Supporting Open Access to Researchers–Bristol Myers Squibb, Vivli, and the Yale Open Data Access Project platforms, 586 requests (48.8%) were approved (i.e. data access granted). The majority were for secondary analyses and/or developing/validating methods (ClinicalStudyDataRequest.com = 262/313 (83.7%); Supporting Open Access to Researchers–Bristol Myers Squibb = 22/30 (73.3%); Vivli = 63/84 (75.0%); the Yale Open Data Access Project = 111/159 (69.8%)); four were for re-analyses or corroborations of previous research findings (ClinicalStudyDataRequest.com = 3/313 (1.0%) and the Yale Open Data Access Project = 1/159 (0.6%)). Ninety-five (16.1%) approved data requests had results disseminated via peer-reviewed publications (ClinicalStudyDataRequest.com = 61/313 (19.5%); Supporting Open Access to Researchers–Bristol Myers Squibb = 3/30 (10.0%); Vivli = 4/84 (4.8%); the Yale Open Data Access Project = 27/159 (17.0%)). Forty-two (6.8%) additional requests reported results through preprints, conference abstracts, or on the platform’s website (ClinicalStudyDataRequest.com = 12/313 (3.8%); Supporting Open Access to Researchers–Bristol Myers Squibb = 3/30 (10.0%); Vivli = 2/84 (2.4%); Yale Open Data Access Project = 25/159 (15.7%)).Conclusion:Across six prominent clinical data sharing platforms, information on studies and request metrics varied in availability and format. Most data requests focused on secondary analyses and approximately one-quarter of all approved requests publicly disseminated their results. To further promote the use of shared clinical data, platforms should increase transparency, consistently clarify the availability of the listed studies and supporting documentation, and ensure that research findings from data requests are disseminated.
      Citation: Clinical Trials
      PubDate: 2021-08-19T04:57:27Z
      DOI: 10.1177/17407745211038524
       
  • Cost-effective clinical trial design: Application of a Bayesian sequential
           model to the ProFHER pragmatic trial

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      Authors: Martin Forster, Stephen Brealey, Stephen Chick, Ada Keding, Belen Corbacho, Andres Alban, Paolo Pertile, Amar Rangan
      Abstract: Clinical Trials, Ahead of Print.
      Background/Aims:There is growing interest in the use of adaptive designs to improve the efficiency of clinical trials. We apply a Bayesian decision-theoretic model of a sequential experiment using cost and outcome data from the ProFHER pragmatic trial. We assess the model’s potential for delivering value-based research.Methods:Using parameter values estimated from the ProFHER pragmatic trial, including the costs of carrying out the trial, we establish when the trial could have stopped, had the model’s value-based stopping rule been used. We use a bootstrap analysis and simulation study to assess a range of operating characteristics, which we compare with a fixed sample size design which does not allow for early stopping.Results:We estimate that application of the model could have stopped the ProFHER trial early, reducing the sample size by about 14%, saving about 5% of the research budget and resulting in a technology recommendation which was the same as that of the trial. The bootstrap analysis suggests that the expected sample size would have been 38% lower, saving around 13% of the research budget, with a probability of 0.92 of making the same technology recommendation decision. It also shows a large degree of variability in the trial’s sample size.Conclusions:Benefits to trial cost stewardship may be achieved by monitoring trial data as they accumulate and using a stopping rule which balances the benefit of obtaining more information through continued recruitment with the cost of obtaining that information. We present recommendations for further research investigating the application of value-based sequential designs.
      Citation: Clinical Trials
      PubDate: 2021-08-19T04:54:48Z
      DOI: 10.1177/17407745211032909
       
  • On the design of early-phase Alzheimer’s disease clinical trials with
           cerebrospinal fluid tau outcomes

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      Authors: Michelle M Nuño, Joshua D Grill, Daniel L Gillen
      Abstract: Clinical Trials, Ahead of Print.
      Background/Aims:The focus of Alzheimer’s disease studies has shifted to earlier disease stages, including mild cognitive impairment. Biomarker inclusion criteria are often incorporated into mild cognitive impairment clinical trials to identify individuals with “prodromal Alzheimer’s disease” to ensure appropriate drug targets and enrich for participants likely to develop Alzheimer’s disease dementia. The use of these eligibility criteria may affect study power.Methods:We investigated outcome variability and study power in the setting of proof-of-concept prodromal Alzheimer’s disease trials that incorporate cerebrospinal fluid levels of total tau (t-tau) and phosphorylated (p-tau) as primary outcomes and how differing biomarker inclusion criteria affect power. We used data from the Alzheimer’s Disease Neuroimaging Initiative to model trial scenarios and to estimate the variance and within-subject correlation of total and phosphorylated tau. These estimates were then used to investigate the differences in study power for trials considering these two surrogate outcomes.Results:Patient characteristics were similar for all eligibility criteria. The lowest outcome variance and highest within-subject correlation were obtained when phosphorylated tau was used as an eligibility criterion, compared to amyloid beta or total tau, regardless of whether total tau or phosphorylated tau were used as primary outcomes. Power increased when eligibility criteria were broadened to allow for enrollment of subjects with either low amyloid beta or high phosphorylated tau.Conclusion:Specific biomarker inclusion criteria may impact statistical power in trials using total tau or phosphorylated tau as the primary outcome. In concert with other important considerations such as treatment target and population of clinical interest, these results may have implications to the integrity and efficiency of prodromal Alzheimer’s disease trial designs.
      Citation: Clinical Trials
      PubDate: 2021-07-30T05:02:36Z
      DOI: 10.1177/17407745211034497
       
  • Drug labeling changes and pediatric hematology/oncology prescribing:
           Measuring the impact of U.S. legislation

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      Authors: Tyler J Benning, Nilay D Shah, Jonathan W Inselman, Holly K Van Houten, Joseph S Ross, Kirk D Wyatt
      Abstract: Clinical Trials, Ahead of Print.
      Background/Aims:The Pediatric Research Equity Act and Best Pharmaceuticals for Children Act are intended to promote the conduct of clinical trials that generate pediatric-specific evidence about drug safety and efficacy. This study assesses the quality of evidence generated through Pediatric Research Equity Act–mandated and Best Pharmaceuticals for Children Act–incentivized clinical trials of hematology/oncology drugs and characterizes subsequent changes in pediatric drug utilization rates.Methods:Trial characteristics (blinding, randomization, and comparator group) were determined for clinical trials that supported pediatric label changes. Using data from OptumLabs® Data Warehouse, a de-identified administrative claims database, we calculated pediatric utilization rates for each drug. We calculated monthly utilization rates from January 2003 (or from the first month in which data were available) to December 2018.Results:We identified 11 hematology/oncology drugs that underwent pediatric label changes under the Pediatric Research Equity Act Pediatric Research Equity Act and/or Best Pharmaceuticals for Children Act, and we identified 15 trials supporting these changes. Of these trials, 36% (5/14) were randomized, 31% (4/13) were blinded, and 36% (5/14) used a comparator group. A median of 49 children (interquartile range 29.5) received the drug under investigation across these trials. Pediatric label changes were not associated with subsequent changes in pediatric drug utilization. Although some drugs saw increased pediatric use after gaining new pediatric indications, this pattern was not consistently observed. In addition, there was no evidence to suggest that drugs were utilized less frequently after they failed to receive pediatric indications.Conclusions:Clinical trials of hematology/oncology drugs conducted under the Pediatric Research Equity Act Pediatric Research Equity Act and Best Pharmaceuticals for Children Act generally have low methodological rigor, and the resulting label changes are not consistently associated with changes in pediatric utilization. Alternative regulatory strategies and study designs may be necessary to maximize the impact of newly generated knowledge on drug utilization.
      Citation: Clinical Trials
      PubDate: 2021-07-16T10:14:22Z
      DOI: 10.1177/17407745211030683
       
  • What do we do with our under-enrolled single-center COVID-19 clinical
           trials'

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      Authors: Shing M Lee, Denise Esserman, Ken Cheung, James Dziura, Peter Peduzzi, Magdalena Sobieszczyk
      Abstract: Clinical Trials, Ahead of Print.

      Citation: Clinical Trials
      PubDate: 2021-07-03T07:08:05Z
      DOI: 10.1177/17407745211027246
       
  • Joint testing of overall and simple effects for the two-by-two factorial
           trial design

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      Authors: Eric S Leifer, James F Troendle, Alexis Kolecki, Dean A Follmann
      First page: 521
      Abstract: Clinical Trials, Ahead of Print.
      Background/aims:The two-by-two factorial design randomizes participants to receive treatment A alone, treatment B alone, both treatments A and B(AB), or neither treatment (C). When the combined effect of A and B is less than the sum of the A and B effects, called a subadditive interaction, there can be low power to detect the A effect using an overall test, that is, factorial analysis, which compares the A and AB groups to the C and B groups. Such an interaction may have occurred in the Action to Control Cardiovascular Risk in Diabetes blood pressure trial (ACCORD BP) which simultaneously randomized participants to receive intensive or standard blood pressure, control and intensive or standard glycemic control. For the primary outcome of major cardiovascular event, the overall test for efficacy of intensive blood pressure control was nonsignificant. In such an instance, simple effect tests of A versus C and B versus C may be useful since they are not affected by a subadditive interaction, but they can have lower power since they use half the participants of the overall trial. We investigate multiple testing procedures which exploit the overall tests’ sample size advantage and the simple tests’ robustness to a potential interaction.Methods:In the time-to-event setting, we use the stratified and ordinary logrank statistics’ asymptotic means to calculate the power of the overall and simple tests under various scenarios. We consider the A and B research questions to be unrelated and allocate 0.05 significance level to each. For each question, we investigate three multiple testing procedures which allocate the type 1 error in different proportions for the overall and simple effects as well as the AB effect. The Equal Allocation 3 procedure allocates equal type 1 error to each of the three effects, the Proportional Allocation 2 procedure allocates 2/3 of the type 1 error to the overall A (respectively, B) effect and the remaining type 1 error to the AB effect, and the Equal Allocation 2 procedure allocates equal amounts to the simple A (respectively, B) and AB effects. These procedures are applied to ACCORD BP.Results:Across various scenarios, Equal Allocation 3 had robust power for detecting a true effect. For ACCORD BP, all three procedures would have detected a benefit of intensive glycemia control.Conclusions:When there is no interaction, Equal Allocation 3 has less power than a factorial analysis. However, Equal Allocation 3 often has greater power when there is an interaction. The R package factorial2x2 can be used to explore the power gain or loss for different scenarios.
      Citation: Clinical Trials
      PubDate: 2021-08-19T04:59:46Z
      DOI: 10.1177/17407745211014493
       
  • Intra-cluster correlations from the CLustered OUtcome Dataset bank to
           inform the design of longitudinal cluster trials

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      Authors: Elizabeth Korevaar, Jessica Kasza, Monica Taljaard, Karla Hemming, Terry Haines, Elizabeth L Turner, Jennifer A Thompson, James P Hughes, Andrew B Forbes
      First page: 529
      Abstract: Clinical Trials, Ahead of Print.
      Background:Sample size calculations for longitudinal cluster randomised trials, such as crossover and stepped-wedge trials, require estimates of the assumed correlation structure. This includes both within-period intra-cluster correlations, which importantly differ from conventional intra-cluster correlations by their dependence on period, and also cluster autocorrelation coefficients to model correlation decay. There are limited resources to inform these estimates. In this article, we provide a repository of correlation estimates from a bank of real-world clustered datasets. These are provided under several assumed correlation structures, namely exchangeable, block-exchangeable and discrete-time decay correlation structures.Methods:Longitudinal studies with clustered outcomes were collected to form the CLustered OUtcome Dataset bank. Forty-four available continuous outcomes from 29 datasets were obtained and analysed using each correlation structure. Patterns of within-period intra-cluster correlation coefficient and cluster autocorrelation coefficients were explored by study characteristics.Results:The median within-period intra-cluster correlation coefficient for the discrete-time decay model was 0.05 (interquartile range: 0.02–0.09) with a median cluster autocorrelation of 0.73 (interquartile range: 0.19–0.91). The within-period intra-cluster correlation coefficients were similar for the exchangeable, block-exchangeable and discrete-time decay correlation structures. Within-period intra-cluster correlation coefficients and cluster autocorrelations were found to vary with the number of participants per cluster-period, the period-length, type of cluster (primary care, secondary care, community or school) and country income status (high-income country or low- and middle-income country). The within-period intra-cluster correlation coefficients tended to decrease with increasing period-length and slightly decrease with increasing cluster-period sizes, while the cluster autocorrelations tended to move closer to 1 with increasing cluster-period size. Using the CLustered OUtcome Dataset bank, an RShiny app has been developed for determining plausible values of correlation coefficients for use in sample size calculations.Discussion:This study provides a repository of intra-cluster correlations and cluster autocorrelations for longitudinal cluster trials. This can help inform sample size calculations for future longitudinal cluster randomised trials.
      Citation: Clinical Trials
      PubDate: 2021-06-05T06:28:35Z
      DOI: 10.1177/17407745211020852
       
  • Simulation-based design of pragmatic trials in psoriatic arthritis using
           propensity scores

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      Authors: Sarah M Weinstein, Laura C Coates, Philip S Helliwell, Alexis Ogdie, Alisa J Stephens-Shields
      First page: 541
      Abstract: Clinical Trials, Ahead of Print.
      Background/Aims:Design of clinical trials requires careful decision-making across several dimensions, including endpoints, eligibility criteria, and subgroup enrichment. Clinical trial simulation can be an informative tool in trial design, providing empirical evidence by which to evaluate and compare the results of hypothetical trials with varying designs. We introduce a novel simulation-based approach using observational data to inform the design of a future pragmatic trial.Methods:We utilize propensity score-adjusted models to simulate hypothetical trials under alternative endpoints and enrollment criteria. We apply our approach to the design of pragmatic trials in psoriatic arthritis, using observational data embedded within the Tight Control of Inflammation in Early Psoriatic Arthritis study to simulate hypothetical open-label trials comparing treatment with tumor necrosis factor-α inhibitors to methotrexate. We first validate our simulations of a trial with traditional enrollment criteria and endpoints against a recently published trial. Next, we compare simulated treatment effects in patient populations defined by traditional and broadened enrollment criteria, where the latter is consistent with a future pragmatic trial. In each trial, we also consider five candidate primary endpoints.Results:Our results highlight how changes in the enrolled population and primary endpoints may qualitatively alter study findings and the ability to detect heterogeneous treatment effects between clinical subgroups. For treatments of interest in the study of psoriatic arthritis, broadened enrollment criteria led to diluted estimated treatment effects. Endpoints with greater responsiveness to treatment compared with a traditionally used endpoint were identified. These considerations, among others, are important for designing a future pragmatic trial aimed at having high external validity with relevance for real-world clinical practice.Conclusion:Observational data may be leveraged to inform design decisions in pragmatic trials. Our approach may be generalized to the study of other conditions where existing trial data are limited or do not generalize well to real-world clinical practice, but where observational data are available.
      Citation: Clinical Trials
      PubDate: 2021-08-25T09:34:54Z
      DOI: 10.1177/17407745211023840
       
  • Interim data monitoring in cluster randomised trials: Practical issues and
           a case study

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      Authors: K Hemming, J Martin, I Gallos, A Coomarasamy, L Middleton
      First page: 552
      Abstract: Clinical Trials, Ahead of Print.
      BackgroundThere is an abundance of guidance for the interim monitoring of individually randomised trials. While methodological literature exists on how to extend these methods to cluster randomised trials, there is little guidance on practical implementation. Cluster trials have many features which make their monitoring needs different. We outline the methodological and practical challenges of interim monitoring of cluster trials; and apply these considerations to a case study.Case studyThe E-MOTIVE study is an 80-cluster randomised trial of a bundle of interventions to treat postpartum haemorrhage. The proposed data monitoring plan includes (1) monitor sample size assumptions, (2) monitor for evidence of selection bias, and (3) an interim assessment of the primary outcome, as well as monitoring data completeness. The timing of the sample size monitoring is chosen with both consideration of statistical precision and to allow time to recruit more clusters. Monitoring for selection bias involves comparing individual-level characteristics and numbers recruited between study arms to identify any post-randomisation participant identification bias. An interim analysis of outcomes presented with 99.9% confidence intervals using the Haybittle–Peto approach should mitigate any concern regarding the inflation of type-I error. The pragmatic nature of the trial means monitoring for adherence is not relevant, as it is built into a process evaluation.ConclusionsThe interim analyses of cluster trials have a number of important differences to monitoring individually randomised trials. In cluster trials, there will often be a greater need to monitor nuisance parameters, yet there will often be considerable uncertainty in their estimation. This means the utility of sample size re-estimation can be questionable particularly when there are practical or funding difficulties associated with making any changes to planned sample sizes. Perhaps most importantly interim monitoring has the potential to identify selection bias, particularly in trials with post-randomisation identification or recruitment. Finally, the pragmatic nature of cluster trials might mean that the utility of methods to allow for interim monitoring of outcomes based on statistical testing, or monitoring for adherence to study interventions, are less relevant. Our intention is to facilitate the planning of future cluster randomised trials and to promote discussion and debate to improve monitoring of these studies.
      Citation: Clinical Trials
      PubDate: 2021-06-22T08:12:15Z
      DOI: 10.1177/17407745211024751
       
  • Stratified randomization for platform trials with differing experimental
           arm eligibility

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      Authors: Subodh Selukar, Susanne May, Dave Law, Megan Othus
      First page: 562
      Abstract: Clinical Trials, Ahead of Print.
      Background:Platform trials facilitate efficient use of resources by comparing multiple experimental agents to a common standard of care arm. They can accommodate a changing scientific paradigm within a single trial protocol by adding or dropping experimental arms—critical features for trials in rapidly developing disease areas such as COVID-19 or cancer therapeutics. However, in these trials, efficacy and safety issues may render certain participant subgroups ineligible to some experimental arms, and methods for stratified randomization do not readily apply to this setting.Methods:We propose extensions for conventional methods of stratified randomization for platform trials whose experimental arms may differ in eligibility criteria. These methods balance on a prespecified set of stratification variables observable prior to arm assignment that remains the same across experimental arms. To do so, we suggest modifying block randomization by including experimental arm eligibility as a stratifying variable, and we suggest modifying the imbalance score calculation in dynamic balancing by performing pairwise comparisons between each eligible experimental arm and standard of care arm participants eligible to that experimental arm.Results:We provide worked examples to illustrate the proposed extensions. In addition, we also provide a formula to quantify the relative efficiency loss of platform trials with varying eligibility compared with trials with non-varying eligibility as measured by the size of the common standard of care arm.Conclusions:This article presents important extensions to conventional methods for stratified randomization in order to facilitate the implementation of platform trials with differing experimental arm eligibility.
      Citation: Clinical Trials
      PubDate: 2021-08-21T07:15:10Z
      DOI: 10.1177/17407745211028872
       
  • Covariate adjustment in subgroup analyses of randomized clinical trials: A
           propensity score approach

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      Authors: Siyun Yang, Fan Li, Laine E Thomas, Fan Li
      First page: 570
      Abstract: Clinical Trials, Ahead of Print.
      Background:Subgroup analyses are frequently conducted in randomized clinical trials to assess evidence of heterogeneous treatment effect across patient subpopulations. Although randomization balances covariates within subgroups in expectation, chance imbalance may be amplified in small subgroups and adversely impact the precision of subgroup analyses. Covariate adjustment in overall analysis of randomized clinical trial is often conducted, via either analysis of covariance or propensity score weighting, but covariate adjustment for subgroup analysis has been rarely discussed. In this article, we develop propensity score weighting methodology for covariate adjustment to improve the precision and power of subgroup analyses in randomized clinical trials.Methods:We extend the propensity score weighting methodology to subgroup analyses by fitting a logistic regression propensity model with pre-specified covariate–subgroup interactions. We show that, by construction, overlap weighting exactly balances the covariates with interaction terms in each subgroup. Extensive simulations were performed to compare the operating characteristics of unadjusted estimator, different propensity score weighting estimators and the analysis of covariance estimator. We apply these methods to the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training trial to evaluate the effect of exercise training on 6-min walk test in several pre-specified subgroups.Results:Standard errors of the adjusted estimators are smaller than those of the unadjusted estimator. The propensity score weighting estimator is as efficient as analysis of covariance, and is often more efficient when subgroup sample size is small (e.g.
      Citation: Clinical Trials
      PubDate: 2021-07-16T10:13:45Z
      DOI: 10.1177/17407745211028588
       
  • Design and analysis of a 2-year parallel follow-up of repeated ivermectin
           mass drug administrations for control of malaria: Small sample
           considerations for cluster-randomized trials with count data

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      Authors: Conner L Jackson, Kathryn Colborn, Dexiang Gao, Sangeeta Rao, Hannah C Slater, Sunil Parikh, Brian D Foy, John Kittelson
      First page: 582
      Abstract: Clinical Trials, Ahead of Print.
      Background:Cluster-randomized trials allow for the evaluation of a community-level or group-/cluster-level intervention. For studies that require a cluster-randomized trial design to evaluate cluster-level interventions aimed at controlling vector-borne diseases, it may be difficult to assess a large number of clusters while performing the additional work needed to monitor participants, vectors, and environmental factors associated with the disease. One such example of a cluster-randomized trial with few clusters was the “efficacy and risk of harms of repeated ivermectin mass drug administrations for control of malaria” trial. Although previous work has provided recommendations for analyzing trials like repeated ivermectin mass drug administrations for control of malaria, additional evaluation of the multiple approaches for analysis is needed for study designs with count outcomes.Methods:Using a simulation study, we applied three analysis frameworks to three cluster-randomized trial designs (single-year, 2-year parallel, and 2-year crossover) in the context of a 2-year parallel follow-up of repeated ivermectin mass drug administrations for control of malaria. Mixed-effects models, generalized estimating equations, and cluster-level analyses were evaluated. Additional 2-year parallel designs with different numbers of clusters and different cluster correlations were also explored.Results:Mixed-effects models with a small sample correction and unweighted cluster-level summaries yielded both high power and control of the Type I error rate. Generalized estimating equation approaches that utilized small sample corrections controlled the Type I error rate but did not confer greater power when compared to a mixed model approach with small sample correction. The crossover design generally yielded higher power relative to the parallel equivalent. Differences in power between analysis methods became less pronounced as the number of clusters increased. The strength of within-cluster correlation impacted the relative differences in power.Conclusion:Regardless of study design, cluster-level analyses as well as individual-level analyses like mixed-effects models or generalized estimating equations with small sample size corrections can both provide reliable results in small cluster settings. For 2-year parallel follow-up of repeated ivermectin mass drug administrations for control of malaria, we recommend a mixed-effects model with a pseudo-likelihood approximation method and Kenward–Roger correction. Similarly designed studies with small sample sizes and count outcomes should consider adjustments for small sample sizes when using a mixed-effects model or generalized estimating equation for analysis. Although the 2-year parallel follow-up of repeated ivermectin mass drug administrations for control of malaria is already underway as a parallel trial, applying the simulation parameters to a crossover design yielded improved power, suggesting that crossover designs may be valuable in settings where the number of available clusters is limited. Finally, the sensitivity of the analysis approach to the strength of within-cluster correlation should be carefully considered when selecting the primary analysis for a cluster-randomized trial.
      Citation: Clinical Trials
      PubDate: 2021-07-03T07:09:24Z
      DOI: 10.1177/17407745211028581
       
  • Clinical trials site recruitment optimisation: Guidance from Clinical
           Trials: Impact and Quality

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      Authors: Christine Zahren, Sonia Harvey, Leanne Weekes, Charlotte Bradshaw, Radhika Butala, John Andrews, Sally O’Callaghan
      First page: 594
      Abstract: Clinical Trials, Ahead of Print.
      Background/Aims:Participants are integral to the success of any clinical research study, yet participant recruitment into clinical trials poses ongoing and complex challenges. It is widely accepted and recognised that clinical trial sites often find it difficult to meet recruitment goals, both in terms of accrual targets and timelines. This can impact the validity of trials or cause major delays for research. There are very few frameworks available to clinical trial sites to improve recruitment. The GREET project (Guidance to Recruitment: Examining Experiences at clinical Trial sites) sought to identify barriers to recruitment and produce formal guidance to optimise recruitment outcomes.Methods:Clinical Trials: Impact and Quality, a collaborative of sector stakeholders, convened a project team with comprehensive knowledge of the Australian clinical trials sector to undertake the GREET project. The project scope included exploration of recruitment issues at a site level across all phases of clinical trials and all types of trial sites. The scope excluded upstream issues such as protocol design and general public clinical trial awareness, participant retention and elements of recruitment outside a site’s capacity to directly influence or control. The project team’s extensive knowledge and experience conducting clinical trials in Australia was used to collaboratively identify a list of 24 key barriers and 12 enablers to site recruitment which formed the basis of the project. Key stakeholder groups were surveyed to challenge project team assumptions. A national and international environmental scan and literature review was conducted to identify best-practice recruitment solutions.Results:A total of 343 people responded to a survey sent to sites, sponsors, and contract research organisations, and 162 people responded to a survey sent to consumers via consumer networks. The key barriers and enablers initially identified by the project team aligned with the key outcomes of the surveys, which in turn assisted in the development of best-practice recommendations in the form of a Clinical Trial Site Recruitment Guide. Recommendations were grouped into four key themes; conducting accurate study feasibility; proactive planning during start-up; selecting optimal recruitment methods; and participant involvement. Early intervention was identified as a key facilitator in maximising improved recruitment outcomes. The GREET Clinical Trial Site Recruitment Guide is publicly accessible on the Clinical Trials: Impact and Quality website.Conclusion:Participant recruitment challenges experienced at a site level are widespread and varied, and there is no universal recruitment solution. However, this project identified that there are interventions and assessments that can be proactively implemented and selectively applied to facilitate improved recruitment outcomes.
      Citation: Clinical Trials
      PubDate: 2021-05-27T09:30:16Z
      DOI: 10.1177/17407745211015924
       
  • Navigating the ethics of remote research data collection

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      Authors: Luke Gelinas, Walker Morrell, Sarah A White, Barbara E Bierer
      First page: 606
      Abstract: Clinical Trials, Ahead of Print.
      COVID-19 has accelerated broad trends already in place toward remote research data collection and monitoring. This move implicates novel ethical and regulatory challenges which have not yet received due attention. Existing work is preliminary and does not seek to identify or grapple with the issues in a rigorous and sophisticated way. Here, we provide a framework for identifying and addressing challenges that we believe can help the research community realize the benefits of remote technologies while preserving ethical ideals and public trust. We organize issues into several distinct categories and provide points to consider in a table that can help facilitate ethical design and review of research studies using remote health instruments.
      Citation: Clinical Trials
      PubDate: 2021-07-07T11:26:00Z
      DOI: 10.1177/17407745211027245
       
  • Challenges and opportunities for conducting a vaccine trial during the
           COVID-19 pandemic in the United Kingdom

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      Authors: M Estée Török, Benjamin R Underwood, Mark Toshner, Claire Waddington, Emad Sidhom, Katherine Sharrocks, Rachel Bousfield, Charlotte Summers, Caroline Saunders, Zoe McIntyre, Helen Morris, Jo Piper, Gloria Calderon, Sarah Dennis, Tracy Assari, Anita Marguerie de Rotrou, Ashley Shaw, John Bradley, John O’Brien, Robert C Rintoul, Ian Smith, Ed Bullmore, Krishna Chatterjee
      First page: 615
      Abstract: Clinical Trials, Ahead of Print.
      The COVID-19 pandemic has resulted in unprecedented challenges for healthcare systems worldwide. It has also stimulated research in a wide range of areas including rapid diagnostics, novel therapeutics, use of technology to track patients and vaccine development. Here, we describe our experience of rapidly setting up and delivering a novel COVID-19 vaccine trial, using clinical and research staff and facilities in three National Health Service Trusts in Cambridgeshire, United Kingdom. We encountered and overcame a number of challenges including differences in organisational structures, research facilities available, staff experience and skills, information technology and communications infrastructure, and research training and assessment procedures. We overcame these by setting up a project team that included key members from all three organisations that met at least daily by teleconference. This group together worked to identify the best practices and procedures and to harmonise and cascade these to the wider trial team. This enabled us to set up the trial within 25 days and to recruit and vaccinate the participants within a further 23 days. The lessons learned from our experiences could be used to inform the conduct of clinical trials during a future infectious disease pandemic or public health emergency.
      Citation: Clinical Trials
      PubDate: 2021-06-22T08:11:55Z
      DOI: 10.1177/17407745211024764
       
  • Microbiota or placebo after antimicrobial therapy for recurrent
           Clostridioides difficile at home: A clinical trial with novel home-based
           enrollment

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      Authors: Dimitri M Drekonja, Aasma Shaukat, Jane H Zhang, Andrew R Reinink, Sean Nugent, Jason A Dominitz, Anne Davis-Karim, Dale N Gerding, Tassos C Kyriakides
      First page: 622
      Abstract: Clinical Trials, Ahead of Print.
      Introduction:Clostridiodes difficile infection is the leading cause of infectious diarrhea in the United States, with substantial morbidity and mortality. Recurrent infection is especially challenging, with each recurrence increasing the likelihood of a successive recurrence, leading to cycles of prolonged symptoms, frequent antimicrobial use, and decreased quality of life. Fecal microbiota transplantation to prevent recurrent infection is a promising intervention with a large effect size in observational studies, but with conflicting results from randomized controlled trials. We are conducting a Veterans Affairs-wide randomized controlled trial utilizing centralized case identification, with enrollment and fecal microbiota transplant administration occurring at the participant’s home. This type of trial design significantly improves trial efficiency, greatly decreases trial cost, increases consistency of trial administration, and most importantly makes nationwide clinical trials in less-common diseases possible.Methods:This is a randomized comparison of capsule-delivered fecal microbiota transplant for the prevention of recurrent Clostridiodes difficile infection, administered after successful initial treatment of recurrent C. difficile infection with standard therapy. The primary endpoint is the incidence of recurrent C. difficile infection or death. Cases are identified by searching the Veterans Affairs Corporate Data Warehouse, with central study coordinators then reaching out to potential participants. Individuals meeting inclusion criteria and interested in participation are scheduled for in-home consent, randomization, and capsule administration, followed by telephone follow-up for 6 months. To mitigate risks of COVID-19, enrollment via video visits has been implemented.Results:A total of 102 participants have been enrolled through January 2021. Centralized case identification and in-home enrollment has facilitated enrollment from 34 unique states, with 38% being from rural or highly rural areas.Discussion:Centralized case identification and in-home enrollment is a feasible and innovative method of conducting randomized controlled trials in the Veterans Affairs system, improving access to clinical research for populations who may have difficulty engaging with the traditional model of clinical trials where enrollment is based at large hospitals in major metropolitan areas.
      Citation: Clinical Trials
      PubDate: 2021-06-22T08:12:31Z
      DOI: 10.1177/17407745211021198
       
  • Using simulated infectious disease outbreaks to inform site selection and
           sample size for individually randomized vaccine trials during an ongoing
           epidemic

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      Authors: Zachary J Madewell, Ana Pastore Y Piontti, Qian Zhang, Nathan Burton, Yang Yang, Ira M Longini, M Elizabeth Halloran, Alessandro Vespignani, Natalie E Dean
      First page: 630
      Abstract: Clinical Trials, Ahead of Print.
      Background:Novel strategies are needed to make vaccine efficacy trials more robust given uncertain epidemiology of infectious disease outbreaks, such as arboviruses like Zika. Spatially resolved mathematical and statistical models can help investigators identify sites at highest risk of future transmission and prioritize these for inclusion in trials. Models can also characterize uncertainty in whether transmission will occur at a site, and how nearby or connected sites may have correlated outcomes. A structure is needed for how trials can use models to address key design questions, including how to prioritize sites, the optimal number of sites, and how to allocate participants across sites.Methods:We illustrate the added value of models using the motivating example of Zika vaccine trial planning during the 2015–2017 Zika epidemic. We used a stochastic, spatially resolved, transmission model (the Global Epidemic and Mobility model) to simulate epidemics and site-level incidence at 100 high-risk sites in the Americas. We considered several strategies for prioritizing sites (average site-level incidence of infection across epidemics, median incidence, probability of exceeding 1% incidence), selecting the number of sites, and allocating sample size across sites (equal enrollment, proportional to average incidence, proportional to rank). To evaluate each design, we stochastically simulated trials in each hypothetical epidemic by drawing observed cases from site-level incidence data.Results:When constraining overall trial size, the optimal number of sites represents a balance between prioritizing highest-risk sites and having enough sites to reduce the chance of observing too few endpoints. The optimal number of sites remained roughly constant regardless of the targeted number of events, although it is necessary to increase the sample size to achieve the desired power. Though different ranking strategies returned different site orders, they performed similarly with respect to trial power. Instead of enrolling participants equally from each site, investigators can allocate participants proportional to projected incidence, though this did not provide an advantage in our example because the top sites had similar risk profiles. Sites from the same geographic region may have similar outcomes, so optimal combinations of sites may be geographically dispersed, even when these are not the highest ranked sites.Conclusion:Mathematical and statistical models may assist in designing successful vaccination trials by capturing uncertainty and correlation in future transmission. Although many factors affect site selection, such as logistical feasibility, models can help investigators optimize site selection and the number and size of participating sites. Although our study focused on trial design for an emerging arbovirus, a similar approach can be made for any infectious disease with the appropriate model for the particular disease.
      Citation: Clinical Trials
      PubDate: 2021-07-03T07:11:25Z
      DOI: 10.1177/17407745211028898
       
  • Improving data monitoring in Australian clinical trials and research: Free
           resources and templates

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      Authors: Lauren Houston, Colin H Cortie, Yasmine Probst, Barbara J Meyer
      First page: 639
      Abstract: Clinical Trials, Ahead of Print.

      Citation: Clinical Trials
      PubDate: 2021-07-07T11:24:00Z
      DOI: 10.1177/17407745211026726
       
 
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