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  Subjects -> PHARMACY AND PHARMACOLOGY (Total: 575 journals)
Showing 1 - 200 of 253 Journals sorted alphabetically
AAPS Journal     Hybrid Journal   (Followers: 24)
AAPS Open     Open Access   (Followers: 4)
AAPS PharmSciTech     Hybrid Journal   (Followers: 6)
AboutOpen     Open Access  
ACS Pharmacology & Translational Science     Hybrid Journal   (Followers: 3)
Acta Pharmaceutica     Open Access   (Followers: 4)
Acta Pharmaceutica Indonesia     Open Access  
Acta Pharmaceutica Sinica B     Open Access   (Followers: 1)
Acta Pharmacologica Sinica     Hybrid Journal   (Followers: 3)
Acta Physiologica Hungarica     Full-text available via subscription  
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 4)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 93)
Advanced Herbal Medicine     Open Access   (Followers: 8)
Advanced Therapeutics     Hybrid Journal   (Followers: 1)
Advances in Pharmacoepidemiology & Drug Safety     Open Access   (Followers: 2)
Advances in Pharmacological and Pharmaceutical Sciences     Open Access   (Followers: 9)
Advances in Pharmacology     Full-text available via subscription   (Followers: 17)
Advances in Pharmacology and Pharmacy     Open Access   (Followers: 5)
Advances in Traditional Medicine     Hybrid Journal   (Followers: 3)
Adverse Drug Reaction Bulletin     Full-text available via subscription   (Followers: 5)
AJP : The Australian Journal of Pharmacy     Full-text available via subscription   (Followers: 8)
Alternatives to Laboratory Animals     Full-text available via subscription   (Followers: 9)
American Journal of Cardiovascular Drugs     Hybrid Journal   (Followers: 20)
American Journal of Drug Discovery and Development     Open Access   (Followers: 3)
American Journal of Health-System Pharmacy     Full-text available via subscription   (Followers: 54)
American Journal of Pharmacological Sciences     Open Access   (Followers: 1)
American Journal of Pharmacology and Toxicology     Open Access   (Followers: 23)
American Journal of Therapeutics     Hybrid Journal   (Followers: 13)
Analytical Methods     Hybrid Journal   (Followers: 8)
Annales Pharmaceutiques Francaises     Full-text available via subscription  
Annals of Pharmacotherapy     Hybrid Journal   (Followers: 56)
Annual Review of Pharmacology and Toxicology     Full-text available via subscription   (Followers: 36)
Anti-Infective Agents     Hybrid Journal   (Followers: 5)
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry     Hybrid Journal   (Followers: 5)
Antibiotics     Open Access   (Followers: 11)
Antibody Therapeutics     Open Access  
Antiviral Chemistry and Chemotherapy     Open Access   (Followers: 1)
Antiviral Research     Hybrid Journal   (Followers: 8)
Applied Clinical Trials     Full-text available via subscription   (Followers: 7)
Archiv der Pharmazie     Hybrid Journal   (Followers: 2)
Archives of Drug Information     Hybrid Journal   (Followers: 4)
Archives of Pharmacal Research     Full-text available via subscription   (Followers: 2)
Archives of Pharmacy and Pharmaceutical Sciences     Open Access   (Followers: 1)
Archives of Razi Institute     Open Access  
Archivos Venezolanos de Farmacología y Terapéutica     Open Access  
Ars Pharmaceutica     Open Access  
Asian Journal of Medical and Pharmaceutical Researches     Open Access  
Asian Journal of Pharmaceutical Research and Health Care     Open Access   (Followers: 2)
Asian Journal of Pharmaceutical Sciences     Open Access   (Followers: 1)
Asian Journal of Pharmaceutics     Open Access   (Followers: 1)
Asian Journal of Research in Medical and Pharmaceutical Sciences     Open Access  
ASSAY and Drug Development Technologies     Hybrid Journal   (Followers: 3)
Australian Journal of Herbal Medicine     Full-text available via subscription   (Followers: 4)
Australian Pharmacist     Full-text available via subscription   (Followers: 7)
Autonomic & Autacoid Pharmacology     Hybrid Journal  
Avicenna Journal of Phytomedicine     Open Access   (Followers: 1)
Bangladesh Journal of Pharmacology     Open Access  
Bangladesh Journal of Physiology and Pharmacology     Open Access  
Bangladesh Pharmaceutical Journal     Full-text available via subscription  
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 14)
Behavioural Pharmacology     Hybrid Journal   (Followers: 2)
Bioanalysis     Full-text available via subscription   (Followers: 11)
Biochemical Pharmacology     Hybrid Journal   (Followers: 10)
BioDrugs     Full-text available via subscription   (Followers: 8)
Biological & Pharmaceutical Bulletin     Full-text available via subscription   (Followers: 3)
Biomarkers in Drug Development     Partially Free   (Followers: 2)
Biomaterials     Hybrid Journal   (Followers: 55)
Biomedical and Environmental Sciences     Full-text available via subscription   (Followers: 1)
Biomedicine & Pharmacotherapy     Full-text available via subscription   (Followers: 2)
Biometrical Journal     Hybrid Journal   (Followers: 9)
Biopharm International     Full-text available via subscription   (Followers: 20)
Biopharmaceutics and Drug Disposition     Hybrid Journal   (Followers: 10)
BMC Pharmacology     Open Access   (Followers: 2)
BMC Pharmacology & Toxicology     Open Access   (Followers: 8)
Brazilian Journal of Pharmaceutical Sciences     Open Access   (Followers: 1)
British Journal of Clinical Pharmacology     Hybrid Journal   (Followers: 30)
British Journal of Pharmacology     Hybrid Journal   (Followers: 17)
British Journal of Pharmacy (BJPharm)     Open Access   (Followers: 2)
Bulletin of Faculty of Pharmacy, Cairo University     Open Access   (Followers: 2)
CADTH Technology Overviews     Free  
Canadian Journal of Pain     Open Access   (Followers: 3)
Canadian Journal of Physiology and Pharmacology     Hybrid Journal   (Followers: 2)
Canadian Pharmacists Journal / Revue des Pharmaciens du Canada     Hybrid Journal   (Followers: 3)
Cancer Biotherapy & Radiopharmaceuticals     Hybrid Journal  
Cancer Chemotherapy and Pharmacology     Hybrid Journal   (Followers: 4)
Cardiovascular Drugs and Therapy     Hybrid Journal   (Followers: 14)
Cardiovascular Therapeutics     Open Access   (Followers: 3)
Cephalalgia Reports     Open Access  
Chemical and Pharmaceutical Bulletin     Full-text available via subscription   (Followers: 1)
Chemical Research in Toxicology     Hybrid Journal   (Followers: 22)
ChemMedChem     Hybrid Journal   (Followers: 9)
Chemotherapy     Full-text available via subscription   (Followers: 3)
Chinese Herbal Medicines     Full-text available via subscription   (Followers: 1)
Chinese Journal of Pharmaceutical Analysis     Full-text available via subscription  
Ciencia e Investigación     Open Access  
Ciência Equatorial     Open Access  
Clinical and Experimental Pharmacology and Physiology     Hybrid Journal   (Followers: 7)
Clinical and Translational Science     Open Access   (Followers: 4)
Clinical Complementary Medicine and Pharmacology     Open Access  
Clinical Drug Investigation     Full-text available via subscription   (Followers: 8)
Clinical Medicine Insights : Therapeutics     Open Access  
Clinical Neuropharmacology     Hybrid Journal   (Followers: 2)
Clinical Pharmacist     Partially Free   (Followers: 12)
Clinical Pharmacokinetics     Full-text available via subscription   (Followers: 28)
Clinical Pharmacology & Therapeutics     Hybrid Journal   (Followers: 45)
Clinical Pharmacology in Drug Development     Hybrid Journal   (Followers: 4)
Clinical Pharmacology: Advances and Applications     Open Access   (Followers: 6)
Clinical Research and Regulatory Affairs     Hybrid Journal   (Followers: 12)
Clinical Therapeutics     Hybrid Journal   (Followers: 34)
Clinical Toxicology     Hybrid Journal   (Followers: 18)
Clinical Trials     Hybrid Journal   (Followers: 18)
CNS Drug Reviews     Open Access   (Followers: 4)
CNS Drugs     Full-text available via subscription   (Followers: 10)
Combination Products in Therapy     Open Access  
Consultant Pharmacist     Full-text available via subscription   (Followers: 2)
Consumer Drugs     Full-text available via subscription  
Contract Pharma     Full-text available via subscription  
Cosmetics     Open Access   (Followers: 4)
CPT : Pharmacometrics & Systems Pharmacology     Open Access   (Followers: 11)
Critical Reviews in Clinical Laboratory Sciences     Hybrid Journal   (Followers: 16)
Critical Reviews in Therapeutic Drug Carrier Systems     Full-text available via subscription   (Followers: 5)
Critical Reviews in Toxicology     Hybrid Journal   (Followers: 25)
Current Bioactive Compounds     Hybrid Journal  
Current Cancer Therapy Reviews     Hybrid Journal   (Followers: 5)
Current Clinical Pharmacology     Hybrid Journal   (Followers: 4)
Current Drug Delivery     Hybrid Journal   (Followers: 6)
Current Drug Discovery Technologies     Hybrid Journal   (Followers: 6)
Current Drug Metabolism     Hybrid Journal   (Followers: 5)
Current Drug Safety     Hybrid Journal   (Followers: 8)
Current Drug Targets     Hybrid Journal   (Followers: 5)
Current Drug Therapy     Hybrid Journal   (Followers: 3)
Current Enzyme Inhibition     Hybrid Journal   (Followers: 1)
Current Issues in Pharmacy and Medical Sciences     Open Access   (Followers: 2)
Current Medical Science     Hybrid Journal  
Current Medicinal Chemistry     Hybrid Journal   (Followers: 13)
Current Molecular Pharmacology     Hybrid Journal  
Current Nanoscience     Hybrid Journal  
Current Neuropharmacology     Hybrid Journal   (Followers: 1)
Current Opinion in Pharmacology     Hybrid Journal   (Followers: 8)
Current Pharmaceutical Analysis     Hybrid Journal   (Followers: 1)
Current Pharmaceutical Biotechnology     Hybrid Journal   (Followers: 10)
Current Pharmaceutical Design     Hybrid Journal   (Followers: 11)
Current Pharmacogenomics and Personalized Medicine     Hybrid Journal   (Followers: 3)
Current Pharmacology Reports     Hybrid Journal  
Current Protocols in Pharmacology     Hybrid Journal  
Current Radiopharmaceuticals     Hybrid Journal   (Followers: 1)
Current Research in Drug Discovery     Open Access   (Followers: 2)
Current Research in Pharmacology and Drug Discovery     Open Access   (Followers: 1)
Current Therapeutic Research     Open Access   (Followers: 6)
Current trends in Biotechnology and Pharmacy     Open Access   (Followers: 8)
Current Vascular Pharmacology     Hybrid Journal   (Followers: 4)
Dhaka University Journal of Pharmaceutical Sciences     Open Access  
Die Pharmazie - An International Journal of Pharmaceutical Sciences     Full-text available via subscription   (Followers: 5)
Dose-Response     Open Access  
Drug and Chemical Toxicology     Hybrid Journal   (Followers: 13)
Drug and Therapeutics Bulletin     Hybrid Journal   (Followers: 8)
Drug Delivery     Open Access   (Followers: 8)
Drug Delivery and Translational Research     Hybrid Journal   (Followers: 2)
Drug Design, Development and Therapy     Open Access   (Followers: 3)
Drug Development and Industrial Pharmacy     Hybrid Journal   (Followers: 29)
Drug Development Research     Hybrid Journal   (Followers: 11)
Drug Discovery Today: Technologies     Full-text available via subscription   (Followers: 12)
Drug Metabolism and Disposition     Hybrid Journal   (Followers: 13)
Drug Metabolism and Pharmacokinetics     Hybrid Journal   (Followers: 6)
Drug Metabolism Letters     Hybrid Journal   (Followers: 3)
Drug Metabolism Reviews     Hybrid Journal   (Followers: 8)
Drug Research     Hybrid Journal   (Followers: 3)
Drug Resistance Updates     Hybrid Journal   (Followers: 3)
Drug Safety     Full-text available via subscription   (Followers: 78)
Drug Safety - Case Reports     Open Access   (Followers: 2)
Drug Target Insights     Open Access  
Drug, Healthcare and Patient Safety     Open Access   (Followers: 10)
Drugs     Full-text available via subscription   (Followers: 122)
Drugs & Aging     Full-text available via subscription   (Followers: 9)
Drugs & Therapy Perspectives     Full-text available via subscription   (Followers: 9)
Drugs : Real World Outcomes     Hybrid Journal   (Followers: 1)
Drugs and Therapy Studies     Open Access  
Drugs in R & D     Full-text available via subscription   (Followers: 2)
Drugs of the Future     Full-text available via subscription   (Followers: 8)
East and Central African Journal of Pharmaceutical Sciences     Open Access   (Followers: 1)
Egyptian Pharmaceutical Journal     Open Access  
EJNMMI Radiopharmacy and Chemistry     Open Access  
EMC - Cosmetologia Medica e Medicina degli Inestetismi Cutanei     Full-text available via subscription  
Emerging Trends in Drugs, Addictions, and Health     Open Access  
Environmental Toxicology and Pharmacology     Hybrid Journal   (Followers: 9)
Epilepsy Research     Hybrid Journal   (Followers: 7)
Ethiopian Pharmaceutical Journal     Full-text available via subscription   (Followers: 1)
EUREKA : Health Sciences     Open Access  
European Journal of Clinical Pharmacology     Hybrid Journal   (Followers: 14)
European Journal of Drug Metabolism and Pharmacokinetics     Hybrid Journal   (Followers: 8)
European Journal of Hospital Pharmacy : Science and Practice (EJHP)     Hybrid Journal   (Followers: 5)
European Journal of Medicinal Plants     Open Access   (Followers: 2)
European Journal of Pharmaceutical Sciences     Hybrid Journal   (Followers: 85)
European Journal of Pharmaceutics and Biopharmaceutics     Hybrid Journal   (Followers: 34)
European Journal of Pharmacology     Hybrid Journal   (Followers: 8)
European Neuropsychopharmacology     Hybrid Journal   (Followers: 9)
European Review for Medical and Pharmacological Sciences     Full-text available via subscription   (Followers: 1)
Experimental and Clinical Psychopharmacology     Full-text available via subscription   (Followers: 7)
Expert Opinion on Drug Delivery     Hybrid Journal   (Followers: 17)
Expert Opinion on Drug Discovery     Hybrid Journal   (Followers: 18)

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Similar Journals
Journal Cover
Clinical Trials
Journal Prestige (SJR): 2.399
Citation Impact (citeScore): 2
Number of Followers: 18  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1740-7745 - ISSN (Online) 1740-7753
Published by Sage Publications Homepage  [1174 journals]
  • Evolving challenges in clinical trials design

    • Free pre-print version: Loading...

      Authors: Colin B Begg
      Pages: 237 - 238
      Abstract: Clinical Trials, Volume 19, Issue 3, Page 237-238, June 2022.

      Citation: Clinical Trials
      PubDate: 2022-06-16T05:11:16Z
      DOI: 10.1177/17407745221101276
      Issue No: Vol. 19, No. 3 (2022)
       
  • Use of information criteria for selecting a correlation structure for
           longitudinal cluster randomised trials

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      Authors: Ehsan Rezaei-Darzi, Jessica Kasza, Andrew Forbes, Rhys Bowden
      Pages: 316 - 325
      Abstract: Clinical Trials, Volume 19, Issue 3, Page 316-325, June 2022.
      Background:When designing and analysing longitudinal cluster randomised trials, such as the stepped wedge, the similarity of outcomes from the same cluster must be accounted for through the choice of a form for the within-cluster correlation structure. Several choices for this structure are commonly considered for application within the linear mixed model paradigm. The first assumes a constant intra-cluster correlation for all pairs of outcomes from the same cluster (the exchangeable/Hussey and Hughes model); the second assumes that correlations of outcomes measured in the same period are higher than outcomes measured in different periods (the block exchangeable model) and the third is the discrete-time decay model, which allows the correlation between pairs of outcomes to decay over time. Currently, there is limited guidance on how to select the most appropriate within-cluster correlation structure.Methods:We simulated continuous outcomes under each of the three considered within-cluster correlation structures for a range of design and parameter choices, and, using the ASReml-R package, fit each linear mixed model to each simulated dataset. We evaluated the performance of the Akaike and Bayesian information criteria for selecting the correct within-cluster correlation structure for each dataset.Results:For smaller total sample sizes, neither criteria performs particularly well in selecting the correct within-cluster correlation structure, with the simpler exchangeable model being favoured. Furthermore, in general, the Bayesian information criterion favours the exchangeable model. When the cluster auto-correlation (which defines the degree of dependence between observations in adjacent time periods) is large and number of periods is small, neither criteria is able to distinguish between the block exchangeable and discrete time decay models. However, for increasing numbers of clusters, periods, and subjects per cluster period, both the Akaike and Bayesian information criteria perform increasingly well in the detection of the correct within-cluster correlation structure.Conclusions:With increasing amounts of data, be they number of clusters, periods or subjects per cluster period, both the Akaike and Bayesian information criteria are increasingly likely to select the correct correlation structure. We recommend that if there are sufficient data available when planning a trial, that the Akaike or Bayesian information criterion is used to guide the choice of within-cluster correlation structure in the absence of other compelling justifications for a specific correlation structure. We also suggest that researchers conduct supplementary analyses under alternate correlation structures to gauge sensitivity to the initial choice.
      Citation: Clinical Trials
      PubDate: 2022-06-16T05:10:02Z
      DOI: 10.1177/17407745221082227
      Issue No: Vol. 19, No. 3 (2022)
       
  • Current recommendations/practices for anonymising data from clinical
           trials in order to make it available for sharing: A scoping review

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      Authors: Aryelly Rodriguez, Christopher Tuck, Marshall F Dozier, Stephanie C Lewis, Sandra Eldridge, Tracy Jackson, Alastair Murray, Christopher J Weir
      Abstract: Clinical Trials, Ahead of Print.
      Background/AimsThere are increasing pressures for anonymised datasets from clinical trials to be shared across the scientific community, and differing recommendations exist on how to perform anonymisation prior to sharing. We aimed to systematically identify, describe and synthesise existing recommendations for anonymising clinical trial datasets to prepare for data sharing.MethodsWe systematically searched MEDLINE®, EMBASE and Web of Science from inception to 8 February 2021. We also searched other resources to ensure the comprehensiveness of our search. Any publication reporting recommendations on anonymisation to enable data sharing from clinical trials was included. Two reviewers independently screened titles, abstracts and full text for eligibility. One reviewer extracted data from included papers using thematic synthesis, which then was sense-checked by a second reviewer. Results were summarised by narrative analysis.ResultsFifty-nine articles (from 43 studies) were eligible for inclusion. Three distinct themes are emerging: anonymisation, de-identification and pseudonymisation. The most commonly used anonymisation techniques are: removal of direct patient identifiers; and careful evaluation and modification of indirect identifiers to minimise the risk of identification. Anonymised datasets joined with controlled access was the preferred method for data sharing.ConclusionsThere is no single standardised set of recommendations on how to anonymise clinical trial datasets for sharing. However, this systematic review shows a developing consensus on techniques used to achieve anonymisation. Researchers in clinical trials still consider that anonymisation techniques by themselves are insufficient to protect patient privacy, and they need to be paired with controlled access.
      Citation: Clinical Trials
      PubDate: 2022-06-22T12:36:46Z
      DOI: 10.1177/17407745221087469
       
  • Proceedings of the University of Pennsylvania 13th annual conference on
           statistical issues in clinical trials: Cluster randomized clinical
           trials—Challenges and opportunities

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      Authors: Susan S Ellenberg, Jonas H Ellenberg
      Abstract: Clinical Trials, Ahead of Print.

      Citation: Clinical Trials
      PubDate: 2022-06-09T01:06:36Z
      DOI: 10.1177/17407745221100226
       
  • Facilitating clinical research through automation: Combining optical
           character recognition with natural language processing

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      Authors: Julie Hom, Janet Nikowitz, Rebecca Ottesen, Joyce C Niland
      Abstract: Clinical Trials, Ahead of Print.
      Background/AimsPerformance status is crucial for most clinical research, as an eligibility criterion, a comorbidity covariate, or a trial endpoint. Yet information on performance status often is embedded as free text within a patient’s electronic medical record, rather than coded directly, thereby making this concept extremely difficult to extract for research. Furthermore, performance status information frequently resides in outside reports, which are scanned into the electronic medical record along with thousands of clinic notes. The image format of scanned documents also is a major obstacle to the search and retrieval of information, as natural language processing cannot be applied to unstructured text within an image. We, therefore, utilized optical character recognition software to convert images to a searchable format, allowing the application of natural language processing to identify pertinent performance status data elements within scanned electronic medical records.MethodsOur study cohort consisted of 189 subjects diagnosed with diffuse large B-cell lymphoma for whom performance status was a required data element for analysis of prognostic factors related to recurrence and survival. Manual abstraction of performance status was previously conducted by a clinical Subject Matter Expert, serving as the gold standard. Leveraging our data warehouse, we extracted relevant scanned electronic medical record documents and applied optical character recognition to these images using the ABBYY FineReader software. The Linguamatics i2e natural language processing software was then used to run queries for performance status against the corpus of electronic medical record documents. We evaluated our optical character recognition/natural language processing pipeline for accuracy and reduction in data extraction effort.ResultsWe found that there was high accuracy and reduced time for extraction of performance status data by applying our optical character recognition/natural language processing pipeline. The transformed scanned documents from a random sample of patients yielded excellent precision, recall, and F score, with
      Citation: Clinical Trials
      PubDate: 2022-05-24T10:29:01Z
      DOI: 10.1177/17407745221093621
       
  • Barriers and enablers to cancer clinical trial participation and
           initiatives to improve opportunities for rural cancer patients: A scoping
           review

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      Authors: Narelle J McPhee, Claire E Nightingale, Samuel J Harris, Eva Segelov, Eli Ristevski
      Abstract: Clinical Trials, Ahead of Print.

      Citation: Clinical Trials
      PubDate: 2022-05-19T06:19:26Z
      DOI: 10.1177/17407745221090733
       
  • Combining factorial and multi-arm multi-stage platform designs to evaluate
           multiple interventions efficiently

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      Authors: Ian R White, Babak Choodari-Oskooei, Matthew R Sydes, Brennan C Kahan, Leanne McCabe, Anna Turkova, Hanif Esmail, Diana M Gibb, Deborah Ford
      Abstract: Clinical Trials, Ahead of Print.
      BackgroundFactorial-MAMS design platform designs have many advantages, but the practical advantages and disadvantages of combining the two designs have not been explored.MethodsWe propose practical methods for a combined design within the platform trial paradigm where some interventions are not expected to interact and could be given together.ResultsWe describe the combined design and suggest diagrams that can be used to represent it. Many properties are common both to standard factorial designs, including the need to consider interactions between interventions and the impact of intervention efficacy on power of other comparisons, and to standard multi-arm multi-stage designs, including the need to pre-specify procedures for starting and stopping intervention comparisons. We also identify some specific features of the factorial-MAMS design: timing of interim and final analyses should be determined by calendar time or total observed events; some non-factorial modifications may be useful; eligibility criteria should be broad enough to include any patient eligible for any part of the randomisation; stratified randomisation may conveniently be performed sequentially; and analysis requires special care to use only concurrent controls.ConclusionA combined factorial-MAMS design can combine the efficiencies of factorial trials and multi-arm multi-stage platform trials. It allows us to address multiple research questions under one protocol and to test multiple new treatment options, which is particularly important when facing a new emergent infection such as COVID-19.
      Citation: Clinical Trials
      PubDate: 2022-05-17T09:29:59Z
      DOI: 10.1177/17407745221093577
       
  • A permutation procedure to detect heterogeneous treatments effects in
           randomized clinical trials while controlling the type I error rate

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      Authors: Jack M Wolf, Joseph S Koopmeiners, David M Vock
      Abstract: Clinical Trials, Ahead of Print.
      Background/AimsSecondary analyses of randomized clinical trials often seek to identify subgroups with differential treatment effects. These discoveries can help guide individual treatment decisions based on patient characteristics and identify populations for which additional treatments are needed. Traditional analyses require researchers to pre-specify potential subgroups to reduce the risk of reporting spurious results. There is a need for methods that can detect such subgroups without a priori specification while allowing researchers to control the probability of falsely detecting heterogeneous subgroups when treatment effects are uniform across the study population.MethodsWe propose a permutation procedure for tuning parameter selection that allows for type I error control when testing for heterogeneous treatment effects framed within the Virtual Twins procedure for subgroup identification. We verify that the type I error rate can be controlled at the nominal rate and investigate the power for detecting heterogeneous effects when present through extensive simulation studies. We apply our method to a secondary analysis of data from a randomized trial of very low nicotine content cigarettes.ResultsIn the absence of type I error control, the observed type I error rate for Virtual Twins was between 99% and 100%. In contrast, models tuned via the proposed permutation were able to control the type I error rate and detect heterogeneous effects when present. An application of our approach to a recently completed trial of very low nicotine content cigarettes identified several variables with potentially heterogeneous treatment effects.ConclusionsThe proposed permutation procedure allows researchers to engage in secondary analyses of clinical trials for treatment effect heterogeneity while maintaining the type I error rate without pre-specifying subgroups.
      Citation: Clinical Trials
      PubDate: 2022-05-09T08:43:10Z
      DOI: 10.1177/17407745221095855
       
  • Risk-proportionate approach to paediatric clinical trials: The legal
           requirements, challenges, and the way forward under the European Union
           Clinical Trials Regulation

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      Authors: Mandy Wan, Elisa Alessandrini, Paul Brogan, Despina Eleftheriou, Adilia Warris, Roger Brüggemann, Mark Turner
      Abstract: Clinical Trials, Ahead of Print.
      BackgroundIt is now widely accepted that there is a need for safety and efficacy data on medicines used in children. In the European Union, legislation has provided the necessary framework obligating and incentivizing pharmaceutical companies to carry out appropriate paediatric research to support the development of new medicines. This change in research culture, that medicines used in children should be appropriately researched in children, has also led to the recognition of the importance of investigator-initiated clinical trials in furthering medical knowledge on the off-label use of authorized medicines for which paediatric data are often limited. However, medicines regulatory authorities of European Union countries have largely adopted a uniform approach to the regulation of both industry-sponsored and investigator-initiated trials and, in doing so, have added disproportionate burden to the conduct of paediatric clinical trials investigating authorized medicines.Case studiesTwo European multinational paediatric clinical trials funded by the conect4children consortium are presented to provide a comparative insight into past challenges and to illustrate how the new framework provided by the European Clinical Trials Regulation (No. 536/2014) addresses these barriers in practice.ConclusionThe European Clinical Trials Regulation gives a strong impetus to a risk-proportionate approach and offers a path for more efficient delivery of investigator-initiated paediatric clinical trials.
      Citation: Clinical Trials
      PubDate: 2022-05-05T09:18:16Z
      DOI: 10.1177/17407745221093812
       
  • An introduction to spillover effects in cluster randomized trials with
           noncompliance

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      Authors: Luke Keele, Hyunseung Kang
      Abstract: Clinical Trials, Ahead of Print.
      In some cluster randomized trials, subjects may not comply with their assigned treatment status. Such treatment noncompliance can create opportunities for spillover effects within clusters. Little research has focused on what can be learned in such context. This article provides a non-technical review of recent work on the complications that arise in cluster randomized trials where some units within treated clusters do not comply with treatment but the treatment spillovers over to these units. We motivate concepts using a hypothetical vaccine cluster randomized trial. We review that standard instrumental variable methods cannot recover the complier average causal effect in the presence of these spillovers. In fact, we review that without additional assumptions, little can be learned about compliance effects or spillover effects. We discuss one additional assumption that allows for bounds on a key causal effect. We also outline an estimator for these bounds.
      Citation: Clinical Trials
      PubDate: 2022-05-05T09:10:49Z
      DOI: 10.1177/17407745221093580
       
  • Reporting of clinical trial safety results in ClinicalTrials.gov for
           FDA-approved drugs: A cross-sectional analysis

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      Authors: Krista Y Chen, Erin M Borglund, Emma Charlotte Postema, Adam G Dunn, Florence T Bourgeois
      Abstract: Clinical Trials, Ahead of Print.
      BackgroundAdverse events identified during clinical trials can be important early indicators of drug safety, but complete and timely data on safety results have historically been difficult to access. The aim was to compare the availability, completeness, and concordance of safety results reported in ClinicalTrials.gov and peer-reviewed publications.MethodsWe analyzed clinical trials used in the Food and Drug Administration safety assessment of new drugs approved between 1 July 2018 and 30 June 2019. The key safety outcomes examined were all-cause mortality, serious adverse events, adverse events, and withdrawals due to adverse events. Availability of safety results was measured by the presence and timing of a record of trial-level results in ClinicalTrials.gov and a corresponding peer-reviewed publication. For the subset of trials with available results, completeness was defined as the reporting of safety results for all participants and compared between ClinicalTrials.gov and publications. To assess concordance, we compared the numeric results for safety outcomes reported in ClinicalTrials.gov and publications to results in Food and Drug Administration trial reports.ResultsAmong 156 trials studying 52 drugs, 91 (58.3%) trials reported safety results in ClinicalTrials.gov and 106 (67.9%) in peer-reviewed publications (risk difference = −9.6%, 95% confidence interval = −20.3 to 1.0). All-cause mortality was reported sooner in published articles compared with ClinicalTrials.gov (log-rank test, p = 0.01). There was no difference in time to reporting for serious adverse events (p = 0.05), adverse events (p = 0.09), or withdrawals due to adverse events (p = 0.20). Complete reporting of all-cause mortality was similar in ClinicalTrials.gov and publications (74.7% vs 78.3%, respectively; risk difference = −3.6%, 95% confidence interval = −15.5 to 8.3) and higher in ClinicalTrials.gov for serious adverse events (100% vs 79.2%; risk difference = 20.8%, 95% confidence interval = 13.0 to 28.5) and adverse events (100% vs 86.8%; risk difference = 13.2%, 95% confidence interval = 6.8 to 19.7). Withdrawals due to adverse events were less often completely reported in ClinicalTrials.gov (62.6% vs 92.5%; risk difference = −29.8%, 95% confidence interval = −40.1 to −18.7). No difference was found in concordance of results between ClinicalTrials.gov and publications for all-cause mortality, serious adverse events, or withdrawals due to adverse events.ConclusionSafety results were available in ClinicalTrials.gov at a similar rate as in peer-reviewed publications, with more complete reporting of certain safety outcomes in ClinicalTrials.gov. Future efforts should consider adverse event reporting in ClinicalTrials.gov as an accessible data source for post-marketing surveillance and other evidence synthesis tasks.
      Citation: Clinical Trials
      PubDate: 2022-04-28T03:26:36Z
      DOI: 10.1177/17407745221093567
       
  • Practical issues in operationalizing the design and outcome evaluation of
           cluster randomized trials

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      Authors: Deborah Donnell
      Abstract: Clinical Trials, Ahead of Print.
      Trial designs using cluster-level randomization are necessary when interventions have intended effects that cannot be measured with individual randomization. When an intervention is intrinsically only able to be delivered to a cluster or when implementation of an individual level intervention is only feasibly implemented at a cluster level, cluster-level randomization is required. In designing the strategy for evaluation of the primary outcome of a cluster randomized trial, there are a multitude of important decisions to consider. While these decisions are guided primarily by the intervention—who benefits, what is the intended effect and when will it be achieved—there are important detailed choices that affect potential bias and statistical power, and implementation considerations that require compromise for considerations of feasibility and practicality. Through the lens of three large completed cluster randomized trials in HIV prevention, we present specific choices made for the overall evaluation plan, together with some of the detailed considerations, compromises and modifications that occurred during trial implementation.
      Citation: Clinical Trials
      PubDate: 2022-04-08T12:14:02Z
      DOI: 10.1177/17407745221087465
       
  • Random effect misspecification in stepped wedge designs

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      Authors: Emily C Voldal, Fan Xia, Avi Kenny, Patrick J Heagerty, James P Hughes
      Abstract: Clinical Trials, Ahead of Print.
      Stepped wedge cluster randomized trials are often analysed using linear mixed effects models that may include random effects for cluster, time and/or treatment. We investigate the impact of misspecification of the random effects structure of the model. Specifically, we considered two cases of misspecification of the random effects in a cross-sectional stepped wedge cluster randomized trials model – fit a linear mixed effects model with random time effects but the true model includes random treatment effects (case 1) or fit a linear mixed effects model with random treatment effect but the true model includes random time effects (case 2) – and derived the variance of the estimated treatment effect under misspecification. We defined two measures of the effect of misspecification: validity and efficiency. Validity is the ratio of the model-based variance of the treatment effect from the mis-specified model divided by the true variance of the treatment effect from the mis-specified model (based on a sandwich estimate of the variance). Efficiency is the ratio of the model-based variance of the treatment effect from the correctly specified model divided by the true variance of the treatment effect from the mis-specified model. We found that validity is less than 1.0 (anti-conservative) in almost all situations investigated with the exception of case 1 with two sequences, when validity could be greater than 1.0. Efficiency is less than 1 in all cases and depends on the intracluster correlation coefficient, the relative magnitude of the variance of the misclassified variance component, and the number of sequences. In general, there is no universal recommendation as to the most robust approach except for the case of a classic stepped wedge cluster randomized trial with only 2 sequences, where fitting a random time model is less likely to lead to anti-conservative inference compared with fitting a random intervention model.
      Citation: Clinical Trials
      PubDate: 2022-03-08T01:13:44Z
      DOI: 10.1177/17407745221084702
       
  • Practical considerations in utilizing cluster randomized controlled trials
           conducted in biopharmaceutical industry

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      Authors: Yixin Fang, Weili He
      Abstract: Clinical Trials, Ahead of Print.
      Cluster randomized controlled trials (cluster RCTs), also known as parallel-arm group-randomized trials, are trials in which the randomized units are groups of participants, as opposed to individual participants. These trials have largely been implemented to address broad public health issues, but with the growing interest in use of real-world data in the regulatory setting, this design may be increasingly considered for industry trials. The key difference between cluster RCTs and traditional RCTs is the intraclass correlation coefficient (ICC) that needs to be considered in cluster RCTs. In this article, we discuss some key practical considerations that are related to ICC in the design, conduct, analysis, and report stages of a cluster RCT. These key considerations related to ICC can lead to improvement in how we translate research findings from cluster RCTs into practices in the biopharmaceutical industry.
      Citation: Clinical Trials
      PubDate: 2022-03-05T09:01:33Z
      DOI: 10.1177/17407745211073484
       
  • Randomization: Beyond the closurization principle

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      Authors: Lawrence H Moulton
      Abstract: Clinical Trials, Ahead of Print.
      Many cluster randomized trials have relatively few numbers of clusters to be randomized. When baseline cluster-level covariates are available prior to randomization, the set of potential allocations can be restricted so as to ensure balance across study arms. This article discusses why and how restrictions can be made, and the ramifications of so doing. The Fisher–Bailey validity is explained, and examples are given regarding the tradeoff between balance and validity.
      Citation: Clinical Trials
      PubDate: 2022-03-02T04:54:22Z
      DOI: 10.1177/17407745221080714
       
  • The ring vaccination trial design for the estimation of vaccine efficacy
           and effectiveness during infectious disease outbreaks

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      Authors: Natalie E Dean, Ira M Longini
      Abstract: Clinical Trials, Ahead of Print.
      The ring vaccination trial is a recently developed approach for evaluating the efficacy and effectiveness of vaccines, modeled after the surveillance and containment strategy of ring vaccination. Contacts and contacts of contacts of a newly identified disease case form a ring, and these rings are randomized as part of a cluster-randomized trial or with individual randomization within rings. Key advantages of the design include its flexibility to follow the epidemic as it progresses and the targeting of high-risk participants to increase power. We describe the application of the design to estimate the efficacy and effectiveness of an Ebola vaccine during the 2014–2016 West African Ebola epidemic. The design has several notable statistical features. Because vaccination occurs around the time of exposure, the design is particularly sensitive to the choice of per protocol analysis period. If incidence wanes before the per protocol analysis period begins (due to a slow-acting vaccine or a fast-moving pathogen), power can be substantially reduced. Mathematical modeling is valuable for exploring the suitability of the approach in different disease settings. Another statistical feature is zero inflation, which can occur if the chain of transmission does not take off within a ring. In the application to Ebola, the majority of rings had zero subsequent cases. The ring vaccination trial can be extended in several ways, including the definition of rings (e.g. contact-based, spatial, and occupational). The design will be valuable in settings where the spatio-temporal spread of the pathogen is highly focused and unpredictable.
      Citation: Clinical Trials
      PubDate: 2022-01-21T08:39:39Z
      DOI: 10.1177/17407745211073594
       
  • Influential methods reports for group-randomized trials and related
           designs

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      Authors: David M Murray
      Abstract: Clinical Trials, Ahead of Print.
      Background. This article identifies the most influential methods reports for group-randomized trials and related designs published through 2020. Many interventions are delivered to participants in real or virtual groups or in groups defined by a shared interventionist so that there is an expectation for positive correlation among observations taken on participants in the same group. These interventions are typically evaluated using a group- or cluster-randomized trial, an individually randomized group treatment trial, or a stepped wedge group- or cluster-randomized trial. These trials face methodological issues beyond those encountered in the more familiar individually randomized controlled trial. Methods. PubMed was searched to identify candidate methods reports; that search was supplemented by reports known to the author. Candidate reports were reviewed by the author to include only those focused on the designs of interest. Citation counts and the relative citation ratio, a new bibliometric tool developed at the National Institutes of Health, were used to identify influential reports. The relative citation ratio measures influence at the article level by comparing the citation rate of the reference article to the citation rates of the articles cited by other articles that also cite the reference article. Results. In total, 1043 reports were identified that were published through 2020. However, 55 were deemed to be the most influential based on their relative citation ratio or their citation count using criteria specific to each of the three designs, with 32 group-randomized trial reports, 7 individually randomized group treatment trial reports, and 16 stepped wedge group-randomized trial reports. Many of the influential reports were early publications that drew attention to the issues that distinguish these designs from the more familiar individually randomized controlled trial. Others were textbooks that covered a wide range of issues for these designs. Others were “first reports” on analytic methods appropriate for a specific type of data (e.g. binary data, ordinal data), for features commonly encountered in these studies (e.g. unequal cluster size, attrition), or for important variations in study design (e.g. repeated measures, cohort versus cross-section). Many presented methods for sample size calculations. Others described how these designs could be applied to a new area (e.g. dissemination and implementation research). Among the reports with the highest relative citation ratios were the CONSORT statements for each design. Conclusions. Collectively, the influential reports address topics of great interest to investigators who might consider using one of these designs and need guidance on selecting the most appropriate design for their research question and on the best methods for design, analysis, and sample size.
      Citation: Clinical Trials
      PubDate: 2022-01-07T05:53:19Z
      DOI: 10.1177/17407745211063423
       
  • Recruiting an underserved, difficult to reach population into a cancer
           trial: Strategies from the Restore-2 Rehabilitation Trial for gay and
           bisexual prostate cancer patients

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      Authors: BR Simon Rosser, Morgan Wright, Chris J Hoefer, Elizabeth J Polter, Nidhi Kohli, Christopher W Wheldon, Ryan Haggart, Kristine MC Talley, Darryl Mitteldorf, Gunna Kilian, Badrinath R Konety, Michael W Ross, William West
      First page: 239
      Abstract: Clinical Trials, Ahead of Print.
      Background/aims:Sexual minorities are small and under-researched populations that are at disproportionate risk for cancer and poor cancer outcomes. Described as a “hidden population,” the principal research challenge has been to develop effective methods to identify and recruit such cancer patients into cancer studies. Online recruitment strategies, as well as targeted clinic recruitment using patient-entered sexual orientation and gender identity data from electronic medical records have potential to transform recruitment, but studies testing the effects of how to recruit using these have not been published.Methods:In 2019, we conducted a naturalistic, three-arm, stratified prospective study to compare three recruitment strategies: (a) clinic based recruitment of prostate cancer patients from gay health and urology clinics; (b) directly from the gay community; and (c) online recruitment (through cancer support, sex/dating, and social sites). For each strategy, we estimated time, workload, and direct costs involved. To study how recruitment strategy may affect sampling, we tested for retention rates, demographic and outcome differences across sites. Using these methods, we successfully recruited 401 gay and bisexual prostate cancer patients into a randomized, controlled, 24-month trial testing an online sexual and urinary rehabilitation curriculum tailored for this population.Results:There were seven key results. First, it is possible to recruit substantial numbers of sexual minority men into prostate cancer studies provided online recruitment methods are used. Second, we observed big differences in dropout during study onboarding by recruitment source. Third, within online recruitment, the online sex/dating application (app) was the most successful and efficient, followed by the cancer support site, and then the social networking site. Fourth, while clinics were the cheapest source of recruitment, they were time intensive and low in yield. Fifth, the cancer support site and sex/dating app recruits differed by several characteristics, with the former being more rehabilitation-focused while the latter were younger and more sexually active. Sixth, we found almost no differences in outcomes across the three online recruitment sites. Seventh, because retention in online studies has been a concern, we confirm very low attrition at 3- and 6 months into the trial.Conclusion:For sexual minority cancer research, more research on how to use sexual orientation and gender identity electronic medical record data for clinic-based recruitment is needed. For other small or hard-to-reach populations, researchers should compare and publish online versus offline recruitment strategies.
      Citation: Clinical Trials
      PubDate: 2022-03-02T04:51:27Z
      DOI: 10.1177/17407745221077678
       
  • A dynamic and collaborative approach to trial recruitment in safetxt, a UK
           sexual health randomised controlled trial

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      Authors: Lauren Jerome, Kimberley Potter, Ona McCarthy, Melissa Palmer, Megan Knight, Caroline Free
      First page: 251
      Abstract: Clinical Trials, Ahead of Print.
      Background/Aims:Recruiting to target in randomised controlled trials is crucial for providing reliable results, yet many trials struggle to achieve their target sample size. Many trials do not report sufficient, if any, details of their recruitment strategy for others to adapt for their own trials. Furthermore, much of the available evidence describes strategies to improve recruitment aimed at participants, as opposed to strategies aimed at engaging and motivating recruiting staff who are deemed essential for recruitment success. The safetxt trial aimed to recruit 6250 participants, aged 16–24 years, who had either tested positive, or received treatment, for chlamydia/gonorrhoea/non-specific urethritis in the last 2 weeks, from across the United Kingdom into a randomised controlled trial investigating a text message intervention to improve sexual health outcomes. In this article, we describe in detail the recruitment strategies we employed that were primarily aimed at recruiters.Methods:Recruitment began in April 2016. We built on our recruitment methods established in the pilot trial and developed several strategies to increase recruitment as the trial progressed including optimising site set-up, monitoring recruitment progress and identifying issues, facilitating shared learning, tailored recruitment materials, sustaining motivation, and communication. We describe these strategies in detail and provide practical examples for each.Results:We combine our strategies for increasing recruitment into one cyclical approach whereby progress is continuously monitored, and interventions to improve recruitment are implemented. The site initiation visits were used to develop a clear recruitment plan and establish good relationships with local site staff. Screening logs were particularly helpful for monitoring recruitment challenges. We facilitated shared learning by organising meetings with recruiting sites and conducting site visits. Tailored recruitment materials helped to promote the trial in clinic environments, and rewards and goals helped sustain motivation among recruiting staff. Finally, at the centre of the approach is good communication which ensured we maintained good relationships with local site staff.Conclusion:We conducted a large, multi-centre trial and successfully recruited to target. Our dynamic collaborative approach to recruitment described in this paper builds upon previous research by combining suggested good practice into one cyclical approach to recruitment, and providing detailed examples of each strategy. It is not possible to attribute a causal link between our approach and recruitment success overall, or with specific sites or recruiting staff. Nonetheless we describe the processes we used to build a good relationship with recruiting staff and sites, and maintain recruitment of large numbers of participants over the 32 months of the trial. Other researchers can use our approach and adapt our examples for their own trials.
      Citation: Clinical Trials
      PubDate: 2022-03-05T10:48:41Z
      DOI: 10.1177/17407745221078882
       
  • Methodological aspects of a randomized within-patient concurrent
           controlled design for clinical trials in spine surgery

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      Authors: A Mechteld Lehr, Wilco CH Jacobs, Rebecca K Stellato, René M Castelein, F Cumhur Oner, Moyo C Kruyt
      First page: 259
      Abstract: Clinical Trials, Ahead of Print.
      Introduction:Randomized controlled trials are considered the highest level of evidence, but their feasibility in the surgical field is severely hampered by methodological and practical issues. Concurrent comparison between the experimental and control conditions within the same patient can be an effective strategy to mitigate some of these challenges and improve generalizability, mainly by the elimination of between-patient variability and reduction of the required sample size. This article aims (1) to describe the methodological aspects of a randomized within-patient controlled trial and (2) to quantify the added value of this design, based on a recently completed randomized within-patient controlled trial on bone grafts in instrumented lumbar posterolateral spinal fusion.Methods:Boundary conditions for the application of the randomized within-patient controlled trial design were identified. Between-patient variability was quantified by the intraclass correlation coefficient and concordance in the primary fusion outcome. Sample size, study duration and costs were compared with a classic randomized controlled trial design.Results:Boundary conditions include the concurrent application of the experimental and control conditions to identical but physically separated sites. Moreover, the outcome of interest should be local, uncorrelated and independently assessable. The spinal fusion outcomes within a patient were found to be more similar than between different patients (intraclass correlation coefficient 32% and concordance 64%), demonstrating a clear effect of patient-related factors. The randomized within-patient controlled trial design allowed a reduction of the sample size to one-third of a parallel-group randomized controlled trial, thereby halving the trial duration and costs.Conclusion:When suitable, the randomized within-patient controlled trial is an efficient design that provides a solution to some of the considerable challenges of a classic randomized controlled trial in (spine) surgery. This design holds specific promise for efficacy studies of non-active bone grafts in instrumented posterolateral fusion surgery.
      Citation: Clinical Trials
      PubDate: 2022-03-17T10:15:53Z
      DOI: 10.1177/17407745221084705
       
  • Timing is everything: The importance of patient-reported outcome
           assessment frequency when characterizing symptomatic adverse events

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      Authors: Bellinda L King-Kallimanis, Vishal Bhatnagar, Erica G Horodniceanu, Ting-Yu Chen, Paul G Kluetz
      First page: 267
      Abstract: Clinical Trials, Ahead of Print.
      ObjectiveAlthough patient-reported symptoms and side effects are increasingly measured in cancer clinical trials, an appropriate assessment frequency has not yet been established. To determine whether differences in assessment frequency affect the apparent incidence and severity of patient-reported symptoms using two well-established patient-reported outcome measures used within the same clinical trial.MethodsWe examined patient-reported outcome results from AURA3 (NCT02151981), a randomized open-label study comparing Tagrisso (osimertinib) with platinum-based chemotherapy in patients with previously treated estimated glomerular filtration rate/T790M mutation-positive metastatic non-small cell lung cancer. The outcome of interest was the proportion of patients in each arm that reported worsening of nausea, vomiting, fatigue, diarrhea, constipation, and appetite loss from baseline measured using the patient-reported outcome—common terminology criteria for adverse event (weekly) or European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (every 6 weeks).ResultsSimilar trends were observed for all six symptoms investigated. Using nausea in the chemotherapy arm as an example, 76% of patients reported any worsening from baseline based on weekly patient-reported outcome—common terminology criteria for adverse event assessments. When using an every 6-week assessment of Quality of Life Questionnaire Core 30 nausea and restricting analysis to an every 6-week assessment for patient-reported outcome—common terminology criteria for adverse event nausea, the proportion of chemotherapy arm patients reporting any worsening of nausea was 40% for both measures. Across the six patient-reported symptomatic adverse events, we observed differential proportions when comparing frequent versus sparse assessment.ConclusionThis analysis demonstrates that more frequent assessment of patient-reported symptomatic adverse events will lead to improved detection, and therefore a more complete understanding of the tolerability of experimental anti-cancer therapies.
      Citation: Clinical Trials
      PubDate: 2022-05-16T05:32:54Z
      DOI: 10.1177/17407745221093935
       
  • Methodological standards for using the patient-reported outcomes version
           of the common terminology criteria for adverse events (PRO-CTCAE) in
           cancer clinical trials

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      Authors: Ethan Basch, Gita Thanarajasingam, Amylou C Dueck
      First page: 274
      Abstract: Clinical Trials, Ahead of Print.

      Citation: Clinical Trials
      PubDate: 2022-05-16T05:32:27Z
      DOI: 10.1177/17407745221093922
       
  • The PROTEUS-Trials Consortium: Optimizing the use of patient-reported
           outcomes in clinical trials

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      Authors: Claire Snyder, Norah Crossnohere, Madeleine King, Bryce B Reeve, Andrew Bottomley, Melanie Calvert, Elissa Thorner, Albert W Wu, Michael Brundage
      First page: 277
      Abstract: Clinical Trials, Ahead of Print.
      Background:The assessment of patient-reported outcomes in clinical trials has enormous potential to promote patient-centred care, but for this potential to be realized, the patient-reported outcomes must be captured effectively and communicated clearly. Over the past decade, methodologic tools have been developed to inform the design, analysis, reporting, and interpretation of patient-reported outcome data from clinical trials. We formed the PROTEUS-Trials Consortium (Patient-Reported Outcomes Tools: Engaging Users and Stakeholders) to disseminate and implement these methodologic tools.Methods:PROTEUS-Trials are engaging with patient, clinician, research, and regulatory stakeholders from 27 organizations in the United States, Canada, Australia, the United Kingdom, and Europe to develop both organization-specific and cross-cutting strategies for implementing and disseminating the methodologic tools. Guided by the Knowledge-to-Action framework, we conducted consortium-wide webinars and meetings, as well as individual calls with participating organizations, to develop a workplan, which we are currently executing.Results:Six methodologic tools serve as the foundation for PROTEUS-Trials dissemination and implementation efforts: the Standard Protocol Items: Recommendations for Interventional Trials-patient-reported outcome extension for writing protocols with patient-reported outcomes, the International Society for Quality of Life Research Minimum Standards for selecting a patient-reported outcome measure, Setting International Standards in Analysing Patient-Reported Outcomes and Quality of Life Endpoints Data Consortium recommendations for patient-reported outcome data analysis, the Consolidated Standards for Reporting of Trials-patient-reported outcome extension for reporting clinical trials with patient-reported outcomes, recommendations for the graphic display of patient-reported outcome data, and a Clinician’s Checklist for reading and using an article about patient-reported outcomes. The PROTEUS-Trials website (www.TheProteusConsortium.org) serves as a central repository for the methodologic tools and associated resources. To date, we have developed (1) a roadmap to visually display where each of the six methodologic tools applies along the clinical trial trajectory, (2) web tutorials that provide guidance on the methodologic tools at different levels of detail, (3) checklists to provide brief summaries of each tool’s recommendations, (4) a handbook to provide a self-guided approach to learning about the tools and recommendations, and (5) publications that address key topics related to patient-reported outcomes in clinical trials. We are also conducting organization-specific activities, including meetings, presentations, workshops, and webinars to publicize the existence of the methodologic tools and the PROTEUS-Trials resources. Work to develop communications strategies to ensure that PROTEUS-Trials reach key audiences with relevant information about patient-reported outcomes in clinical trials and PROTEUS-Trials is ongoing.Discussion:The PROTEUS-Trials Consortium aims to help researchers generate patient-reported outcome data from clinical trials to (1) enable investigators, regulators, and policy-makers to take the patient perspective into account when conducting research and making decisions; (2) help patients understand treatment options and make treatment decisions; and (3) inform clinicians’ discussions with patients regarding treatment options. In these ways, the PROTEUS Consortium promotes patient-centred research and care.
      Citation: Clinical Trials
      PubDate: 2022-01-31T09:10:52Z
      DOI: 10.1177/17407745221077691
       
  • Incorporating estimands into clinical trial statistical analysis plans

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      Authors: Minhee Kang, Michelle A Kendall, Heather Ribaudo, Camlin Tierney, Lu Zheng, Laura Smeaton, Jane C Lindsey
      First page: 285
      Abstract: Clinical Trials, Ahead of Print.
      Background:International Council for Harmonisation (ICH) E9 Statistical Principles for Clinical Trials was developed as a consensus guidance document to encourage worldwide harmonization of the principles of statistical methodology in clinical trials. Addendum E9 (R1) clarified and extended ICH E9 with a focus on estimands and sensitivity analyses. Since the release of E9 (R1), clinical trial protocols have included estimands, but there is variation in how they are presented. Statistical analysis plans (SAPs) are increasingly becoming publicly available (e.g. posting on ClinicalTrials.gov) and present an opportunity to link estimands with planned analyses to present the alignment of trial objectives, design, conduct, and analysis.Methods:A table format was used to create a template for inclusion in SAPs that satisfies ICH E9 (R1) guidance to align statistical analysis to the estimand. The template provides a consistent structure for presentation of estimands and the associated analysis, and is applicable to a wide range of trial designs. We illustrate use of the template with a hypothetical clinical trial in HIV-1.Results:The estimand-to-analysis table template starts with the study objective describing the clinical question of interest as written in the trial protocol. The remainder of the table describes each attribute of the estimand (treatment, target population, variable, intercurrent events, and population-level summary) in the left column (ESTIMAND), while the right column describes how each attribute will be handled using the data collected in the clinical trial (ANALYSIS). The template was applied to a hypothetical, early-phase single-arm trial, modeled after a pediatric trial in HIV, where the objective was to determine the safety of a new antiretroviral drug as part of a combination antiretroviral treatment regimen in the pediatric population. Three intercurrent events were illustrated in the table: death, premature treatment discontinuation before 24 weeks, and pregnancy. An estimand-to-analysis table from a grant application that addresses the primary objective of a placebo-controlled randomized trial is also presented to demonstrate an alternative usage.Conclusion:We found the template to be useful in study design, providing a snapshot of the objective, target population, potential intercurrent events, analysis plan, and considerations for missing data in one place and facilitating discussion among stakeholders. The proposed standardized presentation of estimand attributes and analysis considerations in SAPs will provide guidance to SAP authors and consistency across studies to facilitate reviews.
      Citation: Clinical Trials
      PubDate: 2022-03-08T01:10:22Z
      DOI: 10.1177/17407745221080463
       
  • Accounting for the rarity of the disease when designing clinical trials
           with a focus on pediatric cancers

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      Authors: Audrey Mauguen
      First page: 292
      Abstract: Clinical Trials, Ahead of Print.
      BackgroundClinical trials are challenging in rare diseases like pediatric cancers, where the accrual is limited. In these trials, inference assumptions are the same as in common diseases, that is the sample comes from a quasi-infinite population. This leads to overestimating the variance of the mean treatment effect. The finite-population correction factor correcting this bias is often used in surveys, but not in clinical trials. With few assumptions, the use of this correction factor can improve trials efficiency, showing that the power of those trials is sometimes higher than it appears.MethodsFirst, a simulation study assesses the standard error of the mean treatment effect and coverage of the 95% confidence interval with and without the correction. Second, the analytical power of a z-test with and without the correction is given. Finally, the impact on the sample size calculation is investigated. The impact of assuming a finite population is assessed for varying treatment effect, sample size and population size.ResultsThe simulation results confirm the overestimation of the standard error without the correction factor. When using the correction factor, the gain in power reaches up to 10.1%, 15.3% and 12.3% to detect a difference in treatment effect of 10%, 15% and 20%, respectively. The gain is negligible for n = 30, in scenarios with high power (>95%), and for large populations. This gain in power translates into a decrease in sample size: if the conventional calculation leads to a sample size 10% of the population size, then the sample size can be divided by 1.1; if the conventional calculation leads to a sample size 20% of the population size, then the sample size can be divided by 1.2, in order to reach the planned type I error and power.ConclusionWhen dealing with rare diseases like pediatric cancers, the power of clinical trials might be higher than it appears if using conventional sample sizes. When correcting the variance of the mean using the population size, a gain in efficiency is observed with reasonable sample sizes and treatment differences for very small population sizes, showing that this approach can be useful for some pediatric cancer clinical trials.
      Citation: Clinical Trials
      PubDate: 2022-03-02T04:57:02Z
      DOI: 10.1177/17407745221080728
       
  • Bayesian basket trial design with false-discovery rate control

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      Authors: Emily C Zabor, Michael J Kane, Satrajit Roychoudhury, Lei Nie, Brian P Hobbs
      First page: 297
      Abstract: Clinical Trials, Ahead of Print.
      Background:Recent advances in developing “tumor agnostic” oncology therapies have identified molecular targets that define patient subpopulations in a manner that supersedes conventional criteria for cancer classification. These successes have produced effective targeted therapies that are administered to patients regardless of their tumor histology. Trials have evolved as well with master protocol designs. By blending translational and clinical science, basket trials in particular are well-suited to investigate and develop targeted therapies among multiple cancer histologies. However, basket trials intrinsically involve more complex design decisions, including issues of multiple testing across baskets, and guidance for investigators is needed.Methods:The sensitivity of the multisource exchangeability model to prior specification under differing degrees of response heterogeneity is explored through simulation. Then, a multisource exchangeability model design that incorporates control of the false-discovery rate is presented and a simulation study compares the operating characteristics to a design where the family-wise error rate is controlled and to the frequentist approach of treating the baskets as independent. Simulations are based on the original design of a real-world clinical trial, the SUMMIT trial, which investigated Neratinib treatment for a variety of solid tumors. The methods studied here are specific to single-arm phase II trials with binary outcomes.Results:Values of prior probability of exchangeability in the multisource exchangeability model between 0.1 and 0.3 provide the best trade-offs between gain in precision and bias, especially when per-basket sample size is below 30. Application of these calibration results to a re-analysis of the SUMMIT trial showed that the breast basket exceeded the null response rate with posterior probability of 0.999 while having low posterior probability of exchangeability with all other baskets. Simulations based on the design of the SUMMIT trial revealed that there is meaningful improvement in power even in baskets with small sample size when the false-discovery rate is controlled as opposed to the family-wise error rate. For example, when only the breast basket was active, with a sample size of 25, the power was 0.76 when the false-discovery rate was controlled at 0.05 but only 0.56 when the family-wise error rate was controlled at 0.05, indicating that impractical sample sizes for the phase II setting would be needed to achieve acceptable power while controlling the family-wise error rate in this setting of a trial with 10 baskets.Conclusion:Selection of the prior exchangeability probability based on calibration and incorporation of false-discovery rate control result in multisource exchangeability model designs with high power to detect promising treatments in the context of phase II basket trials.
      Citation: Clinical Trials
      PubDate: 2022-02-07T12:05:20Z
      DOI: 10.1177/17407745211073624
       
  • Effects of patient-reported outcome assessment order

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      Authors: Paul J Novotny, Amylou C Dueck, Daniel Satele, Marlene H Frost, Timothy J Beebe, Kathleen J Yost, Minji K Lee, David T Eton, Susan Yount, David Cella, Tito R Mendoza, Charles S Cleeland, Victoria Blinder, Ethan Basch, Jeff A Sloan
      First page: 307
      Abstract: Clinical Trials, Ahead of Print.
      BackgroundIn clinical trials and clinical practice, patient-reported outcomes are almost always assessed using multiple patient-reported outcome measures at the same time. This raises concerns about whether patient responses are affected by the order in which the patient-reported outcome measures are administered.MethodsThis questionnaire-based study of order effects included adult cancer patients from five cancer centers. Patients were randomly assigned to complete questionnaires via paper booklets, interactive voice response system, or tablet web survey. Linear Analogue Self-Assessment, Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events, and Patient-Reported Outcomes Measurement Information System assessment tools were each used to measure general health, physical function, social function, emotional distress/anxiety, emotional distress/depression, fatigue, sleep, and pain. The order in which the three tools, and domains within tools, were presented to patients was randomized. Rates of missing data, scale scores, and Cronbach’s alpha coefficients were compared by the order in which they were assessed. Analyses included Cochran–Armitage trend tests and mixed models adjusted for performance score, age, sex, cancer type, and curative intent.ResultsA total of 1830 patients provided baseline patient-reported outcome assessments. There were no significant trends in rates of missing values by whether a scale was assessed earlier or later. The largest order effect for scale scores was due to a large mean score at one assessment time point. The largest difference in Cronbach’s alpha between the versions for the Patient-Reported Outcomes Measurement Information System scales was 0.106.ConclusionThe well-being of a cancer patient has many different aspects such as pain, fatigue, depression, and anxiety. These are assessed using a variety of surveys often collected at the same time. This study shows that the order in which the different aspects are collected from the patient is not important.
      Citation: Clinical Trials
      PubDate: 2022-01-28T11:33:24Z
      DOI: 10.1177/17407745211073788
       
  • The value of adherence information during clinical pharmaceutical trials

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      Authors: Emily N Grayek, Baruch Fischhoff, Alexander L Davis, Tamar Krishnamurti
      First page: 326
      Abstract: Clinical Trials, Ahead of Print.
      Background/AimsThe quality of the evidence used to evaluate a drug’s safety and efficacy depends, in part, on how well participants adhere to the prescribed drug-taking regime. There are multiple approaches to measure adherence in clinical trials, varying in their cost and accuracy. We demonstrate a method for evaluating the cost-effectiveness of common adherence monitoring methods, considering the costs and data quality for drugs that differ in how forgiving they are of nonadherence.MethodsWe propose a simulation approach to estimate the value of evidence about adherence, considering both costs of collection and potential errors in interpreting clinical trial results. We demonstrate the approach with a simulated clinical trial of nitrendipine, a common calcium channel blocker. We consider two trial designs, one using pretrial adherence to “enrich” the trial sample and one without an enrichment strategy. We use scenarios combining high and low values of two key properties of a clinical trial: participant adherence and drug forgiveness.ResultsUnder the conditions of these simulations, the most cost-effective adherence monitoring approach depends on both trial participant adherence and drug forgiveness. For example, the enrichment strategy is not cost-effective for the base scenario (high forgiveness and high adherence), but is for other scenarios. We also estimate the effects of evaluable patient analysis, a controversial procedure that excludes nonadherent participants from the analyses, after a trial is completed.ConclusionsOur proposed approach can guide drug regulators and developers in designing efficient clinical trials and assessing the impact of nonadherence on trial results. It can identify cost-effective adherence-monitoring methods, given available knowledge about the methods, drug, and patients’ expected adherence.
      Citation: Clinical Trials
      PubDate: 2022-05-05T09:07:06Z
      DOI: 10.1177/17407745221084127
       
  • Results publications are inadequately linked to trial registrations: An
           automated pipeline and evaluation of German university medical centers

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      Authors: Maia Salholz-Hillel, Daniel Strech, Benjamin Gregory Carlisle
      First page: 337
      Abstract: Clinical Trials, Ahead of Print.
      Background/AimsInformed clinical guidance and health policy relies on clinicians, policymakers, and guideline developers finding comprehensive clinical evidence and linking registrations and publications of the same clinical trial. To support the finding and linking of trial evidence, the World Health Organization, the International Committee of Medical Journal Editors, and the Consolidated Standards of Reporting Trials ask researchers to provide the trial registration number in their publication and a reference to the publication in the registration. This practice costs researchers minimal effort and makes evidence synthesis more thorough and efficient. Nevertheless, trial evidence appears inadequately linked, and the extent of trial links in Germany remains unquantified. This cross-sectional study aims to evaluate links between registrations and publications across clinical trials conducted by German university medical centers and registered in ClinicalTrials.gov or the German Clinical Trials Registry. Secondary aims are to develop an automated pipeline that can be applied to other cohorts of trial registrations and publications, and to provide stakeholders, from trialists to registries, with guidance to improve trial links.MethodsWe used automated strategies to download and extract data from trial registries, PubMed, and results publications for a cohort of registered, published trials conducted across German university medical centers and completed between 2009 and 2017. We implemented regular expressions to detect and classify publication identifiers in registrations, and trial registration numbers in publication metadata, abstracts, and full-texts.ResultsIn breach of long-standing guidelines, 75% (1,418) of trials failed to reference trial registration numbers in both the abstract and full-text of the journal article in which the results were published. Furthermore, 50% (946) of trial registrations did not contain links to their results publications. Seventeen percent (327) of trials had no links, so that associating registration and publication required manual searching and screening. Overall, trials in ClinicalTrials.gov were better linked than those in the German Clinical Trials Registry; PubMed and registry infrastructures appear to drive this difference. Trial registration numbers were more likely to be transferred to PubMed metadata from abstracts for ClinicalTrials.gov trials than for German Clinical Trials Registry trials. Most (78%, 662/849) ClinicalTrials.gov registrations with a publication link were automatically indexed from PubMed metadata, which is not possible in the German Clinical Trials Registry.ConclusionsGerman university medical centers have not comprehensively linked trial registrations and publications, despite established recommendations. This shortcoming threatens the quality of evidence synthesis and medical practice, and burdens researchers with manually searching and linking trial data. Researchers could easily improve this by copy-and-pasting references between their trial registrations and publications. Other stakeholders could build on this practice, for example, PubMed could capture additional trial registration numbers using automated strategies (like those developed in this study), and the German Clinical Trials Registry could automatically index publications from PubMed.
      Citation: Clinical Trials
      PubDate: 2022-04-01T09:47:45Z
      DOI: 10.1177/17407745221087456
       
  • Advanced analytics for clinical trial quality: Commentary on ‘Can
           quality management drive evidence generation'’

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      Authors: Timothé Ménard
      First page: 347
      Abstract: Clinical Trials, Ahead of Print.

      Citation: Clinical Trials
      PubDate: 2022-02-23T10:26:54Z
      DOI: 10.1177/17407745221078991
       
 
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