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Journal of Clinical Epidemiology Jan 2020Factorial designs can allow efficient evaluation of multiple treatments within a single trial. We evaluated the design, analysis, and reporting in a sample of factorial... (Review)
Review
OBJECTIVES
Factorial designs can allow efficient evaluation of multiple treatments within a single trial. We evaluated the design, analysis, and reporting in a sample of factorial trials.
STUDY DESIGN AND SETTING
Review of 2 × 2 factorial trials evaluating health-related interventions and outcomes in humans. Using Medline, we identified articles published between January 2015 and March 2018. We randomly selected 100 articles for inclusion.
RESULTS
Most trials (78%) did not provide a rationale for using a factorial design. Only 63 trials (63%) assessed the interaction for the primary outcome, and 39/63 (62%) made a further assessment for at least one secondary outcome. 12/63 trials (19%) identified a significant interaction for the primary outcome and 16/39 trials (41%) for at least one secondary outcome. Inappropriate methods of analysis to protect against potential negative effects from interactions were common, with 18 trials (18%) choosing the analysis method based on a preliminary test for interaction, and 13% (n = 10/75) of those conducting a factorial analysis including an interaction term in the model.
CONCLUSION
Reporting of factorial trials was often suboptimal, and assessment of interactions was poor. Investigators often used inappropriate methods of analysis to try to protect against adverse effects of interactions.
Topics: Clinical Trials as Topic; Data Interpretation, Statistical; Humans; Research Design
PubMed: 31585174
DOI: 10.1016/j.jclinepi.2019.09.018 -
Journal of Clinical Pharmacology Oct 2018Almost half of recent pediatric trials failed to achieve labeling indications, in large part because of inadequate study design. Therefore, innovative study methods are... (Review)
Review
Almost half of recent pediatric trials failed to achieve labeling indications, in large part because of inadequate study design. Therefore, innovative study methods are crucial to optimizing trial design while also reducing the potential harms inherent with drug investigation. Several methods exist to optimize the amount of pharmacokinetic data collected from the smallest possible volume and with the fewest number of procedures, including the use of opportunistic and sparse sampling, alternative and noninvasive matrices, and microvolume assays. In addition, large research networks using master protocols promote collaboration, reduce regulatory burden, and increase trial efficiency for both early- and late-phase trials. Large pragmatic trials that leverage electronic health records can capitalize on central management strategies to reduce costs, enroll patients with rare diseases on a large scale, and augment study generalizability. Further, trial efficiency and safety can be optimized through Bayesian adaptive techniques that permit planned protocol changes based on analyses of prior and accumulated data. In addition to these trial design features, advances in modeling and simulation have paved the way for systems-based and physiologically based models that individualize pediatric dosing recommendations and support drug approval. Last, given the low prevalence of many pediatric diseases, collecting deidentified genetic and clinical data on a large scale is a potentially transformative way to augment clinical pharmacology research in children.
Topics: Biomedical Research; Child; Clinical Trials as Topic; Humans; Infant; Models, Biological; Pharmacology, Clinical; Research Design
PubMed: 30248192
DOI: 10.1002/jcph.1053 -
Recenti Progressi in Medicina Nov 2019
Topics: Humans; Informed Consent; Observational Studies as Topic; Pragmatic Clinical Trials as Topic; Prospective Studies; Random Allocation; Risk Assessment; Uncertainty
PubMed: 31808438
DOI: 10.1701/3265.32354 -
Recenti Progressi in Medicina Nov 2019
Topics: Control Groups; Data Interpretation, Statistical; Databases, Factual; Equivalence Trials as Topic; Evidence-Based Medicine; Humans; Observational Studies as Topic; Pharmaceutical Preparations; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; Reproducibility of Results; Technology Assessment, Biomedical; Technology Transfer; Time Factors; Treatment Outcome
PubMed: 31808432
DOI: 10.1701/3265.32327 -
Journal of the American Medical... Feb 2019
Topics: Clinical Trials as Topic; Long-Term Care; Residential Facilities; Translational Research, Biomedical
PubMed: 30691618
DOI: 10.1016/j.jamda.2018.12.021 -
Contemporary Clinical Trials Oct 2022Efficiency in clinical trial recruitment and enrollment remains a major challenge in many areas of clinical medicine. In particular, despite the prevalence of heart... (Review)
Review
Efficiency in clinical trial recruitment and enrollment remains a major challenge in many areas of clinical medicine. In particular, despite the prevalence of heart failure with preserved ejection fraction (HFpEF), identifying patients with HFpEF for clinical trials has proven to be especially challenging. In this manuscript, we review strategies for contemporary clinical trial recruitment and present insights from the results of the DELIVER Electronic Health Record (EHR) Screening Initiative. The DELIVER trial was designed to evaluate the effects of dapagliflozin on clinical outcomes in patients with HFpEF. Within this trial, the multicenter DELIVER EHR Screening Initiative utilized EHR-based techniques in order to improve recruitment at selected sites in the United States. For this initiative, we developed and deployed a computable phenotype from the trial's eligibility criteria along with additional EHR tools at interested sites. Sites were then surveyed at the end of the program regarding lessons learned. Six sites were recruited, trained, and supported to utilize the EHR methodology and computable phenotype. Sites found the initiative to be helpful in identifying eligible patients and cited the individualized expert technical support as a critical factor in utilizing the program effectively. We found that the major challenge of implementation was the process of converting traditional inclusion/exclusion criteria into a computable phenotype within an established and ongoing trial. Other significant challenges noted by sites were the following: impact of the COVID-19 pandemic, engagement/support by local institutions, and limited availability of internal EHR experts/resources to execute programming. The study represents a proof-of-concept in the ability to utilize EHR-based tools in clinical trial recruitment for patients with HFpEF and provides important lessons for future initiatives. ClinicalTrials.gov Identifier: NCT03619213.
Topics: COVID-19; Clinical Trials as Topic; Electronic Health Records; Heart Failure; Humans; Multicenter Studies as Topic; Pandemics; Stroke Volume
PubMed: 36100197
DOI: 10.1016/j.cct.2022.106924 -
Trials Jun 2024Randomized controlled trials (RCTs) are rigorous scientific research designs for evaluating intervention effectiveness. However, implementing RCTs in a real-world...
Strengths, challenges, and strategies for implementing pragmatic multicenter randomized controlled trials (RCTs): example of the Personalized Citizen Assistance for Social Participation (APIC) trial.
BACKGROUND
Randomized controlled trials (RCTs) are rigorous scientific research designs for evaluating intervention effectiveness. However, implementing RCTs in a real-world context is challenging. To develop strategies to improve its application, it is essential to understand the strengths and challenges of this design. This study thus aimed to explore the strengths, challenges, and strategies for improving the implementation of a pragmatic multicenter, prospective, two-arm RCT evaluating the effects of the Personalized Citizen Assistance for Social Participation (Accompagnement-citoyen Personnalisé d'Intégration Communautaire: APIC; weekly 3-h personalized stimulation sessions given by a trained volunteer over a 12-month period) on older adults' health, social participation, and life satisfaction.
METHODS
A multiple case study was conducted with 14 participants, comprising one research assistant, seven coordinators, and six managers of six community organizations serving older adults, who implemented the APIC in the context of a RCT. Between 2017 and 2023, qualitative data were extracted from 24 group meetings, seven semi-directed interviews, emails exchanged with the research team, and one follow-up document.
RESULTS
Aged between 30 and 60 (median ± SIQR: 44.0 ± 6.3), most participants were women from organizations already offering social participation interventions for older adults and working with the public sector. Reported strengths of this RCT were its relevance in assessing an innovative intervention to support healthy aging, and the sharing of common goals, expertise, and strategies with community organizations. Challenges included difficulties recruiting older adults, resistance to potential control group assignments, design complexity, and efforts to mobilize and engage volunteers. The COVID-19 pandemic lockdown and health measures exacerbated challenges related to recruiting older adults and mobilizing volunteers and complicated delivery of the intervention. The strategies that mostly overcame difficulties in recruiting older adults were reducing sample size, simplifying recruitment procedures, emphasizing the health follow-up, extending partnerships, and recognizing and supporting volunteers better. Because of the lockdown and physical distancing measures, the intervention was also adapted for remote delivery, including via telephone or videoconferencing.
CONCLUSION
Knowledge of the strengths and challenges of pragmatic RCTs can contribute to the development of strategies to facilitate implementation studies and better evaluate health and social participation interventions delivered under real-life conditions.
TRIAL REGISTRATION
NCT03161860; Pre-results. Registered on May 22, 2017.
Topics: Humans; Social Participation; Female; Male; Middle Aged; Prospective Studies; Adult; Volunteers; Research Design; COVID-19; Randomized Controlled Trials as Topic; Pragmatic Clinical Trials as Topic; Aged; Personal Satisfaction; Multicenter Studies as Topic
PubMed: 38937798
DOI: 10.1186/s13063-024-08248-w -
Healthcare (Amsterdam, Netherlands) Dec 2021While the embedded nature of pragmatic clinical trials (PCTs) can improve the efficiency and relevance of research for multiple stakeholders, embedding research into...
While the embedded nature of pragmatic clinical trials (PCTs) can improve the efficiency and relevance of research for multiple stakeholders, embedding research into ongoing clinical care can also involve ethical and regulatory challenges. An emergent challenge is the management of pragmatic clinical trial collateral findings (PCT-CFs). While PCT-CFs share some features with incidental or secondary findings that are encountered in conventional clinical trials and clinical care, the PCT context differs in ethically relevant ways that complicate PCT-CF identification and management. We report on the results of a two-year multi-method investigation of PCT-CFs. Overall, five core themes emerged: 1) the liminal nature of PCTs and the implications of this for PCT-CFs; 2) the context-specific nature of PCT-CF management; 3) the centrality of institutions; 4) the importance of prospective planning; and 5) patient expectations. Among the central lessons of this work are that prior ethics guidance from other settings cannot easily be adapted to address PCT-CFs, nor can a single approach readily accommodate all PCT-CFs. Moving forward, stakeholders, including researchers, institutions, ethics oversight bodies, and funders, should anticipate and plan for PCT-CFs in the design, conduct, and analysis of PCTs. Future scholarship is needed to examine experiences with PCT-CFs, and the practical and conceptual issues they raise for the future conduct of PCTs.
Topics: Humans; Pragmatic Clinical Trials as Topic; Prospective Studies; Research Design; Research Personnel
PubMed: 34600345
DOI: 10.1016/j.hjdsi.2021.100586 -
European Journal of Clinical Nutrition Dec 2023Evidence-based nutritional recommendations address the health impact of suboptimal nutritional status. Efficacy randomized controlled trials (RCTs) have traditionally... (Review)
Review
Evidence-based nutritional recommendations address the health impact of suboptimal nutritional status. Efficacy randomized controlled trials (RCTs) have traditionally been the preferred method for determining the effects of nutritional interventions on health outcomes. Nevertheless, obtaining a holistic understanding of intervention efficacy and effectiveness in real-world settings is stymied by inherent constraints of efficacy RCTs. These limitations are further compounded by the complexity of nutritional interventions and the intricacies of the clinical context. Herein, we explore the advantages and limitations of alternative study designs (e.g., adaptive and pragmatic trials), which can be incorporated into RCTs to optimize the efficacy or effectiveness of interventions in clinical nutrition research. Efficacy RCTs often lack external validity due to their fixed design and restrictive eligibility criteria, leading to efficacy-effectiveness and evidence-practice gaps. Adaptive trials improve the evaluation of nutritional intervention efficacy through planned study modifications, such as recalculating sample sizes or discontinuing a study arm. Pragmatic trials are embedded within clinical practice or conducted in settings that resemble standard of care, enabling a more comprehensive assessment of intervention effectiveness. Pragmatic trials often rely on patient-oriented primary outcomes, acquire outcome data from electronic health records, and employ broader eligibility criteria. Consequently, adaptive and pragmatic trials facilitate the prompt implementation of evidence-based nutritional recommendations into clinical practice. Recognizing the limitations of efficacy RCTs and the potential advantages of alternative trial designs is essential for bridging efficacy-effectiveness and evidence-practice gaps. Ultimately, this awareness will lead to a greater number of patients benefiting from evidence-based nutritional recommendations.
Topics: Humans; Nutritional Status; Research Design; Pragmatic Clinical Trials as Topic; Adaptive Clinical Trials as Topic
PubMed: 37715007
DOI: 10.1038/s41430-023-01330-7 -
Contemporary Clinical Trials Feb 2023The GetReal Trial Tool is a decision support tool to assess the impact of design choices on generalizability of clinical trials to routine clinical practice, while...
BACKGROUND
The GetReal Trial Tool is a decision support tool to assess the impact of design choices on generalizability of clinical trials to routine clinical practice, while taking into account the risk of bias, precision, acceptability and operational feasibility. This study describes the validation of the GetReal Trial Tool.
METHODS
Twelve experts took part in the GetReal Trial tool validation using the protocols of 6 trials conducted with pragmatic elements. The tool entails 7 domains with a total of 43 questions. A pooled Kappa statistic (95% CI) using random effects model was estimated using Open Meta (analyst) software. The possible operational challenges were collated and discussed with the trialists that conducted the trials.
RESULTS
Agreement in the design choices made for the trial protocols was >50% for all the trials and all teams reached consensus during discussion. The pooled Kappa statistic (95% CI) was 0.236 (0.154-0.318). The GetReal Trial tool highlighted several operational challenges, of which almost half had been experienced previously by the trialists. Out of 25 additional operational challenges mentioned by the trialists, 76% were already highlighted by the tool. The tool was considered helpful to optimize trials right from the design stage.
CONCLUSION
The GetReal Trial Tool helps to scrutinize the choice of study design in the light of Real World Evidence generation. The tool identifies most of the operational challenges experienced by trialists to date. The tool serves the intended purpose of facilitating discussion and understanding more pragmatic design choices and their implications.
Topics: Humans; Research Design; Clinical Trials as Topic; Decision Support Techniques
PubMed: 36529438
DOI: 10.1016/j.cct.2022.107054