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Journal of Clinical Epidemiology Oct 2021Feasibility studies are increasingly being used to support the development of, and investigate uncertainties around, future large-scale trials. The future trial can be...
BACKGROUND AND OBJECTIVE
Feasibility studies are increasingly being used to support the development of, and investigate uncertainties around, future large-scale trials. The future trial can be designed with either a pragmatic or explanatory mindset. Whereas pragmatic trials aim to inform the choice between different care options and thus, are designed to resemble conditions outside of a clinical trial environment, explanatory trials examine the benefit of a treatment under more controlled conditions. There is existing guidance for designing feasibility studies, but none that explicitly considers the goals of pragmatic designs. We aimed to identify unique areas of uncertainty that are relevant to planning a pragmatic trial.
RESULTS
We identified ten relevant domains, partly based on the pragmatic-explanatory continuum indicator summary-2 (PRECIS-2) framework, and describe potential questions of uncertainty within each: intervention development, research ethics, participant identification and eligibility, recruitment of individuals, setting, organization, flexibility of delivery, flexibility of adherence, follow-up, and importance of primary outcome to patients and decision-makers. We present examples to illustrate how uncertainty in these domains might be addressed within a feasibility study.
CONCLUSION
Researchers planning a feasibility study in advance of a pragmatic trial should consider feasibility objectives specifically relevant to areas of uncertainty for pragmatic trials.
Topics: Biomedical Research; Feasibility Studies; Guidelines as Topic; Humans; Pilot Projects; Pragmatic Clinical Trials as Topic; Research Design; Uncertainty
PubMed: 34229091
DOI: 10.1016/j.jclinepi.2021.06.029 -
BMJ Open Dec 2022To describe the extent to which pragmatic trials underachieved or overachieved their target sample sizes, examine explanations and identify characteristics associated...
Reporting of and explanations for under-recruitment and over-recruitment in pragmatic trials: a secondary analysis of a database of primary trial reports published from 2014 to 2019.
OBJECTIVES
To describe the extent to which pragmatic trials underachieved or overachieved their target sample sizes, examine explanations and identify characteristics associated with under-recruitment and over-recruitment.
STUDY DESIGN AND SETTING
Secondary analysis of an existing database of primary trial reports published during 2014-2019, registered in ClinicalTrials.gov, self-labelled as pragmatic and with target and achieved sample sizes available.
RESULTS
Of 372 eligible trials, the prevalence of under-recruitment (achieving <90% of target sample size) was 71 (19.1%) and of over-recruitment (>110% of target) was 87 (23.4%). Under-recruiting trials commonly acknowledged that they did not achieve their targets (51, 71.8%), with the majority providing an explanation, but only 11 (12.6%) over-recruiting trials acknowledged recruitment excess. The prevalence of under-recruitment in individually randomised versus cluster randomised trials was 41 (17.0%) and 30 (22.9%), respectively; prevalence of over-recruitment was 39 (16.2%) vs 48 (36.7%), respectively. Overall, 101 025 participants were recruited to trials that did not achieve at least 90% of their target sample size. When considering trials with over-recruitment, the total number of participants recruited in excess of the target was a median (Q1-Q3) 319 (75-1478) per trial for an overall total of 555 309 more participants than targeted. In multinomial logistic regression, cluster randomisation and lower journal impact factor were significantly associated with both under-recruitment and over-recruitment, while using exclusively routinely collected data and educational/behavioural interventions were significantly associated with over-recruitment; we were unable to detect significant associations with obtaining consent, publication year, country of recruitment or public engagement.
CONCLUSIONS
A clear explanation for under-recruitment or over-recruitment in pragmatic trials should be provided to encourage transparency in research, and to inform recruitment to future trials with comparable designs. The issues and ethical implications of over-recruitment should be more widely recognised by trialists, particularly when designing cluster randomised trials.
Topics: Humans; Databases, Factual; Prevalence; Publications; Sample Size; Pragmatic Clinical Trials as Topic; Patient Selection
PubMed: 36600344
DOI: 10.1136/bmjopen-2022-067656 -
Current Oncology Reports Apr 2020Real-world data (RWD) applications in healthcare that support learning health systems and pragmatic clinical trials are gaining momentum, largely due to legislation... (Review)
Review
PURPOSE OF REVIEW
Real-world data (RWD) applications in healthcare that support learning health systems and pragmatic clinical trials are gaining momentum, largely due to legislation supporting real-world evidence (RWE) for drug approvals. Clinical notes are thought to be the cornerstone of RWD applications, particularly for conditions with limited effective treatments, extrapolation of treatments from other conditions, or heterogenous disease biology and clinical phenotypes.
RECENT FINDINGS
Here, we discuss current issues in applying RWD captured at the point-of-care and provide a framework for clinicians to engage in RWD collection. To achieve clinically meaningful results, RWD must be reliably captured using consistent terminology in the description of our patients. RWD complements traditional clinical trials and research by informing the generalizability of results, generating new hypotheses, and creating a large data network for scientific discovery. Effective clinician engagement in the development of RWD applications is necessary for continued progress in the field.
Topics: Clinical Trials as Topic; Datasets as Topic; Drug Approval; Electronic Health Records; Humans; Molecular Biology; Point-of-Care Systems
PubMed: 32297007
DOI: 10.1007/s11912-020-00904-z -
American Heart Journal May 2021The MITIGATE study aims to evaluate the real-world clinical effectiveness of pre-treatment with icosapent ethyl (IPE), compared with usual care, on laboratory-confirmed...
OBJECTIVE
The MITIGATE study aims to evaluate the real-world clinical effectiveness of pre-treatment with icosapent ethyl (IPE), compared with usual care, on laboratory-confirmed viral upper respiratory infection (URI)-related morbidity and mortality in adults with established atherosclerotic cardiovascular disease (ASCVD).
BACKGROUND
IPE is a highly purified and stable omega-3 fatty acid prescription medication that is approved for cardiovascular risk reduction in high-risk adults on statin therapy with elevated triglycerides. Preclinical data and clinical observations suggest that IPE may have pleiotropic effects including antiviral and anti-inflammatory properties that may prevent or reduce the downstream sequelae and cardiopulmonary consequences of viral URIs.
METHODS
MITIGATE is a virtual, electronic health record-based, open-label, randomized, pragmatic clinical trial enrolling ∼16,500 participants within Kaiser Permanente Northern California - a fully integrated and learning health care delivery system with 21 hospitals and >255 ambulatory clinics serving ∼4.5 million members. Adults ≥50 years with established ASCVD and no prior history of coronavirus disease 2019 (COVID-19) will be prospectively identified and pre-randomized in a 1:10 allocation ratio (∼ 1,500 IPE: ∼15,000 usual care) stratified by age and previous respiratory health status to the intervention (IPE 2 grams by mouth twice daily with meals) vs the control group (usual care) for a minimum follow-up duration of 6 months. The co-primary endpoints are moderate-to-severe laboratory-confirmed viral URI and worst clinical status due to a viral URI at any point in time.
CONCLUSION
The MITIGATE study will inform clinical practice by providing evidence on the real-world clinical effectiveness of pretreatment with IPE to prevent and/or reduce the sequelae of laboratory-confirmed viral URIs in a high-risk cohort of patients with established ASCVD.
Topics: Aged; Female; Humans; Male; Middle Aged; Atherosclerosis; Cardiovascular Diseases; COVID-19; Eicosapentaenoic Acid; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intention to Treat Analysis; Platelet Aggregation Inhibitors; Prospective Studies; Respiratory Tract Infections; Randomized Controlled Trials as Topic; Multicenter Studies as Topic; Pragmatic Clinical Trials as Topic
PubMed: 33516752
DOI: 10.1016/j.ahj.2021.01.018 -
Deutsches Arzteblatt International Sep 2017The randomized, controlled trial (RCT) is the gold standard of scientific evidence for the attribution of clinical effects (benefits and harms) to medical interventions.... (Review)
Review
BACKGROUND
The randomized, controlled trial (RCT) is the gold standard of scientific evidence for the attribution of clinical effects (benefits and harms) to medical interventions. Many different designs for RCTs have been developed in order to counter legitimate critical objections and to better adapt the trials to the continually changing challenges that face clinical research.
METHODS
The diversity and adaptability of randomized trial designs are presented and discussed on the basis of a selective literature review and specific illustrative examples.
RESULTS
A wide range of RCT designs enables adaptation to special research tasks and clinical framework conditions. These include (among others) crossover trials, n=1 trials, factorial RCT designs, and cluster-randomized trials. In addition, adaptive designs such as modern platform trials and pragmatic RCTs with simplified clinical questions and less severely restricted patient groups make broad recruitment of patients possible even in routine clinical practice.
CONCLUSION
Only the randomized allocation of subjects to the treatment and control groups, which is the defining property of RCTs, can adequately ensure that traits of the subjects which might disturb or bias a comparison of two or more medical interventions, will be evenly distributed across groups, regardless of whether these traits are known or unknown. The methodological variants and further elaborations of the RCT that are discussed here will help protect patients by enabling the assessment of the benefits and harms of medical methods and products on the basis of robust evidence even in the present era of rapid innovation.
Topics: Cross-Over Studies; Randomized Controlled Trials as Topic; Research Design
PubMed: 29017690
DOI: 10.3238/arztebl.2017.0635 -
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 -
Journal of Clinical Epidemiology Dec 2022To review the pragmatism of published randomized trials of remdesivir and favipiravir based on the Pragmatic-Explanatory Continuum Indicator Summary (PRECIS-2) framework. (Review)
Review
How pragmatic are randomized trials of remdesivir and favipiravir for in-hospital treatment of COVID-19: a descriptive methodological review of trial design using the PRECIS-2 framework.
OBJECTIVES
To review the pragmatism of published randomized trials of remdesivir and favipiravir based on the Pragmatic-Explanatory Continuum Indicator Summary (PRECIS-2) framework.
STUDY DESIGN AND SETTING
Ten eligible trials were identified from an existing comprehensive living review and were evaluated across the nine PRECIS-2 domains by two independent reviewers.
RESULTS
All 10 trials had mostly pragmatic design characteristics. Four of the domains (i.e., recruitment, setting, organization, and primary analysis) were found to be pragmatic with most trials scoring four or five across the two interventions. In comparison scores for four other design domains (i.e., eligibility, follow-up, flexibility of delivery, and primary outcome) varied across the trials with some design choices being more explanatory.
CONCLUSION
In our descriptive review of randomized controlled trails for two drugs for patients infected with COVID-19 early in the pandemic, we found that most trials had more pragmatic than explanatory characteristics. Some design choices for some of the trials, however, were not consistent with the urgent goal of informing clinical decision making in an epidemic. PRECIS-2 should be used as a guide by trialists, to help them match their trial design choices to the intended purpose of their trial.
Topics: Humans; COVID-19 Drug Treatment; Hospitals; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; Research Design
PubMed: 36265553
DOI: 10.1016/j.jclinepi.2022.10.013 -
Advances in Therapy Mar 2020Traditional efficacy double-blind randomised controlled trials (DBRCTs) measure the benefit a treatment produces under near-ideal test conditions in highly selected... (Review)
Review
Traditional efficacy double-blind randomised controlled trials (DBRCTs) measure the benefit a treatment produces under near-ideal test conditions in highly selected patient populations; however, the behaviour of patients and investigators in such trials is highly controlled, highly compliant and adherent, and non-representative of routine clinical practice. Pragmatic effectiveness trials measure the benefit a treatment produces in patients in everyday "real-world" practice. Ideally, effectiveness trials should recruit patients as similar as possible to those who will ultimately be prescribed the medicine, and create freedom within the study design to allow normal behaviours of patients and healthcare professionals (HCPs) to be expressed. The Salford Lung Study (SLS) was a world-first, prospective, phase III, pragmatic randomised controlled trial (RCT) programme in patients with chronic obstructive pulmonary disease and asthma to evaluate the effectiveness of a pre-licensed medication (fluticasone furoate/vilanterol) in real-world practice using electronic health records and through collaboratively engaging general practitioners and community pharmacists in clinical research. The real-world aspect of SLS was unique, requiring careful planning and attention to the goals of maximising the external validity of the trials while maintaining scientific rigour and securing suitable electronic processes for proper interpretation of safety data. Key learnings from SLS that may inform the design of future pragmatic effectiveness RCTs include: (1) ensuring the trial setting and operational infrastructure are aligned with routine clinical care; (2) recruiting a broad patient population with characteristics as close as possible to patients in routine clinical practice, to maximise the generalisability and applicability of trial results; (3) ensuring that patients and HCPs are suitably engaged in the trial, to maximise the chances of successful trial delivery; and (4) careful study design, incorporating outcomes of value to patients, HCPs, policymakers and payers, and using pre-planned analyses to address scientifically valid research hypotheses to ensure robustness of the trial data.
Topics: Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Clinical Trials, Phase III as Topic; Double-Blind Method; Drug Therapy, Combination; Electronic Health Records; Health Behavior; Humans; Patient Selection; Product Surveillance, Postmarketing; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Reproducibility of Results
PubMed: 31927698
DOI: 10.1007/s12325-019-01192-1 -
Trials Aug 2017Randomised clinical trials are key to advancing medical knowledge and to enhancing patient care, but major barriers to their conduct exist. The present paper presents... (Review)
Review
BACKGROUND
Randomised clinical trials are key to advancing medical knowledge and to enhancing patient care, but major barriers to their conduct exist. The present paper presents some of these barriers.
METHODS
We performed systematic literature searches and internal European Clinical Research Infrastructure Network (ECRIN) communications during face-to-face meetings and telephone conferences from 2013 to 2017 within the context of the ECRIN Integrating Activity (ECRIN-IA) project.
RESULTS
The following barriers to randomised clinical trials were identified: inadequate knowledge of clinical research and trial methodology; lack of funding; excessive monitoring; restrictive privacy law and lack of transparency; complex regulatory requirements; and inadequate infrastructures. There is a need for more pragmatic randomised clinical trials conducted with low risks of systematic and random errors, and multinational cooperation is essential.
CONCLUSIONS
The present paper presents major barriers to randomised clinical trials. It also underlines the value of using a pan-European-distributed infrastructure to help investigators overcome barriers for multi-country trials in any disease area.
Topics: Attitude of Health Personnel; Confidentiality; Cooperative Behavior; Equipment and Supplies; Europe; Evidence-Based Medicine; Health Knowledge, Attitudes, Practice; Humans; Multicenter Studies as Topic; Nutrition Therapy; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; Rare Diseases; Research Design; Research Personnel; Research Support as Topic
PubMed: 28764809
DOI: 10.1186/s13063-017-2099-9 -
BMJ Open Sep 2019Non-specific neck pain causes pain and disability and contributes substantial socioeconomic burden internationally. Up to 50% of adults experience neck pain annually,...
Pragmatic cluster randomised double-blind pilot and feasibility trial of an active behavioural physiotherapy intervention for acute non-specific neck pain: a mixed-methods protocol.
INTRODUCTION
Non-specific neck pain causes pain and disability and contributes substantial socioeconomic burden internationally. Up to 50% of adults experience neck pain annually, leading to reduced the quality of life. An active behavioural physiotherapy intervention (ABPI) may be feasible to manage patients with acute non-specific neck pain to prevent transition to chronicity. A recent pilot and feasibility trial investigating an acute whiplash-associated disorder population found potential value of the ABPI with 95% of participants fully recovered (Neck Disability Index: NDI ≤4, compared with 17% in the standard physiotherapy arm); supporting a definitive trial. Qualitative findings from the physiotherapists supported the potential of the ABPI in a non-specific neck pain population.
METHODS AND ANALYSIS
Two phases: (1) Pragmatic cluster randomised double-blind, parallel 2-arm (ABPI vs standard physiotherapy intervention) pilot and feasibility trial to evaluate the procedures and feasibility of the ABPI for the management of acute non-specific neck pain. Six physiotherapy departments from six public hospitals in Thailand will be recruited and cluster randomised by a computer-generated randomisation sequence with block sampling. Sixty participants (30 each arm, 10 per hospital) will be assessed at baseline and 3 months following baseline for NDI, Numerical Rating Scale for pain intensity, cervical range of motion, fear-avoidance beliefs questionnaire and EuroQol-5 dimensions 5 levels outcomes, and (2) Embedded qualitative study using semistructured interviews to explore acceptability of the ABPI to participants (n=12) and physiotherapists (n=3). Descriptive analysis of the quantitative data and interpretative phenomenological analysis to code and analyse qualitative data (deductive and inductive) will inform feasibility for a future definitive trial.
ETHICS AND DISSEMINATION
This trial is approved by the Naresuan University Institutional Review Board (NUIRB_0380/61).
TRIAL REGISTRATION NUMBER AND STATUS
TCTR20180607001; Recruiting commenced 1 February 2019.
Topics: Acute Pain; Adult; Behavior Therapy; Double-Blind Method; Feasibility Studies; Female; Humans; Interviews as Topic; Male; Middle Aged; Neck Pain; Pain Measurement; Physical Therapy Modalities; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; Surveys and Questionnaires; Thailand; Young Adult
PubMed: 31575571
DOI: 10.1136/bmjopen-2019-029795