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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 -
Current Gastroenterology Reports Aug 2018Since the first clinical trial of cortisone in ulcerative colitis in 1955, remarkable progress has been made in the design and conduct of clinical trials in inflammatory... (Review)
Review
PURPOSE OF REVIEW
Since the first clinical trial of cortisone in ulcerative colitis in 1955, remarkable progress has been made in the design and conduct of clinical trials in inflammatory bowel diseases (IBD). In this review article, we will discuss evolution of clinical trials in IBD over the last 3-5 years.
RECENT FINDINGS
Recognizing limitations intrinsic to clinical disease activity indices in IBD, regulatory authorities have recommended evaluating co-primary endpoints of patient-reported outcomes and endoscopic disease activity in clinical trials. Biomarker-enriched trial enrolment and central endoscopy reading have emerged as critical events in trial recruitment and outcome assessment and have driven placebo response rates down. While trials of novel biologic therapies and advanced small molecules continue at an accelerated pace, pragmatic comparative efficacy trials of treatment strategy aimed at optimizing current therapies (such as early combined immunosuppression [REACT], tight disease control [CALM], therapeutic drug monitoring [TAXIT, TAILORIX]) have directly informed clinical practice. With emphasis on value-based care and population health management, multi-pronged remote monitoring, self-management, and telemedicine approaches in the era of smartphones have re-emerged with promise. Non-conventional therapies such as fecal microbiota transplantation, though still experimental, have provided insight into disease pathogenesis and offered hope for microbial manipulation strategies for treating these complex diseases. Clinical trials have rapidly evolved over the last 5 years not only focusing on novel therapies but also optimizing existing treatment approaches and population health management. Over the next decade, these trials will continue to advance the field, and be readily translatable into clinical practice.
Topics: Clinical Trials as Topic; Endoscopy, Gastrointestinal; Fecal Microbiota Transplantation; Humans; Inflammatory Bowel Diseases; Patient Reported Outcome Measures
PubMed: 30078058
DOI: 10.1007/s11894-018-0648-3 -
Clinical Trials (London, England) Dec 2020Standard approaches to trial design and analyses can be inefficient and non-pragmatic. Failure to consider a range of outcomes impedes evidence-based interpretation and...
BACKGROUND/AIMS
Standard approaches to trial design and analyses can be inefficient and non-pragmatic. Failure to consider a range of outcomes impedes evidence-based interpretation and reduces power. Traditional approaches synthesizing information obtained from separate analysis of each outcome fail to incorporate associations between outcomes and recognize the cumulative nature of outcomes in individual patients, suffer from competing risk complexities during interpretation, and since efficacy and safety analyses are often conducted on different populations, generalizability is unclear. Pragmatic and efficient approaches to trial design and analyses are needed.
METHODS
Approaches providing a pragmatic assessment of benefits and harms of interventions, summarizing outcomes experienced by patients, and providing sample size efficiencies are described. Ordinal outcomes recognize finer gradations of patient responses. Desirability of outcome ranking is an ordinal outcome combining benefits and harms within patients. Analysis of desirability of outcome ranking can be based on rank-based methodologies including the desirability of outcome ranking probability, the win ratio, and the proportion in favor of treatment. Partial credit analyses, involving grading the levels of the desirability of outcome ranking outcome similar to an academic test, provides an alternative approach. The methodologies are demonstrated using the acute stroke or transient ischemic attack treated with aspirin or ticagrelor and patient outcomes study (SOCRATES; NCT01994720), a randomized clinical trial.
RESULTS
Two 5-level ordinal outcomes were developed for SOCRATES. The first was based on a modified Rankin scale. The odds ratio is 0.86 (95% confidence interval = 0.75, 0.99; = 0.04) indicating that the odds of worse stroke categorization for a trial participant assigned to ticagrelor is 0.86 times that of a trial participant assigned to aspirin. The 5-level desirability of outcome ranking outcome incorporated and prioritized survival; the number of strokes, myocardial infarction, and major bleeding events; and whether a stroke event was disabling. The desirability of outcome ranking probability and win ratio are 0.504 (95% confidence interval = 0.499, 0.508; = 0.10) and 1.11 (95% confidence interval = 0.98, 1.26; = 0.10), respectively, implying that the probability of a more desirable result with ticagrelor is 50.4% and that a more desirable result occurs 1.11 times more frequently on ticagrelor versus aspirin.
CONCLUSION
Ordinal outcomes can improve efficiency through required pre-specification, careful construction, and analyses. Greater pragmatism can be obtained by composing outcomes within patients. Desirability of outcome ranking provides a global assessment of the benefits and harms that more closely reflect the experience of patients. The desirability of outcome ranking probability, the proportion in favor of treatment, the win ratio, and partial credit can more optimally inform patient treatment, enhance the understanding of the totality of intervention effects on patients, and potentially provide efficiencies over standard analyses. The methods provide the infrastructure for incorporating patient values and estimating personalized effects.
Topics: Adult; Aspirin; Humans; Ischemic Attack, Transient; Odds Ratio; Platelet Aggregation Inhibitors; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; Research Design; Stroke; Ticagrelor; Treatment Outcome
PubMed: 32666831
DOI: 10.1177/1740774520941441 -
Drug Discovery Today Dec 2018
Topics: Clinical Trials as Topic; Decision Making; Humans; Pharmaceutical Preparations; Research Design
PubMed: 29906514
DOI: 10.1016/j.drudis.2018.06.007 -
Future Oncology (London, England) Oct 2021Oncology trials are the cornerstone of effective and safe therapeutic discoveries. However, there is increasing demand for pragmatism and patient engagement in the... (Review)
Review
Oncology trials are the cornerstone of effective and safe therapeutic discoveries. However, there is increasing demand for pragmatism and patient engagement in the design, implementation and dissemination of oncology trials. Many researchers are uncertain about making trials more practical and even less knowledgeable about how to meaningfully engage patients without compromising scientific rigor to meet regulatory requirements. The present work provides practical guidance for addressing both pragmaticism and meaningful patient engagement. Applying evidence-based approaches like PRECIS-2-tool and the 10-Step Engagement Framework offer practical guidance to make future trials in oncology truly pragmatic and patient-centered. Consequently, such patient-centered trials have improved participation, faster recruitment and greater retention, and uptake of innovative technologies in community-based care.
Topics: Humans; Neoplasms; Patient Advocacy; Patient Participation; Patient-Centered Care; Pragmatic Clinical Trials as Topic; Precision Medicine; Quality of Life; Research Design
PubMed: 34337970
DOI: 10.2217/fon-2021-0556 -
Journal of Evaluation in Clinical... Oct 2019
Topics: Bias; Clinical Trials as Topic; Comparative Effectiveness Research; Evidence-Based Practice; Humans; Treatment Outcome
PubMed: 31063238
DOI: 10.1111/jep.13155 -
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 -
The British Journal of Dermatology Sep 2019
Topics: Pragmatic Clinical Trials as Topic; Research Design
PubMed: 31475345
DOI: 10.1111/bjd.17889 -
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 -
Journal of Clinical Epidemiology Sep 2021We established a large database of trials to serve as a resource for future methodological and ethical analyses. Here, we use meta-data to describe the broad landscape... (Review)
Review
OBJECTIVE
We established a large database of trials to serve as a resource for future methodological and ethical analyses. Here, we use meta-data to describe the broad landscape of pragmatic trials including research areas, identification as pragmatic, quality of trial registry data and enrolment.
STUDY DESIGN AND SETTING
Trials were identified by a validated search filter and included if a primary report of a health-related randomized trial published January 2014-April 2019. Data were collated from MEDLINE, Web of Science, ClinicalTrials.gov, and full text.
RESULTS
4337 eligible trials were identified from 13,065 records, of which 1988 were registered in ClinicalTrials.gov. Research areas were diverse, with the most common being general and internal medicine; public, environmental and occupational health; and health care sciences and services. The term "pragmatic" was seldom used in titles or abstracts. Several domains in ClinicalTrials.gov had questionable data quality. We estimated that one-fifth of trials under-accrued by at least 15%.
CONCLUSION
There is a need to improve reporting of pragmatic trials and quality of trial registry data. Under accrual remains a challenge in pragmatic RCTs despite calls for more streamlined recruitment approaches. The diversity of pragmatic trials should be reflected in future ethical analyses.
Topics: Abstracting and Indexing; Humans; Pragmatic Clinical Trials as Topic; Registries; Research Design
PubMed: 33789151
DOI: 10.1016/j.jclinepi.2021.03.021