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Journal of General Internal Medicine May 2015Research on interventions within the standard of care has enormous potential, yet it also raises several ethical and regulatory challenges. Perhaps the most important is... (Comparative Study)
Comparative Study Review
Research on interventions within the standard of care has enormous potential, yet it also raises several ethical and regulatory challenges. Perhaps the most important is determining what consent process is needed for these "pragmatic" clinical trials. Some argue that pragmatic clinical trials need to obtain in-depth research consent. This approach ensures that patients are informed, but may introduce substantial selection bias and disruption of clinical care. Others argue that trials limited to interventions within the standard of care do not need to obtain research consent at all. While this approach avoids the problems with in-depth consent, it results in patients not knowing whether they are in research. The present manuscript proposes a way to avoid both sets of concerns. It argues that consent for research needs to supplement appropriate consent for standard care only to the extent that the research differs from standard care. Hence, pragmatic trials designed to mirror clinical care can obtain consent with only minimal additions to consent for standard care. This conclusion suggests that it may be possible for many pragmatic trials to obtain consent that is ethically appropriate, satisfies research regulations, and does not introduce substantial selection bias or clinical disruption.
Topics: Female; Humans; Informed Consent; Male; Needs Assessment; Patient Selection; Pragmatic Clinical Trials as Topic; United States
PubMed: 25586870
DOI: 10.1007/s11606-014-3169-2 -
Geriatric Nursing (New York, N.Y.) 2022Randomized controlled trials are considered the most rigorous research design in efficacy and effectiveness research; however, such trials present numerous challenges...
Randomized controlled trials are considered the most rigorous research design in efficacy and effectiveness research; however, such trials present numerous challenges that limit their applicability in real-world settings. As a consequence, pragmatic trials are increasingly viewed as a research design that overcomes some of these barriers with the potential to produce data that are more reproducible. Although pragmatic methodology in long-term care is receiving increasing attention as an approach to improve successful dissemination and implementation, pragmatic trials present complexities of their own. To address these complexities and related issues, experts with experience conducting pragmatic trials, developing nursing home policy, participating in advocacy efforts, and providing clinical care in long-term care settings participated in a virtual consensus conference funded by the National Institute on Aging in Spring 2021. Participants recommended 4 cross-cutting principles key to dissemination and implementation of pragmatic trial interventions: (1) engage stakeholders, (2) ensure diversity and inclusion, (3) assess organizational strain and readiness, and (4) learn from adaptations. Specifically related to implementation, participants provided 2 recommendations: (1) integrate interventions into existing workflows and (2) maintain agility and responsiveness. Finally, participants had 3 recommendations specific to dissemination: (1) package the message for the audience, (2) engage diverse audiences, and (3) apply dissemination and diffusion tools. Participants emphasized that implementation processes must be grounded in the perspectives of the people who will ultimately be responsible for implementing the intervention once it is proven to be effective. In addition, messaging must speak to long-term care staff and all others who have a stake in its outcomes. Although our understanding of dissemination and implementation strategies remains underdeveloped, this article is designed to guide long-term care researchers and community providers who are increasingly aware of the need for pragmatism in disseminating and implementing evidence-based care interventions.
Topics: Humans; Long-Term Care; Nursing Homes; Pragmatic Clinical Trials as Topic
PubMed: 35219533
DOI: 10.1016/j.gerinurse.2022.02.006 -
Journal of Clinical Epidemiology Jan 2020
Topics: Diagnostic Tests, Routine; Humans; Pragmatic Clinical Trials as Topic; Research Design
PubMed: 31924314
DOI: 10.1016/j.jclinepi.2019.12.004 -
BMC Medicine Oct 2022Pragmatic trials aim to generate evidence to directly inform patient, caregiver and health-system manager policies and decisions. Heterogeneity in patient...
BACKGROUND
Pragmatic trials aim to generate evidence to directly inform patient, caregiver and health-system manager policies and decisions. Heterogeneity in patient characteristics contributes to heterogeneity in their response to the intervention. However, there are many other sources of heterogeneity in outcomes. Based on the expertise and judgements of the authors, we identify different sources of clinical and methodological heterogeneity, which translate into heterogeneity in patient responses-some we consider as desirable and some as undesirable. For each of them, we discuss and, using real-world trial examples, illustrate how heterogeneity should be managed over the whole course of the trial.
MAIN TEXT
Heterogeneity in centres and patients should be welcomed rather than limited. Interventions can be flexible or tailored and control interventions are expected to reflect usual care, avoiding use of a placebo. Co-interventions should be allowed; adherence should not be enforced. All these elements introduce heterogeneity in interventions (experimental or control), which has to be welcomed because it mimics reality. Outcomes should be objective and possibly routinely collected; standardised assessment, blinding and adjudication should be avoided as much as possible because this is not how assessment would be done outside a trial setting. The statistical analysis strategy must be guided by the objective to inform decision-making, thus favouring the intention-to-treat principle. Pragmatic trials should consider including process analyses to inform an understanding of the trial results. Needed data to conduct these analyses should be collected unobtrusively. Finally, ethical principles must be respected, even though this may seem to conflict with goals of pragmatism; consent procedures could be incorporated in the flow of care.
Topics: Humans; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; Research Design
PubMed: 36303153
DOI: 10.1186/s12916-022-02569-w -
Circulation Mar 2016Randomized, clinical trials are commonly regarded as the highest level of evidence to support clinical decisions. Good Clinical Practice guidelines have been constructed... (Review)
Review
Randomized, clinical trials are commonly regarded as the highest level of evidence to support clinical decisions. Good Clinical Practice guidelines have been constructed to provide an ethical and scientific quality standard for trials that involve human subjects in a manner aligned with the Declaration of Helsinki. Originally designed to provide a unified standard of trial data to support submission to regulatory authorities, the principles may also be applied to other studies of human subjects. Although the application of Good Clinical Practice principles generally led to improvements in the quality and consistency of trial operations, these principles have also contributed to increasing trial complexity and costs. Alternatively, the growing availability of electronic health record data has facilitated the possibility for streamlined pragmatic clinical trials. The central tenets of Good Clinical Practice and pragmatic clinical trials represent potential tensions in trial design (stringent quality and highly efficient operations). In the present article, we highlight potential areas of discordance between Good Clinical Practice guidelines and the principles of pragmatic clinical trials and suggest strategies to streamline study conduct in an ethical manner to optimally perform clinical trials in the electronic age.
Topics: Clinical Trials as Topic; Humans; Practice Guidelines as Topic; Research Design
PubMed: 26927005
DOI: 10.1161/CIRCULATIONAHA.115.019902 -
Trials Dec 2019All clinical trial investigators have ethical and regulatory obligations to monitor participant safety and trial integrity. Specific procedures for meeting these...
BACKGROUND
All clinical trial investigators have ethical and regulatory obligations to monitor participant safety and trial integrity. Specific procedures for meeting these obligations, however, may differ substantially between pragmatic trials and traditional explanatory clinical trials.
METHODS/RESULTS
Appropriate monitoring of clinical trials typically includes assessing rate of recruitment or enrollment; monitoring safe and effective delivery of study treatments; assuring that study staff act to minimize risks; monitoring quality and timeliness of study data; and considering interim analyses for early detection of benefit, harm, or futility. Each of these responsibilities applies to pragmatic clinical trials. Just as design of pragmatic trials typically involves specific and necessary departures from methods of explanatory clinical trials, appropriate monitoring of pragmatic trials typically requires specific departures from monitoring procedures used in explanatory clinical trials. We discuss how specific aspects of pragmatic trial design and operations influence selection of monitoring procedures and illustrate those choices using examples from three ongoing pragmatic trials conducted by the Mental Health Research Network.
CONCLUSIONS
Pragmatic trial investigators should not routinely adopt monitoring procedures used in explanatory clinical trials. Instead, investigators should consider core principles of trial monitoring and design monitoring procedures appropriate for each pragmatic trial.
Topics: Adolescent; Adult; Aged; Data Accuracy; Humans; Middle Aged; Pragmatic Clinical Trials as Topic; Research Design; Young Adult
PubMed: 31815644
DOI: 10.1186/s13063-019-3869-3 -
Mayo Clinic Proceedings Aug 2023Clinical trials have been the bedrock of research to evaluate the safety and efficacy of new medical, surgical, or other interventions. Traditional "explanatory"... (Review)
Review
Clinical trials have been the bedrock of research to evaluate the safety and efficacy of new medical, surgical, or other interventions. Traditional "explanatory" clinical trials have aimed to explain a biological cause (new treatment) and effect (patient outcome) while controlling for many factors that might impact the evaluation, such as restricted eligibility criteria, frequent follow-up visits, and multiple clinical and laboratory measures. Despite the benefits of a well-controlled clinical trial, compromises have been made that can limit who might benefit from a new intervention, can increase complexity of the conduct of a trial, or that lead to excessively long durations of trials. An alternative approach to evaluate the effectiveness of an intervention is based on "pragmatic" clinical trials, which consider how an intervention affects a patient's condition in the real world, accounting for how to optimize an intervention within the operations of busy and diverse clinical practices. Although we describe explanatory and pragmatic trial designs as separate approaches, there is a continuum of approaches that intersect. Some key points are the need to maintain scientific rigor, increase efficiency of clinical trials operations, ensure that trial results can be generalized to a broad spectrum of patients, and balance the needs of real-world clinical care. Pragmatic trials can leverage technology and telecommunication strategies of decentralized trials to further reach underrepresented and underserved patients to close the health disparity gaps.
Topics: Humans; Research Design; Time Factors; Clinical Trials as Topic
PubMed: 37536808
DOI: 10.1016/j.mayocp.2023.04.013 -
PloS One 2022Child and family social workers in the UK work closely with other agencies including schools and the police, and typically they are based in local authority offices....
BACKGROUND
Child and family social workers in the UK work closely with other agencies including schools and the police, and typically they are based in local authority offices. This study will evaluate the effectiveness of placing social workers in schools (SWIS) on the need for social care interventions. SWIS was piloted in three local authorities in 2018-2020, and findings from a feasibility study of the pilots suggests SWIS may operate through three key pathways: (1) by enhancing schools' response to safeguarding issues, (2) through increased collaboration between social workers, school staff, and parents, and (3) by improving relationships between social workers and young people.
METHODS
The study is a two-arm pragmatic cluster randomised controlled trial building on three feasibility studies which found SWIS to be promising. Social workers will work within secondary schools across local authorities in England. 280 mainstream secondary schools will be randomly allocated with a 1:1 ratio to SWIS or a comparison arm, which will be schools that continue as normal, without a social worker. The primary outcome will be the rate of Child Protection (Section 47) enquiries. Secondary outcomes will comprise rate of referrals to children's social care, rate of Child in Need (Section 17) assessments, days spent in care, and educational attendance and attainment. The study also includes an economic evaluation, and an implementation and process evaluation. Social care outcomes will be measured in July 2022, and educational outcomes will be measured in July 2023. Days in care will be measured at both time points.
DISCUSSION
Findings will explore the effectiveness and cost-effectiveness of SWIS on the need for social care interventions. A final report will be published in January 2024.
TRIAL REGISTRATION
The study was registered retrospectively with the International Standard Randomised Controlled Trial Number registry on 13.11.2020 (ISRCTN90922032).
Topics: Adolescent; Child; Cost-Benefit Analysis; Feasibility Studies; Humans; Parents; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; Retrospective Studies; Schools; Social Work
PubMed: 35679281
DOI: 10.1371/journal.pone.0265354 -
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 -
Neurology Apr 2016We aimed to provide recommendations for addressing comorbidity in clinical trial design and conduct in multiple sclerosis (MS).
OBJECTIVE
We aimed to provide recommendations for addressing comorbidity in clinical trial design and conduct in multiple sclerosis (MS).
METHODS
We held an international workshop, informed by a systematic review of the incidence and prevalence of comorbidity in MS and an international survey about research priorities for studying comorbidity including their relation to clinical trials in MS.
RESULTS
We recommend establishing age- and sex-specific incidence estimates for comorbidities in the MS population, including those that commonly raise concern in clinical trials of immunomodulatory agents; shifting phase III clinical trials of new therapies from explanatory to more pragmatic trials; describing comorbidity status of the enrolled population in publications reporting clinical trials; evaluating treatment response, tolerability, and safety in clinical trials according to comorbidity status; and considering comorbidity status in the design of pharmacovigilance strategies.
CONCLUSION
Our recommendations will help address knowledge gaps regarding comorbidity that interfere with the ability to interpret safety in monitored trials and will enhance the generalizability of findings from clinical trials to "real world" settings where the MS population commonly has comorbid conditions.
Topics: Clinical Trials as Topic; Comorbidity; Humans; Multiple Sclerosis
PubMed: 26888986
DOI: 10.1212/WNL.0000000000002471