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PLoS Medicine Mar 2016In this month's editorial, PLOS Medicine Editorial Board member Anushka Patel and Ruth Webster discuss how applying rules for drug efficacy trials can impede pragmatic...
In this month's editorial, PLOS Medicine Editorial Board member Anushka Patel and Ruth Webster discuss how applying rules for drug efficacy trials can impede pragmatic trials of interventions for noncommunicable diseases.
Topics: Alcohol Drinking; Diabetes Mellitus; Humans; Hypertension; Obesity; Pragmatic Clinical Trials as Topic; Research; Research Design; Sedentary Behavior; Tobacco Use; Translational Research, Biomedical; World Health Organization
PubMed: 27022969
DOI: 10.1371/journal.pmed.1001986 -
Challenges and Lessons Learned From COVID-19 Trials: Should We Be Doing Clinical Trials Differently?The Canadian Journal of Cardiology Sep 2021The COVID-19 crisis led to a flurry of clinical trials activity. The COVID-evidence database shows 2814 COVID-19 randomized trials registered as of February 16, 2021.... (Review)
Review
The COVID-19 crisis led to a flurry of clinical trials activity. The COVID-evidence database shows 2814 COVID-19 randomized trials registered as of February 16, 2021. Most were small (only 18% have a planned sample size > 500) and the rare completed ones have not provided published results promptly (only 283 trial publications as of February 2021). Small randomized trials and observational, nonrandomized analyses have not had a successful track record and have generated misleading expectations. Different large trials on the same intervention have generally been far more efficient in producing timely and consistent evidence. The rapid generation of evidence and accelerated dissemination of results have led to new challenges for systematic reviews and meta-analyses (eg, rapid, living, and scoping reviews). Pressure to regulatory agencies has also mounted with massive emergency authorizations, but some of them have had to be revoked. Pandemic circumstances have disrupted the way trials are conducted; therefore, new methods have been developed and adopted more widely to facilitate recruitment, consent, and overall trial conduct. On the basis of the COVID-19 experience and its challenges, planning of several large, efficient trials, and wider use of adaptive designs might change the future of clinical research. Pragmatism, integration in clinical care, efficient administration, promotion of collaborative structures, and enhanced integration of existing data and facilities might be several of the legacies of COVID-19 on future randomized trials.
Topics: COVID-19; Clinical Trials as Topic; Drug Repositioning; Humans; Pandemics; Randomized Controlled Trials as Topic; Research Design; SARS-CoV-2
PubMed: 34077789
DOI: 10.1016/j.cjca.2021.05.009 -
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 -
British Journal of Clinical Pharmacology Feb 2018Pregnant and breastfeeding women have been rendered therapeutic orphans as they have been historically excluded from clinical trials. Labelling for most approved drugs... (Review)
Review
Pregnant and breastfeeding women have been rendered therapeutic orphans as they have been historically excluded from clinical trials. Labelling for most approved drugs does not provide information about safety and efficacy during pregnancy. This lack of data is mainly due to ethico-legal challenges that have remained entrenched in the post-diethylstilbestrol and thalidomide era, and that have led to pregnancy being viewed in the clinical trial setting primarily through a pharmacovigilance lens. Policy considerations that encourage and/or require the inclusion of pregnant or lactating women in clinical trials may address the current lack of available information. However, there are additional pragmatic strategies, such the employment of pharmacometric tools and the introduction of innovative clinical trial designs, which could improve knowledge about the safety and efficacy of medication use during pregnancy and lactation. This paper provides a broad overview of the pharmacoepidemiology of drugs used during pregnancy and lactation, and offers recommendations for regulators and researchers in academia and industry to increase the available pharmacokinetic and -dynamic understanding of medication use in pregnancy.
Topics: Biomedical Research; Breast Feeding; Clinical Trials as Topic; Drug-Related Side Effects and Adverse Reactions; Female; Government Regulation; Guidelines as Topic; Humans; Pharmaceutical Preparations; Pharmacoepidemiology; Pregnancy; Pregnancy Complications; United States; United States Food and Drug Administration
PubMed: 28925019
DOI: 10.1111/bcp.13438 -
Clinical Trials (London, England) Aug 2020Clinical trials embedded in health systems can randomize large populations using automated data sources to determine trial eligibility and assess outcomes. The suicide...
Clinical trials embedded in health systems can randomize large populations using automated data sources to determine trial eligibility and assess outcomes. The suicide prevention outreach trial used real-world data for trial design and randomized 18,868 individuals in four health systems using patient-reported thoughts of death or self-harm (Patient Health Questionnaire item 9). This took 3.5 years. We consider if using predictive analytics, that is, suicide risk estimates based on prediction models, could improve trial "efficiency." We used data on mental health outpatient visits between 1 January 2009 and 30 September 2017 in seven health systems (HealthPartners; Henry Ford Health System; and Colorado, Hawaii, Northwest, Southern California, and Washington Kaiser Permanente regions). We used a suicide risk prediction model developed in these same systems. We compared five trial designs with different eligibility criteria: a response of a 2 or 3 on Patient Health Questionnaire item 9, a response of a 3, suicide risk score above 90th, 95th, or 99th percentile. We compared the sample that met each criterion, 90-day suicide attempt rate following first eligible visit, and necessary sample sizes to detect a 15%, 25%, and 35% relative reduction in the suicide attempt rate, assuming 90% power, for each eligibility criterion. Our sample included 24,355,599 outpatient visits. Despite wide-spread use of Patient Health Questionnaire, 21,026,985 (86.3%) visits did not have a recorded Patient Health Questionnaire. Of the 2,928,927 individuals in our sample, 109,861 had a recorded Patient Health Questionnaire item 9 response of a 2 or 3 over the study years with a 1.40% 90-day suicide attempt rate and 50,047 had a response of a 3 (suicide attempt rate 1.98%). More patients met criteria requiring a certain risk score or higher: 331,273 had a 90th percentile risk score or higher (suicide attempt rate: 1.36%); 182,316 a 95th percentile or higher (suicide attempt rate 2.16%), and 78,655 a 99th percentile or higher (suicide attempt rate: 3.95%). Eligibility criterion of a Patient Health Questionnaire item 9 response of a 2 or 3 would require randomizing 44,081 individuals (40.2% of eligible population in our sample); eligibility criterion of a 3 would require 31,024 individuals (62.0% of eligible population). Eligibility criterion of a suicide risk score of 90th percentile or higher would require 45,675 individuals (13.8% of eligible population), 95th percentile 28,699 individuals (15.7% of eligible population), and 99th percentile 15,509 (19.7% of eligible population). A suicide risk prediction calculator could improve trial "efficiency"; identifying more individuals at increased suicide risk than relying on patient-report. It is an open scientific question if individuals identified using predictive analytics would respond differently to interventions than those identified by more traditional means.
Topics: Adolescent; Adult; Aged; Electronic Health Records; Eligibility Determination; Female; Humans; Male; Mental Health; Middle Aged; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; Research Design; Risk Assessment; Risk Factors; Sample Size; Suicidal Ideation; Suicide; Suicide, Attempted; Surveys and Questionnaires; Young Adult; Suicide Prevention
PubMed: 32153209
DOI: 10.1177/1740774520910367 -
Journal of Clinical Epidemiology Dec 2022To explore qualitatively the relationship between selected trial design choices and proxies for a scientific and clinical uptake in a cohort of published randomized... (Review)
Review
The relationship between pragmatism, timing, and study size on impact of randomized trials: a qualitative, hypothesis generating study of trials of systemic corticosteroids for COVID-19.
OBJECTIVE
To explore qualitatively the relationship between selected trial design choices and proxies for a scientific and clinical uptake in a cohort of published randomized controlled trials (RCTs) of corticosteroids for COVID-19, to identify design characteristics that may result in trials with potential to eliminate equipoise, achieve uptake, and help reduce research waste.
STUDY DESIGN AND SETTING
A systematic literature search and qualitative, narrative review of published RCTs (up to April 13, 2021) evaluating the effectiveness of systemic corticosteroids in treatment of COVID-19. We extracted information on sample size, number of centers, single-country or multi-country conduct, dates of initiation and of publication, risk of bias and pragmatism scores, and also on an impact measured by citation in scientific literature and in clinical guidelines. We qualitatively compared design features of the highest impact vs. other trials.
RESULTS
Randomised Evaluation of COVID-19 Therapy (RECOVERY) was by the most impactful of the seven eligible RCTs as it was 10 times more frequently cited in peer-reviewed literature and influenced all the selected COVID-19 treatment guidelines. All trials started recruiting from similar dates. RECOVERY was a single-country, multicentre platform trial at low risk of bias, features which also fail to distinguish it from the other trials. RECOVERY was distinguished by more strongly pragmatic design features, more centers, and more rapid recruitment resulting in a larger sample size and early publication.
CONCLUSION
Higher pragmatism scores may contribute to recruiting more centers and more rapid recruitment of patients at each center, leading to larger size, earlier publication, and greater scientific and guideline uptake. By eliminating equipoise, RECOVERY rendered other simultaneous trials redundant. Further work is needed to confirm these findings in a larger quantitative study and to identify the individual contribution of each characteristic of pragmatism to conduct and impact of trials and their interaction in different national contexts. Until then, research waste might be reduced by designing trials with as many of the characteristics of RECOVERY as is feasible.
Topics: Humans; Adrenal Cortex Hormones; COVID-19; Randomized Controlled Trials as Topic
PubMed: 36209914
DOI: 10.1016/j.jclinepi.2022.09.018 -
Journal of the American Society of... Oct 2016Pragmatic clinical trials are conducted under the real-world conditions of clinical care delivery. As a result, these trials yield findings that are highly generalizable... (Review)
Review
Pragmatic clinical trials are conducted under the real-world conditions of clinical care delivery. As a result, these trials yield findings that are highly generalizable to the nonresearch setting, identify interventions that are readily translatable into clinical practice, and cost less than trials that require extensive research infrastructures. Maintenance dialysis is a setting especially well suited for pragmatic trials because of inherently frequent and predictable patient encounters, highly granular and uniform data collection, use of electronic data systems, and delivery of care by a small number of provider organizations to approximately 90% of patients nationally. Recognizing the potential for pragmatic trials to generate much needed evidence to guide the care of patients receiving maintenance dialysis, the Kidney Health Initiative assembled a group of individuals with relevant expertise from academia, industry, and government to provide the nephrology community with information about the design and conduct of such trials, with a specific focus on the dialysis setting. Here, we review this information, and where applicable, use experience from the ongoing Time to Reduce Mortality in End Stage Renal Disease Trial, a large cluster-randomized, pragmatic trial evaluating hemodialysis session duration, to illustrate challenges and solutions to operational, ethical, and regulatory issues.
Topics: Biomedical Research; Humans; Pragmatic Clinical Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 27401689
DOI: 10.1681/ASN.2016030340 -
Journal of Clinical Epidemiology Sep 2017This paper addresses challenges of identifying, enrolling, and retaining participants in a trial conducted within a routine care setting. All patients who are potential...
This paper addresses challenges of identifying, enrolling, and retaining participants in a trial conducted within a routine care setting. All patients who are potential candidates for the treatments in routine clinical practice should be considered eligible for a pragmatic trial. To ensure generalizability, the recruited sample should have a similar distribution of the treatment effect modifiers as the target population. In practice, this can be best achieved by including-within the selected sites-all patients without further selection. If relevant heterogeneity between subgroups is expected, increasing the relative proportion of the subgroup of patients in the heterogeneous trial could be considered (oversampling) or a separate trial in this subgroup can be planned. Selection will nevertheless occur. Low enrollment and loss to follow-up can introduce selection and can jeopardize validity as well as generalizability. Pragmatic trials are conducted in clinical practice rather than in a dedicated research setting, which could reduce recruitment rates. However, if a trial poses a minimal burden to the physician and the patient and routine clinical practice is maximally adhered to, the participation rate may be high and loss to follow-up will not be a specific problem for pragmatic trials.
Topics: Humans; Patient Selection; Pragmatic Clinical Trials as Topic
PubMed: 28502808
DOI: 10.1016/j.jclinepi.2016.12.021 -
JAMA Internal Medicine Sep 2018This database study evaluates the labeling, justifications, and limitations of pragmatic randomized clinical trials published in 2016. (Review)
Review
This database study evaluates the labeling, justifications, and limitations of pragmatic randomized clinical trials published in 2016.
Topics: Humans; Periodicals as Topic; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic
PubMed: 30039169
DOI: 10.1001/jamainternmed.2018.3321 -
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