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Obesity (Silver Spring, Md.) Apr 2021Little is known about the predictors of response to obesity interventions.
OBJECTIVE
Little is known about the predictors of response to obesity interventions.
METHODS
In 450 participants with obesity, body composition, resting energy expenditure, satiety, satiation, eating behavior, affect, and physical activity were measured by validated studies and questionnaires. These variables were used to classify obesity phenotypes. Subsequently, in a 12-month, pragmatic, real-world trial performed in a weight management center, 312 patients were randomly assigned to phenotype-guided treatment or non-phenotype-guided treatment with antiobesity medications: phentermine, phentermine/topiramate, bupropion/naltrexone, lorcaserin, and liraglutide. The primary outcome was weight loss at 12 months.
RESULTS
Four phenotypes of obesity were identified in 383 of 450 participants (85%): hungry brain (abnormal satiation), emotional hunger (hedonic eating), hungry gut (abnormal satiety), and slow burn (decreased metabolic rate). In 15% of participants, no phenotype was identified. Two or more phenotypes were identified in 27% of patients. In the pragmatic clinical trial, the phenotype-guided approach was associated with 1.75-fold greater weight loss after 12 months with mean weight loss of 15.9% compared with 9.0% in the non-phenotype-guided group (difference -6.9% [95% CI -9.4% to -4.5%], P < 0.001), and the proportion of patients who lost >10% at 12 months was 79% in the phenotype-guided group compared with 34% with non-phenotype-guided treatment group.
CONCLUSIONS
Biological and behavioral phenotypes elucidate human obesity heterogeneity and can be targeted pharmacologically to enhance weight loss.
Topics: Anti-Obesity Agents; Clinical Trials as Topic; Female; Humans; Male; Obesity; Precision Medicine; Weight Loss
PubMed: 33759389
DOI: 10.1002/oby.23120 -
Pharmacoepidemiology and Drug Safety Oct 2020There is a need to develop hybrid trial methodology combining the best parts of traditional randomized controlled trials (RCTs) and observational study designs to... (Review)
Review
PURPOSE
There is a need to develop hybrid trial methodology combining the best parts of traditional randomized controlled trials (RCTs) and observational study designs to produce real-world evidence (RWE) that provides adequate scientific evidence for regulatory decision-making.
METHODS
This review explores how hybrid study designs that include features of RCTs and studies with real-world data (RWD) can combine the advantages of both to generate RWE that is fit for regulatory purposes.
RESULTS
Some hybrid designs include randomization and use pragmatic outcomes; other designs use single-arm trial data supplemented with external comparators derived from RWD or leverage novel data collection approaches to capture long-term outcomes in a real-world setting. Some of these approaches have already been successfully used in regulatory decisions, raising the possibility that studies using RWD could increasingly be used to augment or replace traditional RCTs for the demonstration of drug effectiveness in certain contexts. These changes come against a background of long reliance on RCTs for regulatory decision-making, which are labor-intensive, costly, and produce data that can have limited applicability in real-world clinical practice.
CONCLUSIONS
While RWE from observational studies is well accepted for satisfying postapproval safety monitoring requirements, it has not commonly been used to demonstrate drug effectiveness for regulatory purposes. However, this position is changing as regulatory opinions, guidance frameworks, and RWD methodologies are evolving, with growing recognition of the value of using RWE that is acceptable for regulatory decision-making.
Topics: Decision Making; Drug Approval; Humans; Observational Studies as Topic; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; Research Design
PubMed: 31823482
DOI: 10.1002/pds.4932 -
The New England Journal of Medicine Aug 2016
Topics: Follow-Up Studies; Humans; Patient Selection; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 27518663
DOI: 10.1056/NEJMra1510059 -
Epidemiology (Cambridge, Mass.) Mar 2023Observational studies are often the only option to estimate effects of interventions during pregnancy. Causal inference from observational data can be conceptualized as...
BACKGROUND
Observational studies are often the only option to estimate effects of interventions during pregnancy. Causal inference from observational data can be conceptualized as an attempt to emulate a hypothetical pragmatic randomized trial: the target trial.
OBJECTIVE
To provide a step-by-step description of how to use healthcare databases to estimate the effects of interventions initiated during pregnancy. As an example, we describe how to specify and emulate a target trial of COVID-19 vaccination during pregnancy, but the framework can be generally applied to point and sustained strategies involving both pharmacologic and non-pharmacologic interventions.
METHODS
First, we specify the protocol of a target trial to evaluate the safety and effectiveness of vaccination during pregnancy. Second, we describe how to use observational data to emulate each component of the protocol of the target trial. We propose different target trials for different gestational periods because the outcomes of interest vary by gestational age at exposure. We identify challenges that affect (i) the target trial and thus its observational emulation (censoring and competing events), and (ii) mostly the observational emulation (confounding, immortal time, and measurement biases).
CONCLUSION
Some biases may be unavoidable in observational emulations, but others are avoidable. For instance, immortal time bias can be avoided by aligning the start of follow-up with the gestational age at the time of the intervention, as we would do in the target trial. Explicitly emulating target trials at different gestational ages can help reduce bias and improve the interpretability of effect estimates for interventions during pregnancy.
Topics: Female; Humans; Pregnancy; COVID-19; COVID-19 Vaccines; Databases, Factual; Gestational Age; Vaccination; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic
PubMed: 36722806
DOI: 10.1097/EDE.0000000000001562 -
The British Journal of General Practice... Feb 2022
Topics: General Practice; Humans; Pragmatic Clinical Trials as Topic
PubMed: 35091399
DOI: 10.3399/bjgp22X718289 -
Circulation Mar 2021Regulators are evaluating the use of noninterventional real-world evidence (RWE) studies to assess the effectiveness of medical products. The RCT DUPLICATE initiative...
BACKGROUND
Regulators are evaluating the use of noninterventional real-world evidence (RWE) studies to assess the effectiveness of medical products. The RCT DUPLICATE initiative (Randomized, Controlled Trials Duplicated Using Prospective Longitudinal Insurance Claims: Applying Techniques of Epidemiology) uses a structured process to design RWE studies emulating randomized, controlled trials (RCTs) and compare results. We report findings of the first 10 trial emulations, evaluating cardiovascular outcomes of antidiabetic or antiplatelet medications.
METHODS
We selected 3 active-controlled and 7 placebo-controlled RCTs for replication. Using patient-level claims data from US commercial and Medicare payers, we implemented inclusion and exclusion criteria, selected primary end points, and comparator populations to emulate those of each corresponding RCT. Within the trial-mimicking populations, we conducted propensity score matching to control for >120 preexposure confounders. All study measures were prospectively defined and protocols registered before hazard ratios and 95% CIs were computed. Success criteria for the primary analysis were prespecified for each replication.
RESULTS
Despite attempts to emulate RCT design as closely as possible, differences between the RCT and corresponding RWE study populations remained. The regulatory conclusions were equivalent in 6 of 10. The RWE emulations achieved a hazard ratio estimate that was within the 95% CI from the corresponding RCT in 8 of 10 studies. In 9 of 10, either the regulatory or estimate agreement success criteria were fulfilled. The largest differences in effect estimates were found for RCTs where second-generation sulfonylureas were used as a proxy for placebo regarding cardiovascular effects. Nine of 10 replications had a standardized difference between effect estimates of <2, which suggests differences within expected random variation.
CONCLUSIONS
Agreement between RCT and RWE findings varies depending on which agreement metric is used. Interim findings indicate that selection of active comparator therapies with similar indications and use patterns enhances the validity of RWE. Even in the context of active comparators, concordance between RCT and RWE findings is not guaranteed, partially because trials are not emulated exactly. More trial emulations are needed to understand how often and in what contexts RWE findings match RCTs. Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03936049, NCT04215523, NCT04215536, NCT03936010, NCT03936036, NCT03936062, NCT03936023, NCT03648424, NCT04237935, NCT04237922.
Topics: Aged; Female; Humans; Male; Middle Aged; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic
PubMed: 33327727
DOI: 10.1161/CIRCULATIONAHA.120.051718 -
Lancet (London, England) Apr 2017Bullous pemphigoid is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline gives acceptable... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Bullous pemphigoid is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline gives acceptable short-term blister control while conferring long-term safety advantages over starting treatment with oral corticosteroids.
METHODS
We did a pragmatic, multicentre, parallel-group randomised controlled trial of adults with bullous pemphigoid (three or more blisters at two or more sites and linear basement membrane IgG or C3). Participants were randomly assigned to doxycycline (200 mg per day) or prednisolone (0·5 mg/kg per day) using random permuted blocks of randomly varying size, and stratified by baseline severity (3-9, 10-30, and >30 blisters for mild, moderate, and severe disease, respectively). Localised adjuvant potent topical corticosteroids (<30 g per week) were permitted during weeks 1-3. The non-inferiority primary effectiveness outcome was the proportion of participants with three or fewer blisters at 6 weeks. We assumed that doxycycline would be 25% less effective than corticosteroids with a 37% acceptable margin of non-inferiority. The primary safety outcome was the proportion with severe, life-threatening, or fatal (grade 3-5) treatment-related adverse events by 52 weeks. Analysis (modified intention to treat [mITT] for the superiority safety analysis and mITT and per protocol for non-inferiority effectiveness analysis) used a regression model adjusting for baseline disease severity, age, and Karnofsky score, with missing data imputed. The trial is registered at ISRCTN, number ISRCTN13704604.
FINDINGS
Between March 1, 2009, and Oct 31, 2013, 132 patients were randomly assigned to doxycycline and 121 to prednisolone from 54 UK and seven German dermatology centres. Mean age was 77·7 years (SD 9·7) and 173 (68%) of 253 patients had moderate-to-severe baseline disease. For those starting doxycycline, 83 (74%) of 112 patients had three or fewer blisters at 6 weeks compared with 92 (91%) of 101 patients on prednisolone, an adjusted difference of 18·6% (90% CI 11·1-26·1) favouring prednisolone (upper limit of 90% CI, 26·1%, within the predefined 37% margin). Related severe, life-threatening, and fatal events at 52 weeks were 18% (22 of 121) for those starting doxycycline and 36% (41 of 113) for prednisolone (mITT), an adjusted difference of 19·0% (95% CI 7·9-30·1), p=0·001.
INTERPRETATION
Starting patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control in bullous pemphigoid and significantly safer in the long-term.
FUNDING
NIHR Health Technology Assessment Programme.
Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Clinical Trials as Topic; Doxycycline; Equivalence Trials as Topic; Female; Germany; Glucocorticoids; Humans; Male; Middle Aged; Pemphigoid, Bullous; Prednisolone; Treatment Outcome; United Kingdom
PubMed: 28279484
DOI: 10.1016/S0140-6736(17)30560-3 -
Academic Emergency Medicine : Official... Oct 2022Pragmatic clinical trials (PCTs) focus on correlation between treatment and outcomes in real-world clinical practice, yet a guide highlighting key study considerations...
Pragmatic clinical trials (PCTs) focus on correlation between treatment and outcomes in real-world clinical practice, yet a guide highlighting key study considerations and design types for emergency medicine investigators pursuing this important study type is not available. Investigators conducting emergency department (ED)-based PCTs face multiple decisions within the planning phase to ensure robust and meaningful study findings. The PRagmatic Explanatory Continuum Indicator Summary 2 (PRECIS-2) tool allows trialists to consider both pragmatic and explanatory components across nine domains, shaping the trial design to the purpose intended by the investigators. Aside from the PRECIS-2 tool domains, ED-based investigators conducting PCTs should also consider randomization techniques, human subjects concerns, and integration of trial components within the electronic health record. The authors additionally highlight the advantages, disadvantages, and rationale for the use of four common randomized study design types to be considered in PCTs: parallel, crossover, factorial, and stepped-wedge. With increasing emphasis on the conduct of PCTs, emergency medicine investigators will benefit from a rigorous approach to clinical trial design.
Topics: Emergency Medicine; Humans; Pragmatic Clinical Trials as Topic; Research Design
PubMed: 35475533
DOI: 10.1111/acem.14513 -
Pharmacoepidemiology and Drug Safety Sep 2017Real-world evidence (RWE) includes data from retrospective or prospective observational studies and observational registries and provides insights beyond those addressed... (Comparative Study)
Comparative Study
Good practices for real-world data studies of treatment and/or comparative effectiveness: Recommendations from the joint ISPOR-ISPE Special Task Force on real-world evidence in health care decision making.
PURPOSE
Real-world evidence (RWE) includes data from retrospective or prospective observational studies and observational registries and provides insights beyond those addressed by randomized controlled trials. RWE studies aim to improve health care decision making.
METHODS
The International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the International Society for Pharmacoepidemiology (ISPE) created a task force to make recommendations regarding good procedural practices that would enhance decision makers' confidence in evidence derived from RWD studies. Peer review by ISPOR/ISPE members and task force participants provided a consensus-building iterative process for the topics and framing of recommendations.
RESULTS
The ISPOR/ISPE Task Force recommendations cover seven topics such as study registration, replicability, and stakeholder involvement in RWE studies. These recommendations, in concert with earlier recommendations about study methodology, provide a trustworthy foundation for the expanded use of RWE in health care decision making.
CONCLUSION
The focus of these recommendations is good procedural practices for studies that test a specific hypothesis in a specific population. We recognize that some of the recommendations in this report may not be widely adopted without appropriate incentives from decision makers, journal editors, and other key stakeholders.
Topics: Advisory Committees; Decision Making; Delivery of Health Care; Economics, Pharmaceutical; Humans; Internationality; Pharmacoepidemiology; Pragmatic Clinical Trials as Topic; Prospective Studies; Retrospective Studies; Societies, Scientific; Statistics as Topic; Treatment Outcome
PubMed: 28913966
DOI: 10.1002/pds.4297 -
Clinical Trials (London, England) Dec 2021Pragmatic clinical trials are increasingly used to generate knowledge about real-world clinical interventions. However, they involve some distinctive ethical and...
Pragmatic clinical trials are increasingly used to generate knowledge about real-world clinical interventions. However, they involve some distinctive ethical and regulatory challenges. In this article, we examine a set of issues related to incentives and other payments to patients in pragmatic clinical trials. Although many of the ethical concerns related to incentives and payments in explanatory trials pertain to pragmatic clinical trials, the pragmatic features may introduce additional challenges. These include those related to the risk of incentives and payments undermining the scientific validity and social value of pragmatic clinical trials, the sources of data used in pragmatic clinical trials, and when the pragmatic clinical trials are conducted under waivers of consent. Based on our examination of these matters, we offer some preliminary recommendations regarding incentives and payments in pragmatic clinical trials, recognizing that additional data and experiences are needed to refine them.
Topics: Ethics, Research; Humans; Motivation; Policy; Pragmatic Clinical Trials as Topic; Research Design
PubMed: 34766524
DOI: 10.1177/17407745211048178