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Pragmatic randomised controlled trials in COPD and asthma: how to guide clinical practice.

ABSTRACT: The use of real-world evidence (RWE) studies, including pragmatic randomised controlled trials (RCTs; randomised RWE studies), to aid the development of treatment guidelines, is gradually becoming a mainstay within clinical practice. RWE is an integral part of patient-driven decision-making and offers important value to add complimentary evidence to traditional RCTs; these provide a more well-rounded view of the benefits to patient-reported outcomes and improve the external validity of a given treatment versus findings from traditional RCTs alone. Discussions in recent scientific workshops explored the importance of pragmatic RCTs in optimising guideline development and patient care in chronic obstructive pulmonary disease (COPD) and asthma. The Salford Lung Study in patients with COPD (NCT01551758) and asthma (NCT01706198) were the world's first prelicence pragmatic RCTs that compared novel investigational treatments with existing COPD and asthma treatments and, more recently (2021), RWE studies have been used by the American Thoracic Society and the US Food and Drug Administration to support the approval of an immunosuppressant drug in patients receiving lung transplants. This highlights the importance of RWE data in supporting clinical guideline development and emphasises the advantages for the use of pragmatic RCTs in guiding clinical practice.

SUBMITTER: Bakerly ND

PROVIDER: S-EPMC9528570 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Pragmatic randomised controlled trials in COPD and asthma: how to guide clinical practice.

Bakerly Nawar Diar ND Nikitin Kirill K Snowise Neil G NG Cardwell Glenn G Freeman Daryl D Saggu Ravijyot R De Soyza Anthony A

BMJ open respiratory research 20220901 1

The use of real-world evidence (RWE) studies, including pragmatic randomised controlled trials (RCTs; randomised RWE studies), to aid the development of treatment guidelines, is gradually becoming a mainstay within clinical practice. RWE is an integral part of patient-driven decision-making and offers important value to add complimentary evidence to traditional RCTs; these provide a more well-rounded view of the benefits to patient-reported outcomes and improve the external validity of a given t ...[more]

PMID: 36180103

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Project description:BackgroundMany people with clinically significant chronic obstructive pulmonary disease (COPD) remain undiagnosed worldwide. There are a number of small studies which have examined possible methods of case finding through primary care, but no large RCTs that have adequately assessed the most cost-effective approach.Methods/designIn this study, using a cluster randomised controlled trial (RCT) in 56 general practices in the West Midlands, we plan to investigate the effectiveness and cost-effectiveness of a Targeted approach to case finding for COPD compared with routine practice. Using an individual patient RCT nested in the Targeted arm, we plan also to compare the effectiveness and cost-effectiveness of Active case finding using a postal questionnaire (with supplementary opportunistic questionnaires), and Opportunistic-only case finding during routine surgery consultations.All ever-smoking patients aged 40-79 years, without a current diagnosis of COPD and registered with participating practices will be eligible. Patients in the Targeted arm who report positive respiratory symptoms (chronic cough or phlegm, wheeze or dyspnoea) using a brief questionnaire will be invited for further spirometric assessment to ascertain whether they have COPD or not. Post-bronchodilator spirometry will be conducted to ATS standards using an Easy One spirometer by trained research assistants.The primary outcomes will be new cases of COPD and cost per new case identified, comparing targeted case finding with routine care, and two types of targeted case finding (active versus opportunistic). A multilevel logistic regression model will be used to model the probability of detecting a new case of COPD for each treatment arm, with clustering of patients (by practice and household) accounted for using a multi-level structure.A trial-based analysis will be undertaken using costs and outcomes collected during the trial. Secondary outcomes include the feasibility, efficiency, long-term cost-effectiveness, patient and primary care staff views of each approach.DiscussionThis will be the largest RCT of its kind, and should inform how best to identify undiagnosed patients with COPD in the UK and other similar healthcare systems. Sensitivity analyses will help local policy-makers decide which sub-groups of the population to target first.Trial registrationCurrent controlled trials ISRCTN14930255.

Project description:BackgroundOpinions and practices vary around the issue of performing multiple statistical tests in randomised controlled trials (RCTs). We carried out a study to collate information about opinions and practices using a methodological rapid review and a survey, specifically of publicly funded pragmatic RCTs that are not seeking marketing authorisation. The aim was to identify the circumstances under which researchers would make a statistical adjustment for multiplicity.MethodsA review was performed extracting information from articles reporting primary analyses of pragmatic RCTs in one of seven high quality medical journals, in January to June (inclusive) 2018. A survey (Survey Monkey) eliciting opinions and practices around multiplicity was distributed to the 47 registered clinical trials units (CTUs) in the UK.ResultsOne hundred and thirty-eight RCTs were included in the review, and survey responses were received from 27/47 (57%) CTUs. Both the review and survey indicated that adjusting for multiplicity was considered most important for multiple treatment comparisons; adjustment was performed for 11/23 (48%) published trials, and 24/27 (89%) CTU statisticians reported they would consider adjustment. Opinions and practices varied around adjustment for multiplicity arising from multiple primary outcomes and interim analyses. Adjustment was considered less important for multiplicity due to multiple secondary outcomes (adjustment performed for 17/136 [13%] published trials and 3/27 [11%] CTU statisticians would consider adjustment) and subgroup analyses (8/85 [9%] published trials adjusted and 6/27 CTU [22%] statisticians would consider adjustment).ConclusionsThere is variation in opinions about adjustment for multiplicity among both statisticians reporting RCTs and applied statisticians working in CTUs. Further guidance is needed on the circumstances in which adjustment should be considered in relation to primary trial hypotheses, and if there are any situations in which adjustment would be recommended in the context of secondary analyses.

Project description:BackgroundThis paper reports on the cost-effectiveness evaluation of Link-me - a digitally supported, systematic approach to triaging care for depression and anxiety in primary care that uses a patient-completed Decision Support Tool (DST).MethodsThe economic evaluation was conducted alongside a parallel, stratified individually randomised controlled trial (RCT) comparing prognosis-matched care to usual care at six- and 12-month follow-up. Twenty-three general practices in three Australian Primary Health Networks recruited 1,671 adults (aged 18 - 75 years), predicted by the DST to have minimal/mild or severe depressive or anxiety symptoms in three months. The minimal/mild prognostic group was referred to low intensity services. Participants screened in the severe prognostic group were offered high intensity care navigation, a model of care coordination. The outcome measures included in this evaluation were health sector costs (including development and delivery of the DST, care navigation and other healthcare services used) and societal costs (health sector costs plus lost productivity), psychological distress [Kessler Psychological Distress Scale (K10)] and quality adjusted life years (QALYs) derived from the EuroQol 5-dimension quality of life questionnaire with Australian general population preference weights applied. Costs were valued in 2018-19 Australian dollars (A$).ResultsAcross all participants, the health sector incremental cost-effectiveness ratio (ICER) of Link-me per point decrease in K10 at six months was estimated at $1,082 (95% CI $391 to $6,204) increasing to $2,371 (95% CI $191 to Dominated) at 12 months. From a societal perspective, the ICER was estimated at $1,257/K10 point decrease (95% CI Dominant to Dominated) at six months, decreasing to $1,217 (95% CI Dominant to Dominated) at 12 months. No significant differences in QALYs were detected between trial arms and the intervention was dominated (less effective, more costly) based on the cost/QALY ICER.ConclusionsThe Link-me approach to stepped mental health care would not be considered cost-effective utilising a cost/QALY outcome metric commonly adopted by health technology assessment agencies. Rather, Link-me showed a trend toward cost-effectiveness by providing improvement in mental health symptoms, measured by the K10, at an additional cost.Trial registrationAustralian and New Zealand Clinical Trials Registry, ANZCTRN 12617001333303.

Project description:BackgroundDemographics of patients undergoing major abdominal surgery are changing. External validity of relevant RCTs may be limited by participants not resembling patients encountered in clinical practice. We aimed to characterise differences in age, weight, BMI, and ASA grade between participants in perioperative trials in major abdominal surgery and patients in a reference real-world clinical practice sample. The secondary aim was to investigate whether time since trial publication was associated with increasing mismatch between these groups.MethodsMEDLINE and Embase were searched for multicentre RCTs from inception to September 2022. Studies of perioperative interventions in adults were included. Studies that limited enrolment based on age, weight, BMI, or ASA status were excluded. We compared trial cohort age, weight, BMI, and ASA distribution to those of patients undergoing major abdominal surgery at our tertiary referral hospital during September 2021 to September 2022. We used a local, single-institution reference sample to reflect the reality of clinical practice (i.e. patients treated by a clinician in their own hospital, rather than averaged nationally). Mismatch was defined using comparison of summary characteristics and ad hoc criteria based on differences relevant to predicted mortality risk after surgery.ResultsOne-hundred and six trials (44,499 participants) were compared to a reference cohort of 2792 clinical practice patients. Trials were published a median (IQR [range]) 13.4 (5-20 [0-35]) years ago. A total of 94.3% of trials were mismatched on at least one characteristic (age, weight, BMI, ASA). Recruitment of ASA 3 + participants in trials increased over time, and recruitment of ASA 1 participants decreased over time (Spearman's Rho 0.58 and - 0.44, respectively).ConclusionsPatients encountered in our current local clinical practice are significantly different from those in our defined set of perioperative RCTs. Older trials recruit more low-risk than high-risk participants-trials may thus 'expire' over time. These trials may not be generalisable to current patients undergoing major abdominal surgery, and meta-analyses or guidelines incorporating these trials may therefore be similarly non-applicable. Comparison to local, rather than national cohorts, is important for meaningful on-the-ground evidence-based decision-making.

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Pragmatic randomised controlled trials in COPD and asthma: how to guide clinical practice.

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Pragmatic randomised controlled trials in COPD and asthma: how to guide clinical practice.

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