Series: Pragmatic trials and real world evidence: Paper 3. Patient selection challenges and consequences

Rengerink, Katrien Oude; Kalkman, Shona; Collier, Susan; Ciaglia, Antonio; Worsley, Sally; Lightbourne, Alison; Eckert, Laurent; Groenwold, Rolf H H; Grobbee, Diederick E.; Irving, Elaine

doi:10.1016/j.jclinepi.2016.12.021

Cited by 64 publications

(54 citation statements)

References 43 publications

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“…Exclusion of patients from trials matters only if the exclusion criteria are effect modifiers of treatment [27], meaning that the benefits or harms of treatment (or both) systematically vary in the included versus the excluded. This review found that trial evidence is typically derived from narrow populations which are usually selected to have higher risk of outcomes expected to be improved by treatment (e.g., by selective inclusion of patients at high cardiovascular risk) and usually selected to have lower risk of adverse effects (e.g., by selective exclusion of patients with co-morbidity, co-prescribing and frailty).…”

Section: Implications For Policy Practice and Researchmentioning

confidence: 99%

Exclusion rates in randomized controlled trials of treatments for physical conditions: a systematic review

Moralès

Guthrie

2020

Trials

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Background: The generalisability of randomized controlled trials (RCTs) can be uncertain because the impact of exclusion criteria is rarely quantified. The aim of this study was to systematically review studies examining the percentage of clinical populations with a physical health condition who would be excluded by RCTs of treatments for that condition. Methods: Medline and Embase were searched from inception to Feb 11th 2018. Two reviewers independently completed screening, full-text review, data extraction and risk-of-bias assessment. The primary outcome was the percentage of patients in the clinical population who would have been excluded from each examined trial. Subgroup analyses examined exclusion by population setting, publication date and funding source. Results: Titles/abstracts (20,754) were screened, and 50 studies were included which reported exclusion rates from 305 trials of treatments in 31 physical conditions. Estimated rates of exclusion from trials varied from 0% to 100%, and the median exclusion rate was 77.1% of patients (interquartile range 55.5% to 89.0% exclusion). Median exclusion rates for trials in common chronic conditions were high, including hypertension 83.0%, type 2 diabetes 81.7%, chronic obstructive pulmonary disease 84.3%, and asthma 96.0%. The most commonly applied exclusion criteria related to age, co-morbidity and co-prescribing, whereas more implicit criteria relating to life expectancy or functional status were not typically examined. There was no evidence that exclusion varied by the nature of the clinical population in which exclusion was evaluated or trial funding source. There was no statistically significant change in exclusion rates in more recent compared with older trials. Conclusions: The majority of trials of treatments for physical conditions examined excluded the majority of patients with the condition being treated. Almost a quarter of the trials studied excluded over 90% of patients, more than half of trials excluded at least three quarters of patients, and four out of five trials excluded at least half of patients. A limitation is that most studies applied only a subset of eligibility criteria, so exclusion rates are likely underestimated. Exclusion from trials of older people and people with co-morbidity and co-prescribing is increasingly untenable given population aging and increasing multimorbidity. Trial registration: PROSPERO registration CRD42016042282.

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Section: Implications For Policy Practice and Researchmentioning

confidence: 99%

Exclusion rates in randomized controlled trials of treatments for physical conditions: a systematic review

Moralès

Guthrie

2020

Trials

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“…Whether the return of SLCO1B1 results is acted upon by providers and leads to improvement in patient outcomes remains unknown but will be addressed by the trial's outcomes. One risk of applying a pragmatic design to study a precision medicine intervention is that the broad eligibility criteria, a strength of PCTs, may dilute the effect of the intervention . If so, examining the reasons the providers and patients did not act on the information will be critical for interpreting the trial's results.…”

Section: Discussionmentioning

confidence: 99%

Pragmatic Trials in Genomic Medicine: The Integrating Pharmacogenetics In Clinical Care (I‐PICC) Study

Brunette

Miller

Majahalme

et al. 2019

Clinical Translational Sci

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Pragmatic clinical trials (PCTs) have an established presence in clinical research and yet have only recently garnered attention within the landscape of genomic medicine. Using the PRagmatic‐Explanatory Continuum Indicator Summary 2 (PRECIS‐2) as a framework, this paper illustrates the application of PCT principles to The Integrating Pharmacogenetics In Clinical Care (I‐PICC) Study, a trial of pharmacogenetic testing prior to statin initiation for cardiovascular disease prevention in primary care. The trial achieved high engagement with providers (85% enrolled of those approached) and enrolled a representative sample of participants for which statin therapy would be recommended. The I‐PICC Study has a high level of pragmatism, which should enhance the generalizability of its findings. The PRECIS‐2 may be useful in the design and evaluation of PCTs of genomic medicine interventions, contributing to the generation of evidence that can bridge the gap between genomics innovation and clinical adoption.

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“…Instruments to assess the outcome should be sufficiently accurate (ie, valid, reliable, and responsive) and feasible in terms of costs and complexity [41e43]. Deviations from routine clinical practice should be minimized, also to promote the acceptability of measurements to patients and care providers who participate in a study [7,[44][45][46]. It may be beneficial for decision making to apply a predefined cutoff value for continuous outcome measures in a pragmatic trial when resulting categorical outcomes have a clearer meaning for interpretation of trial results at patient level (ie, the probability of recovery).…”

Section: Measuring Outcomesmentioning

confidence: 99%

Series: Pragmatic trials and real world evidence: Paper 6. Outcome measures in the real world

Welsing

Rengerink

Collier

et al. 2017

Journal of Clinical Epidemiology

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Results from pragmatic trials should reflect the comparative treatment effects encountered in patients in real-life clinical practice to guide treatment decisions. Therefore, pragmatic trials should focus on outcomes that are relevant to patients, clinical practice, and treatment choices. This sixth article in the series (see Box) discusses different types of outcomes and their suitability for pragmatic trials, design choices for measuring these outcomes, and their implications and challenges. Measuring outcomes in pragmatic trials should not interfere with real-world clinical practice to ensure generalizability of trial results, and routinely collected outcomes should be prioritized. Typical outcomes include mortality, morbidity, functional status, well-being, and resource use. Surrogate endpoints are typically avoided as primary outcome. It is important to measure outcomes over a relevant time horizon and obtain valid and precise results. As pragmatic trials are often open label, a less subjective outcome can reduce bias. Methods that decrease bias or enhance precision of the results, such as standardization and blinding of outcome assessment, should be considered when a high risk of bias or high variability is expected. The selection of outcomes in pragmatic trials should be relevant for decision making and feasible in terms of executing the trial in the context of interest. Therefore, this should be discussed with all stakeholders as early as feasible to ensure the relevance of study results for decision making in clinical practice and the ability to perform the study.

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Series: Pragmatic trials and real world evidence: Paper 3. Patient selection challenges and consequences

Cited by 64 publications

References 43 publications

Exclusion rates in randomized controlled trials of treatments for physical conditions: a systematic review

Exclusion rates in randomized controlled trials of treatments for physical conditions: a systematic review

Pragmatic Trials in Genomic Medicine: The Integrating Pharmacogenetics In Clinical Care (I‐PICC) Study

Series: Pragmatic trials and real world evidence: Paper 6. Outcome measures in the real world

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