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

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 under-estimated. 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.