Randomised controlled trials in severe asthma: selection by phenotype or stereotype

Abstract

Previous publications have highlighted the disparity between research trial populations and those in clinical practice, but it has not been established how this relates to randomised controlled trials (RCTs) of phenotype-targeted biological therapies in severe asthma.Detailed characterisation data for 342 severe asthma patients within the Wessex Severe Asthma Cohort (WSAC) was compared against comprehensive trial eligibility criteria for published phase IIB and phase III RCTs evaluating biological therapies in severe asthma since 2000.37 RCTs evaluating 20 biological therapies were identified. Only a median of 9.8% (range 3.5–17.5%) of severe asthma patients were found to be eligible for enrolment in the phase III trials. Stipulations for airflow obstruction, bronchodilator reversibility and smoking history excluded significant numbers of patients. A median of 78.9% (range 73.2–86.6%) of patients with severe eosinophilic asthma would have been excluded from participation in the phase III licensing trials of interleukin (IL)-5/IL-5R targeted therapies.Despite including only well characterised and optimally treated severe asthmatics under specialist care within the WSAC study, the vast majority were excluded from trial participation by criteria designed to re-confirm diagnostic labels rather than by biomarker criteria that predict the characteristic addressed by the treatment.

Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline

“…It has long been appreciated that the conventional requirements for a good randomised controlled clinical trial do not reflect the reality of patients seen in the clinics [61][62][63]. Stringent diagnostic requirements are imposed, e.g.…”

“…There could be two reasons for excluding a severe asthmatic patient from a trial of, for example, an anti-type 2 monoclonal [61,63]. The first entirely logical reason would be the absence of any evidence of type 2 activity; the second, far more dubious, the presence of type 2 activation, but a coexistent disqualification such as smoking or the absence of variable airflow obstruction.…”

“…The first entirely logical reason would be the absence of any evidence of type 2 activity; the second, far more dubious, the presence of type 2 activation, but a coexistent disqualification such as smoking or the absence of variable airflow obstruction. The Wessex group recently evaluated 37 randomised controlled trials of type 2 biologicals and found that <10% of patients in the Wessex Severe Asthma Cohort would have been enrolled in landmark phase 3 trials of biological therapies, with commonest reasons for exclusion being failure to demonstrate either or both of fixed and variable airflow obstruction [61]. The exclusion rate for patients with eosinophilic asthma was even higher.…”

Letting the right one in: evaluating the generalisability of clinical trials

“…This has been addressed in the current issue of the European Respiratory Journal, in which BROWN et al [12] assess the eligibility of patients in their tertiary care severe asthma cohort, the Wessex Severe Asthma Cohort (WSAC), to enter RCTs of novel treatments for asthma. Their patients underwent detailed clinical, physiological and biological characterisation, and had confirmed severe asthma as per the American Thoracic Society/European Respiratory Society 2014 definition [13].…”

“…The impact of patient selection criteria was evident from the 37 studies evaluated by BROWN et al [12], all of which evaluated drugs in severe asthma, in which 12 different criteria were used to define airflow obstruction. Some studies allowed one of a number of criteria to be used to demonstrate this and/or bronchodilator reversibility, but this only modestly increased trial eligibility.…”