Eligibility of real-life patients with COPD for inclusion in RCTs: a commentary
Battaglia and Scichilone Respiratory Research
Eligibility of real-life patients with COPD for inclusion in RCTs: a commentary
Salvatore Battaglia 0
Nicola Scichilone 0
0 DIBIMIS, University of Palermo , Palermo , Italy
Randomized clinical trials (RCTs) are performed to provide evidence to support treatment decisions. Based on the nature of those studies and the need to avoid confounding factors, it has been argued that the population selected in RCTs only partially represents the real-life population. This assumption casts doubts on the applicability of the results provided by RCTs in the management of individuals with an established diagnosis of COPD, and advocates the need for complementary studies with a pragmatic design. Herein, we comment on the recent article published by Halpin and colleagues on the Journal [Halpin et al, Respir Res 17:120, 2016], in which higher rates of inclusions in RCTs for COPD are found compared to previous observations. By analyzing the design of the studies and the end results, we conclude that the accumulating evidence contribute to shed lights on how representative is the outpatient population of real life settings.
Clinical trials; COPD research; Clinical practice
We read with great interest the article by Halpin
and coworkers that aimed at determining the
proportion of the general UK patient population with
COPD that would be eligible for inclusion in
randomized clinical trials (RCTs) testing inhaled
longacting bronchodilators . Current knowledge on
the effects of inhaled treatment on the airways of
COPD may have been hampered in the past by
publication bias towards high internal validity, not
sufficiently making the same efforts to test the external
validity of clinical trials.
In the current study , the Authors reported a
recruitment rate of inclusion of 23%, arguing against previous
work from our  and other groups [3–6], which
showed lower rates of inclusion. The Authors suggested
that the study by Scichilone et al  and by Walker et
al.  could have included a different, and less
representative, subset of patients suffering from COPD. We
acknowledge that our conclusions of lower rates of
inclusion in RCTs were made on a much lower number
of patients; however, we respectfully disagree with their
assumption that recruiting patients with a more severe
disease (from hospital clinics) is a study limitation that
raises concerns about the generalisability of the findings.
More severe patients deserve more aggressive treatment
and this could theoretically lead to higher risk of side
effects. Therefore, RCTs should take into account this
cluster of patients in order to achieve higher
Moreover, Halpin and coworkers concluded that RCTs
participants are generally more representative of
outpatients than previously believed. The recruitment rate for
inclusion of 23% by Halpin’s study is actually very similar
to our 17%. This is especially true for the subgroups of
RCTs carried out in initial and final five-year periods
(years 1999–2003 and 2009–2013) that showed an
inclusion rate of 16% and 18%, respectively. The
median eligibility rate falls to 13% in the subgroup of
RCTs on beta-adrenergics and anticholinergics
(LABA/LAMA) combination treatment. This is
worrying since novel inhaled combinations of two
longacting bronchodilators are gaining increasing evidence
in the pharmacological treatment of COPD .
Another aspect that must be highlighted is the possibility
that entire categories of patients could be excluded from
RCTs: this seems the case of atrial fibrillation. Indeed, the
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current GOLD recommendations  recognize atrial
fibrillation as the most frequent cardiac arrhythmia in patients
with COPD, while admitting that “there are no good data
on the use of COPD medication in patients with atrial
fibrillation and these patients have often been excluded
from clinical trials”. In this contest, the probability that a
patient with COPD and concomitant atrial fibrillation is
treated without any scientific evidence or safety data is
high. Similar observations have been produced in chronic
diseases other than COPD [9, 10]. Although under some
conditions the eligibility rate could be as high as 58%,
overall almost three out of four patients from real life settings
are not eligible for RCTs and this should, in our opinion,
limit the RCTs generalisability.
Is therefore the ideal RCT the one that allows to
include a proportion of “real life” patients close to 100%?
It is a possibility. However, an alternative exists: in the
era of personalized medicine, RCTs should aim at
targeting a very small and well-described proportion of
patients, with the totality of patients achieved by pooling
results from several RTCs. This is the opposite of the
The current study has the merit of challenging the
scientific community on what is (should be) the acceptable
eligibility rate that RCTs should achieve in order to be
generalizable to real-life COPD populations. We believe
that our observations may actually complement those of
Halpin and colleagues , and pragmatic observational
studies or ad hoc designed trials should be encouraged
to test the effectiveness of inhaled treatment to fill the
gap between RCTs patients and every-day patients.
Studies such as that by Halpin and coworkers will certainly
help to move towards this direction.
COPD: Chronic obstructive pulmonary disease; LABA: Long acting
beta-adrenergic agonist; LAMA: Long acting muscarinic antagonist;
RCT: Randomized clinical trial; UK: United Kingdom
SB and NS analysed previous data, agreed on the conclusions and wrote the
manuscript. Both authors read and approved the final manuscript.
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