Interpretation
The design of a no-treatment arm where treatment is standard clinical
practice was associated with recruitment failure. This design is
particularly relevant, since we may be over-treating patients while we
are actually in equipoise on whether the intervention is effective at
all. Possibly, in this design specifically, the preference of the doctor
or patient might play a role in the laborious recruitment. A no
treatment arm was also associated with stopping prematurely, supporting
its relevance as a risk factor. In our study ten (52%) of 19 RCTs that
stopped prematurely had a no-treatment arm where in current clinical
practice treatment is expected.
Two typical examples of RCTs with such a design that stopped prematurely
were a trial that compared intrauterine insemination (IUI) with
expectant management in couples with unexplained subfertility, and a
trial that compared immediate delivery with temporizing management in
women between 27+5 and 33+5 weeks of gestation admitted for early-onset
severe preeclampsia with or without HELLP syndrome(33, 81).
Not very surprisingly, the lack of funding and compensation fee per
included patient was associated with recruitment failure. Twelve studies
with recruitment failure had no funding at all, compared with three
studies without recruitment failure. In combination with our outcome
that extending the recruitment period from six to twelve months did not
increase the numbers of RCTs that reached their pre-planned sample size,
this has important clinical, logistic and financial consequences. RCTs
may reach their recruitment target, but in 12 RCTs in our study,
recruitment took up to ten years. It implies that when recruitment is
doomed to fail, it may reach its required sample size in the end, but at
the expense of a lot of endurance and extra funding by a willing
sponsor. On the other hand, RCTs can still be of extreme clinical
importance if the research question is – and remains – relevant. This
is shown by a trial that investigated low-molecular-weight heparin in
women with recurrent pregnancy loss and inherited thrombophilia, which
took 7,5 years to recruit, but results were eagerly awaited and
eventually published in a high impact journal(15).
A preceding pilot study lowers recruitment failure, while a study design
with more than two arms or more than four inclusion criteria might
increase the chance of recruitment failure, although with a wide
confidence interval due to small numbers. We think that a preceding
pilot study helps to notice and resolve potential issues before start of
the actual study, while a study design with more than two arms or more
than four inclusion criteria could result in an overly complex
recruitment process. In a review of the literature on factors limiting
the quality and progress of RCTs not hampered by recruitment failure, a
straightforward study protocol and data collection as well as careful
planning were also identified as key factors for completion(90).
A competing study was not associated with a lower chance on recruitment
failure, which is the opposite of what we expected. We hypothesize that
when more RCTs in the same field are recruiting patients at the same
time, clinicians are more aware of the possibility of including patients
in a particular RCT, or when one RCT recruits rapidly, this might be
“contagious” for the other RCTs.
It is important to note that our results should not withhold clinicians
from conducting RCTs on these research questions. Investigating the
efficacy and safety of treatments and providing robust evidence can be
of the utmost importance. Although it is known that the results of
randomized and nonrandomized studies have a good correlation,
nonrandomized studies tend to show larger treatment effects, and thus
observational studies can be good adjunct to RCTs, but they cannot
replace them(91, 92). More importantly, our study shows that also RCTs
with recruitment that takes many years answer highly relevant clinical
questions and can truly make a big difference in the clinical field.
Principal investigators, sponsors and all who are participating in an
RCT should be aware of the indicators associated with poor recruitment,
and that with dedication and persistence the RCT could be successfully
completed and published.