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.