Central coordination as an alternative for local coordination in a multicenter randomized controlled trial: the FAITH trial experience

Randomized controlled trials (RCTs) are generally perceived as the reference standard for generating valid scientific evidence on the evaluation of medical treatments and interventions [1]. Unfortunately, RCTs continue to be relatively scarce in the orthopedic trauma literature [2]. This may be attributed to the logistical challenges of the implementation of RCTs.

One of the most apparent challenges of RCTs is to recruit the required number of patients as timely and efficiently as possible [3]. Availability of fewer patients than expected usually leads to an extended trial period and increased costs. Multicenter collaborations offer the potential of recruiting more patients within a shorter time period, which can be advantageous if large patient numbers are required or if the targeted population has a low incidence. They also have the advantage of increased generalizability of the results [4, 5]. However, the conduct of multicenter clinical trials requires a complex organization, which applies even more to international trials [6, 7].

Obtaining ethics or Institutional Review Board (IRB) approval is a potential cause of delay, as procedures, documents, and legislation may vary between countries [8]. This process is often time-consuming and it is recommended to have dedicated and well-trained study personnel available to assist participating sites with these administrative tasks [9‐13].

Another challenge in multicenter research is the selection and recruitment of appropriate participating clinical sites. Every participating site should have a devoted and dedicated clinician as site principal investigator. As surgeons often lack the time to spend on research, it is important to have an assisting research team that can adopt many of the time consuming research tasks. Having adequate support can be more important for sites to decide to participate, than offering a financial compensation for participation [14, 15]. The presence of a trial coordinator or assistant will also facilitate an appropriate study infrastructure, which is a requirement for proper study conduct [3, 8, 16‐18]. As community hospitals generally lack such infrastructure, they often cannot participate in multicenter trials. This is unfortunate, as some injuries or interventions are much more frequent in community hospitals than in university hospitals. Their participation in a multicenter trial could therefore positively influence the recruitment rate. Once a large multicenter or multinational RCT has started, a relatively complex organization should be implemented and maintained in order to assure a complete patient follow-up and a high quality in data management [19, 20].

Usually individual sites are required to manage their local ethics procedures and trial logistics. They generally receive per patient payments as compensation. As an alternative option, a single trial coordinator can be appointed to manage all trial-related tasks for multiple sites in a certain geographic area or country, in which travel time is limited and does not include air fares. This is dependent on availability of full financial support, but can relieve local sites from many trial related tasks. This may attract more sites to participate, provide a smoother process of obtaining ethics approval, quicker trial start-up, higher inclusion rates and follow-up completeness.

Similar management strategies have been applied in the FAITH trial (Fixation using Alternative Implants for the Treatment of Hip fractures, NCT00761813). The FAITH trial is an international multicenter study initiated by the IHFRC (International Hip Fracture Research Collaborative) [21]. The primary objective of this trial is to assess the impact of sliding hip screws versus cancellous screw fixation on rates of revision surgery at two years in elderly patients with femoral neck fractures. This trial has been launched in over 60 sites, predominantly situated in the Netherlands, Canada, and the US. All sites in the Netherlands are managed and visited by a single financed national trial coordinator. Most Canadian and US sites have individual local site coordinators and receive per patient payments. The aim of this study was to assess how these strategies affected performance of the FAITH trial.

In this study, trial progression in the Netherlands, where a central trial coordinator managed most tasks for multiple centers in a restricted geographical area, was better than in Canada and the US, where local research assistants were appointed at individual sites. The central trial coordinator system was associated with a shorter trial start-up time, higher inclusion rate, and a higher inclusion percentage. Collection of follow-up data was equally good in both systems.

The process of obtaining ethics approval can be time-consuming and stressful and may yield diverse responses from ethics committees [9‐13]. For the FAITH trial, obtaining ethics approval took longer in the Netherlands than in Canada or the US. This may have been influenced by the time that the trial coordinator or sites needed to assemble forms for the ethics committee. Ethics submissions may have taken longer in the Netherlands at the very start of the trial, when there was no central trial coordinator yet. The longer approval process in the Netherlands may also have been caused by more inefficient medical ethics procedures [10]. In the Netherlands multicenter studies need approval from a central ethics committee that performs a full review of the study documents. Subsequently, ethics committees in participating sites should only advise on local feasibility. This two-step approach was aimed to simplify and shorten the ethics procedures for multicenter trials. It is nevertheless disputable if this goal is currently achieved [10]. In Canada and the US a single procedure for study review and approval is performed at all sites, which may turn out to be more efficient.

The number of resubmissions requested by the ethics committees was lower in the Netherlands, and can therefore not have contributed to the prolonged approval process. The availability of a central trial coordinator with detailed insight and knowledge on the study content could have prevented incorrect submissions in the Netherlands. In all countries remarks of the ethics committees mainly involved the informed consent form and extra information on the study protocol and procedures. Standardization of the ethics approval process is recommended as it may reduce the local differences in ethics approval terms.

Most influential to the differences in trial progression between the countries were the evident differences in inclusion rate and percentage, which were statistically significantly higher for sites in the Netherlands. The availability of the central trial coordinator in the Netherlands made it possible for smaller, non-university sites without a local research infrastructure or coordinator to participate. These sites generally treat more patients from the targeted population (i.e., femoral neck fracture patients) than the large university hospitals, but would normally not have been able or willing to participate in the trial, because they lack a local coordinator. Most of the principal investigators of these sites reported to be very motivated to enroll patients, as the (administrative) burden of participation was relatively low, thanks to the fact that the performance of follow-ups and other trial related tasks were adopted by the central trial coordinator. They declared that this was crucial in their decision to participate. This high devotion and lack of burdensome trial related tasks will probably have contributed to a good inclusion rate. Therefore, the availability of a central trial coordinator can contribute to a fast enrolment, both directly, by motivating local principal investigators to participate and enroll because of the low (administrative) burden of participation, and indirectly, by enabling high-volume hospitals without a local research network to participate. However, differences in accrual between countries may also have been affected by the known intercultural differences in preferred treatments for femoral neck fractures [22]. North American surgeons may have considered less femoral neck fracture patients suitable for internal fixation than Dutch surgeons do, as they are less committed to internal fixation as a preferred treatment. Moreover, surgeons from the US and Canada reported at investigator meetings that North American patients may be less lenient to participate in trials and that they experienced problems at obtaining informed consent [23]. Within the countries, higher accrual was also associated with a large target population, dedicated and compliant principal investigators, and low study related workload for participating surgeons. These are important aspects to pursue when planning a multicenter randomized controlled trial, and can be facilitated by appointing a central trial coordinator.

Comparison of the pre-trial prospective screening data with the actual trial data showed an obvious discrepancy in all countries. It is known that participating surgeons tend to overestimate enrolment numbers based upon a pre-trial screening period [24]. In this study accrual was also much lower than expected from the screening period. The use of pre-trial screening can therefore be debated. However, it may be useful to indicate good dedication to participate and help raise awareness for the upcoming study in potential sites. If a pre-trial screening is deemed necessary, a retrospective approach is recommended, as it is easier and results in similar estimated numbers, compared with a prospective approach [24].

The percentage completed follow-ups was not affected by the availability of a central trial coordinator and was between 70% and 84% for all countries. Follow-ups did seem to be completed within the window a bit less in the Netherlands, although not statistically significant. This was a result of the limitations that we experienced from the central trial coordinator approach. Usefulness of this approach will decrease with an increased sample size and an increased distance between sites. A single person can only manage a certain maximum number of sites and patients. Similarly, there is a maximum to the distance that can be traveled per day. In our study, a single study coordinator to manage 14 sites and 250 patients seemed somewhat limited. The study coordinator had to complete eight follow-ups per patient (four clinical and four telephonic), in 14 sites that were maximum 140 km. apart (maximum 2 hours travel time), resulting in an average of almost 1,000 km traveled per week. In these circumstances it was not always feasible to manage all follow-ups. We feel that it would have been optimal to have one coordinator following a maximum number of 200 patients, in our study. It is also important to have a supporting research team available for assistance if work pressure gets too high for a single person. The central coordinator approach is feasible within European countries, as well as within American/Canadian states.

Finally, a central coordinator may also contribute to the impartiality of the collected data and may prevent biases that could be introduced if the local coordinators/participating doctors are also the treating physician. Obviously, this could not be analyzed or proven in this study.

In summary, trial performance can be influenced by the management strategy chosen. This study shows that the appointment of a central financed trial coordinator to manage all trial related tasks is a feasible alternative for the more traditional approach of appointing trial related tasks to local research assistants at participating sites. Taking important circumstances such as available budget, sample size, and geographical area into account, a central trial coordinator approach can add to the success of a multicenter randomized trial. A central coordinator should be considered when studying injuries that occur more frequently in smaller regional hospitals (without a local research coordinator). It will enable these sites to participate in randomized controlled trials, resulting in a enhanced enrolment rate. It should also be considered when the targeted principal investigators are unable to participate due to the (administrative) burden of participation. However, a central coordinator should only be considered for multiple sites in a restricted geographical area. Depending upon the geographic spread of the sites and the frequency of follow-up a careful estimation should be made of the amount of patients and sites that can be managed by a single coordinator.