Development and assessment of evidence-based strategies towards increased feasibility and transparency of investigator-initiated clinical trials in Switzerland

This work addresses the obligation to minimize research waste by identifying barriers and needs for support in important processes of clinical research and by proposing efficient strategies to improve the quality of research practice. Major sources of waste in clinical research have been identified by the “Increasing Value, Reducing Waste” series in The Lancet in 2014. Two considerations in this series address the problem of inefficient trial management and insufficient research transparency. Collected evidence suggests that inefficient management and monitoring of the procedural conduct of trials are a major source of waste even in well-designed studies addressing important questions. The absence of a continuous oversight of established trial processes endanger completion of trials in a set timeframe or even cause premature discontinuation. Increasing feasibility of clinical trials by providing an evidence-based strategy to effectively support the conduct of clinical trials at the University Hospital of Basel that has the potential to be transferred to the whole academic network for clinical research in Switzerland was aspired in this thesis. Along with feasibility, it is important that information of a trial including results is publicly available. In Switzerland, prospective registration of a clinical trial in a primary trial registry has been made mandatory by law in 2014 (Art 56 Human Research Act). We analyzed research transparency in terms of trial registration and results publication in a local setting in Switzerland to assess the successful implementation and enforcement of national efforts and identify potential barriers.
In a first step, we systematically reviewed existing evidence on effective monitoring strategies both in the medical literature and across international clinical research stakeholder groups. Monitoring strategies varied in their methodological approach but the effectiveness of risk-based and triggered approaches could be shown with moderate certainty. However, we did not find evidence on the effect of these methods on the overall trial conduct. Based on these findings, we then engaged local, national and international stakeholder representatives in the creation of a comprehensive risk-tailored approach integrating monitoring in the broader context of trial management. We systematically reviewed information on risk indicators commonly used to guide monitoring in the academic setting and in industry and identified risk elements extended to the overall management of a clinical trial. In order to continuously visualize the status of identified risk elements throughout the study conduct, we initiated the user-centered development of a supporting study dashboard. The final risk-tailored approach consisted of the following components: A study-specific risk assessment prior to study start, selection and development of data based pathways addressing the identified risks, and the continuous visualization of the status of risk elements in a study dashboard. The generic content of the dashboard provides continuous information and support for risk indicators applicable to almost all clinical trials (Data quality, Recruitment, Retention, and Safety management) and the optional content is based on further study-specific items identified during the risk assessment (e.g. Follow-up visits, Re-consent process, Sampling management, Imaging quality). User-testing of the risk assessment and study dashboards developed on the basis of the assessment revealed that the continuous oversight of most critical elements and support of managing these elements efficiently supports the work routine of principle investigators, trial managers and trial monitors.
In a second project of this thesis, we assessed current trial registration and publication for clinical intervention studies approved by the Ethics Committee North and Central Switzerland (EKNZ) in the last five years. Registration of all clinical trials would provide an overview of what research is being conducted at present and registries constitute an ideal platform for the publication and dissemination of research results.. Identifying factors influencing registration and potential barriers provides a basis for further initiatives to increase trial registration. Prospective trial registration has increased over the last five years and trials with higher risk category, multicenter trials and trials taking advantage of Clinical Trials Unit services were associated with higher registration rates. Although prospective trial registration prevalence has improved within the last five years within the EKNZ approved studies, a strong need for support in the registration process was identified in our qualitative evaluation.
The impact of this work - and whether it eventually increases feasibility and transparency in clinical research critically depends on its implementation, evaluation, and refinement. Sharing current knowledge on effective monitoring strategies with trialists and monitors to choose evidence-based strategies for their trials constitutes a major support for investigator-initiated trials in the academic environment. The advancement of a risk-based trial monitoring approach into a comprehensive risk-tailored approach supporting the overall conduct of a trial and considering trial monitoring as an integrative part of trial management has the potential to efficiently optimize study processes. While an uptake of the study specific risk assessment and the use of a study dashboard as a standard process would be aspired for all RCTs in the future, improving the timeline and resources needed for the development of a study specific dashboard will be important to advance the generation of affordable and efficient dashboards for investigator-initiated trials. Sharing evidence on the registration behavior and perceived barriers by researchers in the local setting of the EKNZ helps to understand underlying processes and test measures for improvement. Supporting researchers in the process of trial registration and educating research institutes and investigators about the need and advantages of trial registration, has the potential to facilitate the implementation of automated processes and SOPs ensuring the registration of all clinical trials. Establishing trial registries as a primary platform for sharing research results should be aspired in the future.