Clinical trials and clinical trials networks

Clinical trials dominate the academic landscape of clinical medicine and inform clinical practice on a global scale. They take advantage of several powerful conceptual advances in the history of medicine such as randomization, concealment of allocation, blinding and statistical analysis. Clinical trials take different forms. For example, assessment of a medication proceeds from experimental discovery to safety, from pharmacokinetic and pharmacodynamic assessment to pilot feasibility studies, from phase I trials in the target condition to phase II randomized clinical trials, and finally to phase III pivotal trials (Table 1). Outside of such typical pharmaceutical company programs, however, clinicians develop investigator-initiated research programs, which mirror such processes and are typically funded by government agencies.1, 2 Often, such investigator-initiated clinical trials are triggered by observational studies that suggest an effect of a particular intervention or drug. Irrespective of such pathways and despite their academic supremacy, clinical trials continue to trigger controversy. Indeed, in some way, they resemble democracy. To paraphrase Churchill, they may well be the worst possible way to achieve robust evidence except for any other approach that has been tried so far in the history of medicine. Controversies relate to their cost, the time needed to achieve completion, the frequency of 'negative' trials, and their limited ability to tackle heterogeneity of treatment effect. Moreover, there is constant tension between clinicians who make decisions about individual patients and trials that deal with populations. Finally, trials can only deal with issues where equipoise (uncertainty as to which treatment is best) exists. Thus, by definition, the difference between the control group and the intervention group must be relatively small.3 Accordingly, trials need to be large to identify such relatively small effects. Finally, the public and academic demand for precision medicine and the inability of large trials to recruit enough patients if only focused on such niche (precision) populations create additional tensions. Therefore, trials and trial medicine are imperfect. Yet, what is the alternative? Opinion-based medicine? Expert-based or eminence-based medicine? Tik-tok or Facebook or WhatsApp or Twitter-based medicine? Clinical trials have delivered confidence on the impact and effectiveness of interventions like statins in hypercholesterolemia, beta-blockers and ACE inhibitors in heart failure, sodium glucose co-transporter type 2 inhibitors (SGLT2i) in chronic kidney disease, diabetes and heart failure, and thrombolysis and clot retrieval in stroke to name but a few.4-6 These treatments have saved millions of lives, hearts, kidneys and brains on a global scale and argue for more and larger trials, not less. They also argue for the creation of structures and systems to deliver such trials and true global relevance by including patients from both high-income and at the very least, middle income countries.7, 8 However, to achieve such goals, it is necessary to develop clinical trials networks and to foster collaborations between networks from different health care jurisdictions. Clinical trials networks have emerged as a powerful tool for fostering collaboration among researchers, institutions and key players in the research process.9, 10 A clinical trial network is a collaborative infrastructure that connects multiple hospitals, research centres, units and investigators to identify important clinical questions and conduct large-scale, multicentre clinical trials.11, 12 The primary objective of clinical trial networks is to accelerate and improve research efficiency, facilitate patient recruitment, and enhance the external validity of study findings.12 Clinical trial networks address the challenge of patient recruitment by reaching out to a broader group of participants across various geographical locations.13 This not only facilitates the enrolment process but also increases the diversity of patients included, enhancing the external validity of the trial results so that all communities can benefit from scientific advances. In addition, the costs of conducting large-scale clinical trials continue to increase and can be prohibitive in some settings.13 Clinical trial networks can potentially optimize resource utilization by distributing the workload and the costs among different participating sites and funding jurisdictions. Research is a collaborative process and clinical trial networks facilitate collaborations, since investigators from different institutions can share their expertise, resources and data. This collective approach fosters a culture of shared knowledge and accelerates scientific discovery. Also, by creating standard protocols and methods across multiple sites, clinical trial networks minimize variability and reduce the risk of violations during the trial execution. Translation of research findings to clinical practice is a key aspect in trial medicine that is often neglected, and the collaborative nature of clinical trial networks potentially expedites this translation. By involving diverse healthcare settings, the network facilitates the implementation of new treatments across a broad spectrum of patient populations. Improved translation has a big impact on the scientific community and patients. Additional potential benefits of clinical trial networks include increased data integrity, the ability to run and manage multiple clinical trials, development of infrastructure that can be reused for subsequent clinical trials, and operational procedures to maintain regulatory compliance.4 Clinical trial networks have demonstrated a profound impact on the scientific community, influencing both the quantity and quality of research output.10, 12, 14 Some barriers might arise when establishing a clinical trial network. The most common barrier is the perceived loss of independence from local sites and investigators.4 In addition, fear of exploitation, concerns regarding authorship and intellectual property, and diversion from individual/local resources to a more centralized approach are frequently discussed as potential problems with clinical trial networks.12 When developing a clinical trial network, it is therefore important to define a clear 'Vision, Mission and Values' statement, foster open and transparent communication, and actively cultivate a collaborative atmosphere, as these elements are essential and mandatory for successful development. Additionally, the early involvement of young investigators is crucial to perpetuate the network. Overall, clinical trial networks represent a significant advancement in medical research. By fostering collaboration, standardizing protocols, and optimizing resource utilization, these networks contribute to the acceleration of the scientific process and the translation of research findings into clinical practice. There is little doubt that the future of clinical trials begins and ends with clinical trial networks. None declared.