Innovative trial approaches in immune-mediated inflammatory diseases: current use and future potential

Abstract

Background Despite progress that has been made in the treatment of many immune-mediated inflammatory diseases (IMIDs), there remains a need for improved treatments. Randomised controlled trials (RCTs) provide the highest form of evidence on the effectiveness of a potential new treatment regimen, but they are extremely expensive and time consuming to conduct. Consequently, much focus has been given in recent years to innovative design and analysis methods that could improve the efficiency of RCTs. In this article, we review the current use and future potential of these methods within the context of IMID trials. Methods We provide a review of several innovative methods that would provide utility in IMID research. These include novel study designs (adaptive trials, Sequential Multi-Assignment Randomised Trials, basket, and umbrella trials) and data analysis methodologies (augmented analyses of composite responder endpoints, using high-dimensional biomarker information to stratify patients, and emulation of RCTs from routinely collected data). IMID trials are now well-placed to embrace innovative methods. For example, well-developed statistical frameworks for adaptive trial design are ready for implementation, whilst the growing availability of historical datasets makes the use of Bayesian methods particularly applicable. To assess whether and how these innovative methods have been used in practice, we conducted a review via PubMed of clinical trials pertaining to any of 51 IMIDs that were published between 2018 and 20 in five high impact factor clinical journals. Results Amongst 97 articles included in the review, 19 (19.6%) used an innovative design method, but most of these were relatively straightforward examples of innovative approaches. Only two (2.1%) reported the use of evidence from routinely collected data, cohorts, or biobanks. Eight (9.2%) collected high-dimensional data. Conclusions Application of innovative statistical methodology to IMID trials has the potential to greatly improve efficiency, to generalise and extrapolate trial results, and to further personalise treatment strategies. Currently, such methods are infrequently utilised in practice. New research is required to ensure that IMID trials can benefit from the most suitable methods.

Design and analysis of umbrella trials: Where do we stand?

“…The adaptive signature design, where several candidate biomarkers can be combined to formulate biomarker defined subgroups ( 74 ), potentially has utility or can be integrated with the umbrella design. The potential use and advantages of adaptive signature designs have been reported elsewhere ( 19 , 74 ) and may be helpful given the immense logistical considerations that are necessary when investigating several biomarker-treatment pairs ( 4 ).…”

“…Though several works have discussed statistical analysis methods for master protocols, they have focused on basket and platform trials (7,15). Moreover, as we argue further later, the current and future potential of umbrella trials in nononcology settings is enormous (18,19). So far, though, published articles on umbrella trials have almost exclusively discussed oncology related considerations.…”

Bayesian borrowing for basket trials with longitudinal outcomes

“…For example, immune‐mediated inflammatory diseases (IMIDs) are a group of distinct conditions which share common inflammatory pathways. Grayling et al have recently considered innovative approaches to IMID trials, including the use of basket trials 3 . IMIDs are associated with chronic morbidity affecting quality of life and leading to premature death, and there is potential for novel trial designs to improve personalised treatment strategies in this area.…”

Bayesian Modelling Strategies for Borrowing of Information in Randomised Basket Trials

“…The potential and growing use of basket trials outside of oncology carries even greater prospects for randomisation as an important feature in the design of future basket trials. Currently, randomised basket trials have been implemented in oncology (IMPACT II trial, NCT02152254), HIV/AIDS (Moore et al, 2021 ), autoimmune and neurological disorders like primary biliary cholangitis (PBC) and Parkinson's disease (Zheng & Wason, 2022 ), auto‐inflammatory syndromes like familial Mediterranean fever and TRAP syndrome (De Benedetti et al, 2018 ), and have been proposed for immune‐mediated inflammatory diseases (Grayling et al, 2021 ). Evidently, development of statistical methodology for randomised basket trials will be of great importance.…”