Uptake of the multi-arm multi-stage (MAMS) adaptive platform approach: a trial-registry review of late-phase randomised clinical trials

Abstract

BackgroundFor medical conditions with numerous interventions worthy of investigation, there are many advantages of a multi-arm multi-stage (MAMS) platform trial approach. However, there is currently limited knowledge on uptake of the MAMS design, especially in the late-phase setting. We sought to examine uptake and characteristics of late-phase MAMS platform trials, to enable better planning for teams considering future use of this approach.DesignWe examined uptake of registered, late-phase MAMS platforms in the EU clinical trials register, Australian New Zealand Clinical Trials Registry, International Standard Randomised Controlled Trial Number registry, Pan African Clinical Trials Registry, WHO International Clinical Trial Registry Platform and databases: PubMed, Medline, Cochrane Library, Global Health Library and EMBASE. Searching was performed and review data frozen on 1 April 2021. MAMS platforms were defined as requiring two or more comparison arms, with two or more trial stages, with an interim analysis allowing for stopping of recruitment to arms and typically the ability to add new intervention arms.Results62 late-phase clinical trials using an MAMS approach were included. Overall, the number of late-phase trials using the MAMS design has been increasing since 2001 and been accelerated by COVID-19. The majority of current MAMS platforms were either targeting infectious diseases (52%) or cancers (29%) and all identified trials were for treatment interventions. 89% (55/62) of MAMS platforms were evaluating medications, with 45% (28/62) of the MAMS platforms having at least one or more repurposed medication as a comparison arm.ConclusionsHistorically, late-phase trials have adhered to long-established standard (two-arm) designs. However, the number of late-phase MAMS platform trials is increasing, across a range of different disease areas. This study highlights the potential scope of MAMS platform trials and may assist research teams considering use of this approach in the late-phase randomised clinical trial setting.PROSPERO registration numberCRD42019153910.

Characteristics, Progression, and Output of Randomized Platform Trials

“…Consequently, the approximately 40% of trials that never added an arm may have incurred higher planning and setup costs compared with traditional RCTs without benefiting from the cost savings of additional arms . A common control arm was used in only 73.2% of platform trials, which is lower than one would expect for a major platform trial advantage (increased efficiency) and is below the percentage previously reported . This finding may underline the belief of many stakeholders that the establishment of collective trial infrastructures (including communication networks, overall data management and monitoring plans, and standardized documents across arms) is reason enough to justify the use of the platform trial design .…”

“…33 A common control arm was used in only 73.2% of platform trials, which is lower than one would expect for a major platform trial advantage (increased efficiency) and is below the percentage previously reported. 23 This finding may underline the belief of many stakeholders that the establishment of collective trial infrastructures (including communication networks, overall data management and monitoring plans, and standardized documents across arms) is reason enough to justify the use of the platform trial design. 22 Nevertheless, the benefits of only submitting an amendment instead of a new application for each added arm, and the quicker activation of sites, compared with new traditional RCTs, need to be balanced with substantial operational, statistical, and legal complexities of platform trials 21,34 Many statistical features of platform trials are currently contended in literature, form the foundation of the platform trial design, and affirm the validity of the trial results.…”

“…22 Empirical evidence about platform trials is needed to gain insight into the actual application of this design in clinical research practice and to learn about its benefits and pitfalls, so that the planning and conduct of platform trials can be further improved. Previous systematic reviews on platform trials are outdated 13,14 ; are restricted to the late-phase, multiarm, multistage design or COVID-19 trials 23,24 ; only investigated a small number of distinct platform trial features 23 ; or did not consider the output of platform trials in terms of completed, prematurely closed, and published trial arms. 25 A comprehensive overview is currently lacking.…”

New clinical trial design in precision medicine: discovery, development and direction

“…This kind of “rolling platform” can move on to test new drugs without stopping the trial or seamlessly including multiple stages of development. 367 This is also good news for some diseases lacking effective treatment drugs, such as Alzheimer’s disease. For example, DIAN-TU is a platform trial that simultaneously evaluated solanezumab and gantenerumab in Alzheimer’s disease.…”

Replacing RCTs with real world data for regulatory decision making: a self-fulfilling prophecy?

“…Thus, the agency would be able to identify opportunities for randomised multi-treatment adaptive platform trials, specifically in smaller populations. The number of these trials is also growing in late phase drug development, showing the feasibility of this concept 34. Having established joint scientific advice procedures, the EMA and health technology assessment bodies could ensure that pre-registration platform trials not only meet the requirements of regulatory approval but also of health technology assessment.…”