How to design a dose-finding study using the continual reassessment method

Abstract

IntroductionThe continual reassessment method (CRM) is a model-based design for phase I trials, which aims to find the maximum tolerated dose (MTD) of a new therapy. The CRM has been shown to be more accurate in targeting the MTD than traditional rule-based approaches such as the 3 + 3 design, which is used in most phase I trials. Furthermore, the CRM has been shown to assign more trial participants at or close to the MTD than the 3 + 3 design. However, the CRM’s uptake in clinical research has been incredibly slow, putting trial participants, drug development and patients at risk. Barriers to increasing the use of the CRM have been identified, most notably a lack of knowledge amongst clinicians and statisticians on how to apply new designs in practice. No recent tutorial, guidelines, or recommendations for clinicians on conducting dose-finding studies using the CRM are available. Furthermore, practical resources to support clinicians considering the CRM for their trials are scarce.MethodsTo help overcome these barriers, we present a structured framework for designing a dose-finding study using the CRM. We give recommendations for key design parameters and advise on conducting pre-trial simulation work to tailor the design to a specific trial. We provide practical tools to support clinicians and statisticians, including software recommendations, and template text and tables that can be edited and inserted into a trial protocol. We also give guidance on how to conduct and report dose-finding studies using the CRM.ResultsAn initial set of design recommendations are provided to kick-start the design process. To complement these and the additional resources, we describe two published dose-finding trials that used the CRM. We discuss their designs, how they were conducted and analysed, and compare them to what would have happened under a 3 + 3 design.ConclusionsThe framework and resources we provide are aimed at clinicians and statisticians new to the CRM design. Provision of key resources in this contemporary guidance paper will hopefully improve the uptake of the CRM in phase I dose-finding trials.Electronic supplementary materialThe online version of this article (10.1186/s12874-018-0638-z) contains supplementary material, which is available to authorized users.

Practicalities in running early-phase trials using the time-to-event continual reassessment method (TiTE-CRM) for interventions with long toxicity periods using two radiotherapy oncology trials as examples

“…This model uses all available data from previously enrolled participants to determine the next participant's dose and subsequently the maximum tolerated dose (MTD). The CRM requires all participants currently on the trial to be followed up for the entire observation window before their data can be used to estimate the next participant's dose [2]. This is not always feasible in practice, especially if the observation period is very long, such as in radiotherapy trials.…”

“…More recently however, continual reassessment method (CRM) designs for early-phase trials are beginning to be discussed outside of the statistical literature [1]. Papers focusing on application are also appearing [2], enabling these designs to become more accessible and more widely implemented.…”

Adaptive trial designs: what is the continual reassessment method?

“…Furthermore, the observation of safety data from the first patient in a study may be required before any other patients can be dosed in that cohort due to several past phase I trial disasters. [5,10,11]…”

“…The trial continues until predefined stopping criteria are met such as a pre-specified maximum number of enrolled patients or sufficient patients being dosed at the proposed MTD. [4,5] Consider Figure 2 from the VIOLA trial. The VIOLA trial was a phase I study looking at the treatment of adult patients with relapsed AML post allogeneic stem cell transplant.…”

A Bayesian phase 2 model based adaptive design to optimise antivenom dosing: application to a dose-finding trial for a novel Russell’s viper antivenom in Myanmar

“…Rule based designs do not use information across dosing levels, and therefore they have limited ability to rapidly identify the desired optimal dose with high confidence [17]. Second, model based designs which do require determining a parametric relationship (model) between the dose and the outcome, termed a dose-response model [18]. The continual reassessment method [19] was the first proposed model based design for dose-finding.…”