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

Abstract

Introduction: The 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.

Methods: To 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.

Results: An 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.

Conclusions: The 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.

Keywords: Adaptive designs; Continual reassessment method; Dose escalation; Dose-finding; Maximum tolerated dose; Phase I trials.

Fig. 1

Number and spacing of doses for a dose-finding trial. The doses in Fig. 2(a) are too low to estimate the MTD, whereas those in Fig. 2(b) are too high. In Fig. 2(c), the target dose lies between two dose levels, so patients will be assigned alternately to an overdose level and an underdose level; the final MTD will likely be at one of these levels. Figure 2(d) illustrates a situation with several dose levels available in the region of the MTD.

Fig. 2

Dose-toxicity relationships for different dose-toxicity functions with varying parameter values

Fig. 3

Example of transforming drug-specific doses to dose labels using prior skeleton probabilities of DLT risk. Two-parameter logistic model with prior average parameter values β₁ = 2 and β₂ = 1 (see Table A1 in Additional file 1: Appendix A for calculations).

Fig. 4

Dose-toxicity scenarios explored in the Matchpoint trial. Red line indicates TTL of 40%

Fig. 5

Flowchart of the trial design process using the CRM

Fig. 6

Results from the dose-finding trial of ssHHT in patients with advanced acute myeloid leukaemia [63] a) Trial conduct and DLTs observed. b) Final posterior mean estimates of DLT probabilities and 95% credible intervals (2.5th and 97.5th percentiles).

Fig. 7

Results from the dose-finding trial of rViscumin in patients with solid tumours [65] a) Trial conduct and DLTs observed. b) Final mean estimates of DLT probabilities and 95% confidence intervals.