TRAFIC: statistical design and analysis plan for a pragmatic early phase 1/2 Bayesian adaptive dose escalation trial in rheumatoid arthritis

Abstract

Background Adaptive model-based dose-finding designs have demonstrated advantages over traditional rule-based designs but have increased statistical complexity but uptake has been slow especially outside of cancer trials. TRAFIC is a multi-centre, early phase trial in rheumatoid arthritis incorporating a model-based design. Methods A Bayesian adaptive dose-finding phase I trial rolling into a single-arm, single-stage phase II trial. Model parameters for phase I were chosen via Monte Carlo simulation evaluating objective performance measures under clinically relevant scenarios and incorporated stopping rules for early termination. Potential designs were further calibrated utilising dose transition pathways. Discussion TRAFIC is an MRC-funded trial of a re-purposed treatment demonstrating that it is possible to design, fund and implement a model-based phase I trial in a non-cancer population within conventional research funding tracks and regulatory constraints. The phase I design allows borrowing of information from previous trials, all accumulated data to be utilised in decision-making, verification of operating characteristics through simulation, improved understanding for management and oversight teams through dose transition pathways. The rolling phase II design brings efficiencies in trial conduct including site and monitoring activities and cost. TRAFIC is the first funded model-based dose-finding trial in inflammatory disease demonstrating that small phase I/II trials can have an underlying statistical basis for decision-making and interpretation. Trial registration Trials Registration: ISRCTN, ISRCTN36667085. Registered on September 26, 2014.

Early phase clinical trials extension to guidelines for the content of statistical analysis plans

“…Use of these trial designs with greater statistical involvement has become more prevalent, accelerated by oncology clinical trials, 12 however, examples are emerging across other disease areas. 13 …”

“…Use of these trial designs with greater statistical involvement has become more prevalent, accelerated by oncology clinical trials, 12 however, examples are emerging across other disease areas. 13 The International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use has provided the E9 guidelines (ICH E9), which state that "although the early phases of drug development consist mainly of clinical trials that are exploratory in nature, statistical principles are also relevant." 14 Because early phase clinical trials use statistical model based designs, the requirement for good quality SAPs, including additional statistical parameters and progression criteria to later phase research, becomes an even greater necessity, 15 16 with trial statisticians having a key role in designing, and undertaking analysis of, early phase clinical trials.…”