Adaptive designs for clinical trials permit alterations to a study in response to accumulating data in order to make trials more flexible, ethical, and efficient. These benefits are achieved while preserving the integrity and validity of the trial, through the pre-specification and proper adjustment for the possible alterations during the course of the trial. Despite much research in the statistical literature highlighting the potential advantages of adaptive designs over traditional fixed designs, the uptake of such methods in clinical research has been slow. One major reason for this is that different adaptations to trial designs, as well as their advantages and limitations, remain unfamiliar to large parts of the clinical community. The aim of this paper is to clarify where adaptive designs can be used to address specific questions of scientific interest; we introduce the main features of adaptive designs and commonly used terminology, highlighting their utility and pitfalls, and illustrate their use through case studies of adaptive trials ranging from early-phase dose escalation to confirmatory phase III studies.

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Adding flexibility to clinical trial designs: an example-based guide to the practical use of adaptive designs

For many years phase I and phase II clinical trials have been conducted separately, but there has been a recent shift to combine these phases. Although a variety of phase I-II model-based designs for cytotoxic agents have been proposed in the literature, methods for molecularly targeted agents (TAs) are just starting to develop. The main challenge of the TA setting is the unknown dose-efficacy relationship that can have either an increasing, plateau or umbrella shape. To capture these, approaches with more parameters are needed or, alternatively, more orderings are required to account for the uncertainty in the dose-efficacy relationship. As a result, designs for more complex clinical trials, e.g. trials looking at schedules of a combination treatment involving TAs, have not been extensively studied yet. We propose a novel regimen finding design which is based on a derived efficacy-toxicity trade-off function. Because of its special properties, an accurate regimen selection can be achieved without any parametric or monotonicity assumptions. We illustrate how this design can be applied in the context of a complex combination-schedule clinical trial. We discuss practical and ethical issues such as coherence, delayed and missing efficacy responses, safety and futility constraints.

An information theoretic phase I-II design for molecularly targeted agents that does not require an assumption of monotonicity.

The main purpose of dose-escalation trials is to identify the dose(s) that is/are safe and efficacious for further investigations in later studies. In this paper, we introduce dose-escalation designs that incorporate both the dose-limiting events and dose-limiting toxicities (DLTs) and indicative responses of efficacy into the procedure. A flexible nonparametric model is used for modelling the continuous efficacy responses while a logistic model is used for the binary DLTs. Escalation decisions are based on the combination of the probabilities of DLTs and expected efficacy through a gain function. On the basis of this setup, we then introduce 2 types of Bayesian adaptive dose-escalation strategies. The first type of procedures, called "single objective," aims to identify and recommend a single dose, either the maximum tolerated dose, the highest dose that is considered as safe, or the optimal dose, a safe dose that gives optimum benefit risk. The second type, called "dual objective," aims to jointly estimate both the maximum tolerated dose and the optimal dose accurately. The recommended doses obtained under these dose-escalation procedures provide information about the safety and efficacy profile of the novel drug to facilitate later studies. We evaluate different strategies via simulations based on an example constructed from a real trial on patients with type 2 diabetes, and the use of stopping rules is assessed. We find that the nonparametric model estimates the efficacy responses well for different underlying true shapes. The dual-objective designs give better results in terms of identifying the 2 real target doses compared to the single-objective designs.

Bayesian adaptive dose-escalation designs for simultaneously estimating the optimal and maximum safe dose based on safety and efficacy.

There is a growing interest in dose finding studies involving continuous outcomes. An important tool to evaluate the performance of any design is a benchmark that provides an upper bound on the performance. While the benchmark for dose finding studies with discrete endpoint is known, no such benchmark for studies with continuous endpoint has been developed. We show that the original benchmark by O'Quigley et al. (2002) and Cheung (2014), when looked at a different perspective, can be generalised to various settings with both discrete and continuous outcomes. We illustrate and compare the benchmark performance in the setting of a Phase I clinical trial with continuous endpoint and in the setting of Phase I/II clinical trial with continuous efficacy. It is found that the proposed benchmark provides an accurate upper bound for model-based dose finding methods and serves as a powerful tool for evaluating designs.

A Benchmark for Dose Finding Studies with Continuous Outcomes

An important tool to evaluate the performance of any design is an optimal benchmark proposed by O’Quigley and others (2002. Non-parametric optimal design in dose finding studies. Biostatistics 3, 51–56) that provides an upper bound on the performance of a design under a given scenario. The original benchmark can only be applied to dose finding studies with a binary endpoint. However, there is a growing interest in dose finding studies involving continuous outcomes, but no benchmark for such studies has been developed. We show that the original benchmark and its extension by Cheung (2014. Simple benchmark for complex dose finding studies. Biometrics 70, 389–397), when looked at from a different perspective, can be generalized to various settings with several discrete and continuous outcomes. We illustrate and compare the benchmark’s performance in the setting of a dose finding Phase I clinical trial with a continuous toxicity endpoint and a Phase I/II trial with binary toxicity and continuous efficacy endpoints. We show that the proposed benchmark provides an accurate upper bound in these contexts and serves as a powerful tool for evaluating designs.

A benchmark for dose finding studies with continuous outcomes

One of the main aims of early phase clinical trials is to identify a safe dose with an indication of therapeutic benefit to administer to subjects in further studies. Ideally therefore, dose-limiting events (DLEs) and responses indicative of efficacy should be considered in the dose-escalation procedure. Several methods have been suggested for incorporating both DLEs and efficacy responses in early phase dose-escalation trials. In this paper, we describe and evaluate a Bayesian adaptive approach based on one binary response (occurrence of a DLE) and one continuous response (a measure of potential efficacy) per subject. A logistic regression and a linear log-log relationship are used respectively to model the binary DLEs and the continuous efficacy responses. A gain function concerning both the DLEs and efficacy responses is used to determine the dose to administer to the next cohort of subjects. Stopping rules are proposed to enable efficient decision making. Simulation results shows that our approach performs better than taking account of DLE responses alone. To assess the robustness of the approach, scenarios where the efficacy responses of subjects are generated from an Emax model, but modelled by the linear log-log model are also considered. This evaluation shows that the simpler log-log model leads to robust recommendations even under this model showing that it is a useful approximation to the difficulty in estimating Emax model. Additionally, we find comparable performance to alternative approaches using efficacy and safety for dose-finding.

Bayesian adaptive dose-escalation procedures for binary and continuous responses utilizing a gain function.

Model-based dose escalation designs have gained increasing interest due to the need for more efficient and informative Phase I trials. The wide-spread implementation of such designs has been hindered by the need for either licensing specialized commercial software or programming the design and simulations from scratch for each project. The R package crmPack provides a simple and unified object-oriented framework for model-based dose escalation designs. This enables the standard use of such designs, while being able to flexibly adapt and extend them. The framework comprises classes and methods for the data structure including the dose grid, statistical models including prior specification, rules for maximum increments, next best dose, and adaptive stopping and cohort sizes. In addition to multiple modified classic continual reassessment method and escalation with overdose control designs with possibly advanced prior specifications (e.g., minimal informative and mixture priors), crmPack currently features dual-endpoint (safety and biomarker) designs and two-part designs. Optional assignment of a small number of patients in each cohort to placebo instead of treatment enables the use in trials outside oncology.

Model-Based dose escalation Designs in R with crmPack

Randomisation schemes are rules that assign patients to treatments in a clinical trial. Many of these schemes have the common aim of maintaining balance in the numbers of patients across treatment groups. The properties of imbalance that have been investigated in the literature are based on two treatment groups. In this paper, their properties for K > 2 treatments are studied for two randomisation schemes: centre-stratified permuted-block and complete randomisation. For both randomisation schemes, analytical approaches are investigated assuming that the patient recruitment process follows a Poisson-gamma model. When the number of centres involved in a trial is large, the imbalance for both schemes is approximated by a multivariate normal distribution. The accuracy of the approximations is assessed by simulation. A test for treatment differences is also considered for normal responses, and numerical values for its power are presented for centre-stratified permuted-block randomisation. To speed up the calculations, a combined analytical/approximate approach is used. Copyright © 2016 John Wiley & Sons, Ltd.

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Wai Yin Yeung

Papers

Bayesian adaptive dose-escalation procedures for binary and continuous responses utilizing a gain function.

Bayesian adaptive dose-escalation designs for simultaneously estimating the optimal and maximum safe dose based on safety and efficacy.

Model-Based dose escalation Designs in R with crmPack

Imbalance properties of centre-stratified permuted-block and complete randomisation for several treatments in a clinical trial