Optimising the design of phase II oncology trials: The importance of randomisation

doi:10.1016/j.ejca.2008.10.029

European Journal of Cancer

Volume 45, Issue 2, January 2009, Pages 275-280

https://doi.org/10.1016/j.ejca.2008.10.029 Get rights and content

Abstract

Oncology trial end-points continue to receive considerable attention, as illustrated by the development and revisions to the RECIST criteria. In this article, we focus the reader away from the issue of end-points for phase II trials and towards what we believe to be an even more important issue, the fundamental need for randomisation in phase II oncology trials, ideally with blinding and dose-ranging. We present arguments to support the proposition that randomisation will enable greater clarity in the interpretation of the phase II trial results, as well as allowing for more precise estimates of the effect size and sample size requirements for definitive phase III trials. Randomisation will also reduce potential bias resulting from inter-trial variability, which inflates both type I and II errors if historical controls are utilised. In the context of a randomised blinded trial, the exact choice of end-point is less critical, although we favour end-points such as the change in tumour size or progression status at a fixed early time point (i.e. 8–12 weeks after randomisation). Although end-points based on RECIST criteria can and should be utilised in randomised phase II trials, we do not believe that revision of the RECIST criteria will result in a fundamental improvement in drug development decisions in the absence of randomised clinical trials at the phase II stage of drug development.

Introduction

The phase II clinical trial plays a central role in oncology drug development. After a phase I trial has determined a tolerable dose for a new agent or combination, a well-designed phase II trial should provide the information required to make a go/no-go decision regarding subsequent phase III testing. As phase III trials require several years, hundreds or thousands of patients and often tens or hundreds of millions of dollars, the information that a quality phase II trial can provide is essential to a decision regarding the potential investment in a larger trial. In this paper, we present a rationale for the expanded use of randomisation in phase II oncology trials, in order to better inform this decision-making process.

Section snippets

Why do we do phase II trials?

Phase II trials should be most appropriately viewed as proof of concept trials, used for the purpose of determining whether a particular agent (or combination) should be studied further.¹ In this sense, they serve a critical filtering mechanism, in which a negative trial should lead to the discontinuation of development of a new agent for the selected indication. Optimising the filtering process is the critical issue: too tight a filter will terminate promising agents improperly, but a too

What are the options for design of phase II trials?

Historically, phase II oncology trial designs can be divided into three categories: non-randomised (single-arm) trials compared to historical controls, randomised trials with multiple-experimental regimens compared to a historical control, and randomised trials including a prospective control arm. In this section, we provide a brief overview of each of these design strategies.

The single-arm trial has been the most frequently used approach to the efficacy evaluation at the phase II level in

When is a non-randomised phase II trial sufficient?

We believe non-randomised phase II trials in oncology should be the exception, not the rule. With that caveat, we acknowledge that such trials may be appropriate for trials in which the desired outcome (e.g. a partial response) will not occur in the absence of the investigational agent, and the rate of that outcome for existing agents or regimens is historically highly reliable. In this context, a positive phase II trial, defined as a response rate greater than some predefined threshold, would

When does a non-randomised phase II trial lead to a phase III trial that fails to achieve success on its primary end-point?

As stated previously, the fundamental assumptions that could justify a single-arm phase II trial are that data from the previous studies provide an adequately robust estimate of the experience of the treated patients from the current trial were they not to have received the experimental therapy, and that the end-point selected for the trial represents a definitive measure of agent activity. Not surprisingly, when these assumptions are violated (which is common), phase III trials have a high

What are the considerations in the design of randomised phase II trials?

Although there has been a debate about the value of formal statistical comparisons in phase II trials, we feel strongly that such comparisons are appropriate, with the caveat that phase II trials do not necessarily need to provide reliable definitive comparisons at a traditional two-sided type I error of 0.05. Given that the purpose of any phase II trial is to determine whether to proceed with further agent development, there is only one outcome of interest, superiority of one or more

Conclusions

Randomisation is greatly underutilised in early clinical trials in oncology. The use of randomised trials allows complete flexibility in the choice of end-points, particularly if blinding can be incorporated. This technique is the most powerful and reliable technique for distinguishing the effect of a drug from a placebo, a necessary predicate for a successful phase III trial. Given the large number of agents now available for clinical testing, the costs of phase III trials, and the limited

Conflict of interest statement

None declared.

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Optimising the design of phase II oncology trials: The importance of randomisation

Abstract

Introduction

Section snippets

Why do we do phase II trials?

What are the options for design of phase II trials?

When is a non-randomised phase II trial sufficient?

When does a non-randomised phase II trial lead to a phase III trial that fails to achieve success on its primary end-point?

What are the considerations in the design of randomised phase II trials?

Conclusions

Conflict of interest statement

J Chronic Dis

Control Clin Trial

Control Clin Trial

Control Clin Trial

Control Clin Trial

Learning versus confirming in clinical drug development

Clin Pharmacol Ther

Predicting the outcome of phase III trials using phase II data: a case study of clinical trial simulation in late stage drug development

Basic Clin Pharmacol Toxicol

Incorporating toxicity considerations into the design of two-stage phase II clinical trials

Biometrics

Designs for group sequential phase II clinical trials

Biometrics

Practical Bayesian guidelines for phase IIB clinical trials

Biometrics

A flexible design for multiple armed screening trials

Stat Med