OP-JNCI190127 1..8

Historically, phase II oncology trials assessed a treatment’s efficacy by examining its tumor response rate in a single-arm trial. Then, approximately 25 years ago, certain statistical and pharmacological considerations ignited a debate around whether randomized designs should be used instead. Here, based on an extensive literature review, we review the arguments on either side of this debate. In particular, we describe the numerous factors that relate to the reliance of single-arm trials on historical control data and detail the trial scenarios in which there was general agreement on preferential utilization of single-arm or randomized design frameworks, such as the use of single-arm designs when investigating treatments for rare cancers. We then summarize the latest figures on phase II oncology trial design, contrasting current design choices against historical recommendations on best practice. Ultimately, we find several ways in which the design of recently completed phase II trials does not appear to align with said recommendations. For example, despite advice to the contrary, only 66.2% of the assessed trials that employed progression-free survival as a primary or coprimary outcome used a randomized comparative design. In addition, we identify that just 28.2% of the considered randomized comparative trials came to a positive conclusion as opposed to 72.7% of the single-arm trials. We conclude by describing a selection of important issues influencing contemporary design, framing this discourse in light of current trends in phase II, such as the increased use of biomarkers and recent interest in novel adaptive designs. The classical paradigm of oncological drug development comprises three phases of clinical trials. In phase I, a treatment’s toxic effects are assessed and the recommended dose(s) for subsequent trials determined. Phase II provides the first assessment of a regimen’s efficacy, with success typically resulting in a confirmatory phase III trial being conducted. Phase II trials thus play a pivotal role, providing the principal evidence for deciding whether to carry out a large phase III trial. The consequences of an incorrect decision at this time can be farreaching: halting the development of an effective regimen could deprive future patients of a valuable treatment option, whereas continuing to develop a futile regimen could waste substantial resources. Accordingly, the optimal approach to conducting phase II trials has received much attention. Historically, given the scarcity of effective anticancer agents in the 1950s, the accepted perspective was that phase II should act as a screening process to efficiently weed out inactive regimens (1,2). For this, a short-term surrogate endpoint for long-term clinical benefit was required. A binary tumor response indicator, later formally defined via RECIST (3), became the endpoint of choice (2). Furthermore, Gehan offered in 1961 a design that would long remain the primary approach to phase II oncology trial design (1). Based on the belief of the day that a response rate of less than 20% was not promising, he recommended that 14 patients be recruited and observed for tumor response. If no response was observed, this would ascertain with 95% confidence that the true response rate was less than 20%. With at least one response observed, a second stage of recruitment and observation would be conducted to accurately estimate the true response rate. Unfortunately, Gehan’s design provided no guidance on whether the observed response rate was clinically meaningful. R EV IE W Received: February 18, 2019; Revised: May 5, 2019; Accepted: June 12, 2019 © The Author(s) 2019. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 1 JNCI J Natl Cancer Inst (2019) 111(12): djz126 doi: 10.1093/jnci/djz126 First published online June 20, 2019