A Review of Perspectives on the Use of Randomization in Phase II Oncology Trials

Abstract

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.

Pathological Complete Response Following Different Neoadjuvant Treatment Strategies for Locally Advanced Rectal Cancer: A Systematic Review and Meta-analysis

“…However, these trials are prone to selection bias as well as optimism in the intervention effect and often fail to demonstrate superiority in subsequent phase III trials. 43,57,58 Nonetheless, randomized phase II trials may also overestimate the treatment effect. 59 We showed these differences between phase II and phase III trials in the analyses for multiagent CRT and for CRT plus consolidation chemotherapy.…”

Bayesian Approaches for Confirmatory Trials in Rare Diseases: Opportunities and Challenges

“…The usual level of rigorous clinical trial evaluation of treatments is required in rare diseases just as much as in more common ones. Although in some cases, particularly in phase II trials, single-arm trials might be considered (see, for example, Grayling et al [5]), randomized controlled trials are to be preferred when this is possible. For example, the European regulatory guidance [2] affirms that "patients with [rare] conditions deserve the same quality, safety and efficacy in medicinal products as other patients; orphan medicinal products should therefore be submitted to the normal evaluation process"; this is also in agreement with U.S. guidance [6].…”

Bayesian enhancement two‐stage design with error control for phase II clinical trials

“…Such high failure rates of phase III trials cause enormous waste of the time and resources, while the reasons behind are complex. 29 It may be mainly due to the small sample size in phase II trials and a lack of correlation between the tumor response and the survival endpoints used in phase III trials. 30 Another possible reason, as pointed out by Shi and Yin, 31 is the extensive use of Simon's design 29,32,33 and its low posterior probability of H 1 when accepting the drug under some circumstances.…”

“…In another investigation, Mandel et al 28 claimed that 91 % phase III studies in glioblastoma failed to show an improvement in overall survival although the prior phase II studies had declared success. Such high failure rates of phase III trials cause enormous waste of the time and resources, while the reasons behind are complex 29 . It may be mainly due to the small sample size in phase II trials and a lack of correlation between the tumor response and the survival endpoints used in phase III trials 30 .…”