Design Issues of Randomized Phase II Trials and a Proposal for Phase II Screening Trials

Abstract

Future progress in improving cancer therapy can be expedited by better prioritization of new treatments for phase III evaluation. Historically, phase II trials have been key components in the prioritization process. There has been a long-standing interest in using phase II trials with randomization against a standard-treatment control arm or an additional experimental arm to provide greater assurance than afforded by comparison to historic controls that the new agent or regimen is promising and warrants further evaluation. Relevant trial designs that have been developed and utilized include phase II selection designs, randomized phase II designs that include a reference standard-treatment control arm, and phase II/III designs. We present our own explorations into the possibilities of developing "phase II screening trials," in which preliminary and nondefinitive randomized comparisons of experimental regimens to standard treatments are made (preferably using an intermediate end point) by carefully adjusting the false-positive error rates (alpha or type I error) and false-negative error rates (beta or type II error), so that the targeted treatment benefit may be appropriate while the sample size remains restricted. If the ability to conduct a definitive phase III trial can be protected, and if investigators feel that by judicious choice of false-positive probability and false-negative probability and magnitude of targeted treatment effect they can appropriately balance the conflicting demands of screening out useless regimens versus reliably detecting useful ones, the phase II screening trial design may be appropriate to apply.

Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial

“…By contrast, we used a clinical outcome for three reasons: the National Institutes of Health want to focus on relapses as a basis for powering a future phase 3 trial, pregnancy decreases relapses, 2 and a small phase 2 trial with monthly MRI scans has already been done. 7 Because this trial was phase 2, we used a signifi cance level of α=0·10 for all analyses, as has been used in cancer trials 27 and in phase 2 trials of stroke, 28 amyotrophic lateral sclerosis, 29 and Parkinson's disease. 30 The use of p<0·10 as signifi cant in phase 2 trials was considered stringent enough to assess the potential for clinical effi cacy of a new intervention, while controlling for false positives and avoiding the much higher costs of the larger sample sizes needed to achieve a p value of less than 0·05.…”

“…30 The use of p<0·10 as signifi cant in phase 2 trials was considered stringent enough to assess the potential for clinical effi cacy of a new intervention, while controlling for false positives and avoiding the much higher costs of the larger sample sizes needed to achieve a p value of less than 0·05. 27,28 For the analysis of time to fi rst relapse, we used Kaplan-Meier analysis and log-rank tests to estimate and compare the proportion of patients with fi rst relapse at each timepoint. We used a Cox proportional hazards model to compare the proportion of patients with relapse at 12 months and 24 months, adjusting for age, baseline EDSS score (<2 vs ≥2), number of relapses in the 12 months before the study (≤1 vs >1), duration of multiple sclerosis (<1 vs ≥1 year), previous glatiramer acetate treatment (never vs past or current), and previous interferon treatment (yes vs no).…”

Are There Circumstances in Which Phase 2 Study Results Should Be Practice-Changing?

“…15 This is often done if there is limited historical control data or if other treatment factors, such as dramatic changes in supportive care, reduce the applicability of historical controls. 17,18 However, unlike randomized phase 3 trials, these studies are not powered to determine true clinical improvement of the experimental therapy compared to the control arm. 19 Instead, they reinforce that the experimental therapy is potentially efficacious and warrants further study in a larger, appropriately powered phase 3 clinical trial.…”

“…This allows patient data from the phase 2 portion to be included in the final analysis, which dramatically shortens the time to study completion and decreases the number of required patients. 18 However, it does necessitate a pre-study commitment of both time and resources for design and study completion for both the phase 2 and phase 3 portions. Table 1 highlights the important factors required to assess the strength of a phase 2 study.…”

“…15,18,20 In general, this design is most appropriate when there is some level of efficacy that has been established for each of the arms. An adaptive method can be used to establish both efficacy and "pick the winner" using a randomized selection design.…”