Practical Considerations and Strategies for Executing Adaptive Clinical Trials

Abstract

There is great potential for clinical trials designed with adaptive features to result in more efficient decision making within a drug development program. However, clinical trials with adaptive features are more complex to implement than traditional designs such as fixed-sample or group sequential. Workarounds and/or inefficiencies in adaptive design (AD) trial execution may result in human and material wastes. Further, they may result in the introduction of operational biases that may potentially negate any gains in designing an AD trial and may even render trial results not interpretable. In this article, we present and share our experience and best practices in AD trial implementation in the areas of resource planning, randomization considerations including the importance of randomization schemes on clinical supply, Interactive Voice Randomization System vendor capability assessment and quality control, clinical supply strategy considerations, enrollment management and patient enrollment modeling and simulation, data quality and interim analysis planning, managing blinding and unblinding, and the use of a data monitoring committee.

Brick tunnel randomization and the momentum of the probability mass

“…Brick tunnel randomization closely approximates the targeted allocation ratio throughout the enrollment, in particular, for small samples. This makes BTR useful in adaptive design dose‐ranging studies , unequal‐allocation studies with a time trend in response or baseline characteristics, and multicenter studies . BTR application in two‐arm response‐adaptive randomization setting, where the allocation ratios are too inconvenient for PBR so that CR is used to allocate patients, should be further explored.…”

“…We will also explain, based on the concept of the center of probability mass, some properties of the BTR resident probabilities observed in earlier work [7].A narrow allocation space of the BTR guarantees that the observed allocation ratio is close to the target one throughout the enrollment; it also reduces the accidental bias associated with the time trend. This is helpful in adaptive design dose-ranging studies [5,24,25], studies with a time trend in response or baseline characteristics, and multicenter studies [7,25]. However, in a single-center open-label trial, where the investigator knows the sequence of previous treatment assignments, it makes the allocation procedure more predictable and thus prone to selection bias.…”

Approaches to expanding the two‐arm biased coin randomization to unequal allocation while preserving the unconditional allocation ratio

“…Variations in the unconditional allocation ratio present a serious problem. First, while perfect blinding eliminates the opportunity for selection bias in a study with an ARP randomization, variations in the unconditional allocation ratio provide potential for selection and evaluation bias even in double‐blind studies . Indeed, if the investigator knows that the probability of the active allocation is much higher than its target allocation ratio at the 2nd, 5th, 8th, and so on allocations, they can assign subjects with better prognosis at these places in the allocation sequence.…”

“…Clinical trials often employ unequal allocation to the treatment arms. With the spread of adaptive design studies, unequal allocation is seen in dose‐ranging studies, multistage studies, studies with treatment selection design, studies with sample size re‐estimation, and studies with response‐adaptive randomization . The common reasons for unequal allocation use in studies of fixed (non‐adaptive) design are power considerations , improved attractiveness, and more extensive experience with the experimental arm in studies with higher allocation to the experimental arm .…”

Adaptive Clinical Trials

“…The team should include a designated data analysis center biostatistician with expertise in adaptive designs, to perform necessary adaptations and analysis and serve as a link between the study sponsor and the DMC. Several recent publications discuss the elements that are important for successful execution of adaptive designs in general (9-10). …”