Benchmarked linear shrinkage prediction in the Fay–Herriot small area model

The empirical best linear unbiased predictor (EBLUP) is a linear shrinkage of the direct estimate toward the regression estimate and useful for the small area estimation in the sense of increasing precision of estimation of small area means. However, one potential difficulty of EBLUP is that the overall estimate for a larger geographical area based on a sum of EBLUP is not necessarily identical to the corresponding direct estimate like the overall sample mean. To fix this problem, the paper suggests a new method for benchmarking EBLUP in the Fay–Herriot model without assuming normality of random effects and sampling errors. The resulting benchmarked empirical linear shrinkage (BELS) predictor has novelty in the sense that coefficients for benchmarking are adjusted based on the data from each area. To measure the uncertainty of BELS, the second-order unbiased estimator of the mean squared error is derived.     

A Bayesian optimal interval design for dose optimization with a randomization scheme based on pharmacokinetics outcomes in oncology

The primary objective of an oncology dose-finding trial for novel therapies, such as molecularly targeted agents and immune-oncology therapies, is to identify the optimal dose (OD) that is tolerable and therapeutically beneficial for subjects in subsequent clinical trials. Pharmacokinetic (PK) information is considered an appropriate indicator for evaluating the level of drug intervention in humans from a pharmacological perspective. Several novel anticancer agents have been shown to have significant exposure-efficacy relationships, and some PK information has been considered an important predictor of efficacy. This paper proposes a Bayesian optimal interval design for dose optimization with a randomization scheme based on PK outcomes in oncology. A simulation study shows that the proposed design has advantages compared to the other designs in the percentage of correct OD selection and the average number of patients allocated to OD in various realistic settings.     

Incorporating historical information to improve dose optimization design with toxicity and efficacy endpoints: iBOIN-ET

In modern oncology drug development, adaptive designs have been proposed to identify the recommended phase 2 dose. The conventional dose finding designs focus on the identification of maximum tolerated dose (MTD). However, designs ignoring efficacy could put patients under risk by pushing to the MTD. Especially in immuno-oncology and cell therapy, the complex dose-toxicity and dose-efficacy relationships make such MTD driven designs more questionable. Additionally, it is not uncommon to have data available from other studies that target on similar mechanism of action and patient population. Due to the high variability from phase I trial, it is beneficial to borrow historical study information into the design when available. This will help to increase the model efficiency and accuracy and provide dose specific recommendation rules to avoid toxic dose level and increase the chance of patient allocation at potential efficacious dose levels. In this paper, we propose iBOIN-ET design that uses prior distribution extracted from historical studies to minimize the probability of decision error. The proposed design utilizes the concept of skeleton from both toxicity and efficacy data, coupled with prior effective sample size to control the amount of historical information to be incorporated. Extensive simulation studies across a variety of realistic settings are reported including a comparison of iBOIN-ET design to other model based and assisted approaches. The proposed novel design demonstrates the superior performances in percentage of selecting the correct optimal dose (OD), average number of patients allocated to the correct OD, and overdosing control during dose escalation process.