arXiv subjects

Jianchang Lin

Publications and source records attributed to Jianchang Lin.

5 recordsLinked to original sources

arXiv2024

BARD: A seamless two-stage dose optimization design integrating backfill and adaptive randomization

One common approach for dose optimization is a two-stage design, which initially conducts dose escalation to identify the maximum tolerated dose (MTD), followed by a randomization stage where patients are assigned to two or more doses to further assess and compare their risk-benefit profiles to identify the optimal dose. A limitation of this approach is its requirement for a relatively large sample size. To address this challenge, we propose a seamless two-stage design, BARD (Backfill and Adaptive Randomization for Dose Optimization), which incorporates two key features to reduce sample size and shorten trial duration. The first feature is the integration of backfilling into the stage 1 dose escalation, enhancing patient enrollment and data generation without prolonging the trial. The second feature involves seamlessly combining patients treated in stage 1 with those in stage 2, enabled by covariate-adaptive randomization, to inform the optimal dose and thereby reduce the sample size. Our simulation study demonstrates that BARD reduces the sample size, improves the accuracy of identifying the optimal dose, and maintains covariate balance in randomization, allowing for unbiased comparisons between doses. BARD designs offer an efficient solution to meet the dose optimization requirements set by Project Optimus, with software freely available at www.trialdesign.org.

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arXiv2023

Considerations for Master Protocols Using External Controls

There has been an increasing use of master protocols in oncology clinical trials because of its efficiency and flexibility to accelerate cancer drug development. Depending on the study objective and design, a master protocol trial can be a basket trial, an umbrella trial, a platform trial, or any other form of trials in which multiple investigational products and/or subpopulations are studied under a single protocol. Master protocols can use external data and evidence (e.g., external controls) for treatment effect estimation, which can further improve efficiency of master protocol trials. This paper provides an overview of different types of external controls and their unique features when used in master protocols. Some key considerations in master protocols with external controls are discussed including construction of estimands, assessment of fit-for-use real-world data, and considerations for different types of master protocols. Similarities and differences between regular randomized controlled trials and master protocols when using external controls are discussed. A targeted learning-based causal roadmap is presented which constitutes three key steps: (1) define a target statistical estimand that aligns with the causal estimand for the study objective, (2) use an efficient estimator to estimate the target statistical estimand and its uncertainty, and (3) evaluate the impact of causal assumptions on the study conclusion by performing sensitivity analyses. Two illustrative examples for master protocols using external controls are discussed for their merits and possible improvement in causal effect estimation.

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arXiv2022

Flexible Seamless 2-in-1 Design with Sample Size Adaptation

2-in-1 design (Chen et al. 2018) is becoming popular in oncology drug development, with the flexibility of using different endpoints at different decision time. Based on the observed interim data, sponsors choose either to seamlessly advance a small phase 2 trial to a full-scale confirmatory phase 3 trial with a pre-determined maximum sample size, or to remain in a phase 2 trial. This approach may increase efficiency in drug development but is rigid and requires a pre-specified fixed sample size. In this paper, we propose a flexible 2-in-1 design with sample size adaptation, while retains the advantage of allowing intermediate endpoint for interim decision. The proposed design reflects the needs of recent FDA's Project FrontRunner initiative to encourage using an earlier surrogate endpoint to potentially support accelerated approval with conversion to standard approval with long term endpoint from the same randomized study. Additionally, we identify the interim decision cut-off to allow conventional test procedure at the final analysis. Extensive simulation studies showed the proposed design require much smaller sample size and shorter timeline than the simple 2-in-1 design, while achieving similar power. A case study in multiple myeloma is used to demonstrate the benefits of the proposed design.

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arXiv2021

Incorporating Surrogate Information for Adaptive Subgroup Enrichment Design with Sample Size Re-estimation

Adaptive subgroup enrichment design is an efficient design framework that allows accelerated development for investigational treatments while also having flexibility in population selection within the course of the trial. The adaptive decision at the interim analysis is commonly made based on the conditional probability of trial success. However, one of the critical challenges for such adaptive designs is immature data for interim decisions, particularly in the targeted subgroup with a limited sample size at the first stage of the trial. In this paper, we improve the interim decision making by incorporating information from surrogate endpoints when estimating conditional power at the interim analysis, by predicting the primary treatment effect based on the observed surrogate endpoint and prior knowledge or historical data about the relationship between endpoints. Modified conditional power is developed for both selecting the patient population to be enrolled after the interim analysis and sample size re-estimation. In the simulation study, our proposed design shows a higher chance to make desirable interim decisions and achieves higher overall power, while controlling the overall type I error. This performance is robust over drift of prior knowledge from the true relationship between two endpoints. We also demonstrate the application of our proposed design in two case studies in oncology and vaccine trials.

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arXiv2020

Principal Stratum Strategy: Potential Role in Drug Development

A randomized trial allows estimation of the causal effect of an intervention compared to a control in the overall population and in subpopulations defined by baseline characteristics. Often, however, clinical questions also arise regarding the treatment effect in subpopulations of patients, which would experience clinical or disease related events post-randomization. Events that occur after treatment initiation and potentially affect the interpretation or the existence of the measurements are called {\it intercurrent events} in the ICH E9(R1) guideline. If the intercurrent event is a consequence of treatment, randomization alone is no longer sufficient to meaningfully estimate the treatment effect. Analyses comparing the subgroups of patients without the intercurrent events for intervention and control will not estimate a causal effect. This is well known, but post-hoc analyses of this kind are commonly performed in drug development. An alternative approach is the principal stratum strategy, which classifies subjects according to their potential occurrence of an intercurrent event on both study arms. We illustrate with examples that questions formulated through principal strata occur naturally in drug development and argue that approaching these questions with the ICH E9(R1) estimand framework has the potential to lead to more transparent assumptions as well as more adequate analyses and conclusions. In addition, we provide an overview of assumptions required for estimation of effects in principal strata. Most of these assumptions are unverifiable and should hence be based on solid scientific understanding. Sensitivity analyses are needed to assess robustness of conclusions.

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