Generalized phase <scp>I‐II</scp> designs to increase long term therapeutic success rate

Thall, Peter F.; Zang, Yong; Yuan, Ying

doi:10.1002/pst.2301

Cited by 4 publications

(4 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For instance, a design may use a benefit-risk trade-off to perform dose escalation while also including randomization. 30,31 In the following sections, we first describe some essential elements of phase 1/2 designs, including efficacy and toxicity endpoints and benefit-risk trade-off, and then provide a more detailed description of efficacy-integrated and two-stage design strategies.…”

Section: Phase 1/2 Dose Optimizationmentioning

confidence: 99%

“…In the generalized phase 1/2 design, a third randomized stage is added to further optimize the dose based on long-term endpoints. 31 Phase 2/3 dose optimization A phase 2/3 design offers an alternative strategy for dose optimization. This design type encompasses a broad range of designs and can serve various purposes, including treatment selection, population selection, and endpoint selection, 60,61 and expediting the drug development process for accelerated approval.…”

Section: Design Choicementioning

confidence: 99%

“…For instance, a design may use a benefit–risk trade-off to perform dose escalation while also including randomization. 30 , 31 …”

Section: Phase 1/2 Dose Optimizationmentioning

confidence: 99%

“…In the generalized phase 1/2 design, a third randomized stage is added to further optimize the dose based on long-term endpoints. 31 …”

Section: Phase 1/2 Dose Optimizationmentioning

confidence: 99%

See 3 more Smart Citations

Statistical and practical considerations in planning and conduct of dose-optimization trials

Yuan,

Zhou,

Liu

2024

Clinical Trials

Self Cite

View full text Add to dashboard Cite

The U.S. Food and Drug Administration launched Project Optimus with the aim of shifting the paradigm of dose-finding and selection toward identifying the optimal biological dose that offers the best balance between benefit and risk, rather than the maximum tolerated dose. However, achieving dose optimization is a challenging task that involves a variety of factors and is considerably more complicated than identifying the maximum tolerated dose, both in terms of design and implementation. This article provides a comprehensive review of various design strategies for dose-optimization trials, including phase 1/2 and 2/3 designs, and highlights their respective advantages and disadvantages. In addition, practical considerations for selecting an appropriate design and planning and executing the trial are discussed. The article also presents freely available software tools that can be utilized for designing and implementing dose-optimization trials. The approaches and their implementation are illustrated through real-world examples.

show abstract

Section: Phase 1/2 Dose Optimizationmentioning

confidence: 99%

Section: Design Choicementioning

confidence: 99%

“…For instance, a design may use a benefit–risk trade-off to perform dose escalation while also including randomization. 30 , 31 …”

Section: Phase 1/2 Dose Optimizationmentioning

confidence: 99%

“…In the generalized phase 1/2 design, a third randomized stage is added to further optimize the dose based on long-term endpoints. 31 …”

Section: Phase 1/2 Dose Optimizationmentioning

confidence: 99%

See 2 more Smart Citations

Statistical and practical considerations in planning and conduct of dose-optimization trials

Yuan,

Zhou,

Liu

2024

Clinical Trials

Self Cite

View full text Add to dashboard Cite

show abstract

A generalized phase 1-2-3 design integrating dose optimization with confirmatory treatment comparison

Zang,

Thall,

Yuan

2024

Biometrics

View full text Add to dashboard Cite

A generalized phase 1-2-3 design, Gen 1-2-3, that includes all phases of clinical treatment evaluation is proposed. The design extends and modifies the design of Chapple and Thall (2019), denoted by CT. Both designs begin with a phase 1-2 trial including dose acceptability and optimality criteria, and both select an optimal dose for phase 3. The Gen 1-2-3 design has the following key differences. In stage 1, it uses phase 1-2 criteria to identify a set of candidate doses rather than 1 dose. In stage 2, which is intermediate between phase 1-2 and phase 3, it randomizes additional patients fairly among the candidate doses and an active control treatment arm and uses survival time data from both stage 1 and stage 2 patients to select an optimal dose. It then makes a Go/No Go decision of whether or not to conduct phase 3 based on the predictive probability that the selected optimal dose will provide a specified substantive improvement in survival time over the control. A simulation study shows that the Gen 1-2-3 design has desirable operating characteristics compared to the CT design and 2 conventional designs.

show abstract

Novel Clinical Trial Designs with Dose Optimization to Improve Long-term Outcomes

Thall,

Zang,

Chapple

et al. 2023

Clinical Cancer Research

View full text Add to dashboard Cite

Conventional designs for choosing a dose for a new therapy may select doses that are unsafe or ineffective, and fail to optimize progression free survival time, overall survival time, or remission duration. We explain and illustrate limitations of conventional dose finding designs, and make four recommendations to address these problems. When feasible, a dose-finding design should account for long-term outcomes, include screening rules that drop unsafe or ineffective doses, enroll an adequate sample size, and randomize patients among doses. As illustrations, we review three designs that include one or more of these features. The first illustration is a trial that randomized patients among two cell therapy doses and standard of care in a setting where it was assumed on biological grounds that dose-toxicity and dose-response curves did not necessarily increase with cell dose. The second design generalizes phase 1-2 by first identifying a set of candidate doses, rather than one dose, randomizing additional patients among the candidates, and selecting an optimal dose to maximize progression free survival over a longer follow up period. The third design combines a phase 1-2 trial and a group sequential randomized phase 3 trial by using survival time data available after the first stage of phase 3 to re-optimize the dose selected in phase 1-2. By incorporating one or more of the recommended features, these designs improve the likelihood that a selected dose or schedule will be optimal, and thus will benefit future patients and obtain regulatory approval.

show abstract

Generalized phase I‐II designs to increase long term therapeutic success rate

Cited by 4 publications

References 37 publications

Statistical and practical considerations in planning and conduct of dose-optimization trials

Statistical and practical considerations in planning and conduct of dose-optimization trials

A generalized phase 1-2-3 design integrating dose optimization with confirmatory treatment comparison

Novel Clinical Trial Designs with Dose Optimization to Improve Long-term Outcomes

Contact Info

Product

Resources

About