자료유형  

 학위논문

Control Number  

0016933019

International Standard Book Number  

9798380326872

Dewey Decimal Classification Number  

614.4

Main Entry-Personal Name  

Chen, Yilin.

Publication, Distribution, etc. (Imprint  

[S.l.] : University of Washington., 2023

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2023

Physical Description  

1 online resource(134 p.)

General Note  

Source: Dissertations Abstracts International, Volume: 85-03, Section: B.

General Note  

Advisor: Carlson, Josh J.

Dissertation Note  

Thesis (Ph.D.)--University of Washington, 2023.

Restrictions on Access Note  

This item must not be sold to any third party vendors.

Summary, Etc.  

요약Tumor-agnostic drugs (TAD), also known as histology-independent treatments, have the potential to benefit patients who currently have limited therapeutic options. TAD typically received accelerated approvals based on basket trials which included a small number of multi-cohort, single-arm studies. However, the evaluation of TAD poses major challenges for health technology assessment agencies, such as the potential heterogeneity in treatment effect by tumor type, the lack of comparative data due to single-arm studies, and variable standard of care (SoC) across tumor types. Consequently, these challenges create significant uncertainty regarding the expected clinical and economic impact of TAD. In Aim 1, I used Bayesian hierarchical models (BHM) to assess heterogeneity in treatment outcomes across tumor types and improve estimates of tumor-specific treatment outcomes from Phase II basket trials, which are crucial for healthcare decision-making. My analysis revealed high heterogeneity and uncertainty in survival endpoints, including median progression-free survival (PFS) and median overall survival (OS), although the treatment effects are more similar when judged by surrogate endpoint at approval. Metrics such as intra-class correlation can be used to quantify the variation between groups, which could inform a recommendation of TAD for use in all tumor types or a restricting subset of patients. The findings from our study are important because they demonstrated that BHM could reduce uncertainty of estimates derived from basket trial evidence, potentially improving confidence in tumor-agnostic decision making, despite small sample sizes in some tumor types. The methods presented in this study can be applied to the future assessment of TAD.In Aims 2 and 3, I address comparative effectiveness and economic value of TAD with single-arm trial evidence. To overcome the challenge of lacking comparators, I created eight external controls using observational data from the TriNetx electronic health databases. The Copula method was employed to simulate correlated trial samples while matching the dependence structure of the trial baseline covariates to that in the real-world population. Additionally, an inverse odds weighting approach was used to further balance the baseline characteristics between the trial and external control arms. Weighted Cox regressions showed that patients with MSI-H/dMMR advanced/metastatic colorectal and endometrial cancers receiving pembrolizumab were associated with significant prolonged PFS but not OS than real-world patients receiving chemotherapies. This analysis demonstrated that incorporating external control data in early phase trials may provide a more comprehensive understanding of treatment effects of tumor-agnostic drugs than relying solely on single-arm trials. Finally, using adjusted efficacy inputs from Aim 1 and external controls from Aim 2, I assessed the economic value of pembrolizumab compared to SoC across 8 tumor types to inform coverage and reimbursement decisions in the United States. A partitioned survival model with three health states (i.e., progression-free, post-progression, and death) was developed to evaluate the cost-effectiveness of pembrolizumab for previously treated patients with advanced or metastatic MSI-H/dMMR cancers. We found substantial variation in the economic value across tumor types, with pembrolizumab being a cost-effective strategy in treating colorectal and endometrial cancers at $150,000 willingness-to-pay per quality adjusted life years threshold, compared to SoC chemotherapies. However, pembrolizumab was not found to be cost-effective in treating other assessed cancers. The main findings from value of stratification estimates suggest that recommendations for using pembrolizumab in specific patient populations, based on comparative effectiveness or net health benefit, could result in greater overall value to the healthcare system compared to a tumor-aggregated recommendation. 

Subject Added Entry-Topical Term  

Epidemiology.

Subject Added Entry-Topical Term  

Biostatistics.

Index Term-Uncontrolled  

Bayesian hierarchical models

Index Term-Uncontrolled  

Comparative effectiveness

Index Term-Uncontrolled  

Cost-effectiveness

Index Term-Uncontrolled  

External controls

Index Term-Uncontrolled  

Heterogeneity

Added Entry-Corporate Name  

University of Washington Pharmacy

Host Item Entry  

Dissertations Abstracts International. 85-03B.

Host Item Entry  

Dissertation Abstract International

Electronic Location and Access  

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Control Number  

joongbu:642438