Martyn, Meredith Anne;
(2024)
Impact of Phase II Trial Design Choice in Oncology.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
This thesis explores the influence of phase II trial design on the success rates of phase III trials in oncology, given that phase III trial failures have been seen to reach 58%. Historically, single-arm phase II trials were considered standard, but the increasing use of randomised-controlled trials in the last two decades has sparked a debate on optimal design choice. This thesis considers the implications of each phase II trial design on the drug development pipeline. A narrative synthesis reveals the need for a methodological simulation study that assesses impact of phase II design choice while considering the following key elements: 1) end-of-phase III trial decisions, 2) both alternative and null hypotheses, 3) historical control error, 4) differing phase endpoints, 5) imperfect correspondence of treatment effect between phases. The first simulation study addresses key elements 1, 2, and 3. However, implementing the remaining key elements; differing phase endpoints and imperfect correspondence; proves challenging. This highlights the struggle seen in practice with using phase II response rates to predict phase III survival outcomes. Therefore, methodology is developed in a proof-of-concept simulation study that considers key elements 1, 4, and 5. Finally, combining the methodology developed throughout, the last study integrates all key elements, drawing parameters from published pairings of phase II-phase III trials. The results compare the effectiveness of each trial design, emphasizing the implications of the chosen design on the overall development plan performance. Additionally, this final study introduces an innovative empirical approach for incorporating imperfect correspondence in simulation studies. This thesis provides valuable insights for phase II investigators in selecting an optimal phase II design that will benefit a drug development plan as a whole, providing an opportunity to improve phase III cancer trial success rates.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Impact of Phase II Trial Design Choice in Oncology |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author [2024]. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10194118 |
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