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Early Clinical Trial Design Recommendations in Oncology Based on Overall Success across Phases I, II, and III

Stark, Amy S. Ruppert
http://rave.ohiolink.edu/etdc/view?acc_num=osu1510592650256558

Abstract Details

2017, Doctor of Philosophy, Ohio State University, Biostatistics.
Conventionally, drug development has spanned three distinct phases, and the success rate for experimental drugs across phases has been less than 15% (Hay, Thomas, Craighead, Economides, and Rosenthal, 2014). Despite increased options for nonstandard early phase designs, lack of familiarity and a perceived increase in complexity have been barriers to their use. Herein, we provide early phase design recommendations for standard and nonstandard designs, considering the trade-offs between performance, design complexity, and ease of implementation. We focus on overall success rate as a performance measure, which quantifies the ability to recognize a favorable drug across phases. Phase I, II, and III trials were simulated for clinical scenarios defined by eight toxicity profiles and two nondecreasing efficacy profiles. Early results showed that correctly selecting the maximum tolerated dose (MTD) greatly impacted overall success rates. Hence, we primarily evaluated phase I dose-finding designs, including the rule-based standard 3+3 design, the CCD, BOIN, mTPI, and mTPI-2 interval designs, and the model-based CRM design. Phase I designs were followed by Simon's optimal phase II design and a randomized group sequential phase III design. A seamless phase I/II SEARS design, integrating toxicity and efficacy data, was also considered. Based on our results, we make the following recommendations for design selection when data informing the shape of the dose-toxicity curve exist. If a large jump in toxicity between dose levels is expected, we recommend the standard 3+3 design, which more often recognized when the MTD had been exceeded and resulted in the highest overall success rates. If gradually increasing toxicity is expected, we recommend a nonstandard design other than the CRM. Nonstandard designs were more aggressive in dosing decisions and MTD estimation than the standard 3+3 design and resulted in higher overall success rates, but the CRM was too aggressive and most frequently overestimated the MTD. If fairly constant and safe toxicity is expected, we recommend the BOIN or CRM designs, which escalated to the highest dose level most frequently and had superior overall success rates. If in addition to a constant and safe toxicity profile, multiple dose levels with favorable efficacy are expected, we recommend a phase I/II SEARS design, which had higher overall success rates and more frequent selection of the lowest dose level with highest efficacy compared to separate phase I and II designs. A phase I/II SEARS design is also recommended if an unconventional nonmonotonic toxicity profile is expected, since overall success rates were 2-3 times higher than when separate phase I and II designs were used. Without data informing the shape of the dose-toxicity curve, we recommend nonstandard phase I designs with a modified excessive toxicity rule that more easily eliminates dose levels due to safety concerns. With this modification, the MTD overestimation error decreased and overall success rates were similar or higher with nonstandard designs versus the standard 3+3 design. Among nonstandard designs, we recommend the modified CCD and BOIN designs, since both perform well and are as transparent and simple as the standard 3+3 design to implement.
Abigail Shoben, PhD (Advisor)
Rebecca Andridge, PhD (Committee Member)
Byrd John, MD (Committee Member)
Hsu Jason, PhD (Committee Member)
204 p.
Biostatistics
clinical trial designs; overall success rate

Recommended Citations

Citations

  • Stark, A. S. R. (2017). Early Clinical Trial Design Recommendations in Oncology Based on Overall Success across Phases I, II, and III [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1510592650256558

    APA Style (7th edition)

  • Stark, Amy. Early Clinical Trial Design Recommendations in Oncology Based on Overall Success across Phases I, II, and III. 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1510592650256558.

    MLA Style (8th edition)

  • Stark, Amy. "Early Clinical Trial Design Recommendations in Oncology Based on Overall Success across Phases I, II, and III." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1510592650256558

    Chicago Manual of Style (17th edition)

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© 2017, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.