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A Systematic Review of Adaptive Seamless Clinical Trials for Late-Phase Oncology Development
Kristine Broglio1, Freda Cooner2, Yujun Wu3
1AstraZeneca, Gaithersburg, MD, USA. kristine.broglio@astrazeneca.com.
Introduction:
Although oncology has seen large scientific and clinical advances over the last decade, it also has one of the lowest success rates for novel agents across therapeutic areas. Adaptive clinical trial design has been a popular option for increasing clinical trial efficiency and the chances of trial success. Seamless clinical trial design are studies in which two or more clinical trial phases are combined into a single study with a pre-specified transition between stages. This integration of phases may enhance efficiency.
Methods:
To understand the precedent for the use of seamless designs, this working group was formed to conduct a comprehensive literature search on seamless clinical trials conducted with confirmatory intent in oncology. Trial design features were extracted into a database and analyzed with descriptive statistics.
Results:
A literature search identified 68 clinical trials meeting inclusion and exclusion criteria. The most common design feature was a gate on treatment efficacy, where the trial would only proceed to the second stage if sufficient efficacy was observed in the first. The next most common feature was a selection of a dose or treatment regimen. Inferentially and operationally seamless designs were approximately equally represented.
Discussion:
Key statistical considerations for seamless phase II/III designs include optimizing design choices by evaluating and comparing operating characteristics across design alternatives as well as showing control of overall Type I error rates. Executing the transition between phases should be evaluated for issues related to accrual, drug production, and procedures to maintain trial integrity.
Conclusions:
While there are unique statistical, regulatory, and operational considerations for seamless designs they are also uniquely suited to many development settings. These include, for example, addressing dose selection under FDA's Project Optimus and addressing the growing use of biomarkers and personalized medicine approaches in cancer treatment.
Insights
Seamless clinical trial designs integrate multiple phases into one study to improve efficiency and success rates in oncology drug development. Key considerations include statistical validity, operational execution, and regulatory compliance for novel cancer therapies.
Area of Science:
- Oncology
- Clinical Trial Design
- Drug Development
Background:
- Oncology faces low novel agent success rates despite advances.
- Adaptive and seamless clinical trial designs aim to improve efficiency and success.
- Seamless designs combine multiple trial phases into a single study for enhanced efficiency.
Purpose of the Study:
- To review the precedent for seamless clinical trial designs in oncology.
- To analyze features of seamless trials with confirmatory intent.
Main Methods:
- Conducted a comprehensive literature search on seamless oncology trials.
- Extracted and analyzed trial design features using descriptive statistics.
Main Results:
- Identified 68 relevant clinical trials.
- Most common feature: efficacy gate for stage progression.
- Dose/regimen selection was another frequent feature.
- Inferential and operational seamless designs were equally represented.
Conclusions:
- Seamless phase II/III designs require careful statistical consideration for operating characteristics and Type I error control.
- Operational aspects like accrual, drug supply, and trial integrity are crucial for phase transitions.
- Seamless designs are well-suited for modern oncology, including dose selection and personalized medicine approaches.
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