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Phase 1 trial design: is 3 + 3 the best?
Aaron R Hansen1, Donna M Graham, Gregory R Pond
1Drug Development Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada M5G 2M9. lillian.siu@uhn.ca.
Background:
Concerns have been recognized about the operating characteristics of the standard 3 + 3 dose-escalation design. Various innovative phase 1 trial designs have been proposed to address the issues and new challenges posed by molecularly targeted agents. However, in spite of these proposals, the conventional design is still the most widely utilized.
Methods:
A review of the literature of phase 1 trials and relevant statistical studies was performed.
Results:
Beyond statistical simulations, sparse clinical data exist to support or refute many of the shortcomings ascribed to the 3 + 3 rule method. Data from phase 1 trials demonstrate that traditional designs identified the correct dose and relevant toxicities with an acceptable level of precision in some instances; however, no single escalation method was proven superior in all circumstances.
Conclusions:
Design selection should be guided by the principle of slow escalation in the face of toxicity and rapid dose increases in the setting of minimal or no adverse events. When the toxicity of a drug is uncertain or a narrow therapeutic window is suggested from preclinical testing, then a conservative 3 + 3 method is generally appropriate. However, if the therapeutic window is wide and the expected toxicity is low, then rapid escalation with a novel rule- or model-based design should be employed.
Insights
The standard 3+3 design is common but not always best for early drug trials. Choosing the right dose escalation method depends on the drug's toxicity and therapeutic window.
Area of Science:
- Clinical Trial Design
- Pharmacology
- Oncology
Background:
- The standard 3+3 dose-escalation design is widely used in phase 1 trials.
- Concerns exist regarding its operating characteristics, especially with molecularly targeted agents.
- Innovative designs have been proposed, but the 3+3 method remains prevalent.
Purpose of the Study:
- To evaluate the effectiveness of the standard 3+3 dose-escalation design.
- To compare traditional designs with novel approaches for phase 1 clinical trials.
- To provide guidance on selecting appropriate dose-escalation strategies.
Main Methods:
- A comprehensive literature review of phase 1 clinical trials.
- Analysis of relevant statistical studies on dose-escalation methods.
- Examination of available clinical data and simulation studies.
Main Results:
- Limited clinical data exist to definitively support or refute criticisms of the 3+3 design.
- Traditional designs have successfully identified doses and toxicities in some phase 1 trials.
- No single dose-escalation method has demonstrated superiority across all scenarios.
Conclusions:
- Dose escalation should balance slow increases with toxicity and rapid increases with minimal adverse events.
- The conservative 3+3 method is suitable for drugs with uncertain toxicity or narrow therapeutic windows.
- For drugs with wide therapeutic windows and low expected toxicity, novel rule- or model-based designs facilitate rapid escalation.
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