Phase 1 trial design: is 3 + 3 the best?

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.