Concentration-controlled or effect-controlled trials: useful alternatives to conventional dose-controlled trials?

Area of Science:

• Clinical Trials Methodology
• Pharmacometrics
• Drug Development

Background:

• Dose-finding trials have historically been confirmatory, overlooking their potential as a learning phase in drug development.
• Alternative trial designs, including randomized concentration-controlled trials (RCCT) and randomized effect-controlled trials (RECT), were proposed to enhance informativeness.
• These alternatives aimed to improve trial efficiency by controlling drug exposure or randomizing based on effect.

Purpose of the Study:

• To review the application and limitations of alternative dose-finding trial designs.
• To propose the randomized biomarker-controlled trial (RBCT) as a potentially more favorable design.
• To identify the primary drivers of the shift towards learning in modern dose-finding trials.

Main Methods:

• Literature survey on the application of RCCT and RECT.
• Discussion of practical challenges and limitations of alternative trial designs.
• Proposal and evaluation of the randomized biomarker-controlled trial (RBCT).

Main Results:

• RCCT has been sparsely applied due to practical complications.
• RECT has not been applied, likely due to limited suitable situations and methodological overlap.
• RBCT offers attractive features like biomarker validation but is unlikely to be extensively used.
• The primary shift towards learning in dose-finding trials is achieved by incorporating learning components into traditional RDCT.

Conclusions:

• Alternative trial designs like RCCT and RECT face significant barriers to widespread adoption.
• The randomized biomarker-controlled trial (RBCT) presents potential benefits but is also unlikely to see extensive use.
• The most impactful evolution in dose-finding trials is the integration of learning elements (e.g., pharmacokinetic/pharmacodynamic modeling, biomarker analysis) into standard randomized dose-controlled trials (RDCT).