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Related Experiment Videos

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

A Grahnén1, M O Karlsson

  • 1Quintiles AB, Uppsala, Sweden. anders.grahnen@quintiles.com

Clinical Pharmacokinetics
|July 4, 2001
PubMed
Summary

Dose-finding trials are shifting from confirmation to learning. While alternative trial designs like randomized concentration-controlled trials (RCCT) and randomized effect-controlled trials (RECT) were proposed, they have seen limited application. The main advancement involves integrating learning components into traditional randomized dose-controlled trials (RDCT).

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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:

Related Experiment Videos

  • 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).