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The case for cross-over trials in phase III

B Jones1, J A Lewis

  • 1Institute of Mathematics and Statistics, The University, Canterbury, Kent, UK.

Statistics in Medicine
|May 15, 1995
PubMed
Summary

Cross-over trials are valuable tools in phase III drug development, despite common misconceptions. Their advantages in study size and patient interaction, along with robust analysis methods, support their continued use in medicine research.

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Area of Science:

  • Clinical Trials Methodology
  • Biostatistics
  • Drug Development

Background:

  • A common belief suggests avoiding cross-over trials in phase III drug development, influenced by past guidance.
  • Historically, cross-over trials have been instrumental in the successful development and regulatory approval of numerous established medicines.
  • Current understanding of medical indications allows for better identification of advantageous scenarios for phase III cross-over trials.

Purpose of the Study:

  • To challenge the prevailing notion that cross-over trials are unsuitable for phase III drug development.
  • To review the disadvantages of cross-over trials and discuss early detection methods.
  • To highlight the key advantages of cross-over trials, including study size and treatment-by-patient interaction.

Main Methods:

  • Review of known disadvantages of cross-over trials compared to parallel group trials.
  • Discussion of methods for detecting potential issues in early trial phases (I and II).
  • Comparative analysis of different cross-over trial analysis strategies using simulation, particularly when baseline measurements are included.

Main Results:

  • Cross-over trials offer significant advantages in study size and understanding treatment-by-patient interactions.
  • Concerns regarding analysis methods do not necessitate avoiding cross-over trials, especially with baseline measurements.
  • Potential risks associated with cross-over trials tend to diminish treatment effect estimates, posing minimal concern for regulators.

Conclusions:

  • Cross-over trials are a valuable and versatile research tool throughout all stages of new medicine development, including phase III.
  • Excluding cross-over trials from phase III drug development is unnecessary and counterproductive.
  • The strategic use of cross-over designs, supported by appropriate analysis, remains beneficial for pharmaceutical research.

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