Therapeutic equivalence: fallacies and falsification

Area of Science:

• Clinical Trials Methodology
• Pharmaceutical Statistics
• Regulatory Science

Background:

• Increasing number of therapeutic equivalence and non-inferiority studies.
• Growing awareness of methodological challenges in these trial designs.
• Regulatory authorities have issued guidance on these trial types.

Purpose of the Study:

• To address common misconceptions in sample size estimation and patient population selection for equivalence/non-inferiority trials.
• To highlight neglected areas such as equivalence margin specification and covariate adjustment.
• To challenge current regulatory advice and interpretations, fostering further debate.

Main Methods:

• Review of existing regulatory guidance on therapeutic equivalence and non-inferiority trials.
• Analysis of common statistical and methodological issues encountered in practice.
• Critical evaluation of interpretations of regulatory advice.

Main Results:

• Prevalence of misconceptions regarding sample size and patient population selection.
• Underemphasis on crucial aspects like equivalence margin specification and covariate adjustment.
• Discrepancies between regulatory advice and practical application/interpretation.

Conclusions:

• Current understanding and application of regulatory guidance for equivalence and non-inferiority trials require refinement.
• Further discussion is needed to clarify methodological standards and address common misconceptions.
• Accurate implementation of these trial designs is critical for pharmaceutical development.