EMA proposes new guideline on non-inferiority trials
The European Medicines Agency (EMA) is proposing a new guideline on sponsors’ use of non-inferiority designs to assess the safety and effectiveness of new drugs in clinical trials. The proposal aims to incorporate the International Council for Harmonisation’s (ICH) guideline on estimand and sensitivity analyses in clinical trials and consolidate existing guidance on inferiority trials.According to a new concept paper, the guideline aims to “provide clarity and advice with respect to the application of the estimand framework for non-inferiority comparisons” and “improve planning of confirmatory trials that include non-inferiority comparisons and therapeutic equivalence comparisons by sponsors and lead to improved scientific advice and regulatory assessment.”
EMA said that non-inferiority trials aim to demonstrate that the efficacy of a new medicinal product is not “considerably inferior” than the current standard therapy. The agency also notes that “specific issues related to non-inferiority and therapeutic equivalence comparisons require considerations different from those encountered in superiority trials.”
The ICH E9(R1) guideline, which took effect in July 2020, “revealed the necessity of specific recommendations about the application of the estimand framework to the non-inferiority and therapeutic equivalence settings.” ICH E9 (R1) and S5(R3) to Take Effect in EU by End of July, Regulatory Focus 18 February 2020).
The paper further notes that the sensitivity of a trial in detecting differences between treatments “is paramount to avoid a false decision on non-inferiority or equivalence comparisons. Lack of sensitivity may be related to the study design and conduct, including the choice of estimand. Therefore, it is important to target an estimand adapted to the specific setting of a non-inferiority or equivalence comparison.”
Besides incorporating ICH E9(R1), EMA proposes that the upcoming guideline consolidate two existing documents on the topic, the Guideline on the Choice of Non-Inferiority Margin, adopted by EMA’s Committee for Medical Products for Human Use (CHMP) in 2005, and CHMP’s 2020 Points to Consider on Switching between Superiority and Non-Inferiority. Both documents address specific issues related to non-inferiority and therapeutic equivalence comparisons.
The forthcoming guideline will address the following: the different types and objectives of non-inferiority and equivalence trials; trial quality and assay sensitivity; estimands, including specific issues relevant to non-inferiority and equivalence comparisons; justifying non-inferiority margins including identifying difficulties in defining the margin; treating missing data related to the estimand and sensitivity analysis; multiplicity issues; and switching between non-inferiority and superiority comparisons.
The deadline to comment is 31 May. EMA proposes to release the draft guidance in October 2024.
EMA concept paper
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