FDA updates statistical approaches for assessing bioequivalence

Regulatory NewsRegulatory News | 02 December 2022 |  By 

The US Food and Drug Administration (FDA) has published a draft guidance updating its principles for assessing in vivo or in vitro bioequivalence studies (BE) for investigational new drugs (INDs), new drug applications (NDAs), abbreviated new drug applications (ANDAs) and supplements to these applications.
The update replaces a previous version in February 2001 and adds new topics such as assessing the bioequivalence for narrow therapeutic index (NTI) drugs and highly variable drugs, using adaptive trial designs, and statistical approaches for filling in missing patient data.
The guidance intends to “help applicants plan and analyze their BE studies with the goal of minimizing the number of assessment cycles necessary for approval.”
FDA defines BE as the “comparison between a test (T) and reference (R) drug product, where T and R can vary depending on the comparison to be performed” such as whether the comparison involves a marketed formulation versus clinical trial formulation, a generic drug versus reference listed drug (RLD), or originally approved formulation versus post approval formulation change.
Guidance incorporates adaptive designs
The guidance incorporates the principles of the adaptive design approach, which “allows for prospectively planned modifications to one or more aspects of the design based on accumulating data from subjects in the trial.”
Adaptive designs “provide ethnical advantages and statical efficiency,” said FDA. When “appropriately implemented” adaptive designs “can reduce resources used, decrease time to study completion, and increase the chance of study success, especially when the prior information needed for the study designs is limited.”
For more details on adaptive designs, sponsors were advised to consult FDA’s November 2019 guidance. (RELATED: FDA Finalizes Guidance on Adaptive Trial Designs, Regulatory Focus, 2 December 2019).
How to plug in missing data
The guidance addresses dealing with missing data caused by events such as a subject’s refusal to continue in the study, the emergence of adverse events, or the subject’s failure to meet scheduled appointees for evaluation.
“Missing data and intercurrent events can introduce problems such as bias, misleading inference, loss of precision and loss of power, which make it hard to interpret the trial outcome,” said FDA.
FDA advises sponsors to consult the International Council for Harmonization’s (ICH) E9(R1) guideline introducing the concept of estimands for handling missing data. (RELATED: ICH E9(R1) and S5(R3) to Take Effect in EU by End of July, Regulatory Focus, 18 February 2020). The training materials were released last January 2022. (RELATED: ICH guidance provides clarity on estimands, sensitivity analysis, Regulatory Focus 31 January 2022).
In other areas, for NTI drugs, FDA advised sponsors to make use of a fully replicated cross-over study design. These studies should pass both the reference-scaled approach and the unscaled average BE limits of 80% to 125%.
The update builds on previous guidances reflecting an evolution of the agency’s thinking on statistical principles for assessing BE. For example, the 1992 guidance established the principles of average BE, meaning that BE should fall within a limit of 80%-125% of the ratio of the product averages. The 2001 guidance introduced the population BE and individual BE approaches for assessing drugs.  
The public has 60 days to comment.
FDA draft guidance


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