An iterative method to protect the type I error rate in bioequivalence studies under two-stage adaptive 2×2 crossover designs.
average bioequivalence (ABE)
generic drug product
significance level adjustment
two-stage adaptive designs (TSD)
type I error control (T1E)
Journal
Biometrical journal. Biometrische Zeitschrift
ISSN: 1521-4036
Titre abrégé: Biom J
Pays: Germany
ID NLM: 7708048
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
13
12
2019
revised:
20
04
2020
accepted:
22
06
2020
pubmed:
2
10
2020
medline:
16
10
2021
entrez:
1
10
2020
Statut:
ppublish
Résumé
Bioequivalence studies are the pivotal clinical trials submitted to regulatory agencies to support the marketing applications of generic drug products. Average bioequivalence (ABE) is used to determine whether the mean values for the pharmacokinetic measures determined after administration of the test and reference products are comparable. Two-stage 2×2 crossover adaptive designs (TSDs) are becoming increasingly popular because they allow making assumptions on the clinically meaningful treatment effect and a reliable guess for the unknown within-subject variability. At an interim look, if ABE is not declared with an initial sample size, they allow to increase it depending on the estimated variability and to enroll additional subjects at a second stage, or to stop for futility in case of poor likelihood of bioequivalence. This is crucial because both parameters must clearly be prespecified in protocols, and the strategy agreed with regulatory agencies in advance with emphasis on controlling the overall type I error. We present an iterative method to adjust the significance levels at each stage which preserves the overall type I error for a wide set of scenarios which should include the true unknown variability value. Simulations showed adjusted significance levels higher than 0.0300 in most cases with type I error always below 5%, and with a power of at least 80%. TSDs work particularly well for coefficients of variation below 0.3 which are especially useful due to the balance between the power and the percentage of studies proceeding to stage 2. Our approach might support discussions with regulatory agencies.
Identifiants
pubmed: 33000873
doi: 10.1002/bimj.201900388
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
122-133Subventions
Organisme : MINECO/FEDER
ID : MTM2015-64465-C2-1-R
Organisme : Ministerio de Economia y Competitividad
ID : 2014 SGR 464
Organisme : Generalitat de Catalunya
Informations de copyright
© 2020 Wiley-VCH GmbH.
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