Between-Batch Pharmacokinetic Variability Inflates Type I Error Rate in Conventional Bioequivalence Trials: A Randomized Advair Diskus Clinical Trial.
Clin Pharmacol Ther
; 101(3): 331-340, 2017 03.
Article
en En
| MEDLINE
| ID: mdl-27727445
We previously demonstrated pharmacokinetic differences among manufacturing batches of a US Food and Drug Administration (FDA)-approved dry powder inhalation product (Advair Diskus 100/50) large enough to establish between-batch bio-inequivalence. Here, we provide independent confirmation of pharmacokinetic bio-inequivalence among Advair Diskus 100/50 batches, and quantify residual and between-batch variance component magnitudes. These variance estimates are used to consider the type I error rate of the FDA's current two-way crossover design recommendation. When between-batch pharmacokinetic variability is substantial, the conventional two-way crossover design cannot accomplish the objectives of FDA's statistical bioequivalence test (i.e., cannot accurately estimate the test/reference ratio and associated confidence interval). The two-way crossover, which ignores between-batch pharmacokinetic variability, yields an artificially narrow confidence interval on the product comparison. The unavoidable consequence is type I error rate inflation, to â¼25%, when between-batch pharmacokinetic variability is nonzero. This risk of a false bioequivalence conclusion is substantially higher than asserted by regulators as acceptable consumer risk (5%).
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Proyectos de Investigación
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United States Food and Drug Administration
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Broncodilatadores
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Combinación Fluticasona-Salmeterol
Tipo de estudio:
Clinical_trials
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Prognostic_studies
Límite:
Adult
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Female
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Humans
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Male
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Middle aged
País/Región como asunto:
America do norte
Idioma:
En
Revista:
Clin Pharmacol Ther
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos