title: Between-Batch Pharmacokinetic Variability Inflates Type I Error Rate in Conventional Bioequivalence Trials: A Randomized Advair Diskus Clinical Trial.
abstract: 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 ∼25%, 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%).
authors.affiliation: Oriel Therapeutics, Inc, Berkeley, California, USA.
authors.forename: E
authors.initials: E
authors.lastname: Burmeister Getz
authors.affiliation: KJC Statistics, Bramhall, Cheshire, UK.
authors.forename: K J
authors.initials: KJ
authors.lastname: Carroll
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Mielke
authors.affiliation: University of California, San Francisco, California, USA.
authors.forename: L Z
authors.initials: LZ
authors.lastname: Benet
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Jones
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001993:Bronchodilator Agents / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D005260:Female; D000068297:Fluticasone-Salmeterol Drug Combination / Q000493:pharmacokinetics*; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D015203:Reproducibility of Results; D012107:Research Design / Q000592:standards*; D013810:Therapeutic Equivalency; D014481:United States; D014486:United States Food and Drug Administration / Q000331:legislation & jurisprudence*
chemical_list: D001993:Bronchodilator Agents; D000068297:Fluticasone-Salmeterol Drug Combination