Table V.

Comparison of Pharmacokinetic Bioequivalence Study Recommendations of International Regulatory Authorities for Locally Acting Orally Inhaled Drug Products

Study design	HC: single dose study EMA: • For purpose of pulmonary deposition, the PK study has to be able to exclude absorption of the active moiety from the GI tract • For safety purpose, the PK study should include the measurement of that amount via the lung and GI tract FDA: • The PK study is recommended in the choice of combination of in vivo and in vitro BE studies, but there is no details on study design. • FP-SX DPI and albuterol MDI: fasting, single dose, two-way crossover
Dose	HC: maximum labeled adult dose EMA: single dose FDA: FP-SX DPI: minimum number of inhalations that is sufficient to characterize a PK profile
Subjects	Similarities: for systemic exposure purpose only, adult healthy subjects are recommended Differences: HC: no additional recommendations EMA: for safety purpose, adult intended patient population FDA: normal healthy males and non-pregnant females, general population
Equivalence acceptance criteria	Similarities: 90% CIs of geometric mean T/R ratio of AUC generally should be within 80.0–125.0% Differences: HC: relative mean of C max (T/R) is within 80.0–12.5.0% for inhaled corticosteroids (12) EMA: T max are also compared; 90% CI for C max ratio (T/R) is within 80.00–125.00%; 90% CIs may recommend tighter limits for narrow therapeutic window; for highly variable drugs, 90% CIs for C max ratio may be widened to 75–133% FDA: 90% CI for C max ratio is within 80.00–125.00%; reference scaled approach can be considered for highly variable drugs

HC Health Canada, EMA European Medicines Association, FDA Food and Drug Administration, PK pharmacokinetic, GI gastrointestinal tract, DPI dry powder inhaler, MDI metered-dose inhaler, CI confidence interval, AUC area under the curve