This article describes the European Union stepwise approach used for the development and assessment of second-entry orally inhaled products. This approach is similar to the approach used for systemically acting products. In some cases, in vitro data can be used to show equivalence without performing in vivo studies (e.g., solutions for nebulization in the case of inhalation products, and oral solutions or Biopharmaceutics Classification System–based biowaivers in the case of systemically acting drugs). If equivalence cannot be shown in the first step, the Applicant can show equivalence in a second step by means of conventional pharmacokinetic bioequivalence studies to assess directly systemic exposure and lung deposition indirectly. The dose absorbed from the lungs should be distinguished from the dose absorbed from the gastrointestinal tract. Then the fraction of dose absorbed (area under the curve) represents the dose that reached the site of action, and the peak exposure gives information on the pattern of deposition within the lungs. This information is more discriminative than any pharmacodynamic or clinical endpoint, because these have flat dose–response curves. If equivalence is not shown with pharmacokinetic data, the Applicant can decide to show equivalence by means of pharmacodynamic or clinical trials, but assay sensitivity must be demonstrated within the study and relative potency should be estimated. This article focuses on the in vitro requirements applicable in the European Union for a waiver of in vivo studies and for waiving studies with all drug product strengths or pharmacokinetic studies in patients. The reasons why in the European Union in vitro data alone can be used to show equivalence are discussed, and some examples are given.
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