Comparison of Europe‘s TE/BE Guidelines for Orally Inhaled Products with FDA’s Weight of Evidence Approach

Herbert Wachtel, Steve Horhota, Stefan Leiner

Background: In Europe, the EMA ‘Guideline on the requirements for clinical documentation for orally inhaled products’ (CPMP/EWP/4151/00 Rev. 1) is the key document defining therapeutic equivalence (TE) between orally inhaled products. This guideline has to be seen as additional to the CPMP/EWP/QWP/1401/98 Rev.1 ‘Guidance on the Investigation of Bioequivalence (BE)’. The stepwise approach defined in the guidelines to show equivalence may raise concerns with respect to a balanced consideration of all (in vitro, pharmacokinetic and pharmacodynamic) aspects. The points to discuss are: i) the assumption that sufficiently similar in vitro data may guarantee similar effects in patients and ii) the procedure of possibly overriding inequivalence demonstrated in vitro and eventually in pK data with PD data. Methods: We quote examples where in vitro methods, e.g. Cascade impaction and data of clinical trials are available. Results: Two case studies are discussed where seemingly similar in vitro data of the respective inhalation products resulted in similar PD, but in different pK data. Conclusions: Even if pharmaceutical products for inhalation provide similar results in one or two aspects (be it in vitro, pK or PD data) obvious differences may still exist which motivate that at least in vitro, pK, and PD data of inhaled products including risk management should be considered in a holistic way. An example of this broad view is the ‘Weight of Evidence Approach’ used in the United States. The studies proposed by FDA enable more informed decisions. In addition, emerging more bio-relevant in vitro methods should be considered.

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