Regulatory Considerations for Approval of Generic Inhalation Drug Products in the US, EU, Brazil, China, and India

Abstract

Abstract. This article describes regulatory approaches for approval of Bgeneric^orally inhaled drug products (OIDPs) in the United States, European Union, Brazil, China and India. While registration of a generic OIDP in any given market may require some documentation of the formulation and device similarity to the Boriginal^product as well as comparative testing of in vitro characteristics and in vivo performance, the specific documentation approaches, tests and acceptance criteria vary by the country. This divergence is due to several factors, including unique cultural, historical, legal and economic circumstances of each region; the diverse healthcare and regulatory systems; the different definitions of key terms such as Bgeneric^and Breference^drug; the acknowledged absence of in vitro in vivo correlations for OIDPs; and the scientific and statistical issues related to OIDP testing (such as how best to account for the batch-to-batch variability of the Reference product, whether to use average bioequivalence or population bioequivalence in the statistical analysis of results, whether to use healthy volunteers or patients for pharmacokinetic studies, and which pharmacodynamic or clinical end-points should be used). As a result of this discrepancy, there are ample opportunities for the regulatory and scientific communities around the world to collaborate in developing more consistent, better aligned, science-based approaches. Moving in that direction will require both further research and further open discussion of the pros and cons of various approaches.

Particle size and gastrointestinal absorption influence tiotropium pharmacokinetics: a pilot bioequivalence study of PUR0200 and Spiriva HandiHaler

“…Current bioequivalence guidance requires that a test product match C max and AUC 0– t of the reference product to conclude bioequivalence . When gastrointestinal absorption contributes to exposure, equivalent efficacy may be concluded by assessing lung deposition using C max or AUC 0–0.5h where lung dose is assessed in a charcoal block study, and equivalent safety may be concluded in a study without charcoal block, as the evaluation of safety requires assessment of exposure resulting from both pulmonary and gastrointestinal absorption . Therefore, consideration must be given to both lung deposited dose and mouth‐throat dose during product development.…”

In Silico Methods for Development of Generic Drug–Device Combination Orally Inhaled Drug Products

“…Considering the device aspect of drug–device combination OIDPs, these products are recommended to provide a user interface that is similar to the RLD with similar operating principles to ensure therapeutic equivalence . The formulation for MDIs should be qualitatively and quantitatively the same as the RLD; for DPIs qualitative sameness is required, and if it is not quantitatively the same the differences should be justified with additional data . Taken together, a potential generic OIDP developer has to balance the appropriateness of passing all FDA‐recommended studies, producing a generic drug–device combination product that can be substituted for the RLD without additional training prior to use and/or without the intervention of a healthcare provider and observing any existing device patents that may exist.…”

“…8 The formulation for MDIs should be qualitatively and quantitatively the same as the RLD; for DPIs qualitative sameness is required, and if it is not quantitatively the same the differences should be justified with additional data. 9 Taken together, a potential generic OIDP developer has to balance the appropriateness of passing all FDA-recommended studies, producing a generic drug-device combination product that can be substituted for the RLD without additional training prior to use and/or without the intervention of a healthcare provider 10 and observing any existing device patents that may exist. Meeting these standards may require many device or even formulation iterations before generating an approvable product.…”

Rethinking bioequivalence and equivalence requirements of orally inhaled drug products

“…Despite the absence of an FDA guidance document on the BE of OIP in general, scientific and regulatory considerations for demonstrating BE between dry powder inhalers (DPI) have been proposed [20], and recently reviewed [21]. The FDA has developed an aggregate weight-of-evidence approach which utilizes in vitro studies, PK equivalence studies, and pharmacodynamic (PD) or clinical endpoint (CE) studies (also called Therapeutic Equivalence (TE) studies), to establish BE of inhalation products [21].…”

“…The FDA has developed an aggregate weight-of-evidence approach which utilizes in vitro studies, PK equivalence studies, and pharmacodynamic (PD) or clinical endpoint (CE) studies (also called Therapeutic Equivalence (TE) studies), to establish BE of inhalation products [21]. Equivalence in all categories of interest is required [22].…”