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

Abstract

This article describes regulatory approaches for approval of "generic" 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 "original" 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 "generic" and "reference" 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.

Fig. 1

Mean eNO response as a function of daily dose of FP. Data collected through an FDA sponsored study with National Jewish Health Center in which nine subjects completed the study. The eNO data were fitted by the E_max model described by E _R = E _0R + (E _maxR * D _R)/(ED _50R+D _R), where E _R = response, D _R = administered dose, E _0R = placebo response in the absence of the drug, E _maxR = fitted maximum drug effect, and ED _50R = dose required to produce 50% of the fitted maximum effect

Fig. 2

Stepwise approach employed in the European Union for systemically acting products and locally applied and locally acting orally inhaled products in comparison to the weight of evidence approach employed in the US-FDA for orally inhaled drug products. The background indicates the legal basis of the application: dotted background for generic applications and striped background for hybrid applications. “Relative potency” refers to the dose-scale analysis of the dose–response curve

Fig. 3

Decision tree for the development and regulatory assessment of orally inhaled products in the European Union. “Relative potency” refers to the dose-scale analysis of the dose–response curve

Fig. 4

Registration process for drugs imported into China, and associated timelines based on the 2013 Technical Review Report by CDE [98]

Fig. 5

Local generic drug registration process and timeline. The process illustrated in this figure is based on current PDR and the timeline is based on the technical review report of 2013 of CDE [81]