Equivalence Considerations for Orally Inhaled Products for Local Action—ISAM/IPAC-RS European Workshop Report

Self Cite

Abstract. This article is part of a series of reports from the "Orlando Inhalation Conference-Approaches in International Regulation" which was held in March 2014, and coorganized by the University of Florida and the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS). The goal of the conference was to foster the exchange of ideas and knowledge across the global scientific and regulatory community in order to identify and help move towards strategies for internationally harmonized, science-based regulatory approaches for the development and marketing approval of inhalation medicines, including innovator and second entry products. This article provides an integrated perspective of case studies and discussion related to in vitro testing of orally inhaled products, including in vitro-in vivo correlations and requirements for in vitro data and statistical analysis that support quality or bioequivalence for regulatory applications.

Section: Product Quality and Equivalencementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In Vitro Testing for Orally Inhaled Products: Developments in Science-Based Regulatory Approaches

Forbes

Bäckman

Christopher

et al. 2015

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“…An asthma stability model was also proposed for inhaled corticosteroids. Home spirometry has been demonstrated to have great power of efficacy assessment, and dose-response correlation could be shown in therapeutic dose ranges [70]. Studies are under way for additional molecules, with results still pending, which may establish PD outcomes with good statistical power for comparability.…”

Section: Pharmacodynamic (Pd) and Clinical Studiesmentioning

confidence: 99%

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

Lee

Saluja

García‐Arieta

et al. 2015

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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.

“…Scenarios where both T and R FP inhalers represented the FP Diskus inhaler were simulated in a crossover design for 10,20,30,40,50,60, and 70 subjects. These scenarios, which can be interpreted as testing different lots of the R product against each other, were used to determine the sample size that is needed to achieve a statistical power of 90% to conclude bioequivalence when T and R are identical.…”

Section: Series 1: Two Identical Productsmentioning

confidence: 99%

“…It usually suffices to demonstrate that the 90% confidence interval for the T/R ratios for the area under the concentration time curve (AUC) and the maximum plasma concentration (C max ) are contained within the bioequivalence acceptance limits of 80%-125% (4,5). For inhaled corticosteroids and other orally inhaled locally acting drug products, however, where plasma concentrations are measured downstream of the lung (site of action) a different approach has been suggested by regulatory agencies for assessing bioequivalence (6)(7)(8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

A Systematic Analysis of the Sensitivity of Plasma Pharmacokinetics to Detect Differences in the Pulmonary Performance of Inhaled Fluticasone Propionate Products Using a Model-Based Simulation Approach

Weber

Hochhaus

2015

Abstract. The role of plasma pharmacokinetics (PK) for assessing bioequivalence at the target site, the lung, for orally inhaled drugs remains unclear. A validated semi-mechanistic model, considering the presence of mucociliary clearance in central lung regions, was expanded for quantifying the sensitivity of PK studies in detecting differences in the pulmonary performance (total lung deposition, central-toperipheral lung deposition ratio, and pulmonary dissolution characteristics) between test (T) and reference (R) inhaled fluticasone propionate (FP) products. PK bioequivalence trials for inhaled FP were simulated based on this PK model for a varying number of subjects and T products. The statistical power to conclude bioequivalence when T and R products are identical was demonstrated to be 90% for approximately 50 subjects. Furthermore, the simulations demonstrated that PK metrics (area under the concentration time curve (AUC) and C max ) are capable of detecting differences between T and R formulations of inhaled FP products when the products differ by more than 20%, 30%, and 25% for total lung deposition, central-to-peripheral lung deposition ratio, and pulmonary dissolution characteristics, respectively. These results were derived using a rather conservative risk assessment approach with an error rate of <10%. The simulations thus indicated that PK studies might be a viable alternative to clinical studies comparing pulmonary efficacy biomarkers for slowly dissolving inhaled drugs. PK trials for pulmonary efficacy equivalence testing should be complemented by in vitro studies to avoid false positive bioequivalence assessments that are theoretically possible for some specific scenarios. Moreover, a user-friendly web application for simulating such PK equivalence trials with inhaled FP is provided.