Food and Drug Administration, Center for Drug Evaluation and Research , Office of Pharmaceutical Science, Office of Generic Drugs, Rockville, Maryland, USA.
J Aerosol Med Pulm Drug Deliv. 2010 Feb;23(1):1-29. doi: 10.1089/jamp.2009.0803.
This March 2009 Workshop Summary Report was sponsored by Product Quality Research Institute (PQRI) based on a proposal by the Inhalation and Nasal Technology Focus Group (INTFG) of the American Association of Pharmaceutical Scientists (AAPS). Participants from the pharmaceutical industry, academia and regulatory bodies from the United States, Europe, India, and Brazil attended the workshop with the objective of presenting, reviewing, and discussing recommendations for demonstrating bioequivalence (BE) that may be considered in the development of orally inhaled drug products and regulatory guidances for new drug applications (NDAs), abbreviated NDAs (ANDAs), and postapproval changes. The workshop addressed areas related to in vitro approaches to demonstrating BE, biomarker strategies, imaging techniques, in vivo approaches to establishing local delivery equivalence and device design similarity. The workshop presented material that provided a baseline for the current understanding of orally inhaled drug products (OIPs) and identified gaps in knowledge and consensus that, if answered, might allow the design of a robust, streamlined method for the BE assessment of locally acting inhalation drugs. These included the following: (1) cascade impactor (CI) studies are not a good 2 predictor of the pulmonary dose; more detailed studies on in vitro/in vivo correlations (e.g., suitability of CI studies for assessing differences in the regional deposition) are needed; (2) there is a lack of consensus on the appropriate statistical methods for assessing in vitro results; (3) fully validated and standardized imaging methods, while capable of providing information on pulmonary dose and regional deposition, might not be applicable to the BE of inhaled products mainly due to the problems of having access to radiolabeled innovator product; (4) if alternatives to current methods for establishing local delivery BE of OIPs cannot be established, biomarkers (pharmacodynamic or clinical endpoints) with a sufficiently steep dose-response need to be identified and validated for all relevant drug classes; and (5) the utility of pharmacokinetic studies for evaluating "local pulmonary delivery" equivalence deserves more attention. A summary of action items for seminars and working groups to address these topics in the future is also presented.
这份 2009 年 3 月研讨会总结报告由产品质量研究院（PQRI）赞助，其提案来自于美国制药科学家协会（AAPS）的吸入和鼻腔技术焦点小组（INTFG）。来自美国、欧洲、印度和巴西的制药行业、学术界和监管机构的代表参加了此次研讨会，目的是介绍、审查和讨论在开发口服吸入药物产品和新药物申请（NDA）、简化新药申请（ANDA）和批准后变更的监管指南中可能考虑的生物等效性（BE）证明建议。该研讨会涉及了证明 BE 的体外方法、生物标志物策略、成像技术、建立局部递药等效性和装置设计相似性的体内方法等相关领域。该研讨会提供了口服吸入药物产品（OIP）当前理解的基础材料，并确定了知识和共识方面的差距，如果得到解答，可能会为局部作用吸入药物的 BE 评估设计一种稳健、精简的方法。这些差距包括以下方面：（1）级联撞击器（CI）研究不能很好地预测肺部剂量；需要进行更多关于体外/体内相关性的详细研究（例如，CI 研究是否适合评估区域性沉积的差异）；（2）对于评估体外结果的适当统计方法，尚未达成共识；（3）虽然完全验证和标准化的成像方法能够提供关于肺部剂量和区域性沉积的信息，但由于难以获得创新产品的放射性标记物，这些方法可能不适用于吸入产品的 BE；（4）如果不能建立用于建立 OIP 局部递药 BE 的当前方法的替代方法，则需要确定和验证所有相关药物类别的具有足够陡峭剂量反应的生物标志物（药效学或临床终点）；（5）评估“局部肺内传递”等效性的药代动力学研究的实用性值得更多关注。还提出了研讨会和工作组未来解决这些问题的行动项目摘要。
