A Model- and Systems-Based Approach to Efficacy and Safety Questions Related to Generic Substitution

副主题2(用于仿制药替代性评价和后评价的药物计量M&S) 小分子的市场评估) 一种基于模型和系统的方法来解决与以下相关的疗效和安全性问题 通用替代 仿制药办公室(OGD)偶尔会收到患者、医生的报告 和/或专业组织对市场上销售的仿制药的治疗不对等 毒品。通常，几乎没有科学证据来确凿地支持这样做的理由 泛型替换后出现的问题。鉴于OGD 2009年的一项研究表明， 通用产品和创新产品的Cmax和AUC的平均差异为4.35%和 1996年至2007年间进行的2,070种生物等效性产品分别为3.56%， 提出了这样一个问题：这些生物不等效性(BIN)信号是真实的还是可感知的。 然而，仿制药可能会很复杂，因为在 口服后的药效学(例如，与硝苯地平有关的降压)或 一天一次口服制剂的不同缓释机制(例如， 哌醋甲酯)。因此，至关重要的是要有一个适当的程序来评估所谓的 治疗不等价性。 这一研究战略的广泛目标是定义一个过程，通过该过程OGD可以具体地 在临床使用条件下评估已批准的仿制药在患者中的潜在BIN 在上市后期间，并调查由以下原因引起的据称的药物不良反应 通用替换。必须建立科学严谨的工作流程，以 挑战仿制药不如参照药有效的观念。结果是 这项研究将有助于向美国公众灌输对仿制药质量的信心 药物和FDA愿意使用循证方法调查 箱子。 我们正在提出一种机械化和量化的研究策略，使用建模和 模拟技术从评估药物等效性(即质量)， 通过生物等效性(即生物制药性能)和治疗等效性 (即临床疗效和安全性概况)，即基于风险的、全面和务实的 解决仿制药上市后风险问题的方法，以及对仿制药上市后风险的解释 使用系统生物学的市场不良事件报告或产品替代投诉 原则。它的目的是研究战略代表的工作流程和分析 仿制药办公室(OGD)系统调查仿制药引起的所谓BIN 毒品替代。我们的方法将作为一项试点研究与 OGD的科学家和临床医生将帮助识别高危的仿制药替代情况 用于评估研究策略的质量和一致性。

Subtopic 2 (Pharmacometric M&S for Generic Drug Substitutability Evaluation and Post- Marketing Assessment of small molecule) A Model- and Systems-Based Approach to Efficacy and Safety Questions Related to Generic Substitution The Office of Generic Drugs (OGD) occasionally receives reports from patients, physicians and/or professional organizations about the therapeutic INequivalence of marketed generic drugs. Frequently, there is little scientific evidence to conclusively support a rationale for problems following generic substitution. Given that a 2009 study by OGD demonstrated that the average difference in Cmax and AUC between generic and innovator products was 4.35% and 3.56%, respectively for 2,070 bioequivalence products conducted between 1996 and 2007, this raises the question of whether these bioINequivalence (BIN) signals are real or perceived. However, generic drugs can be complex because of things like input-rate sensitivity in pharmacodynamics (e.g., hypotension related to nifedipine) following oral administration or different mechanisms of extended release for once-a-day oral formulations (e.g., with methylphenidate). Therefore, it is critical to have a process in place to assess purported therapeutic INequivalence. The broad goal of this research strategy is to define a process whereby the OGD can specifically evaluate the potential BIN of approved generic products in patients under clinical use conditions during the post-marketing period, and investigate purported adverse drug reactions arising from generic substitution. It is essential that a scientifically rigorous workflow be established to challenge the notion that generic drugs don't work as well as reference drugs. The results of this research will help to instill confidence in the American public about the quality of generic drugs and the willingness of FDA to use an evidence-based approach to investigate claims of BIN. We are proposing a mechanistic and quantitative research strategy using modeling and simulation techniques that moves from assessing pharmaceutical equivalence (i.e. quality), through bioequivalence (i.e., biopharmaceutical performance) and on to therapeutic equivalence (i.e., clinical efficacy and safety profile), that is a risk-based, comprehensive and pragmatic approach to addressing issues of post-market risk of generic drugs, and interpretation of post- market adverse event reports or product substitution complaints using systems biology principles. It is intended that the research strategy represent a workflow and analysis for the Office of Generic Drugs (OGD) to systematically investigate purported BIN arising from generic drug substitution. Our approach would be conducted as a pilot study in close collaboration with scientists and clinicians in OGD who would help identify high-risk generic substitution situations for evaluating the quality and consistency of the research strategy.