BIOEQUIVALENCE AND CLINICAL IMPLICATIONS OF GENERIC BUPROPION

仿制药安非他酮的生物等效性和临床意义

• 批准号: 8733057
• 负责人: Evan D. Kharasch
• 金额: $ 100万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8733057
• 关键词: BIOEQUIVALENCE; CLINICAL; IMPLICATIONS; GENERIC; BUPROPION

PROJECT SUMMARY/ABTRACT Ever since the introduction of a generic version in 2006, the antidepressant bupropion XL (300mg extended release) has been plagued with reports of therapeutic inefficacy and increased adverse events. The only formal bioequivalence testing of a 300mg generic bupropion XL (Budeprion XL) with branded Wellbutrin XL (in healthy volunteers) resulted in Budeprion being found non-bioequivalent. Budeprion was thus withdrawn in 2012. This raised significant new concerns: 1) Are other 300mg bupropion XL generics bioequivalent to Wellbutrin XL, and to each other? 2) Are there clinically significant differences between 300mg XL products in antidepressant effectiveness or adverse outcomes (side effects or relapse)? These concerns are pressing, as no other 300mg XL generic has undergone bioequivalence or clinical equivalence testing. No 300mg XL product at all has undergone such testing in patients with major depression. FDA recognized this urgent un- met need, and issued RFA-FD-13-021, "Bioequivalence of generic bupropion". We propose a definitive study, responsive to these concerns and the RFA, to (1) evaluate steady-state bioequivalence between branded and all three currently marketed generic 300mg XL bupropion products in patients with major depressive disorder, (2) determine if patients perceive differences in release patterns, clinical effectiveness, and adverse events between drug products, and (3) determine patients' clinical response using validated objective measures of depression. The Specific Aims are to (1) Determine bioequivalence between branded and generic bupropion 300mg XL products (and between generic products) at steady state in patients with major depressive disorder; (2) Compare patients' self-reported clinical differences (release patterns, antidepressant effectiveness, adverse events) between all bupropion 300mg XL products (brand vs generics, and between generics), using innovative methods for assessing patient perspectives; (3) Compare objective evaluation of patients' clinical response to each bupropion 300mg XL product, using standard, well-validated measures of depression response and side effects; and (4) Compare population-based pharmacometric/pharmaceutical outcomes between bupropion XL products, and to bupropion disposition. A unique investigative team, comprised of a clinical pharmacologist, depression clinical trialist, biostatistician, and national pharmacy benefit manager, brings the data, expertise, and experience to assure timely and unbiased success, and dissemination of results. The results will resolve patient and regulatory agency concerns about quality, bioequivalence, and therapeutic equivalence of bupropion XL generics, and thereby improve the clinical effectiveness and safety of bupropion, and the psychiatric care for the >1 million Americans taking bupropion for the treatment of major depressive disorder. This research also promises to develop a new paradigm for drug safety, using pharmacy benefit manager data on a massive scale for active surveillance monitoring, with the potential for signal detection and intervention much earlier than currently possible by conventional voluntary reporting.

项目概要/摘要 自从 2006 年推出仿制药以来，抗抑郁药安非他酮 XL（300 毫克延长版） 释放）一直受到治疗无效和不良事件增加的报道的困扰。唯一的 对 300 毫克仿制药安非他酮 XL (Budeprion XL) 与品牌 Wellbutrin XL（在 健康志愿者）导致布地朊酮被发现非生物等效性。布地普利翁因此被撤回 2012 年。这引起了新的重大关注：1) 其他 300 毫克安非他酮 XL 仿制药是否与 Wellbutrin XL，以及彼此之间？ 2) 300mg XL 产品之间是否存在临床显着差异？ 抗抑郁效果或不良后果（副作用或复发）？这些担忧十分紧迫，因为 没有其他 300mg XL 仿制药经过生物等效性或临床等效性测试。无 300mg XL 产品根本没有在重度抑郁症患者中进行过此类测试。 FDA 认识到这一紧急情况 满足需要，并发布了 RFA-FD-13-021，“仿制药安非他酮的生物等效性”。我们提出一项明确的研究， 响应这些问题和 RFA，（1）评估品牌和品牌之间的稳态生物等效性 目前上市的所有三种仿制药 300mg XL 安非他酮产品均适用于重度抑郁症患者， (2) 确定患者是否感知到释放模式、临床有效性和不良事件的差异 药物产品之间的差异，以及（3）使用经过验证的客观测量来确定患者的临床反应 沮丧。具体目标是 (1) 确定品牌安非他酮和仿制药安非他酮之间的生物等效性 重度抑郁症患者在稳态时服用 300 毫克 XL 产品（以及非专利产品之间）； (2) 比较患者自我报告的临床差异（释放模式、抗抑郁疗效、不良反应） 所有安非他酮 300mg XL 产品（品牌与仿制药之间，以及仿制药之间）之间的事件），使用 评估患者观点的创新方法； (3)比较患者临床客观评价 使用标准、经过充分验证的抑郁措施对每种安非他酮 300mg XL 产品的反应 反应和副作用； (4) 比较基于人群的药理学/药学结果 安非他酮 XL 产品之间以及安非他酮处置。一个独特的调查小组，由 临床药理学家、抑郁症临床试验师、生物统计学家和国家药房福利经理， 带来数据、专业知识和经验，以确保及时和公正的成功，并传播 结果。结果将解决患者和监管机构对质量、生物等效性和 安非他酮XL仿制药的治疗等效性，从而提高临床有效性和安全性 安非他酮，以及对超过 100 万美国人服用安非他酮治疗重大疾病的精神科护理 抑郁症。这项研究还有望利用药学开发药物安全的新范例 大规模的效益管理者数据可用于主动监视监控，并具有信号潜力 比目前通过传统自愿报告实现的检测和干预要早得多。