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: 8669663
• 负责人: Evan D. Kharasch
• 金额: $ 80万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8669663
• 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 Budeprion was thus withdrawn in 2012.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.

项目摘要/订婚 自2006年引入通用版本以来，抗抑郁剂XL（300mg扩展） 释放）困扰着治疗效率低下和不良事件增加的报道。唯一的 带有品牌wellbutrin XL的300mg通用安非他酮XL（BudePrion XL）的正式生物等效性测试（在 健康的志愿者）导致发现了非生物等效性。因此，布德里翁被撤回 2012年。这引起了重大的新问题：1）其他300毫克安非他酮XL仿制药生物等同于 wellbutrin XL，彼此？ 2）300mg XL产品在临床上存在显着差异 抗抑郁药有效性或不良结果（副作用或复发）？这些担忧是紧迫的，因为 没有其他300mg XL通用具有生物等效性或临床等效性测试。没有300mg XL 产品在严重抑郁症患者中根本进行了此类测试。 FDA认识到这一紧急情况 满足需求，并发行了RFA-FD-13-021，“通用安非他酮的生物等效性”。我们提出了一项确定的研究， 对这些问题和RFA的响应，（1）评估品牌和 目前，这三者目前都在患有严重抑郁症患者的患者中销售仿制药XL安非他酮产品， （2）确定患者是否感知释放模式，临床有效性和不良事件的差异 在药品之间，（3）使用经过验证的客观测量确定患者的临床反应 沮丧。具体的目的是（1）确定品牌和通用安非他酮之间的生物等效性 重度抑郁症患者的稳态稳态XL产物（以及仿制药之间）； （2）比较患者的自我报告的临床差异（释放模式，抗抑郁药的效果，不良 事件）使用所有安非他酮300mg XL产品（品牌与仿制药）之间的事件，使用 评估患者观点的创新方法； （3）比较患者临床的客观评估 使用标准的，验证良好的抑郁量度对每种安非他酮300mg XL产品的响应 反应和副作用； （4）比较基于人群的药物计量/药物结果 在安非他酮XL产品和安非他酮处置之间。一个独特的调查团队，由 临床药理，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，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，生物等效性以及 安非他酮XL仿制药的治疗等效性，从而提高了临床有效性和安全性 安非他人和> 100万美国人的精神病护理 抑郁症。这项研究还有望使用药房开发新的药物安全范式 大规模的福利管理器数据进行主动监视监控，并有可能发出信号 检测和干预措施比常规自愿报告的目前要早得多。