BIOEQUIVALENCE AND CLINICAL IMPLICATIONS OF GENERIC BUPROPION

项目总结/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 已被治疗无效和增加的不良事件的报道所困扰。唯一的 正式生物等效性测试的300毫克通用安非他酮XL（Budeprion XL）与品牌Wellbutrin XL（在 健康志愿者）导致Budeprion被发现非生物等效。布德利翁因此被撤回， 2012.这引起了重大的新问题：1）其他300 mg安非他酮XL仿制药是否与 Wellbutrin XL，和对方？2)300 mg XL产品在以下方面是否存在临床显著差异： 抗抑郁药的有效性或不良后果（副作用或复发）？这些问题是紧迫的，因为 没有其他300 mg XL仿制药进行生物等效性或临床等效性试验。无300 mg XL 产品在所有经历了这样的测试患者严重抑郁症。FDA认识到这一紧急情况， 满足需求，并发布了RFA-FD-13-021，“安非他酮仿制药的生物等效性”。我们提出一个明确的研究， 针对这些问题和RFA，（1）评价品牌和 所有三种目前上市的用于重度抑郁症患者的300 mg XL安非他酮仿制药产品， (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 （3）使用经验证的客观指标确定患者的临床反应， 萧条具体目的是（1）确定品牌安非他酮和仿制安非他酮之间的生物等效性 重度抑郁症患者稳态时的300 mg XL产品（和仿制药之间）; (2)比较患者自我报告的临床差异（释放模式、抗抑郁药有效性、不良反应）， 事件）之间的所有安非他酮300 mg XL产品（品牌与仿制药，以及仿制药之间），使用 创新的方法来评估病人的观点;（3）比较客观评价病人的临床 对每种安非他酮300 mg XL产品的反应，使用标准的，经过充分验证的抑郁症指标 反应和副作用;和（4）比较基于人群的药理学/药学结果 之间的安非他酮XL产品，和安非他酮处置。一个独特的调查小组，由一个 临床药理学家、抑郁症临床试验员、生物统计学家和国家药房福利经理， 带来的数据，专业知识和经验，以确保及时和公正的成功，并传播 结果这些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> 100万服用安非他酮治疗重大疾病的美国人的精神病护理 抑郁症这项研究还有望开发一种新的药物安全模式， 大规模的利益管理者数据，用于主动监督监测，并有可能发出信号 检测和干预的时间比目前常规自愿报告的时间要早得多。

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 Budeprion was thus withdrawn in 2012.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.