BIOEQUIVALENCE AND CLINICAL IMPLICATIONS OF GENERIC BUPROPION

项目摘要/摘要 自2006年推出仿制药以来，抗抑郁药安非他酮XL(300毫克延长 释放)一直饱受治疗无效和不良事件增加的报道的困扰。唯一的 300 mg非专利安非他酮XL与品牌Wellbutrin XL的正式生物等效性试验 健康志愿者)导致布迪肯被发现非生物等效性。因此，布迪肯在#年被撤回。 2012年。这引发了重大的新问题：1)其他300毫克安非他酮XL仿制药是否在生物上等同于 Wellbutrin XL和彼此之间的关系？2)300 mg XL产品在 抗抑郁药物的有效性或不良后果(副作用或复发)？这些担忧迫在眉睫，因为 没有其他300毫克XL仿制药经过生物等效性或临床等效性测试。不是300毫克XL 该产品根本没有在患有严重抑郁症的患者身上进行过这样的测试。FDA认识到这一紧急情况- 满足了需求，并发布了RFA-FD-13-021，“非专利安非他酮的生物等效性”。我们建议进行一项权威性研究， 响应这些关注和RFA，以(1)评估品牌和 这三家公司目前都在销售用于严重抑郁障碍患者的300 mg XL安非他酮仿制药， (2)确定患者是否感觉到释放模式、临床有效性和不良事件的差异 在药物产品之间，以及(3)使用有效的客观措施确定患者的临床反应 抑郁症。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 300 mg XL产品(以及非专利产品之间)在重度抑郁障碍患者的稳态下； (2)比较患者自我报告的临床差异(释放模式、抗抑郁药物有效性、不良反应 事件)所有安非他酮300 mg XL产品之间(品牌与仿制药之间，以及仿制药之间)，使用 创新患者视角评估方法；(3)比较患者临床客观评估 对每个安非他酮300 mg XL产品的反应，使用标准的、经过充分验证的抑郁症测量方法 反应和副作用；以及(4)比较基于人群的药物计量/药物结果 安非他酮XL产品之间，以及安非他酮的处置。一个独特的调查小组，由一名 临床药理学家、抑郁症临床试验专家、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、公正地取得成功并传播 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，从而提高安非他酮的临床疗效和安全性 安非他酮，以及100万美国人服用安非他酮治疗重大疾病的精神护理 抑郁障碍。这项研究还承诺开发一种新的药物安全范例，使用药房 用于主动监控的大规模收益经理数据，具有发出信号的潜力 发现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 Budeprion was thus withdrawn in 2012.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.