Modified Regulatory Pathways to Approve Generic Drugs in the US and a Systematic Review of Their Outcomes.
Modified Regulatory Pathways to Approve Generic Drugs in the US and a Systematic Review of Their Outcomes.
复制标题
修改美国仿制药批准的监管途径及其结果的系统审查。
DOI：
10.1007/s40265-015-0382-1
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发表时间：
2015
期刊：
影响因子：
11.5
通讯作者：
Gagne,JoshuaJ
中科院分区：
文献类型：
--
作者：
Kesselheim,AaronS;Polinski,JenniferM;Fulchino,LisaA;Isaman,DanielleL;Gagne,JoshuaJ
研究背景仿制药的批准依据是药物等效性和生物等效性。一些药物产品具有独特的结构或功能属性，需要修改的方法来确定生物等效性。该系统综述的目的是确定通过修改的生物等效性方法批准的六种药物的实验室或临床结果的研究。数据来源我们对2014年2月在MEDLINE，EMBASE，和《国际药学文摘》，涉及最近六种受修改的监管方法影响的药物：文拉法辛缓释片（Effexor XR）、阿卡波糖（Precose）、依诺肝素（Lovenox）、万古霉素胶囊（万古霉素）、葡萄糖酸铁钠（Ferrlecit）和鲑鱼降钙素鼻喷雾剂（Miacalcin NS）。我们纳入了所有经验性评价（无论是体内还是体外），排除了病例研究、定性分析和药物经济学评价。总结并评价研究的方法学质量，并使用科克伦偏倚风险评估工具评估偏倚。将文献分为美国FDA批准的仿制药研究和非美国FDA批准的仿制药研究。数据提取我们提取了研究药物、研究设计、设置、样本量、人群特征、研究终点和结果以及资金来源。数据合成在检索了1408篇文献和106篇文献的全文后，我们发现26篇文章符合我们的纳入标准-8篇研究FDA批准的版本，18篇研究非FDA批准的版本。在FDA批准的仿制药中，5项依诺肝素研究显示了临床重要性不明的生物活性的微小变化，没有涉及阿卡波糖、文拉法辛ER或万古霉素胶囊的出版物。在非FDA批准的仿制药中，9项依诺肝素研究支持仿制药的生物等效性，尽管3项研究显示药物活性存在微小差异。六项文拉法辛ER的研究中有四项支持仿制药的生物等效性，而两项研究发现与加拿大仿制药缺乏生物等效性。大多数研究要么是非常容易受到偏见（12/26）或无法进行评估的偏见（13/26），部分原因是8项研究的摘要/海报没有完整的reports.ConclusionsPharmaceutical制造商有时会提出有关潜在的通用版本的药物的科学问题;然而，在我们审查的六个案例中，这些公司没有对他们提出的批准前问题进行任何方法学上严格的使用临床终点的批准后测试。尽管在批准前存在争议，但这些仿制药的经验为它们的临床可行性提供了保证。某些仿制药的生物等效性测定需要系统化的批准后研究。
BackgroundGeneric drugs are approved on the basis of pharmaceutical equivalence and bioequivalence. Some drug products have unique structural or functional attributes, necessitating modified approaches to bioequivalence determinations.ObjectiveThe aim of this systematic review was to identify studies that evaluated laboratory or clinical outcomes of six drugs approved via modified bioequivalence approaches.Data SourcesWe conducted a systematic review of articles published through February 2014 in MEDLINE, EMBASE, and International Pharmaceutical Abstracts related to six recent drugs subject to modified regulatory approaches: venlafaxine extended release tablet (Effexor XR), acarbose (Precose), enoxaparin (Lovenox), vancomycin capsules (Vancocin), sodium ferric gluconate (Ferrlecit), and calcitonin salmon nasal spray (Miacalcin NS). We included all empirical evaluations (whether in vivo or in vitro) and excluded case studies, qualitative analyses, and pharmacoeconomic evaluations. Studies were summarized and evaluated on their methodological quality and assessed for bias using the Cochrane Risk of Bias Assessment Tool. Articles were divided into studies of US FDA-approved generics and non-FDA-approved generics available in non-US locations.Data ExtractionWe extracted drug(s) studied, study design, setting, sample size, population characteristics, study endpoints and results, and source of funding.Data SynthesisAfter retrieving 1408 articles and searching through the full text of 106 articles, we found 26 articles that met our inclusion criteria—8 examining FDA-approved versions and 18 examining non-FDA-approved versions. Among FDA-approved generics, five studies of enoxaparin showed minor variations in biologic activities of unclear clinical importance, and no publications involved acarbose, venlafaxine ER, or vancomycin capsules. Among non-FDA-approved generics, nine studies of enoxaparin supported generic bioequivalence, despite three showing minor variations in drug activity. Four of six studies of venlafaxine ER supported generic bioequivalence, while two found a lack of bioequivalence with a Canadian generic version of the drug. Most studies were either highly susceptible to bias (12/26) or were not able to be assessed for bias (13/26), in part because eight studies were abstracts/posters without full reports.ConclusionsPharmaceutical manufacturers sometimes raise scientific concerns related to potential generic versions of their drugs; however, in the six cases we reviewed, these companies did not follow up the pre-approval concerns they raised with any methodologically rigorous post-approval testing using clinical endpoints. Despite their pre-approval controversy, experience with these generic drugs provides reassurance of their clinical interchangeability. Systematized post-approval study of certain generic drug bioequivalence determinations is needed.