首页 > 资讯 > OGD继续收紧缓释产品BE要求

出自识林

2014-12-12 Lachman CONSULTANTS

仿制药办公室（OGD）发布针对专注达Concerta缓释仿制等效产品的生物等效（BE）指南修订版，并采取行动将两种已批准仿制产品的治疗等效代码（Therapeutic Equivalence Evaluations Codes）改为BX（不可替代/治疗不等效），而在此数周后，OGD又发布了一份新的针对布地奈德缓释片的相当繁重的生物等效性指南草案。

指南要求空腹、进食和体外研究来支持仿制等效产品的批准。对于体内药代动力学的研究设计应该是部分或完全的复现设计。此类研究通常应将剂型影响考虑进去。 此外，指南还指出提交者可以使用参考标度平均BE方法，该方法考虑了在建立必须满足的置信区间极限中参照药品所见的可变性。参考标度法背后的理念是仿制药不应使用严于参照药品的标准。该方法仅对高度可变药品适用，且ANDA提交者必须证明参照药品的高可变参数。

同样有趣的是指南草案中的部分AUC要求：

对于空腹和进食研究，推荐的药物动力学参数如下：对数化的AUC8-48, AUC0-t 和Cmax。 其中，AUC8-48指8-48小时内血药浓度vs时间曲线下面积，AUC0-t指0小时到最后可测时间点曲线下面积，Cmax指最大血药浓度。对于部分AUC8-48，至少需有4份非零浓度的测量。

FDA还解释称，“由于推荐使用AUC0-t替代AUC0-∞ ，最后取样时间点应该至少在72小时。”

体外测试看起来也更为严格，OGD要求一份2小时标准酸性阶梯测试肠溶包衣性能和在6个（看清楚，6个！）不同pH值、不同缓冲液下的溶解。此外，该指南草案建议溶出试验“在缓冲阶段不同pH值下用0.5％和不用聚乙二醇鲸蜡硬脂醚进行。此外，申请人还可以在多个pH值介质中使用各种浓度的其它合适类型的表面活性剂（一种或多种），并使用其他适当的装置和旋转速度。”

这是目前所看到的对缓释产品的一些最大量的测试，可能是批准上市后一些缓释仿制产品失败后曝光的结果。Joe Graedon的网站 — 人民药房，在讲述缓释仿制产品时指出：“我们认为，FDA所倚借几十年的用于批准长效仿制配方的规章制度是有缺陷的。它没有考虑小时波动血药水平，而将所有东西都集中到一起叫做AUC（曲线下面积）。这使得FDA批准了一些实际表现远不同于被模仿品牌产品的仿制药。” 尽管我并不总是同意Joe，但在其中一些情况下，确实清楚地显示出FDA从批准后产品的表现中学到更多，而发现问题后也修改了指南并采取了必要的行动。那么系统完善了吗？大概没有。自Hatch-Waxman法案通过后，超过15,000个获批仿制产品中，仅有少数产品有问题。尽管我也认同，假如你作为患者刚巧被这少数几种产品影响到，那么是个大问题。但看起来FDA已经全力以赴地试图确保这些复杂产品也考虑到从类似长效产品了解到的标准。

患者和FDA都经历了其它缓释产品的问题（最著名的安非他酮、美托洛尔、普萘洛尔以及最近的盐酸哌甲酯）。Graedon先生关于其它更老的已上市的缓释产品的担忧比我们或许以为的更加现实……让我们期望不是这样。

一则好消息是，辛辛那提大学神经科学研究所的一项FDA资助研究的初步报告，关于两种已证明生物等效的抗癫痫药物的生物利用度的些微区别是否会在产品替换时对疗效产生负面影响。 该研究没有发现两种药物在疗效、突破发作癫痫或者不良反应概况上有不同。相关研究论文请见此处。

Lachman CONSULTANTS - Bob Pollock先生 2014-12-11
编译：识林-椒 2014-12-12
补充：识林-葳 2015-05-28
识林^TMwww.shilinx.com版权所有，未经许可不得转载。如需使用请联系admin@shilinx.com

OGD Continues Tightening BE Requirements for Extended-Release Products
Written by Bob Pollock • December 11, 2014

Just weeks after the Office of Generic Drugs (OGD ) released a revised bioequivalence (BE) guidance for extended-release generic equivalents of Concerta and took action to revise the therapeutic equivalence code for the two generic approved products to BX (non-substitutable/not therapeutically equivalent), OGD released a new fairly onerous draft BE guidance for Budesonide Extended-Release Tablets (here).

The Guidance calls for a fasting, a fed and an in vitro study to support approval of a generic equivalent. The study designs for the in vivo pharmacokinetic studies should be partial or fully replicate design. Such studies typically take into consideration the subject by formulation effect. In addition, the Guidance suggests that the sponsor may use a referenced-scaled average BE approach, which would take into consideration the variability seen in the reference listed drug (RLD) product in establishing the limits of the confidence interval that must be met. The concept behind the referenced-scaled approach is that the generic should not be held to a stricter standard than the RLD. This approach is useful only for highly variable drug products and the ANDA sponsor must demonstrate the highly variable parameters for the RLD product.

Also interesting is the partial AUC requirements established in the Draft Guidance:

For both fasting and fed studies, the following PK parameters are recommended: Log-transformed AUC8-48, AUC0-t, and Cmax, where AUC8-48 is the area under the plasma concentration vs. time curve from 8 to 48 hours, AUC0-t is the area under the curve from 0 hours to the last measurable time point, and Cmax is the maximum plasma concentration. There should be at least four non-zero measurements of concentrations for the partial AUC8-48.

FDA also explains that ‘[A]s AUC0-t is recommended in place of AUC0-∞, the last sampling time point should be at least at 72 hours."

The in vitro testing appears to be rather rigorous as well, with OGD asking for a standard 2 hour acid stage to test the enteric coating performance, and dissolution at 6 (count them, 6!) different pH values, and in different buffers. In addition, the Draft Guidance recommends that the dissolution testing be conducted “with 0.5% of and without Macrogol Cetostearyl Ether in the buffer stage at different pH values. In addition, the applicant may also use other appropriate type(s) of surfactant in the multi-pH media at various concentrations and use other appropriate apparatus and rotational speed.”

This is some of the most extensive testing we have seen for an extended release product and is likely a result of the some of the failures of extended-release generic products that have come to light after approval and marketing. Joe Graedon’s web site the People’s Pharmacy in speaking about extended-release generic products states: “The rules and regulations that the FDA relied upon for decades to approve long-acting generic formulations was, in our opinion, flawed. It did not take into account hour-to-hour blood levels but lumped everything together into something called the AUC (area under the curve). This allowed the FDA to approve generic drugs that actually performed quite differently from the brand name product they were supposed to be mimicking.” Well, while I don’t always agree with Joe, in some of these cases, it is clear that FDA learned more about the products performance after approval, but did act to revise the guidance and take necessary action when a problem was found. Is the system perfect? – likely not but there are well over 15,000 generic products that have been approved since the passage of Hatch-Waxman and there have only been a handful of product problems. Granted, if you are a patient that was impacted by this handful of products, then it is a big deal, but it looks like the Agency is fully engaged in trying to assure that criteria for these complex products do take into account what they have learned from other similar long-acting products.

Patients and the FDA have both experienced problems with other extended-release products (most notably bupropion, metoprolol, propranolol and most recently methylphenidate). Mr. Graedon’s concern about the other older extended –release products already on the market may be more real than we had perhaps all thought…let's hope not.

One piece of good news is that the preliminary report of an FDA-sponsored study conducted at the University of Cincinnati Neuroscience Institute to determine if slight differences in the bioavailability of two antiepileptic drugs that had been shown to be bioequivalent had a negative impact on therapeutic performance when the products were substituted. The study finds no difference in performance or breakthrough seizures or difference in adverse event profiles. The article regarding the study can be found here.