首页 > 资讯 > FDA发布非达霉素片剂BE指南并回应原研商请愿

出自识林

2016-08-29 Lachman CONSULTANTS

美国FDA于2011年5月批准Cubist制药公司的Dificid（非达霉素）200mg片剂，如万古霉素一样，用于治疗艰难梭菌相关的腹泻。两种药物均全身吸收差，治疗消化道和肠道局部病症。但是，万古霉素在生理学相关的溶出介质范围内比非达霉素更可溶。非达霉素的原研商Cubist于2015年5月7日提交了一份请愿书（FDA-2015-P-1595）,请求FDA要求体外溶出实验、pK实验和临床终点生物等效性（BE）研究。

FDA于在8月23日发布非达霉素片剂BE指南，同时对请愿做出回应。FDA部分准许部分拒绝了原研商的请愿。

FDA的非达霉素BE指南草案概述了对产品仿制版本建立BE的要求。与万古霉素BE指南草案类似，FDA对建立BE提出了各种体外和体内选择。和万古霉素指南草案相似，如果非达霉素的仿制版本在活性和非活性成分方面与参照药品（RLD）定性（Q1）定量（Q2）一致，则不需要临床终点BE研究，企业必须符合体外溶出要求。但除此之外，不同于万古霉素的BE建议，FDA对非达霉素的建议包括体内空腹和进食药代动力学研究，这表明FDA认为全身吸收可能比万古霉素稍高。

如果仿制非达霉素制剂与原研不是Q1和Q2一致的，FDA建议需要开展临床终点BE研究，这同样也与对万古霉素的建议类似。

这是另外一个FDA对不适合通常的体内或体外特征建立生物等效性的产品新的科学考虑的又一个例子。我们已经看到FDA持续对相似产品打破条条框框的考虑，对这些非传统类型产品努力建立仿制药批准路径。

Lachman CONSULTANTS - Bob Pollock先生
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Fidaxomicin BE Recommendations Consistent with FDA's Vancomycin BE Recommendations-Almost!
By Bob Pollock | August 23, 2016 原文地址

Fidaxomicin, like vancomycin, is indicated for treatment of Clostridium difficile-associated diarrhea. Both drugs are poorly absorbed systemically and treat the condition locally in the gut and intestines. Vancomycin, however, appears to be more soluble that fidaxomicin over the range of physiologically-relevant dissolution media. The innovator of fidaxomicin submitted a petition, FDA-2015-P-1595 (here) requesting that the FDA require in vitro testing, pK testing, and a BE study with clinical endpoints.

In a Federal Register notice today (here), the FDA has indicated that it will be responding to the petition, but, as yet, no response has been posted on regulations.gov. The Agency’s draft bioequivalence (BE) Guidance for fidaxomicin (here) outlines the requirements for establishing BE of generic version of the product. Like the vancomycin draft Guidance, there are various in vitro and in vivo options that FDA has set forth for the establishment of BE. Like the vancomycin draft Guidance, if the generic version of fidaxomicin is qualitatively (Q1) and quantitatively (Q2) the same as the reference listed drug (RLD) in terms of active and inactive ingredients, then no BE study with clinical endpoints is required and the firm must meet in vitro dissolution requirements. But in addition, and unlike the vancomycin BE recommendation, the FDA recommendation for fidaxomicin includes in vivo fasting and fed pharmacokinetic studies, which may indicate that FDA believes that systemic absorption may be somewhat greater than that of vancomycin.

If the generic fidaxomycin formulation is not Q1 and Q2 the same as the innovator, FDA recommends that a bioequivalence study with clinical endpoints also be conducted, again this is similar to the vancomycin recommendation.

It will be interesting to read the petition response, which (I assume) will be available and posted soon on regulations.gov. This is another example of FDA’s new scientific look at products that don't fit the usual in vivo or in vitro profile for establishing bioequivalence. We have seen FDA’s continued “outside the box” thinking on similar products in an effort to develop a pathway to generic approval for these non-traditional type products.