首页 > 资讯 > FDA发布38份新BE指南和6份修订指南

出自识林

2016-04-16 Lachman CONSULTANTS

FDA仿制药办公室正以不断的努力保持满足行业获取关于建立仿制药产品生物等效性指南的愿望。4月14日，FDA发布38个药品的新BE指南，6份修订指南（见BE指南更新）。在新发布指南文件中有一些建议，修订指南中有一些有趣的问题，如下所述。

格拉默 Glatiramer

在花费超过7年批准一例盐酸格拉替雷注射剂（Copaxone的仿制药）之后，OGD又花了一年的时间阐明建立生物等效性的批准标准。如最近其它一些复杂产品BE指南文件一样，格拉默文件概述了用于建立活性成分一致性的要求和仿制药产品与参照产品（RLD）定量和定性相同的要求。如果一致性可以通过以下方面证明，文件将允许豁免BE：

1. 基本反应方案等效；
2. 理化性质包括成分等效；
3. 聚合解聚结构特征等效；
4. 生物测定结果等效。

指南文件接着概述了FDA对每个等效性研究的期望。

含铁羧基麦芽糖 Ferric Carboxymaltose

OGD对Injectafer的仿制药版本推荐空腹、单剂量、随机、平行体内研究，以及粒度分布研究。体内研究应采用贫血患者，而不是健康志愿者。在对比性粒度分布研究和在指南中概述的测量其它理化参数时至少应包括三个批次的测试和参照产品。

吉非替尼Gefitinib

FDA对Iressa的仿制药要求标准空腹和进食单剂量交叉研究，然而，由于吉非替尼的致畸性风险，试验中应当仅包括健康男性受试者。

马来酸茚达特罗Indacaterol Maleate

OGD对Arcapta Neohaler（一种干粉吸入器）的仿制药的建议似乎非常繁杂，表明了吸入产品的复杂性。请注意，OGD到现在为止尚未批准干粉吸入器的仿制版本。指南建议各种体内体外研究，以及体内空腹单剂量交叉研究和对比性临床终点研究。祝好运！

曲安奈德Triamcinolone

FDA花费了32年的时间正式概述了这款老的1962年之前的药品的乳膏和软膏剂型的BE要求。虽然要求差不多是人所共知，但FDA现在确立了官方立场。不需要体内研究，但企业需要证明“测试和参照药品（RLD）产品剂型的可接受的对比性理化特性，以建立测试产品是类似的曲安奈德局部用药……在规格方面与RLD相同。”

• 软膏
• 乳膏 RLD 087357
• 乳膏 RLD 089595

环孢菌素（Cyclosporine）胶囊指南的修订版

环抱菌素速释和缓释指南均进行了修订，对空腹和进食研究要求4周期全重复设计试验。FDA援引事实将该产品归为窄治疗指数（NTI）产品，FDA表示：
研究应该是全重复交叉设计，以便：

• 根据参照药品的变异度来标度生物等效性限度
• 对比测试和参照产品的个体内变异度

编译：识林-椒
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Bioequivalence Study Recommendations Published for 35 Products By Bob Pollock | April 14, 2016

In an ever-increasing effort, the Office of Generic Drugs (OGD) is keeping on top of this aspect of industry’s desire to obtain guidance on establishing bioequivalence for generic drug products. Today FDA published new bioequivalence (BE) guidance for 35 drug products and revised guidance for 8 previously issued recommendations. The entire listing of the newly issued and revised guidance document can be seen here. There were some recommendations of note in the group of 35 and some interesting issues seen in the BE guidance revisions, as described below.

Glatiramer

After taking 7+ years to approve a generic glatiramer acetate injection (the generic for Copaxone), it took yet another year for OGD to articulate the approval criteria for establishing bioequivalence. As with some other recent complex product BE guidance documents, the glatiramer document outlines the requirement for establishing sameness of active ingredient and requiring the generic product to be quantitatively and qualitatively the same as the reference listed drug (RLD). The document will permit a waiver of BE if sameness can be demonstrated by:

1. Equivalence of fundamental reaction scheme;
2. Equivalence of physicochemical properties including compositions;
3. Equivalence of structural signatures for polymerization and depolymerization; and
4. Equivalence of biological assay results.

The guidance document goes on to outlie what FDA expectations are for each of the equivalence tests.

Ferric Carboxymaltose

OGD is recommending a fasting, single-dose, randomized, parallel in vivo study, as well as particle size distribution study for a generic version of Injectafer. The in vivo study should employ patients with anemia, not healthy volunteers. At least three lots of test and reference product should be included in the comparative particle size distribution study, as well as in measuring other physicochemical parameters outlines in the guidance.

Gefitinib

FDA requests standard fasting and fed single-dose crossover studies for the generic of Iressa, however, due to the risk of teratogenicity of gefitinib, only healthy male subjects should be included in the testing.

Indacaterol Maleate

The OGD recommendation for the generic of Arcapta Neohaler (a dry-powder inhaler) appears very onerous and is indicative of the complexity of inhaled products. Remember OGD has not approved a generic version of a dry powder inhaler to date. The guidance recommends various in vitro and in vivo studies, as well as an in vivo fasting, single-does crossover study and a comparative clinical endpoint study. Good luck on this one!

Triamcinolone

It took almost 32 years for FDA to officially outline the BE requirements for the cream and ointment dosage forms of this old pre-1962 drug product. While the requirements are fairly well known, FDA now has taken an official positon. No in vivo studies, but firms are required to demonstrate “[a]cceptable comparative physicochemical characterization of the test and reference listed drug (RLD) formulations of the product to establish that the test product is a comparable triamcinolone acetonide topical… identical in strength to the RLD.”

Revision of the Cyclosporine Capsule Guidance

The guidance for both the IR and cyclosporine modified guidance were revised to require a fully replicate 4 period design study for both a fasting and a fed study. Citing the fact FDA has classified this product as narrow therapeutic index (NTI), the Agency says:

The study should be a fully replicated crossover design in order to:

• Scale BE limits to the variability of the reference product; and
• Compare test and reference products’ within-subject variability

Good work, OGD, and for those of us out in industry, we still must guess what revisions to BE guidance documents mean to any approved or pending ANDA.