首页 > 资讯 > FDA否定请愿并修订鲁比前列酮BE指南

出自识林

2015-07-22

2015年7月17日，发布修订版的指南草案鲁比前列酮的生物等效性建议，对2010年版本进行了修订。原研药AMITIZA的生产商，Sucampo制药去年递交了公民请愿，17日当天FDA公布了否定回复信Citizen Petition Denial Response from FDA CDER to Sucampo Pharma Americas LLC 。

鲁比前列酮胶囊介绍：

FDA在2006年1月首次批准了AMITIZA胶囊(NDA 021908)，鲁比前列酮（lubiprostone）是一种前列腺素E1衍生物，可选择性激活位于胃肠道管腔侧表皮细胞膜上的2型氯离子通道(CIC-2)，增加肠液的分泌和肠道的运动性。AMITIZA胶囊适用于成人慢性特发性便秘（CIC）、成人慢性非癌痛阿片诱导性便秘（OIC）的治疗。此外，AMITIZA还适用于18岁以上女性便秘型肠易激综合征（IBS-C）的治疗。

到目前为止，美国还没有这个产品的ANDA获批。中国有5家按化3.1申报临床的，其中一家进口注册的在2015年6月获得临床批件。

Sucampo制药递交的公民请愿简介：

2010年8月的鲁比前列酮生物等效性（BE）草案 ，要求口服胶囊的ANDA进行两个BE研究：
（1）24mcg规格的，进行比较药代动力学（PK）研究；
（2）在CIC成人患者身上进行24mcg规格的比较临床终点研究；
FDA也建议，8mcg规格体内的BE实验可以豁免，基于：
（1）24mcg规格的可接受的BE研究；（2）所有规格的制剂组成相似；（3）所有规格的令人满意的体外溶出度检测。

2014年1月，Sucampo递交了公民请愿，认为：只在CIC成人患者进行研究，不能推断在OIC、IBS-C患者的效果，2010年的指南草案不能充分保证ANDA能与AMITIZA的所有适应症有相同的安全性。
Sucampo要求FDA:

• 在OIC患者身上进行临床终点研究；
  
• 在IBS-C患者身上进行临床终点研究；
• 要求在三类适应症人群中，证明ANDA与AMITIZA有相同的安全性；
• 要求2010年指南草案中的CIC临床终点研究使用自主排便（SBM）频率作为终点。

参考：
Citizen Petition Denial Response from FDA CDER to Sucampo Pharma Americas LLC

Bob Pollock对此事的评论：

此次修订的建议实际上使鲁比前列酮仿制药批准途径变得容易了。

FDA在否定回复信中这样表述：

2010年8月的指南草案推荐了一个PK终点的餐后的BE研究，和一个临床终点的BE研究。过去这个指南适用于所有的可能的仿制药制剂，不管他们与参照药品（RLD）多相似。也就是说，FDA没有对非活性成分与RLD定性定量相同的产品（Q1/Q2 产品）给出单独考虑。经过进一步思考，FDA认为Q1/Q2鲁比前列酮产品不需要比较临床终点研究就可以证明生物等效性。FDA建议拟定鲁比前列酮产品应该提交以下BE研究：

对于拟定Q1/Q2产品，使用定量胶囊溶出度试验，和测量血浆M3代谢物的餐后PK研究来评价生物等效性；

对于与RLD Q1和Q2不相同的拟定仿制药，应进行血浆M3代谢物的餐后PK研究，和CIC患者身上进行比较临床终点研究，来评价生物等效性；

对于与RLD Q1和Q2不相同的拟定仿制药，当ANDA申请人能够以别的方式提供合理的证据证明：辅料的不同不会影响生物等效性，可以使用定量胶囊溶出度试验，和测量血浆M3代谢物的餐后PK研究来评价生物等效性；

FDA也在否定回复信中详细解释了这个决定的理由。当Sucampo认为：因为80-125%的范围，仿制药血药浓度会与RLD有25%的差别时，FDA纠正了这个观点，FDA表述：

换句话说，你的表述认为仿制药会与原研AMITIZA有高达25%的血药浓度差别是不正确的。80-125%的生物等效性限度反映了数十年药物特征变异性的科学研究数据，是用来确保有意义的生物等效性结果的，你的请愿没有呈现任何理由来质疑这个限度或者统计学标准。受试药物与参照药品的峰值浓度有25%差别实际上将必定导致不符合生物等效性限度。FDA使用统计学方法来分析生物等效性研究数据，这样是为了把患者用药过程中转换为仿制药的风险最小化。

之前的BE研究结果表明，仿制药事实上与原研会有3.5-4%差别，可能用两批原研药检测也会有这样的结果。

只有与RLD Q1/Q2产品，FDA允许进行一个PK研究，和一个严格的比较溶出度检测。对其他主要作用机制是在胃肠道局部效果的口服给药产品，FDA也是这样的态度。如果产品与RLD Q1和Q2不相同，FDA建议在检测计划中增加：CIC患者身上进行的临床终点的BE研究。

仿制药办公室将继续评价BE研究的要求，基于得到的新信息和科学数据，将经常修订BE指南。

参考：
FDA BE Lubiprostone Draft Oral RLD 021908 201507
Lachman CONSULTANTS Blog url

编译：识林-榕 2015-07-22
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Bob Pollock 's comments:

FDA Denies Petition and Revises Bioequivalence Guidance for Lubiprostone

However, its revised recommendations (here) actually made the path to approval for a duplicate version of the drug potentially easier for generic entrants.

The FDA stated in its petition denial letter (here) that:

The August 2010 Draft Guidance recommended a fed bioequivalence study with PK endpoints and a bioequivalence study with clinical endpoints. This recommendation applied to all potential generic formulations, without regard to how similar they were to the RLD. That is, we did not give separate consideration for products that have qualitatively (Q1) and quantitatively (Q2) the same inactive ingredients as the RLD (Q1/Q2 products). Upon further reflection, however, we have determined that bioequivalence can be demonstrated for Q1/Q2 lubiprostone products without the need for a comparative clinical endpoint study. We now recommend that ANDAs for proposed lubiprostone products should submit the following bioequivalence studies:

For proposed Ql/Q2 generic lubiprostone products, assess bioequivalence using a quantitative capsule rupture (dissolution) test and a fed PK study measuring the M3 metabolite in plasma

For proposed generic lubiprostone products that are not Q1 and Q2 the same relative to the RLD (i.e., non-Q1/Q2 products), assess bioavailability bioequivalence using a fed PK study measuring the M3 metabolite in plasma as well as a comparative clinical endpoint study in subjects with CIC

For proposed generic lubiprostone products that are not Q1 and Q2 the same relative to the RLD (i.e., non-Q1/Q2 products) where the ANDA applicant can otherwise provide satisfactory evidence that any differences in excipients between the proposed generic product and the RLD do not affect bioequivalence, assess bioequivalence using a quantitative capsule rupture (dissolution) test and a fed PK study measuring the M3 metabolite in plasma

FDA also explained its rationale for its decision in detail in the denial letter and also set the record straight when the innovator noted that, because of the 80-125% confidence interval, that concentration of the generic lubiprostone could be 25% different than that of the reference listed drug (RLD). FDA noted that:

In other words, your statement that a generic lubiprostone product could have up to a 25 percent higher plasma concentration than Amitiza is incorrect. The 80 to 125 percent bioequivalence limits reflects decades of scientific data on the variability of product characteristics, and your petition does not present any reasons to question these limits or the statistical standards used to ensure meaningful bioequivalence results. A 25 percent difference in peak concentration between a test and reference bioequivalence parameters will virtually always result in failure to meet bioequivalence limits. The statistical approach used by us to analyze bioequivalence study data is designed to minimize the risk in situations where the patient is switched to a generic version of a medication he or she is currently taking.

Previous studies of BE results show that generics actually differ by only 3.5-4%, a result that would be expected if two lots of the innovator product were tested against themselves.

The FDA is permitting a pK study only if the generic product is Q1 and Q2 is the same as the RLD, along with a rigorous comparative dissolution testing protocol. This is a position that FDA has taken for other orally administered products whose primary mechanism of action is based on its local effect in the GI tract. If however, the products are not Q1 and Q2, then the FDA is recommending that a BE study with clinical endpoints in chronic idiopathic constipation also be included in the testing regimen.

The Office of Generic Drug continues to evaluate its requirements for BE testing and often revises its guidance based on new information and scientific data that becomes available.