首页 > 资讯 > FDA发布针对两个专注达仿制药的撤市听证会通知

出自识林

2016-10-18 Lachman CONSULTANTS

10月17日，FDA通过两份联邦公报（FR）通告分别宣布两家公司的盐酸哌甲酯缓释片撤市听证会通知（NOOH, Notice of Opportunity for Hearing）【FR通告一；FR通告二】。基于比参照药品（或授权仿制药）显著更高的治疗失败报告，FDA曾表达过对分别由Mallinckrodt和Kremers Urban公司（原先的Kudco公司）生产的强生公司注意力缺陷多动症（ADHD）药品Concerta（专注达®）的这两个已获批仿制产品的治疗等效性（TE, therapeutic equivalence）的担忧。FDA将TE评级从AB变为BX，并要求这两家公司要么自愿将产品撤出市场，要么按照新指南重复生物等效性（BE）研究，新BE指南与FDA之前确定的针对缓释哌甲酯药品的立场有显著差异，大大增加了证明生物等效性的难度。【FDA发布针对多动症治疗药品的生物等效性指南 - 识林资讯 2014/11/11】 两家公司当时都没有选在自愿撤回产品。Kremers Urban公司提交了新的BE研究，但未能满足新BE要求；Mallinckrodt公司没有提交新研究结果，而是在法庭上起诉了FDA。【FDA更改多动症治疗药品的BE要求后续 - 识林资讯 2015/8/19】

所有这些都发生在近两年前，现在FDA正在启动最后的行政措施以永久性的从市场上撤回这两个产品。

识林相关资讯
2015-08-19　FDA更改多动症治疗药品的BE要求后续
2015-06-19　不等效的专注达仿制药召回了吗
2014-12-12　OGD继续收紧缓释产品BE要求
2014-11-15　FDA对专注达两仿制药的治疗等效性担忧
2014-11-11　FDA发布针对多动症治疗药品的生物等效性指南

为做出要求撤回产品申请的NOOH的决定，FDA：

• 继续监测与治疗失败相关的不良反应报告。
• 根据修订后的BE指南的新要求重新分析了原始提交的研究中的数据。
• 开展临床试验模拟，证实了他们的怀疑。
• 审查了一个制造商提交的新的BE研究。
• 对于选择不提交新BE研究的公司的产品开展了自己的BE研究（与新指南一致的单剂量、4种治疗方案、全重复、交叉随机BE研究）。
• FDA认为，根据所有数据，两家公司的产品不与参照产品生物等效，因此应采取行动从市场上撤回这两家公司的产品。

FDA过去曾被批评没有对治疗不等效报告做出及时回应（即安非他酮缓释产品）；然而这需要一个过程（尽管比较拖延）。FDA非常认真的对待治疗不等效报告，因为他们需要在采取任何执法行动之前弄清楚。这也是为什么FDA花费更长的时间批准产品的复杂剂型，以确保产品获得正确地批准，以免损害公众对仿制药的信心。FDA做得漂亮，因为在Hatch-Waxman法案通过后批准了超过两万件ANDA的情况下，只有一小撮针对药品批准后的行动是基于TE关注。

Lachman CONSULTANTS - Bob Pollock先生
编译：识林-椒
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Notice of Opportunity for Hearing Issued for Two Methylphenidate Generics to Concerta By Bob Pollock | October 17, 2016

Yesterday, FDA published two separate Federal Register Notices (here and here) announcing a Notice of Opportunity for Hearing (NOOH) for the withdrawal from marketing of two firms’ methylphenidate extended-release tablets. The Agency had previously expressed concerns regarding the Therapeutic Equivalence (TE) of these two products based on significantly higher reports of therapeutic failure later in the day than the reference listed drug product (and/or authorized generic). The FDA changed the TE code from AB to BX and requested that the firms either voluntarily withdraw their products from the market or repeat new bioequivalence (BE) studies based on new guidance, which the FDA had issued that changes the metrics for establishing BE to conform with new information that became available to the Agency (see here and here). Neither firm chose to voluntarily withdraw its product from the market at that time. One firm submitted a new BE study that also failed the new BE requirements; the other firm did not submit the results of a new study.

That all occurred almost 2 years ago and now the FDA is initiating the beginning of a final administrative action to permanently remove the products from the marketplace.

Leading up to the decision to request an NOOH to withdraw the applications for the products, the FDA:

• Continued to monitor the adverse event reports relating to therapeutic failure later in the day.

Reanalyzed data from the original submitted studies in accordance with the new requirements of the revised BE guidance.

• Performed clinical trial simulations, which confirmed their suspicions.
• Reviewed the new BE study submitted by one of the manufacturers.
• Performed its own BE study (single dose, 4 treatments, fully replicated, crossover randomized BE study consistent with the new guidance) on the product from the firm that chose not to submit a new BE study.
• FDA concluded that, based on all of the data in totality, two firms’ products were not bioequivalent to the reference listed drug product, and thus, takes the action outlined in the FR notice to withdraw both sponsor’s products from the market.

FDA has been criticized in the past for not responding to reports of therapeutic inequivalence in a timely manner (i.e., the bupropion extended-release product); however, there is a process (albeit protracted) to do so. FDA takes reports of therapeutic inequivalence very seriously, as they need to get that right before taking any enforcement action. That is also why FDA takes a longer time to approve complex dosage forms of products to be sure it gets the approval right, so as not to undermine the public’s confidence in generic drugs. FDA does a pretty darn good job, as there have only been a handful of actions against products post-approval based on TE concerns, and that is after the approval of over 20,000 ANDAs since the passage of Hatch-Waxman.