首页 > 资讯 > FDA规定以最终批准日期开始NCE专营权计时

出自识林

2014-05-06 Lachman CONSULTANTS

在请愿拒绝书中，FDA确认根据法规要求新化学实体5年专营权自NDA批准之日开始计时，这在预料之中。虽然一直以此作为标准，但这一案例确实至少在Eisai和UBC 2家公司出现难题，这两家公司在几乎相同的请愿中提起诉求。有问题的产品是含有潜在滥用倾向的药物，清楚地具有作为为首次批准的药物实体，具有5年NCE专营权保证的资质。然而，因为它们属于受管制药品，即使企业已经有FDA的批准在手，仍需要缉毒局（Drug Enforcement Administration, DEA）正式为产品做出管制分级后才能真正销售。

企业在请愿书中争辩，这有失公平。在DEA做出管制分级之前，不能合法地将产品推向市场，而DEA的分级几乎总是发生在NDA批准后，这两家公司申辩认为丧失了5年NCE专营权的市场保护价值。FDA反驳说，批准具有法定和监管意义，企业承诺在DEA管制分级之前，不销售它们的产品，但仍欣然接受最终批准并很快向股东宣布这一最终批准。

从监管角度来讲，在其标签上带有相应的管制标志/号码之前，不允许销售管制药品。这只有在DEA为药品分类之后方能完成。FDA指出，修改标签以包含相应的管制标志/号码的批准后补充是必须的，FDA将允许通过变更待批补充申请（Changes Being Effected，CBE）实施这一变更，这意味着企业向FDA提交补充申请后就可以销售其产品。从批准函中这两家企业了解到，需要在上市前提交一份补充申请，另外单独的声明将有利于确认其申请已被完全批准，仅作为已获批申请的补充提交。

企业争辩认为应该有两项批准程序，一项用于申请批准，另一项用于产品分类管制后上市。FDA不同意这样的做法，指出法规中已经明确阐述了最终批准的定义。同时还准确指出，如果企业并不想要批准函，FDA唯一的其它选择只能是发布完全回复函，这在当时并不是企业希望得到的。FDA还确切地指出，FDA无法发布暂时批准（tentative approval， TA）函，因为法规仅针对505(b)(2)NDA或ANDA申请在除专利保护期或市场专营期以外的其它方面可批准时提供TA函，这两项规定在这里均不适用。另外还有针对NDA的“拒绝批准”法规无法将管制分级问题作为不批准一份NDA的理由。

FDA依靠对书面法规以及其中要求的清楚解读，解释了决定NCE专营权起始时间的依据。虽然FDA承认这可能有失公平，但他们指出，国会解释NCE专营权起始时间问题不同于触发首个上市销售的180天排他性问题，NCE专营权在获得NDA最终批准函之日触发。

由于两家公司的很多利益关系，由于他们可能会在法庭上寻求补救措施，因此可能我们并未看到这一问题的完结。

Lachman CONSULTANTS - Bob Pollock先生 2014-03-27
编译：识林-椒 2014-04-30

Agency Rules Final Approval Date Starts NCE Exclusivity, Even if Firm Can't Go To Market
Written by Bob Pollock • May 05, 2014

In a (not unexpected) petition denial (here), the FDA confirmed the statutory requirement that the 5 year New Chemical Entity (NCE) starts on the date of the letter approving the NDA. While this has long been the standard, this case does have a wrinkle that at least two firms, Eisai and UBC, argued in almost identical petition requests. The products in question were substances with abuse potential and also clearly qualified as first time approvals of the drug entity that guaranteed them 5 year NCE. However, because they were controlled substances, there was a need for the Drug Enforcement Administration to formally schedule the product prior to the firms actually being able to market them, even though the firms had final FDA approval in hand.

How can this be fair, the firms argued in the petition. If they could not legally take their products to market until the DEA scheduled the products, and, since that almost always happens post-NDA approval, their claim was that they lost valuable market protection of their 5 year NCE exclusivity. FDA countered that there is a statutory and regulatory definition of approval, and that the firms actually committed to not market their product until DEA scheduled the drug products, but gladly accepted their final approval and made immediate announcements of their final approval to their stock holders.

It is not permissible from a regulatory standpoint to market a controlled substance until such time as its label bears the appropriate schedule symbol/number on its labeling. This cannot be accomplished until DEA actually scheduled the product. FDA pointed out that, while a post approval supplement was necessary to revise the label to include the appropriate schedule symbol/number, FDA would permit the change to be made by a Changes Being Effected (CBE) supplement, meaning the firm could market its product as soon as they submitted the supplement to the FDA. The firms understood from their approval letters that they would need to submit a supplement before marketing and that acknowledgement alone should have be useful in recognizing that their applications were fully approved, as a supplement can only be submitted to an approved application.

The firms argued that there should be two approvals – one for the application and another for the marketing of the product post scheduling. FDA disagreed, and noted that the definition of final approval is clearly articulated in the statute and the regulations. They also correctly pointed out that, if the firm had not wanted the approval letter, FDA’s only other choice would have been to issue a Complete Response Letter, which was (at the time) not something the firms sought. FDA also properly noted that they were not able to issue a tentative approval (TA) letter because the statute and regulations provide for a TA letter only for 505(b)(2) NDAs or ANDAs when the application was otherwise approvable but for a period of patent protection or period of market exclusivity, neither of which applied in these cases. Also the “refuse to approve” regulations for NDA do not provide the scheduling issue as a reason to not approve an NDA.

FDA relied on the plain reading of the statute and regulations as written, as well as the requirements therein, for the start of NCE exclusivity as the basis for their decision. While they recognized that it might not be fair, they pointed out that Congress spoke to the issue of start of NCE exclusivity differently than it did for 180-day exclusivity, which is triggered at first commercial marketing. NCE exclusivity is triggered on the date of the letter giving final approval to the NDA.

With a lot at stake for both firms, it is possible that we have not seen the end of this issue as it is possible that they may seek a remedy in the courts.

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