2014-04-07 Lachman CONSULTANTS

当心这两件事让您损失惨重！

为了预测和讨论真正读懂仿制药办公室（OGD）的未来走向和整个行业担忧的问题，我将仔细说明两个需要您优先考虑的问题。一个是在审批过程中，另一个在仿制药（ANDA）申请之后。这是为了避免审批时您未能看到正在来临或是的潜在延迟，或是OGD按照法规条款计算ANDA宝贵的180天专营期方式行事的可能变化。

第一条直接明了。确保贵公司待批的ANDA申请中引用的药物主文件(DMF)持有人意识到，需要就作出的任何变更通知ANDA持有人。最近一些公司措手不及，正是因为DMF持有人没能通知ANDA申请人，在ANDA审核前提出修订。当ANDA一步步通过最终审评时，OGD会检查在上一次的DMF审核之后，申请中引用的DMF修订是否提交过。

众所周知，DMF持有人应将需要向ANDA申请人报告的变更通知ANDA申请人（21 CFR 314.420(c)）。但如果公司不知情，申请人如何决定是否需要修订ANDA申请？因此，存在这样的可能，在最终审评流程结束时，临签署批准函之时， OGD会注意到尚未经过FDA审评的修订，如果已经提交了一个或多个DMF，结果如何？您的批准函会被改写。于是，预期的批准将会落空，公司会收到完全回应函，很明显，将显著延迟获得批准的时间。在没有实行仿制药申请人生产商付费法案（GDUFA）之前，或是OGD可能刚好审查了DMF修订，看看是否对批准ANDA申请有影响，这样的事情不会发生；而现在，按照GDUFA法案的规定，对这种额外审评,将会遭遇罚时，您有可能收到一份询问DMF修正案如何影响您的产品的来函。根据已提交给FDA的不同层级的修订数，一旦您修订ANDA申请，您的GDUFA计时钟会重置。如果修订数超过5个微小改动，那您的GDUFA计时将完全停摆。

买方应该注意—确保您申请中引用的DMF持有人意识到必须通知您DMF出现的任何变更，您作为ANDA持有人，必须决定需要为您的申请提供信息有所动作。

第二个问题涉及OGD如何准确决定180天专营期的开始时间。对于您们之中有新接触ANDA规定者，应该明白180天的专营期只授予提交了一份确实完整的ANDA申请的首个申请人，这份申请中包含对作为ANDA申请提交依据的橙皮书中收录的参照药品的现有专利挑战（通常被称为第IV段挑战）。这保证了180天的窗口期，在这一窗口期之内，随后提交的申请不能获批。诞生了一件价值连城的商品！

在2003年《医疗保险现代化法案》（MMA，Medicare Modernization Act）前，曾有两个启动180天专营期的机制—法院最终判决或首个上市销售。然而，MMA条款中取消了法院判决的机制，相反，规定了某些废除180天的专营期的条款，防止药企将本来该用的专营期存留不用。MMA使得首个上市销售作为启动180天专营期的唯一机制。

因为上市销售触发机制的重要性，“首个”符合180天专营期要求的ANDA申请人，需要通知FDA开始市场销售(21CFR 314.107(c)(4))。那么问题在哪里？OGD指出，一些被授予180天专营期的公司未能向OGD及时通知其产品上市销售，因此，OGD难以决定180天的期限何时终止以继续后续的审评。当FDA可以批准后续申请人的ANDA却不能计算180天专营期时，这一问题变得更遭，原因在于首个申请人未能按要求通知FDA使之获悉其起始销售日期。那么FDA的补救措施是什么？21CFR 314.107(c)(4)中相同的法规条款中有一些有趣的语言要求向FDA提供此类通知，但至今为止，我不认为FDA曾使用过。原文如下：“如果申请人未及时通知FDA相关日期[首次上市销售日期]，审批生效日期将被视为首次上市销售日期。”想象一下，一家公司在批准通过后两个月开始上市销售，而没有通知FDA。FDA依据此规定，认定180天的专营期始自两个月前—那么申请人仅能享有4个月的保护政策，而不是应有的6个月。

至今为止，我还没有发现一个FDA行使此监管条例的实例，但是我明白，由于之前有多家公司未能及时提交通知的争议，他们正考虑这样做。那么这个故事的寓意是什么？当您成为享有180天的专营期的首个申请人时，请务必及时通知FDA首次上市销售时间，因为所有后来的申请人都会首先指出是您没有通知FDA。

Lachman CONSULTANTS - Bob Pollock先生 2014-04-01

校译：识林-Kapok 2014-04-06

Two Watch Outs That May Cost You Dearly!

Written by Bob Pollock • April 01, 2014

In trying to read the tea leaves at the Office of Generic Drugs (OGD) and discussing issues that really worry both OGD and industry, I have come across two issues that you need to stay on top of, one during the approval process and the other just after ANDA approval, to avoid a potential delay in approval that you did not see coming or a potential change in the way OGD does business relative to ANDAs subject to the valuable 180-day exclusivity provisions of the Act.

The first is rather straightforward. Make sure the DMF holders cited in your firm's pending ANDAs are aware of the need to notify the ANDA holder of any changes they make. Some firms have been blindsided lately because DMF holders have failed to notify the ANDA applicant of an amendment made to the DMF prior to ANDA approval. As the ANDA moves through the final review, one thing that OGD checks is whether any amendments have been submitted to the DMFs referenced in their applications since the DMF was last reviewed.

We all know that DMF holders are supposed to notify ANDA applicants of changes that may need to be reported to the ANDA (as stated in 21 CFR 314.420(c)), but if the firm does not know, how can the applicants decide if they need to amend their ANDA? So, potentially, at the end of the final review process, just before putting ink on that approval letter, OGD notes that an amendment that had not yet been reviewed by FDA, had been submitted to one or more DMFs, and guess what – your approval letter gets rewritten, and now, instead of an anticipated approval, the firm receives a complete response letter which obviously will significantly delay obtaining approval. This might not have happened pre-GDUFA and OGD might have just reviewed the DMF amendment to see if it could impact their decision to approve the ANDA, but now, under GDUFA rules, there is a time penalty for this additional review and you are likely to get a letter asking how the DMF amendment impacts your product. Depending on the number of tiered amendments you have already submitted to the ANDA, your GDUFA clock will be reset once you amend the ANDA and, if the number of amendments exceeds the 5th minor, then you are off the GDUFA clock altogether.

Let the buyer beware – make certain the DMF holders cited in your application are aware that they must notify you and any changes made to the DMF, and you as the ANDA holder must determine the actions you need to take to provide notice to your application!

The second issue deals with the OGD's ability to accurately determine the start of 180-day exclusivity. For those of you that may be new to the ANDA rules of the road, the 180-day exclusivity is awarded to the first applicant(s) that submit a substantially complete ANDA that contains a challenge to an existing patent (commonly referred to as a paragraph IV challenge) that is listed in the Orange Book for the reference listed drug upon which the ANDA relies is basis for submission. This permits a 180-day window during which no subsequently filed applicant can obtain approval. A very valuable commodity!

Prior to the Medicare Modernization Act (MMA) in 2003, there were two triggers to start the 180-day exclusivity period – a final court decision or first commercial marketing. However, the provisions of the MMA eliminated the court decision trigger, and instead, provided for certain forfeiture provisions of 180-day exclusivity to keep firms from “parking” their exclusivity. The MMA left the first commercial marketing as the only trigger for 180-day exclusivity.

Because of the importance of the commercial marketing trigger, the “first” ANDA applicant(s) eligible for 180-day exclusivity are required to provide notice to the FDA of the date they begin commercial marketing (21CFR 314.107(c)(4)). So where is the problem? OGD has indicated that some firms that are granted 180-day exclusivity fail to provide timely notification to OGD of their first commercial marketing of the product; thus, OGD cannot determine the expiration of such 180-day period to enable it to approve subsequent applications. The problem is exacerbated when the FDA might be able to approve a subsequent applicant's ANDA, but cannot calculate the 180-day period because they were never informed of its start date due to the failure of the first applicant to provide the required notice. So what is FDA's remedy? Well, that same regulatory citation, 21CFR 314.107(c)(4), that requires such notice to be provided to FDA also has some interesting language that, to date, I don't believe FDA has used. It states: “If an applicant does not promptly notify FDA of such date [the date of first commercial marketing], the effective date of approval shall be deemed to be the date of commencement of first commercial marketing.” Wow – imagine a firm that begins commercial marketing two months after the effective date of approval, fails to notify FDA of the date of first marketing and FDA then applies this provision of the regulations and deems the 180-day to have begun two months earlier - the application holder would then really only have the benefit of 4 months of protections, rather than the full 6months it was due.

To date, I am not aware of an instance where the FDA has invoked this regulatory provision, but I understand they are thinking about it because of previous issues where firms did not provide prompt notice. So what is the moral of this story – Be certain to notify the FDA PROMPTLY of the commencement of first commercial marketing when you are a “first” applicant entitled to 180-day exclusivity because all subsequent applicants will be the first to point out your failure to notify to FDA.