Para IV 清单中的一些有趣现象
出自识林
Para IV 清单中的一些有趣现象
笔记 2014-08-23 Lachman CONSULTANTS FDA的第IV段（PIV）数据库的目的是为申请人和潜在申请人提供首个提交机会的信息。FDA这样做有两个原因：1）如果来自FDA的正式接收申请信上的确认日期（申请接受日期）与PIV数据库中提交日期相符，从而使申请人确保他们的产品是首个提交。这减少了很多打给仿制药办公室（OGD）了解他们提交的申请是否具有占据首个提交席位可能性的电话；2）清单还告知潜在申请者至少一个ANDA已经提交了PIV认证，同时允许其他人决定是否希望半路杀出并将自己暴露在潜在的诉讼中。 FDA终于决定于2004年3月2日公布这一清单。虽然已经解除了一些FDA来自于申请人的相关问询的压力，还是有一些有趣的内容。 在这份名单中，我想指出4个项目。前两个从它们提交到现在已经有一年多的时间。正如在过去的文章中解释的有许多原因，如延迟，但是当你第一次看到复杂剂型产品（这里是舌下含片和透皮系统），对所提交的ANDA中生物等效性信息是否声称能证明生物等效性的评价常常会导致可能的延迟。这并不意味着数据有问题，更多的时候是OGD尚未确定就BE研究而言他们在寻找什么。有时必须评估复杂的CMC问题或非活性成分问题，较少的情况下，需要请教OGD之外的人员。但是，尽管有这些问题，12和14个月对于解决问题来说似乎有些漫长。也有可能是OGD没有发布接收信息，但这只有到申请实际批准时才能得知。 吸引我注意的另两个项目是2014年2月26日对醋酸格拉替雷（Glatiramer Acetate）40mg/mL的接收，其原研产品于2014年1月28日批准，以及2014年2月26日提交的酒石酸二氢可待因（Hydrocodone Bitartrate），其原研于2013年10月25日批准。让人感兴趣的是在NDA批准和ANDA提交之间的短暂的时间线。很显然，仿制药公司试图首个提交以尽早争取到潜在的180天专营期的保护，这份渴望需要公司在在NDA批准之前准备好，一旦原研产品被批准就检测他们自己的产品。 几年前，一个原研药企业在担心其它产品对专利的挑战之前有大量的时间；现在，（一些情况下）原始NDA批准后仅几周或几个月的时间就迎来了专利挑战 随着仿制药企业愈加灵活，OGD在40、36或30个月内（根据提交时间）批准或暂时批准这些产品以防止专营期丧失的压力越来越大，尤其是对于一些独特或复杂的产品。
Lachman CONSULTANTS - Bob Pollock先生 2014-08-21 New Paragraph IV Listings – Some Interesting Observations The FDA's paragraph IV (PIV) database is designed to give applicants and potential applicants information relative to first-to-file opportunities. FDA does this for two reasons: 1) it gives applicants assurance that their product is a first-to-file if the acknowledgement date (date acceptable for filing) on their letter from FDA officially receiving their application matches the date of submission in the PIV database. This has eliminated the many calls to the Office of Generic Drugs (OGD) to find out if their submitted application holds a potential first-to-file seat; 2) the listing also informs potential applicants that at least one ANDA has been submitted with a PIV certification and allows others to decide if they wish to enter the fray and expose themselves to litigation. FDA finally decided to begin publishing this listing on March 2, 2004. While it has relieved some of the pressure on FDA relative to inquiries from sponsors, it also generates some interesting reading. In this list (accessed today here), there are four items I would like to point out. The first two are that there has been more than one year since submission of the first two listings. As explained in previous posts, there are a number of reasons for such delays, but when you see first time products for complex dosage forms (in this case, sublingual tablets and a transdermal system), oftentimes the evaluation of whether the bioequivalence information submitted in the ANDA can purport to demonstrate bioequivalence is always a possible cause of delay. That does not mean that there is a problem with the data but more often OGD has not yet determined exactly what they are looking for as far as BE studies go. Sometimes there are complex CMC issues or inactive ingredient issues that must be evaluated and, rarely, sometimes there may be a consult needed outside of OGD. But, despite these issues, 12 and 14 months seems a bit long for resolution. It could also be that OGD missed posting the receipt, but that cannot be known until the application is actually approved. The two other items that caught my eye were the receipt of the Glatiramer Acetate 40mg/mL on February 26, 2014 for a product that was first approved for the innovator on January 28, 2014, and the Hydrocodone Bitartrate submission date of Feb 26, 2014 for an innovator product first approved on October 25, 2013. What is of interest is the short timelines between NDA approval and ANDA submission. It is clear that generic companies are attempting to be first-to- file as early as possible to secure a potential 180-day exclusivity period and this desire has firms working well before NDA approval to be ready to test their products as soon as an innovator is approved. Years ago, an innovator had plenty of time before they had to worry about a challenge to a product with a patent; now, the patent challenge comes (in some cases) only weeks or months after the original NDA is approved. With the generic industry being as nimble as they appear to be, the pressure on OGD to meet approval or tentative approval for these product in the 40, 36 or 30 month period (depending on when they are submitted) to prevent forfeiture of the exclusivity period becomes even greater especially for unique or complex products.
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