首页 > 资讯 > 仿制药办公室“Paragraph IV数据库”中两项有趣的内容

出自识林

2014-03-19 Lachman CONSULTANTS

仿制药办公室“Paragraph IV数据库”中两项有趣的内容

仿制药办公室昨日更新了“Paragraph IV数据库”（PIVDB），两项新增内容值得注意。向尚不熟悉PIVDB数据库的读者简单介绍一下，开发这一数据库旨在为预期的ANDA申请人提供专利保护品种的第一份ANDA何时提交给仿制药办公室的信息。出于两个目的：1）向预期的ANDA申请人提供其他人已就特定产品提交ANDA情况的说明，劝阻旨在通过挑战专利成为抢先申请者的后续申请者；2）给出首个申请者的提交日期，并因此给出以及最先立卷申请的提交日期，企业可了解自己是否有资格获得180天专营期。FDA不提供申请者姓名，仅提供申请日期，并因此了解到在该日期是否有一个或多个申请被提交。

不管如何，现在回到有趣的清单上。所列的一项苯丁酸甘油口服液的ANDA（Hyperion Therapeutics 公司的一项NDA，Ravicti的仿制品）在2013年11月19日提交，在2014年3月10日，也就是首次申请约4个月之后公布。在这一案例中，ANDA在仿制药办公室停留的时间并无异常，但是，尤其是在原NDA获批的仅仅九个月之后，至少已有一家仿制药公司决定提交ANDA并争取首次立卷，有关此产品专营权与专利问题值得关注。

Ravicti是Buphenyl散剂与片剂的活性成分苯丁酸钠的一种新盐/酯。作为一种新盐或酯，按照Hatch-Waxman法案此变更将享有三年的专营期。此外，由于服务于罕见病群体并作为一种新（化学）实体，它享有长达七年的罕见病用药专营期（Orphan Drug Exclusivity，ODE），直至2020年2月1日才将到期。Ravicti仅有一种用法，因此看来在罕见病用药专营期到期前，将不会有ANDA获批。同样有多项专利覆盖该NDA产品。一项药物专利将于2015年2月7日到期，该专利也声称对一种用途具有专有权；然而，两项分别于2030年9月以及2032年3月过期的专利也收录了看起来在失效之前都会阻止仿制药进入的一项用途。如果存在小八条排除可能（排除专利或专营期所保护的用途或信息，如果有其它已获批不受保护的用途），那么有关产品获批用途标签信息以及使用说明还不够明确方面尚有机可乘。这一方面，要么ANDA申请者另有锦囊妙计，要么只是顾虑ANDA获批的中位时间；即便有关专利看起来无效，ANDA能够获批的最早时间,从现在算起，也要等到6年以后了。

另一让我感到血脉喷张的事情则与Namenda XR胶囊的仿制品、盐酸美金刚胺缓释胶囊有关。从提交申请到接受ANDA约花费十个月的时间。通常对完整性与可接受性的审评不需要如此长的时间，很明显仿制药办公室可能在接收并评价ANDA时遇到了困难（可能是生物等效性问题？），或者受到了积压的影响。

仿制药办公室向这一名录中频繁补充新信息，很多时候令人应接不暇。如果自己以及公司对有关内容有兴趣，各位应多加留意。

Lachman CONSULTANTS - Bob Pollock先生 2014-03-11
校译：识林-Kapok 2014-03-18

OGD's Paragraph IV Database and Two Interesting Listings
Written by Bob Pollock • March 11, 2014

The Office of Generic Drugs (OGD) updated its Paragraph IV Database (PIVDB) yesterday and two new entries caught my eye. For those of you not familiar with the PIVDB, it was developed to give prospective ANDA applicants information on when the first ANDA for a patent-protected product was submitted to OGD. This had two purposes: 1) It gave prospective ANDA applicants an indication that someone else had already submitted an ANDA for a particular product which may dissuade subsequent applicants from seeking to file an ANDA to challenge a patent if their sole goal was to be first to file.; 2) It gave the date of submission of the first applicant, and thus, the date of the first to file application(s), and firms would know from that date if they were eligible for award of 180-day exclusivity. The FDA does not provide the name of the applicant, only the date of submission, and thus, there could be either single or multiple applications submitted on that day.

Anyway, now back to the interesting listings. An ANDA for glycerol phenylbutyrate oral solution (a copy of the NDA for Ravicti held by Hyperion Therapeutics) was listed as submitted on November 19, 2013 and posted on 3/10/14 or about 4 months after the original submission. In this case, it is not the length of time the ANDA has been at OGD, but rather the exclusivity and patent issues associated with the product and the jump on first-to-file status that at least one generic firm has decided to seek, especially since the original NDA was approved on February 1, 2013, only 9 months prior to ANDA submission.

Ravicti is a new salt/ester of sodium phenylbuterate, the active ingredient in Buphenyl powder and tablets. Because it was a new salt or ester, it was awarded a period of 3-year Hatch-Waxman exclusivity for this change. In addition, because it serves an orphan population and it is a new entity, it was also awarded 7-year Orphan Drug Exclusivity (ODE) that expires February 1, 2020. Ravicti appears to have a single indication, and thus, it would seem that no ANDA can be approved until that ODE expires. There are also patents that cover the NDA product. A drug substance patent expires on February 7, 2015 and that patent also claims a use; however, there are two additional patents expiring in September 2030 and March 2032 that also include a use that would appear to block generic entry unless invalidated. If there is a little viii carve out potential (excluding a patent or exclusivity protected indication or information if there are other non-protected indications already approved) , it is not obvious from the use codes and the labeling related to the approved use of the product. In that regard, the ANDA applicant must either have something up its sleeve or is just worried about the median time to approval of an ANDA, since it would seem that the earliest that an ANDA could be approved, even if the patents are invalidated, with be about 6 years from now.

The second listing that got my blood flowing was for Memantine Hydrochloride extended-release capsules, a generic form of Namenda XR Capsules. There was an approximate 10-month period from submission to acceptance of the ANDA. While that is not the longest review time for completeness and acceptability we have seen, it certainly indicates that either OGD had a difficult time evaluating the ANDA for receipt (maybe bioequivalence issues?) or their backlog could be a factor.

OGD publishes new additions to the list frequently, and often times, there are more there than meets the eye. You may want to zero in on one of the updates if this sort of thing interests you and your firm.