2014-01-11 Lachman CONSULTANTS

爆炸性消息！12月份简化新药申请ANDA数目激增，GDUFA的目标函可能暴露出仿制药办公室（OGD）的甜甜圈空洞

　　几天前，我写了一篇关于2014财政年前两个月OGD行动的博文（【FDA仿制药办公室2013及2014财年行动 识林资讯 2014-01-05】）。今天，12月份的数据已经公布，令人大吃一惊！主要由于年末临近，12月份成为ANDA申请提交数超多的“臭名昭著”的一个月，创下了惊人的225项ANDA申请的记录。这一数字略微超过了2013财政年所有提交ANDA申请数的23%，打破了2011年12月创下的210项单月提交申请数记录（2011年12月比较特殊，因为时值正电子断层扫描（Position Electron Tomography, PET）产品ANDA的截止月份，在所有210项申请中，约60项是PET产品）。同样是在12月份，OGD批准了30项ANDA，此外，12项ANDA获得了暂时性批准。因此，OGD努力从其工作簿中清除了42项ANDA，却接收了125项ANDA，也就是说，进入到OGD的“积压目录”中的ANDA，反而又多出了183项。
　　到目前为止，2014财年第一季度，OGD批准或暂时批准116项ANDA，但一共收到324项ANDA。如果在整个2014财年期间，每月申请提交和获批速率保持不变，意味着OGD将收到约1300项ANDA，批准/暂时性批准约464项，或者说积压ANDA申请会增加850项。大家意识到这一持续的发展趋势了吗？
　　这导致我们走向OGD的“甜甜圈空洞”，某种程度上类似于美国医疗保险的甜甜圈空洞。越来越明显地看出，在2010年年初至年中关于GDUFA收费和目标的谈判中，一些假设条件被低估了。然而，对于产业界而言，问题在于，如果认真阅读GDUFA的目标部分，找不到ANDA审批决定的目标。我知道，由于申请质量不一，FDA的要求也处在动态的变化之中，再者，对于某些复杂产品，可能存在其独特的挑战，很难（如果不是不可能）为审批设定目标。但事实却是，所有的申请目标都涉及到完全回应函（complete response letters，CRLs）的发布。因此，OGD仍然可以通过及时发布CRLs来达到其规定的或协商的目标。在之前的博文里，我已经指出，真正摆脱申请积压的唯一方法（不是 2012财年之前GDUFA收费积压的申请，而是FDA即将面临的ANDA。或者那些已经收到完全回应函,一旦申请人提交完全回应就将进入OGD议程的申请），是减少ANDA进入最终批准阶段所必须通过的轮次。 需要强调的问题是（可能在GDUFA Ⅱ中），是否前文提到的“GDUFA 目标”有增加审评轮次的趋势，以使得OGD可以实现目前商定的目标。 我当然不希望如此，而且我确信OGD管理层也不希望如此。然而，如果ANDA和补充申请数在最初的申请基数上持续增长，积压的（OGD面临的所有）ANDA和补充申请在一个又一个CRL中循环通过审评流程，难道这就是企业认为其缴纳仿制药生产商付费所应得的吗？我很乐意用“OGD甜甜圈空洞”这一术语来形容这一问题。你可以旁敲侧击，但是空洞依然存在，申请的情况也如此。我们没看到OGD中位审评时间的数据。也没有看到任何积压的ANDA或补充申请的数据。我们上一次看到这些数据时（2013年8月），当时积压的ANDA为2780项，另外560项等待申请者行动，而OGD面临的补充申请数为5601项。
　　基于产业界的学习曲线（仿制药行业确实需要），PDUFA首次实施时，新药审评部门（the New Drug Review Divisions）致力于减少积压，同时在FDA和行业间保持密切合作。这些年来新药团队与申请人之间的早期沟通已经将NDA的首轮批准推到了前所未有的最高水平。当然，面对令人窒息的积压以及一年约1000多项的原始ANDA申请提交，对于OGD而言是一项更具挑战性的主题。但是，借助于PDUFA的成功经验，应用一些早期沟通技巧，与ANDA申请者保持更密切的联系，是大幅提高OGD首轮批准、最终减少积压的一种方法。请记住，Hatch-Waxman法案的目的之一，是使高质量的仿制药产品进入市场，到达消费者手中，减少相关的医疗开支。当然，这也意味着，更快地获得仿制药。
　　我们业内人士需要密切关注这一问题，OGD自称完成了其GDUFA目标时，不为错误的安全感所麻痹，因为行业的最终目的，是缩短审批时间，使高质量产品能够进入市场。
Lachman CONSULTANTS - Bob Pollock先生 2014-01-08
校译：识林-Kapok 2014-01-11

KA-BOOM!! ANDA Submissions Explode in December – The GDUFA Goal Letter May Expose the OGD Donut Hole
Written by Bob Pollock • January 08, 2014

Well, just a few days ago I posted a blog on OGD activity for the first two months of FY 2014. Today, the December numbers came out and holy cow! While December is notoriously a month of heavy submissions due primarily to the end of year rush, this December beat all records at an astonishing 225 ANDAs. That represents a little over 23% of all of the ANDAs that were submitted in FY 2013 and beats the previous single-month record of 210 in December 2011 (and that month was unusual because it represented the deadline for the submission of ANDAs for Positron Electron Tomography [PET] products. Of that 210 total, about 60 were for PET products). Also during the month of December, OGD approved 30 ANDAs and tentatively approved 12 others. So OGD managed to clear 42 ANDAs off its books for good, but received 225 ANDA or a monthly surplus(if you will) of 183 applications that are added to the “backlog” of applications pending before OGD.

So far in the first quarter of FY 2014, OGD approved or tentatively approved a total of 116 applications, but received a total of 324 ANDAs. If the rate of monthly submissions and approvals remains the same over FY 2014, that would mean OGD would receive about 1300 ANDAs and approve/tentatively approve about 464 or a surplus of about 850 ANDAs. Are you seeing a continuing trend developing?

That leads us to the OGD “donut hole”, which might be somewhat analogous to the Medicare donut hole. It is becoming obvious that some of the assumptions used in the negotiations of the GDUFA fees and goals back in early to mid-2010 might have been understated. However, the problem for industry is that, if you read the GDUFA Goal Letter carefully, nowhere is there a goal for approval actions. I know, it is difficult (if not impossible) to set a goal for approval because of the differences in application quality and the dynamic nature of FDA requirements, as well as some unique challenges that certain complex products may pose. However, the fact is that application goals all relate to the issuance of complete response letters (CRLs). Thus, OGD can continue to meet all of its stated and negotiated goals by the issuance of on time CRLs. In previous posts, I have noted that the only way to really get rid of the backlog (not the GDUFA backlog of pre-FY2012 applications, but rather all of the ANDAs that are pending before the FDA or those that have already received CRLs and will come back into OGD’s court when the sponsor submits their complete response) is to reduce the number of cycles that an ANDA must go through to final approval. The question that may need to be addressed(perhaps in GDUFA II) is whether the “GDUFA Goals” as stated may have a tendency to increase the number of review cycles so OGD can meet its currently agreed upon goals. I certainly hope not and I am sure that OGD management also hopes not as well. However, if the number of ANDAs and supplements continues to grow from the original submission pool and the applications and supplements in the backlog (all work before OGD) continues to cycle through the review process with CRL after CRL, is that really what the industry really thought they were buying with generic drug user fees? This issue is what I lovingly term the OGD donut hole. You can nibble around the edges, but the hole still remains- as do the applications. We have not seen any figures from OGD on the median approval times. Nor have we seen any backlog figures for ANDAs or supplemental applications. When we last saw those numbers (August 2013), the backlog of ANDAs was 2780 with another 560 awaiting applicant action and the number of supplements pending OGD was 5601.

The efforts of the New Drug Review Divisions work in getting the backlog down when PDUFA was first implemented relied on an industry learning curve (really needed by the generic industry), but also on close cooperation between FDA and industry. Early communications between the New Drugs groups and sponsors that has over the years boosted first cycle approvals for NDAs to their highest levels. Certainly, this is a much more challenging proposition for OGD when dealing, as it is, with an overwhelming backlog and original ANDA submission of about 1000+ a year. But maybe taking a play from the PDUFA playbook and applying some of the early communication techniques and employing closer contact with ANDA sponsors is a way to significantly boost first-cycle approvals in OGD that will ultimately relieve the “backlog”. Remember, one of the purposes of Hatch-Waxman was to get high quality generic product to market and into the hand of consumers to lower associated healthcare costs. This implies, of course, faster access to generic drugs.

We in industry need to watch this issue closely and not be lulled into a false sense of security when OGD says it met all of its GDUFA Goals, because the ultimate goal for industry is reducing approval time and getting their quality products to market.