2014-02-23 Lachman CONSULTANTS

业界如何做可使其申请质量更高？FDA希望知道！但是，我异议！

我昨日收到了FDA问计如何提高仿制药申请质量的邮件（我相信你们之中许多人也收到了）。FDA已设立了案卷收集公众反馈，同时希望了解将这些建议分享给业界的最佳途径。邮件正文抄录如下： FDA希望听到您的建议！我们已设立公共案卷，收集公众对提高ANDA以及相关修订与补充申请质量的建议。FDA有意了解申请人在研发与准备ANDA提交时所遇到的困难。

FDA同时征求如何将提高ANDA质量的有关建议最好地分享给仿制药行业的办法。

提高ANDA提交的质量将使更多申请被接受立卷，减少修改与易更正缺陷，最终促使更多仿制药获批。

FDA随时欢迎评论，但我们更提倡在2014年3月24日前向http://www.regulations.gov 或“美国食品药品监督管理局案卷管理部，5630 Fishers Lane, Rm. 1061, Rockville”，提交电子版或书面评论。

虽然我对FDA所做的努力表示肯定，但我也不得不为业界说几句话。多年来，对ANDA的要求不断增加，与此同时，FDA一直在探讨对上市后变更、基于风险的ANDA审评以及基于风险的现场检查提供监管纾困的方法。如今我已离开FDA20年，但我猜测这些仍然是我们曾在上世纪八十年代中期，九十年代早期和中期讨论的问题。我当然赞同，质量是保障所有药品安全性与有效性的重中之重，但问题实际上是，什么乐于了解什么，有必要了解什么，（最好加上）什么对药品安全性、有效性与质量的整体保障真正带来影响。

我相信，当这些问题有了清楚的表现时，必将要求那些能提高药品质量的额外信息；但当获益尚未清楚表现时，问题则在于，真正的获益以及它将怎样得以实现。

我可以向你讲述我在这一行业40多年中所看到的其它事情（或许当我就职于仿制药办公室时，我就是未被充分解决的问题的一部分），这就是申请审评的一致性。这是FDA所有级别的审评员共同的问题，从完整性与可接受性审评到化学审评。过去我们提供给企业的建议是——从错误中吸取教训。我们建议他们，将从仿制药办公室收到的缺陷分类，在下一次申请中确保这些问题得以充分解决。企业采纳并实行了我们的建议，但我们多年以来收到的积极反馈却不容乐观。许多接受该建议的多数企业告诉我们，这并不真正奏效，因为他们只是收到来自不同审评员或不同部门另一套不同缺陷。许多企业认为他们是在打移动靶，某种程度上我也认同这一点。

我想现在或许是FDA提出不同问题的时候，我们真正需要什么来保证产品具有它所声称应有的质量并且安全、有效。或许当用一种有意义的方式向业界清晰地阐述该问题时，业界会真正了解什么是所期待的。当大量企业被发现在申请中编造各种类型数据，声称完成了其实并未进行的检测，伪造记录，涂改数据等等，仅需要表明对什么在真正影响质量和反思仿制药丑闻的看法。除此之外，我记起一件从未真正调和的事。FDA收集并于FDA实验室中检验了3500例作弊者的产品样本，并未发现一例具有安全性或有效性问题。现在我还会鼓吹FDA应在发现伪造时寻找其他方法解决问题，或要求仿制药业界面对这一结果时仍遵守那些标准？当然不会！但我确实认为，FDA应该重新评价仿制药审评流程，并了解什么才对一份申请中仿制药产品的有效性与安全性真正至关重要，保证其质量与所依据的橙皮书收录的参照药品（reference listed drug）“相同”。

FDA应该基于风险分析区别对待不同产品，因此对一个与参照药品定性定量完全相同的口服溶液的审评，不应与一个复杂的缓释或迟释产品相同，审评类型、审评深入程度以及批准所要求的数据也不应相同。在经历整套基于风险分析的过程后，难道不应立足于所觉察的风险么？

我明白上文过分简化了这一争论，然而FDA的截止日期——2014年6月20日将很快到来，到时FDA可能向ANDA提交要求三倍数量的生产与稳定性方面的数据； FDA要求“以问题为导向的审评模式”（QbR），并称如果QbR有道理，则将提高审评速度，我们却可能不去看数据背后众多的问题，依旧把不同剂型不同复杂程度的ANDA同等对待； “质量源于设计”（QbD）带来的问题，使得许多ANDA看起来像是一份博士论文，但是仿制药办公室如果还没有可以保持其期望前后一致的清晰指南，又不调整由基于风险的分析带来的那些期望，如何着手处理积压申请并使得申请及时获批，一切仍不清楚。

Lachman CONSULTANTS - Bob Pollock先生 2014-02-14
校译：识林-Kapok 2014-02-21

What Can Industry Do to Make their Applications of Better Quality? FDA Wants to Know! But, I Have a Different Question!
Written by Bob Pollock • February 14, 2014

I received an email yesterday from FDA (as I am sure many of you have) soliciting suggestions on ways to improve the quality of generic applications. FDA has set up a docket to receive your input and also wants to know the best way to share the suggestions with industry. The body of the email is reproduced below:

FDA wants to hear from you! We are establishing a public docket to receive input and suggestions from the public on ways to improve the quality of abbreviated new drug applications (ANDAs) and associated amendments and supplements. Specifically, FDA is interested in hearing about difficulties sponsors are having developing and preparing their ANDA submissions.

FDA is also seeking input on how to best share suggestions for improving the quality of ANDAs with the generic drug industry.

Improving the quality of ANDA submissions will result in more submissions accepted for filing, fewer amendments and easily correctable deficiencies (ECDs), and ultimately, more generic drug approvals.

FDA welcomes comments at any time, but we encourage submission of electronic or written comments tohttp://www.regulations.gov or Division of Dockets Management, Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852 by March 24, 2014.

While I will give the FDA credit for the outreach, I also have to speak up for the industry as well. Over the years the requirements for ANDAs has done nothing but increase and increase, while at the same time FDA has been talking about ways to provide regulatory relief for post approval changes and risk- based review of ANDA and risk-based inspection of facilities. I have been out of FDA for 20 years now and guess what - these were the same things we were talking about in the mid-1980s, the early 1990s and in the mid 1990s. I do agree that quality is of utmost importance to assure safety and effectiveness of all drug products, but the real questions is, what is nice to know and what is essential to know, (or better put) what actually makes a difference to the overall assurance of safety effectiveness and quality of the drug product.

I believe that when there is a clear showing that additional information will increase the quality of a drug product that it should be required, but when there is no clear showing of benefit and the ask is just that, an ask, then what is the real benefit and how will it be realized?

I can tell you something else that I have seen during my 40+ years in this segment of the industry (perhaps I was part of the problem for never being able to adequately address it when I was at OGD), and that is consistency of application review. This is a problem among reviewers at all levels in the Agency, from completeness and acceptability reviews to chemistry reviews. In the past we have provided the following advice to firms - learn from your mistakes. We told them to categorize the deficiencies received from OGD and, in your next submission, make sure you adequately address those issues. Firms took our advice and did just that and the feedback we have gotten over the years has been less than promising. Most of the firms that have adopted that approach have told us it does not really matter because they just get another set of different deficiencies either from a different reviewer or different division. Many in the industry feel like they are trying to hit a moving target and I agree, to a certain extent.

I think it may be time for FDA to ask a different question and that is - what do we really need to assure that a product has the quality it purports to have and is safe and effective? Perhaps if that is clearly articulated in a meaningful way to industry, then maybe industry will really know what is expected. Just to make a point about what really impacts quality and thinking back to the generic drug scandal, when a number of firms were found to have fabricated all types of data in their applications, claimed to have performed tests that were never actually conducted, falsified records, created graphite data, among other things, I remember one thing that I never really was able to reconcile. The FDA collected and tested 3500 samples of products from these cheaters and tested them at FDA labs and not one of the products was found to pose a safety or efficacy problem. Now do I advocate that the FDA should look the other way when fraud is found or that standards should be lessened for generic drugs because of this finding? Absolutely not! But I do think that FDA should reevaluate the generic drug review process to see what is really essential to be in an application for them to make a determination that the generic drug product is safe and effective, has assurance of quality and is the “same as” the reference listed drug (RLD) upon which it is based.

The Agency should treat different products differently based on risk assessment and thus the review of a true oral solution that is qualitatively and quantitatively the same as the RLD should be different than a complex extended or delayed-release product and that should be reflected in the both the type and depth of review and data required for approval. Isn’t after all a risk-based assessment really supposed to be based on the perceived risk?

I know that this oversimplifies the argument, but with the June 20, 2014 deadline coming up soon where the FDA will be asking for three times the amount of data for ANDA submissions from a manufacturing and stability standpoint; with FDA asking for QbR and saying that if the QbR looks reasonable it will likely speed up review and we may not have to look as much behind the scenes into the data but are still treating all ANDAs for different dosage forms and complexity the same; with questions based on QbD making many ANDAs seem like a Ph.D. dissertation, but it is unclear how will OGD ever get a handle on its application backlog and get applications approve in a timely manner without clear guidance as to a consistent set of expectations and without adjusting some of those expectations based on a risk based assessment.