首页 > 资讯 > 进入美国市场的制药企业最抓狂的问题是什么？

出自识林

2016-10-23 Lachman CONSULTANTS

什么问题最能使在美国市场的制药企业抓狂？Lachman咨询公司的Bob Pollock先生就这一问题询问了其客户，下面是他统计出的最常出现的三个问题：1）在检查或重新检查后的合规状态解决问题；2）从FDA获得直接答复；3）关于非活性成分数据库（IID）的最大日暴露量问题如何处理。

合规状态解决

我们听到的大多数合规问题是在企业检查或重新检查之后检查员告诉企业没有问题或不会发布483。根据一些客户的说法，批准可能会因为合规状态的滞后而延迟。我们假设（但不确定）检查结果（即使检查结果与设施检查报告[EIR]一同转发给CDER总部）必须由总部工作人员审查并同意。我可以告诉大家的是，一旦你处在这个位置，除了等待没有什么可以撼动你最终评估结果。我们经常听到这样的问题反馈。我经常接到电话询问能做些什么让事情有所进展 — 在我们的经验来看，唯一可以做的事情就是等待！

虽然CDER控制EIR后的决策过程，但肯定有大量的必须审查的评估积压。然而，似乎唯一拖延ANDA批准的就是最终检查结果，应该有办法加速完成这项具体的审查。20世纪80年代和90年代早期，当有因最终检查决定延误的批准积压时，合规办公室会按每周一次的标准讨论合规审查优先级，这种方式在许多情况下证明是有效的。我们不确定现在的流程是什么，但至少根据我们从客户处得到的回应，这确实是一个令人非常关注的问题。不仅与批准延迟相关，而且是可以与谁讨论，查看是什么导致了延迟的问题。唯一可以确定的是，在更新计算机任务以反映所讨论的设施的当前合规状态之前，不会有任何对ANDA的最终批准行动。

从FDA获得直接答复

显然这并不总是一个问题；然而，我们从企业听到过并且我们亲历了以下情形。申办人发邮件到ASKGDUFA询问一个程序问题。申办人收到回复告诉他们这是一个仿制药办公室（OGD）的问题，因此申办人发送相同的邮件到OGD答疑邮箱，OGD告诉申办人这一问题应由ASKGDUFA回复。还有一些情况下，走了完整的一圈，三封邮件告诉申办人他们需要询问不同的机构，这一圈终止于将问题转送到应该回答问题的原始邮件的收件人。

第二种情形是，申办人对具体指南或程序存在困惑。问题是有潜在的不同解释，申办人寻求澄清并询问哪种解释是正确的，并对不清楚的问题寻求解释。在许多情况下，FDA办公室的回复只是引用指南的具体章节而没有进一步的澄清。企业能够阅读指南文件，但是具体情况或问题并不总是显而易见的。这就是企业为什么会询问。如果没有做出额外的解释澄清问题，只是反向引用到指南通常是没有帮助的。

还有其它情形与这一问题相关，我们不再一一列数。当然，只要你有时间等待，FDA会对许多提出的问题作出充分的答复。

与IID数据库的最大日暴露量（MDE）有关的问题

在完全修订IID以包括FDA在各种剂型中的各种成分的特定非活性成分的MDE列表之前，药品申办人的制剂部门将继续为此焦虑。我不知道解决这一问题的方法，但是确实是个我们几乎每周都会听到的大问题。如果列出量并未作为MDE列出，IID中的信息仅在你的产品的MDE比IID中列出的量少或相等时有用。为什么？因为你不能从IID得知产品是什么，或是如何给药的（即一天一次、两次或更多次），因为许多值仅反映了一种成分在单一剂量单位中的量。在这方面更像“你自己的选择，风险自付”。如果你错了，你会收到一封拒绝接收（RTR）函。我们一直告诉客户，IID目前在这一点上用处有限，并解释申办人可以承担的其它检查类型以减少接收RTR的机会。

以上这些是Pollock先生收集到的最高频率的主要问题。如果你认为有其它应该注意的常见问题，请发送英文邮件至r.pollock@lachmanconsultants.com。Pollock先生将收集这些问题并在将来的资讯中刊登出来供大家参考。识林^®也会继续对这一话题保持关注。

Lachman CONSULTANTS - Bob Pollock先生
编译：识林-椒
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What is Driving Industry Crazy Lately?
By Bob Pollock | October 19, 2016 原文地址

We asked around about what issues were driving firms crazy and these same three issues surfaced most often: 1) getting resolution of compliance status after inspection or re-inspection; 2) getting a straight answer from the Agency; and 3) what to do about maximum daily exposure issues relative to the Inactive Ingredient Database (IID).

Taking each issue in order:

Resolution of Compliance Status

Most of the compliance issues we hear about are after a firm’s inspection or re-inspection where the investigator tells the firm that there are no issues or where there is no 483 issued. According to some of our clients, approvals may be delayed because of this lag time. We assume (but are not sure) that the results (even after forwarded to CDER headquarters with the Establishment Inspection Report [EIR]) must be reviewed and concurred with by HQ staff. I can tell you that, once you are in that position, there is nothing you can seem to do to shake the final evaluation loose except wait. We have heard this time and time again. I often get calls asking what can we do to get things moving – in our experience the only thing you can do is wait!

While CDER does control the decision process post EIR, there must be a significant backlog of evaluations that must be reviewed. It does seem, however, that if the only thing holding up an ANDA approval is the final inspectional clearance, there should be a way to expedite the finalization of that specific review. Compliance review priorities were discussed with the Office of Compliance on a weekly basis when there was a backlog of approvals held up by final inspectional decisions back in the 1980 and early 90s and that proved effective in many cases. We are not certain what the process is now, but at least, according to responses we get from clients, this is an area of great concern. And it is not only associated with the approval delay, but the issue of who one can talk to, to see what is causing the delay. The only thing for certain is that, until the computer designation is updated reflecting current compliance status of the facilities in question, no final approval action on the ANDA can occur.

Getting a Straight Answer from FDA

Obviously this is not always a problem; however, we are hearing from firms and we have personally experienced the following scenarios. A sponsor emails to ASKGDUFA with a procedural question. The sponsor receives a reply telling them that this is an OGD issue, so the sponsor sends the same email to the OGD Question Line and OGD tells the sponsor that the question should be responded to by ASKGDUFA. There have also been instances where the cycle went full circle with three emails telling the sponsor that they needed to ask a different entity, closing the loop with referral back to the original email recipient as the one that should answer the question.

The second scenario is where there is confusion on behalf of a sponsor about a specific Guidance or procedure. The question is phrased to outline the potential different interpretations upon which the sponsor seeks clarification, and asking either which is correct asks for an explanation of something that is not clear. In many instances, the response from the FDA office simply cites back to the specific section of the Guidance without further clarification. Industry can read the Guidance documents, but the clarity for a specific circumstance or issue is not always obvious. That is why industry asks. Reference back to the Guidance is not usually helpful without the extra step of making the requested clarification.

There are other scenarios that occur related to this issue… but you get the drift. And, of course, there are many responses that do respond adequately to the questions that are posed to the Agency, as long as you have the time to wait.

Issues Relative to Maximum Daily Exposure (MDE) in the IID

Until the IID is completely revised to include the FDA’s listing of the MDE for specific inactive ingredients for various ingredients in various dosage forms, the formulation departments of drug sponsors continue to pull their hair out. I don’t know the way to solve this problem, but it is a big issue and one that we hear about almost every week. The information in the IID is only useful if your product’s MDE is less than or equal to the amount listed in the IID, if the listed amount is not listed as an MDE. Why? Because you cannot tell from the IID what the product is or how it might be dosed (i.e., once, twice, or more times a day), as many of the values only reflect the amount of an ingredient in a single dosage unit. In that regard, it becomes more of a “you pay your money, you take your chances”-type situation. And if you are wrong, you get a Refuse-to-Receive (RTR) letter. We tell clients all the time that the IID has limited utility at this point in time and explain the types of other investigations that a sponsor can undertake to lessen the chances of receiving an RTR.

So those are the major issues we are hearing about with the highest frequency. If you would like to let us know about other issues that you are seeing frequently that you think should be raised to your colleagues, please email me at r.pollock@lachmanconsultants.com. I will gather them up and prepare a blog outlining the other most frequent issues (blinded of course), so everyone can say – hey that happens to me too!