FDA No.25: Pre-IND Meeting Between FDA & Sponsor

FDA与Sponro的会议分为四种：Pre-IND meeting, End-of-phase 1 meeting, End-of-Phase 2 meeting, Pre-NDA/BLA meeting，今天推荐这篇Pre-IND meeting的文章给大家。

以下文章来源于Regulatory Affairs，作者Zoey Z

在药物开发生命周期起初，Pre-lnvestigational New Drug (IND)会议是非常有价值的。在初始IND申请提交前，为解决临床试验过程中出现的问题，尤其是当申请人遇到的有关研发产品问题而FDA提供的指南和其他信息不能完全解答时；FDA与申请人可以召开Pre-IND会议。在资源许可范围内，FDA鼓励召开有助于药品审评以及解决药品相关科学问题的会议。早期与FDA工作人员的互动可以帮助防止临床暂停（Clinical Hold）问题的出现。Pre-IND会议也可以为申请人提供有效信息，帮助其准备缺陷信息以提交完整的研究性新药申请(IND)。有效地利用FDA的资源可以使药物开发更有效率、加快申报并节约成本。

FDA鼓励但不强制申请人召开Pre-IND会议，通常上讲，FDA会同意大部分的Pre-IND会议申请。一份IND申请仅能申请一次Pre-IND会议。尽管从递交会议申请到获得反馈信息的时间可能2-3个月，但基于长远考量，这项举措能够加快药物的上市速度，并有助于制定药物研发战略。

01

What Is a Pre-IND Meeting?什么是Pre-IND（IND前,即PIND)会议？

• A Pre-lnvestigational New Drug (IND) meeting is a formal meeting, most frequently the first meeting
• with FDA, where the specific division provides feedback to questions?asked.
• It is a Type B meeting, which means FDA will schedule the meeting within
• 60 calendar days of a meeting request.
• FDA will grant most pre-IND meetings; however, they will generally only?schedule one pre-IND meeting per application (e.g., investigational new?drug, new drug application, biologics license application).
• There is no charge for an FDA meeting.
• PIND会议是一个正式的会议，为最常见的申请人与FDA的第一次会议；FDA具体部门对申请人提出的问题提供反馈。
• 为B类会议，这意味着FDA将在会议请求的60个日历日内安排会议。
• 会议请求后的60个日历日内安排会议。
• FDA将批准大多数PIND会议；但是，他们一般只为每项申请（例如，研究性新药、新药申请、生物制品许可证申请）安排一次预审会议。
• PIND会议不收费。

02

Why: the purpose of the pre-IND meeting packet? 提供pre-IND 会议资料包的目的是什么？

• Provides the historical background information on the chemical development concept
• Provides information on the active ingredient
• Provides an initial clinical and preclinical development strategy
• Provides future development strategy including product scale-up and final formulation, and animal and clinical studies proposed in support of an NDA
• Provides FDA with a clear and concise overview of the planned development program
• Allows FDA the opportunity to comment on a proposed program of development
• 提供有关化学品开发概念的历史背景信息
• 提供有关活性成分的信息
• 提供初步的临床和临床前开发战略
• 提供未来的开发策略，包括产品放大和最终配方，以及为支持NDA而提议的临床前和临床研究
• 向FDA提供计划开发项目的清晰且简明的概述
• 让FDA有机会对拟议的开发计划提出意见

FDA Perspective on Benefits of a?Pre-IND?Meeting

• Identifying and avoiding unnecessary studies
• Ensuring that necessary studies are designed to provide useful information
• Gaining FDA support for a proposed strategy
• Minimizing potential for clinical hold
• Providing an opportunity for creative exchange of ideas
• Obtaining regulatory insight
• Minimizing costs
• Clearly defining endpoints and goals of the development program
• Allowing early interactions/negotiations with FDA

FDA认为Pre-IND会议的益处:

• 识别和避免不必要的研究
• 确保设计必要的研究以提供有用的信息
• 获得FDA对拟议研究策略的支持
• 最大限度地减少临床试验暂停（clinical hold）的可能性
• 为创造性地交流意见提供机会
• 获得监管方面的洞察力/态度
• 将成本降到最低
• 明确界定开发项目的终点和目标
• 允许尽早与FDA进行互动/谈判

特别说明:?会议的主要目的是审查初次进行人体试验所需的动物试验研究，并就试验方案达成一致（已完成的动物试验研究得到的研究数据（剂量和存活时间）是否支持临床试验计划；辅料的安全性；最新的、合适的临床数据对临床研究计划的影响）。会议可讨论Ⅰ期临床试验的设计和范围（样本量、研究设计、临床终点、统计学；安全性监测），新药儿科研究的计划，以及IND申请中数据的最佳呈现方式和形式（参考的信息；委托授权；文献参考；纸质或电子形式）。会议也可讨论现有的CMC信息是否足以支持临床试验计划（药物原料和药品的生产过程及控制过程；药物试验和规格；辅料的化学相容性；已计划的临床试验中确保药物稳定性的必要数据），以及不同的监管计划（突破性疗法；申请快速通道；申报孤儿药）。（转自张钟艺老师文章其中一段）

03

How: requesting?and?preparing for an FDA Pre-IND Meeting申请和准备FDA?Pre-IND(预审,PIND）会议

3.1 Before You Request a Meeting在您申请会议之前：

• Make sure you are actually ready to have a meeting
• Are you ready to provide a comprehensive briefing package to FDA?
• Briefing packages can be due within days of receiving meeting granted?notification, so make sure you are well on your way before?sending a??meeting?request letter.
• Meetings are data driven so make sure data to be included in the?briefing?package will be available.
• 确保实际上已经准备好举行会议
• 您是否已准备好向FDA提供一个全面的简报包(briefing package/PIND package)？
• 简报包可以在收到会议批准通知的几天内完成，所以在发送会议请求信之前，请确保您已经做好了准备。
• 会议是由数据驱动的，所以要确保简报包中包含的数据是可用的。
• When requesting a Pre-IND meeting, contact the supervisory project
• manager in the Division before actual submission
• 1)Confirm appropriate review Division
• 2)Alert them that a meeting request is coming
• 3)Ask questions about tentative scheduling, if desired
• 当要求召开Pre-IND会议时，请在实际提交前与该部门的主管项目经理联系。
• 1)确认适当的审评部门
• 2)提示部门将有会议请求。
• 3)如果需要，询问有关暂定的会议时间（如召开面会面或电话会议）
• Pre-IND meeting can be made via ESG (Electronic Submissions Gateway:
• so have electronic publishing capability established (several reputable
• electronic publishers available if no in-house capability). Although not
• mandatory, this is FDA's preferred method。
• 可以通过ESG（电子提交网关）进行提交IPre-IND 会议。故需要具备电子出版能力（如果内部没有能力，可以选择几个知名的电子出版商）。虽然不是强制性的，但这是FDA的首选推荐方法。

3.2?Pre-IND Meeting??Request???What information should be included in the meeting request?

会议申请中应包括哪些信息？

Sponsors should review the guidance?Formal Meetings with Sponsors and Applicants for PDUFA Products?(PDF - 30KB) for information on formal meetings with sponsors and applicants.?Adequate information in the meeting request is a very important part of having a successful outcome of a pre-IND meeting and should include the following information:

• Meeting objective
• Proposed agenda, including estimated times needed for each agenda item
• Listing of specific questions categorized and grouped by discipline, for example, chemistry, manufacturing, and controls (CMC), pharmacology/toxicology, clinical pharmacology and biopharmaceutics, and clinical investigations
• List of sponsor participants
• List of requested participants from CDER
• Quantitative composition (all ingredients by percent composition) of the drug proposed for use in the study to be discussed
• Proposed indication
• Dosing regimen, including concentration, amount dosed, and frequency and duration of dosing if known
• Proposed meeting date (propose 6-8 weeks in the future)
• When the background packet will be available (at least 4 weeks before the proposed meeting date)

申请人应查阅《与PDUFA产品的发起人和申请人的正式会议》指南（PDF - 30KB），了解与发起人/申请人的正式会议信息。会议请求中的充分信息是PIND?会议取得成功的一个非常重要的部分，应包括以下信息:

• 会议目标
• 拟议的会议议程，包括每个议程项目所需的估计时间
• Note：一般情况下电话/面对面会议需要，书面会议（WRO)不适用
• 列出按学科分类和分组的具体问题：包括但不限于，CMC、药理学/毒理学、临床药理学和生物药理学以及临床研究
• （Note:问题一般建议12个左右）
• 申请人/参会者名单
• Note：一般情况下电话/面对面会议需要，书面会议（WRO)不适用
• CDER提供的参会者名单
• 拟用于讨论的研究药物的定量组成(所有成分的百分比组成)。
• 拟定的适应症
• 给药方案，包括浓度、给药剂量，以及给药频率和持续时间(如适用)
• 拟议的会议日期（建议在未来6-8周内）。
• Note：申请人一般可从会议申请(PIND Request)算起6-8周内
• 背景资料，即PIND?package的提供时间（至少在拟议会议(PIND Meeting)日期前4周）

?Meeting Request Granted会议请求得到批准?

• FDA project manager will send a formal confirmation of?your meeting date/time
• Pay attention to due dates for briefing packages and?number of desk copies requested, otherwise your?meeting may be cancelled/rescheduled
• - No later than 30 days before meeting for Type B Pre-IND
• - After initial Pre-IND meeting, subsequent meeting?packages have varied timelines
• Note which FDA participants will be present and?prepare accordingly
• - List can be requested from PM if not provided
• 若同意开会，FDA的项目经理将向您发送一份正式的会议日期/时间确认书
• 注意简报包（briefing?packages）的到期日期和要求打印的资料数量，否则您的会议可能被取消/改期

??- 对于B类Pre-IND，不迟于会议前30天

??- 在最初的Pre-IND会议之后，随后的会议包有不同的时间安排

• 注意哪些FDA审评官将出席会议并做相应准备

??- 如果没有提供名单，可向PM索取

?Meeting Denied?会议被拒绝?

If a meeting request is denied, the FDA will notify the requester in writing according to the?timelines described in Table 1. The FDA’s letter will include an explanation of the reason for?the denial. Denials will be based on a substantive reason, not merely on the absence of a minor?element of the meeting request or meeting package items. For example, a meeting can be denied?because it is premature for the stage of product development or because the meeting package?does not provide an adequate basis for the meeting discussion.

Thus, the FDA will generally?deny requests for Type A meetings and Type C meetings to discuss the use of a biomarker as a?new surrogate endpoint that has never been previously used as the primary basis for product?approval that do not include an adequate meeting package in the original request. The FDA may also?deny requests for meetings that do not have substantive required elements. A subsequent request to?schedule the meeting will be considered as a new?request (i.e., a request that?merits a new set of time frames as described in section III., Meeting?Types).

如果会议请求被拒绝，FDA将根据表1中描述的时间表书面通知请求者。FDA的信件将包括对拒绝原因的解释。拒绝将基于一个实质性的原因，而不仅仅是会议请求或会议包项目中的一个小元素的缺失。例如，会议被拒绝的原因可能是对产品开发阶段来说还不成熟，或会议并没有为会议讨论提供充分的依据。

因此，FDA通常会拒绝A类会议和C类会议的请求，如以讨论使用新的代用终点，该终点以前从未被用作产品批准的主要依据，而原始请求中没有包括充分的会议资料。FDA也可以拒绝不具备实质性要求内容的会议请求。随后提出的安排会议的请求将被视为一个新的请求（即，一个值得新的时间框架的请求，见会议类型中所述）。

3.3 Pre-IND Package?Pre-IND文件包?

Before the Meeting:会前

??What does the sponsor?should include in a pre-IND meeting packet?

?pre-IND 会议--资料包递交内容包括（申请人准备）：

• Overall program synopsis
• Whether the animal efficacy rule is being considered
• Clinical study synopsis to obtain FDA input on inclusion, exclusion, and endpoints
• Results for in vitro and early in vivo toxicology
• Rationale for safety, based on toxicological profile and safety margin using dose regimen and exposure
• Brief description of the manufacturing scheme for the active pharmaceutical ingredient (API) and formulation for clinical study
• Brief assay descriptions
• Full description of the development plan
• Copy of the meeting request with updates to reflect the most current information
• 方案概要
• 是否考虑动物疗效？
• 临床研究概要，以获得FDA对纳入、排除标准和终点的意见
• 体外和早期体内毒理学的研究结果
• 安全性的理由：基于毒理学特征和使用剂量方案和暴露的安全系数
• 用于临床研究的活性药物成分（API）和制剂的的简要描述
• 简要的实验描述
• 开发计划的完整描述
• meeting request?中更新的信息以反映最新的信息

法规建议：

FDA对简报文件中的信息没有强制性要求；但是，通常提供的信息有：

• 向FDA证明主办方了解其产品的信息。
• 最后的问题，以及
• 背景信息，以便为FDA提供足够的信息来回答所提出的问题。
• 数据应该是总结的和简洁的。
• 一般来说，在会前简报文件提交后或会议期间，不得提出新的信息；然而，有时可能会讨论问题中未涉及的事项。

递交pre-IND 会议--资料包后：

FDA Preliminary Comments

• 24-72 hours before the meeting, FDA will provide preliminary?responses to the Sponsor's questions.
• If preliminary responses answer all the Sponsor's questions, the Sponsor may?choose to cancel the meeting.
• If further clarification is needed for a question, the Sponsor notifies the FDA?Regulatory Project Manager (RPM) about which specific questions need further?discussion.
• The meeting will focus on only those questions.

FDA的初步意见

• 在会议召开前24-72小时，FDA将对主办方的问题做出初步回应。
• Note:此针对电话或面对面会议。
• 如果初步答复回答了主办方的所有问题，主办方可以选择取消会议。
• Note:此针对电话或面对面会议。
• 如果需要进一步澄清某个问题，主办方需要通知FDA监管项目经理（RPM）哪些具体问题需要进一步讨论。
• 会议将只集中讨论申请人申请的问题。

On?the Meeting会中

Meeting Conduct会议安排：

• 1 hour is scheduled for the meeting.
• The FDA RPM chairs the meeting.
• Generally, no presentation is provided by the Sponsor to maximize time for?discussing questions.
• The first 5 minutes are introductions of FDA and Sponsor attendees.
• The next 50 minutes are for discussion of the questions in the order
• requested.
• ? List the primary concern questions first when providing questions to the RPM, so if?time runs out, these primary concerns have been discussed!
• The last 5 minutes are for a statement by the Sponsor of the agreements
• in the meeting.
• 安排1小时的会议。
• FDA的RPM主持。
• 一般来说，申请人不做任何介绍，以最大限度地增加讨论问题的时间。
• 最初的5分钟是介绍FDA和申办方的出席者。
• 接下来的50分钟是按照要求的顺序讨论问题。
• 在向RPM提供问题时，首先列出主要关注的问题；因此如果时间用完，这些主要关 注的问题已被讨论!
• 最后5分钟是申办方对会议达成一致的声明。

Post Meeting会后

• The Sponsor may provide their notes to FDA a few days after the?meeting.
• FDA provides final comments within 30 calendar days after the?meeting.
• 申办方可在会后几天向FDA提供他们的笔记（可选，一般申请人不会主动提交）。
• FDA在会后30个日历日内提供最终意见。

Is the FDA Feedback Binding? FDA的反馈意见是否具有约束力/申请人是否必须采纳？

• The Sponsor can choose to accept the feedback or use an
• alternative strategy. However:
• remember that FDA's guidance is generally based on knowledge of what most?companies in the same field are doing and what FDA has required for other?Sponsors' products.
• FDA can decide when the IND is filed and, when more data are?available, that the guidance they initially provided at the pre-IND?meeting is no longer valid.
• Pre-IND briefing documents should, therefore, be well-written and accurate.
• 申请人可以选择接受反馈意见或使用其他策略。然而：
• 记住FDA的指导通常是基于同一领域的大多数公司正在做的事情以及FDA对其他发起人/申请人产品的要求。
• FDA可以在提交IND时决定，当更多数据可用时，他们最初在Pre-IND会议上提供的指导不再有效。
• 因此，Pre-IND简报文件应撰写良好且准确。
• 法规建议：一般接受，不接受的予以解释说服，并提供其他支持资料呈现在正式的IND申请中。

04

MEETING FORMATS会议形式

延伸内容

There are three meeting formats: face to face, teleconference/videoconference, and WRO as?follows:

(1) Face to face — Traditional face-to-face meetings are those in which the majority of?attendees participate in person at the FDA

(2) Teleconference/Videoconference — Teleconferences/videoconferences are meetings in?which the attendees participate from various remote locations via an audio (e.g.,telephone) and/or video connection

(3) Written response only — WRO responses are sent to requesters in lieu of meetings?conducted in one of the other two formats described above

有三种会议形式。面对面，电话会议/视频会议，以及书面回复（WRO），具体如下：

(1) 面对面 - 传统的面对面会议是指大多数参会者亲自到FDA参加的会议

(2) 电话会议/视频会议--电话会议/视频会议是指与会者通过音频（如电话）和/或视频连接，从不同的远程地点参加的会议

(3) 仅有的书面答复 - WRO答复被发送给请求者，而不是以上述其他两种形式之一进行的会议。

Face-to-face has significant benefits

• Get a sense of FDA's attitude about your?product/program
• Open dialogue provides a quicker path to resolution on?complicated issues
• If you want a face-to-face, make your case in the request?letter!

Written Response Only (WRO)

• If WRO is granted, you can try to push back
• WRO impacts briefing package as you need to provide all?data; no opportunity to discuss in person
• If there are straightforward issues, they can be handled by?WRO, but F2F is recommended at this stage

面对面会议有很大的好处：

• 了解FDA对你的产品/项目的态度
• 公开对话为解决复杂问题提供了更快的途径
• 如果你想要面对面，请在请求信中说明你的情况。

??书面答复(WRO)

• 如果WRO被批准，你可以尝试推回/拒绝
• WRO影响到PIND资料包（briefing package ），因为你需要提供所有数据；没有机会当面讨论
• 如果有直接/简单的问题，可以通过WRO来处理，但在这个阶段建议使用F2F。

总结

PANTONE CATHARANTHUS BLUE

Preparation of schedule for?Pre-IND?meeting?Pre-IND

会议流程工作总结

1. Submit the meeting request with the preferred meeting format:

• face-to-face )
• teleconference/videoconference, or
• written responses.

2. Within 21 days of the meeting request:

• FDA will contact the Sponsor to indicate meeting format, and
• schedule the meeting within 60 days of the initial request.

3. days prior to the meeting, the Sponsor must submit a briefing?document with finalized questions and information to support?FDA's response to questions.

- 1.申请人提交会议申请，并注明首选的会议形式。

? 面对面

? 电话会议/视频会议，或

? 书面回复

- 2.FDA在会议请申请的21天内：

? FDA将联系主办方以说明会议形式，并

? 在最初请求的60天内安排会议

- 3.申请人在会议召开前30天，必须提交一份会议简报文件，其中包括最终确定的问题和支持FDA对问题的回复的支持信息。

Reference:

• 21 Code of Federal Regulations-Part 312.47 Meetings
• Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA?Products-Guidance for Industry
• CDER-Small Business and Industry Assistance: Frequently Asked Questions on?the Pre-lnvestigational New Drug (IND) Meeting