OTP Pre-IND Meetings

Pre-IND Meetings can be valuable for sponsors in procuring feedback on a sponsor’s product development program, especially if a sponsor’s questions are not fully answered by guidance documents and other publicly available resources. A Pre-IND Meeting can also provide information that will assist sponsors in preparing to submit complete investigational new drug (IND) applications and reduce the risk of a clinical hold. The primary purpose of this meeting is to review and obtain feedback on the design of preclinical studies, the design of the initial IND study, and product manufacturing and quality controls needed to initiate human studies. The meeting also provides an opportunity to discuss the plans for studying the product in pediatric populations, the target product profile, the quality target product profile, the design and results of any natural history studies, and the best approach for presentation and formatting of data in the IND.

Timing of Pre-IND Meeting Request

Sponsors are sometimes unsure whether to request an INTERACT or Pre-IND Meeting for the current state of development of their product. See INTERACT Meeting Section for information regarding INTERACT meetings.  In general, a Pre-IND is the appropriate meeting type if:

• The sponsor has defined the manufacturing process to be used for the clinical studies and has developed assays and preliminary lot release criteria.
• The sponsor has completed proof-of-concept (POC) and possibly some preliminary preclinical safety/toxicology studies and desires to move to the definitive toxicology studies.
• The sponsor’s questions involve IND-enabling Chemistry, Manufacturing, and Controls (CMC), pharmacology/toxicology (P/T), and/or clinical trial design issues.

Process for Requesting a Pre-IND Meeting

Sponsors may email meeting requests to cberdcc_emailsub@fda.hhs.gov, with OTPRPMS@fda.hhs.gov in cc line for Regulatory Management Staff awareness. The meeting request should include a list of the specific objectives of the meeting and a list of questions (grouped by disciplines, e.g., CMC, P/T, clinical). To ensure that the appropriate FDA staff are assigned to the meeting, the meeting request should include draft questions. Draft questions submitted in the meeting request can be refined with the submission of the meeting package.

OTP does not send an acknowledgement email or letter following OTP’s receipt of the Pre-IND meeting request. However, as denoted in the table 2 below, by Day 21, OTP will send the decision to grant or deny the meeting request, along with the meeting date, if granted, or reasons for denial. OTP will provide the sponsor with a pre-submission tracking number (PTS) with the meeting confirmation.

The Pre-IND Meeting will be scheduled to occur within 60 days of receipt of the meeting request.

OTP schedules Pre-IND Meetings for 60 minutes.

Pre-IND Meetings are Type B meetings and follow the timelines FDA had established for Type B meetings. For additional information on meeting types, refer to Formal Meetings Between the FDA & Sponsors or Applicants of PDUFA Products Guidance for Industry.

Table 2: Timelines for Pre-IND (Type B) Meetings

OTP Response to Meeting Request**	21 days
Meeting Scheduled or WRO issued***	60 days
Meeting Package Due to OTP	At least 30 days before the scheduled date of the meeting or WRO
Meeting Length	60 minutes
OTP Preliminary Response to Questions in the Package to Sponsor (for all formats except WRO)	NLT* 2 days before the meeting
Sponsor’s Response to FDA Preliminary Response (for all formats except WRO)	NLT than 24 hours before the meeting

*NLT – No Later Than
Source: Table 2 information from the Formal Meetings Between the FDA & Sponsors or Applicants of PDUFA Products Guidance for Industry
**Calendar days from FDA receipt of the meeting request to the date that OTP will respond with the decision to grant or deny the meeting, as well as specifying the format and date of the meeting, if granted.
*** Calendar days from FDA receipt of the meeting request to date the meeting will be held, or the WRO will be issued. 

Common Reasons for Denial of a Pre-IND Meeting Request

The request for a Pre-IND Meeting may be denied based on a substantive reason. If a meeting request is denied, the requestor will be given a reason for the denial. Examples of reasons for denial are included below:

• The meeting request is substantially incomplete based on the omission of one or more of the elements identified in the Formal Meetings Between the FDA & Sponsors or Applicants of PDUFA Products Guidance for Industry.
• The meeting is premature for the stage of the product development program. In some situations, OTP may suggest an INTERACT meeting.
• Based on the information provided in the meeting request, it is not clear if the proposed investigational product would be regulated by CBER.
• The meeting request does not include specific questions, or the questions are not appropriate for a Pre-IND meeting. Examples of inappropriate questions are:
  • The questions are focused on jurisdiction or regulatory pathway. OTP does not use Pre-IND Meetings to answer questions about whether a product is appropriately regulated as a drug, device, and/or biologic or whether the product is appropriately regulated solely under Section 361 of the PHS Act and regulations in 21 CFR Part 1271 or what Center or Office should be the lead in review
• The meeting requestor does not intend to serve as sponsor of clinical studies under IND.  If the meeting requestor intends to manufacture and provide their product to other investigators to conduct IND studies, OTP will not grant a Type B Pre-IND Meeting to discuss product manufacturing. Instead, the meeting requestor may consider submitting the product manufacturing information in a Master File (MF) to OTP so that IND sponsors using the product can cross‑reference the MF. Please refer to SOPP 8301: Receipt and Processing of Master Files for additional information.  
• A previous Pre-IND Meeting was held. OTP grants one Pre-IND per product and clinical indication. A second Pre-IND meeting will not be held to “pre-review” the IND submission; rather, the sponsor should submit their IND.
• Request only contains questions for a single discipline (e.g., CMC or P/T) and/or sponsor indicates intent to request multiple discipline-specific meetings. OTP does not grant more than one Pre-IND Meeting for any specific product and indication. In addition, the review disciplines (e.g., CMC, P/T, clinical) are interdependent, particularly early in development. Therefore, attempts to separate meetings into discipline-specific discussions can lead to inadvertent miscommunication and duplication of effort.
• Sponsors have had multiple interactions with OTP in previous INDs/Pre-INDs with same/similar product.

Pre-IND Meeting Package

Number of Questions

The sponsor’s meeting package should include a limited number of clearly worded and targeted questions that directly address concerns about the product development programs. The number of questions in a meeting package should not exceed what can be reasonably discussed within the duration of the allotted meeting time. For a 60-minute meeting, a maximum of 10 questions (inclusive of sub-questions) would be considered reasonable. For example, Questions 1a, 1b, 1c, 1d, 2, and 3 would be equivalent to 6 questions.

Written Response Only (WRO) is considered to be equivalent to 60-minute meetings. Therefore, the maximum of 10 questions (inclusive of sub-questions) is applicable.

Size of Meeting Package

It is important to include background information sufficient to support the questions in the package. OTP may cancel a meeting if the meeting package is grossly inadequate and does not contain sufficient information to enable FDA to address the questions. However, voluminous meeting packages are discouraged. Meeting packages are typically 50 – 100 pages. OTP will not commit to reviewing packages greater than 250-300 pages or answering questions that require review of this much material.

Timing of Meeting Package Submission

The meeting package for a Pre-IND should be submitted no later than 30 days before the scheduled date of the Pre-IND meeting or WRO (see Table above). OTP will state the date a meeting package is to be submitted in the meeting confirmation notice when the meeting is granted. If the meeting package is not submitted on time, OTP will cancel or reschedule the meeting.

If the meeting package is not provided via the Electronic Submission Gateway (ESG), then the meeting package should be submitted to the cberdcc_emailsub@fda.hhs.gov, with the assigned Regulatory Project Manager (RPM) identified in our meeting confirmation and OTPRPMS@fda.hhs.gov in the cc line. The subject line of the email should include the assigned PTS submission tracking number and meeting briefing package. For example, PS00xxxx: PIND Meeting Package. A cover letter should be included in the briefing package with the inclusion of the assigned PTS submission tracking number. This PTS submission tracking number will help the document room staff associate the meeting package to the correct meeting request. 

Examples of Pre-IND Meeting Package Content (CMC, P/T, Clinical)

Product (CMC)

• Description of the product, manufacturing process and testing conducted (in‑process / final product) to demonstrate product identity, quality, and safety.
• Description of product formulation and storage conditions.
• Discussion of product stability.
• Detailed descriptions of any CMC issues on which feedback is being requested (e.g., sourcing of starting materials, potency assessment).
• Brief discussion of the manufacturing facility, and steps taken to ensure product segregation and tracking. 
• Discussion of the starting materials and control of the starting materials.
• Description of devices that will be used for product administration or cell selection.

Pharmacology /Toxicology

• A comprehensive discussion regarding the justification for all elements of the preclinical program 
• A comprehensive summary of all completed preclinical studies (in vitro and in vivo studies, animal species / models, study designs, resulting data and interpretation)   
• Complete protocols for the proposed definitive preclinical safety / toxicology and distribution studies, with sponsor’s rationale for the respective study design (e.g., animal species/models, dose levels, dosing regimen and procedure, study endpoints, sacrifice intervals)

Clinical

The sponsor should provide a clinical trial protocol synopsis or draft protocol that includes, but is not limited to:

• Trial design
• Objectives
• Intended patient population (e.g., age, severity of disease, phenotype)
  • Eligibility criteria
• Justification for proposed dose(s)
• Dosing regimen
• Delivery procedure, including device (as applicable)
• Study assessments and monitoring plan
• Safety and preliminary efficacy endpoints (e.g., outcome measures)

Examples of Questions Appropriate for a Pre-IND Meeting (CMC, P/T, Clinical)

The maximum number of questions that can be covered in a Pre‑IND Meeting is 10. Sponsors should consider this limitation and identify the most important questions for their specific development program.  Sponsors should also refer to available FDA guidances applicable to their product.

Sponsors should pose clear, focused questions so that OTP can provide advice targeted to the specific product development program. If questions are too broad or general, OTP’s response may also be general.  For example, a question such as “whether the overall proposed manufacturing approach or clinical program is adequate for enabling the IND” is too broad. Additionally, sponsors should not include single multi-topic all-encompassing questions such as ‘are the starting material selection, manufacturing process and analytical testing acceptable.

Examples of the types of clear and focused questions are shown below.

Product (CMC)

• Does the FDA agree with the manufacturing process and control strategy?
• Does the FDA agree that the testing and characterization of the cell banks are adequate?
• Does the FDA agree with the proposed release specifications and testing strategy?
• Does the FDA agree with the stability testing of the drug substance and drug product?
• Is the assay qualification plan sufficient?
• Is the delivery device compatibility plan sufficient?

Pharmacology / Toxicology

• Does the FDA agree that the data from the completed in vitro and in vivo proof‑of-concept (POC) studies are acceptable to initiate the proposed clinical trial?
• Does the FDA agree that the data from the completed biodistribution and toxicology studies are acceptable to support the proposed clinical trial?
• Does the FDA agree that the overall preclinical program is adequate, pending the study results, to support the proposed Phase 1 clinical trial?
• Does the FDA agree that the animal species / model evaluated in the POC and toxicology studies is acceptable?
• Does the FDA agree that the study design for the definitive toxicology study is adequate?

Clinical

• Does OTP agree with the key elements of the proposed clinical study design?
• Is the study population, as described in the enrollment criteria, appropriate for the proposed first-in-human (FIH) study?
• Are the stopping rules adequate for the proposed FIH study?
• Does OTP agree with the approach used to determine the proposed starting dose and dose-escalation plan for the product in the proposed Phase 1 trial?
• Does OTP agree that the study objectives, design and endpoints are acceptable for the FIH study?
• Is safety monitoring acceptable?
• Are the Dose-Limiting Toxicity criteria acceptable?
• Are the staggering intervals appropriate?
• Will vector shedding studies be required?
• The clinical assay, xxx, will be used to determine patient eligibility for study enrollment. Does FDA recommend a Q-Submission to make a study risk determination and the need of a future investigational device exemption?

Examples of Questions Not Appropriate for a Pre-IND Meeting

• Jurisdiction questions
• Questions regarding products other than the product that is the subject of the meeting

Best Practices for Managing Pre-IND Meetings with OTP

Prior to the Pre-IND Meeting

For pre-meetings, as indicated in the table above, OTP will send the preliminary response not later than 2 days before the scheduled meeting.  The sponsor is expected to respond to OTP’s preliminary responses not later than 24 hours prior to the scheduled meeting (see Table 2 above).

• If the sponsor finds that OTP’s preliminary responses and advice are sufficiently clear and complete to obviate the need for further discussion, the sponsor should inform OTP in writing as soon as possible so that OTP may cancel the meeting. These responses would then become the official OTP responses to the sponsor’s questions.
  • If, after cancellation of the meeting, the sponsor subsequently wishes to seek clarification from the preliminary responses, then the sponsor may submit a request for clarification. Find out more about Requests for Clarification. 
• If the sponsor wishes to continue with the meeting, the sponsor should identify which of the original questions in the briefing package they wish to discuss and list the questions in the proposed order of discussion. As a rule, the meeting discussion follows the prioritized order of importance set by the sponsor, with the understanding that all questions may not be addressed due to time constraints.   When referencing questions, the sponsor should use OTP’s preliminary responses document numbering format.
• After receiving OTP’s preliminary response, the sponsor should not submit new questions and new information (e.g., alternative approaches or new proposals to address OTP comments) that were not previously submitted in the original briefing package. OTP preliminary responses are prepared after deliberative review, and usually include cross‑discipline internal discussion of the original meeting package and questions.  OTP will not have adequate time to review new material and have sufficient inter-discipline internal discussion necessary to prepare answers to new questions.  Therefore, sponsors should thoughtfully prepare their meeting package and questions.
  • In some situations, a sponsor may want to develop new questions/alternative approaches in response to OTP’s preliminary responses or discussion at the meeting.  Such new questions/alternative approaches should be submitted as part of the original IND.

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During the Pre-IND Meeting

The meeting is the sponsor’s opportunity to obtain clarifications on OTP preliminary responses. As stated above, during the meeting the OTP team will not be able to provide feedback on new information (e.g., new questions, alternative approaches or new proposals to address OTP comments) that was not previously submitted in the original briefing package.

Sponsors may choose to make a presentation at the beginning of the meeting.  However, because OTP staff will be familiar with the meeting package content and questions, OTP recommends that sponsors forgo a presentation and use the allotted meeting time to obtain clarifications to OTP’s preliminary responses to the sponsor’s questions. 

OTP recommends that time be reserved at the end of the meeting for the sponsor to summarize the major discussion points and action items.

Meeting Summary

OTP will issue a meeting summary within 30 calendar days after the meeting.  OTP’s version of the meeting summary is official and the final record of the meeting.  OTP meeting summaries are not a meeting transcript, but focus on any clarifications (e.g., of unclear preliminary responses), agreements and disagreements, and action items as discussed during the meeting.

The sponsor may submit their version of the meeting summary to the file to summarize their understanding of issues discussed at the meeting. However, OTP may not review such submissions; therefore, the absence of an OTP response to such submissions does not imply OTP concurrence with the sponsor’s version of the meeting summary.

If sponsors disagree with the content of OTP’s meeting summary, OTP’s meeting summary will not be altered except to correct a substantive mistake for the record (on extremely rare occasions).

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Requests for Clarification

A request for clarification may be sought after a Type B Pre-IND meeting, to ensure the requestor’s understanding of OTP's feedback provided in a preliminary response (if the formal meeting was canceled), meeting summary or written response issued by OTP.

Find out more about Requests for Clarification