OTAT 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 [email protected], with [email protected] 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.
OTAT does not send an acknowledgement email or letter following OTAT’s receipt of the pre-IND meeting request. However, as denoted in the table below, by Day 21, OTAT will send the decision to grant or deny the meeting request, along with the meeting date, if granted, or reasons for denial. OTAT 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.
OTAT 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: Timelines for Pre-IND (Type B) Meetings
| OTAT Response to Meeting Request** | 21 days |
|---|---|
| Meeting Scheduled or WRO issued*** | 60 days |
| Meeting package due to OTAT | At least 30 days before the scheduled date of the meeting or WRO |
| Meeting Length | 60 minutes |
| OTAT Preliminary Response to questions in the package to Sponsor (for teleconferences) | NLT* 2 days before the meeting |
| Sponsor’s Response to FDA preliminary response (for teleconferences) | NLT than 24 hours before the meeting |
*NLT – No Later Than
Source: Table 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 OTAT 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.
The format for pre-IND meetings is typically either a teleconference or Written Response Only (WRO). OTAT rarely grants pre-IND meetings as face to face.
A sponsor may request a WRO meeting, or OTAT may determine that the WRO format is appropriate to meet the goals of the meeting request.
OTAT receives a substantial number of meeting requests, and it is challenging to schedule teleconferences for all requests. To manage the workload, OTAT may grant a pre-IND meeting as WRO in some cases where a teleconference is requested by the sponsor. OTAT evaluates each meeting request to determine whether to grant or deny the meeting, and to determine the appropriate format for the meeting.
In determining the format of a pre-IND meeting, OTAT considers:
- Whether the sponsor had a prior pre-IND meeting with OTAT for the same or similar product or indication.
- Whether the sponsor had a previous or current IND for the same or similar product or indication.
- Whether the preclinical testing and manufacturing process for the product use the same/similar platform as other product(s) submitted to OTAT by the same sponsor.
- Whether the questions are straightforward or complex.
- Whether the questions are adequately addressed in current FDA guidance and/or regulations.
The request for a pre-IND meeting may be denied. Denials will be 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, OTAT 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. OTAT 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, OTAT 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 OTAT 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. OTAT grants one pre-IND per product and clinical indication (regardless of change of sponsorship). 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. OTAT 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 OTAT in previous INDs/pre-INDs with same/similar product.
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 12 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 12 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. OTAT 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. OTAT 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). OTAT 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, OTAT will cancel or reschedule the meeting.
The meeting package should be submitted to the [email protected], with the assigned Regulatory Project Manager (RPM) and [email protected] in cc line. The subject line of the email should include the assigned PTS 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 number. This PTS number will help the document room staff associate the meeting package to the correct meeting request.
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)
The maximum number of questions that can be covered in a pre‑IND meeting is 12. 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 OTAT can provide advice targeted to the specific product development program. If questions are too broad or general, OTAT’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 OTAT 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 OTAT 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 OTAT 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?
- Jurisdiction questions
- Questions regarding products other than the product that is the subject of the meeting
Prior to the Pre-IND meeting
For pre-IND teleconferences, as indicated in the table above, OTAT will send the preliminary response not later than 2 days before the scheduled teleconference. The sponsor is expected to respond to OTAT’s preliminary responses not later than 24 hours prior to the scheduled teleconference (see Table above).
- If the sponsor finds that OTAT’s preliminary responses and advice are sufficiently clear and complete to obviate the need for further discussion, the sponsor should inform OTAT in writing as soon as possible so that OTAT may cancel the meeting. These responses would then become the official OTAT responses to the sponsor’s questions.
- If, after cancellation of the pre-IND meeting, the sponsor subsequently wishes to follow-up on topics from the preliminary responses or pose new questions, then the sponsor should submit these follow-up or new questions in the original IND.
- 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 OTAT’s preliminary responses document numbering format.
- After receiving OTAT’s preliminary response, the sponsor should not submit new questions and new information (e.g., alternative approaches or new proposals to address OTAT comments) that were not previously submitted in the original briefing package. OTAT preliminary responses are prepared after deliberative review, and usually include cross‑discipline internal discussion of the original meeting package and questions. OTAT 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 OTAT’s preliminary responses or discussion at the meeting. Such new questions/alternative approaches should be submitted as part of the original IND.
During the pre-IND meeting
The meeting is the sponsor’s opportunity to obtain clarifications on OTAT preliminary responses. As stated above, during the meeting the OTAT team will not be able to provide feedback on new information (e.g., new questions, alternative approaches or new proposals to address OTAT 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 OTAT staff will be familiar with the meeting package content and questions, OTAT recommends that sponsors forgo a presentation and use the allotted meeting time to obtain clarifications to OTAT’s preliminary responses to the sponsor’s questions.
OTAT recommends that time be reserved at the end of the meeting for the sponsor to summarize the major discussion points and action items.
Meeting Minutes
OTAT will issue meeting minutes within 30 calendar days after the meeting. OTAT’s version of the meeting minutes is official and the final record of the meeting. OTAT minutes 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 minutes to the file to summarize their understanding of issues discussed at the meeting. However, OTAT may not review such submissions; therefore, the absence of an OTAT response to such submissions does not imply OTAT concurrence with the sponsor’s version of the minutes.
If sponsors disagree with the content of OTAT’s meeting minutes, OTAT’s meeting minutes will not be altered except to correct a substantive mistake for the record (on extremely rare occasions).
Post-meeting follow-up (teleconference vs. WRO)
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For meetings scheduled as teleconference
The teleconference meeting is the sponsor’s opportunity to obtain clarification on OTAT’s preliminary response. Due to workload, OTAT will not be able to address follow-ups or additional questions, via email or tcon, after the meeting is held. If additional questions arise, the sponsor may submit the questions/alternative approaches or new data in the original IND submission.
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For Written Responses Only
Simple requests for clarification of OTAT WRO may be sent to the Regulatory Project Manager (RPM) within 20 days after receipt of the WRO. The sponsor should include their request for clarifications for all disciplines in a single follow-up request. Generally, only questions of a clarifying nature will be considered, i.e., to confirm something in the WRO issued by OTAT, rather than raising new issues or new proposals.
Examples of such simple requests for clarification include:
- Typos and misstatements by OTAT
- The OTAT responses can be interpreted ambiguously and are unclear to the sponsor (e.g., “Did you mean A or B?”)
Examples of follow-up requests that are beyond clarification and therefore not appropriate:
- Questions related to new information not included in the briefing package
- Questions related to the adequacy of new proposals to address OTAT comments [e.g., new clinical trial designs, study endpoints, new patient population, new/modified assays, new preclinical study design, new materials (i.e., raw materials, source materials)]
If such questions arise, the sponsor may submit these questions, alternative approaches, or new data to the original IND submission.
OTAT will consider the follow-up request, and if determined to be limited to clarification, OTAT will issue a response in writing within 20 calendar days after receipt of the clarifying questions. If OTAT determines that a short teleconference would be the best format for follow-up, then OTAT will attempt to hold this informal teleconference within 20 days after receipt of the request for clarification. OTAT will not provide the sponsor with minutes for such informal teleconference.