The INTERACT Checklist & Submission

Cell and gene therapy companies introduce their product to FDA via the INTERACT submission, and kicks off a multi-year interaction with your review. A successful package leaves FDA with a favorable view of your product, and gives you detailed and instructive feedback to guide your next steps.

There are two aspects to a successful INTERACT submission: the strategy or information itself and presentation of that strategy in your submission. Both can derail a company’s FDA interaction: good presentation can’t save bad strategy, and smart product development strategy lost in translation will have a difficult time aligning with FDA.

The acceptability of your strategy and development plan is very much specific to each cell and gene therapy, but the presentation of that information and submission is more universal. The INTERACT package has a deceptively simple brief: give CBER enough to understand your novel issue, ask no more than ten targeted questions, and keep the whole thing to 50 pages or fewer. Unlike other CBER and CDER interactions, the meeting package or briefing document is submitted with the meeting request, so there is no second chance to fill gaps before FDA evaluates it for completeness.

The hard part is understanding what to include and not include. This checklist walks the entire package, and the question set. Next comes the real fun: working through FDA’s preliminary responses, preparing for the FDA meeting, and making good use of your 60 minutes with the review team!

01 · SUBMISSION 101

The Basics of INTERACT Submissions

The first step in your INTERACT journey begins with having a solid understanding of your product’s development and the areas where you have uncertainty. The goal is alignment with FDA on what is necessary for your next milestone. The easiest way for alignment is outright agreement, but detailed feedback on your approach is just as useful to the conduct of your upcoming studies.

FDA’s preliminary feedback is based solely on your 50-page submission and focuses on your ten questions but frequently includes additional feedback beyond the questions if they see anything that warrants input. To maximize FDA’s feedback, your submission package needs to include all the information that FDA needs to give you good answers to your specific questions as well as understand your program’s overall direction

Think also about your audience when developing that 50-page document: CBER reviewers reading your submission are experts in cell and gene therapies, but not your specific cell and gene therapy. Speak to your review team as experts but provide them with enough details about your product for them to fully understand your product and where you’re headed with your development program.

02 · DRAFT YOUR SUBMISSION

Assemble the a complete submission

The submission is intended to present your product’s development with your specific questions in a way that’s most helpful for FDA review teams. Organize the package to follow the agenda, paginate it, and give it a table of contents. Include enough background to support question and understand your product & program, but no more. OTP explicitly discourages voluminous packages. Here’s an INTERACT structure that you can follow:

Cover Letter: identifies the submission purpose and type, product, abbreviated indication, format of requested feedback, proposed dates for meeting (if requested), and point of contact
Administrative and Product Identification: include all of the following each under its own subsection.
Application number: will be “not yet assigned” for most products
Product name: can be the product’s established/common name and a one line description
Proposed indication
Regulatory status:
Type of meeting: INTERACT
Pediatric study plans: as applicable; if “Not Applicable”, provide brief rationale
Human factors engineering plans: include if the therapy uses a delivery device
Combination product information: if applicable include the constituent parts and primary mode of action, lead center
Suggested dates and times: list three options plus any blackout dates
Background: provides the reviewer team with relevant information, each in subsection:
Disease or Condition: provide a summary of the disease or condition, which can include etiology and natural history. Also list treatment options, if any.
Brief Program Overview: outline your development program including product composition, format, route, mechanism, manufacturing platform, and where the program sits in development
Scientific Rationale: describe the therapeutic hypothesis and published evidence with the core mechanistic claim your program is designed to support. If relying on early product versions (e.g., product in academic lab versus the planned product), address the representativeness
Preview FDA Interactions: Typically none; list any interactions including Pre-RFDs and any discussions for the same product under a different indication.
Proposed Meeting Format: options are written responses only (WRO), teleconference, or virtual face-to-face.
Meeting Purpose and Specific Objectives: summarizes the purpose of the INTERACT and specific topics for FDA feedback
Questions: grouped by topic (FDA discipline) each with the your position and justification, no more than ten (sub-questions still count towards your ten total):
CMC: along with pharm/tox, forms the bulk of the questions
Pharm/Tox: along with CMC, forms the bulk of the questions
Clinical: optional; detailed clinical protocol questions are out of scope, but directional, strategy-level question are appropriate
Regulatory: optional and easy to get wrong; jurisdiction is out of scope, but development strategy can be appropriate
Discussion: this section serves as the data to support FDA review (summaries only; no protocol, full study reports, or raw datasets), and the organization should mirror the questions
CMC: include subsections for drug substance, drug product, components /ancillary materials used in manufacturing, release testing program, stability, potency assay, starting materials, comparability
Pharm/Tox: include subsections for complete pharmacology / proof-of-concept; proposed pharmacology / cell fate studies; toxicology, tumorigenicity, and biodistribution; mechanistic characterization
Clinical: state the intended first-in-human population and how the dose/route will be established. Describe any prior clinical studies or state there are no prior studies.
References
List of Abbreviations: optional; can be deleted for space

You should note that this checklist will set you up to make sure your submission presents your plan in the best possible light, but doesn’t provide assurance that your actual CMC, pharm/tox, and clinical strategy and plan is acceptable to FDA. Whether your specifications are too broad, whether your release testing ensures sufficient control, and whether you’ve selected the right species for testing are all very much tied to your specific product, and warrant a separate review. Don’t skip this last step: the best presentation can’t make up for a proposal that FDA isn’t going to agree to.

03 · SPECIFIC FDA QUESTIONS

Sharpen your topics and questions

The ten questions are the heart of the package. That number is inclusive of sub-questions, so 1a, 1b, 1c, 1d, 2, and 3 already count as six. Each question should be precise, tied to a real development decision, and accompanied by your own position and the reasoning behind it. At the INTERACT stage, your questions will likely be CMC and Pharm/Tox focused, potentially with a high-level clinical or regulatory question.

Keep your questions focused and sharp using the correct regulatory terminology, and without backing FDA into an uncomfortable position. Even though it is sorely tempting to ask, FDA reviewers universally cringe at needing to provide answers to “do you agree my product is safe and efficacious”, “will you approve my IND”, and “is my testing acceptable”. Instead, ask about specific models about animal models and whether the release testing would provide sufficient control; FDA’s answer will typically address the specific question and still end up giving you insight into the broader question you really want to ask.

For cell and gene therapy programs at the INTERACT stage, questions on specifics of donor eligibility, characterization of your cell line or viral vector, identity of drug substance versus drug product, and animal models are all good and immediately helpful to plan your next steps. However, don’t discount questions related to longer-term necessities. Potency assays aren’t truly required until later phase clinical development, but take a long time to develop and refine. With the limited number of interactions, early FDA feedback will help you get it right.

04 · SUBMISSION LOGISTICS

Getting the Submission to FDA

There are many ways to send submissions to CBER, but the easiest way is to submit your INTERACT via email at [email protected]. CBER doesn’t issue acknowledgement emails, but will inform the submission’s point of contact of whether to grant or deny the meeting by Day 21. OTP sends preliminary written responses no later than 5 days before the meeting, and you’ll be expected to respond no later than 3 days before. CBER does not issue a separate meeting summary or minutes, but will annotate and resend the preliminary written feedback if there are any changes based on the meeting. There’s a lot happening between when you receive the written feedback and when you have your FDA meeting, so be sure to make sure the days ahead of the meeting are open.

04 · FDA FEEDBACK AND MEETING PREP

60 minutes with the review team

You’ll receive your written feedback no later than 5 days before the meeting. Read the preliminary responses closely and decide, question by question, whether you still need to meet:

If the responses are clear and complete, you may reply to CBER in writing that the meeting can be cancelled. Those preliminary responses then become official answers and your next interaction with FDA is the pre-IND. However, there’s almost always some value to meeting with the review team. Think carefully before you cancel.
If you want to proceed, confirm your receipt of the feedback and your plan for the meeting.

The chance to discuss your product with the review team is the most valuable part of the process. You’ll have precisely 60 minutes with the review team. You’ll need to carefully prioritize what you’d like to discuss and come well prepared. These meetings can be intimidating for applicants, and having a regulatory expert who’s experienced in leading FDA meetings can make all the difference.

FDA’s stated purpose is to clarify the Agency’s preliminary responses, and clarification comes in all forms. Consider the following when prioritizing your discussion points:

Are there any misunderstandings: If FDA has misunderstood your product, testing, or CMC strategy, resolving this should be high priority
Is FDA’s feedback a showstopper: If FDA’s feedback contains showstopping items, don’t shy away from those. There’s always alternatives to FDA’s feedback, which are ultimately recommendations.
Do you disagree with any of FDA’s recommendations: if FDA recommends an approach that you think is wrong, use the meeting to understand FDA’s underlying request. Understanding more about their thinking will help you present your alternative proposal
Are you unsure how to execute FDA’s feedback: If FDA is recommending testing you’ve never heard of before or you need details to proceed, use the meeting as a chance to ask for more information.

FDA emphasizes that meetings are not an opportunity to present new material. However, clarifications frequently necessitate some degree of new information to explain how the applicant intends to respond. An experienced regulatory expert, especially one with experience on FDA’s side of the table, can find ways to get clarification from FDA without being dinged for “providing new information”. Your FDA expert can also prepare you for the meeting, lead discussions with FDA, and help with any post-meeting actions. And with that, you’re already on track for a Pre-IND!

NEXT STEP: PRE-IND AND BEYOND

Once you have FDA feedback, you’ll start completing the recommended testing and planning for your Pre-IND. Keep track of FDA’s feedback, the meeting discussion, and your regulatory project manager. As your development program progresses, this is the starting point for your Pre-IND interaction.

FDA sources & references

OTP INTERACT Meetings — Package content by discipline, page and question limits, preliminary-response timing, and post-meeting procedures. fda.gov ↗
Formal Meetings Guidance — Meeting request and package content requirements, preliminary responses, and clarification procedures. fda.gov ↗
SOPP 8101.1 — CBER procedures, including reasons a meeting may be denied, rescheduled, or cancelled. fda.gov ↗
OTP Requests for Clarification — When and how to seek clarification of FDA feedback after an INTERACT. fda.gov ↗

Building your INTERACT package?

Deffai helps you sharpen the questions, right-size the package, and turn FDA’s preliminary responses into decisions you can build on.

Johnny Lam, PhD — Head of Regulatory Strategy · Laura Rose, PhD — Cofounder & Chief Regulatory Officer

This document is general educational information about preparing an FDA INTERACT meeting package. It is not legal or regulatory advice and does not create an attorney–client or consulting relationship, nor does it substitute for FDA’s guidance documents, the OTP INTERACT webpage, or SOPP 8101.1. Package expectations and timelines are program-specific and subject to change, and FDA advice is informal and non-binding. Confirm current FDA procedures before submitting.