Early FDA Engagement is Essential

Navigating the FDA review process for investigational new drugs (INDs) is the critical final step for sponsors being permitted to initiate clinical trials and ship investigational product. Early engagement with the FDA is an opportunity to de-risk IND-enabling work that should not be passed on. By initiating dialogue with the FDA months before submitting an IND application, sponsors can address potential challenges, reduce program risks, and establish a collaborative relationship with the agency.

This blog explores the objectives, timing, and practicalities of early FDA interactions, emphasizing their importance in aligning preclinical, manufacturing and clinical development strategies with regulatory expectations.

Why Early FDA Engagement Matters

Engaging the FDA early serves several vital objectives:

1. Introduction and Collaboration:
   Early meetings introduce the sponsor and their technology to the FDA, fostering a collaborative relationship that can be beneficial throughout the drug development lifecycle.
2. De-Risking the Program:
   By seeking feedback early, sponsors can identify and mitigate potential regulatory hurdles, saving time and resources in the long run.
3. Aligning on the IND-Enabling Data Package:
   Sponsors can gain clarity on the specific data requirements for IND submission, ensuring that their preclinical, manufacturing and clinical programs align with FDA expectations.
4. Clinical Development Guidance:
   The FDA can provide valuable input on clinical trial design, including patient population, starting doses, and safety monitoring protocols.
5. Easing the IND Review Process:
   By proactively addressing FDA concerns and pointing the FDA to where these concerns are addressed within the IND application via an IND Reviewer’s Guide, sponsors reduce the number information requests (IRs) during the IND review and de-risk a clinical hold outcome. This approach facilitates an easier efficient review process for the agency.

Timing Your FDA Interactions: Considerations

The timing of FDA engagement depends upon the “drivers” needing FDA feedback. Timelines could be driven by investors/investment need to seek FDA concurrence on plans, or data to support the proposed IND-enabling activities in which you want feedback on. We categorize FDA engagement timing as early, middle, and late-stage interactions with each serving distinct purposes.

1. Early Engagement (~1 Year Before IND Submission)
   1. Objective: Solicit high-level feedback on R&D plans when little or no data is available.
   2. Ideal for:
      • Sponsors new to drug development.
      • Programs involving novel or innovative drugs with unique manufacturing or toxicological challenges.
   3. Focus Areas:
      • Design attributes for preclinical and clinical studies.
      • Manufacturing plans including novel synthesis, starting novel or raw materials, and novel analytical methods
      • Patient population considerations.
   4. Limitations:
      At this stage, feedback is typically broad given the lack of program data. Sponsors should not expect detailed input on starting doses or safety monitoring procedures, as these require data-supported justifications.
2. Mid-Stage Engagement (~6–9 Months Before IND Submission)
   1. Objective: Seek feedback on definitive, IND-enabling activities supported by preliminary data.
   2. Ideal for:
      • Sponsors with early pharmacology proof-of-concept data or safety studies.
      • Programs with defined specifications, methods, and controls for drug manufacturing and testing.
   3. Focus Areas:
      • Manufacturing process development and control strategies.
      • Design of preclinical IND-enabling / definitive studies
      • Clinical trial protocols design and selected study population
   4. Benefits:
      Mid-stage discussions provide more actionable feedback, helping sponsors refine their IND packages and de-risk the future IND application submission.

3. Late-Stage Engagement (~3 Months Before IND Submission)

   1. Objective: Confirm that the IND package is complete and adequate for submission.
   2. Focus Areas:
      • Final validation of manufacturing (CMC) and pharmacology/toxicology (pharm/tox) packages.
      • Feedback on the complete clinical protocol synopsis.
   3. Purpose:
      This stage functions as a “check-the-box” exercise to ensure all requirements are met before IND submission. This scenario presents risk if FDA is not agreement with proposed IND package as there is not sufficient time to mediate or implement studies to generate requested data.

Early FDA Engagement Formats

Depending on the “drivers” seeking FDA feedback, the desired timing to receive FDA feedback, the topics in which FDA feedback is requested will dictate the type of FDA early engagement, as there are multiple options.

• INTERACT - Novel, innovative technologies that present significant challenges with respect to manufacturing to the FDA’s current expectations and regulations as well as challenges to conduct a preclinical safety evaluation to enable the administration of this product to humans are the common themes discussed at an INTERACT Meeting.
• Pre-IND –  A formal opportunity to gather the Agency’s preliminary perspective on critical aspects of the drug development program and de-risk any potential clinical hold issues during FDA review of the initial IND. Pre-IND questions should be focused on the product-specific topics that require FDA feedback to either de-risk IND review or to facilitate more streamlined product development.
• Type C –A Type C is a meeting format that allows for feedback on topics that do not fit into other PUDFA meeting types. A Type C meeting could be requested in follow-up to a Pre-IND meeting if there are significant challenges / risk that arise following receipt of Pre-IND Feedback.
• Type D - A Type D meeting is focused on a narrow set of issues (e.g., often 1, but typically not more than 2 issues and associated questions). A Type D meeting has been utilized to solicit FDA feedback on a narrow topic (i.e. Species Selection for definitive toxicology studies), prior to proceeding to a Pre-IND meeting.

Conclusion

Early and strategic engagement with the FDA is an invaluable part towards advancing towards submission of an IND application. By aligning with the agency’s expectations, sponsors can de-risk their programs, streamline the review process, and set the stage for successful clinical trials. For new and experienced sponsors alike, proactive communication with the FDA is not just beneficial—it’s essential for turning innovative drug concepts into approved therapies.