Regulator : Mid-Stage

Mid-Stage Regulatory Engagement

Protocol Alignment & Design Validation

Mid-stage engagement occurs once the protocol structure is established and key design elements are taking shape. At this point, regulatory discussions shift from exploration to confirmation—ensuring that the proposed design is scientifically sound, operationally feasible, and capable of supporting future regulatory decision-making.

Mid-stage engagement typically focuses on:

Confirmation of primary and key secondary endpoints
Statistical approach, power assumptions, and estimates
Control group selection and comparator justification
Inclusion and exclusion criteria, including diversity considerations
Dose selection, treatment duration, and safety monitoring plans

Mid-Stage Federal Drug Administration (FDA) Meetings

This is a broad overview of formal meeting pathways and other formal FDA programs. This roadmap does not reflect interim conversations that may be held with review divisions. In addition, this document is written as though the drug development plan is following a typical Phase 1,2,3 drug development process. If you do not plan to follow the Phase 1,2,3 process you may need to adapt the roadmap to fit your development plan.

Scope and Use of This Roadmap

This section provides a high‑level overview of formal FDA meeting pathways and selected regulatory programs commonly used during mid‑stage protocol development and design confirmation. It does not reflect informal or interim discussions that may occur with FDA review divisions outside of these structured interactions. This roadmap is written assuming a traditional Phase 1, Phase 2, and Phase 3 drug development pathway; programs following accelerated, adaptive, or non‑traditional development approaches may require modification of the timing, sequencing, or regulatory engagements outlined here.

End of Phase 1 (EOP1) Type B Meeting

Definition

It is intended to discuss the adequacy of Phase 1 data to support Phase 2 dosing, the proposed Phase 2 study design and endpoints, and any additional nonclinical or CMC requirements. The meeting also aims to identify potential regulatory concerns early to avoid delays. In addition, the goal is to review and reach agreement on the design of Phase 2 controlled clinical trials so that such testing will provide sufficient data on the drug’s safety and effectiveness to support a decision on its approvability for marketing. The meeting includes discussion of the need for, as well as the design and timing of, studies of the drug in pediatric patients. For drugs intended to treat life-threatening diseases, FDA will provide its best judgment at that time on whether pediatric studies will be required and whether their submission can be deferred until after approval.

Purpose

To review and reach agreement on the design of phase 2 controlled clinical trials.

EOP1 Meetings review several topics:

PK/PD

Absorption/distribution/metabolism/excretion
Method to determine dose to be administered
Planned maximum dose
Duration of patient exposure-Dose/response relationship
Initial safety analysis, unacceptable toxicities

Proposed phase 2 protocol

Objectives and purpose of the study
Study design
- Subject inclusion/exclusion criteria
  - Study Population
  - Subgroups
- Control group (e.g., placebo arm, use of RWD/RWE)
- Statistical analysis plan-Plans for crossover, early data analysis
- Endpoint selection
  - Established
  - Novel (e.g., new COAs, Biomarker, DHTs)
- Identification of populations for phase 3 trials
- Pediatric studies
- EOP2 for accelerated approval
- Novel or Complex Trial Design (e.g., Master Protocol, Sequential Multiple Assignment Randomized Trials, Bayesian, Adaptive)
- Adequacy of supporting nonclinical data
- Proposed studies/trials to support evaluation of abuse potential
- Adequacy of data quality and measures

Common Characteristics

Timing: After Phase 1 completion, before Phase 2 initiation.
Format: Teleconference, videoconference, or face-to-face.
FDA Response Time: Typically scheduled within 70 days of request.
Participants: Sponsor’s clinical, nonclinical, CMC, and regulatory teams; FDA review division.
Outcome: FDA provides written feedback and meeting minutes summarizing recommendations.

Consider Bringing

Meeting Request Letter: State objectives, proposed agenda, and questions for FDA.
Supporting Data: Tables, figures, and reports relevant to Phase 1 and Phase 2 planning.
Subject Matter Experts: Clinical, regulatory, and CMC experts prepared to address FDA questions.
Briefing Package: Submitted at least 30 days before the meeting, including:
- Summary of Phase 1 results: Safety, PK/PD, tolerability.
- Proposed Phase 2 plan: Study design, endpoints, statistical considerations.
- CMC updates: Any changes since IND submission.
- Nonclinical data: If additional studies were conducted.
- Specific questions for FDA: Focused and prioritized.

Considerations

EOP1 meetings are critical for ensuring Phase 2 trials are designed to meet FDA expectations for safety and efficacy, reducing risk of future delays.

Type C Meeting

Definition

A Type C meeting is any meeting other than Type A, Type B, or Type D that addresses product development and review issues. These meetings often involve complex or novel scientific and regulatory topics that require FDA input outside standard milestones.

Purpose

To provide early consultation between FDA review teams and sponsors on specialized development issues

Example: discuss biomarkers as a new surrogate endpoint:

FDA and industry believe that early consultation between review teams and sponsors is important for development programs where the sponsor intends to use a biomarker as a new surrogate endpoint that has never been previously used as the primary basis for product approval in the proposed context of use.
The purpose of this meeting is to discuss the feasibility of the surrogate as a primary endpoint and identify any gaps in knowledge and how they might be addressed.
Must include preliminary human data indicating impact of the drug on the biomarker at a dose that appears to be generally tolerable.

Example: Ongoing discussion of a Clinical Outcome Assessment development and use:

FDA and industry believe that early consultation between review teams and sponsors is important for development programs where the sponsor intends to use a Clinical Outcome Assessment (COA) as an endpoint that has never been previously used as the primary basis for product approval in the proposed context of use.
The purpose of this meeting is to discuss the feasibility of the COA as an endpoint and identify any gaps in knowledge and how they might be addressed.

Common Characteristics

Early engagement: Occurs before pivotal trials when novel endpoints or strategies are proposed.
Focused discussion: Centers on feasibility, scientific validity, and regulatory acceptability of new approaches.
Data-driven: Requires preliminary evidence to support discussion (e.g., human data showing drug impact on biomarker at a tolerable dose).
Collaborative: FDA and sponsor work together to identify gaps and next steps.

Consider Bringing

Meeting Request Letter: Clearly state objectives and rationale for the meeting.
Briefing Package: Submitted at least 30 days before the meeting, including:
- Background on the biomarker or COA and its proposed context of use.
- Preliminary human data showing drug impact on the biomarker or COA at a dose that appears tolerable.
- Scientific justification for why the endpoint could serve as a surrogate or primary measure.
- Specific questions for FDA focused on feasibility and regulatory considerations.
Supporting Data: Summaries of nonclinical and clinical findings relevant to the discussion.
Subject Matter Experts: Clinical, statistical, and regulatory experts prepared to address FDA questions.

Considerations

These points align with FDA’s official guidance on Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products and the examples you provided.

Type D Meetings

Definition

Type D meetings should be limited to no more than 2 focused topics. If the sponsor has several issues or a complex single issue with multiple questions, a Type C meeting should be requested rather than requesting several Type D meetings. In addition, the issue should not require input from more than 3 disciplines or Divisions.

Purpose

Type D meetings are used when sponsors need FDA input on specific, narrow questions during ongoing development—often in Phase 2 or early Phase 3—without waiting for a major milestone meeting like End-of-Phase 2 (EOP2).

Common Characteristics

Timing: Mid-phase (Phase 2 or early Phase 3), when quick FDA feedback is needed.
Scope: Narrow and focused; not for broad strategy discussions.
Format: Teleconference or videoconference; shorter duration.
Outcome: FDA provides written minutes summarizing recommendations.

Consider Bringing

Meeting Request Letter: Clearly state the specific questions and rationale.
Briefing Package: Concise, focused on the issue at hand; includes:
- Relevant background and data (only what’s needed to answer the questions).
- Proposed solution or approach.
Subject Matter Experts: Only those relevant to the narrow topic.

Considerations

Type D meetings are a strategic tool to keep development moving without waiting for larger milestone meetings.

Resources for Regulator Engagement

Formal PDUFA Meetings with FDA References

Website

Frequently asked questions on the PIND meeting

End of Phase 1 Meeting References

21 CFR 312.82(b)
21 CFR part 312, subpart E
21 CFR part 314, subpart H or I
21 CFR part 601, subpart E or H

Guidance for Industry

End-of-Phase 2A Meetings

End of Phase 2 Meeting References

Pre-NDA/BLA Meeting Questions References

21 CFR 312.47b(2)

Guidances for Industry

Submitting Meeting Request References

CTTI

Clinical Trials Transformation Initiative

Regulator : Mid-Stage

Regulator : Mid-Stage

Trial Design Stage

Mid-Stage Regulatory Engagement

Mid-Stage Federal Drug Administration (FDA) Meetings

Scope and Use of This Roadmap

Definition

Purpose

Common Characteristics

Consider Bringing

Considerations

Definition

Purpose

Common Characteristics

Consider Bringing

Considerations

Definition

Purpose

Common Characteristics

Consider Bringing

Considerations

Resources for Regulator Engagement