Interacting with the FDA on Complex Innovative Trial 

Designs for Drugs and Biological Products

Guidance for Industry

Roadmap for interacting with sponsors on CID Proposals

What is recommended in this guidance? 

This guidance provides recommendations to sponsors and applicants on interacting 

with the FDA on complex innovative trial design (CID) proposals for drugs or 

biological products and describes the type of information FDA recommends 

submitting.

CID Definition 

For the purposes of this guidance, CID includes trial designs that have rarely or 

never been used to date to provide substantial evidence of effectiveness in new drug 

applications or biologics license applications. There is no fixed definition of CID 

because what is considered innovative or novel can change over time.

Guidance Snapshots are a communication tool and are not a substitute for the guidance document.

To learn more about interacting with sponsors on complex innovative trial designs for drugs and 

biological products, read the guidance

*The Bayesian method relies on accurate specification of the prior probability distribution of unknown parameters to control the chance of erroneous conclusions. Prior distributions can be

formed from a variety of sources, including previous trial data or other clinical data, and they can also incorporate features such as down weighting of earlier data relative to contemporaneous 

data or initial skepticism regarding the likelihood of large treatment effects.

SIMULATIONS

End of Phase 2 meetings often 

occur at a stage in the development 

process where preliminary 

plans for Phase 3 trials can be 

discussed, and these preliminary 

plans may suggest the need for 

trial simulations. If a CID proposal 

includes simulations, structuring 

part of the End of Phase 2 

discussions around Phase 3 trial 

simulation plans can help FDA 

reviewers and the sponsor consider 

the scenarios to be explored in 

simulations and the underlying trial 

assumptions, such as accrual rate 

or likely control group outcomes.

MEETING 

WITH FDA

Sponsors should seek early 

interaction with FDA. In general, 

sponsors should use existing 

interaction pathways, including 

Type A, Type B, Type B endofphase, and Type C meetings, 

IND amendment review, and 

possibly pre-IND meetings for 

early-phase studies with novel 

design elements. An additional 

option for interaction is through 

the CID Pilot Meeting Program.

SUBMISSION

DOCUMENTATION

The specific documentation 

needed will depend on the type 

of proposal submitted, but in 

general, documentation should 

include the novel features that are 

planned to be incorporated, the 

timing and details of the planned 

implementation, and how the 

design addresses the underlying 

scientific objectives.

BAYESIAN CID 

PROPOSALS 

If a sponsor chooses to submit 

a Bayesian CID proposal, 

the sponsor should include 

appropriate documentation for 

review, including descriptions and 

rationales for two key items:

1. prior distributions* 

2. study decision criteria for 

primary and key secondary 

endpoints.
Guidance Recap Podcast – Hear Highlights Straight From FDA Staff

Speaker: Dr. Greg Levin, Deputy Director of the Division of Biometrics III in the 

Center for Drug Evaluation and Research’s Office of Biostatistics

Background About the Guidance 

CIDs have the potential to improve trial efficiency, for example making trials smaller 

and faster. However, with these potential advantages come additional challenges, due 

in part to limited experience with these trial designs in regulatory decision-making. 

Due to their complexity and in some cases to their novelty, CID designs often call for 

additional regulatory review documentation. FDA is issuing this guidance to help ensure 

successful interactions between sponsors and the FDA that support the regulatory review 

of CID proposals for trials intended to provide substantial evidence of effectiveness for 

drugs and biologics.

Drug Development Timeline – 

When to Apply the Guidance Recommendations?

During Clinical Development: 

Because CID proposals may involve novel scientific review 

considerations, FDA encourages sponsors of CID proposals 

to seek early interaction with FDA regarding details of their 

CID plans. In general, sponsors should use existing pathways 

for interacting with FDA during the course of the clinical 

development program, including Type A, Type B, Type B 

end-of-phase, and Type C meetings, IND amendment review, 

and possibly pre-IND meetings for early-phase studies with 

novel design elements.

Basic 

Research

Prototype Design

or Discovery Preclinical

Development Phase 1 Phase 2 Phase 3

Clinical Development

Basic 

Research

Prototype Design

or Discovery

Preclinical

Development

FDA Filing 

Approval

Post-Market/

Post-Approval

Studies

Phase 1 Phase 2 Phase 3

Guidance Snapshots are a communication tool and are not a substitute for the guidance document.

To learn more about interacting with sponsors on complex innovative trial designs for drugs and 

biological products, read the guidance.

To see additional Guidance Snapshots, check out the pilot program.

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