Description
This document provides guidance to sponsors and applicants on interacting with the FDA on complex innovative trial design (CID) proposals for drugs or biological products. FDA is issuing this guidance to satisfy, in part, a mandate under section 3021 of the 21st Century Cures Act (Cures Act). In accordance with the Cures Act mandate, this guidance discusses the use of novel trial designs in the development and regulatory review of drugs and biological products, how sponsors may obtain feedback on technical issues related to modeling and simulation, and the types of quantitative and qualitative information that should be submitted for review. Additional recommendations related to the mandate set forth in section 3021 of the Cures Act are addressed in FDA’s guidance on Adaptive Designs for Clinical Trials of Drugs and Biologics (Ref. 1). This guidance finalizes the draft guidance of the same title dated September 2019.
Key Topics
Terms and concepts identified from this document
Scope & Applicability
Product Classes
3Defined in section 201(g) of the FD&C Act; Articles intended for use in diagnosis, cure, mitigation, treatment, or prevention of disease; Product classification based on chemical action or specific intended uses like altering pH
Regulated under section 351(i) of the PHS Act; Virus, therapeutic serum, toxin, vaccine, or protein applicable to prevention or treatment; Alternative regulation category for products meeting device definition
Requires analytical comparability per ICH Q5E
Stakeholders
3Entity responsible for submitting applications under section 524B
Entity submitting development data and knowledge; Entity performing the work process for change
Safety oversight body for interpreting adverse events; Safety oversight body for study design
Regulatory Context
Regulatory Activities
7Rule does not apply to products marketed under an NDA
BLA for biological products
IND for treatment use; Regulatory submission required for clinical trials and expanded access.
formal meetings for routine feedback on IND amendment submissions
Mechanism for applicants to discuss total nitrosamine limits with FDA.
Meeting held prior to IND submission; Meeting to receive feedback before submitting an IND.; Meeting appropriate when manufacturing process is defined and POC completed.; discuss the adequacy of these data at a pre-IND meeting
pilot program for complex innovative trial designs to obtain additional meetings; Examples include randomized, double-blind, placebo-controlled studies.
Document Types
4Innovative trial design element
Single trial infrastructure used in umbrella trials
Provides simulation strategy and outcomes related to alternative dosing regimens
Document defining the design and conduct of the trial
Attributes
3Chance of producing erroneous conclusions
relevance of external data to the proposed trial design
Bayesian inference relies on well-informed specification of the prior
Technical Details
Testing Methods
8Recommended elements of Bayesian CID Proposals
Approaches used in pediatric extrapolation plan; M&S strategies should be applied to support the initial dose selection; Used to summarize reference data or inform the choice of analysis strategy.
Examples of CID include SMARTs
used to determine important aspects of the design and operating characteristics
Method of statistical inference using Bayes' theorem to update probability.
approach to investigate differences in a numeric pain scale
Used to address heterogeneity between prior data and concurrent Phase 3 data.
technique to incorporate information from reference population
Clinical Concepts
4The standard of evidence required for drug approval, which master protocols can contribute to.
Data should be presented in enough detail for FDA to evaluate its quality.
Study of investigational treatment in ambulatory patients.
Non-inferiority study comparing an investigational drug to an active control.
Standards & References
Specifications
3Recommended elements of Bayesian CID Proposals
Recommended elements of Bayesian CID Proposals; implementation details for interim analyses and primary endpoints
should be addressed where applicable in the evaluation of operating characteristics
See Also (8)
- Advanced Manufacturing Technologies Designation Program
- Direct-to-Consumer Prescription Drug Advertisements: Presentation of the Major Statement in a Clear, Conspicuous, and Neutral Manner in Advertisements in Television and Radio Format Final Rule Questions and Answers
- Q4B Annex 8: Sterility Test General Chapter
- Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products: Draft Guidance for Industry
- Failure to Respond to an ANDA Complete Response Letter Within the Regulatory Timeframe Guidance for Industry: Guidance for Industry
- CMC Postapproval Manufacturing Changes for Specified Biological Products To Be Documented in Annual Reports
- Best Practices in Developing Proprietary Names for Human Nonprescription Drug Products; Draft Guidance for Industry: Draft Guidance for Industry
- Best Practices in Developing Proprietary Names for Human Prescription Drug Products; Guidance for Industry: Guidance for Industry