Description
This document provides guidance to sponsors and applicants submitting investigational new drug applications (INDs), new drug applications (NDAs), biologics licensing applications (BLAs), or supplemental applications on the appropriate use of adaptive designs for clinical trials to provide evidence of the effectiveness and safety of a drug or biologic. The guidance describes important principles for designing, conducting, and reporting the results from an adaptive clinical trial. The guidance also advises sponsors on the types of information to submit to facilitate FDA evaluation of clinical trials with adaptive designs, including Bayesian adaptive and complex trials that rely on computer simulations for their design.
Key Topics
Terms and concepts identified from this document
Scope & Applicability
Product Classes
4Defined 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
Minimum sample size expected for reliable safety evaluation
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
nine-valent human papillomavirus vaccine evaluated using adaptive dose selection
Stakeholders
6Entity responsible for submitting applications under section 524B
Safety oversight body for interpreting adverse events; Safety oversight body for study design
Early discussion is recommended when considering adaptations to endpoint selection.
Entity submitting development data and knowledge; Entity performing the work process for change
personnel involved in the adaptive decision-making (e.g., a monitoring committee)
Data monitoring committee; Oversight body that may request interim analysis
Regulatory Context
Regulatory Activities
10Investigational New Drug submissions
Adaptive seamless design for oncology trials
Cancer clinical trials involving dose escalation
Commitments involved with SPAs for trials with complex adaptive designs
Setting for a sponsor to obtain feedback on adaptive features
Regulatory mechanisms for obtaining formal, substantive feedback from FDA
Mechanism for applicants to discuss total nitrosamine limits with FDA.
The number of subjects in confirmatory trials should provide adequate power to evaluate the primary endpoint.
New Drug Application
Biologics License Application
Document Types
8Document where potential trial adaptations must be pre-specified; Document where the source of external information and prior distribution should be documented.; Should contain core elements and adaptive design rationale.
Innovative trial design element
User Safety Warnings section of the package insert
Comprehensive written plan defining how trial integrity will be maintained
Detailed report submitted when simulations are the primary technique for evaluation
Document defining the roles of the adaptation committee
Should reflect the role of the DMC if allocated the responsibility of assessing safety reporting criteria.
Document for protocol execution; The sponsor should develop a statistical analysis plan that is consistent with the trial protocol; Deviations from this plan must be justified
Attributes
5values that are not of primary interest but may affect the statistical comparisons
Statistical risk that can be increased by conventional analysis methods in adaptive designs; Statistical risk that must be controlled in adaptive designs; Key operating characteristic that must be controlled.
adequate statistical power and accounting for planned analyses
Some adaptive design features can lead to statistical bias in the estimation of treatment effects; potential for biased estimation of treatment effects; Evaluation of treatment effect estimates
improve performance on measures such as the mean squared error
Technical Details
Substances
5evaluated for treatment of patients suffering from severe head injury
Therapeutic intervention in heart failure study
Comparator drug in heart failure study
rotavirus vaccine approved based on the REST trial
combination of sacubitril and valsartan used in PARADIGM-HF trial
Testing Methods
10used to determine important aspects of the design and operating characteristics
Flexible trial design used in the STAMPEDE trial
Basis for designed extension of studies
includes interim looks for potential stopping of treatment arm(s) can also include a sample size reassessment
Methods used in Phase I cancer clinical trials
Continual Reassessment Method used in early-phase dose-ranging trials
A type of adaptive design where asymptotic probability distributions can be derived mathematically.
Computationally demanding algorithm used in Bayesian simulations
Used to integrate PK/PD aspects to aid in design with feasible sample sizes.
Example of covariate-adaptive randomization
Processes
6Trial adaptation based on interim analysis
Process of increasing dosage in clinical cohorts
Designed to compare more than one experimental treatment against a control
Adaptive modifications to the patient population based on comparative interim results
Modifications to sample size based on comparative interim results
Guidance for Industry regarding drugs and biologics; The core subject of the guidance; General topic of the guidance and referenced literature
Clinical Concepts
8treated in the PREVAIL II trial using a Bayesian adaptive design
Therapeutic area for adaptive seamless designs
Patient population for new indication
the highest dose of a drug that does not cause unacceptable side effects
additional endpoints specified in addition to the primary endpoint
Measurement of therapeutic effect likely to predict effect on IMM
Marker thought to predict clinical benefit
The choice of which can be adaptively modified based on comparative interim results.; the main outcome measure used to evaluate effectiveness
Identified Hazards
Hazards
1serious gastrointestinal condition evaluated in the REST trial
Standards & References
External Standards
1Source for definitions of surrogate and intermediate endpoints.
Specifications
2Statistical measure associated with performance reporting
Required for designs allowing adaptive modification to the choice of primary endpoint.; rule defined before the trial to guide adaptations; Rule used to make adaptation decisions
ICH References (1)
Statistical Principles for Clinical Trials; Discourages deterministic procedures due to high risk of bias; Notes that the use of Bayesian methods in clinical trials may be considered.
Related CFR Sections (1)
- 21CFR312.21§ 312.21 Phases of an investigation.
An IND may be submitted for one or more phases of an investigation. The clinical investigation of a previously untested drug is generally divided into three phases. Although in general the phases are conducted sequentially, they may overlap. These three phases of an investigation are a follows:Read full regulation →
See Also (8)
- Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies: Draft Guidance for Industry (Status: Draft)
- Frequently Asked Questions – Statement of Investigator (Form FDA 1572): Guidance for Sponsors, Clinical Investigators, and IRBs (Status: Final)
- General Principles for the Development of Vaccines to Protect Against Global Infectious Diseases: Guidance for Industry (Status: Final)
- Questions and Answers on Informed Consent Elements, 21 CFR § 50.25(c): Guidance for Sponsors, Investigators, and Institutional Review Boards (Status: Final)
- Clinical Pharmacogenomics: Premarket Evaluation in Early-Phase Clinical Studies and Recommendations for Labeling (Status: Final)
- Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products: Guidance for Industry (Status: Final)
- Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research Guidance for Industry: Guidance for Industry (Status: Final)
- Standardized Format for Electronic Submission for Marketing Applications Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for Center of Biologics Evaluation and Research Submissions (Status: Draft)