Description
This guidance provides recommendations to sponsors and investigators considering the use of externally controlled clinical trials to provide evidence of the safety and effectiveness of a drug product. In an externally controlled trial, outcomes in participants receiving the test treatment according to a protocol are compared to outcomes in a group of people external to the trial who had not received the same treatment. The external control arm can be a group of people, treated or untreated, from an earlier time (historical control), or it can be a group of people, treated or untreated, during the same time period (concurrent control) but in another setting.
Key Topics
Terms and concepts identified from this document
Scope & Applicability
Product Classes
3RTRT and CTD sections apply to drug products
Requires analytical comparability per ICH Q5E
Scope of the electronic transmission guidance
Stakeholders
3Entity responsible for submitting applications under section 524B
The specific regulatory body sponsors should consult
Responsible for qualifications, training, and trial conduct; Individual responsible for trial conduct and data governance at a site.; May delegate tasks but retains overall responsibility; Person responsible for the conduct of the clinical trial at a trial site; Responsible for trial conduct and participant safety; Responsible for trial conduct, data integrity, and investigational product management.; Individual responsible for trial conduct at a site and informing the institution.; maintaining
Regulatory Context
Regulatory Activities
2clinical trials where outcomes are compared to a group external to the trial; Design and conduct considerations for drug and biological products; The primary study design discussed for drug evaluation
Requirement for drug approval under the FD&C Act
Document Types
8Source of RWD for evaluation of safety or effectiveness.
Original documents, data, and records such as hospital records and clinical charts
Sponsors must include relevant patient-level data in these applications
Defines the standard of veterinary practice and limits for anesthetic regimens
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
Data source for RWD; information submitted to insurers to receive payment for treatments; Data source used to support regulatory decision-making.; Data source used for real-world evidence studies.; Examples of confounders that can be unmeasured or imperfectly measured in electronic health care data, especially in claims data.; Source of real-world data
Administrative data used as a source of RWD.
Document defining the design and conduct of the trial
Attributes
4Time Zero in the designation of trial parameters; Determination of the start date for treatment and external control arms to avoid immortal time bias
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.
May change over time and impact comparability of external control arms
Inclusion and exclusion characteristics of the study population
Technical Details
Substances
1Used to increase development efficiency
Testing Methods
4Framework for describing the treatment effect and designing trials
Analytical methods used to address missing information
A balancing method applied to statistical distributions of covariates
Statistical considerations in clinical trials
Processes
2Trial design using external control arms instead of randomized concurrent controls
Method to re-adjudicate externally controlled data to reduce bias
Clinical Concepts
8Single-arm trial endpoint in oncology
Precise specifications are likely to address many of the key intercurrent events.
The course of a disease over time without intervention
Variables that can bias the results of an externally controlled trial
Events requiring handling strategies within the estimand rationale.; Events occurring after treatment initiation that affect the interpretation of the outcomes.
Discrete clinical event used to identify index date
correlated with female sex in VAD study
Discrete clinical event used to identify index date
Identified Hazards
Hazards
4mitigate potential unwanted bias in learning or performance estimation
Potential error in study variables that can lead to false positives/negatives and bias results.
A factor to be managed in the analysis of real-world data; considering sources of potential bias and confounding; Studies must address two sources of error: systematic error (bias, confounding).
A specific bias mentioned in the framework of pharmacoepidemiological studies; Immortal time bias refers to a period of cohort follow-up time during which an outcome of interest cannot occur.
Standards & References
External Standards
1Response Evaluation Criteria in Solid Tumors used for assessing response rate
Specifications
2Radiologic endpoint in oncology trials
Measures of activity may include PFS
ICH References (3)
Integrated Addendum to ICH E6(R1) document
Choice of Control Group in Clinical Trials.
Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials
Related CFR Sections (3)
- 21CFR601.2§ 601.2 Applications for biologics licenses; procedures for filing.
(a) General. To obtain a biologics license under section 351 of the Public Health Service Act for any biological product, the manufacturer shall submit an application to the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing aRead full regulation →
- 21CFR314.50§ 314.50 Content and format of an NDA.
NDAs and supplements to approved NDAs are required to be submitted in the form and contain the information, as appropriate for the particular submission, required under this section. Three copies of the NDA are required: An archival copy, a review copy, and a field copy. An NDA for a new chemical enRead full regulation →
- 21CFR314.126§ 314.126 Adequate and well-controlled studies.
(a) The purpose of conducting clinical investigations of a drug is to distinguish the effect of a drug from other influences, such as spontaneous change in the course of the disease, placebo effect, or biased observation. The characteristics described in paragraph (b) of this section have been develRead full regulation →
Related MFDS Guidelines
Korean regulatory guidelines covering similar topics
See Also (8)
- Advanced Manufacturing Technologies Designation Program (Status: Final)
- Environmental Assessment of Human Drug and Biologics Applications: Guidance for Industry (Status: Final)
- Content and Format of Chemistry, Manufacturing and Controls Information and Establishment Description Information for a Vaccine or Related Product: Guidance for Industry (Status: Final)
- Providing Regulatory Submissions to the Center for Biologics Evaluation and Research (CBER) in Electronic Format - Biologics Marketing Applications: Guidance for Industry (Status: Final)
- Submission of Abbreviated Reports and Synopses in Support of Marketing Applications. (Status: Final)
- Use of Sterile Connecting Devices in Blood Bank Practices: Guidance for Industry (Status: Final)
- Submitting Marketing Applications According to the ICH/CTD Format: General Considerations (Status: Draft)
- Pharmacogenomic Data Submissions; Examples of Voluntary Submissions or Submissions Required Under 21 CFR 312, 314, or 601 (Status: Final)