Description
To properly inform decision-making by pharmaceutical companies, regulators, patients, physicians, and other stakeholders, clear descriptions of the benefits and risks of a treatment (medicine) for a given medical condition should be made available. Without such clarity, there is a concern that the reported treatment effect will be misunderstood. This addendum presents a structured framework to strengthen the dialogue between disciplines involved in the formulation of clinical trial objectives, design, conduct, analysis and interpretation, as well as between sponsor and regulator regarding the treatment effect or effects of interest that a clinical trial should address.
Key Topics
Terms and concepts identified from this document
Scope & Applicability
Product Classes
3ICH mission regarding safe, effective, and high-quality medicines
Defined 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
Example used for principal stratum strategy regarding infection severity
Stakeholders
2Entity responsible for submitting applications under section 524B
Initial sender type flagged in C.1.8.2
Regulatory Context
Regulatory Activities
2Trials where regulatory interest in the application of these principles will be greater.
The process by which agencies approve or evaluate products based on trial results
Document Types
3Specifies DHT use and data collection methods
Report where the quality management approach is described.; Post-unblinding data changes and deviations from the planned statistical analyses should be reported in the clinical trial report; Document where deviations from the statistical analysis plan are described
Labeling where results of sensitivity analysis may be included
Attributes
4Attributes used for constructing an estimand
Data that would be meaningful for the analysis of a given estimand but were not collected.
Evaluation of robustness and parameter ranges of analytical procedures; Development of a robust multivariate analytical procedure includes scientifically justified sample selection; Capacity of an analytical procedure to meet performance criteria during normal use.; Assessed using retention time models; Performance characteristic to be validated
An attribute used to provide a basis for comparison between treatment conditions
Technical Details
Substances
1Additional treatments that may be considered intercurrent events
Testing Methods
8A specific type of sensitivity analysis to investigate departures from assumptions
Classification of subjects according to the potential occurrence of an intercurrent event on all treatments.
A method of analysis to compute an estimate of the estimand using clinical trial data.
Determining the number of subjects required for a trial based on the estimand
Performed to identify uncertainties that could affect HCEI conclusions.
Statistical analysis aligned to the estimand
Statistical analysis section of the protocol
The primary method of analysis aligned to a given estimand
Processes
2Process of assigning trial participants to treatment or control groups using an element of chance; Process of assigning participants to treatment groups.; Process of assigning participants to groups using chance to reduce bias.
Manufacturing and handling should maintain blinding
Clinical Concepts
5Events requiring handling strategies within the estimand rationale.; Events occurring after treatment initiation that affect the interpretation of the outcomes.
description of the treatment effect of interest using natural, non-technical language; The effect being measured and understood through supplementary and sensitivity analyses.
The Prevention and Treatment of Missing Data in Clinical Trials
Reporting adverse events when engaging with patients.; changes may be related to benefits, tolerability, and/or unintended effects
Events such as death that prevent further measurement of a variable
Identified Hazards
Hazards
1A safety concern that may lead to treatment discontinuation
Standards & References
Specifications
2ICH E9 indicates that it is usually appropriate to plan for analyses based on both the FAS
Consistent results from analyses based on the FAS and the PPS is indicated as increasing confidence
ICH References (2)
Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials
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 MFDS Guidelines
Korean regulatory guidelines covering similar topics
See Also (8)
- E11A Pediatric Extrapolation
- M15 General Principles for Model-Informed Drug Development
- Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product
- Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances
- Rare Diseases: Considerations for the Development of Drugs and Biological Products
- Q3C Impurities: Residual Solvents_2011
- Providing Regulatory Submissions in Electronic Format --Content of the Risk Evaluation and Mitigation Strategies Document Using Structured Product Labeling: Guidance for Industry
- Q4B Annex 5: Disintegration Test General Chapter