Description
The efficacy and safety of medicinal products should be demonstrated by clinical trials that follow the guidance in E6 Good Clinical Practice: Consolidated Guidance adopted by the ICH, May 1, 1996. The role of statistics in clinical trial design and analysis is acknowledged as essential in that ICH guidance. The proliferation of statistical research in the area of clinical trials coupled with the critical role of clinical research in the drug approval process and health care in general necessitate a succinct document on statistical issues related to clinical trials. This guidance is written primarily to attempt to harmonize the principles of statistical methodology applied toclinical trials for marketing applications submitted in Europe, Japan and the United States.
Key Topics
Terms and concepts identified from this document
Scope & Applicability
Product Classes
3Product being tested in clinical trials
Subject of safety and tolerability assessments
The drug being tested in clinical trials for MDS.
Stakeholders
5responsible for justifying omission of studies
Appropriately qualified and experienced individual responsible for statistical work; decisions made after the statistician has had access to the treatment codes
Body that may propose protocol amendments or maintain trial integrity
responsible for ensuring the protocol covers statistical issues; member of the team responsible for the clinical study report; Person responsible for the statistical aspects of the trial
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
7Rule does not apply to products marketed under an NDA
Trials falling into the category of equivalence trials.
Justification for noninferiority margin for early Lyme disease using doxycycline as active control.
Trial designed to show that two treatments do not differ by more than a specified margin.; In an equivalence or noninferiority trial, use of the full analysis set is generally not conservative.; showing response to treatments differs by clinically unimportant amount
The clinical trial design context for the instrument.
Trials designed to provide evidence for claims
sponsors should obtain advice from FDA prior to initiating trials for marketing applications; Clinical trials designed to support a marketing application
Document Types
10Summary of safety and tolerability
required for marketing applications in Japan
required for marketing applications in the EU
required for marketing applications in the United States
structure and content of clinical study reports is the subject of ICH E3
details of any adjustment procedure should be set out in the analysis plan
Basic statistical principle for clinical trials
Source of cumulative clinical trial exposure data
changes should always be described by a protocol amendment
media for data transfer
Attributes
10statistically justified calculation required in the plan
Subset of subjects who complied with the protocol sufficiently
Use of a toxicity grading scale should be prespecified
A similar approach should be adopted to exploring the influence of outliers.
reporting of results that appropriately account for the adaptive design
statistical property of hypothesis tests that should be accurate
A parameter required for sample size calculation.
Property of assessment variables for detecting changes.
feature of acceptable assay performance
Study-wise control recommended for hypothesis testing in subgroups
Technical Details
Substances
1Accountability procedures for the investigational product including placebo; used as a reference in a clinical trial
Testing Methods
10Whether an interim analysis is planned.; Rationale for any interim analysis planned with respect to its purpose and timing.; Analyses conducted while the trial is ongoing for stopping or adapting
Special safety test used in clinical trials
Includes clinical chemistry and hematology used to assess safety
significance tests and confidence intervals
used to exploit relationship of adverse events to duration of exposure
safety and tolerability implications are best addressed by applying descriptive statistical methods
survival analysis methods should be considered for long-term treatment
usual frequentist approach to the analysis of clinical trial data
Data are usually analyzed using analysis of covariance (ANCOVA)
Imputation techniques may also be used in an attempt to compensate for missing data.
Processes
10Trial design considerations
analysis where new questions may emerge from observed data
formal evaluation of quantitative evidence from two or more trials
multiplicity may arise from interim analyses
subgroup or interaction analyses are exploratory
selection of the data transformation method(s) can be driven by the type of data
plan should be reviewed and updated as a result of the blind review; Possible amendments to the way in which the analysis will deal with protocol violations should be identified during the blind review.; carry out the blind review of the planned analysis
The collection of data and transfer of data from the investigator to the sponsor
Group sequential designs are used to facilitate the conduct of interim analysis.; breaking the blind to make treatment comparisons; analysis intended to compare treatment arms prior to formal completion
Grouping defined by important prognostic factors measured at baseline.; Purpose of performing certain screening assessments.
Clinical Concepts
7Safety findings including deaths and post-mortem examinations
Signs requiring immediate cessation of drug use
Committee should complete real-time review of these events.
Studies needed if comparative dissolution similarity is not achieved
Potential risks like low blood pressure or irregular heartbeat from ingredient interactions.
Reason a patient may be unable to complete a PRO measure; Treatment discontinuation due to AE.; Reason for treatment discontinuation or PRO non-completion.
The group for which the device is intended
Identified Hazards
Hazards
1Impact during study sample analysis should be assessed and reported
Standards & References
External Standards
1Hierarchical medical dictionary for coding adverse reactions
Specifications
5variable providing the most clinically relevant evidence for the primary objective
Definitions of measurement units and reference ranges of laboratory variables
Maximum acceptable difference in population means for quantitative attributes; Criteria used to conclude equivalence if the confidence interval is within this range
supportive measurements related to primary or secondary objectives
integration of multiple measurements into a single variable
ICH References (10)
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.
Studies in Support of Special Populations: Geriatrics
Data standard for electronic transmission of individual case safety reports
MedDRA is also known as ICH M1
Provides definitions for seriousness criteria; ICH E2A recommends blinded therapy should not be reported
document remedial actions in the clinical trial report; Structure and Content of Clinical Study Reports standards.
The Extent of Population Exposure to Assess Clinical Safety: For Drugs Intended for Long-term Treatment of Non-Life-Threatening Conditions
Referenced for safety data collection and adverse event reporting plans.
Dose-Response Information to Support Drug Registration
General Considerations for Clinical Studies
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