E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) | Guideline Explorer

Description

Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety, and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

1

Investigational Product

Synonymous with drugs, medicines, medicinal products, vaccines, and biological products.; Product intended to benefit population groups once authorized; The product being tested in the clinical trial.; The product being studied in the clinical trial.; monitoring extent based on the nature of the investigational product; Management, storage, and accountability of the product being tested.; management should be arranged and conducted in accordance with applicable regulatory requirements; The produ

Stakeholders

10

Subject

Providing new information to subjects who have completed their active participation.

Monitor

assigned as contact point for each site

impartial witness

If a subject is unable to read, an impartial witness should be present during the informed consent discussion.

IRB/IEC

Institutional Review Board or Independent Ethics Committee responsible for trial review

Institutional Review Board

Governs top dose in clinical studies

Independent Ethics Committee

Responsible for submission and communication oversight; Safeguard the rights, safety and well-being of trial participants; Reviewing trial conduct and records

Investigator

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

Sponsor

Entity responsible for submitting applications under section 524B

Independent Data Monitoring Committee

Body that may propose protocol amendments or maintain trial integrity

Legally Acceptable Representative

Provides consent for participants unable to do so; Individual who may provide consent on behalf of a participant; Individual authorized to provide consent on behalf of a participant; Provides consent on behalf of participants when appropriate.; An individual or body authorized to consent on behalf of a prospective participant.

Regulatory Context

Regulatory Activities

5

Monitoring

Section 5.18 Monitoring purpose and procedures; The investigator/institution should permit monitoring by the sponsor

clinical trial

assessment of the implications of the information for future clinical trials

Auditing

The investigator/institution should permit auditing by the sponsor

Audit

Sponsor's independent function to assess trial conduct

Inspection

FDA verification of qualified facility status, including for-cause inspections

Document Types

10

Clinical Trial Protocol

Document 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.

Clinical Study Report

CSR supported by ADaM datasets; Contains analysis results and animal listings

Treatment Allocation and Decoding Documentation

Returned to sponsor to document any decoding that may have occurred.

Final Trial Close-Out Monitoring Report

To document that all activities required for trial close-out are completed.

Completed Subject Identification Code List

To permit identification of all subjects enrolled in the trial in case follow-up is required.

Documentation of Investigational Product Destruction

To document destruction of unused investigational products by sponsor or at site.

Investigational Product Accountability at Site

To document that the investigational product(s) have been used according to the protocol.

Monitoring Visit Report

To document site visits by, and findings of, the monitor

Master Randomization List

To document method for randomization of trial population

Certificate of Analysis

Document indicating analytical results of testing; record relied on to control L. monocytogenes in ingredients; document provided for a food prior to or upon receipt of the food; COA documentation

Attributes

9

Source Data

Information in original records necessary for trial reconstruction; Data recorded directly on CRFs considered to be source data.; To document the existence of the subject and substantiate integrity of trial data collected

Certified Copy

A copy used to permanently replace an original essential record.

therapeutic index

Narrow margins may necessitate dose adjustments

Bioavailability

Biological property that may be altered by manufacturing changes; safety narrative should address bioavailability of the ingredients

Dose response

discuss the most important findings from the studies, including the dose response

Sample Size

statistically justified calculation required in the plan

Data Integrity

Responsibility for the integrity of the trial data

expiration dates

Records of investigational products should include expiration dates if applicable.

Confidentiality

Protection of data whose disclosure could lead to patient harm

Technical Details

Substances

3

Investigational Product

Pharmaceutical form of an active ingredient or placebo being tested; Product being tested in the clinical trial; Pharmaceutical form of an active ingredient being tested in a trial

metabolites

Breakdown products of the drug that may be microbiologically active

Excipients

Differences in excipients may affect product stability

Testing Methods

4

Statistical analyses

Method recommended for conducting data analyses of test results

Carcinogenicity

Studies needed prior to marketing in certain adjuvant settings

Genotoxicity

Test-specific consideration; Specific biocompatibility testing consideration.; Biological effect endpoint for consideration; Hazard identification tests used to confirm chemicals are not genotoxic.

Statistical Methods

Analysis of test data and rationale for sample sizes

Processes

7

Randomization

Process 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.

Nonclinical Pharmacology

A summary of the pharmacological aspects of the investigational product

Toxicology

Data required in NDAs including acute, subacute, and chronic toxicity

Pharmacokinetics

Dosing considerations for pregnant women in trials; Study of drug movement in the body, which may change during pregnancy.

Blinding

Manufacturing and handling should maintain blinding

Risk Assessment

Conducted for new impurities observed after registration toxicology studies

Audit Trail

maintained for changes to source data and CRFs

Clinical Concepts

8

Adverse Drug Reaction

Basic term defined in section 2.1.2; Noxious and unintended responses to a medicinal product where a causal relationship is a reasonable possibility.

Serious Adverse Events

SAEs collected during interventional clinical trials

adverse events

Safety events that must be tracked for different updates

Adverse Drug Reactions

Nonserious and serious ADRs from postmarketing sources

Vulnerable Subjects

Subjects likely to be vulnerable to coercion or undue influence

Unexpected Adverse Drug Reaction

Adverse reaction not consistent with product information

Adverse Event

Reactions or events observed in patients; Information described in an ICSR; Information associated with the use of biopharmaceuticals; Clinical information corrected during an amendment; Section D describes the singular subject who experienced one or several adverse events/reactions.; Reactions or events observed in patients or foetuses; The onset of a reaction/event following drug administration.; Reporting of reactions to suspect drugs; Reaction or event reported by the primary source; Reactio

Serious Adverse Event

Adverse events resulting in death, hospitalization, or significant disability.

Identified Hazards

Hazards

1

immediate hazard

Deviations may be implemented to eliminate an immediate hazard to trial subjects.

Standards & References

External Standards

1

Declaration of Helsinki

Ethical principles that are the origin of GCP standards.; Ethical principles for medical research involving human subjects

Specifications

5

Quality Tolerance Limits

prespecified acceptable ranges at the trial level

Normal Value

NORMAL VALUE(S)/RANGE(S) FOR MEDICAL/LABORATORY/TECHNICAL PROCEDURES; Updates to normal value(s)/range(s) for medical/laboratory procedures

Exclusion Criteria

Subject exclusion criteria for selection and withdrawal.

Inclusion Criteria

Subject inclusion criteria for selection and withdrawal.

primary endpoints

Endpoints critical to establish effectiveness for approval

ICH References (10)

ICH E6(R2)

Integrated Addendum to ICH E6(R1) document

ICH Guidance for Structure and Content of Clinical Study Reports

meet the standards of the ICH Guidance for Structure and Content of Clinical Study Reports

ICH Guideline for Structure and Content of Clinical Study Reports

Guidance referenced for trial design and reporting.

ICH E6(R1)

Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting

ICH E2A

Provides definitions for seriousness criteria; ICH E2A recommends blinded therapy should not be reported

ICH E3

document remedial actions in the clinical trial report; Structure and Content of Clinical Study Reports standards.

ICH E7

Studies in Support of Special Populations: Geriatrics

ICH E8

General Considerations for Clinical Studies

ICH E9

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.

ICH E11

Clinical Investigation of Medicinal Products in the Pediatric Population.

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

Failure to ensure that the investigation was conducted according to the investigational plan

21

Failure to submit an Investigational New Drug application (IND)

9

Failure to obtain informed consent

5

Unapproved new drug

5

Misbranded drug

4

Failed to ensure that the investigation was conducted according to the investigational plan

3

Enrollment of subjects who do not meet eligibility criteria

3

Failure to submit INDs for the conduct of clinical investigations

3

Unlicensed biological product

2

unapproved new drugs

2

Recent Cases

Related Warning Letters (10)

Related MFDS Guidelines

Korean regulatory guidelines covering similar topics