Study guide
1.1 The Eleven ICH E6(R3) Principles of GCP & Guideline Structure
ACRP Certified Professional ACRP-CP
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1 Chapter 1: GCP Principles, Roles & Delegation
1.1 The Eleven ICH E6(R3) Principles of GCP & Guideline Structure 1.2 Sponsor & Investigator Responsibilities and Delegation of Authority 1.3 Staff Training, Qualifications & Delegation of Authority Log (DOAL) 1.4 CRO Oversight, Vendor Management & Transfer of Regulatory Obligations (TORO)
2 Chapter 2: Essential Records, Source Documentation & Data Confidentiality
2.1 Essential Records Before, During and After the Trial (ICH E6(R3) Appendix C) 2.2 Trial Master File (TMF) and Investigator Site File (ISF) Structure & Inspection Readiness 2.3 Source Documentation, ALCOAC Principles & Medical Record Standards 2.4 Confidentiality, Privacy & Protection of Participant Personal Information
3 Chapter 3: Monitoring, Quality Management & Audits
3.1 Risk-Based Quality Management (RBQM) & Quality Management Systems (QMS) 3.2 Monitoring Visit Types: Site Selection, SIV, IMV, and Close-Out 3.3 Risk-Based Monitoring (RBM), Centralized Monitoring & Source Data Verification (SDV vs SDR) 3.4 Quality Audits, Regulatory Inspections, Non-Compliance & Root Cause Analysis / CAPA
4 Chapter 4: Site Feasibility, Start-Up, Facilities & Laboratory Operations
4.1 Site Feasibility Assessment, Capability Analysis & Investigator Selection 4.2 Contractual Agreements: Clinical Trial Agreements, Budgets, Indemnification & Financial Arrangements 4.3 Site Initiation Preparation, System Access & Regulatory Greenlight 4.4 Protocol Review, Operational Feasibility & Institutional Approvals 4.5 Site Facilities, Equipment Maintenance, Calibration & Trial Supplies 4.6 Biological Samples & Hazardous Goods: Collection, Storage, Disposal & Shipment
5 Chapter 5: Subject Recruitment, Retention & Study Visits
5.1 Subject Recruitment Strategies, Advertising Guidelines & Ethical Constraints 5.2 Screening, Eligibility Verification & Inclusion/Exclusion Adherence 5.3 Subject Retention, Compliance, Visit Scheduling & Protocol Window Management 5.4 Managing Lost to Follow-Up, Subject Withdrawal & Early Termination Procedures
6 Chapter 6: Protocol Compliance, Deviations & Site Close-Out
6.1 Protocol Compliance, Waivers vs. Violations & Deviation Management 6.2 Investigational Site Close-Out Activities & Final Reconciliations 6.3 Record Retention, Archiving Requirements & Post-Trial Responsibilities
7 Chapter 7: Research Ethics, Vulnerable Populations & Research Integrity
7.1 Historical Milestones: Nuremberg Code, Belmont Report & Declaration of Helsinki 7.2 Ethical Principles: Beneficence, Non-Maleficence, Autonomy, Justice & Equipoise 7.3 Vulnerable Populations (Pediatrics, Pregnant Women, Prisoners, Cognitively Impaired, Economically Disadvantaged) 7.4 Conflict of Interest, Research Misconduct & Fraud in Clinical Research
8 Chapter 8: Informed Consent & Institutional Review Boards (IRB/IEC)
8.1 Informed Consent Elements, Process & Ongoing Consent / Re-Consent Requirements 8.2 Assent in Minors & Legally Acceptable Representative (LAR) Requirements 8.3 IRB/IEC Composition, Functions, Review Types (Full, Expedited, Exempt) & Continuing Review
9 Chapter 9: Safety Reporting & Adverse Event Management (ICH E2A)
9.1 Adverse Events (AE) vs. Adverse Drug Reactions (ADR) & Serious Adverse Events (SAE) Definitions 9.2 Causality Assessment, Expectedness, Reference Safety Information (RSI) & SUSARs 9.3 Expedited Reporting Timelines (7-day fatal/life-threatening, 15-day other serious) & Periodic Safety Updates (DSUR)
10 Chapter 10: Investigational Product (IP) Management & Accountability
10.1 Investigational Product Lifecycle, Labeling, Packaging & Blinding Procedures 10.2 IP Shipping, Receipt, Temperature Monitoring, Excursion Handling & Chain of Custody 10.3 IP Storage, Dispensing, Accountability Logs & Destruction/Return Procedures 10.4 Emergency Unblinding (Code Breaking) Protocols & Subject Safety Procedures
11 Chapter 11: Regulatory Frameworks, Submissions & Product Reference Information
11.1 Stakeholders, Regulatory Institutions & Global Frameworks in Clinical Research 11.2 Protocol Submission, Approval & Amendment Processes 11.3 Investigator's Brochure, Instructions for Use & Reference Product Information 11.4 Regulatory Reporting Requirements Before and After Marketing Authorisation
12 Chapter 12: Clinical Data Management, EDC & Electronic Records
12.1 Electronic Data Capture (EDC), eCRF Design & Clinical Data Management Systems (CDMS) 12.2 Computerised Systems, Data Governance & Audit Trails (ICH E6(R3) Annex 1 §4) 12.3 Data Validation, Edit Checks, Discrepancy / Query Management & Resolution 12.4 Medical Coding (MedDRA, WHO Drug), SAE Reconciliation, Data Transfer & Database Lock
13 Chapter 13: Trial Design, Biostatistics, Data Monitoring & Transparency
13.1 Phases of Clinical Research (Phase 0, I, II, III, IV) & Translational Medicine 13.2 Study Designs: Parallel, Crossover, Factorial, Adaptive & Non-Inferiority / Equivalence 13.3 Randomization Schemes, Stratification, Blinding Methods & Minimizing Bias 13.4 Endpoints (Primary, Secondary, Surrogate, Composite), Sample Size & Biostatistical Concepts (p-values, CI, ITT vs PP) 13.5 Interim Analyses, DSMB/IDMC Oversight & Efficacy and Safety Evaluation Milestones 13.6 Trial Registration, Results Transparency & Communicating Results to Participants
1.1 The Eleven ICH E6(R3) Principles of GCP & Guideline Structure
Key Takeaways Explain This Topic AI
ICH E6(R3) replaced E6(R2) across every ACRP examination beginning July 15, 2026, so the currently open fall testing window is scored entirely against E6(R3).
E6(R3) consolidates the thirteen E6(R2) principles into eleven overarching principles that apply across the whole trial life cycle and are read together, not in isolation.
The guideline is structured as Principles, Annex 1 (interventional trials), Annex 2 (decentralised, pragmatic and real-world-data elements), and Appendices A (Investigator’s Brochure), B (protocol) and C (essential records).
Principle 6 makes Quality by Design and critical to quality factors an explicit GCP requirement, and Principle 7 elevates risk proportionality from background assumption to a stated principle.
Principle 10 confirms that a sponsor may transfer and an investigator may delegate activities, but each retains overall responsibility and oversight for their own activities.
Last updated: August 2026
The Eleven ICH E6(R3) Principles of GCP
Quick Reference: The International Council for Harmonisation (ICH) guideline E6(R3) is the current international ethical and scientific quality standard for designing, conducting, recording and reporting clinical trials. It reached ICH Step 4 for the Principles and Annex 1 on 6 January 2025 , and Annex 2 was adopted on 3 June 2026 ; all three are now published as one consolidated guideline.
Why this is the single most important section in the guide
The Association of Clinical Research Professionals (ACRP) states on the ACRP-CP certification page that "beginning July 15, 2026, the ICH E6(R3) Guideline for Good Clinical Practice will replace E6(R2) across all ACRP examinations." ACRP's own December 2025 announcement is more explicit still: spring 2026 candidates saw unscored E6(R3) pre-test items, and the fall 2026 window (July 15 – October 15) is fully referenced to E6(R3) .
Two consequences follow, and both are frequently missed:
E6(R2) is no longer the operative standard for your exam. If a study resource still teaches "the 13 principles of GCP" as current, it predates the transition. This guide teaches the eleven E6(R3) principles as normative and keeps the thirteen only as a mapping aid.
Only ICH is tested. ACRP states that the exam "is referenced only to the International Conference on Harmonization (ICH) Guidelines. No other regulatory framework is tested, including country-specific regulations (i.e, FDA or EMA)." The permitted reference set is E6(R3), E2A, E8(R1), E9, E9(R1), E11(R1) and the Declaration of Helsinki . Where this guide mentions a national statute, it is labelled as background context, never as a testable rule.
How E6(R3) is structured
E6(R2) was a single running document numbered 1–8 (definitions, principles, IRB/IEC, investigator, sponsor, protocol, Investigator's Brochure, essential documents). E6(R3) abandons that shape entirely:
- Part Contents
- I. Introduction Guideline scope and structure
- II. Principles of ICH GCP The eleven overarching principles, each with numbered sub-points
- III. Annex 1 1 IRB/IEC · 2 Investigator · 3 Sponsor · 4 Data Governance – Investigator and Sponsor
- IV. Annex 2 Additional considerations for decentralised elements, pragmatic elements and real-world data
Appendices A. Investigator's Brochure · B. Clinical Trial Protocol and Protocol Amendment(s) · C. Essential Records for the Conduct of a Clinical Trial
Glossary Defined terms
Exam Watchout: Two renumbering traps. First, the appendix order flips the familiar E6(R2) order — in R2 the protocol was Section 6 and the Investigator's Brochure Section 7, but in R3 the Investigator's Brochure is Appendix A and the protocol is Appendix B . Second, "essential documents " (R2 Section 8) is now "essential records " (Appendix C), a deliberate change that makes the requirement media-neutral rather than paper-centric.
The eleven principles
# Principle (E6(R3) Section II) What it obliges you to do
1 Trials should be conducted in accordance with the ethical principles originating in the Declaration of Helsinki , consistent with GCP and applicable regulatory requirements, and designed and conducted to ensure participants' rights, safety and well-being Participant rights, safety and well-being prevail over the interests of science and society (1.1); safety is reviewed as new information emerges (1.2); risks are weighed against anticipated benefits (1.3); participant selection should be representative of the population the product is intended to benefit (1.4); a qualified physician or dentist holds overall responsibility for trial-related medical care (1.5); identifying information is kept confidential (1.6)
2 Informed consent is an integral feature of ethical conduct; participation is voluntary and based on a process that leaves participants well-informed Consent is freely given and documented before participation; legally acceptable representatives consent for those unable to; assent is collected from minors as appropriate, referencing ICH E11(R1); consent information must be clear and concise ; emergency-situation consent is obtained as soon as possible
3 Trials should be subject to independent review by an IRB/IEC Conduct complies with the protocol that received prior approval or favourable opinion; the IRB/IEC also performs periodic review
4 Trials should be scientifically sound for their intended purpose and based on adequate, current scientific knowledge Nonclinical and clinical information must adequately support the trial; the design reflects current understanding of the condition, the mechanism and the intended population; scientific knowledge is periodically re-reviewed during the trial
5 Trials should be designed and conducted by qualified individuals Everyone involved is qualified by education, training and experience ; the guideline explicitly contemplates physicians, nurses, pharmacists, scientists, ethicists, technology experts, coordinators, monitors, auditors and biostatisticians
6 Quality should be built into the scientific and operational design and conduct Quality is fitness for purpose (6.1); critical to quality (CtQ) factors are identified prospectively (6.2); strategies exist to avoid, detect, address and prevent recurrence of serious noncompliance (6.3)
7 Processes, measures and approaches should be proportionate to the risks to participants and the importance of the data, avoiding unnecessary burden Focus on risks beyond usual medical care for patient trials (7.2); manage risks to CtQ factors proactively (7.3); avoid unnecessary complexity, procedures and data collection (7.4)
8 Trials should be described in a clear, concise, scientifically sound and operationally feasible protocol Objectives are explicit; the protocol and its execution plans — statistical analysis plan, data management plan, monitoring plan — must all be clear, concise and feasible
9 Trials should generate reliable results Information is fit for purpose (9.1); data systems are proportionate (9.2); computerised systems are fit for purpose with risk-based validation (9.3); record integrity, traceability and protection of personal information are maintained (9.4); essential records are retained securely and made available to authorities, monitors, auditors and IRBs/IECs (9.5); trials are registered on publicly accessible databases and results are publicly posted (9.6)
10 Roles and responsibilities should be clear and documented appropriately A sponsor may transfer and an investigator may delegate activities but each retains overall responsibility (10.1); agreements define roles and are documented (10.2); oversight is maintained (10.3)
11 Investigational products should be manufactured under applicable GMP and managed per product specifications and the protocol Quality is preserved through to the participant (11.2); products are used per protocol (11.3); manufacturing, handling and labelling align with treatment assignment and maintain blinding (11.4); labelling follows applicable regulatory requirements (11.5); handling, shipping, storage, dispensing, return and destruction/disposal follow defined processes (11.6)
Mapping the retired thirteen onto the new eleven
You will still meet colleagues — and older question banks — that use the E6(R2) numbering. Use this crosswalk to translate rather than relearn:
- E6(R2) principle E6(R3) home
- 2.1 Helsinki / ethical conduct Principle 1
- 2.2 Risk vs. benefit Principle 1.3
- 2.3 Rights, safety and well-being prevail Principle 1.1
- 2.4 Adequate nonclinical and clinical information Principle 4.1
- 2.5 Scientifically sound, clear protocol Principles 4 and 8 (split)
- 2.6 Prior IRB/IEC approval Principle 3.1
- 2.7 Medical care by qualified physician Principle 1.5
- 2.8 Qualified personnel Principle 5
- 2.9 Freely given informed consent Principle 2.1
- 2.10 Accurate recording, handling, storage Principle 9.4
- 2.11 Confidentiality of records Principle 1.6
- 2.12 GMP for investigational products Principle 11.1
- 2.13 Quality systems and procedures Principle 6
- (no R2 equivalent) 6.2 critical to quality factors / quality by design
- (no R2 equivalent) 7 proportionality as a standalone principle
- (no R2 equivalent) 9.6 registration and public posting of results
- (no R2 equivalent) 1.4 representative participant selection
Exam Watchout: Four concepts have no counterpart in the thirteen. Quality by design, proportionality, trial transparency and representative participant selection are exactly where new E6(R3) items concentrate, because they are the only places where an experienced candidate's E6(R2) instincts give the wrong answer.
- The four ideas that genuinely changed
- 1. Quality by design and critical to quality factors (Principle 6)
Quality is defined as fitness for purpose , not as maximal data. CtQ factors — the attributes fundamental to participant protection and to the reliability and interpretability of results — must be identified before the trial starts , not reconstructed after a finding.
2. Proportionality (Principle 7)
Oversight intensity must track risk. A first-in-human oncology molecule of unknown toxicity and a post-marketing trial of a well-characterised authorised medicine cannot attract the same monitoring intensity. Principle 7.2 sharpens this: for patient trials the focus is on risks that go beyond those of usual medical care .
3. Data governance as a first-class subject (Annex 1 Section 4)
E6(R2) scattered data expectations across sponsor and investigator sections. E6(R3) gives Data Governance its own annex section shared by investigator and sponsor, covering the full data life cycle — capture, metadata and audit trails, review, corrections, transfer and migration, finalisation before analysis, retention and access, and destruction — plus computerised systems (procedures, training, security, validation, release, failure, technical support, user management).
4. Media neutrality
The guideline is written to be media neutral so that paper, electronic data capture, electronic health records, wearables and sensors are all governed by one set of expectations rather than by technology-specific rules.
Realistic exam scenario
Scenario: A sponsor's monitoring plan requires 100% source data verification of every field on every case report form for a Phase III trial of an authorised antihypertensive being studied for a new indication in a low-risk outpatient population. The site has 40 participants and monitoring visits are consuming the coordinator's entire week. The lead monitor argues the plan "cannot be wrong because it is more thorough than GCP requires."
E6(R3) evaluation:
Principle 7.1 and 7.4 are directly violated in spirit. Trial processes must be proportionate to the risks and the importance of the information, and must avoid unnecessary burden on participants and investigators . "More is always safer" is no longer a defensible GCP position.
Principle 7.2 matters because the investigational product already holds a marketing authorisation, so the relevant risk is the increment beyond usual care , not the total risk of treating hypertension.
Principle 6.2 requires the sponsor to have identified CtQ factors prospectively; blanket 100% verification usually signals that this analysis was never performed.
Correct action: the sponsor should revisit the risk assessment and re-target verification onto the critical data supporting the primary endpoint and participant safety. Note that the site cannot unilaterally reduce the sponsor's monitoring — it should raise the burden as a documented issue for the sponsor to resolve.