Key Principles of GCP in the Context of ICH E6(R3)

Part of Good Clinical Practice (GCP) — ICH E6(R3): Introduction to Clinical Research and GCP.

About 6 minutes. Free, in your language, no account needed.

Why this matters

The Principles are the part of ICH E6(R3) that applies to every trial, everywhere, always. Annex 1 explains how to apply them to interventional trials. If a situation is not covered by a written procedure, the Principles are what you reason from. Inspectors ask why you did something, not only whether a form was signed.

From 13 flat principles to 11 categories

The previous revision, E6(R2), presented Good Clinical Practice (GCP) as a flat list of 13 principles. R3 replaced that list. R3 has 11 numbered principle categories, and each category contains numbered sub-points that expand it.

E6(R3) also states that the principles are interdependent: they "should be considered in their totality to assure ethical trial conduct and reliable results."

Building the house: the 11 categories

A trial is built like a house. You set foundations, agree a blueprint, obtain materials, build, inspect, then hand over. The 11 categories map onto those stages.

Foundation setting

1. Ethical conduct. Trials follow the ethical principles that originate in the Declaration of Helsinki. Rights, safety and well-being of participants "should prevail over interests of science and society". New safety information is reviewed in a timely way. Foreseeable risks are weighed against anticipated benefits. Participant selection "should be representative of the population groups that the investigational product is intended to benefit". A qualified physician, or other qualified healthcare professional where local requirements allow, holds overall responsibility for trial-related medical care. Confidentiality follows applicable privacy and data protection requirements.

2. Informed consent. Participation is voluntary. The consent process must leave participants, or their legally acceptable representatives, well-informed. Consent is freely given and documented before participation. Information must be "clear and concise so as to be understandable". The process takes account of the participant, the trial design, the setting and the possible use of technology. In emergencies, consent is sought as soon as possible under an IRB/IEC-approved process.

3. Independent review. Trials are reviewed independently by an Institutional Review Board or Independent Ethics Committee (IRB/IEC). Conduct follows the protocol that received prior approval or favorable opinion. The IRB/IEC reviews the trial periodically.

Blueprint and study design

4. Scientific soundness. Trials must be scientifically sound for their intended purpose. There must be adequate nonclinical and clinical information to support the trial. The design reflects the current state of knowledge, which is reviewed periodically to see whether the trial needs modifying.

5. Qualified individuals. Trials are designed and conducted by people qualified by education, training and experience. E6(R3) names the range of expertise that may be needed: "physicians, nurses, pharmacists, scientists, ethicists, technology experts, trial coordinators, monitors, auditors and biostatisticians".

6. Quality built in. Quality is designed into the trial, not inspected into it afterwards. Principle 6.1 states that "Quality of a clinical trial is considered in this guideline as fitness for purpose." Principle 6.2 requires that critical to quality factors "should be identified prospectively". Principle 6.3 completes the category: strategies should be implemented to avoid, detect, address and prevent recurrence of serious noncompliance with GCP, the trial protocol and applicable regulatory requirements.

7. Proportionality. Processes and measures are proportionate to the risks to participants and to the importance of the data. For trials involving patients, "the focus should be on risks that go beyond those associated with usual medical care". Trials should be operationally feasible. The sponsor "should not place unnecessary burden on participants and investigators."

8. A clear protocol. The trial is described in a clear, concise, scientifically sound and operationally feasible protocol. Objectives are explicit. The execution plans, including the statistical analysis plan, data management plan and monitoring plan, must also be clear and feasible.

Construction, inspection and handover

9. Reliable results. The quality and amount of information must be fit for purpose. Systems for data capture, management and analysis must be fit for purpose and proportionate. Computerized systems "should be fit for purpose (e.g., through risk-based validation, if appropriate)". Record integrity and traceability are maintained and personal information is protected. Essential records are retained securely and made available on request. Transparency includes timely registration on publicly accessible databases and public posting of results, and communication of results to participants should be considered, in language that is objective and non-promotional.

10. Clear roles. Roles and responsibilities are clear and documented appropriately. The key sentence is: "The sponsor may transfer or the investigator may delegate their tasks, duties or functions (hereafter referred to as activities), but they retain overall responsibility for their respective activities." Agreements define roles, and appropriate oversight is maintained.

11. Investigational product quality. Investigational products are manufactured according to applicable Good Manufacturing Practice (GMP) standards. They are managed according to the product specifications and the protocol. Handling, manufacturing and labeling must align with treatment assignment and maintain blinding. Labeling follows applicable regulatory requirements. Processes must cover handling, shipping, storage, dispensing, returning and destroying or otherwise disposing of the product.

In practice

Dr. Sarah wants to exclude all participants over 75 years from her hypertension site, to reduce paperwork and comorbidity questions. The protocol does not exclude them.

Principle 1 answers her directly. Participant selection should be representative of the population the product is intended to benefit. Hypertension is common in older adults. Excluding them at site level would also be a protocol deviation, which engages Principle 3 and Principle 10.

Ana raises it with the monitor. Dr. Sarah instead requests extra screening support from the sponsor, which is a resource question, not an eligibility question. The site enrolls the population the protocol defines.

A rule you cannot justify from the Principles is usually a habit, not a requirement.

Key takeaways