The ICH GCP E6(R3) guideline is essential for clinical trial professionals, offering a gold standard for ethical and scientific conduct in research. While GCP training often nails the theory, it’s the implementation that can leave teams scratching their heads.

The updated E6(R3) principles are scheduled for implementation in the EU on July 23, 2025, and in Switzerland during the summer of 2025. The European Medicines Agency (EMA) and Swissmedic confirmed that these elements will become legally effective in the EU on 23 July 2025, after which the current E6(R2) remains valid until then.

These principles demand more than just understanding. They require action.

This post breaks down each of the 11 ICH GCP E6(R3) principles, explaining what they mean and how you can apply them to real-world clinical trials. Whether you’re a sponsor, CRO, or site representative, this guide provides actionable insights to help you embed these principles into your workflows.

ICH GCP E6(R3): Applying Principles in Clinical Trials

11 ICH GCP E6(R3) Principles & How To Apply Them in Real-World Clinical Trials

As a clinical research training organisation, we at TASK Research Academy know the importance of understanding and applying the principles outlined in ICH GCP E6(R3).

Here are the 11 principles of ICH GCP E6(R3) and how you can apply them in your clinical trial.

Let’s turn those scratching heads into confident nods!

1. Participant Rights, Safety, and Well-Being First

What it means: Clinical trials must place the rights, safety, and well-being of participants above all else, aligning with ethical guidelines such as the Declaration of Helsinki.

Why it matters: Protecting the welfare, confidentiality and participants’ autonomy isn’t just ethical; it’s critical to the credibility of your research. Trials that neglect this principle risk poor outcomes and compliance penalties.

Practical application:

  • Timely Review and Sign-Off of Safety Laboratory Reports – Ensure that all safety lab results are reviewed and formally signed off promptly to detect potential adverse events and maintain continuous participant safety monitoring.
  • Conduct Ongoing Risk Assessments – Regularly assess and reassess trial risks to proactively identify and address emerging safety concerns throughout the study.
  • Balance Data Quality with Participant Well-Being – Recognise the dual responsibility of investigators and site staff to meet trial timelines and data standards while prioritising the safety and well-being of each participant.

2. Voluntary and Clear Informed Consent

What it means: Participation in clinical trials should always be an informed, voluntary choice made with a clear understanding of benefits and risks.

Why it matters: Without consent, trials risk ethical violations and a loss of trust in research organisations.

Practical application:

  • Use Clear, Plain Language for Participant Communication – Take ample time to explain the study, its procedures, and potential risks using simple, non-technical language. Provide documents that clarify complex protocol terms to ensure participants fully understand what participation entails.
  • Keep Participants Informed Throughout the Trial – Inform participants of any significant updates or changes that occur during the study. When necessary, obtain re-consent at the next available opportunity to confirm continued agreement.
  • Respect Voluntary Consent and Participant Choices – Emphasise that signing the consent form is voluntary, and participants may withdraw consent at any time without penalty. Honour decisions not to participate in optional sub-studies or to withhold biological samples, ensuring their rights and preferences are respected.

3. An Independent Review of Clinical Trials is Key

What it means: Trials must undergo independent review by an Institutional Review Board (IRB) or an Independent Ethics Committee (IEC).

Why it matters: Independent reviews ensure objectivity, ethical adherence, and compliance.

Practical application:

  • Submit All Participant-Facing Materials for Ethics Review – Ensure that all materials intended for participants, including advertisements, informed consent forms, diaries, and questionnaires, are submitted to the Ethics Committee (IRB/IEC) for review and approval before use.
  • Maintain Ongoing Communication with the Ethics Committee – Schedule regular updates with the Ethics Committee to review protocol amendments, safety updates, and any significant changes in study conduct. This promotes transparency and sustained oversight.
  • Report Major Protocol Deviations and Safety Events Promptly – Notify the Ethics Committee of all serious or significant protocol deviations, adverse events, and emerging risks in accordance with their required timelines and standard operating procedures.
  • Implement Changes Only After Ethics Approval – Submit all protocol and informed consent amendments for review and receive formal ethics approval before implementing any changes at the site.

4. Sound Scientific Protocol

What it means: Trials should be designed based on up-to-date scientific knowledge and clearly state objectives, methodologies, and expected outcomes.

Why it matters: A robust protocol prevents unnecessary amendments, wasted resources, and unreliable results.

Practical application:

  • Involve Diverse Stakeholders in Protocol Development – Engage a broad range of stakeholders, including investigators, study coordinators, nurses, scientists, and community advisory boards, during protocol design to ensure the study is both scientifically robust and operationally feasible.
  • Conduct a Protocol Dry-Run Before Site Initiation – Organise a simulation or dry-run of key study procedures with the site team before enrolling participants. This helps test workflows, identify operational gaps, and ensure that staff are confident in executing the protocol as intended.
  • Incorporate Flexibility Where Scientifically Justified – Build adaptability into the protocol by allowing acceptable ranges for certain procedures or visit windows. This flexibility can reduce protocol deviations and minimise the need for formal amendments without compromising scientific integrity.
  • Align Protocol Objectives with Trial Capabilities – Ensure the protocol’s scientific goals are achievable within the trial’s logistical, ethical, and regulatory framework. Avoid overcomplicating the design with unnecessary endpoints or procedures that do not contribute directly to the primary objectives.

5. Qualification and Expertise from Start to End

What it means: Trials must be overseen and conducted by qualified professionals with training and experience suited to their tasks.

Why it matters: Unqualified personnel increase risks, impact results, and undermine trial integrity.

Practical application:

  • Assign Roles Based on Qualifications and Scope – Ensure all staff are formally approved, appropriately trained, and delegated based on their qualifications and professional scope. Team members must only perform tasks they are competent and authorised to carry out.
  • Conduct Protocol-Specific Training Before Study Work Begins – Train all site personnel on the protocol, procedures, and trial expectations before they begin any study-related duties. This promotes consistency across team members and sites, reducing the risk of errors and safeguarding participant safety.
  • Prioritise Relevant Certifications and Experience – Hire and assign staff who hold up-to-date ICH GCP training and other relevant qualifications. Ongoing professional development should be encouraged to maintain competency throughout the trial lifecycle.
  • Retrain When Knowledge Gaps Are Identified – If a protocol deviation or error reveals a training gap, retrain the relevant staff promptly and document the session details. Use this as a corrective action to prevent recurrence and reinforce accountability.
  • Maintain Complete Training Records – Keep thorough, up-to-date documentation of all training activities, including initial, refresher, and corrective training, as part of the essential trial records.

6. Quality by Design (QbD)

What it means: Quality should be built into the trial design by identifying critical-to-quality factors early.

Why it matters: A QbD approach reduces inefficiencies, missed data, and systemic errors.

Practical application:

  • Engage Stakeholders Early – Involve key stakeholders, including investigators, study coordinators, nurses, and data managers, in protocol design workshops and feasibility reviews before finalising the protocol. This helps ensure the protocol is operationally realistic and minimises the risk of early amendments.
  • Base the Trial on Sound Scientific and Safety Data – Confirm that sufficient safety and efficacy data (from nonclinical studies, prior trials, or real-world evidence) support the planned route, dose, duration, and target population. This safeguards participants and strengthens the scientific validity of the trial.
  • Define What Quality Looks Like – Identify and prioritise the critical data points and processes that directly affect participant safety and primary endpoints. Focus resources and monitoring on these elements to ensure they are consistently reliable.
  • Build Quality into Design and Execution – Ensure the trial design, procedures, data collection, and site operations are structured to produce high-quality, usable data. Quality should be proactive and embedded from the start, not inspected later.

7. Risk-Based Approach

What it means: Trial processes, monitoring, and management should be proportional to participant risks and data importance.

Why it matters: Focusing resources on high-risk areas improves efficiency and trial outcomes.

Practical application:

  • Proactively Identify Critical Risks – Before trial initiation, assess and document risks that could meaningfully impact participant safety or the reliability of key data (Critical to Quality factors). Continue to reassess these risks throughout the trial as new information becomes available.
  • Establish Site-Level Quality Oversight Systems – Implement routine internal checks at the site to review source documentation and data entries. Designate trained team members to help detect and correct errors early. This internal review supports overall trial quality and reduces reliance on external monitoring alone.
  • Leverage Centralised Monitoring and Risk Management Tools – Sponsors can assign centralised monitors in addition to site CRAs to analyse real-time data trends, spot inconsistencies, and track high-risk indicators. Use risk management software to flag and act on emerging issues proactively.
  • Prioritise and Investigate Significant Deviations – Focus your attention on deviations that pose real risk to participant safety or data integrity. Conduct root cause analyses for these events and implement corrective and preventive actions (CAPA). Use findings to adjust processes and training where necessary.
  • Reassess Risks Regularly – Conduct ongoing risk reviews throughout the trial lifecycle to ensure controls remain effective and responsive. This helps prevent repeat issues and supports continuous improvement.

8. A “Can-Do” Protocol

What it means: Protocols should be clear, concise, and operationally feasible.

Why it matters: Overly complex protocols lead to higher dropout rates and data inconsistencies.

Practical application:

  • Design Fit-for-Purpose Protocols – Develop protocols that are clear, concise, and focused on essential data. Avoid unnecessary complexity and procedures that do not directly support the trial’s objectives or participant safety.
  • Align with Real-World Workflows – Simplify protocol procedures to fit within the day-to-day operational capacity of sites. Ensure visit schedules, assessments, and data collection points are realistic and executable without overburdening staff or participants.
  • Incorporate Patient and Site Input Early – Engage with site teams and patient representatives during protocol development to identify potential pain points and improve feasibility. Their insights help refine procedures and improve recruitment, retention, and compliance.

9. Reliable Results

What it means: Trials should deliver results that are transparent, accurate, reproducible, and scientifically valid.

Why it matters: Reliable data builds trust with regulators, sponsors, and the medical community.

Practical application:

  • Use Validated Electronic Data Capture (EDC) Systems – Adopt validated EDC platforms to reduce transcription errors, ensure data integrity, and streamline query resolution. Ensure that all users are trained and that system access is properly controlled.
  • Ensure System and Process Validation – Validate all systems and tools used in data collection, management, and analysis, from laboratory equipment to statistical software, to confirm the accuracy, consistency, and reproducibility of results.
  • Robust Protocol Deviation Management – Promptly document all protocol deviations in the participant’s source notes, update the cumulative deviation log, and record relevant deviations in the eCRF. Accurate tracking ensures deviations are considered in the data analysis, supporting transparency and reliability.
  • Promote Transparency Over Perfection – Build a culture of openness where deviations are reported truthfully. Reinforce that recording accurate data, even when deviations occur, is more valuable than attempting to mask errors. Transparency ensures scientific validity and regulatory trust.

10. Clear Responsibilities Across the Lifecycle

What it means: Everyone involved must understand and adhere to their defined roles and responsibilities.

Why it matters: Poor accountability can lead to compliance failures and delayed timelines.

Practical application:

  • Maintain a Detailed Delegation of Duties Log – At trial initiation, create and keep an up-to-date Delegation of Duties Log, signed by the Principal Investigator, clearly specifying each team member’s responsibilities, such as informed consent, adverse event documentation, and investigational product handling.
  • Provide Role-Specific Training – Deliver tailored training sessions aligned with each staff member’s delegated tasks (e.g., consent processes, sample management) and maintain comprehensive training records for every team member.
  • Perform Regular Compliance Checks – Implement periodic site audits or coordinator-led spot checks to verify that only authorised personnel perform delegated duties, such as signing source documents or managing investigational products. Document all findings and corrective actions taken.

11. Good Manufacturing Processes (GMP)

What it means: Investigational products should meet Good Manufacturing Practice standards across all lifecycle stages, from production to disposal.

Why it matters: This ensures product quality and protects trial participants.

Practical application:

  • Verify Shipment Integrity and Maintain Proper Storage – Upon receipt of investigational product (IP), site staff must inspect the shipment conditions, especially temperature logs, to confirm that the cold chain was maintained during transit. Store IP securely in temperature-controlled, restricted-access areas following protocol and manufacturer guidelines.
  • Enforce Strict IP Accountability and Label Verification – Implement rigorous processes to verify that IP labelling matches the approved specifications (e.g., batch number, expiry date, protocol ID). Maintain detailed logs of IP dispensing, returns, and destruction to ensure full traceability and prevent errors.
  • Train Staff to Identify and Report Product Quality Issues – Equip site personnel to detect anomalies such as broken vials, discolouration, or particulate matter. Require immediate notification of the sponsor and manufacturer, and quarantine any suspect product until a thorough investigation is completed.

Implementing the 11 ICH GCP E6(R3) Guidelines: Small Steps Lead to Big Impact

The E6(R3) update offers a comprehensive and adaptable framework that aligns with modern research needs. But applying it successfully means taking meaningful actions at every step of your trial process.

Begin small.

Embed these principles one by one into your workflows, focusing on what’s critical to trial success.

The reward? More efficient trials, higher-quality data, and, most importantly, better protection for participants.

Your Starting Point = TASK Research Academy

Here is a list of our resources to help you get started:

At TASK Research Academy, we’re passionate about empowering confident and competent research teams. Our training is self-paced and fully online, but behind every module is a responsive, dynamic support team ready to help.

Let’s not wait for implementation deadlines to take action.

Be proactive. Be prepared. Be compliant.

Contact us for more information.