> For the complete documentation index, see [llms.txt](https://whri.gitbook.io/whristatresources.com/llms.txt). Markdown versions of documentation pages are available by appending `.md` to page URLs; this page is available as [Markdown](https://whri.gitbook.io/whristatresources.com/summary-of-ich-e6-r3-good-clinical-practice-and-comparison-with-ich-e6-r2.md). # Summary of ICH E6(R3) Good Clinical Practice and Comparison with ICH E6(R2) This document is intended for research investigators, statisticians, data managers, coordinators, and study teams involved in the design, conduct, oversight, analysis, and reporting of clinical trials. It summarizes the updated ICH E6(R3) Good Clinical Practice (GCP) guideline and highlights key changes from ICH E6(R2), with a focus on practical implications for protocol development, ethics and regulatory submissions, risk-based quality management, data governance, monitoring, statistical planning, and trial documentation. While relevant across diverse types of interventional health research, it is particularly aligned with investigator-initiated trials, multi-site studies, trials using electronic data systems or decentralized elements, and projects requiring clear traceability from protocol to final analysis and reporting. ### Purpose of this summary The purpose of this document is to summarize the new ICH E6(R3) Good Clinical Practice guideline and explain how it differs from the previous ICH E6(R2) previous version. I recently attended 5th US FDA / UK MHRA / Health Canada Symposium: Regulatory Perspectives in Good Clinical Practice, Bioequivalence, and Good Pharmacovigilance Practice, by Regulatory Operations and Enforcement Branch Health Canada, Government of Canada. What I appreciated the most was the emphasis on quality by design, critical thinking, and proportionate risk-based approaches. In clinical research, quality is not something added at the end. It starts with the research question, protocol, endpoints, SAP, data flow, documentation, and understanding what is truly critical for participant safety and credible evidence. I though to summarize the changes in the ICH E6(R3) compared to the previous version of the document. The idea behind this document is to help teams developing new study to understand what has changed, why the guideline was revised, and what this means in practical terms for trial planning, conduct, oversight, data management, and analysis. The new guidelines also emphasize the importance of critical thinking when designing and executing the trial. Critical thinking is important because not all clinical trials have the same risks, procedures, data sources, or operational challenges. Without critical thinking, GCP can become a checklist exercise, where teams document many things but may miss the issues that affect participant safety or the credibility of the results. ICH E6(R3) encourages study teams to make thoughtful decisions about what is essential, what can go wrong, and where quality efforts should be focused. This helps prevent important errors, reduce unnecessary burden, and ensure that trial procedures are meaningful for the specific study rather than copied automatically from another trial. ICH E6(R3) is not simply a small update to ICH E6(R2). It is a major rewrite and reorganization of the GCP guideline. The latest version keeps the central goal of GCP: protecting trial participants and ensuring reliable clinical trial data. However, it updates the structure and expectations to better reflect modern clinical trials, including decentralized trial elements, electronic systems, risk-based monitoring, computerized data collection, and more diverse trial designs. ### What ICH E6(R2) focused on ICH E6(R2) was an integrated addendum to the earlier E6(R1) guideline. It was developed to modernize GCP by adding more emphasis on quality management, electronic records, risk-based monitoring, and sponsor oversight. In practice, ICH E6(R2) was important because it moved GCP away from a purely checklist-based approach and introduced more explicit expectations for: * sponsor oversight * risk-based monitoring * electronic systems * essential documents * data reliability * quality management However, E6(R2) was still structured around the older E6(R1) framework. This meant that newer clinical trial models, decentralized approaches, digital tools, and complex data flows were not always fully integrated into the logic of the guideline. ### Why ICH E6(R3) was introduced ICH E6(R3) was introduced because clinical trials have changed since the original GCP guideline and the E6(R2) addendum. Modern trials may include electronic consent, remote visits, wearable devices, electronic health records, decentralized procedures, central monitoring, adaptive designs, pragmatic trial elements, external service providers, and complex data systems. The new guideline responds to this by emphasizing flexibility, proportionality, critical thinking, quality by design, and risk-based approaches. Instead of treating every trial activity as equally important, E6(R3) asks trial teams to identify what is critical to participant safety and reliable results. This is one of the most important conceptual changes. Under E6(R3), trial teams should not simply ask, “Did we complete every checklist item?” They should ask, “What matters most for this trial, and how do we protect those critical elements?” ### Structure of the ICH E6(R3) document ICH E6(R3) has a different structure from ICH E6(R2). ICH E6(R2) followed the traditional GCP structure, with sections focused on investigators, sponsors, clinical trial protocols, investigator brochures, and essential documents. The finalized ICH E6(R3) guideline begins with overarching GCP principles and includes Annex 1, which provides more detailed guidance for interventional clinical trials. The document also includes appendices on the investigator’s brochure, clinical trial protocol and protocol amendments, and essential records. Annex 2 is not included in the finalized ICH E6(R3) Step 4 document. It has been issued separately as a draft guideline and is intended to address additional trial designs and data sources. Therefore, in this summary, the main comparison focuses on the finalized ICH E6(R3) Principles and Annex 1, with Annex 2 noted only as a separate draft document. This new structure makes ICH E6(R3) more flexible. The main principles provide the overall GCP framework, while Annex 1 and the appendices provide practical detail for interventional clinical trials and trial documentation. ### Key difference 1: from prescriptive compliance to proportionality One of the biggest differences between ICH E6(R2) and ICH E6(R3) is the stronger emphasis on proportionality and risk-based approaches. In E6(R2), GCP was often interpreted as a set of standard procedures applied similarly across trials. This sometimes led to over-documentation, unnecessary monitoring, and processes that were not always matched to the actual risk or complexity of the study. ICH E6(R3) encourages a more proportionate approach. This means that trial procedures, monitoring, documentation, data checks, and oversight should be appropriate for the trial’s risks, complexity, and critical data. A proportionate approach does not mean lowering standards. It means focusing effort where it has the greatest value: protecting participants, preserving their rights and safety, and ensuring that trial results are dependable and interpretable. Risk-based thinking should begin during trial planning. Study teams should identify what could go wrong, how serious the consequences would be, and what can be done to prevent or detect important problems. The focus should be on activities and data that are critical to quality, such as eligibility assessment, informed consent, randomization, intervention delivery, primary endpoint measurement, safety reporting, data integrity, and major protocol deviations. For example, in a trial where the primary endpoint is collected through participant-reported questionnaires at 12 weeks, missing or incorrectly completed questionnaires may be a critical risk. In that case, monitoring and data quality checks should focus on follow-up completion, correct questionnaire administration, visit windows, and database checks for the primary outcome. Less important administrative fields may not require the same level of review if they do not affect participant safety or the primary analysis. The same principle applies to monitoring and documentation. A low-risk behavioural intervention trial may not require the same intensity of monitoring as a high-risk drug trial or a complex multi-site study. However, all trials still require appropriate oversight, reliable data, and clear documentation of key decisions. The goal is meaningful traceability, not excessive paperwork. In practical terms, trial teams should identify critical-to-quality factors, assess risks related to those factors, implement controls to reduce important risks, monitor whether those controls are working, update the approach when new risks appear, and document why the selected approach is appropriate for the trial. Compared with E6(R2), E6(R3) makes risk-based quality management more central across the full trial lifecycle, including trial design, conduct, data governance, oversight, analysis, and reporting. **Practical meaning:** * Identify which trial activities and data are critical to quality. * Focus monitoring and quality control on the most important risks. * Avoid unnecessary procedures that do not improve participant safety or data reliability. * Match documentation and oversight to the trial’s risk, complexity, and data sources. * Document why the selected approach is appropriate for the trial. ### Key difference 2: stronger quality by design Another significant difference between ICH E6(R2) and ICH E6(R3) is the stronger emphasis on quality by design. This means that quality should be built into the trial from the beginning, rather than relying only on monitoring, auditing, or data cleaning after problems have already occurred. In E6(R2), quality management was already introduced, but E6(R3) connects it more clearly to trial planning. Study teams are expected to identify the aspects of the trial that are most important for participant safety, participant rights, and reliable interpretation of results, and then design the protocol, database, monitoring plan, and statistical analysis plan to protect those critical elements. These essential elements are often described as critical-to-quality factors. Examples include correct eligibility assessment, informed consent before study procedures, appropriate randomization, accurate intervention delivery, complete and consistent collection of the primary outcome, timely safety reporting, maintenance of blinding where applicable, and clear handling of missing data and protocol deviations. For example, if the primary endpoint is measured at 12 weeks, the quality of that 12-week assessment is critical. The protocol should define the endpoint, visit window, measurement tool, and scoring method. The database should capture the information needed to analyze the endpoint correctly, and the statistical analysis plan should explain how the endpoint will be analyzed and how missing or out-of-window assessments will be managed. Quality by design also supports simplicity and relevance. Trials should avoid collecting unnecessary data simply because the information may be interesting later. Each data element should have a clear purpose, such as eligibility assessment, baseline description, intervention adherence, safety monitoring, outcome analysis, subgroup analysis, or required reporting. Unnecessary data collection increases burden, missing data, and the risk of inconsistent information. In practical terms, quality by design requires alignment between the protocol, consent process, database, monitoring plan, statistical analysis plan, and final reporting. These documents should work together as one system. Compared with E6(R2), E6(R3) places stronger emphasis on initiative-taking planning, prevention of important errors, and focusing quality efforts on what matters most for participant protection and credible trial results. **Practical meaning:** * Do not wait until data cleaning to discover that the primary outcome was collected incorrectly. * Review the protocol, database, visit schedule, monitoring plan, and statistical analysis plan together. * Identify where errors would seriously affect participant safety or trial interpretation. * Build checks into the study process before recruitment starts. * Avoid unnecessary data collection that does not support safety, analysis, or reporting. ### Key difference 3: stronger risk-based quality management E6(R2) introduced risk-based quality management, but E6(R3) makes it more central to trial conduct. Risk-based quality management means that the study team should identify, evaluate, control, communicate, review, and report risks that matter to participant safety and data reliability. This does not mean ignoring lower-risk activities. It means focusing effort where mistakes would have the greatest impact. For example, if the primary outcome is measured at 12 weeks, then missing or inconsistent 12-week assessments are a major risk. If eligibility criteria include a lab value, then incorrect lab interpretation before randomization is a major risk. **Practical meaning:** * Identify risks before the trial starts. * Decide which risks are most important. * Design procedures to reduce those risks. * Monitor whether those risks are occurring during the trial. * Update the risk plan if current issues appear. ### Key difference 4: broader acceptance of modern trial designs and technologies E6(R3) is written to support modern clinical trials more clearly than E6(R2). This includes trials using electronic systems, remote procedures, decentralized elements, electronic data capture, digital health technologies, and different data sources. E6(R2) added some expectations for electronic records and systems, but E6(R3) goes further by recognizing that technology is now part of the normal clinical trial ecosystem. **Practical meaning:** * Describe which electronic systems are used. * Document how data are captured, transferred, stored, corrected, and protected. * Ensure that electronic systems are fit for purpose. * Consider data traceability from source to final analysis dataset. * Define who has access to which systems and why. ### Key difference 5: stronger data governance E6(R3) places greater emphasis on data governance. This is especially important for statisticians and data teams. Data governance means that the trial must have clear processes for how data are collected, managed, protected, corrected, transferred, analyzed, and retained. In E6(R2), data reliability was important, but E6(R3) makes the full data lifecycle more explicit. **Practical meaning:** * Explain where each data element comes from. * Define whether the data are source data, transcribed data, derived data, or analysis data. * Document data corrections and audit trails. * Define data access permissions. * Make sure the analysis dataset can be traced back to the original source. * Ensure that derived variables are reproducible. I already prepared a detailed documentation about the data governance, data management, and data preparation as part of the WHRI analytical framework. Based on the updated E6(R3) GCP guidelines it’s also an important pillar of clinical trial design and implementation. ### Key difference 6: clearer responsibilities for sponsors, investigators, and service providers E6(R3) provides clearer expectations about roles and responsibilities. This is especially important because modern trials often involve multiple parties: sponsors, investigators, contract research organizations, statisticians, data managers, laboratories, technology vendors, and other service providers. A key message is that tasks can be delegated, but responsibility cannot simply disappear. The sponsor and investigator must maintain appropriate oversight of delegated activities. **Practical meaning:** * Define who is responsible for each trial activity. * Document delegated tasks. * Ensure that service providers are qualified for their assigned tasks. * Make sure oversight is proportionate to the importance and risk of the delegated activity. * Avoid unclear situations where “everyone thought someone else was responsible.” ### Key difference 7: less focus on collecting everything, more focus on what matters E6(R3) encourages relevance and critical thinking. This is different from a culture where teams collect excessive data “just in case.” The innovative approach supports collecting data that are necessary for participant safety, trial conduct, endpoint evaluation, and interpretation of results. **Practical meaning:** * Not to recommend collecting variables unless they have a clear purpose. * Link each variable to the protocol, safety monitoring, baseline description, outcome analysis, subgroup analysis, or reporting requirement. * Reduce unnecessary data burden on participants and study teams. * Focus on data that are meaningful and dependable. This is important because excessive data collection increases workload, missing data, cleaning burden, and risk of error without necessarily improving the trial. ### Key difference 8: more emphasis on critical thinking E6(R3) expects trial teams to use critical thinking. This means decisions should be justified based on the trial context, not copied automatically from another study. For example, the monitoring plan, data checks, visit schedule, and documentation requirements should be appropriate for the trial. **Practical meaning:** * Explain why a procedure is needed. * Avoid unnecessary complexity. * Document key decisions. * Focus on what protects participants and supports reliable conclusions. * Adapt processes to the trial design, risk, and data sources. ### Key difference 9: stronger connection between protocol, data, and analysis E6(R3) supports a more integrated view of clinical trial quality. The protocol, data collection, monitoring, and analysis should not be separate disconnected activities. For statisticians, this is especially important. The final analysis depends on decisions made much earlier, including outcome definition, visit schedule, database design, missing data coding, and protocol deviation tracking. **Practical meaning:** Review the protocol before the database is finalized. Check whether the database captures all variables needed for the SAP. Define derived variables before analysis. Make sure visit windows match the primary endpoint. Ensure that protocol deviations can be identified and summarized. Align tables and figures with the protocol and SAP. Here I would like to add my own tip. Design the table shells before starting the analysis. This should be an integrated part of the SAP that is related to the study protocol. ### Key difference 10: trial documentation should be fit for purpose E6(R3) does not remove documentation requirements. Instead, it encourages documentation that is meaningful, necessary, and proportionate. Documentation should show what was planned, what was done, who was responsible, what changed, and why. **Practical meaning:** * Document important decisions. * Keep version-controlled protocols, SAPs, datasets, and outputs. * Maintain traceability from raw data to results. * Avoid unnecessary paperwork that does not support participant safety or data credibility. * Make sure the trial could be understood and reviewed later. **A summary comparison of the two documents is presented in Table 1 (See appendix 1)** The below summary shows side by side changes of the older and new guidelines documents. If you have experience running the clinical trials based on the ICH E6 R2, this summary table might help you to transmission to the ICH E6 R3 guidelines. ### What this means for investigators For investigators, the main message is that clinical trial quality starts at the design stage. Investigators need to define the research question, population, intervention, comparator, outcomes, and follow-up schedule clearly before recruitment begins. Investigators should also understand that delegation does not remove responsibility. Even if a coordinator, statistician, data manager, CRO, or vendor performs part of the work, the investigator still needs appropriate oversight of trial conduct at the site. ### What this means for sponsors For sponsors, E6(R3) means that trial oversight should be risk-based, proportionate, and documented. Sponsors need to identify critical-to-quality factors, select qualified service providers, oversee delegated activities, and ensure that trial systems and data processes are fit for purpose. The sponsor should not rely on generic procedures alone. The sponsor should be able to explain why the selected trial processes are appropriate for the specific study. ### What this means for statisticians and data teams For statisticians and data teams, E6(R3) is highly relevant because it strengthens the connection between trial design, data collection, and analysis. The statistician should be involved early enough to review the following. Its essential not only for the clinical trial design but for any analysis plan: * research question * primary and secondary outcomes * sample size * randomization * visit schedule * data collection forms * missing data coding * protocol deviation tracking * SAP * analysis-ready dataset structure * final tables and figures A major practical message is that analysis quality cannot be fixed at the end if the trial was not designed and documented properly at the beginning. ### To summarize ICH E6(R3) represents a shift from a compliance-driven interpretation of GCP toward a more flexible, proportionate, risk-based, and quality-by-design approach. The new guideline keeps the core principles of participant protection and reliable data, but places stronger emphasis on critical thinking, modern trial designs, technology, data governance, and fit-for-purpose documentation. Compared with E6(R2), E6(R3) asks trial teams to focus more clearly on what is critical to participant safety and the credibility of trial results. In practical terms, this means that clinical trial teams should not only follow procedures but also understand why each procedure is needed. The protocol, consent process, database, monitoring plan, statistical analysis plan, and reporting approach should all be aligned from the beginning of the trial. There is a list of resources related to clinical trials, ethics and other institution (PHSA/UBC) related practices summarized at the end of this document under resources. For any question related to clinical trail please contact WHRI senior statistician at ### APPENDIX 1 – Table 1 ICH E6(R2) vs ICH E6(R3): Practical Comparison | Topic | ICH E6(R2) | ICH E6(R3) | Practical meaning | | ---------------- | ------------------------------------ | ----------------------------------------------------------------- | --------------------------------------------------------- | | Overall approach | Addendum to older E6 structure | Major rewrite and reorganization | Need to retrain teams and update SOPs | | Trial quality | Introducing quality management | Stronger quality by design | Build quality into protocol and database from the start | | Risk management | Risk-based monitoring introduced | Risk-based quality management is central | Focus on risks that affect safety and reliability | | Proportionality | Less explicit | Strong emphasis | Requirements should match trial risk and complexity | | Technology | Electronic records addressed | Broader digital/data ecosystem | Need stronger data governance and system oversight | | Data | Data reliability emphasized | Full data lifecycle and governance emphasized | Need traceability from source to analysis dataset | | Monitoring | Risk-based monitoring added | Monitoring linked to critical-to-quality factors | Monitoring should focus on what matters most | | Responsibilities | Sponsor/investigator roles described | Roles of sponsors, investigators, and service providers clarified | Delegation must be documented and overseen | | Documentation | Essential documents emphasized | Fit-for-purpose documentation emphasized | Document what is necessary and meaningful | | Mindset | Compliance-oriented | Critical-thinking-oriented | Trial teams must justify decisions based on trial context | *Note: This table summarizes practical differences between ICH E6(R2) and the finalized ICH E6(R3) Principles in Annex 1.* ### Resources #### International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use documents *ICH E6(R3) Good Clinical Practice guideline* Annex 1 Annex 2 Endorse in November 2024 and is now under public consultation *ICH E6 R2 addendum* #### PHSA and/or UBC related documentation, guidelines and training *PHSA Clinical Trials Resource Library* Useful for SOPs, guidance documents, work instructions, forms, and templates. It also states that team members participating in regulated clinical trials must have documented SOP training *PHSA Clinical Trial Support* Describes PHSA support for Health Canada/FDA-regulated clinical trials, including trial management, quality management, data analytics, reporting, CTMS, e-regulatory, eSOURCE, eCONSENT, and monitoring support. *PHSA Research Process Map* Especially useful for your document because it covers protocol development, quality, risk management, statistical analysis planning, monitoring, data systems, trial registration, study initiation, and project completion *C\&W REB E-Consent Guidance* Good local guidance for electronic consent; it explicitly discusses ICH-GCP E6 electronic data handling and validation requirements in regulated clinical trials. *PHSA / UBC C\&W REB Assurance of Compliance* Useful if you need to mention that UBC-affiliated REBs operate in compliance with TCPS2, FDA/HHS requirements, and ICH E6 GCP where applicable. *PHSA Policy on Signing FDA Form 1572* Useful for industry-sponsored or FDA-related trials conducted in Canada; it references ICH GCP E6, Health Canada regulations, and TCPS2 *UBC Clinical Research Ethics General Guidance Notes* Main UBC clinical REB guidance page. It applies to UBC-affiliated clinical REBs, including CREB, Providence, C\&W, and BC Cancer REB. Reliable source for ethics/process context. *UBC RISe Modules* Useful for explaining ethics submission infrastructure. It states UBC REBs meet criteria under TCPS2, ICH-GCP, and U.S. human-subject protection requirements. *UBC Post-Approval Guidance Notes* Good for amendments, renewals, completion, protocol deviations, and unanticipated problems. It explicitly references ICH GCP expectations for REB written procedures. *UBC Article 13.2.4: Electronic Informed Consent* Useful for e-consent and regulated clinical trials; it references validation requirements under ICH E6 5.5.3. *UBC Research Ethics Contact / REB criteria page* States that UBC REBs meet criteria under TCPS2, ICH-GCP, and U.S. human-subject protection requirements. Useful for institutional context. --- # Agent Instructions This documentation is published with GitBook. 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