ICH GCP E6(R2) vs E6(R3): Key Differences and Practical Implications for Clinical Trials 

Introduction to E6(R2) vs E6(R3

Good Clinical Practice (GCP) is the international regulatory standard that has defined how clinical trials are designed, conducted, monitored, and reported for decades. First published by the International Council for Harmonisation (ICH) in 1996 under the “E6” guideline, GCP’s overarching goal has always been to protect trial participants and ensure the reliability and credibility of the data generated.  

The last major revision, ICH E6(R2), was adopted in 2016 and introduced greater emphasis on sponsor oversight, risk management, and electronic documentation. Since then, the clinical research landscape has changed dramatically: 

• Decentralized, hybrid, and adaptive trials have become common, 

• Digital tools such as eConsent, eSource, and remote monitoring are widely adopted, 

• Regulators and patients alike expect greater transparency and flexibility, 

• The use of real-world data (RWD) and real-world evidence (RWE) has expanded rapidly. 

In response, in January 2025 the ICH E6(R3) guideline was finalized, and it came into force in the European Union on 23 July 2025. The new edition is an evolution towards Quality by Design (QbD), proportionality to risk, broader integration of technology, and stronger patient-centricity. 

Quality by Design (QbD) is a structured approach to clinical trial design that focuses on building quality into the study from the very beginning. Instead of relying primarily on retrospective checks or exhaustive monitoring, QbD requires sponsors to: 
– identify Critical-to-Quality factors (CtQFs) that directly impact participant safety and data reliability, 
– assess and mitigate risks related to those factors, 
– design trial processes and procedures that are proportionate to the level of risk,
– involve stakeholders, including investigators and patients, in planning. 

In short, QbD shifts the emphasis from “detecting errors later” to “designing out errors upfront. 

This article explores the key differences between E6(R2) vs E6(R3) and provides practical examples of what these changes mean for sponsors, CROs, and research sites. 

1. Quality Approach: Quality by Design (QbD) – E6(R2) vs E6(R3)

R2: Quality was primarily understood as extensive oversight, detailed documentation, and frequent inspections. The 2016 revision emphasized sponsor oversight of delegated tasks, introduced the concept of risk-based monitoring, and reinforced requirements for electronic systems and data integrity. However, in practice, quality management still relied heavily on exhaustive checks and 100% Source Data Verification (SDV), with errors detected retrospectively rather than prevented. 

R3: Introduces Quality by Design (QbD) – quality should be embedded in the trial from the outset. The focus is on identifying Critical-to-Quality factors (CtQFs) that directly affect participant safety and data reliability and designing processes to protect those factors. 

Principles of QbD include: 

• Identification of CtQFs, 
• Risk assessment, 
• Proportional oversight, 
• Prioritization of critical data, 
• Engagement of patients and investigators in trial design. 

Example: 

In a neurological study, CtQFs include seizure frequency and serious adverse events (SAEs) – requiring full verification. Secondary endpoints such as cognitive test scores can be monitored centrally through trend analysis.

2. Flexible Scope: From Randomized Controlled Trials s to Decentralized Trials – E6(R2) vs E6(R3)

R2: The framework was designed mainly for traditional randomized controlled trials (RCTs) conducted at physical sites. Although risk-based concepts were introduced, they were applied within the context of site-based monitoring and conventional trial structures. Unconventional designs such as adaptive or decentralized trials were not explicitly addressed, leaving uncertainty for sponsors. 

R3: Extends applicability to adaptive, pragmatic, hybrid, and decentralized clinical trials (DCTs), explicitly recognizing direct-to-patient models, home health services, and the use of real-world data (RWD). 

Example: 

In a pediatric trial, investigational medicine is shipped directly to the child’s home. Parents confirm receipt via a mobile app, while the investigator monitors adherence remotely. Under R2, parents would have had to travel monthly to the trial site for drug collection. 

3. Digital Technologies: eConsent, eSource, and Remote Monitoring – E6(R2) vs E6(R3)

R2: Recognized electronic case report forms (eCRFs) and allowed electronic records, but paper remained the gold standard, particularly for informed consent. Electronic systems had to be validated, but regulators still expected extensive paper archiving. Centralized monitoring was mentioned, yet rarely implemented due to lack of detailed guidance. 

R3: Provides clear endorsement of digital tools such as eConsent, eSource, centralized and remote monitoring, and emphasizes ALCOA++ principles for data integrity. 

ALCOA++ is an extended framework for data integrity in clinical research. It builds on the original ALCOA principles (Attributable, Legible, Contemporaneous, Original, Accurate) by adding requirements such as Completeness, Consistency, Endurance, Availability, Traceability, and Transparency. Together, these principles ensure that clinical trials data is reliable, verifiable, and trustworthy throughout its lifecycle. 

Example: 

In a metabolic trial, participants use eConsent via an app: they watch a short explanatory video, answer comprehension questions, and provide electronic consent. The investigator has a full audit trail, ensuring the participant has truly understood the study. 

4. Patient Perspective 

R2: The patient’s role was mainly passive. Guidelines focused on protecting participant safety and rights but did not emphasize patient engagement, experience, or burden. Protocols were often designed around site and sponsor needs rather than participant convenience. 
R3: Moves towards patient-centricity – requiring assessment of participant burden (e.g., travel, visit frequency, and lifestyle disruption), transparent communication, and active involvement of patients in study design. 

Example: 

In a pulmonary study, participants no longer need to travel to the site every two weeks. Instead, they receive a home spirometer that automatically uploads lung function data, reducing patient burden while improving the frequency of measurements. 

5. Responsibilities of Sponsors and Investigators 

R2: Responsibilities were rigidly defined. Sponsors carried broad accountability, with heavy emphasis on continuous oversight of CROs and vendors. The guideline reinforced the need for contracts and documentation but left little room for proportional flexibility based on risk. 

R3: Encourages proportional allocation of responsibilities. Oversight and controls should be adapted to the type of study and risk level, acknowledging the growing role of specialized technology vendors. 

Example: 

In a dermatology study, a vendor manages a mobile app used by patients to upload skin images. Under R3, the sponsor is not required to verify every photo individually but must ensure vendor oversight and data quality through documented processes. 

6. Monitoring and Documentation 

R2: Strongly associated with onsite monitoring and complete verification of data. Although risk-based monitoring was introduced, in practice most sponsors and CROs defaulted to full SDV. Documentation requirements remained extensive, often leading to high administrative burden. 

R3: Embeds Risk-Based Monitoring (RBM) as the standard, with a combination of centralized, remote, and targeted approaches. Documentation should be agile – focused on critical data and decisions rather than exhaustive records. 

Example: 

In a metabolic study, HbA1c levels are defined as CtQ and undergo full verification. Secondary parameters, such as body weight, are monitored centrally using dashboards and flagged only if anomalies are detected. 

7. Regulatory Oversight 

R2: Inspections centered primarily on documentation compliance – whether the trial master file and site records were complete and consistent. Regulators expected sponsors to “prove compliance” through paper and records. 

R3: Inspections shift towards evaluating the quality-by-design process. Regulators will request evidence of CtQ identification, risk management strategies, and decision logs, reflecting how quality was proactively built into the study. 

Example:  

During an inspection, the sponsor presents the CtQ matrix, RBQM plan, and decision log, demonstrating how identified risks were managed and how critical data quality was safeguarded throughout the study. 

8. Benefits and Challenges in Implementing E6(R3) 

E6 R3 offers a modernized, flexible, patient-centered framework. It enables innovation, supports digital transformation, and reduces unnecessary burden. At the same time, it challenges organizations to adapt SOPs, validate systems, and retrain staff to meet higher expectations. 

Benefits: 

• Stronger patient-centricity and reduced participant burden, 

• Flexibility to design adaptive and decentralized clinical trials, 

• Real-time insights through digital technologies. 

Challenges: 

• Variability across jurisdictions in recognizing electronic signatures, 

• Significant investment in IT systems and validation, 

• Need to update SOPs and train staff in QbD and RBQM approaches, 

• Preparing for inspections focused on processes and design decisions rather than paperwork alone. 

Summary of E6(R2) vs E6(R3)

E6(R3) does not replace the foundations of Good Clinical Practice but redefines how they should be applied in today’s environment. The guideline shifts the focus from exhaustive documentation to quality built into the design, from rigid oversight to proportional risk-based management, and from paper-heavy processes to digital innovation. 

For sponsors and CROs, this means updating Standard Operating Procedures (SOPs), implementing Risk-Based Quality Management (RBQM) tools, validating IT systems, and preparing for a new type of regulatory inspection. While challenging, these changes bring opportunities: trials can be more efficient, more flexible, and more patient-friendly. Organizations that embrace E6(R3) early will be better positioned to succeed in the evolving clinical research landscape. 

Frequently Asked Questions (FAQ) about E6(R2) vs E6(R3)

References 

1. ICH HARMONISED GUIDELINE GUIDELINE FOR GOOD CLINICAL PRACTICE E6(R3), International Council for Harmonisation, access date: 23.09.2025   

2. ICH E6 Good Clinical Practice Scientific Guideline, European Medicines Agency, access date: 23.09.2025   

3. GENERAL CONSIDERATIONS FOR CLINICAL STUDIES E8(R1), International Council for Harmonisation. https://database.ich.org/sites/default/files/E8-R1_Guideline_Step4_2021_1006.pdf, access date: 23.09.2025  

4. The Impact of ICH E6(R3) on GCP: Implementing New Expectations in a Culture of Quality. Association of Clinical Research Professionals (ACRP). https://acrpnet.org/2025/02/06/the-impact-of-ich-e6r3-on-gcp-implementing-new-expectations-in-a-culture-of-quality. Accessed: 23.09.2025. 

5. ICH E6(R3) is Here – What You Need to Know. WCG Clinical. Accessed: 23.09.2025. 

6. Adoption of ICH GCP Guideline E6(R3), Swissmedic, https://www.swissmedic.ch/swissmedic/en/home/news/mitteilungen/einfuehrung-leitlinie-ich-gcp-e6-r3.html. Accessed: 23.09.2025. 

7. The ICH E6(R3) Guideline: A Major Update to Good Clinical Practice. FDA Law Blog. Accessed: 23.09.2025. 

8. Risk-Based Quality Management (RBQM) Implementation Guidance. TransCelerate. https://www.transceleratebiopharmainc.com/assets/risk-based-monitoring-solutions/ Accessed: 23.09.2025. 

9. Guidance on Good clinical practice for clinical trials, Medicines and Healthcare products Regulatory Agency (MHRA). . Accessed: 23.09.2025. 

10. Guideline on computerised systems and electronic data in clinical trials, European Medicines Agency.  , Accessed: 23.09.2025.