International Council for Harmonisation E6 (R3): The Good Clinical Practice, recent developments, and global perspective

Introduction

Good Clinical Practice (GCP) is the cornerstone of ethical and scientifically sound clinical research, ensuring that the rights, safety, and well-being of trial participants are protected while generating credible and reliable study data. The ICH Guideline E6 has long been the global reference standard for GCP compliance, shaping regulatory expectations across multiple regions. With the release of ICH E6 (R3), the GCP framework has undergone a significant transformation, reflecting the evolving complexities of modern clinical trials.[1]

The Evolution of International council for Harmonisation E6: From R1 to R3

The ICH E6 guidelines have evolved through three major versions – R1, R2 and R3 – each playing a pivotal role in shaping modern GCP [Table 1].

Table 1.

Comparison of three revisions of ICH E6

Aspect	ICH E6 R1 (1996)	ICH E6 R2 (2016)	ICH E6 R3 (2025)
Focus	Ethical and scientific standards	RBM and data integrity	RBQM and digital integration
Monitoring approach	Traditional on-site monitoring	RBM	RBQM
Technology	Paper-based data collection	Acknowledged electronic records and audit trails	Promotes digital health tech, decentralized trials, and remote access
Data integrity	Basic GCP compliance	Emphasis on audit trails and e-record reliability	Strong data governance, AI and automation, and full traceability
Participant protection	Informed consent and ethics	Reinforced ethical oversight	Adds digital/remote consenting, greater stakeholder engagement
Design philosophy	Protocol-focused	Monitoring-centric	Quality by design, critical-to-quality factor emphasis
Global applicability	Harmonization across US, EU, and Japan	Global compliance with some flexibility	Harmonized + adaptable, aligns with regional needs

RBQM=Risk-based quality management, RBM=Risk-based monitoring, ICH=International Council for Harmonisation, GCP=Good Clinical Practice, AI=Artificial intelligence

• R1 (1996) laid the foundational framework for ethical and scientific standards in clinical trials. It harmonized global requirements across the US, EU, and Japan, focusing on protecting participants and ensuring reliable trial data. Its key aid was establishing a uniform global standard for GCP compliance during the early era of clinical research

• R2 (2016) responded to growing complexities in clinical research by introducing Risk-based monitoring (RBM) and permitting flexibility in monitoring strategies. It also acknowledged the increasing role of digital systems by addressing electronic data capture and audit trails. R2’s contribution was in making trials more efficient and adaptable, especially through modern monitoring techniques

• R3 (2025) represents a paradigm shift with its comprehensive risk-based quality management (RBQM) approach, promotion of digital and decentralized trial methods, and stronger emphasis on data integrity and participant-centricity. The aid of R3 lies in aligning GCP with 21^st-century trial innovations, such as real-world evidence (RWE), artificial intelligence (AI)-driven oversight, and remote consenting, all while maintaining rigorous ethical standards.

R3 Key Improvements

The ICHs E6 (R3) guideline introduces substantial updates to the GCP framework, reflecting advancements in clinical trial methodologies and technologies since the previous E6 (R2) version with the aim to make clinical trial processes more flexible, efficient, and risk based, while ensuring participant safety and data integrity.

• Enhanced RBQM: While E6 (R2) introduced RBM, E6 (R3) expands this to a comprehensive RBQM approach, integrating proactive risk assessment at all trial stages[2,3]

• Quality by design: E6 (R3) shifts toward designing trials with quality in mind from the outset, reducing unnecessary documentation and emphasizing on critical-to-quality factors[3]

• Use of digital technology and decentralization: Unlike E6 (R2), which lacked specific guidance on digital technologies, E6 (R3) supports and explicitly gives guidance on the use of electronic records, remote monitoring, and digital health technologies[3]

• Stronger data governance and integrity: E6 (R3) proposes a stricter and extensive data security, audit trails, and traceability, ensuring electronic and remote trial data meet high-quality standards[3]

• Better protection for participants and ethical considerations: E6 (R3) encourages greater stakeholder engagement in the trials. Also allows for remote and digital consenting enhancing flexibility of the consenting process.[3]

E6 R3 and India

In September 2024, CDSCO proposed its draft revision of the Indian GCP guidelines after its introduction in 2001. Excepting for a few key differences in the implementation methods and focus points, the Indian draft at its core is similar to the parent guideline E6 R3, from which it is adopted. Both guidelines promote risk-based approaches for monitoring trials, prioritizing on critical-to-quality factors and application of adaptive oversight strategies. Proactive quality management beginning right from trial design to execution has been stressed upon.

Both support the use of electronic records, e-consent, and other digital technologies as well as throwing light on conducting decentralized trials with remote monitoring to improve trial efficiency.[3,4]

As opposed to the ICH guidelines which encourage automated AI-based monitoring for efficiency, Indian guidelines focus on balancing this technological adoption with manual oversight by the local authorities. India’s approach is more flexible, accommodating both digital and traditional data collection methods, while ICH E6 (R3) mandates electronic data integrity for consistency in global trials. While ICH E6 (R3) prioritizes efficiency, India’s GCP especially focuses on ethical protections and participant comprehension in diverse populations preventing their exploitation in clinical trials and makes trials more accessible to local researchers and sponsors.[4]

While ICH E6 (R3) is globally harmonized and technology-driven, India’s GCP draft prioritizes regional adaptability, participant protection, and affordability. Both guidelines share common GCP principles, but India’s framework addresses local challenges such as language barriers, regulatory delays, and socioeconomic disparities, ensuring clinical trials remain ethical, accessible, and inclusive within the country.

Multiregional Clinical Trials

ICH E6 (R3) also has a key role to play in simplifying Multiregional Clinical Trials (MRCTs), where one trial runs across several regulatory regions. MRCTs facilitate quicker drug development, improved generalizability of the data, and fairer access to innovations. Harmonized yet adaptable guidance within E6 (R3) allows sponsors to implement common protocols while being flexible with respect to local requirements. This is particularly precious for nations such as India, Japan, and EU regions, where regional variations are required for cultural or regulatory purposes. Implementation of E6 (R3) can reinforce India’s engagement in international MRCTs through consistency with global data standards, ethics, and conduct of trials, ultimately promoting global cooperation and convergence of regulations.[5]

Pitfalls

While E6 R3 is an update, fixing few issues posed by the previous version R2, it presents its own set of challenges, especially for developing countries.

Resource constraints

Financial and Human Resources: Developing countries often face limitations in financial and human resources dedicated to clinical research. This scarcity can hinder the effective implementation of comprehensive GCP guidelines, which require substantial investment in training, infrastructure, and ongoing oversight.[6]

Research environment

Lack of Established Research Culture: In some developing countries, there may be a less established culture of clinical research, leading to challenges in participant recruitment, adherence to protocols, and data quality assurance.[6]

Infrastructure and technological gaps

Limited Access to Advanced Technology: Implementing modern GCP guidelines often requires advanced technological infrastructure for data collection, monitoring, and analysis. Developing countries may lack access to such technologies, making compliance more challenging.[6]

Training and expertise

Need for Specialized Training: There is often a shortage of professionals trained in the latest GCP standards and clinical trial methodologies in developing countries, necessitating significant investment in education and capacity-building initiatives.[6]

Conclusion

The transition from ICH E6 (R2) to E6 (R3) marks a significant evolution in GCP, shifting toward a more flexible, risk-based, and technology-driven approach to clinical trials. However, the true impact of E6 (R3) will depend on how effectively it is implemented across diverse regulatory and operational landscapes.

For countries like the USA and EU nations, the focus will be on refining existing frameworks, integrating AI-driven monitoring and ensuring seamless adoption of decentralized trial methodologies.[7,8] In contrast, nations like India must address regulatory alignment, workforce training, infrastructure gaps, and digital transformation to fully leverage the benefits of E6 (R3).

The way forward requires a collaborative global effort, where regulatory agencies, sponsors, contract research organizations, and investigators work together to:

• Develop region-specific implementation strategies that balance flexibility with compliance

• Invest in research capacity-building through specialized training in RBM and digital tools

• Foster stronger regulatory harmonization by aligning local guidelines with global best practices

• Leverage RWE and adaptive designs to enhance trial efficiency.

As the clinical trial landscape becomes more patient-centric and technology-integrated, ICH E6 (R3) will serve as a blueprint for the next generation of ethical, efficient, and high-quality research. By embracing its principles proactively, stakeholders can accelerate innovation while safeguarding participant rights and data integrity, ultimately shaping a future where clinical trials are more accessible, robust, and globally harmonized.