Authors:
MedSurgPI: Gerald L. Klein, MD; Roger E. Morgan, MD; Freddy Byrth; Marion Stamp-Cole, Stephen Haworth, MD
SMART BioWorks: Eric Hacherl, PhD
Exquisite Biomedical Consulting: Shabnam Vaezzadeh, MD
Global Life Sciences Alliance: Denise McNerney
Independent DSMB Coordinator: Jamie Lazar
LBF BioPharma Consulting: Larry Florin
The Brown Group: Gail Brown, MD
Drug Development
New Guidelines from ICH E6(R3)
The International Council for Harmonisation (ICH) Guideline E6(R3), Good Clinical Practice revision represents a pivotal step toward modernizing clinical trial conduct and oversight. This update redefines how sponsors, investigators, and Medical Affairs teams manage quality and risk, emphasizing participant protection, data integrity, and responsible use of digital technologies.
1. Dynamic Risk Assessments (DRA): From Static to Adaptive Oversight
ICH E6(R3) suggests that sponsors develop a risk-based approach to clinical trial/development oversight, with the intensity and focus of activities such as monitoring, data review, and auditing adjusted based on the clinical trial’s complexity and potential impact on the study participants. Importantly, R3 builds upon prior versions of ICH E6 that emphasized Quality by Design (QbD), reinforcing that proactive, design-level quality principles should guide how risks are identified, prioritized, and managed throughout the study lifecycle.
Continuous evolution: These risk assessments should be periodically reviewed and, if needed, updated/changed based on the availability of new/additional data, changes in sites (number, geographic location, operational instructions, etc.), or technology (systems, site-facing interfaces, etc.) that may introduce new risks.
Adaptive monitoring: Replace standardized monitoring plans with real-time, adaptive strategies triggered by defined indicators:
Protocol deviations
Missing or inconsistent data
Emerging safety trends or unexpected adverse events
Independent oversight: Medical monitors and Data Safety Monitoring Boards (DSMBs) play a greater role in interpreting risk signals and ensuring participant safety, extending beyond passive review to include adaptive, data-informed interventions.
This shift aligns with regulatory trends emphasizing quality by design (QbD), risk-based monitoring (RBM), and fit-for-purpose quality systems—concepts central to ICH E8(R1) and E6(R3) alignment. At the heart of this evolution is a focus on “Critical-to-Quality” (CtQ) factors, as oversight activities should concentrate on the processes and data that are essential to assuring participant safety and the accumulation of reliable, interpretable patient data. A key crux of E6(R3) is the shift away from traditional, exhaustive source data verification (SDV) toward data-driven, centralized (statistical) monitoring strategies with a keen focus on critical data.
2. Reaffirming Participant Safety, Rights, and Well-Being
ICH E6(R3) reaffirms its ethical foundation: participant protection is paramount. Beyond compliance, sponsors must ensure participants are fully informed, empowered, and respected throughout the trial.
Transparency and accessibility: Investigators must have real-time access to new safety data, protocol amendments, and risk communications to ensure timely action at the site level.
Participant communication: Sponsors and Clinical Research Organizations (CROs) must provide safety information that is clear, understandable, and culturally appropriate, supporting autonomy and continued informed consent.
Ethical obligation: Sponsors are responsible not only for data collection but for safeguarding trust which is crucial for sustaining public confidence in research.
3. Digital Tools: From Operational Efficiency to Ethical Rigor
The guideline acknowledges the growing role of digital and decentralized technologies but reframes their purpose beyond efficiency and cost containment to ensure scientific validity and ethical implementation.
Fit-for-purpose validation: All digital tools (ePRO, wearables, AI analytics) must undergo formal validation to confirm they accurately capture, store, and transmit data as intended.
Ethical use and governance: Establish clear frameworks for data privacy, participant consent, and system reliability, particularly when technology intermediates participant interaction.
Integration with quality management: Digital systems should integrate seamlessly into the trial's risk-based quality framework to reinforce, not replace, scientific and ethical rigor.
Medical Affairs
Upholding Oversight and Quality
1. Medical Affairs (MA) teams serve as the interface between science, ethics, and communication, ensuring post-marketing and real-world activities align with ICH E6(R3) expectations. As AI becomes embedded in literature surveillance, scientific communication, medical review, and real-world data workflows, MA teams must ensure these tools are used responsibly, transparently, and in alignment with ICH E6(R3)’s quality and data-integrity principles.
2. System validation and data integrity: All computerized systems under MA control must be fully validated with robust audit trails, user-access controls, and metadata capture (author, reviewer, approver, time/date stamps). This applies to:
Key Opinion Leader (KOL) and stakeholder tracking (Customer Relationship Management) platforms
Publication planning and review systems
Real-world evidence and registry databases
AI-assisted content generation, literature monitoring, and medical insight analytics tools
3. Vendor oversight and accountability: Contracts with scientific vendors, communications agencies, and publication partners should clearly define:
Scope of work and deliverables
Delegated responsibilities and accountability
Oversight structure (Medical Affairs vs. vendor roles)
Performance metrics: timeliness, data accuracy, conflict-of-interest management, GxP compliance
Vendor training requirements: GCP, data privacy, and quality expectations
Clearly define Intellectual Property (IP) and practices to maintain IP protections
4. Documentation and training: Maintain oversight logs documenting all delegated activities and ensure team members receive training in essential areas, including, but not limited to:
Vendor selection and qualification criteria
Delegation and accountability management
Vendor audits and quality oversight procedures ensuring that participant care and safety decisions are made by competent professionals
Scope of work, deliverables, and agreed Key Performance Indicators (KPI)s
These practices demonstrate due diligence and establish clear traceability—key principles reinforced in ICH E6(R3).
Key Takeaway
ICH E6(R3) is not merely a compliance exercise; it's a call to rethink trial oversight as a living system. The guideline promotes balance between flexibility and accountability, urging organizations to align quality, ethics, and innovation at every stage of the trial lifecycle. For sponsors, CROs, and Medical Affairs teams, success depends on transparency, adaptability, and a proactive approach to risk management—hallmarks of modern, patient-centered research.