On September 29th, the Society for Clinical Data Management (SCDM) annual conference in Baltimore hosted one of the most significant regulatory events of the year: a town hall bringing together officials from six major global regulatory agencies to discuss two transformative topics shaping the future of clinical research: ICH E6(R3) and Artificial Intelligence in Clinical Research.
As the moderator of this session, I had the privilege of facilitating dialogue between industry professionals and representatives from the FDA, Health Canada, MHRA, BfArM, DKMA, and the Swedish Medical Products Agency. This responsibility was passed to me by Jonathan Andrus, CRIO Co-CEO and long-time SCDM board member and current Treasurer, who has historically hosted and moderated these regulatory town halls. The collaborative spirit and regulatory alignment demonstrated during this session signals a new era of harmonized oversight and innovation in clinical trials.
Largest Panel of Global Regulators at SCDM
The town hall featured an exceptional panel of regulatory experts:
- Lisbeth Bregnhøj, GCP Inspector, The Danish Medicines Agency (DKMA)
- Torsten Stemmler, Head of GCP Inspection Unit, Federal Institute for Drugs and Medical Devices Germany (BfArM)
- Cheryl Grandinetti, Associate Director for Clinical Policy, Division of Clinical Compliance Evaluation, Office of Scientific Investigations, Office of Compliance, CDER, U.S. Food and Drug Administration
- Kassa Ayalew, Division Director, Division of Clinical Compliance Evaluation (DCCE), U.S. Food and Drug Administration
- Annie Saha, Associate Director for Strategic Initiatives, Digital Health Center of Excellence, CDRH | Associate Director for Data Science and Artificial Intelligence Policy (acting), Office of Medical Policy, CDER, U.S. Food and Drug Administration
- Daniel Bjermo, Pharmaceutical Inspector GCP at Swedish Medical Products Agency
- Rachel Mead, Senior GCP Inspector, MHRA
- Myriam Salem, National Compliance and Enforcement Supervisor, Clinical Trial Compliance Program (CTCP), Health Canada
- Alicja Kasina, Senior Compliance and Enforcement Advisor, Clinical Trial Compliance Program (CTCP), Health Canada
This diverse representation of international regulatory authorities underscored a critical message: global regulators are working in harmony to modernize clinical trial oversight.
ICH E6(R3): Quality by Design Meets Regulatory Reality
The FDA’s presentation on ICH E6(R3) provided crucial insights into how regulators view the implementation of the newest updates to the Good Clinical Practices guidance. The adoption of ICH E6(R3) on January 6, 2025, marked a fundamental shift in how we approach clinical trial quality.
Three Foundational Concepts
Grandinetti emphasized three interconnected principles that form the backbone of ICH E6(R3):
- Quality by Design (Principle 6): Building quality into trial design from the outset, rather than attempting to inspect it in after the fact
- Risk Proportionality (Principle 7): Ensuring oversight and resources are commensurate with actual risks to participant safety and data integrity
- Fit-for-Purpose Clinical Trial Quality (Principle 9): Focusing on whether trials meet their objectives while protecting participants and generating reliable results
The emphasis on building robust systems aligns with the principle that quality outcomes should emerge naturally from well-designed processes rather than relying solely on downstream verification. We need to create systems that inherently produce quality outcomes.
Addressing Industry Concerns About Inspection Alignment
One of the key takeaways for the audience was the frank acknowledgment of industry hesitations around ICH E6(R3) implementation. Industry stakeholders have expressed concerns about inconsistent inspector interpretation of risk-proportionate approaches and fears that inspection practices may not align with the risk-based framework.
The FDA’s response demonstrated commitment through active participation in the Pharmaceutical Inspection Co-operation Scheme (PIC/S) GCP Expert Circle, established in 2022 specifically to:
- Harmonize inspection standards worldwide among 56 regulatory authorities
- Develop training and practical guidance for GCP inspections
- Promote a framework where inspection activities focus on the trial’s critical to quality (CTQ) factors
- Support efficient, risk-based regulatory oversight aligned with ICH E6(R3) principles
Clinical trials are taking place on a global scale, and this commitment to inspector training and harmonization should provide sponsors, CROs, and sites with greater confidence that adopting risk-based approaches will be consistently recognized and appropriately evaluated across global regulatory inspections.
Connecting ICH E6(R3) to the AWC Standard
Perhaps most importantly for compliance professionals, the FDA drew a direct line between the Quality by Design framework and the regulatory criteria for an adequate and well-controlled (AWC) study under 21 CFR 314.126. This connection is critical: ICH E6(R3)’s quality framework isn’t separate from regulatory requirements—it is the pathway to meeting them.
By ensuring study design elements and conduct focus on key objectives, selecting fit-for-purpose designs and endpoints, maintaining broad but appropriate enrollment criteria, and prespecifying analytical approaches, sponsors can simultaneously achieve both ICH E6(R3) compliance and the substantial evidence standard required for drug approval.
For organizations using modern clinical trial platforms, this alignment is particularly relevant. Systems like CRIO, which enable centralized oversight, protocol-driven data collection, and risk-based monitoring, embody the principles of Quality by Design that regulators are seeking. The ability to demonstrate that quality has been built into trial design and execution becomes a significant advantage during regulatory review and inspection.
Artificial Intelligence: From Rapid Adoption to Regulatory Framework
The FDA’s presentation on AI in drug and biological product development revealed just how quickly this landscape is evolving. The numbers tell a compelling story:
- Center for Drug Evaluation and Research (CDER) has received over 800 submissions involving AI since 2016
- Submissions have increased exponentially, from 2 in 2018 to 248 INDs in 2024
- Oncology (208 submissions), gastroenterology (104), and neurology (94) lead therapeutic areas
- Use cases span the entire drug development lifecycle: patient selection, outcome prediction, confounding adjustment, pharmacometric modeling, digital twins, external controls, and post-market safety monitoring
CDER’s Core Principles for AI Regulation
The FDA outlined three guiding principles that should inform how the industry approaches AI in clinical research:
- Adaptive Regulation: A technology-enabling, responsive, iterative approach to accelerate adoption while maintaining patient safety
- Risk-Based Regulation: Moving from one-size-fits-all regulation to a data-driven, segmented approach commensurate with AI model risk
- Collaborative Regulation: Aligning regulation by engaging a broad ecosystem including tech companies, biotech, pharma, patients, and regulators
The First Global AI Draft Guidance
In January 2025, the FDA released the first AI draft guidance globally: “Considerations for the Use of Artificial Intelligence to Support Regulatory Decision-Making for Drug and Biological Products.” This groundbreaking document provides a risk-based framework to establish and evaluate the credibility of an AI model output for a particular context of use (COU).
The guidance introduces critical concepts:
- Credibility: Trust, established through the collection of evidence, in the performance of an AI model for a particular COU
- Context of Use: The specific role and scope of the AI model to address a question of interest
- Seven-Step Framework: A structured approach from defining the question of interest through documenting results and determining model adequacy
What makes this guidance particularly valuable is its acknowledgment of both FDA and industry needs. The agency needed a framework to determine if AI use is appropriate and how to evaluate AI outputs. The clinical research industry needed clarity on what is in scope for FDA oversight, how much information will be required, and how to engage with the agency on AI uses.
The guidance explicitly encourages early engagement through various pathways depending on context of use, including the Model-Informed Drug Development Program, Real-World Evidence Program, Digital Health Technology Program, Complex Innovative Trial Design Meeting Program, and others.
What This Means for Clinical Trial Technology
For clinical trial platforms that incorporate or enable AI capabilities, this guidance provides crucial clarity and a path forward. The emphasis on documenting the model development process, evaluation methodology, and risk assessment aligns well with validated, compliant systems.
Organizations implementing AI for clinical trial optimization, whether for patient recruitment, site selection, data quality monitoring, or risk-based oversight now have a clear regulatory framework to guide their approach. The key is demonstrating that AI models are fit-for-purpose, that their outputs are credible for the specific context, and that appropriate risk mitigation strategies are in place.
The Q&A Session: Practical Insights from Regulators
The second half of the town hall featured an insightful discussion with questions from attendees across data management, regulatory affairs, and clinical operations roles. Several themes emerged:
Regulatory Alignment Is Real, Not Aspirational
Representatives from multiple agencies confirmed active collaboration through bilateral agreements (FDA/EMA, FDA/MHRA, FDA/Health Canada) and multilateral forums (PIC/S). This isn’t merely coordination, it is substantive alignment on inspection standards, guidance interpretation, and enforcement approaches.
Risk-Based Approaches Are Expected, Not Optional
Multiple panelists emphasized that regulators expect sponsors to conduct risk assessments during trial design and implement targeted strategies for high-risk areas. The days of uniform, maximum oversight across all trial elements regardless of their criticality are ending.
Documentation of Quality-by-Design Thinking Matters
Regulators want to see evidence that quality considerations were built into design decisions, not retroactively applied. Documenting the rationale for critical-to-quality (CTQ) factor identification, risk assessment outcomes, and mitigation strategies strengthens both submissions and inspection readiness.
Technology Enablement Requires Validation and Training
Whether discussing AI models or electronic source systems, panelists consistently emphasized the importance of validation, user training, and maintaining audit trails. Technology is welcome but it must be implemented in a compliant, documented manner.
Key Takeaways for Clinical Research Professionals
For Sponsors and CROs:
- Embrace ICH E6(R3) with confidence: Global regulatory alignment and inspector training initiatives mean risk-based approaches will be consistently recognized, regardless where these inspections are taking place
- Document your Quality by Design approach: Clearly articulate CTQ factors, risk assessments, and how trial design addresses quality from the outset
- Engage early on AI applications: Use the formal pathways outlined in the FDA guidance to discuss planned AI uses before implementation
- Invest in compliant technology platforms: Systems that enable central oversight, protocol-driven data collection, and risk-based monitoring align with regulatory expectations
For Clinical Investigators and Sites:
- Understand the CTQ factors for your trials: Site staff should know what elements are most critical to participant safety and data integrity
- Leverage technology that reduces burden while enhancing quality: Electronic source systems that are validated and supported align with both E6(R3) principles and inspector expectations
- Expect risk-proportionate monitoring: Sponsors implementing E6(R3) properly will focus resources on high-risk areas, potentially reducing unnecessary oversight of low-risk elements
- Maintain inspection readiness: Documentation of training, validation, and quality processes remains essential regardless of trial design
For Data Management Professionals:
- Central data oversight is increasingly important: As trials become more complex and distributed, centralized monitoring and data review capabilities are essential
- AI applications in CDM need clear documentation: Whether using AI for data cleaning, query generation, or quality assessment, follow the seven-step framework
- Standardization supports quality: Data standards, protocol-driven data collection, and consistent data structures facilitate both quality and regulatory review
How CRIO Supports the Evolving Regulatory Landscape
The regulatory alignment demonstrated at this town hall validates the approach CRIO has taken in platform design and implementation. By providing centrally-developed, protocol-driven electronic source forms to investigator sites, CRIO enables the Quality by Design principles that regulators are seeking.
Key CRIO capabilities that align with ICH E6(R3) and emerging regulatory expectations include:
- Central eSource with investigator oversight: Ensures consistent data collection while maintaining appropriate investigator control and endorsement of data
- Risk-based monitoring support: Enables centralized, remote oversight focused on CTQ factors and high-risk areas
- Validation and documentation: Comprehensive validation certificates and documentation support both sponsor diligence and inspection readiness
- Audit trail and data integrity: Built-in compliance with 21 CFR Part 11 requirements for electronic records and signatures
- Remote regulatory assessment readiness: Read-only reviewer access facilitates efficient FDA remote regulatory assessments without compromising data integrity
As the FDA presentation emphasized, operational efficiencies should not be the primary driver—rather, technology should enable the collection of reliable data that supports regulatory decision-making for safety, effectiveness, and quality of drugs. This is precisely the balance CRIO strikes: reducing site burden while enhancing data quality and regulatory compliance.
Looking Forward: A New Era of Collaborative Regulation
The SCDM Regulatory Town Hall demonstrated something remarkable: global regulators are not just coordinating but they’re actively collaborating to create a harmonized, modern framework for clinical trial oversight. The alignment on ICH E6(R3) principles and the FDA’s leadership in AI guidance signal a willingness to embrace innovation while maintaining rigorous standards for participant protection and data reliability.
For clinical research professionals, this represents an opportunity. By adopting Quality by Design principles, implementing risk-proportionate approaches, and leveraging compliant technology platforms, organizations can simultaneously improve trial efficiency and strengthen regulatory confidence.
The message from regulators was clear: engage early, document your thinking, build quality into design, and don’t hesitate to have conversations about innovative approaches. The regulatory landscape is evolving to support and not to impede the modernization of clinical trials.
For more insights into regulatory compliance, electronic source implementation, and quality by design in clinical trials, explore our resources at https://clinicalresearch.io/blog/.
Marc Wartenberger is the Senior Director of Security, Corporate QA & Compliance at CRIO and served as moderator for the SCDM 2025 Regulatory Town Hall. His extensive work with regulatory bodies including serving as host for SCDM’s regulatory town halls and participation in the SCDM Regulatory Council has positioned him at the forefront of dialogue between industry and regulators on evolving GCP standards.