ICH E6 R2 to R3 Sponsor Responsibility Changes
By Rhizome Team
ICH E6(R3) represents a significant evolution in Good Clinical Practice guidelines, introducing notable changes to sponsor responsibilities compared to E6(R2). These updates reflect modern clinical trial practices including risk-proportionate approaches, quality-by-design principles, and expanded oversight requirements.
Understanding the differences between E6(R2) and E6(R3) sponsor responsibilities is essential for sponsors transitioning to the updated guideline. The changes emphasize quality management systems, service provider oversight, data integrity, and cybersecurity considerations.
This analysis identifies the key sponsor responsibility emphases and explicit requirements in E6(R3) that represent practical change areas sponsors must implement when transitioning from R2 to R3.
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what are the differences in sponsor responsibility changes from ICH e6 r2 to r3?
Answer
Because the provided sources do not include the actual ICH E6(R2) sponsor-responsibility text (only that E6(R2) was adopted in 2016 and which sections were updated) 12, I cannot quote-and-compare R2 vs R3 line-by-line. What I can do from the sources is identify the notable sponsor-responsibility emphases and explicit requirements in E6(R3) that represent the practical “change areas” sponsors must implement when transitioning to R3.
1) Sponsor responsibility is explicitly framed as “risk-proportionate” across the full trial life cycle
E6(R3) states that sponsor responsibility “entails the implementation of risk-proportionate approaches” to protect participants and ensure reliable results “throughout the clinical trial life cycle.” 3 This is a prominent framing statement for the sponsor section in R3. 3
2) Quality-by-design and operational feasibility are made explicit sponsor duties in trial design
E6(R3) requires sponsors to “incorporate quality into the design” by identifying critical to quality factors and managing risks to those factors. 3 It also explicitly requires sponsors to ensure trials are “operationally feasible,” avoid unnecessary complexity, and ensure protocols/tools are “fit for purpose, clear, concise and consistent,” and not place unnecessary burden on participants/investigators. 3
3) Clearer up-front allocation of roles/activities and documentation of agreements
E6(R3) adds explicit sponsor obligations to:
- Ensure sufficient resources. 11
- Determine roles and allocate trial-related activities prior to initiating trial activities. 11
- Document agreements with investigators/institutions, service providers, and other parties (e.g., IDMC/adjudication committees) prior to initiating activities, and update agreements when significant changes occur. 11
It also reinforces at a principles level that roles/responsibilities should be “clear and documented,” and that even when activities are transferred/delegated, the sponsor/investigator “retain overall responsibility” and must maintain oversight. 21
4) Expanded and more operationalised expectations for service-provider outsourcing and oversight
E6(R3) is very explicit about outsourcing:
- Any sponsor trial-related activities transferred to a service provider must be documented in an agreement; activities not transferred remain with the sponsor. 5
- Even if transferred, “ultimate responsibility…resides with the sponsor,” including participant protection and data reliability; service providers should implement quality management and report incidents that might impact safety/results. 5
- Sponsor must assess suitability/selection of service providers, have access to relevant information (e.g., SOPs/metrics), and ensure oversight of important transferred activities, including subcontracting. 5
This is complemented by Annex 2’s emphasis that sponsor oversight becomes more complex with “myriad of data sources…various operational approaches…and the number of service providers involved,” and sponsors should have processes for appropriate oversight, including oversight of service providers and their essential records. 31
5) Multi-sponsor trials: explicit requirement for documented responsibility allocation (or shared responsibility by default)
E6(R3) explicitly recognises trials may have “one or several sponsors” and requires a documented agreement setting out respective responsibilities; if not specified, the responsibility lies with all sponsors. 518
6) More detailed sponsor oversight expectations (beyond monitoring) including escalation and decision impact assessment
E6(R3) sponsor oversight includes ensuring:
- Trial processes/data are of sufficient quality for reliable results and participant safety. 4
- Compliance with protocol, regulatory requirements, and ethical standards. 4
- Trial-specific criteria for “important protocol deviations.” 7
- Decisions are assessed for impact on participant rights/safety/well-being and reliability, with risks managed throughout planning/conduct/reporting. 7
- Oversight measures are fit-for-purpose and tailored to trial complexity/risks; selection/oversight of investigators and service providers are “fundamental features.” 7
- Timely escalation and follow-up of issues. 7
7) Quality management is specified as a sponsor “system” with risk management mechanics (including quality tolerance limits) and reporting in the CSR
E6(R3) requires sponsors to implement a quality management system across all stages, using a proportionate, risk-based approach (quality by design; critical-to-quality factors) and to describe the quality management approach in the clinical trial report. 7
It also provides detailed risk management steps (identify/evaluate/control/communicate) and explicitly introduces setting “pre-specified acceptable ranges (e.g., quality tolerance limits at the trial level)” and evaluating deviations beyond those ranges for systemic issues/actions. 15 Sponsors must periodically review risk controls and summarise/report important quality issues and remedial actions in the clinical trial report. 9
8) Stronger, more procedural sponsor duties for noncompliance (root cause analysis, CAPA, notifications)
E6(R3) requires proportionate action to secure compliance, and when significant noncompliance is discovered, the sponsor should perform root cause analysis, implement corrective and preventive actions, and confirm adequacy (unless justified). 8 For serious noncompliance, the sponsor should notify regulatory authority and/or IRB/IEC and/or investigator as appropriate per local requirements, and consider termination of an investigator/institution/service provider if persistent. 8
9) More explicit sponsor responsibilities for data integrity, privacy/cybersecurity, and data-system governance
E6(R3) includes detailed sponsor responsibilities for data and records, including:
- Ensuring integrity/confidentiality of data and applying QC focused on higher criticality data and relevant metadata. 27
- Pre-specifying data to be collected and methods in the protocol; where needed, include additional details (e.g., data flow diagram) in protocol-related documents like a data management plan. 27
- Implementing measures to protect privacy/confidentiality of personal information. 25
- Having processes for reporting to relevant parties (including regulators) “incidents (including security breaches) that have a significant impact on the trial data.” 25
- Maintaining a record of important computerised systems used in the trial (use/functionality/interfaces/validation status/responsibility). 25
Annex 2 further stresses privacy/confidentiality safeguards including cybersecurity, especially when service providers need participant personal information (e.g., shipping IP to participants, home nursing) and when using DHTs/RWD; sponsors should address risk of disclosure from a data breach. 31
10) New/clearer sponsor obligations around investigator interaction with data (navigation instructions; investigator endorsement)
E6(R3) states the sponsor should:
- Ensure the investigator receives instructions on how to navigate systems/data/metadata for participants under their responsibility. 25
- Seek investigator endorsement of their reported data at predetermined important milestones. 25
11) Safety responsibilities remain sponsor-led but are more explicitly described as ongoing evaluation + structured reporting arrangements
E6(R3) states the sponsor is responsible for “ongoing safety evaluation” of the investigational product(s). 8 It requires aggregation/review of relevant safety information and potential updates to protocol/IB/consent materials. 8 It also details safety reporting expectations (periodic updates, expedited SUSAR reporting, expectedness assessment vs RSI/product info, urgent safety issues, and prospectively agreed alternative reporting arrangements described in the protocol). 14
Annex 2 adds an operational expectation for trials with decentralised/pragmatic elements: sponsors should ensure safety information from multiple sources is captured and made accessible to the investigator in a timely, “actionable” manner. 31
12) Record retention/ownership transfer and “change of sponsorship” communication
E6(R3) requires sponsors to notify investigators/institutions/service providers about retention requirements and when records are no longer needed, report transfer of ownership of essential records as required, and “also inform the investigator if sponsorship of the trial changes.” 17