Examining Sponsor Oversight & Service Provider Management Under ICH GCP E6(R3)
In our recent review of regulatory guidelines, inspection reports from agencies such as the EMA and MHRA, and various published recommendations, one central finding emerged: sponsor oversight and vendor management consistently rank among the top reasons for inspection findings under E6(R2) and even earlier.
For instance, MHRA inspection report summaries—dating back to 2006, well before the release of E6(R2)—have repeatedly highlighted deficiencies in sponsor oversight of clinical research. Similarly, EMA reports have consistently identified issues related to the sponsor’s responsibilities regarding contracts and agreements. A recent EMA report from 2023 , for example, noted 23 findings (8 of which were classified as major) specifically related to contract and agreement issues (may include sites).
Moreover, the MHRA Inspectorate has long provided detailed commentary on these topics. In its Sponsor Oversight – Part 1 and Sponsor Oversight – Part 2 blog posts, the MHRA emphasizes the critical nature of clearly defined sponsor responsibilities, robust oversight practices, and proactive risk management. These resources reinforce the need for sponsors to not only delegate tasks through written contracts but also to maintain vigilant oversight throughout the trial process.
Moreover, the MHRA Inspectorate has long provided detailed commentary on these topics. In its Sponsor Oversight – Part 1 and Sponsor Oversight – Part 2 blog posts, the MHRA emphasizes the critical nature of clearly defined sponsor responsibilities, robust oversight practices, and proactive risk management. These resources reinforce the need for sponsors to not only delegate tasks through written contracts but also to maintain vigilant oversight throughout the trial process.
Under EU regulation, sponsor responsibilities are clearly outlined:
EU Regulation 514 – CHAPTER XI: Sponsor and Investigator
Article 71 – Sponsor: “A clinical trial may have one or several sponsors. Any sponsor may delegate, in a written contract, any or all of its tasks to an individual, a company, an institution or an organisation. Such delegation shall be without prejudice to the responsibility of the sponsor, in particular regarding the safety of subjects and the reliability and robustness of the data generated in the clinical trial.”
EU Regulation 514 – CHAPTER XI: Sponsor and Investigator
Article 71 – Sponsor: “A clinical trial may have one or several sponsors. Any sponsor may delegate, in a written contract, any or all of its tasks to an individual, a company, an institution or an organisation. Such delegation shall be without prejudice to the responsibility of the sponsor, in particular regarding the safety of subjects and the reliability and robustness of the data generated in the clinical trial.”
In ICH GCP E6(R2), sponsor oversight and vendor management were addressed as follows:
Section 5.2 – Contract Research Organization (CRO):
5.2.1 – CRO Responsibilities:
“A sponsor may transfer any or all of the sponsor's trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The CRO should implement quality assurance and quality control.”
5.2.2 – Written Agreement for CRO:
“Any trial-related duty and function that is transferred to and assumed by a CRO should be specified in writing.”
Addendum:
“The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf, including trial-related duties and functions that are subcontracted to another party by the sponsor’s contracted CRO(s).”
5.2.3 – Retention of the Responsibilities not assumed by the CRO:
“Any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor.”
5.2.1 – Applicability of the requirements:
“All references to a sponsor in this guideline also apply to a CRO to the extent that a CRO has assumed the trial-related duties and functions of a sponsor.”
While these topics were always scrutinized, they were not as clearly highlighted or structured in E6(R2), leaving many sponsors uncertain about how to comply.
Section 5.2 – Contract Research Organization (CRO):
5.2.1 – CRO Responsibilities:
“A sponsor may transfer any or all of the sponsor's trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The CRO should implement quality assurance and quality control.”
5.2.2 – Written Agreement for CRO:
“Any trial-related duty and function that is transferred to and assumed by a CRO should be specified in writing.”
Addendum:
“The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf, including trial-related duties and functions that are subcontracted to another party by the sponsor’s contracted CRO(s).”
5.2.3 – Retention of the Responsibilities not assumed by the CRO:
“Any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor.”
5.2.1 – Applicability of the requirements:
“All references to a sponsor in this guideline also apply to a CRO to the extent that a CRO has assumed the trial-related duties and functions of a sponsor.”
While these topics were always scrutinized, they were not as clearly highlighted or structured in E6(R2), leaving many sponsors uncertain about how to comply.
What Changed in E6(R3)?
With ICH GCP E6(R3) already published and its implementation on the horizon, there is a growing belief—and our hypothesis—that the revised sections on sponsor and service provider (no longer “vendor” or “CRO”) oversight could help minimize these recurrent issues, if organizations commit to robust implementation.
Comparative Table: ICH GCP R2 vs. R3
Below is a detailed comparison of the sections and text from ICH GCP E6(R2) and E6(R3) concerning vendor / service provider management and sponsor oversight:
With ICH GCP E6(R3) already published and its implementation on the horizon, there is a growing belief—and our hypothesis—that the revised sections on sponsor and service provider (no longer “vendor” or “CRO”) oversight could help minimize these recurrent issues, if organizations commit to robust implementation.
Comparative Table: ICH GCP R2 vs. R3
Below is a detailed comparison of the sections and text from ICH GCP E6(R2) and E6(R3) concerning vendor / service provider management and sponsor oversight:
Expanded Sponsor Oversight in E6(R3)
In E6(R2), sponsor oversight was briefly addressed by stating that:
E6(R3) further clarifies and expands this requirement through Section 3.9 – Sponsor Oversight, which includes:
3.9.1: Ensuring that trial design, conduct, processes, and data quality meet standards for participant safety and reliable results.
3.9.2: Verifying that all trial processes comply with the protocol, regulatory requirements, and ethical standards.
3.9.3: Establishing trial-specific criteria for identifying important protocol deviations.
3.9.4: Assessing decisions for their potential impact on participant safety and data integrity, with appropriate risk management throughout the trial.
3.9.5: Tailoring oversight measures to the trial’s complexity and risk, with a focus on the selection and oversight of both investigators and service providers.
3.9.6: Ensuring timely escalation and follow-up of issues.
3.9.7 & 3.9.8: Considering the establishment of an Independent Data Monitoring Committee (IDMC) and/or endpoint assessment/adjudication committees to review safety and efficacy endpoints.
3.9.9: Mandating that any committee impacting safety or trial results include qualified members, have written procedures (e.g., charters), and document their decisions.
Why These Changes Matter
Historically, inspection findings have highlighted several critical gaps:
We consistently observe the same issues during the conduct of GCP audits.
By explicitly structuring these requirements in E6(R3), regulators aim to close these gaps. If sponsors fully embrace the revised guidelines—updating their SOPs, training programs, agreements, and daily operations—the frequency of these inspection findings could significantly decrease.
Will E6(R3) Reduce Inspection Findings?
Potentially, yes. The revised sections in E6(R3) provide clearer expectations and a more robust framework for sponsor oversight and vendor management. However, realizing these benefits depends on sponsors making meaningful operational changes. Merely acknowledging the new text without adapting internal practices will likely lead to the same challenges observed under E6(R2).
In E6(R2), sponsor oversight was briefly addressed by stating that:
“The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf, including trial-related duties and functions that are subcontracted to another party by the sponsor’s contracted CRO(s).”
E6(R3) further clarifies and expands this requirement through Section 3.9 – Sponsor Oversight, which includes:
3.9.1: Ensuring that trial design, conduct, processes, and data quality meet standards for participant safety and reliable results.
3.9.2: Verifying that all trial processes comply with the protocol, regulatory requirements, and ethical standards.
3.9.3: Establishing trial-specific criteria for identifying important protocol deviations.
3.9.4: Assessing decisions for their potential impact on participant safety and data integrity, with appropriate risk management throughout the trial.
3.9.5: Tailoring oversight measures to the trial’s complexity and risk, with a focus on the selection and oversight of both investigators and service providers.
3.9.6: Ensuring timely escalation and follow-up of issues.
3.9.7 & 3.9.8: Considering the establishment of an Independent Data Monitoring Committee (IDMC) and/or endpoint assessment/adjudication committees to review safety and efficacy endpoints.
3.9.9: Mandating that any committee impacting safety or trial results include qualified members, have written procedures (e.g., charters), and document their decisions.
Why These Changes Matter
Historically, inspection findings have highlighted several critical gaps:
- Poorly defined roles and responsibilities between sponsors and service providers.
- Inconsistent issue escalation, leading to repeated protocol deviations and data quality concerns.
- Insufficient monitoring and auditing of vendor activities, resulting in incomplete or inaccurate trial documentation.
We consistently observe the same issues during the conduct of GCP audits.
By explicitly structuring these requirements in E6(R3), regulators aim to close these gaps. If sponsors fully embrace the revised guidelines—updating their SOPs, training programs, agreements, and daily operations—the frequency of these inspection findings could significantly decrease.
Will E6(R3) Reduce Inspection Findings?
Potentially, yes. The revised sections in E6(R3) provide clearer expectations and a more robust framework for sponsor oversight and vendor management. However, realizing these benefits depends on sponsors making meaningful operational changes. Merely acknowledging the new text without adapting internal practices will likely lead to the same challenges observed under E6(R2).
Conclusion
Ultimately, whether E6(R3) helps reduce recurrent audit and inspection findings hinges on each organization’s commitment to implementing its clarified expectations. By strengthening sponsor oversight, clarifying service provider responsibilities, and enforcing a risk-based, quality-focused approach, E6(R3) offers significant potential to improve compliance outcomes. The challenge now lies in translating these regulatory clarifications into concrete, everyday practices.
Stay tuned for our next article—where we will demonstrate practical strategies and steps for sponsors to implement these guidelines effectively. For additional insights, please also book the R2-R3 transition training using this helpful resource.
Ultimately, whether E6(R3) helps reduce recurrent audit and inspection findings hinges on each organization’s commitment to implementing its clarified expectations. By strengthening sponsor oversight, clarifying service provider responsibilities, and enforcing a risk-based, quality-focused approach, E6(R3) offers significant potential to improve compliance outcomes. The challenge now lies in translating these regulatory clarifications into concrete, everyday practices.
Stay tuned for our next article—where we will demonstrate practical strategies and steps for sponsors to implement these guidelines effectively. For additional insights, please also book the R2-R3 transition training using this helpful resource.