Three Key Impacts of ICH E6(R3) on RBQM and Oversight 

The International Council for Harmonisation draft guideline, ICH E6(R3), released on May 19, 2023, provides implications for Risk-Based Quality Management (RBQM). 

Considering the updates, John Sikora, Associate Principal Consultant at Halloran presented at Momentum’s annual GCP Inspection Readiness conference. John’s presentation, “Examining the Impact of ICH E6 (R3) on RBQM, Oversight Procedures and GCP Inspection Readiness Preparation,” highlighted changes to three major ICH principles and the implications of those updates. 

Here is an overview of the three major ICH principles and key insights from the presentation. 

Culture of Quality  

A theme resonating throughout the conference was creating a culture of quality, which requires incorporating quality principles and tactics into clinical trial design from the beginning and championing the importance of quality throughout the entire organization.  

A culture of quality is captured in the first ICH principle – Quality by Design. The updates in this section of ICH E6 (R3) emphasize quality “should be implemented to identify the factors critical to ensuring trial quality and the risks that threaten the integrity of those factors and ultimately the reliability of the trial results.”  

John emphasized, “Quality by Design needs to be included right from the start of clinical trial outline and protocol drafting stages. We’ve observed our clients recognize the importance of including a quality management mindset by bringing in a quality representative as early as the protocol design stage, helping the clinical team identify quality risks. Historically, an organization’s quality representative was not typically included in the protocol design and development phase.”  

The changes to ICH E6 (R3) highlight the importance of including quality representation at this stage. A quality team member can bring the perspective of highlighting areas in the draft protocol where there may be elevated risks. The cross-functional trial team will subsequently be able to address these risks directly in the draft protocol or include the considerations in their risk management plan. From there, input from external stakeholders, such as patients and healthcare professionals, can be incorporated to create a final protocol that adequately captures quality fundamentals. 

Critical to Quality Factors 

The updates to the section on Critical to Quality (page 5, #7) specify “Clinical trial processes and risk mitigation strategies implemented to support the conduct of the trial should be proportionate to the importance of the data being collected and risks to trial participant safety and reliability,” noted John.  

It is critical to have early cross-functional engagement to identify Critical to Quality factors and potential risks to de-risk the protocol from the drafting stages. Too often, we observe that not all internal and external functional areas are included from the outset of clinical trial preparation and protocol drafting. Therefore, important risks may be overlooked, negatively impacting the overall trial conduct and outcome.  

For example, a trial team may work diligently with internal cross-functional team members to finalize the protocol, then provides the CRO (Contract Research Organization) who is executing the trial with a finalized version of the protocol. Because the protocol has been finalized and executed, this gives little opportunity to the CRO, an important stakeholder in this example, to provide feedback on Critical to Quality factors and risks that can be built directly into the protocol. This stresses the importance of early cross-functional engagement to avoid and mitigate risks before the trial begins. 

Risk-Based Quality Management  

We are also seeing Risk-Based Quality Management (RBQM) increasingly used in clinical trials. RBQM is a mindset. It’s a consultative approach in which an organization builds into clinical trials the potential for likely risks, continually monitors for risk signals, and mitigates risk potential before it undermines data integrity, patient rights, or patient safety. All these efforts propel a trial to become inspection ready. 

However, it is important to understand RBQM should be implemented from the earliest stages in the trial design phase rather than in later stages. Effective quality management through this approach requires incorporation of the prior two principles of Quality by Design and Critical to Quality factors. From there, risk identification, assessment, control, review, and communication can be applied proportionally to the level of risk and the clinical trial phase.  

RBQM requires strong sponsor oversight throughout the entire study. There are five areas of oversight risk with processes to mitigate such risks: 

• Planning: Risks are typically associated with a lack of cross-functional input and documentation. Frequent risk reviews that include the appropriate cross-functional stakeholders can go a long way in avoiding major pitfalls. 
• Design: Including protocol and trial design, project plans, Standard Operating Procedures (SOPs), and systems. Without adequate oversight in this area, risks may be overlooked from the start. Beginning with a quality mindset can mitigate future issues.  
• Trial Conduct: Good oversight requires a clear understanding of the multiple monitoring approaches that can be implemented and the development of an oversight strategy that covers on-site, remote, centralization, and risk-based monitoring. Issue escalation and management are key in risk protection during trial conduct. Additional issues can arise during trial conduct through a lack of alignment with service providers. To ensure alignment with service providers, it is important to review their processes, understand where the gaps may be, and develop a plan to address gaps and risk mitigation.  
• Analysis: Corrective and preventative actions (CAPAs) should be completed for any meaningful errors that occur throughout the trial.  
• Reporting: Sponsors should practice mock inspections and storyboards to avoid undocumented lessons learned that could lead to repeat errors. Sponsors should also initiate the development of storyboards at the initiation of the clinical trial so they can be updated by the team throughout the lifecycle of the trial, rather than at the conclusion of the trial when it becomes more difficult to recall. 

The sponsor is responsible for the quality and integrity of their studies and should take the necessary steps to minimize risk. Questions about the implications of ICH E6(R3) and your quality management system, connect with Halloran’s quality and compliance team.