Next in our series outlining changes to ICH GCP E6 R3 between the May 2023 draft and January 2025 final version: changes to the Quality Management section of Sponsor Responsibilities, which has been rewritten to re-cast the role of quality management in a clinical trial, as well as clarify the steps in the risk management process. For clarity, bold = new text and italics = superseded text.  

• The introductory paragraph in Section 3.10, Quality Management, now states that "quality management includes the design and implementation of efficient clinical trial protocols....in order to ensure the protection of participants' rights, safety and well-being and the reliability of trial results." The bolded text replaces the word "support" in the previous version. We are sorry to report that ICH still does not appreciate the value of the Oxford Comma.
• Step 3.10.1 on Risk Identification now specifies that risks should be identified "prior to trial initiation and throughout trial conduct."  Previously, this step stated that risks should be considered across processes used in the clinical trial; it now states that risks should be considered "across the processes and systems, including computerized systems, used in the clinical trial" and adds examples of "trial design" and "blinding" to the examples of processes to be considered. 
• Step 3.10.2 on Risk Evaluation now states that sponsors should evaluate "identified risks and existing controls" instead of "potential risks," which makes it a bit clearer that Risk Identification is the part of the process where potential risks are considered and risks are identified; the next step, Risk Evaluation, is where the identified risks are assessed for likelihood of occurrence, detectability, and impact. (See here for compelling reasons why this is NOT a good idea!)
• Step 3.10.1.3 on Risk Control previously stated, "Risk mitigation activities may be incorporated in protocol design and implementation, monitoring plans, agreements between parties defining roles and responsibilities, systematic safeguards to ensure adherence to SOPs, and training in processes and procedures."  It now states, "Risk mitigation activities may be incorporated, for example, in protocol design and implementation, monitoring plans, agreements betrween parties defining roles and responsibilities, and training." The previous "safeguard" wording was never clear, but it is interesting that quality control steps and oversight activities are not cited as risk mitigation.
• Step 3.10.1.3 on Risk Contract changes "The sponsor should set acceptable ranges to support this process within which variation can be accepted" to "the sponsor should set pre-specified acceptable ranges (e.g., quality tolerance limits at the trial level) to support the control of risks to critical to quality factors." It also clarifies that the pre-specified ranges "reflect limits that when exceeded have the potential to impact participant safety or the reliability of trial results."  The phrase "quality tolerance limits," which first appeared in R2, did not appear in the May 2023 R3 draft, reportedly because of pushback from smaller companies - but now it's back, although only "where relevant."
• Step 3.1.5 on Risk Review now adds that "additional risk control measures may be implemented as needed" during the risk review stage, emphasizing that risk management is an iterative process.
• Step 3.1.6 on Risk Reporting now states that the sponsor should summarize and report "important quality issues...and the remedial actions taken and document them in the clinical trial report."  Previously, it said that sponsors should summarize and report "the risks and the remedial actions taken." This is a fairly significant change, as sponsors are now off the hook for reporting the risks (potential quality issues) they identified up front, but on the hook for reporting actual quality issues that occurred.