Revisions to the Quality Management section of E6 were the subject of much scuttlebutt pre-release. Word on the street was that the stakeholders providing input to the draft revision objected to the requirement for "quality tolerance limits" in risk management, because they are difficult to implement for small studies and small sponsors.  The result of that donnybrook is that the term "quality tolerance limits" was removed from R2, but the concept remains.  In other news, this section commits the grave outlining sin of a sub-section numbered "1" without a sub-section numbered "2."  Below are the key changes.

• The term "Critical Process and Data" has been replaced throughout with "critical to quality factors" to align with E8 R1. The first step in the risk management process, identification of critical processes and data, has now been removed, likely because the "critical to quality factors" are intended to be identified during protocol design.
• R2 stated that risks should be considered at the "system level" (e.g., Standard Operating Procedures, computerized systems, and personnel) and the "clinical trial level."  R3 simply states that risks should be considered across the clinical trial level.
• The R2 term "error" has been replaced with "harm/hazard," such as, "The sponsor should evaluate potential risks by considering the likelihood of harm/hazard occurring."
• R2 stated that sponsors should decide which risks to reduce and which to accept.  R3 removes this statement, suggesting that no risk can be accepted.
• R2 stated that sponsors should pre-define quality tolerance limits which, if exceeded, would trigger an investigation to potential further action.  R3 keeps this requirement but does not use the term "quality tolerance limits."

Why the controversy over this term? Quality tolerance limits are useful signals in trials with large numbers of participants and visits. For example, in a large trial, the team might define a percentage of eligibility violations that would trigger an investigation and subsequent corrective and preventative action to ensure that all future participants were eligible.  In a small trial for a rare disease, though, the study team's tolerance for eligibility violations may be zero; upon notification of an issue, the team might leap into action, following up with the site, the site monitor, and other sites to nip the problem in the bud.