We are continuing our series recapping changes from the draft to final versions of ICH GCP E6 R3. Today, we tackle the half-page Noncompliance section (3.12). Although it's short, we have a surprising amount to say about it.  Punctuation errors!  Style choices!  Diction!  And even one or two substantive changes!  Let's go. 

Step 3.12.2, which states that the sponsor should perform a root cause analysis and implement CAPAs for non-compliance, rewords the first sentence so the punctuation error "trial participant's [sic] rights, safety or well-being..." is eliminated.  The bolded words have been inserted as follows:  "Where the sponsor identifies issues that are likely to significantly impact the rights, safety or well-being of the trial participant(s) or the reliability of trial results (i.e., serious noncompliance), the sponsor should notify the regulatory authority and/or IRB/IEC, in accordance with applicable regulatory requirements, and/or investigator, as appropriate." "In accordance with applicable regulatory requirements" recognizes the different notification requirements for regulatory authorities and IRBs/IECs.  "And/or investigator" is an important addition:  If the non-compliance does not involve a particular investigator, but affects them, they should be notified.  (While we're splitting grammar and punctuation hairs we should note in this blog we use the inclusive "they" rather than "he or she" to refer to a single investigator, site monitor, participant, or individual of any sort - a style choice the ICH has also adopted, and which we applaud.)

In step 3.12.3, which discusses how persistent non-compliance should be handled,  the draft was confined to site noncompliance, but the final version includes both site and service provider non-compliance.  The final version  uses the term "significant noncompliance" rather than "serious noncompliance," likely to avoid confusion with the definition of "serious" used for adverse events. Previously the draft said that the sponsor "should terminate" persistently noncompliant sites; this has been softened to "should consider terminating" persistently non-compliant sites or service providers. In addition to notifying regulatory authorities and IRBs/IECs as required, the final version also states that sponsors should "take actions to minimize the impact on the trial participants and reliability of results."