Under what circumstance must the sponsor conduct a root cause analysis according to ICH E6?

The requirement for a sponsor to conduct a root cause analysis is primarily tied to issues that impact the integrity of the trial and the safety and well-being of participants. If noncompliance affects the subject population or trial reliability, it indicates a significant deviation from the set protocols, which could compromise the data collected and the overall validity of the trial results. This situation necessitates a thorough investigation to identify the reasons behind such noncompliance so that appropriate corrective and preventive measures can be put in place. Root cause analysis ensures that the underlying issues are understood and addressed, enhancing the reliability of the trial and safeguarding the interests of study participants.

Other scenarios, such as having too few participants, encountering delays, or exceeding budget, may require attention and management but do not inherently necessitate a root cause analysis focused on the trial's compliance and integrity in the same way that noncompliance affecting the participant population or reliability would. These issues may be operational or logistical but do not directly endanger the fundamental compliance with regulatory standards essential for the trial's ethical and scientific validity.