SOCRA Protocol Deviations and Violations 4 — Questions and Answers
Question 1: Under ICH E6, when may an investigator implement a deviation from the protocol without prior sponsor agreement and IRB approval?
- When the site coordinator believes the change will improve enrollment
- When the change only affects logistical or administrative aspects of the study
- When it is needed to eliminate an immediate hazard to trial subjects (Correct answer)
- When the subject verbally requests a change in their visit schedule
Correct answer: When it is needed to eliminate an immediate hazard to trial subjects
ICH E6 permits deviating without prior approval only when needed to eliminate an immediate hazard to subjects.
Question 2: After implementing an urgent deviation to protect a subject, what must the investigator do next per ICH E6?
- Wait until the next continuing review to tell the IRB
- Inform only the subject's primary care physician
- Record it in the subject's chart and take no further action
- Submit the deviation, its reasons, and any proposed amendment to the IRB, sponsor, and regulators as required, as soon as possible (Correct answer)
Correct answer: Submit the deviation, its reasons, and any proposed amendment to the IRB, sponsor, and regulators as required, as soon as possible
ICH E6 4.5.4 requires prompt submission of the deviation, its reasons, and any proposed amendment to the IRB, sponsor, and regulatory authorities as required.
Question 3: A sponsor grants a prospective waiver allowing a site to enroll a subject who fails an inclusion criterion. How does FDA view this?
- It is acceptable if the medical monitor documents approval
- It is a protocol change that needs IRB approval before it is implemented (Correct answer)
- It is permitted if the subject signs an additional consent form
- It needs only to be reported in the final study report
Correct answer: It is a protocol change that needs IRB approval before it is implemented
FDA treats prospective, intentional deviations such as eligibility waivers as protocol changes needing IRB review and approval before they are implemented.
Question 4: A subject's Week 8 visit happens 2 days outside the protocol window, with no impact on safety or key endpoints. How is this usually handled?
- The visit date in the CRF is corrected to fall within the window
- The subject is withdrawn from the study
- Documented as a minor deviation and reported per sponsor and IRB policy (Correct answer)
- Reported to FDA within 24 hours as a serious violation
Correct answer: Documented as a minor deviation and reported per sponsor and IRB policy
Window deviations with no safety or data-integrity impact are usually minor and are documented and reported according to sponsor and IRB requirements.
Question 5: A monitor finds dosing errors happening repeatedly at one site. What is the most appropriate response?
- Replace the investigator right away without any assessment
- Perform root cause analysis and carry out a CAPA plan such as retraining and process changes (Correct answer)
- Record each error separately with no further follow-up
- Leave the affected subjects' dosing data out of the database
Correct answer: Perform root cause analysis and carry out a CAPA plan such as retraining and process changes
Recurring deviations call for root cause analysis and corrective and preventive action to stop them from happening again.
Question 6: A monitor finds that a subject's screening blood draw happened before the informed consent form was signed. How should this be classified?
- An acceptable practice if consent was signed the same day
- A data entry error to be fixed by back-dating the consent
- An important or major deviation affecting subject rights that must be reported per IRB policy (Correct answer)
- A minor administrative deviation with no reporting needed
Correct answer: An important or major deviation affecting subject rights that must be reported per IRB policy
Doing study procedures before informed consent violates subject rights under 21 CFR 50 and is an important deviation.
Question 7: Under 21 CFR 312.56(b), what must a sponsor do when an investigator is not complying with the protocol?
- Send a written warning and keep shipping study drug
- Exclude the site's data and take no further action
- Ask the IRB to decide whether the site should continue
- Promptly secure compliance, or stop the investigator's participation and notify FDA (Correct answer)
Correct answer: Promptly secure compliance, or stop the investigator's participation and notify FDA
21 CFR 312.56(b) requires the sponsor to secure compliance promptly, or to end the investigator's participation, recover the drug, and notify FDA.
