Drug Evaluation Committee 2014-02 Response to Deviations from the Study Protocol to Avoid Immediate Hazards
Related classification: clinical trial contracting procedures
Date of first publication: June 2014
Question
We are currently in the process of revising the SOP, and a question has arisen regarding the procedure for emergency deviations in clinical trials.
Article 46 Guidance 4 of the GCP stipulates that "...in such cases, the investigator shall submit the details of the deviation or change and the reason for it (・・・・) to the sponsor and the head of the site and to the Clinical Trial Review Committee via the head of the site as soon as possible to obtain approval, and shall also submit a written request for approval to the head of the site and the head of the site for the approval of the investigator and the approval of the head of the site. The approval of the head of the site and the agreement of the sponsor via the head of the site must also be obtained in writing. The actual procedure at our hospital is as follows. The actual procedure at our hospital is that when an emergency deviation occurs, the investigator submits a "report on deviation from the study protocol to avoid immediate risk" to the hospital director and the sponsor. The hospital director requests the opinion of the Clinical Trial Review Committee with a "Request for Clinical Trial Review" and notifies the sponsor and investigator of the instructions and decision with a "Notification of Clinical Trial Review". The sponsor notifies the hospital director of the review results in the "Notification of Deviation from the Clinical Trial Protocol to Avoid Immediate Risk".
Question 1
According to the GCP, the results of the investigational review committee and the sponsor's review of the deviation seem to be independent from each other. However, I think it would be more realistic to obtain the "Notice of Deviation from the Study Protocol to Avoid Immediate Risk" prior to the Trial Review Committee meeting, so that the Trial Review Committee can consider the appropriateness of the deviation in light of the sponsor's opinion.
Question 2
If the result of the review by the sponsor is "we cannot agree," what is the expected procedure after that?
Opinion of the Pharmaceutical Manufacturers Association of Japan (PMAJ)
Question 1
According to Article 46 Guidance 4 of the GCP, the "Report on Deviation from the Study Protocol to Avoid Immediate Risk" submitted by the investigator must be approved by the Clinical Trial Review Committee, approved by the head of the site, and agreed upon by the sponsor. However, the order in which the sponsor's agreement, the approval of the clinical trial review committee, and the approval of the head of the site are to be obtained is not specified.
Deviations to avoid immediate hazards must be reported promptly to the Trial Review Committee and the sponsor from the viewpoint that the safety of subjects and protection of their human rights are of paramount importance. Some deviations may require immediate review by the Trial Review Committee without waiting for the sponsor's opinion.
The review for approval by the Clinical Trial Review Committee and for agreement by the sponsor are conducted from different standpoints. The former examines from an independent standpoint the validity of the investigator's decision to avoid immediate risk to the subject as medically unavoidable, while the latter examines whether the investigator's decision can be agreed upon by those responsible for the overall clinical trial. Therefore, the review by the Trial Review Committee regarding the deviation should be considered separately from the receipt of the "Notification of Deviation from the Study Protocol to Avoid Immediate Risk" from the sponsor.
Question 2
If the sponsor does not agree, it means that such a deviation cannot be made in the future, even if it is to avoid an immediate risk to the subject, and the sponsor and investigator should discuss how to prevent recurrence, including alternative risk avoidance methods, and whether the trial can continue or not.