Deviations from the protocol, or non-compliances, are inevitable across a multi-centered study. Some deviations can be prevented by the investigational site study staff, such as in exclusionary criteria noted in the medical history. Other deviations, such as missed visits due to the subject’s schedule, can not be avoided. According to 21 CFR 812.46(a), it is the responsibility of the sponsor to ensure that the selected investigators are compliant with any conditions of approval of the reviewing IRB. The investigator, according to 21 CRF 812.110 (b), is responsible for conducting the trial in compliance with the conditions of approval of the reviewing IRB. Additionally, investigators are responsible for maintaining records relating to deviations, including dates of and reasons for, according to 21 CFR 812.140(a)(4).
In the agreements between the sponsor and the investigator, the sponsor may outline additional detailed expectations for reporting non-compliances to the sponsor, IRB, or FDA based on seriousness and increased risk to enrolled subjects.
For monitors, the regulations and agreements between the sponsor and investigators are the parts of medical device monitoring that remain constant during a trial across all sites for one particular sponsor. However, a monitor may be responsible for upwards to 10 sites for one study, all with different reviewing IRBs that have different reporting policies. What does a monitor need to know?
Again, looking back to the regulations, 21 CFR 56.108(b)(1) and (2) requires IRBs to follow written procedures for reporting any unanticipated problems involving risks to human subjects or others and instances of serious or continuing noncompliance with the requirements or determinations of the IRB. The regulations allow for IRBs to create their own written procedures establishing time lines that investigators are responsible for following as outlined in 21 CFR 812.110(b). IRBs often stratify deviations to the protocol based on the risk to the subject or seriousness of the deviation. For instance, a deviation relating to the inclusion or exclusion criteria or the informed consent may require reporting with in 10 days. However, a missed subject completed questionnaire may require reporting at continuing review or not at all.
As monitors, it is important to be aware of a site’s IRB reporting policies for reporting deviations. Discussing these reporting policies throughout the trial during monitoring visit with the research coordinators is also important. Often, it is in the discussion between the monitors and the research coordinators that generates valuable questions regarding interpretation of the IRB reporting policies. The monitors bring a different perspective to the table when reviewing policies and understanding the reporting requirements. It is also the job of the monitor, as a representative of the sponsor, to ensure that the site is compliant with the IRB reporting policies.
Recently at a site, the following example unfolded. During subject source document review, the monitor noted that a subject was not prescribed aspirin through 30-days post procedure as required by the protocol. The monitor and the coordinator discussed the deviation and the events that resulted in the deviation. The monitor and coordinator worked together to identify ways to prevent the deviation in the future. The coordinator documented the date and reason for the deviation according to sponsor requirements. The research coordinator did not think that the deviation met the IRB’s reporting requirements. The monitor reviewed the reporting policies and interpreted them differently from the coordinator. The coordinator called the IRB and confirmed that this deviation was considered minor and required reporting at continuing review.
The monitor returned to the site for the next periodic monitoring visit, after the submission and approval of the continuing review, and noted that the deviation was had not been reported. The policies did not outline the next steps for the site, resulting in the coordinator contacting the IRB for further direction.
To ensure that a sponsor is following 21 CFR 812.46(a), monitors must ensure that an investigator and his delegated study staff are not only conducted the study according to the federal regulations, agreements between the sponsor and the investigator, the protocol, but also, the conditions of approval as required by the IRB.
Do you have any tips in ensuring compliance of the study site to IRB reporting requirements? How important do you think IRB reporting requirements are to conducting a clinical trial at the site? What are other important reminders for monitors to be aware of relating to IRB reporting requirements and protocol deviations? Please share your thoughts here.
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