Investigators are required to promptly report to the IRB all unanticipated problems involving risks to human subjects or others under Title 21 of the Code of Federal Regulations (21 CFR) part 56 (Institutional Review Boards), part 312 (Investigational New Drug Application), and part 812 (Investigational Device Exemptions). Sponsors and investigators should differentiate those unanticipated problems that must be reported to the IRB and those that do not. The University of Chicago policy is consistent with guidance set forth by OHRP (presented January 15, 2007) and the FDA (presented January 14, 2009) when determining what related events require review by the Institutional Review Board.
Unanticipated problems involving risks to subjects or others refer to a problem, event or information item that is not expected, given the nature of the research procedures and the subject population being studied; and which suggests that the research places subjects or others at a greater risk of harm or discomfort related to the research than was previously known. The IRB considers unanticipated problems, in general, to include any incident, experience, or outcome that meets ALL of the following criteria:
- unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol, investigator’s brochure, drug or device product information, informed consent document, or other research materials; and (b) the characteristics of the subject population being studied, including underlying diseases, behaviors, or traits;
- related or possibly related to participation in the research (possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and
- suggests that the research places subjects or others at a risk of unknown harm or addition/increased frequency of harms (including physical, psychological, economic, legal, or social harm) than was previously known or recognized.
Unanticipated problems may be adverse events, protocol deviations, noncompliance or other types of problems, but MUST meet all of the criteria listed above.
When reviewing a particular incident, experience, or outcome reported as an unanticipated problem by the investigator, the IRB may determine that the incident, experience, or outcome does not meet the criteria for an unanticipated problem.
Unanticipated problems occurring in research that is federally funded may or may not require further reporting to appropriate institutional officials, the department or agency head (or designee), and OHRP. The IRB has the authority, under HHS regulations at 45 CFR 46.109(a), to require, as a condition of continued approval by the IRB, submission of more detailed information by the investigator(s), the sponsor, the coordinating center, or DSMB/DMC about any unanticipated problem occurring in a research protocol.
It is the responsibility of the investigator to ensure that written notification of unanticipated problems is submitted to the IRB. The investigator must complete an “Unanticipated Problem” report form with his/her original signature (or electronic signature in AURA) and attach any additional information necessary in evaluating the report (such as laboratory or autopsy reports). All other events or adverse events that do not meet reporting criteria can be submitted as a summary at the time of continuing review. All events that do not meet the IRB reporting criteria and are not submitted as a summary at the time of continuing review will be returned to the Principal Investigator.
In reviewing the unanticipated problem, in order to ensure adequate protection of the welfare of subjects, the IRB will consider whether the event impacts the risk/benefit ratio and may need to reconsider approval of the study, require modifications to the study, or revise the continuing review timetable. Furthermore, the IRB may suspend or request further changes to an individual study due to safety concerns.
The IRB maintains submitted unanticipated problem reports in the protocol file or electronic file; notification of review of these reports is sent to the PI.
All Internal and External Unanticipated Problems must be reported to the IRB in a timely manner following investigator’s knowledge of the event. (Includes adverse events, protocol deviations, non-compliance, and other events that meet reporting criteria) For Internal Fatal/Life-Threatening Unanticipated Problems, the PI should notify the IRB Chair by phone immediately and consider voluntarily halting subject enrollment.
Unanticipated changes and protocol deviations are also considered “Unanticipated Problems.” It is the expectation of the IRB that all approved protocol procedures are being followed without alteration unless the IRB has been informed of a protocol change or deviation.
Reporting Unanticipated Changes
The federal regulations require the IRB to review and approve proposed changes to research studies prior to initiation of these changes, except when changes are “necessary to eliminate apparent immediate hazards to the subject” [45 CFR 46.103(b)(4)(iii)]. The majority of proposed changes are reviewed through submission of amendments. Any changes that are made to eliminate apparent immediate hazards to a subject should be reported in a timely manner using the “Unanticipated Problem” report form to the IRB and an amendment should be submitted for the next deadline to change the protocol to eliminate future hazards of this type, as appropriate.
In the event that such a change is implemented to eliminate immediate hazards to a subject, enrollment of new subjects should be halted until the IRB has had an opportunity to consider such changes. The reviewer may also recommend that the subjects on the study be provided specific information about the change and the cause of the change.
Reporting Deviations/Non Compliance
An IRB is asked to ensure prompt reporting of serious or continuing noncompliance with regulations or noncompliance with the IRB’s own requirements/determinations [45 CFR 46.103(b)(5)]. Deviations from the approved protocol, i.e., changes made without prior IRB approval, fall into this category of noncompliance. Deviations must be reported to the IRB along with a description of the effect of the deviation on subject safety and a description of how similar events will be avoided in the future.
A protocol deviation occurs when the study departs from the IRB-approved protocol in any way without the investigator first obtaining IRB approval.
Deviations range in seriousness according to how the changes may impact subject safety, the degree of noncompliance with federal and state regulations, and the degree of foreknowledge of the event. Anticipated changes to a protocol should always be reported prior to the event occurrence unless an immediate change is necessary to protect subject safety.
Repeated deviations of the same type may be an indication that an amendment is needed to permanently change study criteria.
A major deviation is one that may impact subject safety or alter the risk/benefit ratio, compromise the integrity of the study data, and/or affect subjects’ willingness to participate in the study. Major deviations should be reported in a timely manner following the investigator’s knowledge of the deviation. Reports should be made using the “Unanticipated Problem” report form.
A minor deviation is one that does not impact subject safety, compromise the integrity of the study data, or affect subjects’ willingness to participate in the study. Minor deviations should be summarized at the time of continuing review on the continuing review form.