Adverse Events That Are Unanticipated Problems Involving Risk To Subjects Or Others
General Reporting Requirements for Adverse Events
Outlined below are the requirements for reporting to the IRB. Note that investigators may have additional reporting obligations as specified by the study sponsor or oversight agency. Investigators who serve as sponsor-investigators of an IND or IDE also have additional reporting obligations to the FDA. Sponsor-investigators must also maintain a log of adverse events. Maintenance of an adverse event log is a best practice for all clinical investigators.
Unless subject to different IRB reporting requirements by a federal agency, investigators must report to the IRB:
- Internal Adverse Events that are (i) Unexpected, (ii) Related or Possibly Related to the Research Intervention, and (iii) serious or otherwise suggests that the research places the subject or others at a greater risk of harm (including physical, psychological, economic or social harm) than was previously known or recognized.
- External Adverse Events that are (i) Unexpected; (ii) Related to the Research Intervention and (iii) Serious or otherwise suggests that the research places subjects or others at greater risk than was previously recognized.
Please note that the vast majority of Adverse Events will not meet the definition of an Unanticipated Problem Involving Risk to Subjects or Others and need not be reported to the IRB. Expected Adverse Events or Adverse Events which are determined by the investigator to be unrelated to the Research Intervention will not be reviewed by the IRB. The flow chart below provides an algorithm for determining whether an adverse event meets the definition of an unanticipated problem involving risk to subjects or others.
General IRB Reporting Timelines for Adverse Events
Adverse Events that meet the University IRB’s reporting requirements must be reported to the IRB office as follows:
Internal Adverse Events
- Internal Adverse Events which are unexpected, fatal or life-threatening, and related or possibly Related to the Research Intervention must be reported to the IRB within 24 hours of learning of the event. (Note: It is recognized that the information available during this 24-hour period may not be sufficient to permit accurate completion of the required adverse event reporting forms. However, the IRB should, at a minimum, be notified of the fatal or life-threatening internal adverse event during this time frame, with subsequent follow-up submission of a more detailed written report.)
- All other internal Adverse Events will be reported to the IRB within 10 working days of the investigator learning of the event.
External Adverse Events
- External Adverse Events which are Unexpected, Serious AND suggest that the research places subjects or others at greater risk than was previously recognized and Related to the Research Intervention will be reported to the IRB within 30 working days of their receipt by the University/UPMC investigator. (Note: Only sponsor-generated safety reports that meet the Adverse Event reporting of the IRB should be submitted to the IRB.)
- Ideally, adverse events occurring in subjects enrolled in a multicenter study should be submitted to a monitoring entity for review and analysis.
- The report of the adverse event to the University of Pittsburgh IRB should include confirmation as to whether the external site reported the event to their IRB and to a monitoring entity.
- The external adverse event reported to the IRB will be placed on a Committee agenda for review as determined by the IRB Chair/Vice Chair.
- The University IRB may act with regard to the local study in response to the external adverse event (e.g., suspend the local study enrollment, but will not report the event to a federal agency or sponsor, unless required by the local action).
Procedure for Submission of Adverse Events
ELECTRONIC SUBMISSIONS: For studies approved through the OSIRIS and PittPRO electronic submission system, the electronic online submission process must be utilized in order to submit a report. The smart form questions will collect specific information required for review by the IRB. Investigators can find detailed information regarding the reporting process in the Guidance (pending).
Unanticipated Problems Involving Risk to Subjects or Others and Non-compliance
- Unanticipated problems which meet the following definition of “any accident, experience or outcome” that meets all three of the following criteria must be reported:
- unexpected in terms of nature, severity, or frequency;
- related, or possibly related, to a subject’s participation in the research;
- places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized;
Examples of types of unanticipated problems that must be reported to the IRB include:
- any accidental or intentional deviation from the IRB-approved protocol that involves risks (e.g., missed safety labs, incorrect dosing or labeling);
- any deviation from the protocol taken without prior IRB review to eliminate apparent immediate hazard to a given research subject;
- any publication in the literature, safety monitoring report, interim result, or other finding that indicates an unexpected increase in the risk to benefit ratio of the research;
- any complaint of a subject that indicates an unanticipated risk or which cannot be resolved by the research staff;
- any other untoward event that affects the welfare or the privacy, confidentiality or other rights of research subjects or members of their family (e.g. lost or stolen research data);
- any other untoward event that presents a risk to investigators and research staff involved in the conduct of the research.
2. Incidents of non-compliance, which meet the following must be reported:
- Failure on the part of the investigator or any member of the study team to follow the terms of University of Pittsburgh IRB approved protocol or to abide by applicable laws or regulations, or University of Pittsburgh IRB policies that:
- adversely affect that rights and welfare of human subjects, or
- significantly compromises the quality of the research data
Incidents of non-compliance on the part of research participants which do not involve risk need not be reported to the IRB (i.e., failure to turn in medication diary).
Examples of non-compliance that must be reported to the IRB include (but are not limited to):
- Performing non-exempt human subject research without obtaining prospective University IRB approval;
- Implementing protocol modifications without obtaining prospective IRB approval;
- Initiating research activities prior to obtaining consent
- Altering from the informed consent process as described in the IRB approved protocol
- Having research activities performed by individuals who are not sufficiently trained or credentialed to perform the task.
- Obtaining consent using an outdated consent form, when the new consent form contained new information that may have caused the subject to change their mind about participating;
- Conducting research during a lapse in IRB approval;
- Not adhering to inclusion/exclusion criteria;
- Enrolling more subjects than were approved in the protocol of a greater than minimal risk study;
- Performing research at an unapproved site:
- Failure on the part of IRB staff involved in research review or oversight to abide by applicable laws or regulations, or University of Pittsburgh IRB policies.
3. Incidents of non-compliance which are not required to be submitted to the IRB:
Incidents of non-compliance which do not meet criteria for reporting should be logged in real time and should be available upon request. An example of a non-compliance log is available on the HRPO website. The IRB expects that the investigator and study team will regularly monitor the log.
Non-Compliance Log requirements are mandatory for:
- Greater than minimal risk studies
- Studies that meet the federal definition of a “clinical trial”
- Studies for which reporting is required by the funding agency
Non-Compliance logs are not required to be submitted at annual review but must be available upon request. Failure to maintain a log as required may be determined by the IRB to represent serious or continuing noncompliance.
Non-Compliance Logs are recommended but non-mandatory for all other studies.
Examples of non-compliance that are not reportable but should be documented in a log:
- Obtaining consent using an outdated consent form when there were no substantive differences between the consent form that was used and the consent form that should have been used (i.e., dates in the footer)
- Protocol deviations that do NOT adversely affect the rights and welfare of human subjects or significantly compromise the quality of the research data
- Subject non-compliance that doesn’t involve risk or alter the data
- Performing non-safety related research procedures outside the protocol specified window, i.e., involuntarily administering a questionnaire outside of the protocol specified window.
General Reporting Requirements for Unanticipated Problems Involving Risk to Human Subjects or Others and Non-Compliance:
Investigators are to submit all Unanticipated Problems Involving Risks to Human Subjects or Others that are Possibly or Definitely Related to the research and incidents of reportable Non-compliance within 10 working days of the investigator becoming aware of the reportable event/reportable new information.
Submission Format for Reporting Unanticipated Problems Involving Risks to Human Subjects or Others and incidents of Reportable Non-Compliance:
ELECTRONIC SUBMISSIONS: For studies approved through the OSIRIS and PittPRO electronic submission systems, the electronic online submission process must be utilized in order to submit a report. The smart form questions will collect specific information required for review by the IRB. Investigators can find detailed information regarding the reporting process in the Guidance (pending).
PAPER SUBMISSIONS: Investigators are required to submit reports utilizing the form entitled “Report of Unanticipated Problems Involving Risks to Subjects or Others and Non-compliance,” which is available on the IRB website.