OHRP has guidance on this topic: Unanticipated Problems Involving Risks & Adverse Events Guidance.  Please refer to Policy 801 and Guidance for Reporting Research Events and Non-compliance. If unsure, please contact your navigator or the IRBO for assistance.

The OHSRP office of Compliance and Training is responsible for the following:

• Coordinating review and management of events that occur during the conduct of Intramural Research Program (IRP) human subjects research (HSR) activities that are reported by study investigators in the electronic IRB system.  The process is described in this flow diagram.
• Responding to questions from investigators, study staff members about event reporting
• Addressing administrative aspects of monthly meetings of the Research Compliance Review Committee (RCRC), which is a duly convened NIH IRB with nine specific members who review research related events that rise to the level of possible serious and/or continuing noncompliance
• Conducting investigations of alleged noncompliance with federal regulations and NIH policy related to protection of human subjects that are/were under the jurisdiction of an NIH IRB or that may involve additional alleged noncompliance within the NIH HRPP
• Providing follow-up and as needed, additional investigation related to participants who contact Compliance and Training with concerns related to their participation in NIH HSR
• Reporting to the Health & Human Services (HHS) Office for Human Research Protections (OHRP) and, as applicable, FDA, all NIH IRB/RCRC IRB determinations of serious and/or continuing non-compliance, Unanticipated Problems (UPs), or NIH IRB suspension or termination of IRB approval within 30 days of the determination, suspension or termination of IRB approval 
• Facilitating Quality Assurance (QA)/Quality Improvement (QI) reviews of NIH IRB activities
• Responding to questions related to the training required for investigators who conduct HSR overseen by the NIH IRB
• Creating HSR related educational materials for NIH investigators, staff and IRB members and coordinating monthly OHSRP Education Series sessions

You can contact the office of Compliance & Training email for questions and information.

Reportable events, from an NIH HRPP perspective, are those that occur during the course of human subjects research that require notification to the NIH IRB. For the purposes of NIH policy, reportable events that require expedited reporting include non-compliance, unanticipated problems involving risks to participants or others (also referred to as UPs), major deviations, deaths related or possibly related to research activities, new information that might affect the willingness of participants to enroll or continue participation in the study, and suspension or termination of research activities. Additional information about these events that require expedited reporting in the electronic IRB system is provided below.

• Deaths that are at least possibly related to research need to be reported in the electronic IRB system within 24 hours of the investigator becoming aware.
• The following research-related events need to be reported in the electronic IRB system within 7 calendar days of the investigator becoming aware:
  • Major Deviation: Major deviations from the IRB-approved protocol are those that have, or may have the potential to negatively impact, the rights, welfare, or safety of the participant, or to substantially negatively impact the scientific integrity or validity of the study.
  • Unanticipated Problem (UP): An Unanticipated Problem is any incident, experience, or outcome that meets all three of the following criteria:

1. 1. 1. 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 and informed consent document; and (b) the characteristics of the participant population being studied; and
      2. 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
      3. Suggests that the research places participants or others (which may include research staff, family members or other individuals not directly participating in the research) at a greater risk of harm (including physical, psychological, economic, or social harm) related to the research than was previously known or expected.

• • New information that might affect the willingness of a participant to enroll or remain in the study
  • Non-compliance: Noncompliance means failure of an investigator to follow the applicable laws, regulations, or institutional policies governing the protection of human subjects in research, or the requirements or determinations of the Institutional Review Board (IRB), whether the failure is intentional or not.
  • Any suspension or termination of research activities including holds on new enrollment placed upon the research by the study sponsor, NIH or IC leadership, or any regulatory agency
  • FDA Form 483 or any other official communication regarding an inspection issued regarding an NIH research protocol and/or investigator within 7 calendar days of receipt of the communication. This should be submitted as an attachment to the report submitted in the electronic IRB system.
• Information is also available in Policy 801, Reporting Research Events and the accompanying Guidance-Reporting Research Events and Non-compliance found under policies 801 and 802 on the OHSRP webpage HRPP Policies & Guidelines.

• When NIH is not the Reviewing IRB, the NIH Site PI/Lead Investigator must report research related events to the Reviewing IRB in accordance with that IRB’s instructions. Additionally, if the reportable event occurred at an NIH site, or directly impacts the NIH site, NIH PI/Lead Investigator must also report to the OHSRP office of Compliance and Training in the NIH electronic IRB system within 7 calendar days of the NIH PI//Lead Investigator becoming aware of the event.
• When the Reviewing IRB is an external IRB, and the event occurred at a non-NIH site or does not directly impact an NIH site, the NIH PI/Lead Investigator is required to ensure that the reporting requirements of the Reviewing IRB are followed. The investigator does not also report these events to the OHSRP office of Compliance and Training, except as follows:
  • External IRB determinations of serious and/or continuing non-compliance about an NIH investigator: If the NIH is relying on an external IRB and the Reviewing IRB makes a determination of serious and/or continuing non-compliance regarding an NIH investigator, the NIH PI/designee must report this in the NIH electronic IRB system within 7 calendar days of any member of the NIH research team being notified of the determination by the Reviewing IRB. The NIH PI must provide the OHSRP office of Compliance and Training with documentation from the Reviewing IRB.
  • Suspension or termination of research activities at NIH by an external IRB: If the NIH is relying on an external IRB and the Reviewing IRB suspends or terminates NIH research activities, this must be reported within 7 calendar days of any NIH member of the research team being notified.

An event form is the communication method used to submit specific protocol-related events that require expedited reporting in the electronic IRB system.

• Major Deviations are deviations from the IRB-approved protocol that have, or may have the potential to, negatively impact, the rights, welfare or safety of the participant, or to substantially negatively impact the scientific integrity or validity of the study.
• Minor Deviations are deviations that do not have the potential to negatively impact the rights, safety, or welfare of participants or others, or the scientific integrity or validity of the study.

• Enrollment of a participant who did not meet all inclusion/exclusion criteria
• Performing a study procedure that has not been approved by the IRB 
• Failure to report an Unanticipated Problem to IRB and/or sponsor of the study 
• Study visit conducted outside the required timeframe that, in the opinion of the investigator, may impact the safety of the participant
• Failing to obtain legally effective consent prior to initiating research procedures-this includes failure to obtained signed consent when required 
• Medication errors, such as administering the wrong study drug to a participant or the wrong dose of the right study drug 
• Implementation of recruitment procedures that have not been IRB-approved

• Receiving completed questionnaires back from participants where items are missing
• Completing a study visit outside of the required timeframe when, in the opinion of the investigator, there are no safety implications.
• Use of an expired consent form in which the information contained is not substantively different than the currently approved consent unless the deviation occurs repeatedly
• Minimal over-enrollment
• A signed copy of the consent form was not given to the participant
• Documentation deficiencies in the consent form such as: 
  • A missing investigator signature 
  • The participant signs the consent form but does not print their name in the signature block
• Note: When a participant does not sign and date the consent form prior to the initiation of research, the event is considered a major deviation.

Investigators must provide the following information to the IRB in summary format at the time of continuing review, or when otherwise specifically requested by the IRB. Investigators should provide a high-level summary of these events that have occurred since the time of the last IRB review and not a line-item listing:

• Major and minor protocol deviations
• Noncompliance reported to the IRB that is not related to a protocol deviation
• Adverse Events and Serious Adverse Events that do not meet the definition of an UP
• UPs reported to the IRB

• All Events Forms submitted in the NIH electronic IRB system are forwarded to the OHSRP office of Compliance and Training.
• Upon receipt of the event form, a Compliance Analyst reviews the form and determines if the form has been filled out correctly and includes all information required to fully understand the event(s).
• If additional information from investigators is needed, a stipulation is sent (via NIH electronic IRB system) to address deficiencies, errors, or questions related to the event form.
• The event forms are presented for consideration at the weekly meeting attended by OHSRP leadership and staff from OHSRP Compliance and Training.
• After the weekly review meeting, documentation indicating OHSRP leadership’s determination of the event is sent via NIH electronic IRB system in an outcome letter to the PI and the study team within 24-48 hours of the meeting.
  • Events that are possible UPs on protocols overseen by the NIH IRB are forwarded to the NIH IRB for review, and the NIH IRB will subsequently provide the PI with an outcome letter.
  • Events that represent noncompliance that is considered possible serious and/or continuing noncompliance are forwarded to the Research Compliance Review Committee (RCRC) for review, and the office of Compliance and Training will subsequently provide the PI with an outcome letter.
  • Events that are not referred for review by the IRB or the RCRC are acknowledged in the outcome letter with one of the following and will indicate if any additional action is needed:
    • Acknowledgement that this event has been reported in the NIH electronic IRB system
    • Noncompliance that is neither serious nor continuing
    • Major deviation that is not serious or continuing noncompliance
    • Minor deviation that is not serious or continuing noncompliance
    • The event does not constitute non-compliance by the study team
    • The event does not meet the definition of an unanticipated problem (UP)
    • The event does not meet the definition of a reportable event that needs to be reported

• This flow diagram will help determine whether the event needs to be reported to the IRB in an expedited manner or whether it can be reported as part of a high-level summary at the time of the CR.
• For additional information, please refer to Policy 801, Reporting Research Events and the accompanying Guidance-Reporting Research Events and Non-compliance found under policies 801 and 802 on the OHSRP webpage HRPP Policies & Guidelines.

Any questions about an event form can be sent to the mailto:OHSRPCompliance@od.nih.gov.  You will be provided a response within 24 hours, Monday-Friday except for federal holidays.

The step by step guide about completing an event form can be used when completing an event form.

An instruction sheet about reporting a death in NIH electronic IRB system can be found here.

• Provide complete and comprehensive answers to the required questions on the event form and to follow-up questions posed by the Compliance Analysts after their review of your submission.
• If the event is being reported outside of the required reporting window, an explanation of the delay must be provided on the reporting form.
• If the event form being submitted reports that consent was not obtained prior to the start of research, list all of the research procedures that occurred prior to obtaining the participant’s consent.
• Compliance and Training as well as members of OHSRP leadership who initially review the event forms submitted in the electronic IRB system, as well as the IRB or RCRC members who review event(s) referred to the board, pay particular attention to what corrective action has been taken or will be taken to mitigate the problem and prevent it from recurring. In most cases, a robust explanation in this regard is required.
• Electronically attach any relevant supporting documents when you submit the event form in the electronic IRB system such as:
  • If the event was reviewed by the DSMB, attach the DSMB’s follow-up report of its review.
  • If an autopsy is available, attach it with the submission.

• For FDA regulated studies, investigators are required to report events to the study sponsor as described in the protocol and to immediately (i.e., no longer than 10 days) report Serious Adverse Events (SAE)s or Unanticipated Adverse Device Effect (UADEs) to the study sponsor.
• If the event is also an actual or suspected UP that occurred on your study, you should also submit an event form to the IRB within 7 calendar days of becoming aware of the event.
• OHSRP office of Compliance and Training must be provided a copy of any official FDA communication regarding an inspection (e.g., FDA Form 483) issued regarding an NIH research protocol and/or investigator. This must occur within 7 calendar days of receipt of the FDA communication.

Information regarding when IND Safety Reports should be submitted with an event form and how to classify the information in the report (UP vs. New Information) can be found in the section of the OHSRP website that has FAQs related to IND Safety Report Submissions.

• The RCRC is responsible for reviewing possible serious or continuing non-compliance in human subjects research for which the NIH IRB is the Reviewing IRB (whether the protocol is currently open or closed), or for human subjects research conducted by NIH Investigators without IRB approval, that has been referred from the office of Compliance and Training.
• The RCRC has the final authority to determine whether there is non-compliance that is serious and/or continuing and to determine corrective action.
• As a duly convened committee, the RCRC may exercise the full authority of an IRB including suspension or termination of IRB approval of research.
• The determination by the RCRC is provided in writing to the Principal Investigator and study contacts.

• When the reported event is referred for RCRC review, you (as the PI) will be notified via NIH electronic IRB system in an outcome letter. You will also receive an email noting the date and time of the RCRC meeting at which the event will be reviewed. This email also explains that, if you choose to do so, you may attend the meeting to address the RCRC and answer any questions posed by the Committee members. You should respond to this email.
• You are also invited to provide, in advance of the meeting, any additional written information that you believe will be helpful to the RCRC members in their review of the event. You should provide any supplemental written information 7-10 days in advance of the scheduled RCRC meeting.
• After the meeting, an Analyst from the Office of Compliance & Training will send you an outcome letter via NIH electronic IRB system notifying you about the RCRC determination of the event and informing you of any required follow-up action item/s or stipulations.

• Investigators are expected to comply with NIH HRPP Policy 104, Managing Research-Related Complaints from Subjects.
• You should communicate respectfully with the participant who has the concern/complaint.
• You should report the participant’s research-related complaint to the study PI.
• The PI will address the complaint as soon as feasible, and/or refer the matter to other NIH or IC offices, as appropriate.
• If the investigator is unable to resolve the participant’s complaint, the OHSRP office of Compliance and Training should be contacted to provide assistance in handling and responding to complaints.
• You should document the participant’s concern in the medical (e.g., CRIS) or research record.
• Unresolved participant complaints should be reported at the time of the CR.

• While designated contacts are identified in the consent form and include the PI and any other study investigator specifically listed on the form, if the participant wants to speak with a non-study team member about a concern, they can contact the IRB Office as listed in the consent form. Participants seen at the Clinical Center (CC) may also contact the NIH CC Patient Representative.
• Institutes/Centers (ICs) who have investigators who conduct human subjects research at other locations that do not have a designated Patient Representative may also have specific individuals or offices within the IC listed on the ICF who participants can contact about their study related concerns.
• Participants may also bring their concerns or complaints to OHSRP.
• To the extent that the participant has explained their concern, you should document the participant’s concern in the medical (e.g., CRIS) or research record.
• Unresolved participant complaints should be reported at the time of the CR.

• You can find these requirements in NIH Policy 103, Education Program, and additional information can be found in the accompanying Guideline for Investigator HSR Training.
• See additional information about this topic on the OHSRP website CITI training FAQs. You can also send questions to the OHSRP office of Compliance & Training via email.

Information on how to check required training records can be found at the Training FAQs link on the OHSRP website.

If the investigator is covered by the NIH FWA, they should click on the green box labeled “CITI Training” on the NIH CITI Training page to gain entry to the NIH CITI portal and complete the required CITI course/refresher.  Additional Information related to expired CITI training can be found by going to the NIH CITI Training page on the OHSRP website and clicking on the green box labeled “Expired CITI Training.”

• NIH HRPP Policy 301, Informed Consent, describes the requirements for informed consent when human subjects research is conducted.  
• Additional information about how to handle situations such as use of the short form process when you have an unexpected enrollment of a participant who is non-English speaking and who cannot read the English long form as well as other situations (e.g., consent obtained via telephone and how to document such a process) can be found under the OHSRP website FAQs Everything you need to know about consent.