- 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:
- 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
- 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 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 483or 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 RNI Smart Form in PROTECT using the section on the PROTECT Smart Form titled “Attach files containing supporting information.”
What is the difference between Major vs. Minor Protocol Deviation?
- 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.
What research-related events are examples of Major Protocol Deviations?
- 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
What research-related events are examples of Minor Protocol Deviations?
- 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
Which research events also need to be reported to the NIH IRB (Compliance and Training) by NIH investigators in an expedited timeframe when NIH is the not the Reviewing IRB?
- 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 Additionally, when the Reviewing IRB is an external IRB, and the reportable event occurred at an NIH site, or directly impacts the NIH site, the NIH PI must also report to the OHSRP office of Compliance and Training using the RNI Smart Form in PROTECT within 7 calendar days of the NIH PI becoming aware of the event.
- When the Reviewing IRB is an external IRB, and the event occurred at a non-NIH site, the NIH PI/Lead Investigator is required to ensure that the reporting requirements of the Reviewing IRB are 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 using the RNI Smart Form in PROTECT 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.
Which research-related events do not require expedited reporting and can be reported at the time of Continuing Review (CR)?
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:
- The Modification/Continuing Review Form in PROTECT requires investigators to check off boxes about the occurrence of various events since the initial review or the last continuing review such as the following examples: NO subjects experienced unexpected harm; Anticipated adverse events have NOT taken place with greater frequency or severity than expected; NO unanticipated problems involving risks to subjects or others, NO other relevant information regarding this study, especially information about risks; NO non-compliance has occurred (including minor or major deviations) etc.
- For any items that are unchecked the PI must provide an explanation.
What happens once I have submitted a RNI Smart Form in PROTECT?
- All RNI Smart Forms submitted in PROTECT are reviewed by a Compliance Analyst at the OHSRP office of Compliance and Training
- Upon receipt of the RNI 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 there is information in the RNI Smart Form that needs to be added/corrected or if there are questions, the Compliance Analyst will send a “Request Pre-Review Clarification” to the study team. The “Add Comment” function can also be used.
- The RNI Smart 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 decision about the event is sent via PROTECT in an “Acknowledgement” 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 a letter sent to the team and include, as needed, any request for additional action.
How do I know if need to report an event to the IRB in an expedited time frame or, alternatively, at the time of Continuing Review (CR)?
- This flow diagram will help determine whether the event needs to be reported via a Reportable New Event Form in an expedited
- 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.
Who do I contact if I have questions about an event form?
Any questions about an event form can be sent via e-mail to OHSRPCompliance@od.nih.gov. You will be provided a response within 24 hours, Monday-Friday except for federal holidays.
Where can I get step by step instructions about completing an RNI Smart Form?
Refer to the section titled “Create and Submit Reportable New Information” in the PROTECT NIH Researcher’s Guide.
Are there any specific/additional considerations that should be taken into account when completing an RNI Smart Form?
- Provide complete and comprehensive answers to the required questions on the RNI Smart 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 RNI Smart Form in the section where the event is described.
- 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 RNI Smart Forms 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 RNI Smart Form, for example:
- 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.
When do I report research-related events for my FDA regulated study?
- For FDA regulated studies, investigators are required to report events to the study sponsor as described in the protocol.
- For studies FDA regulated device studies, investigators are also required to immediately report (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 a RNI Smart Form in PROTECT 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 and should be reported in PROTECT using an RNI Smart Form.
How do I know if I need to submit IND Safety Reports to the NIH IRB?
Information regarding when IND Safety Reports should be submitted with a RNI Smart Form. Information about how Safety Reports should be classified in the RNI Smart Form (UP vs. New Information) can be found in the OHSRP website FAQs related to IND Safety Report Submissions.
What is the responsibility of the Research Compliance Review Committee (RCRC)?
- 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.
- 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.
I am the PI for a study for which an event has been referred to the RCRC. What does this mean and what should I expect?
- When the reported event is referred for RCRC review, you (as the PI) will be notified in PROTECT by the Compliance Analyst. 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 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 in PROTECT notifying you about the RCRC determination of the event and informing you of any required follow-up action items.
Compliance in Dealing with Participant Related Concerns/Complaints
What happens if a participant on my study expresses concerns about the conduct of the study?
- 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.
What happens if a participant on my study expresses concerns about the conduct of the study and wants to talk with someone other than the study team?
- 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.
Compliance with Training Requirements for Investigators Conducting Human Subjects Research
Where can I find human subjects research (HSR) training requirements if I am an investigator on a protocol overseen by the NIH IRB.
- 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.
How can I see if investigators on my protocol are up to date on the required human subjects research training?
Information on how to check required training records can be found at the Training FAQs link on the OHSRP website.
What should investigators on protocols overseen by the NIH IRB do in order to come into compliance with NIH policy if their human subjects research training has expired?
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.
Compliance with Requirements for Obtaining Informed Consent
Where can I find information about policy and processes related to obtaining informed consent on my protocol so that I can be compliant and avoid deviations from the required processes?
- 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 General and short form consent processes.
We welcome ideas from the IRP community for future educational materials and training sessions, so send us your ideas! Please also feel free to contact us with any questions via the link to our mailbox below.
For questions and additional information, please contact: OHSRPCompliance@od.nih.gov
Compliance and Training Team
Margaret Sanders, RN MSN MA CIP
Director, Compliance & Training
Brenna Hansen, BSN MSHS RN OCN®
Compliance & Training Analyst
