The UC Davis IRB requires investigators to report certain events or circumstances that occur during the conduct of a study, these are known as “reportable events.” The IRB must be notified of any events that require prompt reporting within five (5) or ten (10) working days of the research staff having knowledge of the event. Minor deviations must be logged by the investigator.
In This Section
- What is the Requirement?
- How do I Comply with the Requirement?
- New Risk Information Guidance
- Non-Compliance Guidance
- IRB Review of Reports
- Frequently Asked Questions
There are two categories of reportable events:
Events that Require Prompt Reporting (See Appendix A of the Investigator Manual for printable version.)
Report the following information items to the IRB within 5 business days
- Information that indicates a new or increased risk, or a new safety issue, for example:
- New information (e.g., an interim analysis, safety monitoring report, publication, sponsor report, or investigator. finding) indicating an increase in the frequency or magnitude of a previously known risk, or reveals a new risk.
- Failure to follow the protocol due to the action or inaction of anyone conducting protocol procedures (e.g. nursing staff, IDS pharmacy staff, and laboratory staff) that resulted in harm to subjects or others or that indicates subjects or others might be at increased risk.
- Subject complaint that indicates subjects or others might be at increased risk of harm or at risk of a new harm.
- An investigator brochure, package insert, or device labeling is revised to indicate an increase in the frequency or magnitude of a previously known risk, or describe a new risk.
- Withdrawal, restriction, or modification of a marketed approval of a drug, device, or biologic used in a protocol.
- Changes significantly affecting the conduct of the clinical trial or increasing the risk to participants.
- Serious harm experienced by a subject or other individual, which in the opinion of the investigator and or sponsor is unexpected and probably related (>50% likely; “Don’t know” = <50%) to the research procedures. In the event of a disagreement, the sponsor’s assessment supersedes the investigator’s assessment.
- A harm is “serious” when it meets any of the following criteria; 1.) results in death; 2.) is life-threatening (places the subject at immediate risk of death from the event as it occurred); 3.) results in inpatient hospitalization or prolongation of existing hospitalization; 4.) results in a persistent or significant disability/incapacity; 5.) results in a congenital anomaly/birth defect; 6.) based upon appropriate medical/psychological judgment, may jeopardize the subject’s health and may require medical, counseling, or surgical intervention to prevent one of the other outcomes listed in this definition; or 7.) results in criminal or civil liability or damaging of the subject’s financial standing, employability, or reputation.
- A harm is “unexpected” when its specificity or severity are inconsistent with risk information previously reviewed and approved by the IRB in terms of nature, severity, frequency, and characteristics of the study population.
- A harm is “probably related” to the research procedures if in the opinion of the investigator, the research procedures more likely than not caused the harm.
- Change to the protocol done without prior IRB review to eliminate an apparent immediate hazard to a subject.
Report the following information items to the IRB within 10 business days:
- Non-compliance with the federal regulations governing human research or with the requirements or determinations of the IRB, or an allegation of such non-compliance.
- Failure to follow the protocol due to the action or inaction of anyone conducting protocol procedures (e.g. nursing staff, IDS pharmacy staff, and laboratory staff) that results in harm to the integrity of the research data. Minor deviations (as defined in HRP-001) do not require prompt reporting.
- Breach of confidentiality (inappropriate disclosure of or access to confidential information).
- Complaint of a subject that cannot be resolved by the research team.
- Premature suspension or termination by the sponsor, investigator, or institution.
- Incarceration of a subject in a study not approved by the IRB to involve prisoners.
- Inquiry by a federal agency and any reports (e.g., FDA Form 483).
- Ancillary approvals (e.g. CoC, SCRO) that do not result in a protocol revision; written reports by study monitors and auditors that include reportable events that have not yet been reported; Data Safety Reports that include a recommendation to terminate or modify a study.
- Unanticipated adverse device effect (any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects).
- Other: information or situations that do not meet any of the above criteria.
If information contained within a report has previously been submitted to the IRB Administration, do not submit a second time unless the updated report includes new information that would affect or revise the IRB’s previous determination. Information that does not fall under any of the categories does not require reporting to the IRB.
Minor deviations are a change to, or non-compliance with, the research protocol that does not have a significant effect on the subject’s rights, safety or welfare, and/or on the integrity of the data. Minor deviations are considered by the class of event that occurred rather than the specific instance or case in question. For example, missed safety labs caused by researcher oversight are always a reportable event regardless of whether or not the specific subject experienced any harm as a result. Minor deviations may result from the action or inaction of the participant, researcher, or research staff.
Examples of minor deviations include:
- Follow up visits occurring outside the protocol required time frame because of the participant’s schedule
- Blood samples being obtained at times close to but not precisely at the time points specified in the protocol
- Failure to collect an ancillary self-report questionnaire
- Failure to use the IRB stamped Consent Form when consenting a subject
- Missing or incorrect dates on signed Informed Consent documents
- Over-enrollment of subjects on minimal risk studies
- Use of translated consent documents without first submitting to the HRP for review and approval
- CITI training lapsed 30 days or less as long as no research procedures were conducted by the research staff with the lapsed training during this time which could have a significant effect on a subject’s rights, safety, or welfare (e.g. informed consent, study drug administration, etc.) and/or on the integrity of the data (e.g. eCRF locking, collection of vital signs directly from a subject, etc.).
- Continuing reviews submitted 15 days or less after the administrative due date
While the UCD IRB does not require a report of minor deviations, if the Sponsor requires that they are reported to the IRB, they may be included in the Project Event Summary Table at the time of annual renewal. Regardless of Sponsor requirements, a local log of minor deviations should be maintained in the research file by the PI or their delegate.
Questions to determine if your event is a minor deviation or a reportable deviation:
- Was the event caused by the subject’s failure to comply with the protocol procedures? For example, did the subject miss a scheduled appointment?
- Did the event pose a risk of harm to the subject’s:
- a. Safety or welfare
- b. Rights
- Could the event affect the validity of the study by data loss or compromise?
- Is there a practical solution, CAPA, to ensuring that the event doesn’t occur again?
If the answer to question 1 is “yes” or the answer to questions 1-4 are all “no”, this is a minor deviation and not reportable. If the answer to question 1 is “no” and the answer to any of questions 2-4 is “yes”, this is a reportable deviation.
Another way to think of this is using the following flowchart:
FDA guidance states that changes to the protocol or investigational plan to minimize or eliminate immediate hazards or to protect the life and well-being of research participants (e.g., to limit exposure to COVID-19) may be implemented without IRB approval or before filing an amendment to the IND or IDE, but are required to be reported afterwards. These changes should be recorded as minor deviations and submitted to the IRB at continuing review.
Events that Require Prompt Reporting
Submit a Report of New Information to notify the IRB within the required time frame.
To avoid non-compliance for late reporting, you must submit a report within the required timelines, even if additional information is still pending. Required information can be added to the report after it has been submitted the IRB. If a required element is incomplete at the time of submission, please state what is missing in the “Description” field or Project Mail. Examples of elements that can be updated after the initial report include, but are not limited to:
- PI Signature
- Root cause analysis
- Corrective and Preventative Action Plan (CAPA)
At the time of Continuing Review, use the Project Event Summary Table to provide the IRB a summary of reportable events that occurred during the approval period.
Report information that indicates a new or increased risk, or a new safety issue within five (5) working days of receipt of the information. New risk information may be included in:
- Data safety monitoring reports
- Revised investigator brochures
- Interim analysis reports
- Data safety monitoring reports
- New package insert or device label
- Sponsor letter to investigators
- IND safety reports that describe an event as unexpected and probably related to the study.
In some instances, the following events might indicate a new or increased risk:
- Protocol violation that harmed a subject
- Subject complaint or withdrawal
- A change to the protocol done without IRB approval to eliminate an apparent immediate hazard to a subject
- Any change that significantly increases the risks to participants.
Non-Compliance is a failure to comply with the requirements of an applicable law, regulation, or institutional policy pertaining to the protection of human subjects, and/or with the requirements or determinations of an IRB that results in harm to subject’s rights, safety or welfare, or on the integrity of the data. Non-compliance results from the action or inaction of anyone conducting protocol procedures. In the case of research funded or conducted by the Department of Defense (DOD), Non-Compliance includes failure of a person, group, or institution to act in accordance with Department of Defense (DOD) instruction 3216.02, its references, or applicable requirements.
Reports of non-compliance that result in harm to the rights or welfare of research subjects must be reported as new risk information with (5) business days of becoming aware of the non-compliance. Reports of non-compliance that result in harm to the integrity of the data must be reported to the IRB within ten (10) working days of becoming aware of the non-compliance. The report should include sufficient information for the IRB to make the required determination. For example, always indicate whether the non-compliance had any effect on the participant’s welfare or rights. In other words, was the participant harmed in any way due to the non-compliance? If so, what was the harm? Review the Non-compliance Reporting Guide for assistance.
Whenever any non-compliance is reported, you will be asked to include a description of the actions that have been or will be taken to correct the non-compliance and the actions that will be taken to prevent future, similar non-compliance. This plan is referred to as the Corrective and Preventive Action Plan (CAPA). Please note that an adequate preventive action plan almost never consists solely of training. Instead, a process revision, checklist, calendar or other tool should usually be used to prevent similar events in the future. Once accepted by the IRB, you should ensure that the CAPA plan is followed and conduct a follow-up internal audit to assess whether the plan actually prevented mistakes.
Examples of non-compliance include:
- Missing safety assessments.
- Missing signed HIPAA Authorizations or Informed Consent documents.
- Enrollment of a subject who does not meet eligibility criteria in a greater than minimal risk study.
- Failure to submit required reports to the IRB in a timely manner.
The following are descriptions of the determinations that could be made during the review:
- Unanticipated problems involving risks to participants or others (UPIRTSO):
UPIRTSOs include events such as deaths, life-threatening experiences, injuries, breaches of confidentiality that occur during or after the research study when the fact that the event occurred was:
- Unexpected in terms of nature, severity, or frequency, given (a) the research procedures described in the protocol-related documents, and (b) the characteristics of the subject population being studied; AND
- The event, incident, experience, or outcome may reasonably be regarded as caused by or probably caused by the procedures involved in the research; AND
- Harmful: The analysis of the event suggests that 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.
In most instances, a single event is not a UPIRTSO because there are no data to show that the one event indicates that others may be at risk of harm.
In many instances the principal investigator of a clinical trial will indicate that the event is related, and the sponsor will indicate that the event is unrelated or only possibly related. Since the sponsor has the aggregate data from which to make an analysis, the sponsor is in the best position to determine relatedness.
A determination of UPIRTSO generally warrants consideration of substantive changes in the research protocol or informed consent process/document, or other corrective actions, in order to protect the safety, welfare, or rights of subjects or others involved in the conduct of the study.
When this determination is made, the IRB must also determine:
1. Whether the risks of the research are reasonable in relation to any expected benefit that might stem from the research;
2. Whether revisions to the protocol might mitigate the risk; and
3. Whether the informed consent document must be revised to include the new risk information (the consent document must describe all foreseeable risks of the research)
If the IRB determines the informed consent document must be revised, it will ask the investigator to halt enrollment of new participants until the revised consent form is approved. If an investigator has identified potential participants, s/he may submit an addendum to the previously approved consent form. The addendum can be used to provide the risk information to the newly enrolling participants and would need to be signed along with the main consent form.
- Non-Compliance, Serious Non-Compliance, Continuing Non-Compliance due to action or inaction of investigator or research team member
The IRB must review reports of non-compliance and determine whether the event is (1) serious non-compliance; (2) continuing non-compliance or (3) non-compliance that is not serious or continuing. In some instances, reports of non-compliance could also result in a UPIRTSO determination.
Serious non-compliance is non-compliance that adversely affects the rights or welfare of subjects or the integrity of the research data.
Continuing non-compliance is a pattern of non-compliance that suggests the likelihood that, without intervention, instances of non-compliance will recur, or a repeated unwillingness to comply, or a persistent lack of knowledge of how to comply.
If the IRB determines that the event fits within the definition of serious or continuing non-compliance, the IRB must submit a report of the non-compliance to applicable regulatory authorities and institutional officials.
1.What is the difference between non-compliance and a deviation from the protocol, and do they need to be reported to the IRB?
Non-Compliance is a failure to comply with the requirements of an applicable law, regulation, or institutional policy pertaining to the protection of human subjects, or with the requirements or determinations of an IRB that results in harm to subject’s rights, safety or welfare, or on the integrity of the research data. Non-compliance results from the action or inaction of anyone conducting protocol procedures. A deviation is a failure to follow the protocol procedures or sponsor’s requirements.
Deviations that do not result in harm to subject’s rights, safety or welfare, or on the integrity of the data are considered a minor deviations and do not need to be reported to the IRB at the time they occur. The PI must track these events. If the Sponsor requires reporting of these events, they may be included in the Project Event Summary Table submitted at the time of Continuing Review.
Deviations that do result in harm to the subject’s rights, safety or welfare, or on the integrity of the data are events that require prompt reporting. If the deviation was the result of the action or inaction of the researcher or research staff, there may be a finding of non-compliance. Events that result in harm to subject’s rights, safety or welfare must be reported to the IRB within 5 business days of knowledge of the event. Events that result in harm to the integrity of the data must be reported to the IRB within 10 business days of knowledge of the event.
2. What is the difference between an adverse event that is “possibly related” versus “probably related,” and does it matter when submitting to the IRB?
The IRB only requires adverse events believed to be “probably related” (along with unexpected and serious) to be submitted to the IRB. If the event is determined to be more than 50% likely related to the study drug/study procedures, we consider this to be “probably related” and must be submitted to the IRB within five (5) working days.
Anything less than 50% likely related is considered “possibly related” or unknown. Unless otherwise indicated by the sponsor, possibly related adverse events (including those that are unexpected and serious) do not need to be submitted to the IRB as an RNI (HRP-214). However, should a follow up report come through that changes the relatedness from possibly to related or probably related, you must submit a copy of the adverse event report to the IRB within five (5) working days.
3. Research Compliance and Integrity completed an audit of our study, and we just received their report. Do I need to submit this report to the IRB?
Perhaps. Audit reports includes any information that requires reporting (e.g. non-compliance), it should be submitted to the IRB. If the report includes an event that requires prompt reporting, it should be submitted as Reportable New Information within the required time-frame. If only minor deviations are described in the report, the report can be submitted at Continuing Review.
4. I received a monitoring visit report (or a follow up). Do I need to submit this report to the IRB?
Perhaps. If the monitoring report or follow-up report includes any information that requires reporting (e.g. new risk information, non-compliance, etc.), it should be submitted to the IRB. If the report includes an event that requires prompt reporting, it should be submitted as Reportable New Information within the required time frame. If only minor deviations are described in the report, the report can be submitted at Continuing Review.
5. I received an IND Safety Report from the sponsor. The report states that I must submit a copy to the IRB according to IRB requirements. Must I submit this report?
Perhaps. If the IND safety reports includes information about an adverse event that is unexpected (the event wasn’t expected or the frequency or severity of the event was not expected), serious, and the event is related or probably related to the study (see FAQ question 2 above for the definition of probably related).