During and after the course of a research study, the Principal Investigator (PI) is responsible for informing the IRB of any adverse events or problems that may increase the anticipated risk or decrease the anticipated benefit. These events include local and non-local serious adverse events, and unexpected adverse events that are possibly or probably related to the research interventions, procedures, or assessments.
Note: PIs of protocols reviewed and approved through the UT System IRB Reciprocity Agreement must report local adverse events to the IRB on which they are reliant.
An adverse event is any untoward or unfavorable medical occurrence in a human research study participant, including any abnormal sign, symptom, clinical event, or disease that occurs during the subject’s participation in the research, whether or not it is considered related to the subject’s participation in the research.
Adverse events encompass clinical, physical, and psychological harms. They occur most commonly in biomedical research, although they can also occur in social and behavioral research.
Local and Non-Local
In the context of multi-center research projects, adverse events are characterized as either Local or Non-Local adverse events. When investigators are participating in a multi-center studies, Local adverse events are those experienced by subjects enrolled by the investigator(s) under the UT Southwestern IRB jurisdiction; whereas Non-Local adverse events are those experienced by subjects enrolled by investigators at another institution(s) engaged in the same research study. In the context of a single center research study conducted by an investigator under the UT Southwestern IRB, all adverse events would be considered Local.
Investigational New Drug/Investigational Device Exception (IND/IDE) Safety Report
For the purposes of this guidance, IND/IDE Safety Report refers to reports from sponsors informing researchers using the same drug or device in a different trial, about adverse events or reactions occurring in trials not conducted by an investigator under the UT Southwestern IRB jurisdiction, or adverse experiences reported in the context of usual clinical use of the study drug/device.
Serious Adverse Event
A serious adverse event is any event that:
- Results in death
- Is life-threatening (places the subject at immediate risk of death)
- Results in inpatient hospitalization or prolongation of existing hospitalization
- Results in a persistent or significant disability/incapacity
- Results in a congenital anomaly/birth defect, or
- Based upon appropriate medical judgment, may jeopardize the subject’s health and may require medical or surgical intervention to prevent one of the other outcomes listed in this definition.
Note: A “Serious adverse event” is by definition an event that meets any of the above criteria. Serious adverse events may or may not be related to the research project. A serious adverse event determination does not require the event to be related to the research. That is, events completely unrelated to the condition under study and events that are expected in the context of the condition under study may both be serious adverse events. As examples, a car accident requiring overnight hospitalization would be a serious adverse event for any research participant; likewise, in a study investigating end-stage cancer care, any hospitalization or death would be a serious adverse event, even if the event observed is a primary clinical endpoint of the study. As shown below in the table and the decision tree, not all serious adverse events must be reported to the IRB.
The term “unanticipated problem” is found, but not defined, in the regulations for the Protection of Human Subjects at 45 CFR 46, and the FDA regulations at 21 CFR 56. Guidance from the regulatory agencies considers unanticipated problems to include any incident, experience, or outcome that meets each of the following criteria:
- Related or possibly related to participation in the research, and
- 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. Note: Any serious adverse event would always suggest a greater risk of harm.
a) Only a small subset of adverse events occurring in human subjects participating in research will meet the three criteria above and be determined an unanticipated problem.
b) If an adverse event is determined to be an “unanticipated problem” consideration will be given to the necessity for commensurate changes in the protocol and/or informed consent process/document or other corrective actions in order to protect the safety, welfare, and/or rights of research subjects.
Unanticipated problems invoke additional reporting requirements (i.e., NIH, Office for Human Research Protections [OHRP], FDA). The IRB will assist the investigator in documenting and reporting unanticipated problems to the appropriate federal agencies.
Please use the chart and diagrams below to determine which adverse events, and other research-related information requires reporting to the IRB and the local IRB reporting timeframes. A printable version of this chart is available.
|Type of Event||Conditions||When to Report|
|Local Adverse Event
(Occurring to a subject enrolled on a protocol under the UT Southwestern IRB jurisdiction)
||Within 2 working days of PI awareness|
|Non-Local Serious Adverse Event
(Occurring in the same multi-site study as is conducted by the PI at UT Southwestern, but at a different site)
||Within 10 working days of PI awareness|
|Reportable events related to a Humanitarian Use Devices (HUD)||
||Within 2 working days of PI awareness|
Other Types of Events or Safety Information
|Type of Event or Infomation||When to Report|
|External audit or monitoring report with findings||Within 10 working days of PI awareness|
|Other safety information or publication that suggests a change to the risk/benefit ratio of the research|
|Safety hold on study activities due to new or unexpected risk(s)|
Protocol Violations and Other Research-Related Incidents
|Type of Violation or Incident||Definition||Examples||When to Report|
|Protocol Violation||Any intentional or accidental change to, or noncompliance with, the IRB approved protocol that does, or has the potential to,increase the risk or decrease benefit, and/or affect the subject’s rights, safety or welfare, and/or the integrity of the data.||
||Within 10 working days of PI awareness|
|Protocol Change Without Prior IRB Approval||Necessary to avoid immediate and apparent harm to participants||Within 2 working days of occurrence|
|Complaint||A compliant made by a subject, subject’s family, or others, which is unresolved by the research team, or which indicates increased or unexpected risks||Within 10 working days of occurrence|
||Within 2 days of PI awareness
(if the incident meets the reporting criteria for a local adverse event)
Additional Important Information on Adverse Event Reporting
- Investigators are responsible for monitoring all local adverse events according to the data safety monitoring plan and reporting in summary format to the IRB at Continuing Review.
- Investigators may have adverse event reporting requirements (e.g., to an industry sponsor, Data Safety Monitoring Committee, the FDA or the NIH) in addition to IRB reporting requirements. It is the investigator’s responsibility to know and comply with any additional reporting requirements.
- To maintain confidentiality, subject names should not be included on individual adverse event reports or in summary reports to the IRB. Instead, please redact the name, use subject ID numbers or other random code to identify subjects in these reports.
- Individual adverse events that do not meet the criteria for reporting to the IRB. For example, adverse events that are expected, are not serious, and/or not related to the research do not need to be reported. If the study sponsor requires submission of these events to the IRB, the events should be summarized and submitted at continuing review.
- Individual study sponsor IND/IDE safety reports that do not meet the local or non-local reporting criteria. These are generally reports from sponsors informing researchers using the same drug or device in a different trial, about adverse events or reactions occurring in trials not conducted by an investigator under the UT Southwestern IRB jurisdiction, or adverse experiences reported in the context of usual clinical use of the study drug/device. Individual Safety Reports on studies not conducted by an investigator under UT Southwestern IRB jurisdiction will not be acknowledged by the IRB without a sponsor-provided analysis of the event, an explanation of how the event meets the regulatory reporting criteria, and a discussion of any planned modifications or other actions necessary to protect subjects.
Any adverse event occurring in one or more subjects participating in a research protocol, the nature, severity, or frequency of which is not consistent with either:
- The known or foreseeable risk of adverse events associated with the procedures involved in the research that are described in (a) the protocol-related documents, such as the approved research protocol, any applicable investigator brochure, and the current IRB-approved informed-consent document; and (b) other relevant sources of information, such as product labeling and package inserts; or
- The expected natural progression of any underlying disease, disorder, or condition of the subject(s) experiencing the adverse event, and the subject’s predisposing risk factor profile for the adverse event.
The vast majority of adverse events occurring in the context of research are expected in light of (1) the known toxicities and side effects of the research interventions/procedures; (2) the expected natural progression of subjects’ underlying diseases, disorders, and conditions; and (3) subjects’ predisposing risk factor profiles for the adverse events. Thus, most individual adverse events do not meet the first criterion and do not need to be reported.
“Possibly related” means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures or interventions involved in the research. In general, adverse events that are determined to have at least a reasonable relationship to the research procedures or interventions would be considered related to participation in the research.
“Probably related” means that it is likely, but uncertain, that the incident, experience, or outcome was caused by the procedures or interventions involved in the research.
"Unrelated" means that the adverse event(s) are solely caused by the underlying disease, disorder, or condition, or by events that are clearly unrelated to the research project or condition under study.
Adverse events that are unexpected, related (definitely, probably, or possibly) to participation in research and serious suggest that the research places subjects or others at increased risk than was previously known or recognized. These adverse events would warrant consideration of substantive changes in the protocol, consent document or other corrective actions in order to protect the safety of subjects, with consideration including but not limited to sponsor and data safety monitoring committee oversight, IRB review, and investigator determinations. In rare occasions, it may be advisable to temporarily suspend research in order to adequately assess the event(s) and make any necessary changes.
However, adverse events that do not meet the definition of “serious” may still suggest the possibility of increased risk of harm to subjects or others (i.e., adverse events, although expected, occurred at a greater frequency or severity that previously known or anticipated). It is important to recognize that greater risk of harm is not limited to adverse events that are “serious.”
Investigators are responsible for:
- Timely, accurate and complete adverse event reporting as described in this guidance.
- Safety monitoring according to the IRB-approved data safety monitoring plan. This includes monitoring for, and maintaining documentation of, adverse events whether or not they meet the criteria for reporting to the IRB.
- Ensuring that adverse events are reported to the monitoring entity (e.g., the research sponsor, a coordinating or statistical center, an independent medical monitor, or a DSMB/DMC) as required under the monitoring provisions described in the IRB-approved protocol.
- Evaluating whether adverse events or other safety-related information may affect subject’s willingness to continue participation in the study, and/or whether changes to the protocol or consent document are indicated to protect the safety and welfare of subjects.
- Conducting causality assessment and follow-up of all local study related adverse events and other safety-related information (such as sponsor or DSMB updates, or holds on study activities due to safety concerns).
- Providing the IRB with a progress report at continuing review as outlined in the eIRB continuing review smart form. The progress report should include a summarization of the investigator’s overall assessment of any adverse events and any other new information that has become available in order for the IRB to determine if the risk/benefit ratio has changed. The investigator’s assessment may be a statement that expected adverse events have not occurred at a greater frequency or severity than previously anticipated; and/or a report from a monitoring entity such as a Data Safety Monitoring Board (DSMB), Data Safety Committee (DSC), the research sponsor, or coordinating center.
Adhering to IRB reporting requirements will be monitored as part of the IRB’s routine administrative monitoring activities. Findings of non-compliance will be handled in accordance with the UT Southwestern IRB policy on regulatory non-compliance.
External Audits and Monitoring Reports
If notified that a study will be reviewed or audited by the US Food and Drug Administration (FDA), the Office for Human Research Protections (OHRP) or other external regulatory oversight agency, the Principal Investigator musdt promptly notify the IRB office of the impending audit or review. If the Principal Investigator is given advance notice of an audit by an external entity, the IRB staff can help the study team to gather essential documents and can be available to help answer the auditor's questions about human subject protections at UT Southwestern. The IRB also may wish to send a representative to observe proceedings of any "exit interview" which may occur. The written report of any audit findings by FDA or other regulatory agencies must be forwarded to the IRB for its records.
The PI also must notify the IRB office should the Sponsor, or any internal monitoring or compliance group, having findings resulting in a protocol modification or other corrective action(s) to protect subjects, indicate serious or continuing non-compliance or involve other regulatory actions.
Other activities, such as sponsor-initiated audits or monitoring visits, should be reported to the IRB if there are significant findings that could potentially affect the safety, rights, or welfare of subjects, and/or as required by the study sponsor. Routine site monitoring reports or data queries do not require reporting to the IRB unless there are findings that meet the above reporting criteria.
Data Safety Monitoring Reports
For ongoing trials, the IRB is responsible for considering new information arising from interim data safety monitoring by the PI, Data Safety Monitoring Board (DSMB), or Data Safety Committee (DSC). Investigators are responsible for assuring that the IRB is made aware of significant new information that arises about a clinical trial. Such information may include DMC recommendations to the sponsor. Data Safety Monitoring Reports should be reported to the IRB, even when no problems have been identified and the DSMB has recommended continuation of the trial as designed. In the absence of a formal DSMB/DSC, the PI should provide reports to the IRB in accordance with the approved Data Safety Monitoring Plan.
Federal regulations require that no changes be made to research protocols without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.
A protocol violation is an intentional or accidental change to, or noncompliance with, the IRB approved protocol that does, or has the potential to increase risk or decrease benefit, and/or affect the subject’s rights, safety or welfare, and/or the integrity of the data. Protocol violations are to be reported to the IRB even if no actual harm results to the subject.
Minor protocol deviations are intentional or accidental changes to, or noncompliance with, the IRB approved protocol that do not have the potential to affect the subject’s rights, safety or welfare, and/or on the integrity of the data. Protocol deviations do not require reporting to the IRB, but should be documented in the study records.
It is the responsibility of the principal investigator to ensure that all individuals involved in the conduct of the research follow the IRB-approved research protocol. When changes to the protocol are necessary, a modification (MOD) request must be submitted to the IRB for review and approval prior to implementation of the changes. Note: If a change must be implemented immediately to avoid an immediate, apparent hazard, this should be reported to the IRB within two (2) working days of the occurrence.
Office of Human Research Protections (OHRP)
Food and Drug Administration (FDA)
NIH Office of Biotechnology Activities (OBA)
“Reporting of Incidents Related to Research Subject to the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acids to the National Institutes of Health (NIH) Office of Biotechnology Activities (OBA)”