Effective date: 8/17/2016
The Principal Investigator (PI) is responsible for informing the IRB of any reportable events or problems that may increase the subject’s anticipated risk or decrease the anticipated benefit by participating in the research. These events include local and external events or other problems that are unexpected and at least probably related to the research interventions, procedures, or assessments.
NOTE: PIs of protocols reviewed and approved through a non-UT System IRB must report local 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, economic, social, and psychological harms. They occur most commonly in biomedical research, although they can also occur in social and behavioral research.
A non-adverse event is any event that results in an increased risk of harm (physical, psychological, social, etc.), but did not result in actual harm to the subject. New information or other errors may represent a non-adverse event which would require reporting. For example: the research pharmacy inadvertently administers 10 times the study dose of investigational medication and the subject does not experience any adverse effects from the increased dose. This is a situation where there was an increased risk; however, the subject did not experience any adverse reactions. A breach of confidentiality is another example of a possible non-adverse event.
In the context of multi-center research projects, events are characterized as either Local or External. When investigators are participating in multi-center studies, Local events are those experienced by subjects enrolled by the investigator(s) under the UT Southwestern IRB jurisdiction. In the context of a single-center research study conducted by an investigator under the UT Southwestern IRB, all events would be considered local.
External events are those experienced by subjects enrolled by investigators at another institution(s) or in a related study. Examples of external events include:
- Information from related studies
- Literature searches
- IND/IDE Safety Reports
- Data and Safety Monitoring Board (DSMB), Data Monitoring Committee (DMC), and Data Safety Committee (DSC) reports
- FDA Black Box Warnings
- Safety holds due to new or unexpected risks
- New information or publications
- External audits or monitoring reports with findings
Serious Adverse Event
A “Serious Adverse Event” is by definition an event that meets any of the following criteria
- 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: 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, not all serious adverse events must be reported to the IRB.
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs)
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 ALL three (3) of the following criteria:
- Unexpected in nature, frequency, or severity (i.e., generally not expected in a subject’s underlying condition, or not expected as a risk of the study; therefore, not included in the investigator’s brochure, protocol, or informed consent document, AND
- Definitely or probably 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.
- Not all UPIRSOs are adverse events
- Only a small subset of adverse events occurring in human subjects participating in research will meet all three (3) criteria above and be determined an unanticipated problem.
- 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 document/process or other corrective actions in order to protect the safety, welfare, and/or rights of research subjects.
Noncompliance consists of conducting research in a manner that disregards or violates rules, regulations (state or federal), and policies and standards of conduct that govern human subjects research, and/or failure to follow the requirements and determinations of the IRB. Noncompliance may be minor or serious and sporadic or continuing.
Serious noncompliance consists of conducting research in a manner that adversely affects subjects’ safety or the safety of others, increases risks to subjects, or violates the rights and welfare of participants (any of which may also be an unanticipated problem). Serious noncompliance may affect the subject’s willingness to participate in research or may affect the integrity of the data (which may also be scientific misconduct).
A persistent failure to adhere to the laws, regulations, or policies governing human research is considered continuing noncompliance. Continuing noncompliance is a pattern of recurring (in one or more protocols simultaneously or over a period of time) or ongoing instances of actions or omissions (noncompliance) which indicate:
1. an underlying deficiency in knowledge of the regulations and/or IRB requirements, or
2. a possible inability or unwillingness to comply with regulations and/or IRB requirements. Instances may or may not constitute serious noncompliance.
- Unanticipated problems and serious or continuing noncompliance invoke additional reporting requirements (i.e., NIH, Office for Human Research Protections (OHRP), FDA, etc.). The IRB will assist the investigator in documenting and reporting unanticipated problems and serious/continuing noncompliance to the appropriate federal agencies and other authorities.
Please use the table below to determine which events and other research-related information requires prompt reporting to the IRB and the local IRB reporting timeframes. A printable version of this table is available.
|Type of Event||Conditions||When to Report|
|Local Serious Adverse Event UPIRSO (Life Threatening or Fatal events experienced by subjects enrolled by the investigator(s) under UTSW IRB jurisdiction)||
||Within 48 hours of PI awareness|
|Local UPIRSO (Events experienced by subjects enrolled by the investigator(s) under UTSW IRB jurisdiction)||
||Within 5 business days of PI awareness|
|External UPIRSO (Events experienced by subjects enrolled by investigators at another institution(s) or in a related study that is also being conducted at UTSW)||
||Within 10 business days of PI awareness|
|Anticipated events or other problems(Expected events/problems listed in the protocol and informed consent document)||
For anticipated events, track and summarize at continuing review
For unanticipated events that meet all 3 criteria for UPIRSO, follow either local or external (as applicable) UPIRSO reporting requirements
|Reportable events related to a Humanitarian Use Device (HUD)||
||Within 48 hours of PI awareness|
NOTE: DSMB/DMC/DSC reports do not require prompt reporting to the IRB unless they meet UPIRSO criteria. DSMB/DMC/DSC reports that do not meet UPIRSO criteria should be summarized and submitted to the IRB at continuing review.
Protocol Violations, Protocol Deviations, and Other Research-Related Incidents
|Type of Violation or Incident||Definition||Examples||When to Report|
|Protocol Deviation||Any unintentional or accidental change to, or noncompliance with, the IRB-approved protocol that does not, or does not have the potential to, adversely affect the subject’s rights, safety, or welfare, and/or the integrity of the data.||
||Track and summarize at continuing review|
|Protocol Violation (Possible Noncompliance)||Any intentional or accidental change to, or noncompliance with, the IRB-approved protocol that does, or has the potential to, adversely affect the subject’s rights, safety, or welfare, and/or the integrity of the data.||
||Within 10 business days of PI awareness|
|Protocol Change Without Prior IRB Approval||Necessary to avoid immediate and apparent harm to participants (Local UPIRSO)||
||Within 5 business days of occurrence (see Local UPIRSO above)|
|Major Complaints||A complaint 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 business days of PI awareness|
Additional Important Information on Prompt Reporting
- Investigators are responsible for monitoring all adverse events and non-adverse events according to the protocol data safety monitoring plan and reporting in summary format to the IRB at continuing review.
- Investigators may have adverse event reporting requirements (e.g., Sponsor, DSMB/DMC/DSC, FDA, NIH, etc.) 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 reports or in summary reports to the IRB. Instead, please redact the name and use subject ID numbers or other random code to identify subjects in these reports. You may use and submit the IRB local event tracking tool for tracking events.
- Individual adverse events or other problems that do not meet the criteria for reporting to the IRB. For example, adverse events that are expected and/or not related or possibly related to the research do not need to be promptly reported, but should be tracked and summarized to the IRB at continuing review. If the study sponsor requires submission of these events to the IRB, the events should be summarized and submitted to the IRB at continuing review.
- Routine DSMB/DMC/DSC reports (indicating to continue the study as planned), individual study sponsor IND/IDE safety reports, or other reports that do not meet the UPIRSO 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 IND/IDE safety reports on studies not conducted by an investigator under UT Southwestern IRB jurisdiction will not be acknowledged by the IRB without an 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. These types of routine reports should be summarized and submitted to the IRB at continuing review.
An event occurring in one or more subjects participating in a research protocol is considered unexpected if the nature, severity, or frequency of occurrence 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 possibility that the incident, experience, or outcome may have been caused by the procedures or interventions involved in the research although the relationship is uncertain (i.e., there is not enough information to determine causality). Usually, events assessed as possibly related do not result in modifications to the investigator’s brochure, protocol, or informed consent document.
“Probably related” means that it is likely that the incident, experience, or outcome was caused by the procedures or interventions involved in the research. In general, events that are determined to have at least a reasonable relationship to the research procedures or interventions would be considered probably related to participation in the research. Usually, events assessed as probably related would result in modifications to the investigator’s brochure, protocol, and/or informed consent document.
"Unrelated" means that the incident, experience, or outcome was solely caused by the underlying disease, disorder, or condition, or by events that are clearly unrelated to the research project or condition under study.
Events, incidents, experiences, or outcomes that are unexpected, related (definitely or probably) to participation in research, and serious suggest that the research places subjects or others at increased risk than was previously known or recognized. These events would warrant consideration of substantive changes in the protocol or informed consent document or other corrective actions in order to protect the safety of subjects, with consideration including but not limited to sponsor and DSMB/DMC/DSC 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, 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., an event, 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 event reporting as described in this guidance.
- Safety monitoring according to the IRB-approved protocol 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/DSC) 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 informed 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/DMC/DSC updates, or study holds 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 DSMB/DMC/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 PI must promptly notify the IRB office of the impending audit or review. If the PI 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 prompt reporting to the IRB unless there are findings that meet the above reporting criteria.
Data and Safety Monitoring Reports
For ongoing trials, the IRB is responsible for considering new information arising from interim protocol data safety monitoring by the PI or a DSMB/DMC/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 recommendations to the sponsor. DSMB/DMC/DSC reports should be reported to the IRB at continuing review, even when no problems have been identified and it has been recommended to continue the trial as designed. In the absence of a formal DSMB/DMC/DSC, the PI should provide reports to the IRB in accordance with the approved protocol data safety monitoring plan to the IRB at continuing review.
Protocol Deviations and Minor Complaints
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. It is the responsibility of the PI 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.
A protocol deviation is an unintentional or accidental change to, or noncompliance with, the IRB-approved protocol that does not, or does not have the potential to, adversely affect the subject’s rights, safety, or welfare, and/or the integrity of the data. Protocol deviations do not require prompt reporting to the IRB, but should be documented in the study records and tracked and summarized to the IRB at continuing review.
NOTE: If a change must be implemented immediately to avoid an immediate or apparent hazard prior to obtaining IRB approval, this must be promptly reported to the IRB within five (5) business days of the occurrence.
Minor complaints made by a subject, subject’s family, or others which are resolved by the research team and do not indicate increased or unexpected risks do not need to be promptly reported to the IRB. Summarize minor complaints and their resolutions to the IRB at continuing review.
NOTE: Refer to the table for reporting requirements of major complaints, complaints that are not resolved by the research team, or complaints that indicate increased or unexpected risks for subjects or others.
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)”
Office of Human Research Protections (OHRP)