Involving Risks to Participants or Others; and
Other Events Requiring Prompt Reporting
Federal regulations require the IRB to ensure that investigators promptly report “any unanticipated problems involving risk to subjects or others”. [See 45CFR46.103(b)(5) and 21CFR56.108(b)(1)].
Unanticipated Problems are any incident, experience or outcome that is unexpected, related or possibly related to participation in research and suggests a greater risk of harm to subjects or others.
It is important to remember that Unanticipated Problems must meet 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 subject 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 subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized
- Adverse events focus on the harm; Unanticipated problems focus on the “risk of harm”.
When conducting research with human subjects unanticipated problems occur that include other types of incidents, experiences, and outcomes that are not considered adverse events. These might include social or economic harm instead of the physical or psychological harm associated with adverse events. An example of social harm can include an incident where identifiable sensitive data was left unprotected and unauthorized individuals gained access to the information.
Unanticipated Problems also place subjects or others at increased risk of harm, but no harm may actually occur. The increased risk of harm is the key factor here. Subjects should always be informed of increased risk associated with the research and steps should be taken to eliminate or minimize the risk where possible.
Adverse events are generally defined very broadly and include any event meeting the following definition:
- Any untoward or unfavorable physical or psychological occurrence in a human subject;
- Can include any unfavorable or abnormal sign, symptom or disease (abnormal physical exam or laboratory finding);
- Could be temporally associated with participation in research; but
- Does not necessarily have to have a causal relationship with participation in research
Summarizing the Relationship between Adverse Events and Unanticipated Problems
The general relationship between adverse events and unanticipated problems can be summarized with the following three key points:
- The vast majority of adverse events occurring in research with human subjects are not unanticipated problems.
- Only a small proportion of adverse events are unanticipated problems;
- Unanticipated problems include other incidents, experiences and outcomes that are not adverse events.
Step I. Assessing whether the Adverse Event or Problem is Unexpected
To determine if the adverse event or problem is unexpected consider the following:
- Look to see if the nature, severity or frequency of the adverse event is part of the known or foreseeable risks described in the:
- investigator brochure
- product labeling or package inserts
- informed consent document
- Look to see if the nature, severity or frequency of the adverse event is part of the subject’s expected natural progression of an underlying disease, disorder,
or condition under study; or part of the subject’s predisposing risk factor profile.
If the event or problem is listed in the documents described in (1) or due to the conditions of (2), then the event or problem is probably not unexpected.
At times it may be difficult to determine if a particular event or problem is unexpected for example, when looking at higher rates of frequency, without a thorough analysis of appropriate data on all subjects enrolled in the research.
Step II. Assessing whether the Adverse Event or Problem is related to or possibly related to participation in research
According to federal guidelines, unanticipated problems are always related to participation in research. However, adverse events may be caused by one or more of the following:
- the procedures involved in the research;
- an underlying disease, disorder, or condition of the subject;
- other circumstances unrelated to either the research or an underlying disease, disorder, or condition of the subject;
Adverse events or problems that are at least partially caused by (1) are considered to be related to participation in research.
Adverse events or problems determined to be solely caused by (2) or (3) would be considered unrelated to participation in research.
Determinations about the relatedness of adverse events or problems to participation in research often result in probability statements that fall along a continuum between definitely related to the research and definitely unrelated to participation in research.
The relatedness of an adverse event or problem is usually indicated by one of the following categories:
- Not related
- Unlikely related
- Possibly related ◄
- Probably related
- Definitely related
“Possibly related” to participation in research is an important threshold for determining whether a particular adverse event or problem represents an unanticipated problem.
Federal policy defines “possibly related” as follows: There is a reasonable possibility that the adverse event may have been caused by the procedures involved in the research.
Step III. Assessing whether the Adverse Event or Problem suggests that the research places subjects or others at a greater risk of harm.
The most important subset of adverse events representing unanticipated problems are those adverse events or problems that are unexpected, related or possibly related to participation in research, and are considered serious. Such events always suggest that the research places subjects or others at a greater risk of physical or psychological harm than was previously known or recognized. As a result, consideration of substantive changes in the research protocol or informed consent process/document or other corrective actions are often warranted to protect the safety, welfare, or rights of subjects.
Federal policy defines serious adverse event as any adverse event that results in:
- Life threatening experience
- Hospitalization or prolongation of hospitalization
- Persistent or significant disability or incapacity
- Congenital anomaly/birth defect; or
- Based upon appropriate medical judgment may jeopardize subject’s health and may require medical or surgical intervention to prevent any of the other outcomes listed in this definition.
However, unanticipated problems also include adverse events or problems that are unexpected and related or possibly related to participation in research, and suggest that the research places subjects or others at a greater risk of harm, but are not considered serious.
Additional guidance on unanticipated problems and adverse events can be found at the OHRP website and the FDA website by following the links provided.
LSUHSC-S Requirements: Reporting Unanticipated Problems or Other Events Requiring Prompt Reporting
The investigator must determine if the event or problem is either an internal adverse event or an external adverse event or problem.
Internal Adverse Events or Problems are defined as those adverse events or problems experienced by subjects enrolled by the investigators at this institution (LSUHSC-S). This also includes all LSUHSC-S affiliate sites and any institution using LSUHSC-S’s IRB for review of research.
External Adverse Events or Problems are defined as those adverse events or problems experienced by subjects enrolled by investigators at other institutions engaged in the clinical trial.
Investigators must report possible unanticipated problems to the IRB within five (5) working days of receiving notice of the event, if the event requires immediate intervention to prevent serious harm to participants or others.
Investigators must report all other possible unanticipated problems occurring at the internal (this institution – LSUHSC-S) and external (other institutions) to the IRB as soon as possible but no later than ten (10) business days from the date of the event or from the date the investigator is notified of the event.
Events to be reported include:
- Any event, including on-site and off-site adverse events, injuries, side effects, deaths, or other problems, which in the opinion of the local PI, was unanticipated, involved risk to participants or others, and was possibly, probably or definitely related to the research.
- Any accidental or unintentional change to the IRB-approved protocol that involves risks or has the potential to recur
- Any deviation from the protocol taken without IRB approval protocol to eliminate apparent immediate hazard to a research participant\
- Any publication in the literature, safety monitoring report, (including Data and Safety Monitoring Reports), interim result, or other finding that indicates an unexpected change to the risk/benefit ratio of the research
- Any breach in confidentiality
- Any complaint of a participant that indicates an unanticipated risk or that cannot be resolved by the research staff
- Any local death, whether anticipated or not that could be possibly related to research
- Incarceration of a participant
- Any other possibly related event which in the opinion of the investigator constitutes an unanticipated risk.
- Addition of a black box warning on any drug used in your research
If a study is completed and closed at the local site (LSUHSC-S) and external events occurring in studies at other institutions are reported to the local site, the PI should report the event: (1) if the event meets the IRB definition as detailed above; and (2) the local PI determines that this event may affect risk to participants who have completed the study.
Examples of what Investigators Report to the IRB:
Within 5 working days
As soon as possible but within five (5) working days, the investigator must report to the
- Any changes to the protocol that were taken to eliminate an apparent hazard to a participant in an emergency.
- Any deviations from the investigational plan for an investigational device taken to protect the life or physical well-being of a participant in an emergency.
- Any serious adverse event that is possibly, probably or definitely related to the research, regardless of whether the event occurred at an internal (LSUHSC-S) site or external (other institution) performance site.
- Death of a LSUHSC-S study participant that is possibly, probably or definitely related to the research;
- Death of a non-LSUHSC-S study participant that is possibly, probably or definitely related to the research;
Within 10 working days
As soon as possible but in all cases within ten (10) working days, the investigator must report to the IRB:
- Any non-fatal internal unanticipated problem occurring at a performance site under LSUHSC-S IRB oversight;
- Any non-fatal external unanticipated problem occurring at non-LSUHSC-S sites;
- Information that indicates a change to the risks or potential benefits of the research.
- For example: An interim analysis or safety monitoring report indicates that frequency or magnitude of harms or benefits may be different from those initially presented to the IRB; or a paper is published from another study that shows the risks or potential benefits of the research might be different from those initially presented to the IRB.
- A breach of confidentiality
- Change in FDA labeling or withdrawal from marketing of a drug, device, or biologic used in a research protocol.
- Change to the protocol taken without prior IRB review to eliminate an apparent immediate hazard to a research subject.
- Incarceration of a subject enrolled in a protocol not approved to enroll prisoners.
- Event that requires prompt reporting to the sponsor.
- Sponsor-imposed suspension for risk.
- Complaint of a subject when the complaint indicates unexpected risks or a situation that cannot be resolved by the research team.
- Protocol violation (i.e., an accidental or unintentional change to the IRB-approved protocol) that harmed subjects or others; or that indicates subjects or others may be at increased risk of harm.
- Safety monitoring reports and DSMB reports from the sponsor
- Safety monitoring reports that indicate a change to the risk / benefit ratio.
Investigators or the study team must report possible unanticipated problems to the
HRPP Office in writing using the Unanticipated Problem & Other Events Requiring
Prompt Reporting Form.
The written report should contain the following:
- Detailed information about the possible unanticipated problems, including relevant dates;
- Any corrective action, planned or already taken, to ensure that the possible unanticipated problem is corrected and will not occur again.
- An assessment of whether any subjects or others were placed at risk as a result of the event or suffered any physical, social, or psychological harm and any plan to address these consequences.
- Any other relevant information.
- Any other information requested by the HRPP Office.
A report of a possible unanticipated problem involving risks to participants or others will be immediately forwarded by HRPP Office staff to the IRB Chair if the HRPP Office staff believes that immediate intervention may be required to protect participants or others from serious harm.
Upon receipt of a report of a possible unanticipated problem from someone other than
the investigator or study staff, the IRB director will notify the PI on the study when
Non-Prompt Reporting Events
For submission of anticipated problems/events that have been described in the protocol,
consent form or investigator’s brochure or to submit required adverse events that do not
meet the LSUHSC-S requirements for prompt reporting, submit a Non-Prompt Reporting Form as an attachment at the time of continuing review with the Continuing Review Application Form.
This form is also to be used when the sponsor requires prompt reporting to the LSUHSC-S IRB but the event does not meet LSUHSC-S requirements for prompt reporting.