Unanticipated Problems Involving Risks to Subject or Others and
Adverse Events
19.1 Definitions
Unanticipated Problem Involving Risks to Participants or Others (Unanticipated
Problem): Any event or information that was unforeseen and indicates that the research
procedures caused harm (including physical, psychological, economic, or social harm) to
participants or others, or indicates that participants or others are at increased risk of harm than
was previously known or recognized.
Adverse Event: Any unfavorable and unintended sign (including abnormal laboratory finding),
symptom, or disease temporally associated with the use of a medical treatment or procedure,
regardless of whether it is considered related to the medical treatment or procedure (attribution
of unrelated, unlikely, possible, probable or definite).
Unanticipated event: Any adverse experience where the nature, severity or frequency is not
identified in the investigational brochure described in the application form or detailed in the
consent form. This can also include noncompliance issues such as over enrollment of subjects
without prior COMIRB approval.
Possibly related: In the opinion of the PI, the adverse event is unlikely to be related to the
study intervention, drug or device.
Probably related: In the opinion of the PI, it is more likely than not that the adverse event is
related to the study intervention, drug or device.
Definitely related: In the opinion of the PI, it is very likely that the adverse event is related to
the study intervention, drug or device.
Related to the research: An event is “related to the research procedures” if in the opinion of
the principal investigator, it was more likely than not [probably] to be caused by the research
procedures or if it is more likely that not [probably] that the event affects the rights and welfare
of current participants.
Internal event / problem: An occurrence involving research subjects enrolled in a project
approved by COMIRB and directed by a principal investigator employed by the University of
Colorado Denver (or affiliate site) or one whose project is under the purview of the COMIRB).
External event / problem: An occurrence involving research subjects enrolled in multi-center
research projects that do not fall under the purview of the COMIRB (i.e. sites other than UCD,
UCH, VAMC, and Denver Health).
Prompt Reporting: Reportable events must be submitted to COMIRB within 5 working days of
the event or knowledge of the event.
19.2 Reportable Events
Investigators must report the following to COMIRB within 5 days:
 An actual unforeseen harmful or unfavorable occurrence to participants or others that
relates to the research protocol (injuries, psychological events, drug errors).
 Adverse events which in the opinion of the principal investigator are both unexpected
and probably or definitely related to the intervention/ drug or device.
 An unforeseen development that potentially increases the likelihood of harm to
participants or others in the future.
 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 than initially presented to the
COMIRB.
 A paper is published from another study that shows that the risks or potential
benefits of your research may be different than initially presented to the
COMIRB.
 A problem involving data collection, data storage, privacy or confidentiality.
 Incarceration of a participant in a protocol not approved to enroll prisoners.
 Pregnancy of a participant or spouse in a protocol that specifically exclude
pregnancy due to the potential risks of the intervention or treatment on the fetus.
 Change to the protocol taken without prior COMIRB review to eliminate an
apparent immediate hazard to a research participant.
 Complaint of a participant when the complaint indicates unexpected risks or
cannot be resolved by the research team.
 Protocol violation (meaning an accidental or unintentional change to the COMIRB
approved protocol) that harmed participants or others or that indicates
participants or others may be at increased risk of harm.
 Study related event that requires prompt reporting to the sponsor, if it meets the
above definition of an unanticipated problem.
 Sponsor imposed suspension for risk.
 Noncompliance by the PI or research team
 Any other problem that caused a risk to the participant or others
19.3 Reporting
Principal investigators or their designee should report the above events using the unanticipated
report form within 5 days.
The unanticipated problem form should also be used to submit the following documents to
COMIRB for prompt review if they meet the criteria for an unanticipated problem:
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Medwatch reports
IND reports
DSMB or other safety review reports
Investigational Brochures changes
Changes to Package Inserts
Audit reports
Complaints
If the information provided in these documents does not meet the definition of an unanticipated
problem as outlined above then this information should be submitted as a modification to
approved documents or at continuing review, in aggregate format, as additional safety
information.
At the time of continuing review, the PI should submit an aggregate summary of all adverse
events occurring in the last review period that did not meet the definition of an unanticipated
problem, so that COMIRB can ensure adequate safety monitoring is occurring for the study. If
there is a study monitor (safety officer, DMC, or DSMB) reviewing all adverse events, COMIRB
will delegate the review of these events to that monitor.
At the time of continuing review, the PI should submit an aggregate summary of all protocol
violations occurring in the last review period that did not meet the above criteria for reporting to
COMIRB within five days.
19.4 COMIRB Review of Reports
If the COMIRB Chair or designee considers that either (1) the problem was foreseen OR (2) the
problem was not related (not at least probably related) to the research design or procedures OR
(3) no participants or others were harmed AND participants or others are not at increased risk of
harm, the IRB Chair or Director indicates on the unanticipated problem checklist that the
problem is not an unanticipated problem. The form is filed in the protocol record, the
determination is communicated to the investigator and no further action is taken.
If the unanticipated problem requires investigation because it is a complaint, or to determine if it
potentially is either serious noncompliance or continued noncompliance, then it is handled
according to section 20 below. A report of the sub-committee will then be submitted to the IRB to
be reviewed as an unanticipated problem.
If the COMIRB Chair considers that the problem is an unanticipated problem, but that the risk is
no more than minimal, the chair or designee will review:
1.
2.
3.
4.
5.
The currently approved protocol
The currently approved COMIRB application form
The currently approved consent document
Previous reports of unanticipated problems involving risks to participants or others
The report of the unanticipated problem involving risks to subjects or others
After reviewing all of the materials, the chair or designee will take appropriate action depending
on the nature of the risk involved, including modification of the protocol or the consent form, if
applicable. The chair or designee uses the “Unanticipated problem checklist for Chairs” to
record the results of the review. The results of the chair or designee’s review will be recorded
in the protocol record, communicated to the investigator, reported to the COMIRB panel, and
referred to the COMIRB Office to be handled according to the reporting procedures.
If the chair considers that changes to the consent form or protocol modifications are required,
the convened IRB is to review the unanticipated problem involving risks to participants or
others, unless the change is a minor change. For example, the addition of new risks to the
consent or a change in procedures indicates that the problem involves more than minimal risk
to participants and is to be reviewed by the convened IRB. All reported unanticipated problems
where the risk
is more than minimal will be reviewed at a convened COMIRB panel meeting. Based on the
information received from the investigator, the COMIRB Chair may suspend research to
ensure protection of the rights and welfare of participants prior to review by the panel.
Suspension directives made by the panel Chair or COMIRB Director must be reported to the
next meeting of the convened panel and reported to the institution and federal agencies in
accordance with the reporting policy detailed below.
All panel members are provided a copy of the Unanticipated Problem Form and
supporting documents provided by the investigator. At least one panel member is
provided:
1.
2.
3.
4.
The currently approved protocol
The currently approved consent document
Previous reports of unanticipated problems involving risks to participants or others
The investigator’s brochure, if one exists
The primary reviewer uses the “Unanticipated problem – full board reviewer checklist.” If the
panel considers the event to not represent an unanticipated problem, the results of the review
are recorded in the protocol record, communicated to the investigator and no further action is
taken.
If the panel considers the event to represent an unanticipated problem, where the risk is
more than minimal, the panel will consider the following actions:
1. Modification of the protocol
2. Modification of the information disclosed during the consent process
3. Providing additional information to current participants (This must be done
whenever the information may relate to the participant’s willingness to continue
participation)
4. Providing additional information to past participants
5. Requiring current participants to re-consent to participation
6. Alteration of the frequency of continuing review
7. Observation of the research or the consent process
8. Requiring additional training of the investigator
9. Notification of investigators at other sites
10. Termination or suspension of the research
11. Obtaining additional information
The results of the panel review are recorded in the protocol record, communicated to
the investigator and referred to the COMIRB Office to be handled according to the
reporting procedures described below.
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