Unanticipated Problems Involving Risks to Subjects or Others (UPIRSO)

• Adverse event - Any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptoms, or disease, temporally associated with the subject’s participation in the research, whether considered related to the subject’s participation in the research. Adverse events encompass both physical and psychological harms.
• 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.
• Life-threatening event - any experience that places the subject, in the view of the investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that, had it occurred in a more severe form, might have caused death.
• Related - In the opinion of the Investigator, the experience was caused or possibly caused by the research procedures. If there is insufficient information to determine whether the internal event is related, it should be reported as it is related.
• Serious Adverse Event (SAE) – In the opinion of the Investigator or Sponsor, the adverse event results in: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect, or requires medical or surgical intervention to prevent one of the previously listed outcomes.
• Internal event/problem - occurrence involves research subjects enrolled in a project approved by the University of Kentucky IRB and directed by a principal investigator employed by the University of Kentucky or one whose project is under the purview of the University of Kentucky IRB.  [UK internal events/problems are reported to the IRB/IBC on the “UK INTERNAL PROMPT REPORTING FORM”.]
• External event/problem - occurrence involves research subjects enrolled in multi-center research projects that do not fall under the purview of the University of Kentucky IRB.  [External events/problems are reported to the IRB on the “UK EXTERNAL PROMPT REPORTING FORM”.]

The following are examples to help illustrate the application of the UPIRSO criteria. For Investigator-Initiated FDA Clinical Investigations, also refer to the FDA reporting requirements for studies conducted with an Investigational New Drug (IND) or Investigational Device Exemption (IDE).  

• Low white blood cell count and anemia in a subject participating in a chemotherapy study (expected)
• The subject in a study testing a leg brace is diagnosed with COVID-19 (unrelated)
• The subject has an abnormal lab test result, but the elevation is within protocol expectations of up to a one-time upper limit of normal (expected)
• The subject in a medical device study is critically injured as a passenger in a car collision (unrelated)
• A male subject in a neurocognitive study was diagnosed and treated at an emergency department with an inflamed prostate. There is no known relationship with the drug, and the subject meets the demographic profile for which this condition commonly occurs. (unrelated)
• In a behavioral study on seasonal depression, a subject answers an interview question indicating they have considered self-harm.  A subject answering questions regarding self-harm is expected and is one of the study endpoints being assessed. However, the study protocol includes safeguards, including a warm hand-off to a mental health professional and follow-up support. (expected)

The following are examples to help illustrate the application of the UPIRSO criteria. For Investigator-Initiated FDA Clinical Investigations, also refer to the FDA reporting requirements for studies conducted with an Investigational New Drug (IND) or Investigational Device Exemption (IDE).  

• The subject in a Phase II investigational drug study is hospitalized and diagnosed with acute hepatic injury. The subject has no underlying liver disease and reports no injury or other extenuating circumstances. The investigator's brochure does not report prior instances of liver injury; however, mildly elevated liver enzymes were found in 2% of phase I participants. This scenario illustrates a serious event not previously identified in severity in the previous research or investigational plan. The absence of an underlying condition and related mild events suggests a possible causal relationship.
• Study drug dispensing error that resulted in the subject receiving but not taking the wrong dosage of the study drug. While harm did not occur in this scenario, drug errors hold potential for new risks to subjects. The event warrants a root-cause analysis and perhaps corrective action to ensure proper dosing.
• During a Phase IV post-approval drug study, the FDA issues a black box warning for the marketed product. The warning clearly meets the related criteria, and the severity of the event is unexpected and holds potential for harm to subjects or others. A black box warning is the highest level warning communicated by the FDA.
• Subject with no known allergies is treated for an unexpected allergic response warranting urgent care. The subject is a participant in a clinical trial. Upon inquiring, the sponsor’s medical monitor cannot rule out an association with the study drug. Seeking guidance from a sponsor’s medical monitor may help solidify information or fill in gaps that could signify a possible trend.
• A flash drive containing identifiable research data is stolen from the study team. Information includes responses to surveys on engagement in questionable business practices. The scenario adds new unanticipated risks that are related to research and presents the potential for harm to subjects/others.

If the sponsor requires the PI to submit reports to the IRB that do not meet the prompt reporting criteria above, the PI may submit the “IRB Cover Form for Non-Prompt Reporting of Problems/Adverse Events.“ However, upon review, the IRB may request additional information, including but not limited to questions from the Internal Prompt Reporting Form.

At the time of Continuation or Annual Administrative Review, the PI submits a written summary of both unanticipated problems and available information regarding adverse events since the last IRB initial, continuing, or annual administrative review. For multi-site studies, the written summary should describe external events determined to be unanticipated problems involving risks to subjects. The amount of detail provided in such a summary will vary depending on the type of research being conducted; in many cases, such a summary could be a brief statement that there have been no unanticipated problems and that adverse events have occurred at the expected frequency and level of severity as documented in the research protocol, the informed consent document, and the investigator’s brochure (if applicable). The summary must include the PI’s assessment of whether the problems/adverse events warrant changes for the protocol, consent process, or risk/benefit ratio (per the instructions provided in the Continuation and Annual Administrative Review Report Form).