Unanticipated Problems
Federal regulations [45CFR46.103(b)(5) and 21CFR56.108(b)(1)] require the IRB to ensure that researchers promptly report “any unanticipated problems involving risk to subjects or others” (UPIRTSOs). The IRB defines a UPIRTSO as any problem or event which in the opinion of the local researcher was unanticipated, serious and at least possibly related to the research procedures. These should be reported to the IRB within 10 working days using the UPIRTSO form found on the IRB’s Web site at http://www.research.umn.edu/irb/download/ . This form must be signed by the principal investigator.
Timeline
A researcher should promptly assess unanticipated problems that occur on the study. Once a researcher has determined that an event constitutes a UPIRTSO, it should be reported to the IRB within 10 working days using the UPIRTSO form found on the IRB’s Web site at http://www.research.umn.edu/irb/download/ . A UPIRTSO must be reported within this time frame, even if the event itself is not yet resolved.
Criteria
Any serious event (including on-site and off-site adverse events, injuries, side effects, deaths or other problems) which in the opinion of the local researcher was unanticipated, involved risk to subjects or others, and was possibly related to the research procedures;
Any serious accidental or unintentional change to the IRB-approved protocol that involves risk or has the potential to recur;
Any deviation from the protocol taken without prior IRB review to eliminate apparent immediate hazard to a research subject;
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 that may involve risk to the subject or others;
Any complaint of a subject that indicates an unanticipated risk or that cannot be resolved by the research staff; or
Any other serious and possibly related event which in the opinion of the researcher constitutes an unanticipated risk.
When assessing an unanticipated problem, the researcher should consider the following 3 criteria. All 3 criteria must be met to constitute a UPIRTSO:
Anticipated (expected) problems are those that are already described as potential risks in the consent form, listed in the Investigator’s Brochure or part of an underlying disease. These do NOT meet the IRB’s definition of UPIRTSO and should be reported in summary form only at the time of IRB continuing review, regardless of whether serious or related. For example, if death is an expected outcome, this event should be reported only at the time of continuing review.
Serious problems/events are those which in the opinion of the local researcher involve risk to subjects or others. Examples include death, hospitalization, disability as well as breach of confidentiality. Non-seriousproblems/events do NOT meet the IRB’s definition of UPIRTSO and should be reported in summary form only at the time of IRB continuing review.
Problems/events that are unanticipated and serious should be reported to the IRB within 10 days only if in the opinion of the local researcher they are possibly, probably or definitely related to the research procedures. Those serious, unanticipated problems/events that the local researcher deems unlikely or not relateddo NOT meet the IRB’s definition of UPIRTSO and should be reported in summary form only at the time of IRB continuing review.
Responsibility
The IRB relies on the U of M researcher to provide an assessment of whether UPIRTSO criteria are met for a given event. As the person most familiar with and ultimately responsible for the conduct of the study, the researcher should provide his or her informed opinion of whether an event meets UPIRTSO criteria. The IRB will then review the researcher’s assessment of the event to determine if any changes to the approved study should be made as a result of the report.
Regardless of whether an event occurred with the U of M researcher’s own subjects (on-site) or with subjects in the same study at a different site (off-site), the U of M researcher (local researcher) must assess whether the event constitutes a UPIRTSO and if so, report it to the IRB.
Death is not necessarily a UPIRTOS. If death is an expected outcome for a particular group of subjects (i.e. patients with advanced cancer), then the death of a subject though serious, is not unexpected and so does not meet the IRB’s definition of UPIRTSO. Any death of a subject which cannot be attributed to underlying disease would be unexpected. However, if the unexpected death is not believed to be related to the research (i.e. car accident), then it does not meet the IRB’s definition of UPIRTSO.
Non-Qualifiers
All problems/events that do not meet the IRB’s definition of UPIRTSO should be reported to the IRB in summary form (using a table or spreadsheet) at the time of continuing review. Accompanying documentation (sponsor report forms, etc.) should not be included with this summary and if received will be returned to the researcher.
Adverse Events
Some unanticipated problems iunvolving risk to subjects or others are characterized as adverse events. Not all adverse events are unanticipated or require reporting:
What is meant by adverse event?
According to FDA regulations (21 CFR 312.32), a "serious adverse drug experience" with respect to human clinical experience includes "any experience that suggests a significant hazard, contraindication, side effect, or precaution." This includes "any experience that is fatal or life? threatening, is permanently disabling, requires inpatient hospitalization, or is a congenital anomaly, cancer, or overdose."
With respect to results obtained from tests in laboratory animals, a "serious adverse drug experience" means any experience suggesting a "significant risk for human subjects, including any finding of mutagenicity, teratogenicity, or carcinogenicity."
"Unexpected adverse experiences" means any adverse experience that is neither identified in nature, severity, or frequency of risk in the information provided for IRB review nor mentioned in the consent form.
Written reports are required by the IRB whether the study sponsor requires such a report or not. In some instances, an unusual event occurs at a study site other than the University of Minnesota; a written report is still required to ensure that the risks and benefits of participation have not changed. (see UPIRTSO reporting requirements: http://www.research.umn.edu/irb/download/).
All written reports should be sent to the IRB and include: 1.) the facts of the case, including the date and description of the event; 2.) verification of whether the is related to the study procedures or drugs or to the subject’s underlying condition; 3.) steps that have been taken to address the problem; and 4.) verification of whether the event provides new information about the study’s risks that should be conveyed to participants in a revised consent form or letter.
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