Report a Study Event

1. Adverse event (AE): An AE is any untoward or unfavorable medical occurrence in a human subject, including any  abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject’s participation in the research, whether or not considered related to the subject’s participation in the research.   The PI should consider the following details of the AE:

• Local or External: A local event is an event experienced by subjects enrolled by the investigator at his or her institution, where as an external event is an event experienced by subjects enrolled by investigators at other institutions engaged in a multi-center clinical trial.
• Expected or Unexpected: An unexpected event is any AE in which the nature, severity, or frequency is not consistent with either the risks of the research described in the research documentation (e.g. protocol, informed consent form, investigator’s brochures, etc.) or any other relevant sources of information such as product labeling or package inserts, OR the event is not consistent with the  natural progression of any underlying condition of the subject(s) experiencing the event (modified from 21 CF 312.32 (a)).  An expected event is an AE not meeting the above criteria.
• Serious Adverse Event (SAE):Any adverse event temporally associated with the subject’s participation in the research and meets any of the following criteria:
  • Results in death;
  • Is life-threatening (places the subject at immediate risk of death);
  • Requires inpatient hospitalization or prolongs hospitalization;
  • Results in a persistent or significant disability/incapacity;
  • Results in a congenital anomaly/birth defect; or
  • Any other adverse event that may jeopardize the subject’s health and may require medical or surgical intervention to prevent one of the other outcomes listed above.
• Relationship: The following should be used to assess AE relationship to study participation.  If there is any uncertainty regarding AE causality, then the event must be assessed as possibly related to research participation and reported to the IRB as indicated.
  • Definitely related: The event was caused by study participation, and an alternative cause is unlikely.
  • Probably related: There is a reasonable possibility that the event is likely to have been caused by study participation.  The AE has a timely relationship to the study procedure(s) and follows a known pattern of response, but a potential alternative cause may be present.
  • Possibly Related:An AE is possibly related when there is a reasonable possibility that the event might have been caused by study participation. A possibly related event may follow no known pattern of response and an alternative cause seems more likely. In other circumstances there may be significant uncertainty about the cause of the event, or a possible relationship to study participation cannot reasonably be ruled out.
  • Unrelated: The cause of the AE is known and the event is in no way related to any aspect of study participation.  Often, the cause of an unrelated AE is disease progression. 

Unanticipated Problem Involving Risk to Subjects or Others (UPIRTSO): Any incident, experience, or outcome that meets all of the following criteria:

1. Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures and (b) the characteristics of the subject population being studied;
2. Related or possibly related to a subject’s participation in the research; and
3. Suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) related to the research than was previously known or recognized.

UPIRTSO events must be reported regardless of whether they occur during the study, after study completion, or after participant withdrawal or completion. If the study has been closed with the IRB, please notify the IRB via email at hsppofc@louisville.edu.

An event that is determined to be a UPIRTSO must be reported to appropriate entities under the HHS regulations at 45 CFR 46.103(a) and 46.103(b)(5). Additional regulatory requirements for reporting unanticipated problems involving risks to subjects and others may be found in 45 CFR 46.103(b)(5)(i) and 21 CFR 56.108(b)(1).

The following Venn diagram summarizes the general relationship between adverse events and unanticipated problems: 

The diagram illustrates three key points:

1. The majority of AEs occurring in human subjects are not unanticipated problems (area A).
2. A small proportion of adverse events are unanticipated problems (area B).
3. Unanticipated problems include other incidents, experiences, and outcomes that are not adverse events (area C).  OHRP Guidance on Reviewing and Reporting UPIRTSOs

A protocol deviation is any change, divergence, or departure from the study design or procedures of a research protocol that is under the investigator’s control and that has not been approved by the IRB.
Upon discovery, the Principal Investigator is responsible for reporting protocol deviations to the IRB. Any change, divergence, or departure from the study design or procedures of a research protocol that affects the subject's rights, safety, or wellbeing and/or the completeness, accuracy and reliability of the study data constitutes a protocol violation. Changes or alterations in the conduct of the trial which do not have a major impact on the subject's rights, safety or well-being, or the completeness, accuracy and reliability of the study data are considered minor protocol deviations.

Major Deviations/Violations

Examples (the list of examples is intended as a guide, is not all-inclusive, and can vary depending on specific scenarios and circumstances:

If sponsored attach correspondence with sponsor and their response in IRIS.

1. Failure to obtain informed consent or research authorization, i.e., there is no documentation of informed consent/research authorization or Informed consent/research authorization obtained after initiation of study procedures.
2. Informed consent/research authorization obtained by someone other than individuals authorized by IRB to obtain consent/research authorization, e.g. someone other than a licensed physician investigator or key personnel.
3. Inappropriate documentation of informed consent/research authorization, including missing subject signature, missing signature of person who obtained informed consent.
4. Deviation has harmed or posed a significant or substantive risk of harm to the research subject.
   1. subject received the wrong treatment or incorrect dose.
   2. subject met withdrawal criteria during the study but was not withdrawn.
   3. subject received an excluded concomitant medication.
5. Deviation compromises the scientific integrity of the data collected for the study.
   1. subject was enrolled but does not meet the protocol's eligibility criteria.
   2. Failure to treat research subjects per protocol procedures that specifically relate to
   3. primary efficacy outcomes. (if it involves patient safety it meets 4)a. above)
   4. Changing the protocol without prior IRB approval.
   5. Inadvertent loss of samples or data.
6. Enrollment of a subject who did not meet all inclusion/exclusion criteria.
7. Performing study procedure not approved by the IRB.
8. Failure to report an unanticipated problem or serious adverse event to the IRB and/or sponsor.
9. Failure to perform a required lab test that, in the opinion of the PI, may affect subject safety or data integrity.
10. Drug/study medication dispensing or dosing error.
11. Study visit conducted outside of required timeframe that, in the opinion of the PI, may affect subject safety.
12. Failure to follow safety monitoring plan.
13. Enrollment of subjects after IRB-approval of study expired.
14. Failure to submit continuing review application to the IRB before study expiration.
15. Use of invalid consent form, i.e. consent form without IRB approval stamp, or outdated/expired consent form/research authorization.
16. Omitting an approved portion of the protocol.

Minor Deviations/Violations

Examples (the list of examples is intended as a guide, is not all-inclusive, and can vary depending on specific scenarios and circumstances)

1. Implementation of unapproved recruitment procedures except for the purpose of subject safety
2. Missing original signed and dated consent form/research authorization (only a photocopy available)
3. Missing pages of executed consent form/research authorization
4. Copy not given to the person signing the form/research authorization
5. Someone other than the subject dated the consent form/research authorization
6. Failure to follow the approved study procedure that, in the opinion of the PI, does not affect subject safety or data integrity
7. Study procedure conducted out of sequence
8. Failure to perform a required lab test
9. Missing lab results
10. Study visit conducted outside of required time frame
11. Failure of subject to return study medication
12. Over-enrollment.

1. Changes made to the research without prior IRB approval in order to eliminate apparent immediate harm (notify the IRB within 5 business days).
2. Any accidental or unintentional change to the IRB approved research protocol or plan that involved risks or has the potential to recur.
3. Any publication in the literature, safety monitoring report, interim result, or other finding that indicates an unexpected change to the risks or potential benefits of the research.
4. Any complaint of a participant that indicates an unanticipated risk or that cannot be resolved by the research staff.
5. Any non-compliance or continuing non-compliance. See HRPP Chapter 3.7
6. Any other event appropriate to the local context.