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Reporting Adverse Events, Unanticipated Problems Involving Risk to Participants or Others, and Protocol Violations

Researcher Responsibility to Report Adverse Events/Unanticipated Problems Involving Risk to Participants or Others/Protocol Violations

Federal regulations require that UCI have written procedures for ensuring prompt reporting of unanticipated problems involving risk to subjects or others to the IRB, appropriate UCI officials, the funding agency or study sponsors, and federal department or agency heads including the Office for Human Research Protections (OHRP), the Food and Drug Administration (FDA), when applicable. Per UCI IRB policy the following events or problems must be reported to the UCI IRB within the specified timeframe via the electronic Adverse Events/Unanticipated Problems (AE/UP) reporting process.

The IRB will review the AE/UP report in a timely manner and determine whether the reported event is an unanticipated problem involving risk to participants or others (hereinafter referred to as unanticipated problems). Unanticipated problems will be reported to the appropriate entities per UCI IRB policy.

Reportable Events/Problems
Report any event/problem listed below to the IRB within the specified timeframe
1

Any unexpected, internal adverse events or external adverse events that occur anytime during the conduct of the research study or during the follow-up period after the research, which in the opinion of the UCI Investigator includes the following components:

  1. Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the IRB-approved documents, such as the protocol and informed consent document; and (b) the characteristics of the subject population being studied;
  2. Related or possibly related to participation in the research (possibly related means there is a reasonable possibility that the incident, experience, or problem may have been caused by the procedures involved in the research); and
  3. Suggests that the research places subjects at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.

Report within 10 working days of the researcher becoming aware of the event.
2

Any internal, serious adverse event that is,

  1. Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the IRB-approved documents, such as the protocol and informed consent document; and (b) the characteristics of the subject population being studied; and
  2. Related or possibly related to participation in the research (possibly related means there is a reasonable possibility that the incident, experience, or problem may have been caused by the procedures involved in the research).

Report within 5 working days of the researcher becoming aware of the event.
3

Any external adverse event that occurs anytime during the conduct of the research study or during the follow-up period after the research, which in the opinion of the UCI Investigator:

  1. changes the study’s risk/benefit profile; and/or
  2. necessitates submission of an e-MOD request to revise the IRB-approved consent document(s) and/or the IRB-approved protocol.

Report within 10 working days of the researcher becoming aware of the event.
4

An event/problem that affects the safety and welfare of subjects and requires prompt reporting to the sponsor.

Report within 10 working days of the researcher becoming aware of the event.
5

Any permanent or temporary hold on some or all research activities.

Report within 10 working days of the researcher becoming aware of the event.
6

Early termination of the study due to a change in the risk/benefit profile.

Report within 10 working days of the researcher becoming aware of the event.
7

Any change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic used in an IRB approved research study due to adverse events or unanticipated problems.

Report within 10 working days of the researcher becoming aware of the event.
8

Protocol Violations

Report within 5 working days of the researcher becoming aware of the event.
9

Any change to the IRB-approved protocol conducted without prior IRB approval to eliminate an apparent immediate hazard to a research subject.

Report within 5 working days of the researcher becoming aware of the event.
10

Any publication in the literature, any safety monitoring reports, interim results, or other reports that indicates an unexpected change to the risk/benefit profile of the research.

Report within 10 working days of the researcher becoming aware of the event.
11

Any breach in confidentiality that caused harm or places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm), such as a data breach*.

Report within 10 working days of the researcher becoming aware of the event.
12

Any complaint by a subject that indicates an unexpected risk or which cannot be resolved by the UCI Investigator.

Report within 10 working days of the researcher becoming aware of the event.
13

Other event/problem that involved subjects or others and which in the opinion of the UCI Investigator includes the following three components:

  1. Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the IRB-approved documents, such as the protocol and informed consent document; and (b) the characteristics of the subject population being studied;
  2. 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
  3. 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.

Report within 5 working days of the researcher becoming aware of the event.

The IRB will accept other reports when Investigators are unsure whether the event/problem should be reported.

NOTE:

  1. When changes to the IRB-approved documents (e.g., protocol narrative, informed consent form) are necessary, the Researcher must submit an electronic Modification (e-MOD) Request. Please reference the e-AE/UP number when submitting the e-MOD request.
  2. Reasonable judgment must be used when determining what constitutes a reportable event, experience, or problem. Researchers must consider the psychological, emotional, economic and social harms, not merely physical harms. When in doubt, it is best to err on the side of reporting the event or contacting the HRP staff for guidance.
  3. A follow-up report is required to be submitted via the e-AE/UP process if the AE is not resolved as expected or if the AE results in a chronic condition or death.

* A data security breach (e.g., a stolen laptop or misplaced thumb drive) constitutes an unanticipated problem and must be reported to the IRB via the e-AE/UP within 10 working days. It is also recommended that you contact the NACS Response Center at (949) 824-2222 to report that a potential security breach has occurred and request immediate notification of the NACS security staff and the Security Breach Lead Campus Authorities. Send additional information via email to security@uci.edu with a copy to security-lca@uci.edu.

Adverse Events

Adverse events are untoward or undesirable experiences associated with research, 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.

Adverse events may be the result of:

Most adverse events are not reportable to the IRB. The majority of adverse events that occur in the context of research are expected: (1) the known toxicities and side effects of the research procedures; (2) the expected natural progression of the subjects’ underlying diseases, disorders, and conditions; and (3) subjects’ predisposing risk factor profiles for adverse events.

UNEXPECTED ADVERSE EVENT: Any adverse event occurring in one or more subjects in a research protocol, the nature, severity, or frequency of which is not consistent with either:

  • the known or foreseeable risk of adverse events associated with the procedures involved in the research that are described in (a) the IRB-approved documents (e.g., applicable investigator brochure, current protocol narrative, current informed consent document), and (b) other relevant sources of information, such as product labeling and package inserts; or
  • the expected natural progression of any underlying disease, disorder, or condition of the subject(s) experiencing the adverse event and the subject’s predisposing risk factor profile for the adverse event.

Unexpected adverse events as defined above are reportable to the IRB via the e-AE/UP process if in the opinion of the UCI Researcher, the event is related to the research procedures. That is, if the event could at least possibly be caused by the research activities, and suggests that the research places the subjects at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized. See the List of Reportable Events/Problems.

SERIOUS ADVERSE EVENT: is any adverse event temporally associated with the subject’s participation in research that meets any of the following criteria:

  • results in death, #
  • is life-threatening situation,
  • requires inpatient hospitalization or prolongation of existing hospitalization,
  • results in persistent or significant disability/incapacity,
  • results in a congenital anomaly/birth defect,
  • any other adverse events based upon the Researcher’s medical judgment, that may jeopardize the subject’s health and may require medical or surgical intervention to prevent one of the other outcomes listed in this definition.

Serious adverse events as defined above are reportable to the IRB via the e-AE/UP process if in the opinion of the UCI Researcher, the event is “unexpected” and “related” to the research procedures. See the list of Reportable Events/Problems. Note the following exception:

# Clinical Investigations exception: All internal, serious adverse events resulting in death that, in the judgment of the UCI Investigator, appear unrelated to the research procedures must still be reported to the IRB via the Internal Unrelated SAE Summary Log at the time of Continuing Review.

Protocol Violations

PROTOCOL VIOLATION: Accidental or unintentional change to, or non-compliance with the IRB approved protocol without prior sponsor and IRB approval. Violations generally increase risk or decrease benefit, affects the subject's rights, safety, or welfare, or the integrity of the data.

Protocol Violations are reportable events and must be submitted to the IRB via the e-AE/UP reporting process within 5 working days of the researcher becoming aware of the event. See the list of Reportable Events/Problems.

Examples of protocol violations:

  1. Failure to obtain valid informed consent (e.g., obtained verbal consent when IRB requires signed informed consent)
  2. Loss of laptop computer that contained identifiable, private information about subjects
  3. Accidental distribution of incorrect study medication

Protocol Deviations

PROTOCOL DEVIATION: Accidental or unintentional changes to, or non-compliance with the research protocol that does not increase risk or decrease benefit or; does not have a significant effect on the subject's rights, safety or welfare; and/or on the integrity of the data. Deviations may result from the action of the subject, researcher, or research staff.

A deviation may be due to the research subject’s non-adherence, or an unintentional change to or non-compliance with the research protocol on the part of a researcher. Examples of a deviation include:

  1. A rescheduled study visit
  2. Failure to collect an ancillary self-report questionnaire
  3. Subject’s refusal to complete scheduled research activities

Deviations are NOT reportable to the IRB. Investigators may report deviations to the Human Research Protection (HRP) staff by submitting the Tracking Log for Non-reportable Events. The HRP staff will confirm that the event does not qualify as a reportable event and send an acknowledgment to the researcher. If the event/problem is determined to be reportable, the Lead Researcher will be required to submit an e-AE/UP report.

It is the responsibility of the Lead Researcher to ensure that all research staff involved in the conduct of the research follows the IRB-approved research protocol. When modifications are necessary, an e-MOD request should be submitted to the IRB for review and approval prior to implementation of the changes.

Safety Reports/External Adverse Events

Safety Report (SR) alerts are issued by the FDA or the study sponsor to inform all researchers using the same pharmacological compound about serious adverse events or reactions that have occurred in patients/subjects. These events, considered external adverse events, may occur on the same clinical investigation being conducted by a UCI investigator, or more often these SR events occur on different clinical investigation using the same pharmacological compound as the UCI investigator.

It is the UCI Investigator’s responsibility to ensure that each external adverse event is reviewed to determine whether the event is reportable to the IRB. External adverse events should be submitted to the IRB within the 10 working day timeframe if in the opinion of the UCI researcher the event is: [See 1 and 3 on the List of Reportable Events or Problems]

OR the event:

Safety Reports that do not meet the 10 working day reporting timeframe are NOT reportable to the IRB. The researcher should initial and date the Safety Report and file with research documentation.

Reporting Methods and Timeframes

The following are types of events/problems require reporting to the IRB. If the event/problem does not fit the categories, the event is not reportable to the IRB; however may be reportable to the sponsor. Please notify the IRB within the specified reporting timeframe, followed by follow-up reports, as required.

Type of Event/Problem Reporting Timeframe Reporting Method

Any

  • internal, serious adverse event,
  • protocol violation,
  • change to the protocol without prior IRB approval to eliminate an apparent immediate hazard to a research subject [see # 9]
  • other event/problem involving subjects or others tht is unexpected, related or possibly related to the research, and caused harm to others or places others at a greater risk of harm as a result of the research [see # 13]

5 working days

e-AE/UP report

Any other event/problem described in the list of Reportable Events/ Problems

10 working days

e-AE/UP report

Any external adverse event described in the list of Reportable Events/ Problems (e.g., Safety Report)
  1. 10 working days if event constitutes a reportable event [see # 1 and 3 on the list]
  2. If not on list, reporting NOT required
  1. e-AE/UP report
  2. none

Any protocol deviation
  1. Reporting NOT required
  2. Researchers may report deviation to HRP staff
  1. none
  2. Tracking Log for Non-reportable Events

Any internal, unrelated death as determined by UCI Investigator
[REQUIRED FOR CLINICAL INVESTIGATIONS ONLY]

At time of Continuing Review

Internal Unrelated
SAE Summary Log

Important Notes when completing e-AE/UP report:

  1. In order to maintain the subject's privacy, please do not include any names and/or other personal identifiers in the report and remember to remove all identifiable, private information from any supporting documentation you provide the IRB.
  2. If the event/problem requires submission of an e-MOD request, please remember to submit a highlighted or underlined version of the revised document(s).
  3. If an internal event/problem is unresolved at the time of initial reporting, a follow-up report is required to be submitted via the e-AE/UP process if the AE is not resolved as expected or if the AE results in a chronic condition or death.

Reporting DSMB Interim Reports to the IRB

The Lead Researcher is expected to review any Data and Safety Monitoring interim report and determine whether the report indicates a change in the risk/benefit profile. If the report indicates a change in the risk/benefit profile, an e-AE/UP report should be submitted [see #10 on the list of Reportable Events/Problems] to the IRB along with an e-MOD request. Be sure to reference the e-AE/UP number when submitting the e-MOD request. If there is no change in the risk/benefit profile, the DSMB report should be submitted along with the Summary Log, if applicable, at the time of continuing review.

IRB Actions Regarding Unanticipated Problems Involving Risk to Participants or Others

The IRB will review e-AE/UP reports in a timely manner and determine whether the reported event constitutes an unanticipated problem involving risk to participants or others. The IRB will consider a range of possible actions:

The IRB will report any unanticipated problems involving risk to participants or others to the Lead Researcher, appropriate UCI officials, the funding agency or study sponsor, if applicable, the Office for Human Research Protections, and other applicable regulatory authorities.

IRB Authority to Suspend or Terminate Approval

The IRB also has the authority to suspend or terminate approval of research that has been associated with unexpected serious harm to participants. When an IRB Committee takes such action, it is required to provide a statement of reason for the action and to promptly report this action to the Lead Researcher, Department Chair or School Dean, and other UCI officials, the funding agency or study sponsor, if applicable, the Office of Human Research Protections, and possibly other regulatory authorities.

Serious Adverse Event Reporting Requirements for Human Gene Transfer Research

Lead Researchers of human gene transfer (a.k.a. "gene therapy") protocols have extra adverse event reporting responsibilities. In addition to submitting AE/UP reports to the UCI IRB, they also must complete and submit the NIH Office of Biotechnology Activities' (OBA) Serious Adverse Event report form when a subject on a gene transfer protocol experiences a hospitalization or a death. If the gene transfer study is supported by an external sponsor, this reporting should be coordinated with the sponsor.

Failure to report gene transfer SAEs to the federal oversight bodies (FDA, NIH-OBA) may result in sanctions for the individual researcher and for the institution. For more information regarding the additional AE reporting responsibilities for human gene transfer research, please contact a UCI biomedical IRB Administrator.

Serious Adverse Events or Unanticipated Problems Involving Risk to Participants or Others Related to a Humanitarian Use Device (HUD)

Whenever the physician or health care provider receives or otherwise becomes aware of information, from any source, that reasonably suggests that a HUD has or may have caused or contributed to the death or serious injury of a patient, the physician or health care provider must report such findings to the FDA and the IRB as soon as possible, but no later than 5 working days after the physician first learns of the event/problem. This reporting is in addition to, not a substitute for, FDA and/or manufacturer reporting requirements in accordance with 21 CFR 803.30.

The physician or health care provider must promptly report any FDA action regarding the death or serious injury to the patient to the IRB.