HRPP policies & procedures manual

408: Adverse events and unanticipated problems involving risks to subject or others

1. Purpose

This policy establishes the process to determine which unanticipated problems involve risks to subjects and others.

2. Policy

2.1 Definitions:

Unanticipated problems involving risks to subjects or others: Unanticipated problems indicating that the subjects or others are at increased risk of harm.

Risks: The occurrence of harm or the probability that harm or an increased risk of harm might occur. The harm may be physical, psychological, financial, social, economic, or legal.

Others: Individuals who are not research subjects.

2.2 Investigator’s responsibility

Investigators must report to the IRB as soon as possible, but in all cases within seven (7) working days after the event had been made known to the investigator, any of the following:

  1. Adverse events which, in the opinion of the investigator, are serious, unexpected and related:
    • An adverse event is “unexpected” when its specificity and severity are not accurately reflected in the informed consent document or study protocol.
    • An adverse event is “related to the research procedures” if, in the opinion of the investigator, it was more likely than not to be caused by the research procedures or if it is more likely than not that the event affects the rights and welfare of current subjects.
  2. Serious adverse event
    • Event that results in death, a life-threatening experience, inpatient hospitalization, prolongation of hospitalization, persistent or significant disability or incapacity, congenital anomaly, or birth defect
  3. Serious problem that results in:
    • Substantive harm or damage (or risk of substantive harm or damage)to the safety, rights, or welfare of research subjects, research staff, or others, or
    • An adverse event or problem in the research is also considered serious when medical, surgical, behavioral, social, or other intervention is needed to prevent above #2.
  4. Information that indicates a change to the risks or potential benefits of the research; for example:
    • An interim analysis indicates that the subjects have a lower rate of response to treatment than initially expected.
    • Safety monitoring indicates that a particular side effect is more severe or more frequent than initially expected.
    • A paper is published from another study that shows that an arm of the research study is of no therapeutic value.
  5. A breach of confidentiality
  6. Change in FDA labeling or withdrawal from marketing of a drug, device, or biologic used in a research protocol
  7. Change to the protocol taken without prior IRB review to eliminate an apparent immediate hazard to a research subject
  8. Incarceration of a subject in a protocol not approved to enroll prisoners
  9. Event that requires prompt reporting to the sponsor
  10. Complaint from a subject when the complaint indicates unexpected risk or cannot be resolved by the research team
  11. Protocol violation (which an accidental or unintentional change to the IRB- approved protocol) caused harm to subjects or others or indicates that the subjects or others are at an increased risk of harm
  12. Sponsor-imposed suspension for risk
  13. 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)

The investigator must complete the adverse event form and attach any associated documents such as MedWatch form, medical record notations, and correspondence from the sponsor, etc.

The investigator is responsible for the documentation, investigation and follow-up of unanticipated problems that occur at the site in which the investigator is responsible for the conduct of the research.

2.3 Review of the event or problem

The ORA director will review the event or problem within 5 days of receiving the event or problem. If appropriate to the event or problem, the chair and/or institutional official (IO) will also review. One of the following determinations will be made.

  1. The event is NOT an unanticipated problem involving risk to subjects or others (because the event is either anticipated or does not indicate that the subjects are at increased risk of harm).

Take no action, document review, and put on IRB agenda for reporting purposes.


  1. The event or problem is considered an unanticipated problem involving risks to subjects or others because the problem (1) is unanticipated and (2) indicated that the subjects are at increased risk of harm.

The ORA director, IRB chair and/or IO may determine that immediate action is needed to ensure the subjects’ safety and request that the investigator suspend some or all of the research pending review of the event at the next convened IRB meeting. Suspensions will follow IRB procedures for suspension and termination.

Actions that may be taken during or after the investigation of an adverse event or unanticipated problem
  • Modification of the research protocol
  • Modification of the information disclosed during the consent process
  • Additional information provided to past subjects
  • Notification of current subjects (required when such information may relate to subjects’ willingness to continue to take part in the research)
  • Requirement that current subjects re-consent to participation
  • Modification of the continuing review schedule
  • Modification of the inclusion/exclusion criteria
  • Monitoring of the research
  • Implementation of additional procedures to monitor the subjects
  • Monitoring of the consent
  • Suspension of the research
  • Termination of the research
  • Request for more information pending final decision
  • Refer to other organizational entities (e.g., legal counsel, institutional official), or
  • Other actions appropriate for the local content

The determination will be reported in the minutes and the investigator will be notified.

2.4 Notification

No action required:  If the event is determined not be an unanticipated problem involving risks to subjects or others, no action will be required.

The investigator will be notified within five (5) business days of the ORA director’s, IRB chair’s and/or IO’s determination and action(s). If the event is determined to be an unanticipated problem involving risks to subjects or others, the event will be reported to the appropriate individuals. A copy of this report will also be disseminated to the IRB members at the next convened IRB meeting.

3. Research sponsored by the Department of Energy

When following DOE regulations and guidance: Researchers must promptly (within 2 working business days) report the following to the ORA director of human subjects protection:

  • Any significant adverse events, unanticipated risk, and complaints about the research, with a description of any corrective actions taken or to be taken
  • Any suspension or termination of IRB approval of research
  • Any significant non-compliance with HRPP procedures or other requirements
  • The timeframe for “promptly” is defined as within 48 hours

Any compromise of personally identifiable information must be reported immediately (within one working business day).

4. Applicable regulations and guidelines

45 CFR 46.103(b) (5)(i)

21 CFR 56.108(b)(1)

21 CFR 312.32

21 CFR 812.3(s)

5. Forms

Adverse event report

6. Procedures employed to implement this policy & assignment of responsibility

Who Task
ORA director, IRB chairReview all reports of serious adverse events & unanticipated problems involving risks to subjects or others and immediately triage as appropriate. Determine if the event is (1) serious, (2) unanticipated and (3) related; within 5 days of receipt.

If applicable, present the facts to the IRB at a convened IRB meeting
IOIf reportable, notify within 15 business days all appropriate individuals and agencies.