Adverse Event or Safety Information

OHRP defines Adverse Events as: 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.

UCSF requires submission of Adverse Events that qualify as: Any unexpected, physical, psychological or social research-related event which is definitely, probably or possibly related to the study; where the risk is not included, or exceeds the nature, severity, or frequency described in the protocol, study consent form, Investigator’s Brochure or other study information previously reviewed and approved by the IRB.

What, When and How to Report AEs

See the Post-Approval Reporting Requirements Summary Sheet for one-page summary of the information below.

Federal regulations from OHRP require the IRB to ensure that investigators promptly report "any unanticipated problems [UPs] involving risk to subjects or others." The FDA, study sponsors and institutional policy include similar, but not identical, reporting requirements. The IRB/HRPP reviews the reports and determines whether they meet the institutional definition of a UP, among other things.**

**UCSF is required by federal regulation to regularly and routinely report any unanticipated problems involving risks to subjects or others, or any serious or continuing noncompliance events that occur at UCSF as well as others in the institution as appropriate. Reports are submitted to the following agencies as applicable:

Agency

Regulatory Requirement

Applicability by

Study Status

Department of Health and Human Services’ Office of Human Research Protections (OHRP) 45 CFR 46.103(a) and (b)(5) Federally Funded or Federally Conducted Studies
The Food and Drug Administration (FDA)

21 CFR 6.108(b)(1),

21 CFR 312.53(c)(1)(vii),

21 CFR 312.66
Studies involving an Investigational Product (Drug, Device or Biologic)
Department of Defense Human Research Protection Office (DoD HRPO) 32 CFR 216 DODI 3216.02 Studies funded or conducted by the DoD

The Post-Approval Reporting Requirements chart below describes which adverse events (AEs), other events and safety information updates need to be reported to the IRB/HRPP and how/when to submit the report.

Contact the IRB at (415) 476-1814 or [email protected] and speak with the QIU Analyst of the day with questions. See the Protocol Violation or Incident page for info on reporting for these types of events.

Type of Event

When to Report*

Reporting Form

*The SF VA Medical Center (SFVAHCS) has has a shorter timeline and different definitions than UCSF for reporting certain categories of post-approval events. See the SFVAHCS guidance page and VHA Handbook 1058.01 for specific examples.

Adverse Events

Internal (on-site) adverse event that PI determines to be

  1. Definitelyprobably or possibly related AND
  2. Serious or unexpected

Within 5 working days of UCSF PI awareness

Internal, related deaths and life-threatening events: Report immediately

iRIS Adverse Event Reporting Form

External (off-site) adverse event that UCSF PI determines

  • changes the study risks or benefits, OR
  • necessitates modification to the IRB-approved consent document(s), and/or the IRB-approved application/protocol

Within 10 working days of UCSF PI awareness

iRIS Adverse Event Reporting Form

Other Types of Events or Safety Information

Audit or Monitoring Report with significant findings

DSMB/DMC Report

Hold on Study Activities due to unexpected risk or required by any oversight entity e.g. UCSF, FDA, OHRP

Updated Investigator Brochure

Within 10 working days of awareness iRIS Reporting Form

Other Safety Information or Publication

Pharmacy Packet Inserts

Change to risk language - within 10 working days of awareness

No change to risk language - reporting not required

iRIS Reporting Form

Reporting Reminders:

If an internal (on-site) AE is noted as “unresolved” at the time of initial reporting, a follow-up report is required if the AE does not resolve as expected, or if the AE results in a chronic condition or death.

Do not include subject names or other direct identifiers on the AE Reporting Form or attachments.

When submitting the Continuing Review Form, complete the sections regarding reportable AEs and other safety information.

Submitting in iRIS

Follow these steps to submit the report. For additional assistance, read the quick guide called "Submitting Post-approval Forms" in the Help section of iRIS.

Go to My Studies under the IRB Study Assistant. Open the active study for which you want to submit the report.

To determine when and which form to submit, review the guidance above. Click Add New Form to start a blank form. You can copy a previous form by selecting the form you want to copy and clicking Copy Form. The copied form will open automatical

Anyone listed on the study can sign off and submit it.

  • Open the first study again and click on the Adverse Event Reporting Form or Reporting Form link
  • Click the "Apply to Multiple" icon next to the correct form
  • Check the boxes next to the studies for which you wish to submit this form. Click the "Save a Copy of the Selected Form" button
  • You will then need to open each of the studies you selected, open the copied form and submit the form

 

Definitions and Types of AEs

OHRP defines Adverse Events as: 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.

UCSF requires submission of Adverse Events that qualify as: Any unexpected, physical, psychological or social research-related event which is definitely, probably or possibly related to the study; where the risk is not included, or exceeds the nature, severity, or frequency described in the protocol, study consent form, Investigator’s Brochure or other study information previously reviewed and approved by the IRB.

  • AEs that occur in study participants who were enrolled through a UCSF or UCSF affiliated study site
  • AEs that occur in a study under the direct supervision of a UCSF PI and for which the IRB of record
  • AEs that occur in study participants who are not enrolled at a UCSF or affiliated study site. These AEs occur at sites that are under the oversight of another IRB.
  • The PI typically receives notification of these events from the study sponsor and these AEs are usually referred to as Sponsor Safety Reports or Safety Memos
  • These reports should be submitted on the iRIS ‘Reporting Form’

An AE that may be reasonably anticipated to occur as a result of the study procedures or study participation and should thus be described in the research proposal, the informed consent document and Investigator’s Brochure (when applicable), or is part of the normal disease process or pro

An adverse event is defined as being unexpected if the event exceeds the nature, severity or frequency described in the current IRB Application including the protocol, consent form and investigator brochure (when applicable). An unexpected AE also includes any AE that meets any of the following criteria:

  • Results in subject withdrawal from study participation
  • Due to an overdose of study medication
  • Due to a deviation from the IRB approved study protocol

Any AE that results in any of the following outcomes:

  • Death,
  • Life-threatening adverse experience**
  • Inpatient hospitalization or prolongation of existing hospitalization
  • Persistent or significant disability/incapacity
  • Congenital anomaly/birth defect, or cancer
  • Any other experience that suggests a significant hazard, contraindication, side effect or precaution that may require medical or surgical intervention to prevent one of the outcomes listed above
  • Event that changes the risk/benefit ratio of the study

*If the IRB-approved protocol definition of SAE differs from the IRB definition of SAE presented here, the protocol-specific definition should be employed. 

** A life-threatening adverse experience is any AE that places the patient or 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.

    Any prospective, human research study that is designed to answer specific questions about the effects or impact of a particular biomedical or behavioral intervention, or are designed to answer specific questions about human physiology.

    Various entities — including the UCSF PI, the IRB/HRPP, a UCSF oversight entity such as the Cancer Center or CRS, the study sponsor, the SF VAMC, the FDA, etc. — may place a hold on study accrual or other study activity. A hold is sometimes also called a “suspension” or “pause."

    With one exception, any hold that is placed on study accrual or other activity is reportable to the IRB. The one exception occurs when the IRB Application and/or the sponsor’s protocol submitted to the IRB includes a planned hold on accrual/activity.

    For instance, the IRB-approved protocol may indicate that after accrual of n subjects, accrual will cease until a safety analysis can be completed, after which accrual may re-start unless a safety issue is discovered. Thus, a planned hold and subsequent resumption of study accrual/activity need not be reported to the IRB as it has already been approved by the IRB. However, if a planned hold yields new safety information or any other unanticipated problem, or necessitates a change to the consent form or IRB Application, then it should be reported to the IRB.

    See the VHA Handbook 1058.01 and SF VAMC guidance.

    Serious AE (SAE): An SAE is an AE in human research that results in death, a life-threatening experience, inpatient hospitalization, prolongation of hospitalization, persistent or significant disability or incapacity, congenital anomaly, or birth defect. An AE is also considered serious when medical, surgical, behavioral, social, or other intervention is needed to prevent such an outcome.

    Unanticipated (Unexpected): The terms “unanticipated” and “unexpected” refer to an event or problem in VA research that is new or greater than previously known in terms of nature, severity, or frequency, given the procedures described in protocol-related documents and the characteristics of the study population.

    Related AE or a Related Problem: A “related” AE or a “related” problem in VA research is an AE or problem that may reasonably be regarded as caused by, or probably caused by, the research (see 21 CFR 312.64).

    Determining Cause

    It is imperative that the investigator assess AE causality in terms of overall study participation and make an independent determination as to whether the AE was thought to be related to any study-related activity (i.e., study intervention, test article administration, study-related tests or procedures).

    Use the following definitions to assess the AE relationship to study participation:

    An AE is definitely related to study participation if it is clear that the event was caused by study participation. A definitely related event has a strong temporal relationship and an alternative cause is unlikely.

    An AE is probably related when 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.

    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.

    The cause of the AE is known and the event is in no way related to any aspect of 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. Often, the cause of an unrelated AE is disease progression.

    Important Reminders: 

    • An AE may be unrelated to the experimental intervention, but nevertheless related to study participation. 
      • ​Example: Study participation requires one or a series of IV drug infusions that would not otherwise be given as part of standard clinical care. A participant develops thrombophlebitis at the IV access site. This AE should be assessed as definitely related to research participation.
    • Keep information involving AEs determined to be unrelated to research participation in the study files for follow up, documentation and reference.

    What Not to Report to the IRB/HRPP

    Do not submit the following items to the IRB/HRPP. Keep them in your study files and comply with outside reporting requirements (if/when applicable).

    Do not submit non-reportable study sponsor IND/IDE safety reports to the IRB.

    Note: The actual study sponsor safety reports should be kept in your study files unless the AE meets the IRB 10-working-day reporting criteria, in which case the IND or IDE Safety Report should be included with submission of the Adverse Event Reporting Form.

    Individual reports of internal (on-site) AEs determined to be unrelated to research participation should not be reported to the IRB. Instead, these events should be documented, referenced and retained in the PI’s study files for follow-up. The IRB no longer accepts AE Summary Log reports of AEs that do not meet the IRB reporting criteria.

    IRB/HRPP Review of Adverse Event Reports

    The IRB/HRPP will review the AE report and determine if a) the risk-benefit ratio continues to be acceptable, b) the research protocol and informed consent document accurately and completely present risk information, c) current subjects should be advised of newly identified risks and d) the event meets the definition of an Unanticipated Problem involving risk to participants or others. 

    Track the report using the Submission History feature in iRIS. 

    Acknowledge the report — no letter is issued.

    Request additional information about the adverse event or other safety information.

    Refer the AE report (or other safety information) to the IRB if it appears to meet the institutional definition of an Unanticipated Problem (UP) involving risk to participants or others. The IRB may query you for additional information and will inform you if the UP determination is made.

    Report the event to OHRP, appropriate University officials, study sponsors and FDA (for studies under FDA oversight) if a full IRB panel review determines that the event report or safety information is an UP.

    Flag the report and monitor the study for additional AEs.

    Require a modification to the study protocol and/or informed consent document.

    Temporarily suspend enrollment and/or study treatment.

    Permanently suspend or terminate approval of research that has been associated with unexpected serious harm to participants.

    An unexpected, research-related event where the risk exceeds the nature, severity, or frequency described in the protocol, study consent form, Investigator’s Brochure or other study information previously reviewed and approved by the IRB.

    Investigator Roles and Responsibilities

    Your initial IRB Application must include a plan for safety monitoring, reporting of AEs and/or unanticipated problems involving risks to subjects, descriptions of interim safety reviews, and the procedures for communicating these results to the IRB, study sponsor (when applicable) and federal regulatory authorities (when applicable).

    Investigators are responsible for the accurate documentation, causality assessment and follow-up of all definite, probable and possible study related AEs and safety-related information (such as sponsor or DSMB updates and holds on study activities due to safety concerns).

    • Evaluate an AE’s impact on the risk/benefit ratio of the study
    • Evaluate whether new information may affect participants’ willingness to continue participation in the study, and if so, inform participants of new information according to a plan described to the HRPP
    • When appropriate make changes to the informed consent document and/or IRB Application/protocol resulting from an AE, and submit a modification to the IRB for review and approval
    • When appropriate, ask subjects to sign an updated informed consent document describing new information

    Investigators are required by law to inform the IRB and other entities (such as governmental or other sponsors) of any AE or other safety-related information in accordance with each entity’s regulations, policies and guidelines.

    It is the investigator’s responsibility to submit any independent DSMB report to the IRB when it becomes available, as these events may require reassessment of the study protocol or consent documents.

    Prior to and at the time of continuing review it is the investigator’s responsibility to keep the IRB informed of any safety-related information or AEs that result in a change to the risk/benefit ratio described in the currently approved IRB Application, even if these events did not occur at UCSF.

    Special AE Reporting Requirements

    Use reasonable judgment to determine what constitutes an AE. Such events do not have to be physical in nature. Attention must be paid to psychological, emotional, and social harm, and overall subject well-being. If in doubt, it is best to err on the side of reporting the event or contacting the IRB.

    In accordance with Appendix M-I-C-4 of the NIH Guidelines, investigators who have received authorization from the FDA to initiate a human gene transfer protocol must immediately report in writing any SAE to the IRB, Biological Safety Committee (IBC) and NIH Office of Biotechnology Activities (OBA). This should be followed by the submission of a written report to each group when additional pertinent information becomes available. Reports submitted to the NIH OBA may be sent by: email to [email protected]; by fax to (301) 496-9838; or by mail to the Office of Biotechnology Activities, National Institutes of Health, 6705 Rockledge Drive, Suite 750, MSC 7985, Bethesda, Maryland 20892-7985, Phone: (301) 496-9838.

    When submitting reports to the OBA, use either a copy of the OBA Adverse Event Reporting Form or another form that includes the required information on the event (as described in Appendix M). Completed copies of the form submitted to OBA, as well as the IRB Adverse Event Report, should be submitted to the IRB and IBC.

     

    Last updated: May 4, 2022