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THE COMMITTEE ON HUMAN RESEARCH

UCSF GUIDANCE ON RESEARCH TOPICS AND ISSUES

ADVERSE EVENT REPORTING (Revised June 2006)

•	Brief Overview
•	What, When and How to Report to the CHR/HRPP
•	What Not to Report to the CHR/HRPP
•	Explanations of Various Types of Adverse Events
•	Determining Cause
•	CHR/HRPP Review of Adverse Event Reports
•	Investigator Roles and Responsibilities
•	Special Adverse Event Reporting Requirements
•	Research Activities Not Involving Drugs, Biologics, Procedures Or Devices
•	Summary of All CHR/HRPP Post-Approval Reporting Requirements

Brief Overview

Under federal regulations for the protection of human subjects in research, investigators have an obligation to report certain adverse events (AE) occurring in research subjects. The Department of Health and Human Services regulations (45 CFR 46.103(b)(5)) require institutions to have “written procedures for ensuring the prompt reporting to the Institutional Review Board, appropriate institutional officials, and federal departments or agencies, any unanticipated problems involving risks to human subjects or others.”* Although the requirements are similar but not identical, the Food and Drug Administration (FDA), study sponsors and institutional policy also include requirements for reporting events that may affect the safety of human research subjects.

The UCSF Committee on Human Research (CHR) reviews reports of AEs submitted by the Principal Investigators to determine:

• if the risk-benefit ratio continues to be acceptable
• if the research protocol and informed consent document accurately and completely present risk information to research subjects
• whether subjects already enrolled should be advised of newly identified risks
  

In addition, the CHR reviews reports to determine whether an event meets the definition of an Unanticipated Problem involving risk to participants or others (UP). The CHR/HRPP is required to report all UPs to the DHHS Office for Human Research Protection (OHRP), appropriate University and affiliate officials, study sponsors, and to the FDA for studies under FDA regulatory oversight. Some reports of Adverse Events or other safety information may meet the HRPP institutional definition of an UP. When this appears to be the case, the CHR may query you for additional information. The CHR will inform you if this determination is made.

What, When, and How to Report to the CHR/HRPP

Please use this chart to determine which adverse events, other events, and safety information updates need to be reported and how/when to submit the report. Please click here for a PDF version of the Post-Approval Reporting Requirements chart.

Notes on AE reporting:

• Whenever the Status Report for Renewal Application is submitted to the CHR (i.e., at the time of continuing review or a major modification), please complete the appropriate sections of the Status Report regarding reportable AEs and other safety information.
• Subject deaths occurring in non-interventional studies (i.e., surveys, interviews and observational-only studies) do not need to be reported.
• For reasons of confidentiality, subject names must not be included in any AE reports. Subject identifiers such as enrollment numbers should be used instead.
• If an internal (on-site) AE is noted as “unresolved” at the time of initial reporting, a follow-up report will be required if the AE does not resolve as expected, or if the AE results in a chronic condition or death.
• Investigators may have AE reporting requirements (e.g., to an industry sponsor, the FDA or the NIH) in addition to HRPP reporting requirements. It is the investigator’s responsibility to know and comply with these additional requirements.

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What Not to Report to the CHR/HRPP

Reports of AEs Clearly Not Related to Research: With one exception, individual reports of internal (on-site) AEs determined to be unrelated to research participation should not be reported to the HRPP. Instead, these events should be documented, referenced, and retained in the PI’s study files for follow-up. The one exception is unrelated internal (on-site) deaths in an interventional study, which should be documented in real-time on an AE Summary Log and reported to the CHR at the time of continuing review (study renewal or major modification).

Study Sponsor IND/IDE Safety Reports That Do Not Meet HRPP 10-Working-Day Reporting Criteria: Do not submit non-reportable Study Sponsor IND/IDE Safety Reports to the CHR unless they are summarized by the UCSF PI. If the study sponsor requires submitting this information to the CHR, use the information contained in these reports to prepare an AE Summary Log of these events to be submitted at the time of continuing review (i.e., study renewal or major modification).

Important Note: The actual Study Sponsor Safety Reports should be kept in your study files unless the AE meets the CHR 10-working-day reporting criteria, in which case the IND or IDE Safety Report should be included with submission of the HRPP’s External (off-site) AE Reporting Form.

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Explanations of Various Types of Adverse Events

Expected Adverse Event is 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 progression.

Unexpected Adverse Event – An adverse event is defined as being unexpected if the event exceeds the nature, severity, or frequency described in the current CHR 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, or
• Due to a deviation from the CHR approved study protocol

Serious Adverse Event (SAE) is 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, or
• 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 occurring in a gene therapy study,
• Event that changes the risk/benefit ratio of the study.

Internal (on-site) vs. External (off-site) Adverse Events
Internal (on-site) Adverse Events are

• AEs that occur in study participants who were enrolled through a UCSF or UCSF affiliated study site, or
• AEs that occur in a study under the direct supervision of a UCSF Principal Investigator (PI) and for which the CHR is the Institutional Review Board (IRB) of record.
  

External (off-site) Adverse Events are

• 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.

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Determining Cause

One of the most important components of AE reporting is determining the cause of the AE. 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).

Important note: 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.

The following definitions should be used to assess the AE relationship to study participation:

Definitely Related: 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.

Probably Related: 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.

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. If there is any uncertainty regarding AE causality then the event must be assessed as possibly related to research participation and reported to the CHR as indicated. Often, the cause of an unrelated AE is disease progression.

Important note: Information involving AEs determined to be unrelated to research participation must be retained in the investigator’s study files for followup, documentation and reference.

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CHR/HRPP Review of Adverse Event Reports

Upon receipt of the AE report an in-office CHR/HRPP review will be conducted. Possible subsequent actions may include:

• Note and place the report in the HRPP study file
• Request additional information
• Refer the AE report (or other safety information) to the CHR if it appears to meet the HRPP’s institutional definition of an Unanticipated Problem (UP) involving risk to participants or others
• Report event to OHRP, appropriate University officials and study sponsors and FDA (for studies under FDA oversight) if a full CHR 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.
  

Important Note: The CHR does not routinely provide a receipt for submitted reports.

Investigator Roles and Responsibilities

•	Develop A Safety Plan: As part of an initial CHR application, a research proposal 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 CHR, study sponsor (when applicable) and federal regulatory authorities (when applicable).
•	AE Recognition & Assessment: 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).
•	Investigators are required to:
	•	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 study application/protocol resulting from an AE, and submit to the CHR an appropriate modification for review and approval.
	•	When appropriate, ask subjects to sign an updated informed consent document describing new information.
•	Timely and Complete AE Reporting: Investigators are required by law to inform the CHR 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.
•	Data Safety Monitoring Board Reports (DSMB): It is the investigator’s responsibility to submit any independent DSMB report to the CHR when it becomes available as these events may require reassessment of the study protocol or consent documents. See HRPP Post-Approval Reporting Requirements for a summary of when and how to report DSMB reports.
•	Reassess Safety Plan As Needed: Prior to and at the time of continuing review it is the investigator’s responsibility to keep the CHR informed of any safety-related information or AEs that result in a change to the risk/benefit ratio described in the currently approved CHR application, even if these events did not occur at UCSF.

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Special Adverse Event Reporting Requirements

Human Gene Transfer Research

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 CHR, Biological Safety Committee (IBC) and NIH Office of Biotechnology Activities (OBA) (formerly the Office of Recombinant DNA Activities). 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 oba@od.nih.gov ; 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 CHR Adverse Event Report, should be submitted to the CHR and IBC.

Research Activities Not Involving Drugs, Biologics, Procedures Or Devices

Reasonable judgment must be used 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 CHR.

Summary of All CHR/HRPP Post-Approval Reporting Requirements

For a summary of what, when and how to report all events and information that meets HRPP reporting requirements, please see HRPP Post-Approval Reporting Requirements. In addition to information on reporting Adverse Event and other safety information, this summary includes information on reporting a:

• Major Violation
• Immediate Protocol Change to Protect Participant Safety
• Research-Related Incident, including
  • Problem with the Consent or Recruitment Process
  • Concern/Complain
  • Lapse in Approval
  • Loss of Adequate Resources
  • Breach of Confidentiality