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THE COMMITTEE ON HUMAN RESEARCH

UCSF GUIDANCE ON RESEARCH TOPICS AND ISSUES

REPORTING VIOLATIONS AND INCIDENTS IN RESEARCH PROTOCOLS (Revised June 2006)

Brief Overview

•	Federal regulations for the protection of human participants in research require that changes in the conduct of a CHR-approved research protocol receive prior CHR review and approval.
•	When changes to the protocol are necessary to immediately protect the safety of research participants or others, those changes may be initiated without prior CHR approval. However, those changes must be reported to the CHR/HRPP within 5 working days of initiation.
•	Changes in the conduct of a CHR-approved research protocol that are under the investigator’s control and made without prior CHR approval, are considered to be protocol violations. All major study-related violations must be reported to the CHR/HRPP.
•	Incidents are any problematic or unanticipated events that are not protocol violations and that may adversely impact on the study participants or the conduct of the study. All major study-related incidents must be reported to the CHR/HRPP.
•	The CHR reviews reports to determine whether an event meets the definition of an Unanticipated Problem involving risk to participants or others (UP) and/or an instance of Serious or Continuing Noncompliance (SCNC). The CHR/HRPP is required to report all UPs and instances of SCNC to the DHHS Office for Human Research Protection (OHRP), appropriate University officials, study sponsors, and to the FDA for studies under FDA regulatory oversight. Some reports of protocol Violations or Incidents may meet the HRPP institutional definitions of an UP and/or SCNC. 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.

At the time of submission of a continuing renewal application (i.e., a renewal submission or a major modification), investigators are required to complete the appropriate section of the Status Report for Renewal Application to briefly summarize all protocol violations and incidents that occurred since the last continuing renewal.

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Protocol Violations

Protocol violations are any unapproved changes, deviations or departures from the study design or procedures of a research project that are under the investigator’s control and that have not been reviewed and approved by the CHR. Protocol violations are divided into two categories: major (reportable) or minor (non-reportable) violations.

Major (reportable) Protocol Violations
Major protocol violations are any unapproved changes in the research study design and/or procedures that are within the investigator’s control and not in accordance with the CHR-approved protocol that may affect the participant's rights, safety or well-being, or the completeness, accuracy and reliability of the study data. All major violations must be reported to the CHR/HRPP. HRPP criteria for defining major violations include any of the following:

• The violation has harmed, or posed a significant or substantive risk of harm, to the research participant.
• The violation resulted in a change to the participant’s clinical or emotional condition or status.
• The violation has damaged the scientific completeness or soundness of the data collected for the study.
• The violation is evidence of willful or knowing misconduct on the part of the investigator(s).
• The violation involves serious or continuing noncompliance with federal, state or local regulations.

Examples of major protocol violations include, but are not limited to: 1) Enrollment of participants who did not meet the eligibility requirements 2) Failure to obtain informed consent prior to any study-specific tests/procedures 3) Failure to follow protocol procedures that specifically relate to the primary safety or efficacy endpoints of the study.

Minor (non-reportable) Protocol Violations (also known as Protocol Deviations)
Minor protocol violations are any unapproved changes in the research study design and/or procedures that are within the investigator’s control and not in accordance with the CHR-approved protocol that do not have a major impact on either the participant’s rights, safety or well-being, or the completeness, accuracy and reliability of the study data. Minor protocol violations are not reportable to the CHR/HRPP, but should be documented in the study files. HRPP criteria for minor violations include all of the following:

• The violation did not harm or pose a significant risk of substantive harm to the research participant, and
• The violation did not result in a change to the participant’s clinical or emotional condition or status, and
• The violation did not damage the completeness, accuracy and reliability of the data collected for the study, and
• The violation did not result from willful or knowing misconduct on the part of the investigator(s).

Examples of minor protocol violations include, but are not limited to: 1) Routine safety lab work for a participant without new clinical concerns and a history of previously normal lab values is inadvertently omitted at a study visit or performed outside the protocol-defined window. The lab will be performed at the next opportunity and is expected to remain within normal limits. 2) Investigators miss giving a study required self-administered quality of life questionnaire to a participant.

What are not considered to be protocol violations?
Changes, deviations or departures from the study design or procedures that are due to a study participant’s non-adherence are not considered to be protocol violations. However, study participant non-adherence to the study design and/or procedures should be documented in the research records and should be reported to the CHR/HRPP as an incident if the event adversely impacts the study participant’s safety or well-being, or if a pattern of protocol departures indicate a need for changes in the protocol or informed consent document(s).

Examples: 1) Study participant did not return for a scheduled study visit. 2) Participant refused a blood draw.

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What Is a Protocol Enrollment Exception?

To allow enrollment of a single individual who does not meet entry criteria of a CHR-approved protocol, the Principal Investigator may submit a written request for a one-time enrollment exception as a protocol modification request to the CHR. Obtaining prior approval for an enrollment exception modification avoids a protocol violation. An enrollment exception request applies only to a single individual. Such a request should be rare and justified in terms of serving the best interests of the potential study participant. The enrollment exception request will be referred to the appropriate Chair who will evaluate the level of CHR review required.

When the CHR approves an enrollment exception, data should be collected using the standard case report forms and reported in the scientific evaluation of the study.

IMPORTANT NOTES:
• Prior CHR approval is required before a one-time one-individual exception to the enrollment criteria of an approved protocol can be made.
• An enrollment exception usually requires the additional approval of the study sponsor.
• If use of this option is being considered, researchers should call the CHR office at 476-1814 and ask to speak with a committee analyst responsible for modifications in order to expedite the request and to make sure the paperwork is in order.

Example: A potential study participant meets all study entry criteria with the exception that inclusion criteria specify that participants must have an MRI within 14 days prior to enrollment; however a potential participant’s most recent MRI is 18 days prior to enrollment. A one-time modification may be granted because the change does not significantly affect the welfare of the participant or the protocol design.

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Incidents

What is a Major (reportable) Incident?
A major study-related incident is any problematic or unanticipated event involving the conduct of the study or participant participation that may occur during the course of the research project. Major Incidents are reportable to the HRPP.

One type of particularly significant reportable incident involves the situation when changes to the protocol are necessary to eliminate or reduce an apparent immediate hazard to the safety of research participants or others. Such changes must be reported to the CHR within 5 working days of initiating the changes in the study procedures.

Important note: With one exception, regulations require prior CHR approval for proposed changes in the ongoing conduct of research studies, even though the changes may be sponsor-initiated or sponsor-approved modifications. The one exception is when changes to the protocol are necessary to eliminate or reduce an apparent immediate hazard to the safety of research participants. Under this one exception, regulations allow changes to be initiated without prior CHR approval. However, please note that such changes must be reported to the CHR/HRPP as an incident within 5 working days of initiating the changes in the study procedure(s). The incident report should consider whether an appropriate modification to the study application/protocol and/or consent document(s) is necessary.

An example of a change to the protocol that is necessary to eliminate or reduce an apparent immediate hazard to the safety of research participants is the immediate dose reduction or discontinuation of a study treatment based on new toxicity information from an interim Data Safety Monitoring Board (DSMB) review or a study sponsor report. In this case, a change in the approved study drug dose may be implemented immediately, with subsequent submission of a corresponding modification application.

 

Other examples of study-related incidents include, but are not limited to: 1) Receipt of a complaint or concern from a potential or enrolled study participant that involves risk of harm to participants or others 2) Inappropriate behavior of study participants and/or research personnel 3) Problems encountered during study recruitment or the informed consent process 4) Problems with the study design in which a majority of participants have difficulty adhering to the study schedule of procedures 5) Potential breach of study participant’s privacy or confidentiality 6) Withdrawal or significant reduction in, resources necessary to adequately and safely conduct study activities.

IMPORTANT NOTES:
• Investigators are obligated to make a good faith effort to resolve any study-related concern or complaint they receive. Any significant complaint/concern must also be reported to the HRPP as a study-related incident.
• Any unanticipated problem involving potential risk to participants or others must be reported to the CHR.

What is a Minor (non-reportable) Incident?
A minor study-related incident is any event involving the conduct of the study or participant participation that may occur during the course of the research project but which is not problematic or involve significant potential to harm the participant(s) or others. Minor incidents are not reportable to the CHR/HRPP.

An example of a minor incident is receipt, and subsequent resolution by the study team, of a participant complaint regarding overdue study payment.

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CHR/HRPP Review of Violation and Incident Reports

Upon receipt of a Violation or Incident 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 Violation or Incident report (or other related 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 and/or an instance of Serious or Continuing Noncompliance
• 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 is an UP or (after investigation) determines an instance of Serious or Continuing Noncompliance
• Flag the report and monitor the study for additional Violation or Incident reports
• 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 and/or serious or continuing noncompliance.
  

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

Summary of All CHR/HRPP Post-Approval Reporting Requirements

For a summary of when and how to report all events and information that meet HRPP reporting requirements, please see HRPP Post-Approval Reporting Requirements. In addition to information on reporting Violations and Incidents, this summary includes information on reporting:

• Internal and External Adverse Events
• Other Types of Events or Information, including:
  • Audits and Monitoring Reports
  • DSMB/DMC Reports
  • Other Safety Information or Publications
  • Updated Investigator Brochures
  • Holds on Study Activities