Reporting Expectations for Reportable Events

A privacy violation (or breach) is, generally, an impermissible use or disclosure under the Privacy Rule that compromises the security or privacy of the protected health information such that the use or disclosure poses a significant risk of financial, reputational, or other harm to the affected individual. Certain exceptions may apply. The Office of Ethics, Integrity and Compliance has the ultimate authority to determine whether a breach has occurred, after it is reported and reviewed.

An information security violation is, generally, an impermissible use or disclosure under the Privacy or Security Rules that compromises the security of the protected health information such that the use or disclosure poses a significant risk of financial, reputational, or other harm to the affected individual. Certain exceptions may apply. The Office of Culture, Ethics, and Compliance, OHC, or the Office of Professionalism and Ethics has ultimate authority to determine whether a breach has occurred, after it is reported and reviewed.

NOTE: This term applies to Clinical Investigations and to in vitro bioavailability or bioequivalence studies in humans (including specimens) that are exempt from IND requirements.

An AE (see below) or an SAE may also meet the definition of an UP and  , as described below.

A Serious Adverse Event (SAE) is an adverse event (AE) that results in any of the following:

• Death meets the criteria of an SAE when the death is suspected to be attributable to an outcome of a research AE.
• Life-threatening experience. Meets the criteria of SAE if the research participant was at substantial risk of dying at the time of the AE, or the use or continued use of the device or other medical product might have resulted in the death of the participant.
• Initial hospitalization. Meets the criteria of SAE if the admission was the result of the AE. Emergency Department visits that do not result in admission to the hospital should be evaluated for one of the other serious outcomes (e.g., life-threatening, required intervention to prevent permanent impairment or damage; other serious medically important event).
• Prolongation of hospitalization. Meets the criteria of SAE if the hospitalization of the research participants was prolonged as a result of the AE.
• Persistent or significant disability or incapacity. Meets the criteria of SAE if the AE resulted in a substantial disruption of the research participant’s ability to conduct normal life functions, i.e., the AE resulted in a significant, persistent or permanent change, impairment, damage or disruption in the participant’s body function/structure, physical activities or quality of life.
• Congenital anomaly or birth defect. Meets the criteria of SAE when it is suspected that exposure to a medical product prior to conception or during pregnancy may have resulted in an adverse outcome in the child.

The need for medical, surgical, behavioral, social, or other intervention to prevent outcomes such as the above. Meets the criteria of SAE when it is believed that medical or surgical intervention was necessary to preclude permanent impairment of a body function, or prevent permanent damage to a body structure, due to the use of a medical product.

Non-compliance occurs when conducting human research in a manner that intentionally or unintentionally disregards or violates regulations, policies, or procedures governing human research.

Non-compliant actions may range from minor to serious, be unintentional or willful, and may occur only once or several times. Examples may include (but are not limited to):

• Protocol deviations
• Modifications to the research without IRB approval
• Non-Exempt human research conducted without prior IRB approval
• Research interventions conducted when participants have not provided their legally effective informed consent (unless this requirement was waived by the IRB)
• Failure to properly obtain informed consent by using an invalid or outdated consent form that does not contain all of the information that might affect an individual’s willingness to participate in the research
• Misadministration of and investigational drug or biologic
• Misuse of an investigational device
• Significant privacy or information security breaches such as accessing, obtaining, or reviewing PHI without proper approvals, and losing or misplacing files including PHI or failure to implement information security policies or technical safeguards for PHI
• Implementing more than minor protocol changes without IRB approval, except when necessary to eliminate apparent immediate hazards or to protect the life or physical well-being of the research participant
• Enrollment of an ineligible research participant into a clinical trial without prospective IRB approval and, if applicable, sponsor approval
• Failure to monitor the research participants for safety
• Failure to report a significant adverse event (SAE) or unanticipated problem involving risks to participants or others (UP), or
• Failure to obtain prospective IRB approval of a substantive change in the conduct of human research, except when necessary to eliminate apparent immediate hazards or to protect the life or physical well-being of the research participant.

In general, serious non-compliance is non- compliance that adversely affects the rights and welfare of the research participants. Such events may include, for example, an action or omission that substantively increases the risk of harm or causes adverse harm to a research participant or another individual;

• Substantively decreases the safety, rights or welfare of a research participants or another individual;
• Substantively decreases potential benefits to a research participant or another individual;
• Substantively adversely alters the risk/benefit ratio of the research;
• Substantively compromises the integrity of the research;
• Substantively compromises the integrity or effectiveness of the USC Human Research Protections Program;
• Substantively adversely impacts ethical principles; or
• Meets other criteria, provided by OHRP, FDA, the Funding Department/Agency, or the Sponsor.

In general, continuing non-compliance is a pattern of repeated non-compliance when an individual demonstrates inability, unwillingness, irresponsibility or a disregard for compliance with the regulations, USC HRPP and University policies, or the IRB requirements or determinations of research, particularly after an individual has received notice by the IRB that an action must be taken to correct a previous, similar, or related non-compliance concern.

In general, minor (non-serious) non-compliance is non-compliance that does not adversely affect the research participant’s rights or welfare. See also: protocol deviation. In general, examples may include, but are not limited to the following:

• Failure to obtain IRB approval of a minor protocol change;
• Unplanned deviation from the approved research protocol that does not affect the welfare of or pose potential risk to a single study participant;
• Over-enrollment of a small number of research participants in a study that is no greater than minimal risk;
• Failure to document informed consent with the signature of the investigator obtaining informed consent; or

Clinical staff accessing, obtaining, or reviewing any protected health information (PHI) for research purposes without first obtaining the appropriate research approvals, provided that 1) the activity did not involve any interventions or interactions with the individuals about whom the data pertains; 2) the records were only reviewed by healthcare personnel; and 3) the data remained secure.

*Must be reported to the full board if the event meets the requirements to be reported within 10 days.

In general, a protocol deviation is an unplanned excursion from the protocol that is not implemented or intended as a systematic change. A protocol deviation could be a limited prospective exception to the protocol (e.g., agreement between sponsor and investigator to enroll a single subject who does not meet all inclusion/exclusion criteria).

Examples:

• • An investigator fails to perform a test or examination as required by the protocol
  • A research participant fails to complete scheduled visits as required by the protocol

An Administrative Hold is a voluntary action by an investigator to stop temporarily or permanently some or all approved research activities. Administrative holds are not suspensions or terminations. Protocols on administrative hold remain open and require continuing review. An FDA clinical hold is an order issued by FDA to the sponsor of an IND application to delay a proposed clinical investigation or to suspend an ongoing investigation. All or some of the investigations conducted under an IND application may be placed on clinical hold.

An Enrollment Hold is an action by the IRB, sponsor, or PI, or senior leadership, which prohibits the enrollment of new research participants.

*Must be reported to the full board if the event meets the requirements to be reported within 5 days.

An unanticipated problem involving risks to participants or others (UP) in general is to include any incident, experience, or outcome that meets ALL of the following criteria:

• unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the research participants population being studied;
• 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
• suggests that the research places the research participants or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.

An UP generally will warrant consideration of substantive changes in the research protocol or informed consent process/document or other corrective actions in order to protect the safety, welfare, or rights of research participants or others. Examples of corrective actions or substantive changes that might need to be considered in response to an unanticipated problem include:

• changes to the research protocol initiated by the investigator prior to obtaining IRB approval to eliminate apparent immediate hazards to research participants;
• modification of inclusion or exclusion criteria to mitigate the newly identified risks;
• implementation of additional procedures for monitoring research participants;
• suspension of enrollment of new research participants;
• suspension of research procedures in currently enrolled research participants;
• modification of informed consent documents to include a description of newly recognized risks; and
• provision of additional information about newly recognized risks to previously enrolled research participants.
• For more information, see the OHRP guidance on Problems Involving Risks and Adverse Events.

An unexpected adverse event is defined as any adverse event in which the specificity or severity of which is not consistent with the current investigator brochure; or, if an investigator brochure is not required or available, the specificity or severity of which is not consistent with the risk information described in the general investigational plan or elsewhere in the current application.

For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the Investigator Brochure only referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the investigator brochure only listed cerebral vascular accidents.

Unexpected, as used in this definition, refers to an AE that has not been previously observed (e.g., included in the investigator brochure), rather than from the perspective of such experience not being anticipated from the pharmacological properties of the pharmaceutical product.

An unexpected adverse event is defined as any adverse event in which the specificity or severity of which is not consistent with the current investigator brochure; or, if an investigator brochure is not required or available, the specificity or severity of which is not consistent with the risk information described in the general investigational plan or elsewhere in the current application.

For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the Investigator Brochure only referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the investigator brochure only listed cerebral vascular accidents.

Unexpected, as used in this definition, refers to an AE that has not been previously observed (e.g., included in the investigator brochure), rather than from the perspective of such experience not being anticipated from the pharmacological properties of the pharmaceutical product.

See also SAE and UP.

An Unanticipated Adverse Device Effect is 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 research participants.

Committee Data and Safety Monitoring Board (DSMB) reports.

NOTE: This term applies to Clinical Investigations and to in vitro bioavailability or bioequivalence studies in humans (including specimens) that are exempt from IND requirements.

See also (Unanticipated) Serious Adverse Event (SAE), or Unexpected Adverse Event (UAE) for related information.

The FDA regulations use different terms for AEs, including “adverse device effect,” “adverse drug event,” “unanticipated problems” and “unanticipated adverse device effect”.

An adverse event (or AE) is any untoward physical or psychological occurrence in a research participant. An AE can be any unfavorable and unintended event including an abnormal laboratory finding, symptom, or disease associated with the research or the use of a medical investigational test article. An AE does not necessarily have to have a causal relationship with the research.