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HRPP Policy - Reportable Events
About This Policy
- Effective date:
- Last updated:
- Policy Contact:
IU Human Subjects Office
This policy applies to:
- The conduct of human subjects research under the oversight of the IU IRBs
- Clinicians under the oversight of the IU IRBs wishing to use a Humanitarian Use Device (HUD) for treatment or diagnosis, and the IU IRBs approving the use of the HUD
In accordance with federal regulations and the IU HRPP Policy on the IRB Review Process, the IRB must ensure the relationship of risks to benefits to subjects remains reasonable throughout the conduct of the study, subjects are provided with the information necessary to make an informed decision about participation or continuation in the study, and data is adequately monitored to ensure ongoing safety of subjects. To that end, investigators conducting human subjects research and clinicians using a HUD must report events which may represent unanticipated problems and/or serious and/or continuing noncompliance (i.e., reportable events) to the IRB.
The following reportable events may constitute unanticipated problems involving risks to subjects or others or serious and/or continuing noncompliance and must be reported to the IRB within five (5) business days of the study team becoming aware of the event, regardless of the level of review of the study (i.e., full Board, expedited, exempt) or the study status (i.e. Open to Enrollment, Closed by Investigator, etc.):
- Conduct of human subjects research without IRB approval, including:
- Conduct of research without submitting for IRB review
- Conduct of research prior to receiving IRB notification of final approval
- Initiation of substantive changes (i.e., changes that would affect the subjects' willingness to participate, such as changes to study procedures, risks and/or benefits) to the human subjects application and/or protocol without prior IRB approval, including changes necessary to eliminate apparent immediate hazards to the subject
- Inclusion of vulnerable subject populations without specific IRB approval
- Conduct of research when IRB approval has expired or been suspended or terminated
- Subject interactions or review of identifiable research data by individuals who have not completed appropriate investigator requirements (e.g., COI disclosure and CITI training)
- Adverse events (either locally or at an external site) assessed by the PI, or appropriately trained and qualified designee, as (1) unexpected, (2) related or possibly related to study participation, AND (3) suggesting that the research places subjects or others at greater risk of harm than was previously known
- Unanticipated adverse device effects
- Use of a HUD which caused or contributed to a death or serious injury (i.e., injury or illness that is life threatening, results in permanent impairment of a body function or permanent damage to a body structure, or necessitates medical or surgical intervention to preclude permanent impairment of a body function or permanent damage to a body structure)
- Major protocol deviations/protocol noncompliance that occurred and may, in the opinion of the PI, or appropriately trained and qualified designee, (1) impact subject safety and/or (2) affect the integrity of the data
- Consent and/or authorization issues, including:
- Failure to obtain consent and/or authorization from subjects, including obtaining consent from someone who cannot legally consent for the subject
- Failure to obtain the subject's signature on the informed consent and/or authorization (unless a waiver of documentation of consent has been granted) prior to the subject starting study procedures
- Enrolling subjects using a consent which does not include all known risks, or continuation of subject participation without notification of newly identified risks
- Other major deficiencies in the informed consent or HIPAA authorization process or documentation
- Minor deficiencies in the informed consent or HIPAA authorization process or documentation, occurring within a one-year period and affecting ten (10) or more subjects
- Subject complaints that indicate an unexpected risk and/or that affect the rights and welfare of human subjects
- Study suspensions or holds related to risk, safety, or compliance issues
- Incidents that may compromise information security, subject privacy, and/or confidentiality (i.e., subject data breach)
- Local audit reports (i.e., Quality Improvement Office audits, VA audits)
- Failure to submit amendments which update risks, benefits, or procedures within sixty (60) days of receipt, or promptly report events when required per IU HRPP Policies.
- Conduct of human subjects research without IRB approval, including:
In addition to section 2.1, the following reportable events must also be reported to the IRB within five (5) business days of the study team becoming aware of the event, regardless of the level of review of the study (i.e., full Board, expedited, exempt):
- Local research deaths which are unanticipated and related to the research must be reported verbally to the IRB immediately, followed by a written report
- Local serious adverse events (SAEs) which are unanticipated and related to the research
- Serious problems
- Apparent serious and/or continuing noncompliance
- Any suspension or termination of VA research by, or at the direction of, any entity external to the facility
Any other adverse events, SAEs, unanticipated problems involving risks to subjects or others, or apparent noncompliance must be reported to the IRB in accordance with Section 2.4.
In addition to section 2.1, the following reportable events must also be reported to the IRB within five (5) business days of the clinician becoming aware of the event:
- When use of a HUD caused or contributed to a death serious injury
The following reportable events do not meet the criteria for prompt reporting must be reported to the IRB at the time of renewal, if applicable:
- Protocol deviations that do not affect subject safety or data integrity
- Minor noncompliance
- Adverse events that were not promptly reported, occurred at a site under the oversight of the IU IRB, and occurred at a greater frequency and/or severity than was previously expected based on the protocol, informed consent document, and/or investigator's brochure
Noncompliance which is determined by Human Subjects Office (HSO) staff to be not apparent serious or continuing noncompliance must be reported at the time of next study renewal, if applicable.
Studies that do not require renewal, including studies in Clinical Follow-Up or Data Analysis Only, may report these events at the time of study closure.
Promptly reportable events are submitted via KC IRB. After submission, HSO staff verify whether the event represents a promptly reportable event pursuant to this policy. For items classified as noncompliance, the University Director, HRPP, a HSO Associate Director, or a HSO Senior Research Compliance Consultant will further review the item to determine if the report may constitute serious or continuing noncompliance. If the item is determined not to meet prompt reporting criteria or is determined to be not apparent serious or continuing noncompliance, HSO staff will communicate this to the study team and withdraw the item from further review. If staff determines that prompt reporting is appropriate, they submit the report to a convened IRB meeting for review and possible action.
The convened IRB reviews the report to determine whether the research protocol still satisfies the requirements for IRB approval under 45 CFR 46.111. In particular, the IRB considers whether risks to subjects are still minimized and reasonable in relation to the anticipated benefits, if any, to the subjects and the importance of the knowledge that may reasonably be expected to result.
The convened IRB determines whether the event is an unanticipated problem involving risks to subjects or others (UPIRTSO) and/or serious or continuing noncompliance.
- If the IRB determines that a report does represent a UPIRTSO or serious or continuing noncompliance, the determination is reported to appropriate institutional officials, regulatory agencies (e.g., OHRP, FDA), and others pursuant to the IU HRPP Policy on IRB Reporting.
- If the IRB determines that the report does not represent a UPIRTSO or serious or continuing noncompliance, no further reporting is required.
Local Research Deaths
- The IRB must alert the Office of Research Oversight (ORO) by email or telephone within 2 business days after receiving such notification and provide relevant information as requested. The VA facility Director and the ACOS/R&D must receive concurrent notification.
- Within 5 business days after receiving written notification of the death, the IRB Chair or a qualified IRB member-reviewer must determine and document whether any actions are warranted to eliminate apparent immediate hazards to subjects.
- The IRB must review the death and the determination of the IRB Chair or qualified IRB member-reviewer at its next convened meeting and must determine and document that:
- The death was both unanticipated and related to the research; or
- There is insufficient information to determine whether the death was both unanticipated and related to the research; or
- The death was not unanticipated and/or the death was not related to the research.
- Regardless of the determination under the above bullets, the convened IRB must also determine and document whether any protocol or informed consent modifications are warranted. If modifications are warranted, the convened IRB must determine and document whether or not research personnel must notify or solicit renewed/revised consent from previously enrolled subjects; and if so, when such notification or consent must take place and how it must be documented.
- The IRB must notify the VA facility Director and the ACOS/R&D of its determinations under the above bullets within 5 business days of the determinations.
- The VA facility Director must report the determinations to ORO within 5 business days after receiving the IRB’s notification.
IRB Review of Serious Adverse Events (SAEs) and Serious Problems
- Within five (5) business days after receiving written notification of a SAE or serious problem, the IRB Chair or a qualified IRB member-reviewer must determine and document whether any actions are warranted to eliminate apparent immediate hazards to subjects.
- The convened IRB must review the incident and the determination of the IRB Chair or qualified IRB member-reviewer at its next convened meeting and must determine and document that:
- The incident was serious and unanticipated and related to the research; or
- There is insufficient information to determine whether the incident was serious and unanticipated and related to the research; or
- The incident was not serious, and/or the incident was not unanticipated, and/or the incident was not related to the research.
- The convened IRB must also determine and document whether any protocol or informed consent modifications are warranted. If so, the convened IRB must determine and document whether or not research personnel must notify or solicit renewed/revised consent from previously enrolled subjects; and if so, when such notification or consent must take place and how it must be documented.
- The IRB must notify the VA facility Director and the ACOS/R&D in writing within 5 business days after its convened meeting if:
- Actions were taken to eliminate apparent immediate harm to subjects; or
- The IRB determined that the incident is serious and unanticipated and related to the research, or there was insufficient information to make the determination; or
- Protocol or informed consent modifications were warranted.
- The VA facility Director must report the situation to the ORO within 5 business days after receiving the IRB’s notification.
Apparent Serious and/or Continuing Noncompliance
- The convened IRB must review any report of apparent serious and/or continuing noncompliance at the next convened IRB-01 meeting, not to exceed 30 business days after the notification. The IRB Chair may take interim action as needed to eliminate apparent immediate hazards to subjects.
- The convened IRB must determine and document whether or not serious and/or continuing noncompliance actually occurred. If the IRB determines that serious and/or continuing noncompliance occurred:
- A documented IRB determination is also required as to whether remedial actions are needed to ensure present and/or future compliance.
- IRB must notify the VA facility Director and the ACOS/R&D within 5 business days after making its determinations.
- The VA facility Director must report the determination to ORO within 5 business days after receiving the IRB’s notifications.
- If the apparent serious or continuing noncompliance was identified by a Research Compliance Office (RCO) audit, the IRB must notify the RCO within 5 business days after its determination.
- The IRB must track the determinations for use in the VA facility Director Certification.
Individuals found to be in violation of this policy may be subject to sanctions relating to their participation in research with human subjects, up to and including permanent suspension or debarment from engaging in research with human subjects at Indiana University.Back to top
IU HRPP Guidance
Related Guidance Documents
- AAHRPP Standards
- Element 1.5.D
- Element II.2.D
- Element II.2.F
- 45 CFR 46, especially 46.108(b)(3) and 46.111
- 21 CFR 56, especially 56.108(b)
- FDA Guidance: Guidance for Clinical Investigators, Sponsors and IRBs: Adverse Event Reporting to IRBs Improving Human Subject Protection
- OHRP Guidance: Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events
- VHA Handbook 1058.01-Research Compliance Reporting Requirements
- VHA Handbook 1058.03-Assurance of Protection for Human Subjects Research
adverse event Any untoward or unfavorable occurrence, including medical, physical, and psychological harms, in a human subject associated with the subject's participation in the research, whether or not considered related to the subject's participation in the research.
audit (see also for-cause (directed) audit, internal audit, and not-for-cause (scheduled) audit) A systematic and independent examination of study-related activities and documents to determine whether the evaluated study-related activities were conducted, and the data were recorded, analyzed, and accurately reported, according to applicable federal regulations, state laws, and institutional policies. Includes audits, monitoring visits, and compliance inspections.
authorization Per the Privacy Rule, an individual's permission to allow a covered entity to use or disclose the individual's protected health information (PHI) described in the authorization for the purpose(s) and to the recipient(s) stated in the authorization.
confidentiality The assurance that certain information about individuals, which may include a subject's identity, health, behavior, or lifestyle information, or a sponsor's proprietary information, will not be disclosed without permission from the subject or sponsor.
continuing noncompliance (see also noncompliance, minor noncompliance, observed or apparent noncompliance, serious noncompliance) A pattern of the same or similar instances of noncompliance, occurring in reasonably close proximity, which continues to occur after discovery of noncompliance and implementation of a preventive action plan, or results from failure to implement a preventive action plan approved by the IRB.
device (medical device) As regulated by the FDA, an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is: 1) recognized in the National Formulary, or the United States Pharmacopeia, or any supplement to them; 2) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals; or 3) intended to affect the structure or any function of the body of man or other animals, and; which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes. See FDA Guidance for Industry and FDA Staff on Classification of Products as Drugs or Devices and Additional Product Classification Issues.
enrollment Enrollment begins at the time of consent for the study. For research for which consent is not required, enrollment begins at time of data collection or when the subject agrees to participate.
HIPAA The Health Insurance Portability and Accountability Act of 1996. See also Privacy Rule.
humanitarian use device (HUD) As regulated by the FDA, a medical device intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in fewer than 4,000 individuals in the United States per year.
informed consent An ongoing process by which a subject (or, his or her legal representative) voluntarily confirms his or her willingness to participate in a particular research project in accordance with the IU HRPP Policy on Informed Consent.
interaction Includes communication or interpersonal contact between research personnel and the subject.
life threatening Diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted, and diseases or conditions with potentially fatal outcomes, where the endpoint of the clinical trial analysis is survival. Also includes severely debilitating, meaning diseases or conditions that cause major irreversible morbidity (e.g., blindness, loss of arm, leg, hand, or foot).
major protocol deviation (see also protocol deviation) May affect subject safety and/or the integrity of study data.
minor noncompliance (see also noncompliance, continuing noncompliance, observed or apparent noncompliance, serious noncompliance) Noncompliance that is neither serious nor continuing and which does not affect the scientific soundness of the research plan or the rights, safety, or welfare of human subjects.
noncompliance (see also continuing noncompliance, minor noncompliance, observed or apparent noncompliance, serious noncompliance) Any action or activity associated with the conduct or oversight of research involving human subjects that fails to comply with federal or state regulations, requirements of VHA Handbook 1200.05, or institutional policies governing human subjects research or the requirements or determinations of the IRB.
observed or apparent noncompliance (VA; see also noncompliance, continuing noncompliance, minor noncompliance, serious noncompliance) Noncompliance that does not require further information to confirm its occurrence.
privacy Refers to persons and their interest in controlling the access of others to themselves.
protocol deviation (see also major protocol deviation) An alteration/modification to the IRB-approved protocol that is not approved by the IRB prior to its initiation or implementation.
regulatory agencies Government organizations, anywhere in the world, that set standards, establish policies, advocate laws, and provide oversight of specified activities within a country, such as the United States Food and Drug Administration (FDA).
related or possibly related There is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research.
reportable event An event which may represent noncompliance or an unanticipated problem involving risks to subjects or others. Reportable events are reported to the IRB in accordance with the IU HRPP Policy on Reportable Events.
research A systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge (Synonymous with clinical investigation For research subject to FDA regulations, any experiment that involves a test article and one or more human subjects, and that either must meet the requirements for prior submission to the FDA under §505(i), §507(d), or §520(g) of the Food, Drug & Cosmetic Act, or need not meet the requirements for prior submission to the FDA under these sections of the act, but the results of which are intended to be later submitted to, or held for inspection by, the FDA as part of an application for a research or marketing permit. The term does not include experiments that must meet the provisions of part 58 regarding nonclinical laboratory studies (21 CFR 50.3(c)).) The following activities are deemed not to be research under this definition: Scholarly and journalistic activities (e.g., oral history, journalism, biography, literary criticism, legal research, and historical scholarship), including the collection and use of information that focus directly on the individuals about whom the information is collected; Public health surveillance activities, including the collection and testing of information or biospecimens, conducted, supported, requested, ordered, required, or authorized by a public health authority. Such activities are limited to those necessary to allow a public health authority to identify, monitor, assess, or investigate potential public health signals, onsets of disease outbreaks, or conditions of public health importance (including trends, signals, risk factors, patterns in diseases, or increases in injuries from using consumer products). Such activities include those associated with providing timely situational awareness and priority setting during the course of an event or crisis that threatens public health (including natural or man-made disasters); Collection and analysis of information, biospecimens, or records by or for a criminal justice agency for the activities authorized by law or court order solely for criminal justice or criminal investigative purposes; Authorized operational activities (as determined by each agency) in support of intelligence, homeland security, defense, or other national security missions.
research personnel (See also investigator, IU-affiliated research personnel, non-key personnel, non-affiliated research personnel, principal investigator (PI), Student, Fellow, Resident PI, site-specific PI) Individuals engaged in human subjects research; specifically, individuals who interact or intervene with human subjects or access identifiable information for research purposes. May also be called investigators.
serious adverse event (SAE) Any adverse event that results in death, a life-threatening experience, inpatient hospitalization, prolongation of hospitalization, persistent or significant disability/incapacity, congenital anomaly, or birth defect, or that requires medical or surgical intervention to prevent such an outcome.
serious noncompliance (see also noncompliance, continuing noncompliance, minor noncompliance, observed or apparent noncompliance) Noncompliance which: Significantly increases the probability and/or magnitude of risk to subjects beyond what was previously recognized for the study; Significantly compromises the rights and welfare of subjects; For greater than minimal risk research, compromises the research such that important conclusions can no longer be reached, or; Results from significant disregard for policies and/or regulations intended to protect human subjects and results in actual harm to subjects. For VA research, also includes noncompliance which (1) presents a genuine risk of substantive harm to the safety, rights, or welfare of human research subjects, research personnel, or others, including their rights to privacy and confidentiality of identifiable private information, or (2) substantially compromises a facilities' HRPP.
serious problem (VA) For research subject to VA regulations, problem that may reasonably be regarded as (1) involving substantive harm, or a genuine risk of substantive harm, to the safety, rights, or welfare of human research subjects, research staff, or others; or (2) substantively compromising the effectiveness of a facility's human research protection or human research oversight programs.
suspension Temporary cessation of some or all activities in a currently approved research study.
termination Determination made by the IRB to permanently withdraw approval for some or all activities of a currently approved research study.
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.
unanticipated problem involving risks to subjects or others (UPIRTSO) In general, this includes any incident, experience, or outcome that meets all of the following criteria: 1) is 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 subject population being studied; 2) is 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 3) suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.
unexpected adverse event (UAE) Any adverse event occurring in one or more subjects participating in a research protocol, the nature, severity, or frequency of which is not consistent with either 1) the known or foreseeable risk of adverse events associated with the procedures involved in the research that are described in (a) the protocol-related documents, such as the IRB-approved research protocol, summary safeguard statement, any applicable investigator brochure, and the current IRB-approved informed consent document, and (b) other relevant sources of information, such as product labeling and package inserts; or 2) the expected natural progression of any underlying disease, disorder, or condition of the subject(s) experiencing the adverse event and the subject's predisposing risk factor profile for the adverse event.
written/in writing Writing on a tangible medium (e.g. paper) or in an electronic format.Back to top