HRPP Policy - Reportable Events

The following reportable events that occur in research under the oversight of the IU IRB may constitute unanticipated problems involving risks to subjects or others or serious and/or continuing noncompliance and must be reported to the IU IRB within five (5) business days of the study team becoming aware of the event, regardless of the level of review of the study or the study status:

• Conduct of human subjects research without IRB approval, including:
  • Conduct of research without submitting study 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 closed, 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  (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the study-related documents, and (b) the characteristics of the subject population being studied, (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 that, in the opinion of the PI, or appropriately trained and qualified designee, 
  • Placed subjects at greater risk of harm (including physical, psychological, economic, or social harm),
  • Caused actual harm to subjects or others, OR
  • For greater than minimal risk research, compromised the integrity of the study data such that the subject’s data can no longer be used in analysis of study outcomes
• Consent, assent, and/or authorization issues, including:
  • Failure to obtain consent, assent, and/or authorization from subjects, including obtaining consent or authorization from someone who cannot legally act on behalf of the subject
  • Conduct of research after subject decides not to participate, dissents, or withdraws from the research
  • For subjects originally enrolled as minors with parental permission, failure to obtain consent prior to direct interaction after a subject turns eighteen years of age
  • For subjects originally enrolled via consent of a legally authorized representative, failure to obtain consent prior to direct interaction after a subject gains consent capacity
  • Following use of a short form consent, failure to re-consent the subject on a translated consent form unless an exception applies
  • For greater than minimal risk research, failure to obtain the subject's signature on the informed consent
  • When use of a witness is required, failure to document the involvement of a witness in the consent process
  • Enrolling subjects or continuation of subject participation using an inaccurate consent that could affect the subject’s willingness to participate (such as omission of study procedures, risks, and/or benefits)
• Research billing compliance error which results in a subject being incorrectly billed for research procedures
• Complaints about the conduct of the research
• Study suspensions or holds related to risk, safety, or compliance issues
• Disclosure or release of identifiable subject data outside the research team, which:
  • May place the subject at risk of criminal or civil liability or be damaging to the subject’s financial standing, employability, educational advancement, or reputation, and/or
  • Is determined by the appropriate covered entity’s HIPAA Privacy Officer, after review, to be a reportable breach as such term is defined in the HIPAA Privacy Rule
• Local audit reports with any findings which meet prompt reporting criteria described in this Policy (e.g., Quality Improvement Office audits, VA audits)
• Failure to submit amendments which update risks, benefits, or procedures within sixty (60) days of receipt
• Failure to promptly report events when required per IU HRPP Policies.
• Failure to report required information to the IRB at the time of renewal. Specifically,
  • Systemic failure to report minor protocol deviations and/or minor noncompliance at time of renewal
  • For multi-site research where IU is serving as the IRB of record for external sites, failure to report information related to external sites at time of renewal
• IRB or HRPP noncompliance, including:
  • Failure to provide the required level of IRB review
  • Failure to assign an appropriate expiration date to research which results in IRB review being conducted less frequently than required
  • Failure to communicate to the study team in a timely manner a study suspension or termination
  • Any other error that may significantly compromise the rights or welfare of subjects

The following reportable events that occur in research under the oversight of an external IRB may constitute unanticipated problems involving risks to subjects or others or serious and/or continuing noncompliance and must be reported to the IU HRPP within one (1) month of the study team becoming aware of the event, regardless of the level of review of the study or the study status:

• Conduct of human subjects research without IRB approval, including:
  • Conduct of research without submitting study for IRB review
  • Conduct of research prior to receiving IRB notification of final approval
  • Initiation of substantive changes (e.g., 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
  • Inclusion of vulnerable subject populations without specific IRB approval
  • Conduct of research when IRB approval has expired or been closed, 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)
• Major protocol deviations that, in the opinion of the PI, or appropriately trained and qualified designee,
  • Placed subjects at greater risk of harm (including physical, psychological, economic, or social harm),
  • Caused actual harm to subjects or others, OR
  • For greater than minimal risk research, compromised the integrity of the study data such that the subject’s data can no longer be used in analysis of study outcomes
• Consent, assent, and/or authorization issues, including:
  • Failure to obtain consent, assent, and/or authorization from subjects, including obtaining consent or authorization from someone who cannot legally act on behalf of the subject
  • Conduct of research after subject decides not to participate, dissents, or withdraws from the research
  • For subjects originally enrolled as minors with parental permission, failure to obtain consent prior to direct interaction after a subject turns eighteen years of age
  • For subjects originally enrolled via consent of a legally authorized representative, failure to obtain consent prior to direct interaction after a subject gains consent capacity
  • For greater than minimal risk research, failure to obtain the subject’s signature on the informed consent
  • When use of a witness is required, failure to document the involvement of a witness in the consent process
  • Enrolling subjects or continuation of subject participation using an inaccurate consent that could affect the subject’s willingness to participate (such as omission of study procedures, risks, and/or benefits)
• Research billing compliance error which results in a subject being incorrectly billed for research procedures
• Complaints about the conduct of the research
• Study suspensions or holds related to compliance issues
• Disclosure or release of identifiable subject data outside the research team, which:
  • May place the subject at risk of criminal or civil liability or be damaging to the subject’s financial standing, employability, educational advancement, or reputation, and/or
  • Is determined by the appropriate covered entity’s HIPAA Privacy Officer, after review, to be a reportable breach as such term is defined in the HIPAA Privacy Rule
• Local audit reports with any findings which meet prompt reporting criteria described in this Policy (e.g., Quality Improvement Office audits, VA audits)
• Failure to promptly report events when required per IU HRPP Policies

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:

• Local research deaths which are unexpected and related or possibly related to the research
• Apparent unanticipated problems involving risks to subjects or others
• Apparent serious and/or continuing noncompliance
• Information security and privacy incidents
• Other events involving VA Human Research Protection Programs reportable to ORO

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 this policy.

Promptly reportable events are submitted via Kuali Protocols.

For items classified as noncompliance, the University Director, HRPP, an Associate Director, or an Assistant Director will further review the item to determine if the report may constitute serious or continuing noncompliance.  If the item is determined to be not apparent serious or continuing noncompliance, HRPP staff review and accept the report without review by the convened IRB.  A report of events reviewed and determined to be not apparent serious or continuing noncompliance under this paragraph is provided periodically to the convened IRB.

If the event meets prompt reporting criteria and review by the convened IRB is required, the report is submitted  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 Reporting to Oversight Agencies.
• If the IRB determines that the report does not represent a UPIRTSO or serious or continuing noncompliance, no further reporting is required.

Promptly reportable events are submitted via Kuali Protocols and reviewed by a qualified HRPP staff member.

Local Research Deaths

• VA personnel must ensure oral notification is provided to the IRB immediately (i.e., within one hour) upon becoming aware of any local research death of a human subject that is believed to be both unexpected and related or possibly related to participation in a VA non-exempt human subjects research study. VA personnel must also ensure that follow-up written notification is provided to the IRB within one (1) business day of becoming aware of such a death.
• Within one (1) business day after receiving written notification of the death, the IRB Chair or another qualified IRB voting member must assess and document whether any actions are warranted to eliminate apparent immediate hazards to subjects and, if so, initiate those actions.
• In response to the written notification, the IRB must:
  • Review the written notification, the immediate hazard assessment of the IRB Chair or other qualified IRB voting member, and the actions taken to date at its next convened meeting, not to exceed 30 calendar days after the date of written notification.
  • Determine and document within 30 calendar days of the convened IRB’s initial review:
    • Whether the death was both unexpected and related or possibly related to participation in the research; and
    • What, if any, protocol or informed consent modifications are warranted.
      • If modifications are warranted, the convened IRB must determine and document whether or not investigators 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 medical facility Director, the RCO, and the ACOS/R&D in writing of its determinations within five (5) business days after making those determinations.
• If the IRB is unable to make a determination on the matter within 30 calendar days of the convened IRB’s initial review due to insufficient information or due to a lack of sufficient time to complete its review, the IRB must notify the VA medical facility Director, the RCO, and the ACOS/R&D in writing no later than five (5) business days after the determination was due. The VA medical facility Director, or designee, must notify the appropriate ORO workgroup within five (5) business days after receiving the IRB’s written notification that it is unable to make a determination.
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Apparent UPIRTSO

• VA personnel must ensure written notification is provided to the IRB within five (5) business days after becoming aware of an apparent UPIRTSO involving a VA non-exempt human subjects research study. An apparent UPIRTSO is an apparent incident, experience or outcome that is: unexpected and related or possibly related to participation in the research and indicative of the research placing subjects or others at substantively greater risk of harm than was previously known or recognized. An apparent unexpected SAE that is related or possibly related to participation in human subjects research constitutes an apparent UPIRTSO.
• Within five (5) business days after receiving written notification of an apparent UPIRTSO, the IRB Chair or another qualified IRB voting member must assess and document whether any actions are warranted to eliminate apparent immediate hazards to subjects and, if so, initiate those actions.
• In response to the written notification, the IRB must:
  • Review the written notification, the immediate hazard assessment of the IRB Chair or other qualified IRB voting member, and the actions taken to date at its next convened meeting, not to exceed 30 calendar days after the date of written notification. NOTE: Incidents covered by this paragraph may call for immediate attention and require the IRB to convene an emergency session prior to its next scheduled meeting.
  • Determine and document within 30 calendar days of the convened IRB’s initial review:
    • Whether the incident, experience, or outcome was unexpected and related to or possibly related to participation in the research and indicative of the research placing subjects or others at substantively greater risk of harm than was previously known or recognized (i.e., whether the incident, experience or outcome constituted an actual UPIRTSO); and
    • What, if any, protocol or informed consent modifications are warranted.
      • If modifications are warranted, the convened IRB must determine and document whether or not investigators must notify or solicit renewed or revised consent from previously enrolled subjects; and if so, when such notification or consent must take place and how it must be documented.
• If the IRB determines that the incident, experience, or outcome constituted a UPIRTSO, it must notify the VA medical facility Director, the RCO, and the ACOS/R&D in writing of its determinations within five (5) business days after making those determinations.
• If the IRB is unable to make a determination on the matter within 30 calendar days of the convened IRB’s initial review due to insufficient information or due to a lack of sufficient time to complete its review, the IRB must notify the VA medical facility Director, the RCO, and the ACOS/R&D in writing no later than five (5) business days after the determination was due. The VA medical facility Director, or designee, must notify the appropriate ORO workgroup within five (5) business days after receiving the IRB’s written notification that it is unable to make a determination.
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Apparent serious and/or continuing noncompliance

• VA personnel must ensure that the IRB is notified, in writing, within five (5) business days after becoming aware of any apparent serious or continuing noncompliance with applicable laws, regulations, policies, and agreements pertaining to non-exempt human subjects research. This includes, but is not limited to, serious or continuing noncompliance with the Common Rule, local VA medical facility policies and SOPs related to human subjects research, if developed, IRB-approved protocols, and the requirements or determinations of the IRB. NOTE: Information Security and Privacy Incidents (described below) that involve non-exempt human subjects research may also constitute apparent serious or continuing noncompliance under this paragraph.
• In response to the written notification, the IRB must:
  • Review the written notification at its next convened meeting, not to exceed 30 calendar days after the date of written notification.
  • Determine and document within 60 calendar days of the convened IRB’s initial review:
    • Whether or not serious or continuing noncompliance actually occurred; and if so,
    • What, if any, remedial actions are needed to resolve present noncompliance or prevent future noncompliance.
• If the IRB determines that serious or continuing noncompliance actually occurred, it must notify the VA medical facility Director, the RCO, and the ACOS/R&D in writing of its within five (5) business days after making those determinations.

Other Events Involving VA Human Research Protection Programs Reportable to ORO

• The IRB must notify the VA medical facility Director, the RCO, and the ACOS/R&D in writing within five (5) business days of becoming aware of any of the following, after which the VA medical facility Director, or designee, must notify ORO within five (5) business days:
  • The suspension or early termination of a non-exempt VA human research study by the IRB or IO due to the study not being conducted in accordance with applicable regulations, policies, agreements, or IRB requirements or due to concerns about the safety, rights, or welfare of human subjects or others, if such suspension or termination is not otherwise reportable per the requirements of paragraphs 7.a., b. or c. NOTE: The notification of suspension or early termination of a non-exempt VA human research study by the IRB or IO must include a statement of the reason for the IRB's or IO’s action.
  • The termination or non-renewal of the HHS-OHRP registration of any IRB relied upon by the VA medical facility for review and oversight of VA research.

Information Security and Privacy Incidents

• VA personnel must ensure written notification is provided to the IRB within five (5) business days after becoming aware of any apparent information security or privacy incidents related to VA human subjects research, including any inappropriate access, loss, theft, noncompliant storage, transmission, removal or destruction of PHI or other VA research information deemed to be sensitive; theft, loss or noncompliant destruction of equipment containing PHI or other VA research information deemed to be sensitive; or uses and disclosures of PHI for research without legal authority (e.g., without a valid authorization or waiver of authorization).
• In response to the written notification, the IRB must:
  • Review the incident in accordance with requirements set forth above, as applicable.
  • Consult with the ISO, PO or Records Management official, as applicable, when determining whether and what remedial actions are warranted.
• Committee determinations must be reported, if required by and in accordance with above, as applicable.

Promptly reportable events are subject to post-submission follow-up by the HRPP.  QIO staff may contact study teams to follow up on corrective and preventive action (CAPA) plans described in the Reportable Event Form and/or audit report.  When an event is selected for CAPA plan follow-up, research personnel must respond to the request within fourteen (14) days unless an extension is granted by QIO staff.