Office of Human Research Ethics SOP 1401: Promptly Reportable Information

Title

Office of Human Research Ethics SOP 1401: Promptly Reportable Information

1. Purpose

Regulations require an organization to establish and follow written procedures for ensuring prompt reporting and review of: unanticipated problems involving risk to subjects or others (UPIRSO), serious or continuing non-compliance, suspensions and terminations of IRB approval, changes made to research without IRB approval, and other significant information to the IRB, organizational officials, and applicable federal agencies.  This SOP provides definitions and procedures for the reporting of promptly reportable information to the UNC-Chapel Hill IRB.

In conducting a review of noncompliance, UPIRSO, and other reportable events, the IRB will also consider whether the event or issue was caused by, contributed to, or otherwise related to other determinations (e.g., a report submitted as UPIRSO, may also be considered for serious, and continuing noncompliance).

In previous versions of the UNC-Chapel Hill SOP’s and electronic submission system this was known as New Safety Information (NSI) however, as not all information that requires prompt reporting is due to safety issues or changes in risk the nomenclature has been revised to Promptly Reportable Information (PRI).Until the Promptly Reportable Information submission is available in IRBIS, investigators are required to submit through IRBIS as outlined in Table 1 and 2 using the New Safety Information submission.

1.1 - Applicability to Studies with Reliance Agreements

Investigators conducting research under the oversight of UNC-Chapel Hill’s IRB, must comply with the reporting requirements of UNC-Chapel Hill’s IRB as outlined in Table 1 and their institution’s internal reporting requirements, if applicable. Investigators conducting research under the oversight of an external IRB must comply with the reporting requirements of the external IRB and the internal reporting requirements outlined in Table 2. 

2. Responsibility

Investigators and study personnel are responsible to evaluate and report promptly reportable information.  Also, any individual (e.g., subject, family member, colleague, or other personnel) may report to the UNC-OHRE leadership, IRB Chairs, Vice Chancellor for Research’s Office, or the Institutional Official any allegations of noncompliance or other problems they have observed.

3. Definitions

Unanticipated problems involving risk to participants or others (UPIRSO).  Unanticipated problems involving risks to subjects or others (also known as UPIRSO, UPIRTSO, UPs, UAPs) refer to any incident, experience, outcome, or new information that:

  1. Is unexpected (in terms of nature, severity, or frequency); and
  2. Is at least possibly related to participation in the research; and
  3. Indicates that subjects or others are at a greater risk of harm (including physical, psychological, economic, legal or social harm) than was previously known or recognized.

UPIRSOs also encompass Unanticipated Adverse Device Effects, as defined below, and information that sponsors are required to report to the FDA in IND Safety Reports under 21 CFR 312.32.

Unexpected.  The incident, experience or outcome is not expected (in terms of nature, severity, or frequency) given the research procedures that are described in the study-related documents, such as the IRB-approved research protocol/research plan and informed consent documents; and the characteristics of the subject population being studied.

Related. There is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research.

Adverse Event.  For the purposes of these procedures and table, an adverse event (AE) is any untoward or unfavorable occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject’s participation in the research, whether or not considered related to the subject’s participation in the research.  Adverse events encompass both physical and psychological harms.  They occur most commonly in the context of biomedical research, although on occasion, they can occur in the context of social and behavioral research.

IND Safety Report. The sponsor must notify the FDA and all participating investigators (i.e., all investigators to whom the sponsor is providing drug under its INDs or under any investigator's IND) in an IND safety report of potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later than 15 calendar days after the sponsor determines that the information qualifies for reporting as defined in 21 CFR 312.32. In each IND safety report, the sponsor must identify all IND safety reports previously submitted to the FDA concerning a similar suspected adverse reaction and must analyze the significance of the suspected adverse reaction in light of previous, similar reports or any other relevant information.  Such reports must be accompanied by confirmation that the sponsor has submitted the report to the FDA.

Serious Unexpected Suspected Adverse Reaction.  For clinical trials subject to the FDAs IND regulations, a Serious Unexpected Suspected Adverse Reaction refers to an adverse event or suspected adverse reaction which is considered “serious” if, in the view of either the investigator or sponsor, it results in any of the following outcomes:

  • Death,
  • a life-threatening adverse event,
  • inpatient hospitalization or prolongation of existing hospitalization,
  • a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect.
  • Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.  21 CFR 312.32(a)

Noncompliance is defined as any failure to follow:

  • Applicable federal regulations, state or local laws, institutional policies, or other institutional oversight governing human subject protections, or
  • The requirements or determinations of the IRB, including the requirements of the approved investigational plan (i.e., protocol deviations). 

Noncompliance can result from performing an act that violates these requirements or failing to act when required.  Noncompliance may be minor or sporadic or it may be serious or continuing.  Any “Noncompliance” that is not potential Serious Noncompliance” nor “Continuing Noncompliance” is not promptly reportable as an PRI and must be documented in the research record (e.g., study deviation log) with a Corrective and Preventive Action Plan, as applicable.  Although in many scenarios a CAPA is appropriate, other deviations, such as out of study window visit due to subject needing to travel would not necessitate a CAPA, provided appropriate documentation is included.  The documentation is subject to review by the IRB and agents of the UNC-CH HRPP.

Serious Noncompliance is defined as noncompliance that increases risk of harm to subjects; adversely affects the rights, safety, or welfare of subjects; or adversely affects the integrity of the data or the research.  

Continuing Noncompliance is defined as a pattern of repeated noncompliance which continues after it has been identified that noncompliance occurred, including inadequate effort to take corrective actions or comply with IRB requirements within a reasonable timeframe. 

The identification of noncompliance is not restricted to the IRB, and may include, but is not limited to: auditors, monitors, UNC-CH’s CTQA Program, principal investigator, other IRBs, and the study team.

Complaint is defined as a concern expressed by subjects or others about the conduct of the study or a subject’s participation. 

Root Cause is defined as the initiating, most basic cause of a problem that may or may not lead to a chain of causes or other problems. If the root cause is identified and resolved it should prevent recurrence. The root cause of an event or a problem must be identified to establish an appropriate Corrective and Preventive Action Plan. Root Cause Analysis (RCA) is a formal process for identifying and documenting the root cause and the downstream effects

Corrective and Preventive Action Plan (CAPA) is defined as the plan that is submitted in response with a PRI report as it outlines what corrective actions will be taken to act on the event or problem that has already occurred and what preventive actions are being taken to eliminate the root cause of a potential problem.

Rights is defined as the entitlement of human subjects for adequate protections based on the ethical principles and regulations underpinning human subjects research.

Welfare is defined as a state of physical, psychological, social, economic, and legal well-being.

Suspension is defined as a temporary withdrawal of approval by the IRB of some or all research activities associated with a study. Research activities may include, but are not limited to the following: recruitment, screening/enrollment, research intervention/interaction, follow-up. IRB approval may be suspended by either the Chair or the convened IRB. Suspended research remains under the jurisdiction of the IRB and is subject to continuing review.

Termination is defined as permanent withdrawal of IRB approval of all research activities associated with a study. IRB approval may only be terminated by the convened IRB. Terminated research is no longer subject to continuing review.

Study Deviation Log is defined as a record of all deviations, events or issues that occur at a study site for both observational and interventional clinical research studies.  This log should be maintained with the Study Records (e.g., study binder, regulatory binder, study file) and should be made available upon request for review by the IRB and the Sponsor’s monitor.   Each entry in the log should be reviewed to determine if it meets the “Promptly Reportable Criteria” as outlined in this SOP, and if so, also report to the IRB as outlined in Table 1 and Table 2.  This log may also be referred to as Protocol Deviation Tracking log. 

4. Reporting

Investigators must report events or issues as defined in Table 1 and Table 2 to the IRB as soon as possible but within 7 calendar days after the investigator identifies that an event has occurred primarily through “Promptly Reportable Information” submission type in IRBIS.  There are several promptly reportable events that are to be submitted through alternate methods as outlined in Table 1 and Table 2.

Adverse events in FDA-regulated clinical trials must be reported to the sponsor in compliance with FDA regulations and sponsor requirements. Unless specifically required by the IRB for a given protocol, the UNC-Chapel Hill IRB does not accept reports of adverse events that are not also an unanticipated problem involving risks to subjects or others (UPIRSO). 

Study deviations that did not harm subject(s) or others or place subject(s) or others at increased risk should be documented by the investigator in a deviation log.  This log is subject to review by the UNC-Chapel Hill OHRE, IRBs or other agencies of the UNC-CH HRPP.

Anyone may report concerns of possible noncompliance, complaints, or concerns to the OHRE or IRB verbally, by email, or other means.  In such cases, the reporting party is responsible for making these reports in good faith, maintaining confidentiality and, unless reporting anonymously, cooperating with any subsequent fact-finding in relation to the report.

The PI and all other research team members are responsible for the safety and welfare of all subjects enrolled in their studies.  When investigators or team members are made aware of complaints or concerns from subjects, the investigator or team members should try to resolve the complaint, a “Promptly Reportable Information” submission is required to be submitted if the investigators or team members are unable to resolve the issue or it otherwise meets the criteria as outlined in Table 1 and 2. Investigators are encouraged to contact the OHRE Leadership or Compliance Manager when they are having difficulty resolving a complaint or concern, and whenever circumstances warrant.

If an individual, whether investigator, study staff or other, is uncertain whether there is cause to report any event or information that may be considered Promptly Reportable Information, a report should be submitted, or they can directly consult with the UNC-Chapel Hill’s OHRE leadership or compliance staff to discuss the situation informally.

Table 1, Promptly Reportable Information for studies for which the UNC IRB is the IRB of record and has oversight responsibilities

Table 2, Promptly Reportable Information for studies for which the UNC IRB has ceded review and oversight to an external IRB

4.1 - Management and Evaluation of Promptly Reportable Information

A. Eliminate Immediate Hazard to Subject

The first step is for investigators to eliminate any apparent immediate hazard to subject(s) or others. Immediate corrections do not require IRB approval prior to initiation so long as the actions are necessary to eliminate apparent immediate hazards but must be reported to the IRB by including a description in the initial report of Promptly Reportable Information.  Immediate corrections may include, but are not limited to: notification of subjects, stopping enrollment or administration of investigational product.

B. Evaluation of Event

Once apparent immediate hazards to the subject have been eliminated, the next step is the evaluate the event to determine if the event was unexpected, related to research participation, and increased risk of harm (See Definition of UPIRSO), serious or continuing noncompliance, or otherwise identified in Table 1 or Table 2.  If the event meets the criteria of needing to be submitted, the IRB submission should include the following information:

  • Detailed information about the event or issue, including relevant dates. The report should identify the affected subjects by their study codes and not by their names or other personal identifiers. 
  • A detailed evaluation of unexpectedness, relatedness, and increased risk. 

C. Identification of Root Cause

After the event has been identified the root cause of an event or a problem must be identified to establish an appropriate Corrective and Preventive Action Plan. Root Cause Analysis (RCA) is a formal process for identifying and documenting the root cause and the downstream effects. Some methods of RCA include brainstorming, the 5 Whys, flowcharting, fishbone diagrams and affinity diagrams. For more information about completing a formal Root Cause Analysis, please contact the Office of Clinical Trials.

The root cause can be identified by asking basic questions, such as:

  • What was the error?
  • How did it occur?
  • How widespread?
  • Why did it occur?

The results of the root cause should be included in the PRI Submission.

D. Establishing a Corrective and Preventive Action (CAPA) Plan

Once the root cause has been identified, the next step is to develop a corrective and preventive action plan (CAPA) to eliminate the root cause. Consistent with quality improvement methodology, it is expected that CAPA plans are thoroughly documented, implemented, and that the effectiveness of the CAPA plan is evaluated over time, as appropriate.  When reviewing a report of UPIRSO, Serious Noncompliance, Continuing Noncompliance, Suspension or Termination of IRB approval, HHS Office of Human Research Protection and the FDA assesses most closely the adequacy of the actions taken by the institution to address the problem.  The following information should be included in the PRI Submission to meet the expectation from regulatory and accreditation bodies.

CAPA plan elements:

  • Description of the corrective and preventive actions taken or planned by the study team.
    • If subjects will be reconsented, or have information shared with them, ensure that the submission describes the subjects’ current participation and outlines who will be re-consented vs notified (See SOP# 1101) and draft notification, addendum section and guidance on what is appropriate when), how they will be reconsented or notified, and when will subjects be reconsented or notified.  Outline to the IRB as to why the reconsent or notification plan is appropriate considering the population, the subjects’ status in the study lifecycle in relation to the new risk or event.
  • Date(s) on which the action(s) were taken or are planned.
  • The personnel who are responsible for the implementation of each action.
  • Plan/procedures to evaluate the effectiveness of the CAPA plan, personnel who are responsible for the evaluation, and the timeframe for the evaluation.
  • Process by which the CAPA plan will be amended if it is found to be ineffective.

Documentation of CAPA plan. Suggested format:

  • Action type (corrective or preventive)
  • Action description
  • Responsible party
  • Due date
  • Plan for effectiveness check
  • Outcome of effectiveness check
  • Plan for amending the CAPA

4.2 - Submission

The UNC-Chapel Hill requires that the PI sign-off on PRI submissions to ensure they have evaluated the risk and ensure no additional changes or immediate actions to reduce risks to subjects need to occur, unless there are extenuating circumstances as permitted by OHRE Leadership or IO (e.g., PI left the institution or was hospitalized unexpectedly).  The IRB or OHRE Staff may request additional information to assess the event and CAPA.  If the report cannot be completed in its entirety within the required time period, the report should describe what information is still needed and when the investigator anticipates that a follow-up report will be submitted.  The IRB will review the report and make the final determination regarding the sufficiency of the CAPA as outlined in SOP 1402.

During large study or department audits where multiple findings or events have occurred, please contact OHRE Leadership or the Compliance Manager prior to submitting to identify the most appropriate way to submit in the electronic system. 

5. Promptly Reportable Information Follow-up Reports

Follow-up reports can be submitted once a Promptly Reportable Information Report has been resolved. Follow-up reports can be submitted if there is a request to follow-up from the IRB, additional information about the event is identified, an appeal of determinations is requested or a revised CAPA needs to be submitted. 

6. External Adverse Event Reports

It is neither useful nor necessary under the regulations for reports of individual adverse events occurring in subjects enrolled in multicenter studies to be distributed routinely to investigators or IRBs at all institutions conducting the research. In general, the investigators and IRBs at all these institutions are not appropriately situated to assess the significance of individual external adverse events. Individual adverse events should only be reported to investigators and IRBs at all institutions when a determination has been made that the events meet the criteria for a UPIRSO. Ideally, adverse events occurring in subjects enrolled in a multicenter study should be submitted for review and analysis to a monitoring entity (e.g., the research sponsor, a coordinating or statistical center, or a DSMB/DMC) in accordance with a monitoring plan described in the IRB-approved protocol.

Contact Information

Policy Contact

Office of Human Research Ethics
CB 7097
720 Martin Luther King Jr. Blvd.
Bldg # 385, Second Floor
Chapel Hill, NC 27599

Ph: 919-966-3113
Fax: 919-966-7879

Details

Article ID: 132230
Created
Thu 4/8/21 9:26 PM
Modified
Fri 3/18/22 4:54 PM
Effective Date
If the date on which this document became/becomes enforceable differs from the Origination or Last Revision, this attribute reflects the date on which it is/was enforcable.
10/01/2021 12:00 AM
Issuing Officer
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Issuing Officer Title
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Vice Chancellor
Last Review
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10/01/2021 12:00 AM
Last Revised
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10/01/2021 12:00 AM
Next Review
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09/30/2022 12:00 AM
Origination
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06/02/2017 12:00 AM
Responsible Unit
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IRB and Human Research Ethics