Research

Human Research Protection Program Policy and Procedure Manual - Section 8

8 Unanticipated Problems Involving Risks to Participants or Others and Adverse Events

8.1 Purpose

8.2 Definitions

8.3 Data Safety Monitoring Plan

8.4 Procedures

8.4.1 Reporting

8.4.2 Submission of Reports

8.4.3 IRB Procedures for Handling Reports of Possible Unanticipated Problems

8.4.3.1 Review by IRB Staff and Chair

8.4.3.2 IRB Review

8.4.3.3 Reconsideration of the IRB Decision

 

8 Unanticipated Problems Involving Risks to Participants or Others and Adverse Events
8.1 Purpose

These procedures describe how the University complies with DHHS and FDA regulations which state that unanticipated problems involving risks to participants or others must be reported to the IRB, institutional officials, and relevant federal agencies and departments.

 

8.2 Definitions

Unanticipated problems involving risk to participants or others.  Unanticipated problems involving risks to participants or others include any adverse event that is (1) unexpected, (2) serious, and (3) related or possibly related to participation in the research.  Unanticipated problems also includes unexpected adverse events, regardless of severity, that the IRB determines represent risk to participants or others.  Unanticipated problems also includes events that are not categorized as adverse events, are not directly related to an individual participant’s participation in a study, but represent risk to participants or others. 

 

Adverse Event. An adverse event (AE) is defined as any untoward physical or psychological occurrence in an individual participating in research. An AE can be any unfavorable or unintended event including abnormal laboratory finding, symptom, or disease associated with the research or the use of a medical investigational test article.

 

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.

 

Serious Adverse Event.  A serious adverse event (SAE) is defined as death, a life threatening experience, hospitalization (for a person not already hospitalized), prolongation of hospitalization (for a patient already hospitalized), persistent or significant disability or incapacity, congenital anomaly and/or birth defects, or an event that jeopardizes the participant and may require medical or surgical treatment to prevent one of the preceding outcomes.

 

Unexpected Adverse Event.  An unexpected adverse event (UAE) is any adverse event and/or reaction, the specificity or severity of which is not consistent with the risk information provided in the protocol, informed consent, current investigator brochure, or product labeling.

 

Adverse Device Effect. An adverse device effect (ADE) is any adverse event/effect caused by or associated with the use of a device that is unanticipated and has not been included in the protocol or the Investigator’s Brochure.

 

Related. An event is “related” if it is likely to have been caused by the research procedures.

 

Substantive Action. An action taken by an IRB that materially alters the substance and meaning of a protocol, informed consent form or process, or investigator status, including, but not limited to, restriction, suspension or termination of a study or investigator participation, and actions taken to prevent future occurrence(s) of the AE in research.

 

Unexpected Death. The death of a research participant in which a high risk of death is not projected, as indicated by the written protocol, informed consent form, or sponsor brochure. This definition does not include deaths associated with a terminal condition unless the research intervention clearly hastened the participant’s death. A participant’s death that is determined to be clearly not associated with the research is also not an “unexpected death” for purposes of the reporting requirements of these procedures.

 

8.3 Data Safety Monitoring Plan

For all research that is more than minimal risk, the initial research plan submitted to the IRB should describe the procedures for safety monitoring, reporting of adverse events and/or unanticipated problems involving risks to participants or others, descriptions of interim safety reviews and the procedures planned for transmitting the results to the IRB. This description should include information regarding an independent Data and Safety Monitoring Board (DSMB), if one exists, or an explanation why an independent data safety monitor is not necessary.

 

8.4 Procedures
8.4.1 Reporting

Investigators must report all possible unanticipated problems to the IRB within five (5) days of receiving notice of the event, if the event requires immediate intervention to prevent serious harm to participants or others. Investigators must report all other possible unanticipated problems occurring at the local research site and non-local research sites to the IRB as soon as possible and no later than ten (10) business days from the date of the event or from the date the investigator is notified of the event.

 

Investigators must promptly report (according to the above schedule) the following events to the IRB if the events occur within thirty (30) days of participants’ active participation:

  1. Adverse events which in the opinion of the principal investigator are both unexpected and related.
  2. An unanticipated event related to the research that exposes individuals other than the research participants (e.g., investigators, research assistants, students, the public, etc.) to potential risk
  3. Information that indicates a change to the risks or potential benefits of the research. For example:
    • An interim analysis or safety monitoring report indicates that frequency or magnitude of harms or benefits may be different than initially presented to the IRB.
    • A paper is published from another study that shows that the risks or potential benefits of your research may be different than initially presented to the IRB.
  4. A breach of confidentiality.
  5. Incarceration of a participant in a protocol not approved to enroll prisoners.
  6. Change to the protocol taken without prior IRB review to eliminate an apparent immediate hazard to a research participant.
  7. Complaint of a participant when the complaint indicates unexpected risks or cannot be resolved by the research team.
  8. Protocol violation (meaning an accidental or unintentional change to the IRB approved protocol) that harmed participants or others or that indicates participants or others may be at increased risk of harm.
  9. Event that requires prompt reporting to the sponsor.
  10. Sponsor imposed suspension for risk.
  11. Any other event that indicates participant or others might be at risk of serious, unanticipated harms that are reasonably related to the research.

 

8.4.2 Submission of Reports

Investigators or the study team must report possible unanticipated problems to RPO in writing.  The written report should contain the following:

  1. Detailed information about the possible unanticipated problems, including relevant dates.
  2. Any corrective action, planned or already taken, to ensure that the possible unanticipated problems is corrected and will not occur again.
  3. An assessment of whether any participants or others were placed at risk as a result of the event or suffered any physical, social, or psychological harm and any plan to address these consequences.
  4. Any other relevant information.
  5. Any other information requested by RPO.

 

A report of a possible unanticipated problem involving risks to participants or others will be immediately forwarded by RPO staff to the IRB Chair if the RPO staff believes that immediate intervention may be required to protect participants or others from serious harm.

 

Upon receipt of a report of a possible unanticipated problem from someone other than the investigator or study staff, the IRB director or RPO staff will notify the PI on the study when appropriate.

 

8.4.3 IRB Procedures for Handling Reports of Possible Unanticipated Problems
8.4.3.1 Review by IRB Staff and Chair

  1. The IRB chairperson, and/or other experienced individuals designated by the IRB chairperson, receives and reviews the report of the event considered to be an unanticipated problem.  The IRB chairperson (or designee) will make the final determination as to whether the event is to be regarded as an unanticipated problem.  All events determined to be unanticipated problems will be reported to the relevant regulatory agencies and institutional officials, as necessary, according to the procedures in this document.

  2. Unanticipated problems for which no modifications to the protocol or informed consent process/documents are needed, as determined by the IRB chairperson (or designee), may be:

    (a) filed in the IRB records without further review by the convened IRB
    (b) at the discretion of the IRB chairperson (or designee) referred to the rest of the IRB members for review and further action, as appropriate, at a convened meeting.

    For external adverse events, if the central monitoring entity or the PI did not propose any modifications to the protocol or informed consent process/document, but the IRB chairperson (or designee) believes that modifications are needed in response to the external adverse event(s), the IRB chairperson (or designee) requests in writing that the PI discuss the proposed modifications with the study sponsor or coordinating center and submit a response or necessary modifications for review by the IRB. These modifications then are handled in accordance with procedures below.

    The IRB or the IRB chairperson (or designee) has authority to require submission of more detailed contextual information by the PI, the sponsor, the study coordinating center, or DSMB/DMC about any adverse event occurring in a research protocol as a condition of the continuation of the IRB’s approval of the research.

  3. Unanticipated problems for which modifications to the protocol or informed consent process/documents are needed, either as requested by the PI or determined by the IRB chairperson (or designee), will be handled as follows:

    (a) If all proposed modifications represent minor changes, the IRB chairperson (or designee) may review and, if appropriate, approve the modifications under an expedited review procedure. The related report of the external adverse event may be: (i) filed in the IRB records without further review by the convened IRB or, (ii) at the discretion of the IRB chairperson (or designee), referred to the rest of the IRB members for review and further action, as appropriate, at a convened meeting.

    (b) If any of the proposed modifications represent more than a minor change, or if the IRB chairperson (or designee) determines for any reason that he or she should not approve the proposed modifications under an expedited review procedure, the proposed modifications must be forwarded to the other IRB members for review at a convened meeting.

  4. If the IRB chairperson (or designee) determines that modifications in addition to those proposed by the PI are needed in response to an external adverse event, the IRB chairperson (or designee) requests in writing that the PI submit a response or the necessary additional modifications for review by the IRB.

 

8.4.3.2 IRB Review

 

  1. All IRB members will receive the event report. The full IRB will make findings and recommendations based on the following considerations:
    (a) whether the reported event is an unanticipated problem involving risks to participants or others according to the definition in this policy.
    (b) what action in response to the report is appropriate.
    (c) whether suspension or termination of approval is warranted.
    (d) whether further reporting to Institutional and/or federal officials is required.
  2. If the IRB finds that the event is not an unanticipated problem involving risks to participants or others, according to the definition in the policy, the IRB may recommend any of the following actions:
    (a) no action
    (b) requiring modifications to the protocol
    (c) revising the continuing review timetable
    (d) modifying the consent process
    (e) modifying the consent document
    (f) providing additional information to current participants (e.g. whenever the information may relate to the participant’s willingness to continue participation)
    (g) providing additional information to past participants
    (h) requiring additional training of the investigator and/or study staff
    (i) other actions appropriate for the local context
  3. If the IRB finds that the event is an unanticipated problem involving risks to participants or others, according to the definition in the policy, the IRB may recommend any of the following actions:
    (a) requiring modifications to the protocol
    (b) revising the continuing review timetable
    (c) modifying the consent process
    (d) modifying the consent document
    (e) providing additional information to current participants (e.g. whenever the information may relate to the participant’s willingness to continue participation)
    (f) providing additional information to past participants
    (g) requiring additional training of the investigator and/or study staff
    (h) reconsidering approval
    (i) requirement that current participants re-consent to participation
    (j) monitoring of the research
    (k) monitoring of the consent
    (l) referral to other organizational entities (e.g., legal counsel, risk management, institutional official)
    (m) suspending the research
    (n) terminating the research
    (o) other actions appropriate for the local context
  4. If a report suggests that participant safety is at risk, the IRB may immediately suspend or terminate the research.  Any suspension or termination of research by the IRB must be promptly reported to the IO, and OHRP, and FDA (if FDA-regulated research) through the IO. This should be done in writing.
  5. If, after reviewing a report, the IRB finds that the event is an unanticipated problem involving risks to participants or others or that suspension or termination of approval is warranted, the IRB will:
    (a) notify the investigator in writing of its findings, with copies to the Chair of the investigator’s department and/or research unit, and the investigator’s supervisor, and
    (b) report its findings and recommendations to the Vice President for Research for further reporting to the appropriate federal officials (ORO, OHRP, and FDA).

 

8.4.3.3 Reconsideration of the IRB Decision

The notice to the investigator of the IRB determination will inform the investigator that he or she has ten (10) business days from receipt of the notice to request reconsideration of the IRB decision by sending the IRB a written request for reconsideration including the basis of the investigator’s request.

  1. If an investigator requests reconsideration, the investigator’s written request is considered at the next available IRB meeting; and the IRB makes a determination whether to uphold, reverse or modify its decision.  The IRB notifies the investigator of the final outcome.
  2. If the IRB receives a request for reconsideration from the investigator, the IRB should notify the Vice President for Research of the request and of the final outcome.
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