[VAPHS IRB ADVERSE EVENT REPORTING POLICY]{.underline}

[Policy Date 5-15-07]{.underline}

Definitions:

1.  [Adverse Event (AE)]{.underline}. Any untoward physical or
    psychological occurrence in a human subject participating in
    research. An AE can be any unfavorable or unintended event including
    abnormal laboratory finding, symptom or disease associated with the
    research or use of a medical investigational test article. An AE
    does not necessarily have to have a causal relationship with the
    research, or any risk associated with the research, the research
    intervention, or the assessment.

    a.  [Serious Adverse Event (SAE).]{.underline} A SAE is defined as:

        i.  Death;

        ii. A life threatening experience;

        iii. Hospitalization (for a person not already hospitalized);

        iv. Prolongation of hospitalization (for a patient already
            hospitalized);

        v.  Persistent or significant disability or incapacity;

        vi. Congenital anomaly and/or birth defects; or

        vii. An event that jeopardizes the subject and may require
             medical or surgical treatment to prevent one of the
             preceding outcomes.

    b.  [Unanticipated/Unexpected Adverse Event]{.underline}. Any
        adverse event and/or reaction, the specificity or severity of
        which is not consistent with the VAPHS IRB approved informed
        consent, protocol, investigator brochure, or product labeling.

    c.  [Internal Adverse Event]{.underline}. An adverse event
        experienced by a subject enrolled by the investigator(s) at
        VAPHS.

    d.  [External Adverse Event]{.underline}. An adverse event
        experienced by a subject enrolled by investigators at other
        institutions engaged in the same clinical trial or a different
        clinical trial using the same investigational agent or
        intervention.

2.  [Unanticipated Adverse Device Effect]{.underline}. (a) Any serious
    adverse effect on health or safety or (b) 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 (c)
    any other unanticipated serious problem associated with a device
    that relates to the rights, safety, or welfare of subjects.

3.  [Imminent Threat of Adverse Event in Research]{.underline}. Any
    situation in which an adverse event in research has not yet
    occurred, but is likely to occur, as determined by an IRB, research,
    or clinical team member, without preventative measures.

4.  [Substantive Action**. **]{.underline}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.

5.  [Unexpected Death.]{.underline} The death of a research subject 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
    subject's death. A subject's death that is determined to be clearly
    not associated with the research is also not an "unexpected death"
    for purposes of reporting requirements.

6.  [Unanticipated Problems Involving Risks to Subjects or
    Others]{.underline}. Those events that (a) are not expected (in
    terms of nature, severity or frequency) given the nature of the
    research procedures and the subject population being studied; (b)
    related or possibly related to participation in the research;
    and (c) suggest 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.

**[A. Adverse Events (21 CFR 312.66)]{.underline}**

1.  **IRB Reporting Guidelines**

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a.  **Internal Adverse Events:**

> Reporting Levels:
>
> At the time of review all VAPHS protocols are assigned an Adverse
> Event Reporting Level which corresponds to the types of internal
> adverse events which must be reported to the IRB as described below:

-   Adverse Event Reporting Level 1 (AE1): Studies designated AE1 are
    required to report all serious adverse events and all unanticipated
    adverse events, regardless of the relatedness to the research.
    Typically, studies designated AE1 will be interventional studies.
    All studies involving the use of an investigational drug or device
    will be designated AE1

-   Adverse Event Reporting Level 2 (AE2): Studies designated AE2 are
    required to report only serious adverse events possibly or probably
    related to the study procedures and unanticipated adverse events
    that are possibly or probably related to the study procedures.
    Typically, studies designated AE2 will be observational, registry,
    or tissue banking studies.

> Investigators involved in the conduct of IRB-approved research studies
> shall report internal adverse events to the IRB Office within the
> following timeframes:

-   All fatal adverse events, whether expected or unexpected must be
    reported to the IRB within [1 business day]{.underline} of the
    investigator becoming aware of the event. For studies designated
    AE1, fatal adverse events must be reported regardless of the
    relatedness to the research. For AE2 studies, only those fatal
    events that are possibly or probably related to the research need to
    be reported. (*Note: It is recognized that the information available
    during this 24 hour period may not be sufficient to permit accurate
    completion of the required adverse event reporting forms. However,
    the IRB should, at a minimum, be notified of the fatal adverse event
    during this time frame, with subsequent follow-up submission of a
    more detailed written report.*)

-   All serious, but not fatal events, whether expected or unexpected,
    shall be reported to the IRB within [3 business days]{.underline} of
    the investigator becoming aware of the reaction. This will include
    all serious, but not fatal, events regardless of relatedness to the
    research for AE1 studies and only those serious, but not fatal
    events that are, at a minimum, possibly related to the research for
    AE2 studies.

-   All unexpected, but not serious adverse events shall be reported to
    the IRB within [5 business days]{.underline} of the investigator
    becoming aware of the reaction. This will include all unexpected,
    but not serious adverse events, regardless of relatedness to the
    research for AE1 studies, and all unexpected, but not serious
    adverse events that are, at a minimum, possibly related to the
    research for AE2 studies.

b.  **External Adverse Events:**

> When an investigator receives a report of an external adverse event,
> the investigator should review the report and assess whether the
> report identifies the adverse event as being:

1)  Unanticipated/Unexpected

2)  Related or possibly related to participation in the research; and

3)  Serious or otherwise one that 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.

> If the investigator determines that all three of the above criteria
> have been met, the event must be reported to the IRB [within 5
> business days]{.underline} of the investigator's notification of the
> event.

If the event does not meet all three of the above criteria, the event
must be reported to the IRB at the time of continuing review (as
described in Section 2c below)

2.  **Submission Procedures**:

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a.  Adverse Events meeting the IRB Reporting Guidelines (as described in
    Sections 8A1a and 8A1b) will be submitted to the IRB Office on the
    VAPHS Adverse Event Report Form.

b.  The PI completes the Adverse Event Report Form, provides a brief
    written summary of the event and submits the form and summary to the
    IRB office. (Note: When the study is part of a multi-site trial or
    is a pharmaceutical industry sponsored trial, a standard AE
    reporting form may already be in use to provide details of the event
    to the sponsor. These reports can be attached to the VAPHS AE
    Reporting Form in lieu of a written summary. If the PI recognizes
    that the Adverse Event involves risk to subjects or others and a
    modification to the IRB consent and/or protocol is required, he/she
    may also submit revised copies of the consent and/or protocol, as
    well as a Modification Request Form. The IRB Office will provide the
    investigator with a written receipt of the submission.

    c.  In addition, all external adverse events (regardless of whether
        they meet the reporting guidelines described in 8A1b) will be
        summarized and reported to the IRB on the VAPHS External Adverse
        Event Log at the time of continuing review.

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3.  **Review Procedures:**

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a.  The IRB Office Staff forward the report to the IRB Chairperson,
    Vice-Chairperson or a qualified member of the IRB designated by the
    Chairperson to review the report. The reviewer will use the AE
    Evaluation Form to determine if the event raises new concerns about
    risks to subjects or others.

b.  If the event does not raise new concerns (if, for example, the
    likelihood, severity and specificity are adequately described in the
    protocol, investigator's brochure, and informed consent document),
    the reviewer should document this determination in writing. The
    report along with documentation of the reviewer's determination (as
    indicated on the AE Evaluation Form) is placed in the IRB Research
    Application (Protocol) file and listed on the agenda of the next IRB
    meeting.

c.  If the event is determined by the IRB reviewer to raise new concerns
    about risks to subjects or others, the reviewer will forward the
    report, with the reviewer's recommendations (as indicated on the AE
    Evaluation Form), for review at the next convened meeting of the
    full board;

d.  During the meeting of the convened IRB, the committee determines
    whether the event meets the definition of an unanticipated problem
    and whether further action is required.

> The board's decision will be documented in the meeting minutes.

e.  In instances where the reviewer has immediate concerns about the
    safety and welfare of research subjects that cannot wait until the
    next scheduled meeting of the fully convened IRB, he/she has the
    authority to take immediate action(s) (e.g., call for an emergency
    meeting of the convened board, suspend study procedures, etc.) as
    appropriate, as long as the justification for such actions is
    documented. The convened IRB will review the report, with the
    reviewer's recommendations at the next meeting and make a
    determination as in d. above.

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4.  **Notification(s):**

> It is the responsibility of the IRB Chair or designee to provide
> prompt written notification of the review of all adverse events and
> the subsequent actions taken. A copy of the notification will be
> maintained in the IRB file.

5.  **Reporting**

> Adverse events will be reported to VAPHS Officials and the appropriate
> regulatory agencies as required and described in the IRB SOPs.