***NIA Adverse Event and Serious Adverse Event Guidelines***

# BACKGROUND

This guideline describes the requirements and processes for reporting
adverse events and unanticipated problems to the National Institute on
Aging (NIA). It incorporates guidelines provided by the Office of Human
Research Protections (OHRP) of the Department of Health and Human
Services (DHHS) and describes Food and Drug Administration (FDA)
reporting requirements. NIH is obligated to ensure that researchers
comply with their approved reporting procedures.  Clinical trial
investigators funded by NIA are obligated under federal regulations to
appropriately inform the Institute of adverse events and unanticipated
problems, and NIA is required to ensure that the appropriate procedures
are in place to support this reporting. 

# DEFINITIONS 

Definitions are from the January 2007 OHRP *Guidance on Reviewing and
Reporting Unanticipated Problems Involving Risks to Subjects or Others
and Adverse Events, OHRP Guidance*,
<http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm> **.**

## Adverse Event (AE): 

Any untoward or unfavorable medical occurrence in a human study
participant, including any abnormal sign (e.g. abnormal physical exam or
laboratory finding), symptom, or disease, temporally associated with the
participants' involvement in the research, whether or not considered
related to participation in the research.

##  Serious Adverse Event (SAE): 

Any adverse event that:

-   Results in death

-   Is life threatening, or places the participant at immediate risk of
    death from the event as it occurred

-   Requires or prolongs hospitalization

-   Causes persistent or significant disability or incapacity

-   Results in congenital anomalies or birth defects

-   Is another condition which investigators judge to represent
    significant hazards

## Unanticipated Problem: 

Defined by DHHS 45 CFR part 46 as any incident, experience, or outcome
that meets all of the following criteria:

-   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 study
    population;

-   related or possibly related to participation in the research (in
    this guidance document, 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);

-   suggests that the research places participants or others at a
    greater risk of harm (including physical, psychological, economic,
    or social harm) than was previously known or recognized.

## Adverse Events (FDA) versus Unanticipated Problems (OHRP)

To summarize,

-   All adverse events are not necessarily unanticipated problems

-   All unanticipated problems are not necessarily adverse events

-   Some events may be both.

# RESPONSIBILITIES

Both the NIA and the investigators it funds have responsibilities with
respect to safety reporting.

## NIA

NIA program staff members are responsible for providing:

-   Assistance to extramural investigators in understanding and applying
    adverse event and serious adverse event guidelines and for ensuring
    compliance with OHRP guidance in all NIA funded clinical research.

-   Oversight of these guidelines, which includes periodic review and
    revision as relevant rules and regulations change.

-   Assurance that the Data and Safety Monitoring Plan (DSM Plan)
    addresses reporting of adverse events, serious adverse events, and
    unanticipated problems.

-   Verification that all corrective action plans have been adequately
    implemented.

-   Assurance that the study has an independent safety monitoring body
    commensurate with study risk (Data and Safety Monitoring Board or
    Safety Officer).

-   Ongoing oversight of the safety reporting process to assure that
    potential safety issues are addressed.

## Investigators

Investigators conducting clinical research are responsible for:

-   Assurance that their protocols are conducted in compliance with
    these guidelines.

-   Submission of IRB-approved protocol to the NIA program office. The
    protocol must include a DSM Plan that is commensurate with the study
    risk and reflects this guideline.

    -   DSM plan describes plans for adverse events, serious adverse
        events, and unanticipated problems commensurate with nature and
        complexity of study.

    -   Recipients of Serious Adverse Event and Unanticipated Problem
        reports must include IRBs, DSMB or Safety Officer, and NIA.

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-   Adherence to the DSM with respect to timely submission of adverse
    events, serious adverse events, and unanticipated problems.

# REPORTING PROCESSES

Adverse Events (AEs), Serious Adverse Events (SAEs), and Unanticipated
Problems have specific reporting procedures.

## Adverse Event Reporting

All AEs are collected on an Adverse Event Form, a sample of which is
shown in [Adverse Event
Form](http://www.nia.nih.gov/NR/rdonlyres/A96956C9-0E49-49C5-B8DA-6B5B127E103A/9866/AdverseEventsForm.doc)
document. AEs and/or laboratory abnormalities must be reported. All AEs
experienced by the participant during the time frame specified in the
protocol (e.g., from the time study drug administration through the end
of the study) are to be reported, as outlined in the protocol.

Please note that the AE form contains a column to indicate whether the
event is SERIOUS. Thus, SAEs are a subset of the reported AEs.

Routine reporting of AEs is described in the DSM Plan and may be monthly
or quarterly as determined with the NIA staff and / or the DSMB/Safety
Officer

## Serious Adverse Event Reporting

All SAEs, unless otherwise specified in the protocol and approved by the
IRB and NIA or DSMB (as applicable), require expedited reporting by the
Principal Investigator to the study\'s safety monitoring bodies. An
expedited report of an SAE can be submitted by telephone, fax, or email
and must be reported to the independent safety monitoring body (i.e.,
DSMB or Safety Officer) and the NIA within 24 hours of the event being
reported to the Investigator or as specified in the DSM.

The expedited report should be followed by detailed, written SAE report
as soon as possible. Follow up information may be required and asked for
by the independent safety monitoring body directly, or through the NIA
or its representative. A sample of the SAE reporting form used for NIH
Intramural Programs is shown in the [Serious Adverse Event
Form](http://www.nia.nih.gov/NR/rdonlyres/A96956C9-0E49-49C5-B8DA-6B5B127E103A/9867/SeriousAdverseEventsForm.doc)
document.

FDA guidelines for reports they must receive from the sponsor with
respect to drug interventions are as follows:

-   Unexpected fatal or life threatening experiences associated with the
    use of the drug (21 CFR 312\[.32\[c\] \[ii\] \[2\]) - must be
    reported to the FDA by telephone or by facsimile transmission as
    soon as possible but no later than seven calendar days after the
    sponsor's initial receipt of the information if the intervention is
    under an Investigative New Drug (IND) application.

    If an adverse drug experience was not initially determined to be
    reportable but the results of an investigation show that the
    experience is reportable under the above paragraph, the experience
    should be submitted to the FDA in a written safety report as soon as
    possible, but in no event later than 15 calendar days after the
    determination is made.

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-   Other adverse experiences associated with the use of the drug that
    are both serious and unexpected must be reported to the FDA within
    15 calendar days after the sponsor's initial receipt of the
    information.

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-   If the drug is marketed and not under an IND (21 CFR 314.80\[(c) (1)
    (i)\], a serious and unexpected adverse drug experience must be
    reported to the FDA within 15 calendar days of initial receipt of
    the information by the applicant.

## Unanticipated Problems (UP)

Investigator institutions must have written procedures for ensuring
prompt reporting to the IRB and NIA, and others as appropriate, of any
Unanticipated Problem involving risks to study participants or others
(45 CFR 46.103(b)(5)). The Unanticipated Problems reporting procedures
must include a corrective plan and measures to prevent reoccurrence. It
is recommended that such events be reported within 48 hours to NIA
unless they are also SAEs.

Reports of Unanticipated Problems, as defined above, should be forwarded
to OHRP using <ohrp@osophs.dhhs.gov>, typically within two weeks of the
event.

The [AE/SAE Process
Flow](http://www.nia.nih.gov/NR/rdonlyres/A96956C9-0E49-49C5-B8DA-6B5B127E103A/9840/AE_SAEProcessFlow.doc)
chart provides an algorithm of the reporting process.

# CLASSIFYING ADVERSE EVENTS

Adequate review, assessment, and monitoring of adverse events require
that they be classified as to ***severity***, ***expectedness***, and
potential ***relatedness*** to the study intervention. Study protocols
must include a description of how adverse events will be classified in
these terms. These classifications determine the reporting requirements.

## Severity 

Classifications often include the following:

-   ***Mild:*** Awareness of signs or symptoms, but easily tolerated and
    are of minor irritant type causing no loss of time from normal
    activities. Symptoms do not require therapy or a medical evaluation;
    signs and symptoms are transient.

-   ***Moderate:*** Events introduce a low level of inconvenience or
    concern to the participant and may interfere with daily activities,
    but are usually improved by simple therapeutic measures; moderate
    experiences may cause some interference with functioning

-   ***Severe:*** Events interrupt the participant's normal daily
    activities and generally require systemic drug therapy or other
    treatment; they are usually incapacitating

Severity is not synonymous with seriousness. A ***severe*** rash is not
likely to be an ***SAE.*** Likewise, a ***severe*** headache is not
necessarily an ***SAE.*** However, ***mild*** chest pain may result in a
day's hospitalization and thus is an ***SAE.***

##  Expectedness 

AEs must be assessed as to whether they were expected to occur or
unexpected, meaning not anticipated based on current knowledge found in
the protocol, investigator brochure, product insert, or label.
Categories are:

-   ***Unexpected -*** nature or severity of the event is not consistent
    with information about the condition under study or intervention in
    the protocol, consent form, product brochure, or investigator
    brochure.

-   ***Expected -*** event is known to be associated with the
    intervention or condition under study.

## Relatedness 

The potential event relationship to the study intervention and/or
participation is assessed by the site investigator. A comprehensive
scale in common use to categorize an event is:

-   *Definitely Related*: The adverse event is clearly related to the
    investigational agent/procedure -- i.e. an event that follows a
    reasonable temporal sequence from administration of the study
    intervention, follows a known or expected response pattern to the
    suspected intervention, that is confirmed by improvement on stopping
    and reappearance of the event on repeated exposure and that could
    not be reasonably explained by the known characteristics of the
    subject's clinical state.

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-   *Possibly Related:* An adverse event that follows a reasonable
    temporal sequence from administration of the study intervention
    follows a known or expected response pattern to the suspected
    intervention, but that could readily have been produced by a number
    of other factors.

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-   *Not Related:* The adverse event is clearly not related to the
    investigational agent/procedure. - i.e. another cause of the event
    is most plausible; and/or a clinically plausible temporal sequence
    is inconsistent with the onset of the event and the study
    intervention and/or a causal relationship is considered biologically
    implausible.

***References***

January 2007 OHRP Guidance *on Reviewing and Reporting Unanticipated
Problems Involving Risks to Subjects or Others and Adverse Events,*
<http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm> 21 CFR 312.50, General
Responsibilities of the Sponsor,
<http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.50>

21 CFR 312.32(a), IND Safety Reports,
<http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.32>

ICH E6 5.0 Sponsor, Good Clinical Practices,
<http://www.ich.org/LOB/media/MEDIA482.pdf>