# **SOP 11**

**ADVERSE EVENT REPORTING PROCEDURES**

## 1.0 PURPOSE AND SCOPE

#### Purpose and Scope

> This SOP specifies the requirements for reporting adverse events. This
> SOP describes the methods to be used for the receipt, investigation,
> and reporting of adverse events that occur during clinical studies.

## 2.0 RESPONSIBILITIES

## 

2.1 The PI is responsible for accurate and timely reporting of AE in the
CRF, to the IRB, *the R&D Committee*, and the Sponsor.

2.2 The PI and/or study coordinators are responsible for recording all
new clinical experiences, exacerbation, and/or deterioration of any
existing clinical condition occurring after a study subject has entered
the study on the appropriate form in the CRF. They will also provide
follow-up information on all AE, until resolution or an appropriate end
point is reached.

2.3 The PI is also responsible for reporting all serious or unexpected
adverse events immediately (within 24 hours after learning of the event)
to the Sponsor. The PI will also report all serious and unexpected
adverse events to the IRB *and R&D Committee* in a timely manner, which
in no case shall exceed ten (10) working days after learning of the
event.

2.4 The Sponsor is responsible for a complete and accurate
investigation, reporting, and timely filing of AE reports to the FDA or
any other regulatory body.

2.5 The Sponsor is responsible for advising the PI that all Serious
Adverse Events (SAE) and Investigational New Drug (IND) safety reports
must be reported immediately.

2.6 The Sponsor\'s Medical Director will review all AE reports. It is
the Sponsor's responsibility to follow the progression of all SAE until
resolution or appropriate end points are reached and determine whether a
SAE is unexpected and associated with the drug/device.

2.7 The PI and/or study coordinator are responsible for reviewing with
the subject all AE information during study visits. The PI and/or study
coordinator is also responsible for the following:

1\) Document the AE in the CRF and the source documents.

2\) The study coordinator must notify the PI immediately when any AE is
reported. The PI evaluates the medical condition, reports the
information in the source documents and CRF, and manages it
appropriately.

3\) After review and approval, the PI and/or study coordinator must
report the AE to the Sponsor immediately for accurate and timely
recording and reporting. The event is also recorded on the CRF, managed
medically as appropriate, and the event is followed until resolution. A
SAE Form and a description of the SAE and treatment if any must be
filled and submitted to the IRB *and R&D Committee* within ten (10)
working days after learning of the event.

4\) The PI is encouraged to consult with the Sponsor and report any
unusual and unexpected reactions to both the Sponsor and the IRB
"Because no definition of alarming reaction is provided, investigators
are left to their discretion (Good Clinical Practice)."

5\) All PI site staff members are responsible for communicating reports
of any SAE to the PI.

> 6\) *For the VA Research Service, the R&D Committee must receive
> copies of all serious and unexpected adverse events. The VA research
> pharmacist should receive copies of all serious and unexpected adverse
> events involving investigational drugs.*

**[3.0 DEFINITIONS]{.underline}**

3.1 In order to ensure proper understanding of this SOP, the following
definitions are provided:

3.1.1 Adverse Event- A medical event occurring during a clinical study
that can represent a new symptom experienced by a study subject or an
exacerbation or worsening of an existing condition.

3.1.2 Serious Adverse Event- (FDA 21 CFR 312.32) Any adverse drug
experience occurring at any dose that results in any of the following
outcomes:

> 1\) Death.
>
> 2\) A life threatening event.
>
> 3\) Requires or prolongs inpatient hospitalization.
>
> 4\) Persistent or significant disability/incapacity.

5\) A congenital anomaly or birth defect.

Important medical events that may not result in death, be
life-threatening or require hospitalization may be considered a serious
adverse drug experience when, based upon appropriate medical judgment,
they may jeopardize the subject and may require medical or surgical
intervention to prevent one of the outcomes listed in this definition.

3.1.3 Unexpected Adverse Event (21 CFR 312.32):

> 1\) Studies Conducted Under an Investigational New Drug (IND)- Any AE;
> the specificity or severity of which is not consistent with the
> current Investigator Brochure or product labeling.
>
> 2\) Studies Conducted Under The New Drug Approval (NDA)- Any AE not
> listed in the current labeling or is different from current labeling
> because of greater severity or specificity. This includes an event
> that may be symptomatically and pathophysiologically related to an
> event listed, but differs from the event because of greater severity
> or specificity. An AE that results in death is unexpected unless the
> labeling indicates a possible fatal outcome.

3.1.4 Associated With The Use Of The Drug (21 CFR 312.32)- A reasonable
possibility exists that the event may have been caused by the drug.

3.1.5 Increased Frequency- An increase in the rate of occurrence of a
particular AE, e.g., an increased number of reports of a particular AE
after adjustment for drug/device exposure.

3.1.6 Unanticipated Adverse Device Effect- Any SAE on health or safety
or 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 or any other unanticipated serious problem associated
with a device that relates to the rights, safety, or welfare of
subjects.

3.1.7 Disability- A substantial disruption of a person(s) ability to
conduct normal life functions.

3.1.8 Life-Threatening Adverse Drug Experience- Any adverse drug
experience that places the patient or subject at immediate risk of death
from the reaction as it occurred, i.e., it does not include a reaction
that, had it occurred in a more severe form, might have caused death.

**[4.0 REPORTING PROCEDURES]{.underline}**

4.1 Any clinical study event that is judged to be an AE should be
recorded on the CRF and on the AE form during the course of the study.
The PI and/or study coordinator ensures this information is captured
during every study subject visit. This form and the information remain a
part of the CRF and are filed appropriately. All supportive information
is filed in the source document.

4.2 Whenever a study subject has reported ANY AE, the study coordinator
discusses the event IMMEDIATELY with the PI (if possible while the study
subject is there) who must evaluate the event.

4.3 If the AE is not serious, the information is recorded on the CRF,
managed medically as appropriate, and the event is followed until
resolution.

4.4 If the AE is \"serious", all SAE are reported to the PI who reports
them to the Sponsor immediately for accurate and timely recording and
reporting. The SAE is also recorded on the CRF, managed medically as
appropriate, and the event is followed until resolution.

4.5 If the event is an \"unanticipated" adverse device effect, the PI is
required to report to the Sponsor, IRB*, and R&D Committee* as soon as
possible but not later than ten (10) working days after the PI first
learns of the event.

4.6 In addition, the PI reviews all completed AE forms for determination
of SAE that require reports to the Sponsor.

4.7 The PI informs the Sponsor immediately of knowledge of a SAE. All
information available on the event (hospital records, lab tests,
discharge summaries, etc.) is forwarded to the Sponsor so they can
determine whether the SAE is unexpected or associated and the reporting
outcome of the SAE. As additional information becomes available on the
SAE, it should be forwarded to the Sponsor.

4.8 All SAE reports shall be sent to the IRB *and R&D Committee* within
ten (10) days of learning of event occurrence.

**[5.0 RECEIPT OF ADVERSE EVENTS FROM SPONSOR (IND SAFETY
REPORTS)]{.underline}**

5.1 All IND safety reports (AE) received from the Sponsor will be
forwarded to the PI. The PI will send copies to all staff involved in
the study as well as the research pharmacist if investigational drugs
are involved in the study.

5.2 The PI and/or study coordinator will file copies of these SAE and AE
in the regulatory binder for that study, also known as the study file
notebook.

5.3 Records of all adverse drug/device events and source documents
should be kept for the same period as other study documents.

M. Rita I. Young

Associate Chief of Staff for Research