Clinical and Translational

Science Institute / CTSI

at the University of California, San Francisco

Welcome to Online Training for

Clinical Research Coordinators

Adverse Events in Clinical Trials:

Definitions and Documentation

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Monday, February 3, 14
 Objectives

Recognize the difference between a non-serious adverse

event and Serious Adverse Events (SAEs).

Recognize a Suspected Adverse Reaction

Recognize Unexpected or Unanticipated Adverse Events

Differentiate between Severity and Serious Adverse Events

Understand Documentation Best Practice

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 Before Beginning,
Lets Review Principles of Subject Safety
Protecting safety is a Federal mandate requiring investigators to report
certain adverse events (see investigator commitments on FDA form 1572).
Terminology used in this module are derived from
- FDA 21 312.32 Code of Federal regulations,
- Safety Reporting Requirements for INDs and BA/BE Studies FDA
Guidance, December 2012
- International Conference of Harmonization ICH E-6 Good Clinical
Practices
Protecting safety is an institutional mandate from the UCSF CHR/IRB.
Safety is often one of the protocol objectives when testing new therapies
so adverse event data must be collected and reviewed by the Principal
Investigator.
Stopping rules are often clearly identified in terms of types and frequency
of SAEs; the risk versus benefit ratio is a key variable on whether
enrollment to a study can continue.
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 Definitions of Adverse Events

Adverse'event'means'any'
untoward'medical'
occurrence'associated'with'
the'use'of'a'drug'in'humans,'
whether'or'not'considered'
drug'related.''
21 CFR 312.32(a)

Monday, February 3, 14
 Definitions of Adverse Events
ICH E6 Section 1.2

An adverse event (also referred to as an adverse

experience) can be any unfavorable and unintended sign
(e.g., an abnormal laboratory finding), symptom, or disease
temporarily associated with the use of a drug, without
any judgment about causality or relationship to the drug.

An adverse event can arise from any use of the drug (e.g.,
off-label use, use in combination with another drug) and
from any route of administration, formulation, or dose,
including an overdose.

Monday, February 3, 14
 Definitions of Adverse Events

Indicates a change in the subjects health status

since baseline right before taking the study drug.

When toxicity of the study drug is a hypothesis,

you will see on the calendar, a baseline physical
exam to be completed either at Day 0 or Day -5
prior to dosing.

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 Definitions of Adverse Events

Baseline would include all of the below:

Pre-existing conditions that are ongoing during
the clinical trial
- Hypertension
- Diabetes
Concomitant medications taken prior to
participation in the clinical trial
- Anticoagulants to prevent thrombosis
- Steroids for autoimmune condition
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Monday, February 3, 14
 Definitions of Adverse Events
Examples of Adverse Events which are not related
to [or caused by] the study drug but if they occur
while the subject is on study, would have to be
collected, reviewed by PI and tracked:
- Transfusion reactions
- Accidental injuries
- Surgery

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 Definitions of Adverse Reaction
A suspected adverse reaction means any
adverse event for which there is a reasonable
possibility that the drug caused the adverse
event.

Reasonable possibility means there is

evidence to suggest a causal relationship
between the drug and adverse event.

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 Definition of a Serious Event or
Serious Suspected Adverse Reaction
21 CFR 312.32 (a)

An adverse event or suspected adverse reaction 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.
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Monday, February 3, 14
 A Life Threatening Adverse Drug
Experience Defined
Any adverse experience that places the subject, in the
view of the investigator, at immediate risk of death from
the reaction as it occurred, or it is suspected that the use
or continued use of the product would result in the
patients death.

Examples include:
hemorrhaging and internal bleeding with rapid drop in
blood pressure;
Loss of consciousness from increase in pressure on
the brain

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Monday, February 3, 14
 Hospitalization Defined

Admission to the hospital for longer than 24

hours or prolonga5on of a hospital stay due to
adverse event.

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 Disability Defined

A substantial disruption of a persons ability to

conduct normal life functions.

Examples include: loss of speech; fatigue so

great the subject cannot get out of bed at all;
loss of memory; and paralysis.

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 Congenital Anomaly Defined

Exposure to a medical product prior to

conception or during pregnancy resulting in
an adverse outcome in the child.

Thalidomide is the best example

of a drug causing congenital anomalies with
babies born with deformed arms and legs.

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Monday, February 3, 14
 Definition of a Serious Event or
Serious Suspected Adverse Reaction
21 CFR 312.32 (a)
One final outcome that makes an event or reaction
serious:
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 patient or
subject and may require medical or surgical
intervention to prevent one of the outcomes listed
in this definition.
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 Examples of Important Medical Events

Allergic bronchospasm requiring intensive

treatment in an emergency room or at home

Blood dyscrasias

Convulsions that do not result in inpatient

hospitalization,

Development of drug dependency

or drug abuse.
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Monday, February 3, 14
 What is Expected versus Unexpected
when Defining Adverse Events or
Suspected Adverse Reactions
Expected toxicities from the study drug if found in the following:
Safety information on approved products is reflected in product
labeling (Package Insert)
Up-to-date safety information on the products under investigation is
found in the Investigators Brochure (IB)
From these sources the protocol and the informed consent is
written to explain to describe what risks we currently expect from
this study drug.
Safety profile of other drugs in the same class
Unexpected means that the event experienced by the subject is
not listed in any of the documents above.
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Monday, February 3, 14
 Definition of an
Unexpected Adverse Event
Unexpected: An adverse event or suspected adverse reaction
is considered "unexpected" if it is not listed in the investigator
brochure or is not listed at the specificity or severity that has
been observed; or, if an investigator brochure is not required or
available, is not consistent with the risk information described in
the general investigational plan or elsewhere in the current
application, as amended.
21 CFR 312.32 (a)

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 Examples of an
Unexpected Adverse Event
Hepatic necrosis would be unexpected (by virtue of greater
severity) if the investigator brochure only referred to elevated
hepatic enzymes or hepatitis.

Cerebral thromboembolism and cerebral vasculitis would be

unexpected (by virtue of greater specificity) if the
investigator brochure only listed cerebral vascular accidents

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 Definition of Severity vs. Serious

Refers to the intensity of the event and can be used with any
event, without regard to whether or not it meets the federal
criteria for serious.is expressed in grades of severity.
Responsibility of the principal investigator to concur with all
intensity assessments added to the database for the events
identified in the subject.

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 Examples of Grading
Severity/Intensity Ranges
Grade 1: Asymptomatic or mild symptoms; clinical or
diagnostic observations only; no intervention indicated
Grade 2: Moderate; minimal, local or noninvasive intervention
indicated; limiting age-appropriate instrumental ADL
Grade 3: Severe; or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization
indicated; disabling; limiting self care ADL
Grade 4: Life-threatening ; urgent intervention indicated.
Grade 5: Death related to an AE
References:
http://www.fda.gov/downloads/BiologicsBloodVaccines/
GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm091977.pdf
http://evs.nci.nih.gov/ftp1/CTCAE/
CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf
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 Example of Future use of Grading
Adverse Events during the Clinical Trial
When a drug gets approved to be used in clinical practice,
prescribing information will refer to the intensity grading scales
to assist physicians managing patient care.
For patients who develop prolonged Grade 2 diarrhea lasting
more than 48 hours or greater than or equal to Grade 3
diarrhea, withhold [drug name] until diarrhea resolves to
Grade 1 or less, and resume [drug name] with appropriate
dose reduction.

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 IND Safety Reports
All SAE reports sent from Site Principal Investigators to the Sponsor must be
prepared as an IND Safety Report and then tracked as sent to all of the other site
investigators with the expectation both the PI and the IRB will review them.
PI/CRC receives of safety report/letter
PI determines need to:
Update informed consent
Risk/benefit analysis change to subjects
PI and CRC report to UCSF CHR, in a timely manner
Follow CHR requirements
Keep a log of IND Safety Report receipt date, event, date reported to CHR,
informed consent updated (yes/no) for the sponsor
File in study files
21 CFR Subpart B section 312.32(c)(1)IND safety reports . The sponsor must
notify 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
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 Where are Adverse Events or
Reac1ons Documented?
ANSWER: During the course of the study, the CRC will find them in the
Medical Record, Laboratory reports, Radiology reports, Surgical reports,
Infusion Center nursing notes, subject diaries, subject surveys or
questionnaires.
Documentation of all adverse events should be written and signed by
qualified clinicians in the subjects medical record which will serve as
original source. This includes lab and radiology reports often need PI
initials to show review.
Non-serious and serious adverse events
Unanticipated events
Report all directly observed events (rash etc)
Events elicited from the subject
Events spontaneously volunteered by subject
Laboratory, EKG or other test results that meet protocol requirements for
classification as adverse event
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 CRC Role in Adverse Event Collection
Best Practice
Review data entry for adverse events and serious adverse events provided
by the sponsor or investigator developed data entry. It will clue you in on
what needs to be tracked.
All adverse events and suspected adverse reactions are collected from
source documentation and the CRC abstracts the events
Documentation can be within UCSF medical records, but at times the CRC
will also have to have the subject or family send outside source
documentation. If you will have to request records on your own, you will
need a HIPAA release form signed by the subject for the outside institution.
Report all SAEs immediately to the Principal Investigator upon
identification or notification from family.
NOTIFY: MD/NP assigned to the study for subjects medical care in the
event the study drug needs to be stopped, per protocol. The CRC assists
clinical staff to manage the subject. Certain drugs to treat the adverse
event can be forbidden by the protocol.it is the CRCs role to know the
protocol details to assist the clinicians.

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 Tips and Tricks

Print AE Tracking Tool from Database

Oncore and some sponsor databases allow print out
of AEs entered, in a table format, so this can be
reviewed by the Principal Investigator; then ideally
signed or initialed by the PI as having reviewed
causality, severity grades, description of the event.

The CRC must collect and enter this safety data

accurately but cannot take responsibility for
assessing the events.

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 Tips and Tricks
Collecting Adverse Events

Events that are NOT linked pathophysiologically, or

temporarily, are reported as separate events
Example
Subject is admitted to the hospital with Heart Failure
Subject develops sepsis while in the hospital as a
result of the venous catheter and this prolongs the
hospitalization.
Two SAEs for this subject: One for Heart Failure
and one for Sepsis
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 Coding of Adverse Events
Process of converting investigators verbatim
documentation terms to standardized Preferred
Terms (PT)
Standardization allows sorting of AEs and grouping
of like events.
PT used to calculate incidence of AE.
Currently the most used coding dictionary is:
MedDRA (Medical Dictionary for Regulatory
Activities) Is available in OnCore and many large
pharmaceutical safety databases.

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 Be Aware of the Need for Accurate Coding
as you Abstract Clinician Dictation
Coding problems may lead to missing safety signals; can be a
real challenge for the CRC and the monitor from the drug
company will want to make sure that data entered is coded
correctly
Examples:
Splitting same AE among similar PTs
- Hypertension, high blood pressure, etc.
Lumping different terms to same PT
- Leg edema, face edema, etc.
Lack of adequate term/definition
- Drug hypersensitivity, Metabolic syndrome, Serotonin
syndrome

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 Takeaways
Documentation of the subjects baseline medical history,
physical examination, medications and treatments is critical
for evaluating the subjects safety, and adverse events during the
study period
CRC is responsible for abstracting and tracking the adverse events and
adverse reactions in manner that helps the Principal Investigator review
before entering this into a sponsor database.
Understand protocol-specific adverse event definitions and what is
required to be reported in addition to those meeting the federal
definitions.
MD/NP evaluation of the subject cases and IND Safety Reports for the
need to modify the informed consent when changes to risk have been
identified.
Be consistent and use scientific terminology when reporting AEs; get
assistance from your investigators!
It is all about subject safety and human subject protection!

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