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>> Elizabeth Ness:
Hello, my name is Liz Ness.

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And I'm the director
of the Office of Education

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and Compliance in the 
Center for Cancer Research

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at the National Cancer Institute.

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Identifying and 
monitoring  adverse events

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is critical to protecting
research participants

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and ensuring
data integrity.

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Welcome to a four-part series
on adverse events.

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Part one, will focus
on AE definitions.

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Part two, will focus on AE
assessment and documentation.

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Part three, will focus
on reporting of adverse events

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or investigational new drug

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and investigational 
device exemption studies.

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And the final module,
part four,

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focuses on reportable
events to the IRB,

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which includes more than
just adverse event reporting.

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Understanding the 
various definitions

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associated with adverse events

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is the first step to
understanding adverse events.

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At the end of part one,

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I hope that you will be able
to define the following;

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an adverse event;
a serious adverse event;

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a life-threatening event;
an unexpected adverse event;

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a suspected adverse reaction;

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and finally, an unexpected
adverse device effect.

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Let's first take a look
at a summary definition

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of an adverse event.

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An adverse event
is any unwanted sign, symptom,

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or disease that was not seen

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before an individual's
research participation,

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or a worsening
of a baseline symptom

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regardless of expectedness
or relationship to research.

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It is important to note
that multiple clinical terms

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have been used to convey
an adverse event

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including toxicity,
side effect, acute

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or late effect, complication,
adverse drug reaction.

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However, all of the terms
you see on this slide

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imply that an intervention
caused the adverse event.

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Which as the 
previous  slide showed,

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is not what the definition
of an adverse event

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is in clinical research.

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The purposes of adverse event
monitoring or surveillance,

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especially for those events
related to this study

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intervention
or procedures include;

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identifying events
that may have immediate effect

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on the safety of our
research participants; helps --

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they help to inform
our regulators, investigators,

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and others of new
and important information

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about adverse events;

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and finally, they provide
a summary of adverse experiences

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in order to develop the --

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a drug or regimen
toxicity profile.

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The first slide with
the AE definition

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is sort of what I refer
to as my summary slide.

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So, now let's take a 
look at the evidence

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that helps to support
that definition.

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So, there
are various definitions

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from different regulators.

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The first, the 
U.S. Department of Health

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and Human Services 
regulations at 45 CFR part 46,

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actually does not define
or use the term adverse event.

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However, the Office
for Human Research Protection,

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or OHRP,

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which provides leadership
in the protection

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of our research participants
and the welfare of them,

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they do define adverse event
in a guidance document.

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In their guidance on reviewing

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and reporting
unanticipated problems

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involving risks to 
subjects or others,

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and adverse events,

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the term adverse event
is used very broadly.

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And includes an event meeting
the following definition,

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“any untoward or unfavorable
medical occurrence

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in a human subject,

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including any 
abnormal sign, for example,

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an abnormal physical 
exam or laboratory

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finding, symptom,
or disease temporally associated

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with the subject's 
participation in the research,

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whether or not considered

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related to the subject's
participation in the research”.

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This definition has been
modified from the definition

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of adverse events in the --

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from the 1996 International
Council for Harmonisation,

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or ICH E6 Guidelines
for Good Clinical Practice.

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Which we'll look at shortly.

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Under the FDA investigational
new drug application regulations

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found at 21 CFR part 312,
the FDA defines an adverse event

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as any untoward
medical occurrence

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associated with the use
of a drug in humans,

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whether or not 
considered drug related.

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And finally, the International
Council for Harmonisation

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of Technical Requirements
for Pharmaceuticals for Human

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Use Good Clinical
Practice Guidelines,

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or simply ICH GCP,
defines an adverse event

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as any untoward
medical occurrence

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in a research 
participant administered

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a pharmaceutical product
and which does not necessarily

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have a causal 
relationship with a treatment.

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You can see how
this is similar then

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to OHRP's
guidance definition.

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However, please note
that at the time of this taping,

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there is a draft version
of GCP Guidelines,

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which provides a slightly varied
definition of adverse event.

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The draft guidelines,
which came out in May of 2023,

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defines an adverse event as any
unfavorable medical occurrence

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in a trial participant.

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The adverse event
does not necessarily

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have a causal relationship
with the treatment.

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So, it is slightly different,
intent the same.

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So, let's take a look 
at a few more definitions

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associated with adverse events.

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We're going to take
a look at serious,

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life-threatening,
unexpected, SAR, and UADE.

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So, a little bit
of alphabet soup there.

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So, a serious adverse event

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is based on the outcome
of the adverse event.

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It doesn't have anything to do

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with how severe
the adverse event was.

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And this is used to help
determine reportability

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to our regulators,

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whether that's to the 
IRB or to the FDA.

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So, a serious adverse event
is an adverse event

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that results in
any of the following;

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a death, life-threatening
adverse drug experience;

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an inpatient hospitalization
or prolongation

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of an existing
hospitalization;

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persistent
or significant incapacity

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or substantial disruption
of the ability

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to conduct
normal life functions;

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a congenital anomaly
birth defect;

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or an important
medical event,

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or IME, that may
not result in death,

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be life-threatening,
or require a hospitalization,

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but may be considered serious

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when based on appropriate
medical judgment,

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it may jeopardize
the patient or the subject

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and may require medical
or surgical intervention

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to prevent one of the outcomes
listed in this definition.

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An example of that is
an allergic bronchospasm

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requiring intensive treatment

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either in an emergency 
room or at home.

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So, let's take a moment to 
look at the definitions

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that are associated then
with the SAE definition.

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One of those
is life-threatening.

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A life-threatening event
is an adverse event

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or a suspected
adverse reaction if,

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in the view of either
the investigator or the sponsor,

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it occurs -- its occurrence
places the patient or subject

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at immediate risk of death.

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It does not include
an adverse event

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or a suspected
adverse reaction that,

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had it might been more severe,
it might have caused death.

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And again, that's an example --

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the example of the
allergic bronchospasm

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fits this category as well.

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So, regulations and guidances

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don't really define
what an expected event is,

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but rather when an event
is deemed unexpected.

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So, when looking
at the FDA definition

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under the IND application,
when assessing an adverse event

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to determine if you 
need to report this

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in what we refer to
as an expedited manner,

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which we'll talk more
about in part three,

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an adverse event then would be
considered unexpected if;

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it wasn't listed
in the investigator brochure;

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or at the specificity or
severity that has been observed;

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or if the investigator 
brochure is not required

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or not available,

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that it's not consistent with
the general risk information

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described in
the investigational plan,

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otherwise known as a protocol,

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or elsewhere
in the IND application;

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if it's mentioned in the IB

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as occurring with the drug class
or anticipated --

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or it's anticipated

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based on pharmacological
properties of the drug,

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but it may not be
specifically mentioned

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in the investigator brochure.

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So, here are the definitions
of -- for OHRP and ICH GCP

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for an unexpected
adverse event.

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So, OHRP guidance defines
an AE that's not described

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in terms of the nature,
severity, or frequency.

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Or in GCP definition,
it's an adverse reaction,

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the nature or severity
of which is not consistent

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with what is known already
about the product,

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such as what's found
in the investigator brochure

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or a package insert.

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So, a couple of other
FDA definitions to look at.

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I had mentioned previously
a suspected adverse reaction.

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And a SAR, S-A-R,
is basically an adverse event

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related to the drug being
studied on a clinical trial.

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FDA's definition is any AE
for which there is a reasonable

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possibility that the drug
caused the adverse event.

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And reasonable possibility means
there is evidence to suggest

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a causal relationship between
the drug and the adverse event.

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And that bolded and underlined
"evidence" is really key.

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This can include
a single occurrence

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of an adverse event
that's uncommon

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and known to be strongly
associated with drug exposure.

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Or one or more occurrences
of an adverse event

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that is not commonly
associated with drug exposure,

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but is otherwise uncommon
in the population

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that has been exposed
to the drug.

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Or finally, an aggregate
analysis of specific events

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observed in a clinical trial

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that indicates
those events occur

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more frequently
in the drug treatment group

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than in a concurrent group
or a historical control group.

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And then finally, in device
research,

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the FDA regulations

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don't specifically define
serious or life-threatening.

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But understanding
these definitions,

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as we have already
looked at them,

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will help you to understand
and to know when you have

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an unanticipated
adverse device effect, or UADE.

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This is any serious adverse
effect on the health or safety

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of any life-threatening problem
or death caused by

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or associated with a device,
if that effect, problem,

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or death was not previously
identified in nature,

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severity, or degree of incidences

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in the investigational 
plan or application.

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Or any other
unanticipated serious problem

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associated with the device
that relates to the rights,

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safety, or welfare of the subjects.

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So, slightly different,

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but you see common threads
of nature and severity.

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So, in closing, 
adverse event surveillance

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helps to ensure the safety
of our research participants.

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It's critical to understand
that the definition of an AE

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is regardless of the
expectedness or relationship

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to the research.

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And that there are
other definitions

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that we have reviewed that
will assist you in determining

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if and how an adverse event
will be reported to sponsors

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or other regulatory bodies.

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So, let's test your knowledge.

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What is the definition
of an adverse event?

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Is it, A, a known toxicity
of the study agent?

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B, any untoward sign or symptom

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that occurs during the course
of a clinical trial?

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C, any adverse event
which the PI decides to report

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during the course
of a clinical trial?

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Or a side effect
caused by the study agent?

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And the correct answer
is actually B.

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Remember, toxicity, side effect,

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imply an attribution
or a relationship,

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which is not part of the
definition of an adverse event.

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And the PI needs to follow what
the definition of an A is --

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AE is not just make
that decision on themselves.

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And one more test
your knowledge.

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What type of adverse event
is the following scenario?

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A research participant
slips on an icy sidewalk

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and suffers a leg fracture
requiring an inpatient surgery.

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The investigator says
this is not related

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to the investigational product.

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So, A, it's not
an adverse event at all.

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B, it's an AE only.
C, it's an adverse reaction.

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D, it's a serious adverse event.
And the correct answer is D.

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It is an SAE,
or a serious adverse event.

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Thank you for listening to part
one of Adverse Events.