>> Elizabeth Ness: Hello, my name is Liz Ness.
And I'm the director of the Office of Education
and Compliance in the Center for Cancer Research
at the National Cancer Institute.
Identifying and monitoring adverse events
is critical to protecting research participants
and ensuring data integrity.
Welcome to a four-part series on adverse events.
Part one, will focus on AE definitions.
Part two, will focus on AE assessment and documentation.
Part three, will focus on reporting of adverse events
or investigational new drug
and investigational device exemption studies.
And the final module, part four,
focuses on reportable events to the IRB,
which includes more than just adverse event reporting.
Understanding the various definitions
associated with adverse events
is the first step to understanding adverse events.
At the end of part one,
I hope that you will be able to define the following;
an adverse event; a serious adverse event;
a life-threatening event; an unexpected adverse event;
a suspected adverse reaction;
and finally, an unexpected adverse device effect.
Let's first take a look at a summary definition
of an adverse event.
An adverse event is any unwanted sign, symptom,
or disease that was not seen
before an individual's research participation,
or a worsening of a baseline symptom
regardless of expectedness or relationship to research.
It is important to note that multiple clinical terms
have been used to convey an adverse event
including toxicity, side effect, acute
or late effect, complication, adverse drug reaction.
However, all of the terms you see on this slide
imply that an intervention caused the adverse event.
Which as the previous slide showed,
is not what the definition of an adverse event
is in clinical research.
The purposes of adverse event monitoring or surveillance,
especially for those events related to this study
intervention or procedures include;
identifying events that may have immediate effect
on the safety of our research participants; helps --
they help to inform our regulators, investigators,
and others of new and important information
about adverse events;
and finally, they provide a summary of adverse experiences
in order to develop the --
a drug or regimen toxicity profile.
The first slide with the AE definition
is sort of what I refer to as my summary slide.
So, now let's take a look at the evidence
that helps to support that definition.
So, there are various definitions
from different regulators.
The first, the U.S. Department of Health
and Human Services regulations at 45 CFR part 46,
actually does not define or use the term adverse event.
However, the Office for Human Research Protection,
or OHRP,
which provides leadership in the protection
of our research participants and the welfare of them,
they do define adverse event in a guidance document.
In their guidance on reviewing
and reporting unanticipated problems
involving risks to subjects or others,
and adverse events,
the term adverse event is used very broadly.
And includes an event meeting the following definition,
“any untoward or unfavorable medical occurrence
in a human subject,
including any abnormal sign, for example,
an abnormal physical exam or laboratory
finding, symptom, or disease temporally associated
with the subject's participation in the research,
whether or not considered
related to the subject's participation in the research”.
This definition has been modified from the definition
of adverse events in the --
from the 1996 International Council for Harmonisation,
or ICH E6 Guidelines for Good Clinical Practice.
Which we'll look at shortly.
Under the FDA investigational new drug application regulations
found at 21 CFR part 312, the FDA defines an adverse event
as any untoward medical occurrence
associated with the use of a drug in humans,
whether or not considered drug related.
And finally, the International Council for Harmonisation
of Technical Requirements for Pharmaceuticals for Human
Use Good Clinical Practice Guidelines,
or simply ICH GCP, defines an adverse event
as any untoward medical occurrence
in a research participant administered
a pharmaceutical product and which does not necessarily
have a causal relationship with a treatment.
You can see how this is similar then
to OHRP's guidance definition.
However, please note that at the time of this taping,
there is a draft version of GCP Guidelines,
which provides a slightly varied definition of adverse event.
The draft guidelines, which came out in May of 2023,
defines an adverse event as any unfavorable medical occurrence
in a trial participant.
The adverse event does not necessarily
have a causal relationship with the treatment.
So, it is slightly different, intent the same.
So, let's take a look at a few more definitions
associated with adverse events.
We're going to take a look at serious,
life-threatening, unexpected, SAR, and UADE.
So, a little bit of alphabet soup there.
So, a serious adverse event
is based on the outcome of the adverse event.
It doesn't have anything to do
with how severe the adverse event was.
And this is used to help determine reportability
to our regulators,
whether that's to the IRB or to the FDA.
So, a serious adverse event is an adverse event
that results in any of the following;
a death, life-threatening adverse drug experience;
an inpatient hospitalization or prolongation
of an existing hospitalization;
persistent or significant incapacity
or substantial disruption of the ability
to conduct normal life functions;
a congenital anomaly birth defect;
or an important medical event,
or IME, that may not result in death,
be life-threatening, or require a hospitalization,
but may be considered serious
when based on appropriate medical judgment,
it may jeopardize the patient or the subject
and may require medical or surgical intervention
to prevent one of the outcomes listed in this definition.
An example of that is an allergic bronchospasm
requiring intensive treatment
either in an emergency room or at home.
So, let's take a moment to look at the definitions
that are associated then with the SAE definition.
One of those is life-threatening.
A life-threatening event is an adverse event
or a suspected adverse reaction if,
in the view of either the investigator or the sponsor,
it occurs -- its occurrence places the patient or subject
at immediate risk of death.
It does not include an adverse event
or a suspected adverse reaction that,
had it might been more severe, it might have caused death.
And again, that's an example --
the example of the allergic bronchospasm
fits this category as well.
So, regulations and guidances
don't really define what an expected event is,
but rather when an event is deemed unexpected.
So, when looking at the FDA definition
under the IND application, when assessing an adverse event
to determine if you need to report this
in what we refer to as an expedited manner,
which we'll talk more about in part three,
an adverse event then would be considered unexpected if;
it wasn't listed in the investigator brochure;
or at the specificity or severity that has been observed;
or if the investigator brochure is not required
or not available,
that it's not consistent with the general risk information
described in the investigational plan,
otherwise known as a protocol,
or elsewhere in the IND application;
if it's mentioned in the IB
as occurring with the drug class or anticipated --
or it's anticipated
based on pharmacological properties of the drug,
but it may not be specifically mentioned
in the investigator brochure.
So, here are the definitions of -- for OHRP and ICH GCP
for an unexpected adverse event.
So, OHRP guidance defines an AE that's not described
in terms of the nature, severity, or frequency.
Or in GCP definition, it's an adverse reaction,
the nature or severity of which is not consistent
with what is known already about the product,
such as what's found in the investigator brochure
or a package insert.
So, a couple of other FDA definitions to look at.
I had mentioned previously a suspected adverse reaction.
And a SAR, S-A-R, is basically an adverse event
related to the drug being studied on a clinical trial.
FDA's definition is any AE for which there is a reasonable
possibility that the drug caused the adverse event.
And reasonable possibility means there is evidence to suggest
a causal relationship between the drug and the adverse event.
And that bolded and underlined "evidence" is really key.
This can include a single occurrence
of an adverse event that's uncommon
and known to be strongly associated with drug exposure.
Or one or more occurrences of an adverse event
that is not commonly associated with drug exposure,
but is otherwise uncommon in the population
that has been exposed to the drug.
Or finally, an aggregate analysis of specific events
observed in a clinical trial
that indicates those events occur
more frequently in the drug treatment group
than in a concurrent group or a historical control group.
And then finally, in device research,
the FDA regulations
don't specifically define serious or life-threatening.
But understanding these definitions,
as we have already looked at them,
will help you to understand and to know when you have
an unanticipated adverse device effect, or UADE.
This is any serious adverse effect on the health or safety
of 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 incidences
in the investigational plan or application.
Or any other unanticipated serious problem
associated with the device that relates to the rights,
safety, or welfare of the subjects.
So, slightly different,
but you see common threads of nature and severity.
So, in closing, adverse event surveillance
helps to ensure the safety of our research participants.
It's critical to understand that the definition of an AE
is regardless of the expectedness or relationship
to the research.
And that there are other definitions
that we have reviewed that will assist you in determining
if and how an adverse event will be reported to sponsors
or other regulatory bodies.
So, let's test your knowledge.
What is the definition of an adverse event?
Is it, A, a known toxicity of the study agent?
B, any untoward sign or symptom
that occurs during the course of a clinical trial?
C, any adverse event which the PI decides to report
during the course of a clinical trial?
Or a side effect caused by the study agent?
And the correct answer is actually B.
Remember, toxicity, side effect,
imply an attribution or a relationship,
which is not part of the definition of an adverse event.
And the PI needs to follow what the definition of an A is --
AE is not just make that decision on themselves.
And one more test your knowledge.
What type of adverse event is the following scenario?
A research participant slips on an icy sidewalk
and suffers a leg fracture requiring an inpatient surgery.
The investigator says this is not related
to the investigational product.
So, A, it's not an adverse event at all.
B, it's an AE only. C, it's an adverse reaction.
D, it's a serious adverse event. And the correct answer is D.
It is an SAE, or a serious adverse event.
Thank you for listening to part one of Adverse Events.