>> Liz Ness: Welcome to Part 2 of Adverse Events,
Assessment and Documentation.
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.
Assessment of adverse events and timely documentation
is crucial to research participant safety
and a critical component of good clinical practice.
At the end of Part 2,
I hope you'll be able to describe the components
of a quality adverse event assessment and documentation
as well as the common data elements
that are collected on an adverse event case report form.
When you are assessing safety
and or toxicity in a clinical trial,
you need to first assess
and document how the participant is doing at baseline
before beginning any component of the research.
So, you want to assess the signs and symptoms that are present
when the participant starts treatment.
So, for example, this could be the first day
immediately pre-dosing or receiving the intervention.
It usually doesn't include those signs and symptoms that occurred
and resolved between the time of eligibility screening
and the starting of dosing.
Those often are considered part of medical history
and are added to a medical history case report form.
And you would need to have some type of a description
such that you knew how severe that baseline symptom was.
Please note though that some sponsors
required the research teams to record adverse events from
when the patient signs the consent
through the first study intervention.
This should be defined in the protocol
or at least in the case report form instruction manual.
Assessment of an adverse event
is done by the principal investigator
or their designee who is a member of the research team.
Typically, these are other licensed individuals.
And it includes determining the severity
as well as the cause of the event.
It is this assessment plus the expectedness
and outcome of the event that determine the timelines
for reporting an adverse event to the IRB, sponsor,
or other regulatory or oversights groups.
The reporting will be done in AE Part 3 and Part 4.
Using controlled vocabularies to represent clinical concepts
is the best way to describe an adverse event
or to select an adverse event term.
MedDRA, or the Medical Dictionary
for Regulatory Activities, and SNOMED,
or the Systematized Nomenclature of Medicine Clinical Terms,
are two most common sources for medical terminology.
MedDRA is widely used in clinical trials,
whereas SNOMED Clinical Terms is used for clinical care data,
often in your, maybe, electronic health record.
In oncology, the clinical -- the common toxicity,
the CTCAE or the Common Terminology Criteria
for Adverse Events
is used, which is a combination of MedDRA terms,
which we'll talk more about in a minute,
and a severity rating scale,
which will be described later in this session.
Though the CTCAE was initiated in oncology,
other disease specialties do use this as well for their standard
in determining an AE term or severity
or use it as a model to create a similar type
of severity rating scale.
So, MedDRA is a clinically validated international
medical terminology dictionary with each term
having a unique code
and what is referred to as a concept ID.
It was initially developed in 1994 by ICH to facilitate
the sharing of regulatory information internationally.
MedDRA is used by the biopharmaceutical industry
and regulatory authorities for AE classification.
The structure of MedDRA is actually very logical.
There are five levels to the MedDRA hierarchy,
arranged from very specific to very general,
or very general to very specific.
The first highest level is called a SOC
or a System Organ Class
for which they're in the version of 26
that was released in March of 2023.
There are 27 SOCs.
These are the highest level of the terminology
and they're distinguished
by anatomic or physiological systems
such as infections or infestations
or purposes such as surgical or medical.
Then there is a High-Level Group Term,
a subordinate to the SOC, a High-Level Term,
which is subordinate to the term above,
the High-Level Group Term, a Preferred Term,
which represents a single medical concept,
and then a Lowest Level Term,
which is related to a single preferred term
as synonyms or quasi-synonyms.
And here is an example of the Preferred Term, fatigue,
which is found in the System Organ Class of general disorders
and administrative site conditions,
a High-Level Group Term of general systems disorders NEC
or not elsewhere classified,
a High-Level Term of asthenic conditions,
Preferred Term of fatigue.
And then when you look at the various Lower-Level Terms,
you can see that these often represent
how our research participants
might express an adverse event term of fatigue,
such as, "I'm feeling washed out."
"I'm just tired all the time." "I feel very weary."
"I'm exhausted." And that's then how we can take
what the research participant says,
what we see documented in a medical record,
and determine what might be the most appropriate,
let's say Preferred Term, that can be used
and then shared across regulatory agencies.
So, understanding and measuring severity is also important.
So, in clinical trials,
typically there are rating scales
that are used to measure severity.
The severity of an AE often determines
if dosing interruptions,
modifications, or maybe even a discontinuation needs to be
implemented according to what the protocol says.
Rating scales can be used for eligibility criteria.
They can also include how the severity of the adverse event
is to be measured,
even if only providing descriptions
for mild, moderate, or severe.
And here you can see some definitions of mild,
moderate, and severe.
So, mild, there is an awareness of a sign, a symptom,
or an adverse event, but it's easily tolerated.
Moderate means that it's uncomfortable,
that it's causing some interference
with usual activities of daily living,
or that it may warrant some additional investigation.
And severe is incapacitating their ability
to do their usual activities
or having significant effect on their clinical status
that further warrants intervention.
And sometimes, you know, my definition of mild
might be different than your definition of mild.
So, it is important to try to hone in on this in a protocol
when defining what severity an adverse event is.
As I mentioned, in oncology,
we utilize what we call the CTCAE.
The National Cancer Institute Cancer Therapy Evaluation
Program actually developed the original CTC,
which was Common Toxicity Criteria, in 1983
to help aid in recognizing and assessing the severity,
or what's referred to as grading of adverse effects
on chemotherapy. The name was changed since,
as I mentioned in Part 1 of Adverse Events,
toxicity has an implication of an association
with the intervention.
And as we know, adverse events do not have that association.
These became fundamentally agreed upon terms
for adverse events within oncology research.
But as I mentioned, it has gone to other disciplines as well.
And it's organized by MedDRA terms
using the System Organ Class
minus the product issue system organ classification.
And the AE term is a Lowest Level Term,
which can be rolled up then to a Preferred Term.
This is just a brief evolution of CTCAE.
Initially, there were categories and adverse event terms.
You can see with each version,
there were an increase in categories,
which with Version 4 in 2010
was harmonized with MedDRA's System Organ Class.
And then the AE terms have also exponentially grown.
You'll notice that the current Version 5.0
has 837 adverse event terms.
And as you saw in a couple of slides previously,
the MedDRA Lower-Level Terms,
there were, you know, almost 88,000.
So, these are certainly subsets
of what is commonly seen in oncology research.
I will note as of this taping as well Version 6 is in the works
and is waiting for a finalization
with the fall release of MedDRA, which typically is in September.
They do sort of a point version --
point one version release in the fall
with their main version releases in the early spring,
typically in March.
If a condition is not listed, since there's only 837 terms,
each of the SOCs has what we refer to as an Other category,
so that a term can be applied there.
And I'll show you how you would then
determine what severity rating.
But let's take a look of an AE term.
I selected anemia.
It falls within the blood and lymphatic system disorder SOC.
And the SOCs in general are located alphabetically.
And the adverse event terms
also are listed alphabetically within a SOC.
And as I mentioned, each SOC has an Other AE term.
All of the AE terms have a definition that you see here
as well as different grades.
So, when you read -- when you're reading CTCAE,
semicolons are read as or statements.
And sometimes you will see what's called an em-dash
or a line, which indicates that that grade
or that severity rating is not appropriate.
For an example of then how to use this
in reviewing a lab result, if you have a hemoglobin of 8.1,
but the physician feels based on the symptoms of the participant
that they need a blood transfusion.
At face value, the lab value itself looks like it would mean
that that would be a Grade 2 event.
However, when a transfusion is indicated,
the comma or the semicolon in Grade 3 reads
as an or statement. So, or a transfusion indicated.
So, a hemoglobin of 8.1 with a participant
who might be symptomatic and is in need of a transfusion
becomes a Grade 3 anemia as an adverse event.
Here is another example.
And I chose this example of diarrhea
as an adverse event term
to indicate how important baseline assessment really is.
So, you can see the SOC here of gastrointestinal disorders.
And you can see that the grading or the definitions
within each grade talk about an increase over baseline.
So, it's really critical to understand
what the normal bowel pattern is of a research participant,
especially when you may anticipate changes
in their bowel pattern
given what you know about the products
or the interventions within that clinical trial.
You can also notice here that you have an increase
or limiting self-care ADLs.
So, self-care ADLs are those ADLs
that you do for yourself such as bathing, feeding,
and then there's other ADLs called instrumental ADLs
that are part of some of the definitions.
And I think of those
as when you're not able to do for others,
such as going to the grocery store
or preparing a meal for your family.
So, since not all terms are available that are in MedDRA,
other is an AE term, and then you describe that.
And this is the descriptions for each of the grades here.
And again, you would use the semicolons as an or statement.
So, if you had a term that wasn't available
you would look to the other grading scale
and determine which definition or description it falls in
to select the appropriate grade.
So, for those of you that do utilize CTCAE.
It is available on a smartphone or tablet.
It has a great, easy search feature.
This is just snapshots from the app from my phone.
This pulls up the System Organ Class of blood
and lymphatic system disorders.
And when I went and plugged-in anemia, I can see --
you can see the same grading scale with the definition here
that I noted in a few slides previously.
There's also a PDF version on NCI's website,
and that also, you know, you can search
using the PDF search feature.
So, the FDA also has a guidance document
for grading adverse events in prevention clinical trials.
And so, you can see here
they use a similar system of Grades 1 through 4,
and that is found in the guidance document
entitled here on the slide.
But regardless of how an adverse event is assessed for severity
or which grading scale you use.
The protocol ideally should help provide you
with that information to guide you
in having consistent assessments of severity rating.
Once the severity of an adverse event is established,
the next step really is to find the cause
or the attribution of the event.
Is the event related to the study agents,
the patient's, you know,
underlying condition that's being studied,
or underlying pre-existing conditions?
So, determining the attribution is done by the PI
or a provider designee who's knowledgeable about the product
and about the protocol.
I always think of determining an attribution or causality
as not just a science, but an art.
And here are some following things that can be --
some questions that you can ask to help the research team
determine that attribution.
What do you already know about the drug, the therapy,
or the classification of the drug?
So, the expectedness.
What is the temporal relationship of the event
to the study therapy or intervention?
Does the adverse event improve or disappear
when the drug or the therapy is stopped?
If the drug or therapy is reintroduced,
does the adverse event reappear?
Does it reappear at the same time point?
Does it reappear at the same severity rating?
Is the adverse event a result of signs
or symptoms of the underlying disease being studied?
Is it a worsening of baseline symptoms?
Is the adverse event a result of an underlying concurrent
on medical condition or the use of a concurrent medication?
So, those are some questions.
And so, what are our options for then
assigning those attributions or causalities.
So, there's sort of two approaches.
This approach one is what I call the dichotomized approach.
So, you either think that it's related.
So, there's a reasonable causal relationship
between the adverse event,
and I'll explain the blanks in a minute,
or it's not related.
There's no reasonable causal relationship.
Then there's what I call the five degrees of separation
or five options where you have definite,
which means it's clearly related;
probable, likely related;
possible, maybe related; unlikely, doubtfully related;
or unrelated, clearly related.
And the trick is really filling in the blank.
So, if the AE is related to the investigational product,
the commercial agent, the underlying comorbid disease,
when you fill in that blank, that will then help you to know
if you have any reporting responsibilities to the IRB
or to your sponsor,
who in turn may then need to report to the IRB --
or to the FDA, my apologies.
The IRB is looking at the relatedness to the research.
So, all components of the research,
whereas the sponsor is often really looking
for the relatedness to the product.
So, teasing this out is extremely important.
And we always do want to tease out
and try to determine how to fill in that blank and determine,
is there a relatedness or not?
And if the relatedness is to something else
other than the research,
we do owe it to our participants to determine that
and to find out that cause.
So, when we start thinking about assessing of adverse events,
it really comes from our participants,
you know, review of systems,
physical exam findings, laboratory
and other radiologic results,
or, you know, EKG results, things like that.
But again, before starting on a clinical research study,
especially a clinical trial,
a good baseline assessment is needed.
And that does include finding what is abnormal.
So, what laboratory values are already abnormal?
In a review of systems, what are the current symptoms
that an individual may be experiencing?
It's also important to assess their concomitant
or current medications.
Because sometimes a change in those,
or if a medication was recently introduced,
possibly a day before starting on an intervention,
then the assessment might be a little bit different.
So, all of this baseline information
is extremely critical.
So, adverse event information should be collected really,
as I mentioned, you know, from either the time of consent,
if that's what the sponsor wants,
or the initiation of the study intervention,
or the start of a placebo lead-in period
or there may be an observational or washout type of period
to establish what the baseline condition of the individual is,
which is a little bit different than the baseline going in.
There could be two baselines, if you will,
if you have a placebo lead-in
or some type of an observational period.
So, before documentation of an adverse event,
the research team really does need to understand
how AEs should be collected.
In order to prevent bias, collection of adverse events,
participants should not be questioned specifically
regarding what we might anticipate could occur.
So, if we do know, for example,
that there could be a change in bowel habits,
we wouldn't want to necessarily say,
"Have you had experienced any diarrhea?
Have you experienced constipation?"
But we would want to ask a general question of,
"Have you had any changes in, you know, your bowel pattern
or your bowel habits." So, that's really important.
Ideally, the adverse events should be spontaneously reported
or elicited from the participant during open-ended questioning,
during the examination, or during the evaluation
of the examination review or review of systems.
Adverse events do need to be followed
until resolution or stabilization.
There are some adverse events that may never resolve.
For example, with an oncology patient
who has brain metastasis and receives brain radiation,
the hair on their head or alopecia may not ever return.
There're also some drugs that might have a toxicity
of a neuropathy. That neuropathy may improve,
but it may never be able to completely go away.
So, those are a couple of examples
of sort of the stabilization.
So, further decreasing of severity,
but not a total resolution.
So, all adverse events should be documented
in a participant's medical record,
or in some cases for healthy volunteers,
if a medical record is not required
for the institution's policy,
it may be documented in a research record
or potentially on a case report form
if that has been prearranged with the sponsor.
The documentation includes, you know, the adverse event itself,
when it started, any workup or treatment that is needed.
It is important that all healthcare providers,
professionals who are interacting
with the research participant,
understands what is happening and what the research team,
the PI, thinks the causality of the adverse event is.
When that information isn't being shared,
it could lead to the potential, you know, treatment of the event
with a medication that's prohibited on the protocol.
Or it could impact, you know, another provider's ability
to provide an accurate assessment and plan
if they're not a member of a research --
of the research team directly.
So, a quality progress note, documenting an adverse event
does need to include the date of the adverse event.
It also could be important to note the time,
especially when dealing with infusion reactions.
The time from the start of the infusion
can be extremely helpful in further developing a product
and the timing of potentially the rate of infusion
as an example.
Treatment for the event and indicating if no treatment
is needed or further treatment or an earlier repeat of a lab.
Those are all examples of sort of a treatment.
There should be a description of the adverse event
such that it can be assessed for severity
or graded depending upon the rating scale that is used.
As I mentioned, the adverse event attribution
is important to document, again, for other health care providers,
and when the adverse event begins to resolve,
worsen, or improve.
So, recording of adverse events, also known as data abstraction,
is when we take what has been documented
in the source document,
the medical record or the research record,
and we abstract that onto a case report form.
And that is going to be dependent on the protocol.
Some protocols may want all adverse events recorded.
Others may only want Grade 2 through 5
adverse events recorded.
But the protocol should clearly outline
what types of adverse events that have been documented
need to be recorded on a case report form
and used for further data analysis.
Though adverse event case report forms can vary
from institution or sponsor,
most forms contain similar information.
They contain what is the adverse event term,
the date of the adverse event, the severity, the treatment,
the attribution, the treatment, the attribution,
and when the adverse event resolves,
or when the grade of the adverse event ends,
and a new grade begins.
So, always refer to the protocol for these recording,
what I call recording exceptions,
and the case report form instruction manual.
Both of those are going to be very helpful
when it comes to then the documentation of the events
in the research database or on the research case report form.
So, in closing, assessment of adverse events
is critical for protecting our research participants
in developing toxicity profiles for a drug or intervention.
A quality baseline assessment is the first step
in assessing an adverse event.
Adverse events assessment includes
asking open-ended questions
as well as reviewing results from physical exams,
laboratory, imaging reports, other medical reports.
All adverse events should be documented
in either the medical or research record.
So, all health care providers caring for the participant
can be aware of the event as well as its cause.
And the attribution of the adverse event should be assessed
by the PI or provider designee and shouldn't be taken lightly.
There are several questions that need to be addressed
to achieve
the most accurate attribution or causality of the event.
While all adverse events are documented,
not all adverse events
may need to be recorded on the case report form.
And even fewer will need to be reported to sponsors
and regulatory authorities,
which will be discussed in Parts 3 and 4.
So, let's test your knowledge.
The attribution of an adverse event can be determined
by the study coordinator on the research team,
if they are a nurse.
True or false?
And the answer is false.
The severity and relationship of an AE
is completed by the PI or a provider coordinator.
But not the study coordinator who may be a registered nurse.
No matter how talented that coordinator is,
the responsibility lies with the PI.
Thank you for listening to Part 2 of Adverse Events.