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>> Liz Ness: Welcome to part
three of Adverse Events,

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investigational new drug
and investigational device

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exception reporting.

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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 for the 
Center for Cancer Research.

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In part three, I'll be 
talking about adverse events

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that require expedited 
reporting to the sponsor

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and then to the FDA under
the IND or IDE regulations,

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including timeliness of reporting

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and the responsibilities of the
investigator and the sponsor.

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Events to be reported
in expedited manner

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to various regulatory groups

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should be defined
in the protocol,

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include the 
timelines for reporting,

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and indicate the appropriate
form or database to be used.

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As you can see
on the slide here,

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these are the applicable
regulations and guidances

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related to IND
and IDE AE reporting.

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So, let's jump into AE

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reporting under the IND
application regulations.

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Per the FDA, the PI
must immediately report

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to the sponsor
any serious adverse event,

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whether or not considered

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related to
the investigational product,

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including those listed
in the protocol

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or investigator brochure,
and must include an assessment

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of whether there is
a reasonable possibility

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that the investigational product
caused the event.

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Sponsors will typically
have an SAE form

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or a database that you need
to use to report the SAE

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or some sponsors may require you
to use the FDA mandatory

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Med Watch Form 3500-A.

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Also, many sponsors,
that the concept of immediately

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reporting that stated
in the regulations,

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most sponsors allow
for a 24-hour reporting

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which is acceptable
with the FDA.

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But be aware that not all SAEs
may need to be reported

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to the sponsor
in an expedited manner.

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Refer to your protocol
for exceptions

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to expedited reporting.

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Sponsors may also require
events to be reported,

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such as all pregnancies,
regardless of the outcome,

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overdose of any drug
while on protocol,

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or development of a previously
undiagnosed cancer, for example.

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They may have separate forms
or the sponsor

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may want you to use the same
SAE form or SAE process,

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so please be aware
of that as well.

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Some studies have
additional events

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that will need to be reported
in an expedited manner

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to the sponsor ultimately then,
potentially to the FDA,

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that are not SAE's but may have
a scientific or medical concern

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with the development
of the product.

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These may be referred
to as adverse events

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of special interest or AESIs.

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These are non-serious
that might be a precursor

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of a more serious
medical condition or important

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because they may have
an impact on quality of life.

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For example,
a protocol may require

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that all bleeding events greater
than a Grade One or even Grade

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One be considered an AESI.

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So please be aware of that

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also should be stated
in your protocol.

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Though the expedited report
forms or databases

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may be different
from sponsor to sponsor,

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they all have similar
key components.

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There's reporter information,

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patient or participant
demographic information,

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information about
the investigational product

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or the study agent,
including the dates given,

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the dose, the route
of the administration,

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possibly even the lot number,

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especially with something
like a vaccine product,

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and an event description
including the severity

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and the type of seriousness
and the attribution,

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as well as a narrative summary.

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One of the most important parts
of the report,

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in my opinion,
is the narrative summary.

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The recipient of these SAE
reports very likely

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does not know anything

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about the participant
and their history.

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The narrative helps to provide
that background information

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necessary
to assess the event and support

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the investigator’s
attribution of the event.

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So, the narrative
should include information

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that helps to describe
the event,

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information that puts the event
into perspective.

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So that could be
including important relative

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participant history,

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such as underlying
medical conditions,

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prior surgeries
or other procedures,

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potentially family history,

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recent events
that may contribute --

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be a contributing factor
concomitant medications,

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for example.

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It also may be helpful
or even requested by the sponsor

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to provide
supporting documentation.

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This could include
an inpatient hospitalization

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discharge summary,
or a lab or imaging results.

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This can then just be referred
to in the narrative summary,

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such as see in patient
hospitalization

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discharge summary
for more information

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and not include that
in the narrative.

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So, if you consider
the following scenario,

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which does happen frequently,

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you have a member
of the research team

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receives a phone message
from the participant

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or a family member stating that
the participant was hospitalized

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and no additional
information was given.

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You know that
because hospitalization

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is deemed a serious,
it’s deemed serious.

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So there was an AE,
an event that occurred,

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that resulted
in a hospitalization.

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Most likely this is going
to need to be reported

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to your sponsor
in an expedited manner,

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so within that immediate
or 24-hour time frame.

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So, what do you do
with limited information

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that you received
in a voice message?

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So, it's helpful if
your research team

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is not the primary
treating physician

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or even the primary institution

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for your research participant,
contact them.

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Maybe the patient is coming
to your research site

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but they have a local physician
and they --

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participant contacted
that local physician

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and they told them
to go to the hospital.

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So, that local physician
may know more

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about what the event is,
or you may be able to contact

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or even double check
your own institution

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to make sure that
they weren't hospitalized there.

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And submit what you have.

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Include in
your narrative summary.

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What was the most recent
clinical evaluation?

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What was the date?
How were they doing?

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Maybe you haven't yet done
an initial, you know, visit.

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Include what you have
at baseline.

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What you have
with their history.

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Provide you know a summary
of what you do know

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and include a plan
for completing

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and getting the rest
of that information.

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And as you will see,

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the sponsor has time frames
for reporting to the FDA,

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which is why SAEs are reported
in, you know, within 24 hours.

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So, it's going to be important
for the sponsor to get

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as much follow-up information
as soon as it becomes available.

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And that's typically done then
with an additional

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or an amended SAE report.

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So as a general rule, follow up
is required

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or a follow-up report

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is required to be submitted
to the sponsor

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when there is a change
in the severity attribution

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or maybe the actual
event itself.

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Maybe there was a symptom
that the participant

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was admitted
to the hospital

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with that actually then
turned into an actual diagnosis

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and that diagnosis then is
the more appropriate AE term.

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If you have a change in the --
or any new information,

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let's say, about a death
that becomes available.

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So, you have a death.

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You have an initial
potential cause of death,

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but an autopsy
is going to be done.

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So, you would want to, then,

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after you receive
that autopsy report,

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make sure that you do
a follow up

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if that cause of death
then is different,

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and obviously
if you get requested

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by a, you know, any regulatory
or oversight group,

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this could be the sponsor.
This could be even an IRB.

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You'd want to give them
additional information.

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But as a general rule,
follow up isn't required

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or a follow-up report

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is not specifically required
if the adverse --

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if you're just letting
the sponsor know

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the AE has resolved.

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But again, that can be
very sponsor dependent,

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but the routine
adverse event case report form

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would certainly have that end
date for that adverse event.

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But be aware of that

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and follow what
your sponsor requirements are.

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So now we'll focus on what
the IND sponsors responsibility

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is for reporting to the FDA
and this could include

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your biopharmaceutical
industry sponsors,

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but it could also include
an investigator who also --

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who holds an investigator
held IND.

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So, the IND sponsor must report
any suspected adverse reaction

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or adverse reaction
to the study treatment

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that is both serious
and unexpected.

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So, you can see why it's
important to first understand

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the definitions associated
with adverse events,

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as was presented in part one.

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You know what the suspected
adverse reaction is,

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as well as what the definition
for serious and unexpected is.

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There are potentially
three types of reports a sponsor

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will be sent to the FDA:

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A seven-day report, a 15-day
report, and a follow up report.

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So, let's take a look
at those individually.

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The first is a 15-day
IND safety report,

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sometimes referred to as an ISR.
The sponsor must notify the FDA

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and all participating
investigators of any IND

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from a clinical trial

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or other sources
as soon as possible,

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but no later than
15 calendar days

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after the sponsor determines

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that the information
qualifies for reporting.

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This would include all serious
and unexpected suspected

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adverse reactions
also referred to as a SUSAR.

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We have talked about this again.

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These definitions are extremely
important to understand.

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It also includes findings
from other studies,

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findings from animal
or in vitro testing,

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or an increased rate
of occurrence

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of serious suspected
adverse reactions.

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The sponsor must report any
suspected adverse reaction

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that is both serious
and unexpected

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if there is evidence to suggest
that causal relationship

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between the investigational
product and the adverse event.

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As mentioned in part
one of adverse events,

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this can include a single
occurrence of an adverse event

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that's uncommon

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but known to be strongly
associated with drug exposure.

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This could be some type
of hepatic injury or angioedema.

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One or more occurrences
of an event

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that is not commonly
associated with the product

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but is otherwise uncommon
in the population

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exposed to the drug,
such as, say, a tendon rupture,

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or then aggregate analysis
of specific events

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observed in a clinical trial
such as known consequences

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of underlying disease or
condition under investigation,

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or other events that commonly
occur in the study population

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independent of drug therapy that
indicates those events occur

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more frequently
in the drug treatment group

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than in the concurrent
or historical control group.

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So, this could be even
something as related to death

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due to progressive disease.

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The FDA considers SUSARs
as unanticipated problems

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and reportable
by the investigator to the IRB,

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which I'll discuss further
in part four.

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The sponsor must report,
as I had mentioned,

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any findings from other studies.

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And this typically
is epidemiologic studies

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or a pooled analysis

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from multiple studies
or clinical studies,

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whether or not they were
conducted under an IND.

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Sometimes INDs continue
even after a product

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has been initially approved
and the sponsor considers

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that there could be a suggestion
of significant risks

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to humans
exposed to the product.

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Ordinarily, these findings
would be reported in safety

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related changes
to the protocol,

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but sometimes
issuing that IND safety report

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is a quicker way
to get that information out,

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followed then by an update
to the protocol, consent,

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or investigator brochure.

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I also mentioned
that the sponsor must report

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00:15:53,510 --> 00:15:56,940
any findings from animal
or in vitro testing

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00:15:56,940 --> 00:16:01,660
whether or not conducted by
the sponsor themselves or others

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00:16:01,660 --> 00:16:06,630
that suggest significant risk
in human exposure to the drug,

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00:16:06,630 --> 00:16:10,580
such as teratogenic
or carcinogenic effects.

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00:16:10,580 --> 00:16:13,150
We have to remember that,
especially in early --

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00:16:13,150 --> 00:16:16,950
in phase one and sometimes even
early phase two studies,

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00:16:16,950 --> 00:16:19,050
animal studies
and in vitro testing

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00:16:19,050 --> 00:16:22,790
may still be ongoing
to help assess

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00:16:22,790 --> 00:16:27,710
for these types of toxicities
in animals

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00:16:27,710 --> 00:16:31,030
that could then impact humans.

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00:16:33,190 --> 00:16:36,790
And then finally,
the last example outlined

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00:16:36,790 --> 00:16:40,460
in an IND safety report
is that the sponsor must report

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00:16:40,460 --> 00:16:43,540
any clinically
important increases

267
00:16:43,540 --> 00:16:47,570
in the rate of serious
adverse reaction

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00:16:47,570 --> 00:16:50,980
over what is listed
in the protocol

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00:16:50,980 --> 00:16:53,420
or in the investigator brochure.

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00:16:55,300 --> 00:16:59,530
There's also a seven-day
IND safety report.

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00:16:59,530 --> 00:17:04,690
The sponsor must also notify
the FDA of any unexpected fatal

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00:17:04,690 --> 00:17:08,950
or life threatening suspected
adverse reaction

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00:17:08,950 --> 00:17:10,480
as soon as possible,

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00:17:10,480 --> 00:17:13,890
but no later than
7 calendar days

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00:17:13,890 --> 00:17:18,880
following the sponsors
initial receipt of information

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00:17:18,880 --> 00:17:22,860
and this is why
your research team

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00:17:22,860 --> 00:17:26,520
reports to the sponsor
within 24 hours.

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00:17:26,520 --> 00:17:30,480
The sponsor needs to make
that initial assessment

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00:17:30,480 --> 00:17:33,510
upon the receipt
of an SAE report

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00:17:34,040 --> 00:17:38,560
if this potentially could meet
the requirement

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00:17:38,560 --> 00:17:43,540
of a seven-day
report to the FDA.

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00:17:45,840 --> 00:17:51,160
The sponsor also needs to
promptly investigate, obviously,

283
00:17:51,160 --> 00:17:54,050
all of the safety information
it receives.

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00:17:54,050 --> 00:17:56,190
They may need to ask,
as I mentioned,

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00:17:56,190 --> 00:18:01,330
for additional information from
the submitter of the SAE report

286
00:18:01,330 --> 00:18:03,360
or from the research site.

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00:18:03,360 --> 00:18:05,700
Any relevant
or additional information

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00:18:05,700 --> 00:18:08,090
that the sponsor does obtain

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00:18:08,090 --> 00:18:12,290
that pertains to a previously
submitted IND safety report

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00:18:12,290 --> 00:18:15,280
does need
to be submitted to them,

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00:18:15,280 --> 00:18:19,490
to the FDA, as a follow up
to that IND safety report

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00:18:19,490 --> 00:18:23,350
and it should be submitted,
you know, without any delay,

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00:18:23,350 --> 00:18:27,580
but no later than 15 calendar
days

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00:18:27,580 --> 00:18:31,220
after the sponsor receives
any of this new information.

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00:18:32,780 --> 00:18:37,300
So, for safety reports involving
clinical trials in the US,

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00:18:37,300 --> 00:18:43,490
the FDA typically would like the
sponsor to submit a mandatory

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00:18:43,490 --> 00:18:47,680
MedWatch form,
which is the FDA form 3500a.

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00:18:49,080 --> 00:18:52,230
Sometimes a narrative
might be more applicable,

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00:18:52,230 --> 00:18:53,750
especially when you --

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00:18:53,750 --> 00:18:56,650
the IND safety report
is in reference

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00:18:56,650 --> 00:19:00,560
to overall findings
or pulled analysis,

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00:19:01,560 --> 00:19:05,630
or from, you know,
in vitro animal studies,

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00:19:05,630 --> 00:19:07,890
epidemiologic studies,
et cetera.

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00:19:08,700 --> 00:19:12,310
Also, the Council
for International Organizations

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00:19:12,310 --> 00:19:16,500
and Medical Sciences, or CIOMS

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00:19:16,500 --> 00:19:22,200
I form can be used for foreign
suspected adverse reactions

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00:19:22,200 --> 00:19:27,520
instead of the FDA form.
And so sometimes research --

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00:19:27,520 --> 00:19:33,400
the PI's will see a CIOMS
form versus a MedWatch form

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00:19:33,400 --> 00:19:39,180
comes through from a sponsor
as an IND safety report.

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00:19:39,970 --> 00:19:42,500
But in an IND safety report,

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00:19:42,500 --> 00:19:46,820
regardless of what format
the sponsor must identify

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00:19:46,820 --> 00:19:49,660
all previous IND safety reports

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00:19:49,660 --> 00:19:54,870
submitted that concern a similar
suspected adverse reaction

314
00:19:55,530 --> 00:19:57,920
and must analyze
the significance

315
00:19:57,920 --> 00:20:00,170
of the suspected
adverse reaction

316
00:20:00,170 --> 00:20:05,330
in light of the previously
submitted or similar reports.

317
00:20:05,330 --> 00:20:09,830
This does need to be obviously
then be communicated to the PI.

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00:20:10,690 --> 00:20:14,080
So, what happens when the PI
gets the IND safety report?

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00:20:14,080 --> 00:20:15,680
How is that handled?

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00:20:17,040 --> 00:20:19,780
So, an investigator
will receive a safety report.

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00:20:20,330 --> 00:20:23,360
The investigator should review
the report and assess

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00:20:23,360 --> 00:20:29,210
whether it identifies that
the adverse event is unexpected,

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00:20:29,210 --> 00:20:32,880
related or possibly related
to participation in research

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00:20:33,660 --> 00:20:38,180
and serious or otherwise
puts or suggests

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00:20:38,180 --> 00:20:41,210
that the research places
the subject at greater risk

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00:20:41,210 --> 00:20:43,330
of harm
than was previously known.

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00:20:44,010 --> 00:20:47,200
Unfortunately, there are
a lot of IND safety reports

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00:20:47,200 --> 00:20:49,490
that are sent to the PI,

329
00:20:50,560 --> 00:20:53,860
who then communicates them
to the research team

330
00:20:53,860 --> 00:20:59,410
that don't really impact
an immediate protocol

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00:20:59,410 --> 00:21:06,320
or change needed to a protocol.
So not all IND safety reports

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00:21:06,320 --> 00:21:09,760
are what I would consider
to be true SUSARs,

333
00:21:10,760 --> 00:21:13,720
but they come --
the sponsor feels they want

334
00:21:13,720 --> 00:21:17,770
that information
communicated nonetheless.

335
00:21:17,770 --> 00:21:20,050
So, the PI does need to review

336
00:21:20,050 --> 00:21:23,530
and make sure
that they understand

337
00:21:23,530 --> 00:21:27,220
if the protocol will be amended
or and

338
00:21:27,220 --> 00:21:29,600
or the consent
will need to be amended.

339
00:21:30,640 --> 00:21:33,430
They will need to, you know,
make those amendments.

340
00:21:34,270 --> 00:21:36,840
They do need to inform
the research team

341
00:21:38,230 --> 00:21:42,000
and let the team know if the
amendment is going to be needed,

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00:21:43,050 --> 00:21:48,290
refer to the IRB policy of,
if it is a true SUSAR,

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00:21:48,290 --> 00:21:51,560
on how is that then
reported to the IRB.

344
00:21:52,130 --> 00:21:57,160
And then finally informing
participants and documenting

345
00:21:57,160 --> 00:22:00,290
their willingness
to continue on the study.

346
00:22:01,060 --> 00:22:04,020
It also could even
impact enrollment.

347
00:22:04,020 --> 00:22:07,260
Maybe enrollment
will need to be halted.

348
00:22:07,880 --> 00:22:11,750
So, it does -- we do need to
as part of continuing,

349
00:22:11,750 --> 00:22:13,480
you know, informed consent,

350
00:22:13,480 --> 00:22:16,540
make sure that our participants
are aware of that

351
00:22:16,540 --> 00:22:19,740
even before there may be
a new consent document

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00:22:19,740 --> 00:22:23,950
that the participant
is required to sign

353
00:22:23,950 --> 00:22:25,910
and that would all be related

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00:22:25,910 --> 00:22:30,730
to the nature of the IND safety
report itself.

355
00:22:32,350 --> 00:22:34,150
So, few reminders.

356
00:22:34,150 --> 00:22:37,100
Expedited reporting
of an adverse event

357
00:22:37,100 --> 00:22:40,160
and for FDA regulated research

358
00:22:40,160 --> 00:22:43,150
is very much driven
by the regulations.

359
00:22:43,150 --> 00:22:45,300
The time frames and what.

360
00:22:46,520 --> 00:22:49,530
So, it's important
to keep that in mind,

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00:22:49,530 --> 00:22:52,990
these are a subset
of all adverse events.

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00:22:53,530 --> 00:22:59,100
All of the information captured
about the expedited event

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00:22:59,100 --> 00:23:02,110
must be present
in the source document

364
00:23:02,110 --> 00:23:05,560
and be found in an adverse
event case report form.

365
00:23:05,560 --> 00:23:11,500
So, all of the SAE information
grade attribution term

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00:23:11,500 --> 00:23:16,820
should be in the regular routine
adverse event case report form.

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00:23:17,360 --> 00:23:21,050
And remember that some events
that initially appear to meet

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00:23:21,050 --> 00:23:25,360
expedited reporting requirements
may actually be excluded

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00:23:25,360 --> 00:23:29,590
from expedited
reporting per the protocol.

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00:23:29,590 --> 00:23:33,720
So, remember to check
your protocol to make sure

371
00:23:33,720 --> 00:23:37,910
if you have exceptions
to expedited reporting.

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00:23:37,910 --> 00:23:42,230
Because that -- the protocol
will trump the regulations

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00:23:42,230 --> 00:23:45,520
in terms of the 24-hour
reporting of an SAE

374
00:23:45,520 --> 00:23:47,270
to the sponsor.

375
00:23:47,270 --> 00:23:52,180
All expedited report forms
and responses

376
00:23:52,180 --> 00:23:55,410
do need to be placed
in the regulatory file.

377
00:23:56,730 --> 00:24:00,120
Again, I had already mentioned
the investigator

378
00:24:00,120 --> 00:24:02,690
sponsored studies
that must follow both

379
00:24:02,690 --> 00:24:05,450
the investigator
reporting requirements

380
00:24:05,450 --> 00:24:09,050
as well as the response
or reporting requirements.

381
00:24:11,460 --> 00:24:13,260
So, I did want to just,
you know,

382
00:24:13,260 --> 00:24:17,250
I talked about FDA and INDs,
but I --

383
00:24:17,250 --> 00:24:20,310
some of you may be
wondering about devices.

384
00:24:20,310 --> 00:24:23,410
The reporting requirements
for the investigator and sponsor

385
00:24:23,410 --> 00:24:25,070
for events

386
00:24:25,070 --> 00:24:28,900
under the Investigational Device
Exemption Regulations

387
00:24:28,900 --> 00:24:32,390
includes reporting
to the sponsor or the FDA

388
00:24:32,390 --> 00:24:34,160
and to the IRB as well.

389
00:24:34,760 --> 00:24:41,850
An investigator needs to submit
to the IDE sponsor

390
00:24:41,850 --> 00:24:45,070
and to the reviewing IRB
or the IRB of record

391
00:24:45,590 --> 00:24:50,050
of any unanticipated
adverse device effect occurring

392
00:24:50,050 --> 00:24:53,610
during the investigation
as soon as possible,

393
00:24:53,610 --> 00:24:55,840
but no later
than 10 working days

394
00:24:55,840 --> 00:25:01,180
after the investigator
learns about the effect.

395
00:25:01,180 --> 00:25:06,040
So again, refer to the sponsor
as well as to the IRB

396
00:25:06,040 --> 00:25:08,970
in terms
of the submission formats.

397
00:25:11,160 --> 00:25:15,150
And then the sponsor,
who's conducting the evaluation

398
00:25:15,150 --> 00:25:18,530
of the unanticipated
adverse device effect,

399
00:25:18,530 --> 00:25:23,100
will report the results
of the evaluation to the FDA

400
00:25:23,100 --> 00:25:28,110
and to all of the reviewing IRBs
and participating investigators

401
00:25:28,110 --> 00:25:31,910
within 10 working days 
after the sponsor

402
00:25:31,910 --> 00:25:35,110
first received notice
of the device effect.

403
00:25:35,690 --> 00:25:38,160
The submission should include
a cover letter

404
00:25:38,700 --> 00:25:42,110
summarizing the sponsors
analysis of the event

405
00:25:42,110 --> 00:25:47,290
and the FDA's mandatory
MedWatch form that 3500a.

406
00:25:47,290 --> 00:25:51,580
The sponsor should submit
additional reports, obviously,

407
00:25:51,580 --> 00:25:55,050
concerning on the 
effect as appropriate

408
00:25:55,050 --> 00:25:57,390
or as requested by the FDA.

409
00:25:58,910 --> 00:26:02,710
So, in summary, adverse event
reporting involves both routine

410
00:26:02,710 --> 00:26:06,830
and expedited 
reporting by the PI

411
00:26:06,830 --> 00:26:11,160
and Research team to the sponsor
and the sponsor to the FDA.

412
00:26:11,160 --> 00:26:15,730
It's important to know
your sponsor’s expedited AE

413
00:26:15,730 --> 00:26:17,170
reporting requirements,

414
00:26:17,170 --> 00:26:19,550
including the 
timeliness, the format.

415
00:26:20,150 --> 00:26:23,430
Remember the narrative summary
is extremely important

416
00:26:24,360 --> 00:26:27,800
and also be aware
of any exclusions

417
00:26:27,800 --> 00:26:30,520
to expedited
reporting to the sponsor.

418
00:26:32,410 --> 00:26:34,580
So, let's do a 
knowledge check here.

419
00:26:35,240 --> 00:26:37,280
Per the FDA regulations,

420
00:26:38,760 --> 00:26:42,130
and I'll say the IND 
regulations and investigator

421
00:26:42,130 --> 00:26:45,320
is to report
an SAE to the sponsor,

422
00:26:45,320 --> 00:26:51,020
fill in the blank: immediately,
24 hours within seven days

423
00:26:51,020 --> 00:26:52,860
or at the next monitoring visit.

424
00:26:54,300 --> 00:26:57,150
And the correct 
answer is immediately.

425
00:26:58,700 --> 00:27:03,080
The sponsor --
the regulations say immediately,

426
00:27:03,080 --> 00:27:07,080
the sponsor may say
that's 24 hours.

427
00:27:07,080 --> 00:27:09,150
So, do refer to your protocol.

428
00:27:10,280 --> 00:27:14,120
So, thank you for listening
to part three of Adverse Events.