>> Liz Ness: Welcome to part three of Adverse Events,
investigational new drug and investigational device
exception reporting.
My name is Liz Ness,
and I'm the director of the Office of Education
and Compliance for the Center for Cancer Research.
In part three, I'll be talking about adverse events
that require expedited reporting to the sponsor
and then to the FDA under the IND or IDE regulations,
including timeliness of reporting
and the responsibilities of the investigator and the sponsor.
Events to be reported in expedited manner
to various regulatory groups
should be defined in the protocol,
include the timelines for reporting,
and indicate the appropriate form or database to be used.
As you can see on the slide here,
these are the applicable regulations and guidances
related to IND and IDE AE reporting.
So, let's jump into AE
reporting under the IND application regulations.
Per the FDA, the PI must immediately report
to the sponsor any serious adverse event,
whether or not considered
related to the investigational product,
including those listed in the protocol
or investigator brochure, and must include an assessment
of whether there is a reasonable possibility
that the investigational product caused the event.
Sponsors will typically have an SAE form
or a database that you need to use to report the SAE
or some sponsors may require you to use the FDA mandatory
Med Watch Form 3500-A.
Also, many sponsors, that the concept of immediately
reporting that stated in the regulations,
most sponsors allow for a 24-hour reporting
which is acceptable with the FDA.
But be aware that not all SAEs may need to be reported
to the sponsor in an expedited manner.
Refer to your protocol for exceptions
to expedited reporting.
Sponsors may also require events to be reported,
such as all pregnancies, regardless of the outcome,
overdose of any drug while on protocol,
or development of a previously undiagnosed cancer, for example.
They may have separate forms or the sponsor
may want you to use the same SAE form or SAE process,
so please be aware of that as well.
Some studies have additional events
that will need to be reported in an expedited manner
to the sponsor ultimately then, potentially to the FDA,
that are not SAE's but may have a scientific or medical concern
with the development of the product.
These may be referred to as adverse events
of special interest or AESIs.
These are non-serious that might be a precursor
of a more serious medical condition or important
because they may have an impact on quality of life.
For example, a protocol may require
that all bleeding events greater than a Grade One or even Grade
One be considered an AESI.
So please be aware of that
also should be stated in your protocol.
Though the expedited report forms or databases
may be different from sponsor to sponsor,
they all have similar key components.
There's reporter information,
patient or participant demographic information,
information about the investigational product
or the study agent, including the dates given,
the dose, the route of the administration,
possibly even the lot number,
especially with something like a vaccine product,
and an event description including the severity
and the type of seriousness and the attribution,
as well as a narrative summary.
One of the most important parts of the report,
in my opinion, is the narrative summary.
The recipient of these SAE reports very likely
does not know anything
about the participant and their history.
The narrative helps to provide that background information
necessary to assess the event and support
the investigator’s attribution of the event.
So, the narrative should include information
that helps to describe the event,
information that puts the event into perspective.
So that could be including important relative
participant history,
such as underlying medical conditions,
prior surgeries or other procedures,
potentially family history,
recent events that may contribute --
be a contributing factor concomitant medications,
for example.
It also may be helpful or even requested by the sponsor
to provide supporting documentation.
This could include an inpatient hospitalization
discharge summary, or a lab or imaging results.
This can then just be referred to in the narrative summary,
such as see in patient hospitalization
discharge summary for more information
and not include that in the narrative.
So, if you consider the following scenario,
which does happen frequently,
you have a member of the research team
receives a phone message from the participant
or a family member stating that the participant was hospitalized
and no additional information was given.
You know that because hospitalization
is deemed a serious, it’s deemed serious.
So there was an AE, an event that occurred,
that resulted in a hospitalization.
Most likely this is going to need to be reported
to your sponsor in an expedited manner,
so within that immediate or 24-hour time frame.
So, what do you do with limited information
that you received in a voice message?
So, it's helpful if your research team
is not the primary treating physician
or even the primary institution
for your research participant, contact them.
Maybe the patient is coming to your research site
but they have a local physician and they --
participant contacted that local physician
and they told them to go to the hospital.
So, that local physician may know more
about what the event is, or you may be able to contact
or even double check your own institution
to make sure that they weren't hospitalized there.
And submit what you have.
Include in your narrative summary.
What was the most recent clinical evaluation?
What was the date? How were they doing?
Maybe you haven't yet done an initial, you know, visit.
Include what you have at baseline.
What you have with their history.
Provide you know a summary of what you do know
and include a plan for completing
and getting the rest of that information.
And as you will see,
the sponsor has time frames for reporting to the FDA,
which is why SAEs are reported in, you know, within 24 hours.
So, it's going to be important for the sponsor to get
as much follow-up information as soon as it becomes available.
And that's typically done then with an additional
or an amended SAE report.
So as a general rule, follow up is required
or a follow-up report
is required to be submitted to the sponsor
when there is a change in the severity attribution
or maybe the actual event itself.
Maybe there was a symptom that the participant
was admitted to the hospital
with that actually then turned into an actual diagnosis
and that diagnosis then is the more appropriate AE term.
If you have a change in the -- or any new information,
let's say, about a death that becomes available.
So, you have a death.
You have an initial potential cause of death,
but an autopsy is going to be done.
So, you would want to, then,
after you receive that autopsy report,
make sure that you do a follow up
if that cause of death then is different,
and obviously if you get requested
by a, you know, any regulatory or oversight group,
this could be the sponsor. This could be even an IRB.
You'd want to give them additional information.
But as a general rule, follow up isn't required
or a follow-up report
is not specifically required if the adverse --
if you're just letting the sponsor know
the AE has resolved.
But again, that can be very sponsor dependent,
but the routine adverse event case report form
would certainly have that end date for that adverse event.
But be aware of that
and follow what your sponsor requirements are.
So now we'll focus on what the IND sponsors responsibility
is for reporting to the FDA and this could include
your biopharmaceutical industry sponsors,
but it could also include an investigator who also --
who holds an investigator held IND.
So, the IND sponsor must report any suspected adverse reaction
or adverse reaction to the study treatment
that is both serious and unexpected.
So, you can see why it's important to first understand
the definitions associated with adverse events,
as was presented in part one.
You know what the suspected adverse reaction is,
as well as what the definition for serious and unexpected is.
There are potentially three types of reports a sponsor
will be sent to the FDA:
A seven-day report, a 15-day report, and a follow up report.
So, let's take a look at those individually.
The first is a 15-day IND safety report,
sometimes referred to as an ISR. The sponsor must notify the FDA
and all participating investigators of any IND
from a clinical trial
or other sources as soon as possible,
but no later than 15 calendar days
after the sponsor determines
that the information qualifies for reporting.
This would include all serious and unexpected suspected
adverse reactions also referred to as a SUSAR.
We have talked about this again.
These definitions are extremely important to understand.
It also includes findings from other studies,
findings from animal or in vitro testing,
or an increased rate of occurrence
of serious suspected adverse reactions.
The sponsor must report any suspected adverse reaction
that is both serious and unexpected
if there is evidence to suggest that causal relationship
between the investigational product and the adverse event.
As mentioned in part one of adverse events,
this can include a single occurrence of an adverse event
that's uncommon
but known to be strongly associated with drug exposure.
This could be some type of hepatic injury or angioedema.
One or more occurrences of an event
that is not commonly associated with the product
but is otherwise uncommon in the population
exposed to the drug, such as, say, a tendon rupture,
or then aggregate analysis of specific events
observed in a clinical trial such as known consequences
of underlying disease or condition under investigation,
or other events that commonly occur in the study population
independent of drug therapy that indicates those events occur
more frequently in the drug treatment group
than in the concurrent or historical control group.
So, this could be even something as related to death
due to progressive disease.
The FDA considers SUSARs as unanticipated problems
and reportable by the investigator to the IRB,
which I'll discuss further in part four.
The sponsor must report, as I had mentioned,
any findings from other studies.
And this typically is epidemiologic studies
or a pooled analysis
from multiple studies or clinical studies,
whether or not they were conducted under an IND.
Sometimes INDs continue even after a product
has been initially approved and the sponsor considers
that there could be a suggestion of significant risks
to humans exposed to the product.
Ordinarily, these findings would be reported in safety
related changes to the protocol,
but sometimes issuing that IND safety report
is a quicker way to get that information out,
followed then by an update to the protocol, consent,
or investigator brochure.
I also mentioned that the sponsor must report
any findings from animal or in vitro testing
whether or not conducted by the sponsor themselves or others
that suggest significant risk in human exposure to the drug,
such as teratogenic or carcinogenic effects.
We have to remember that, especially in early --
in phase one and sometimes even early phase two studies,
animal studies and in vitro testing
may still be ongoing to help assess
for these types of toxicities in animals
that could then impact humans.
And then finally, the last example outlined
in an IND safety report is that the sponsor must report
any clinically important increases
in the rate of serious adverse reaction
over what is listed in the protocol
or in the investigator brochure.
There's also a seven-day IND safety report.
The sponsor must also notify the FDA of any unexpected fatal
or life threatening suspected adverse reaction
as soon as possible,
but no later than 7 calendar days
following the sponsors initial receipt of information
and this is why your research team
reports to the sponsor within 24 hours.
The sponsor needs to make that initial assessment
upon the receipt of an SAE report
if this potentially could meet the requirement
of a seven-day report to the FDA.
The sponsor also needs to promptly investigate, obviously,
all of the safety information it receives.
They may need to ask, as I mentioned,
for additional information from the submitter of the SAE report
or from the research site.
Any relevant or additional information
that the sponsor does obtain
that pertains to a previously submitted IND safety report
does need to be submitted to them,
to the FDA, as a follow up to that IND safety report
and it should be submitted, you know, without any delay,
but no later than 15 calendar days
after the sponsor receives any of this new information.
So, for safety reports involving clinical trials in the US,
the FDA typically would like the sponsor to submit a mandatory
MedWatch form, which is the FDA form 3500a.
Sometimes a narrative might be more applicable,
especially when you --
the IND safety report is in reference
to overall findings or pulled analysis,
or from, you know, in vitro animal studies,
epidemiologic studies, et cetera.
Also, the Council for International Organizations
and Medical Sciences, or CIOMS
I form can be used for foreign suspected adverse reactions
instead of the FDA form. And so sometimes research --
the PI's will see a CIOMS form versus a MedWatch form
comes through from a sponsor as an IND safety report.
But in an IND safety report,
regardless of what format the sponsor must identify
all previous IND safety reports
submitted that concern a similar suspected adverse reaction
and must analyze the significance
of the suspected adverse reaction
in light of the previously submitted or similar reports.
This does need to be obviously then be communicated to the PI.
So, what happens when the PI gets the IND safety report?
How is that handled?
So, an investigator will receive a safety report.
The investigator should review the report and assess
whether it identifies that the adverse event is unexpected,
related or possibly related to participation in research
and serious or otherwise puts or suggests
that the research places the subject at greater risk
of harm than was previously known.
Unfortunately, there are a lot of IND safety reports
that are sent to the PI,
who then communicates them to the research team
that don't really impact an immediate protocol
or change needed to a protocol. So not all IND safety reports
are what I would consider to be true SUSARs,
but they come -- the sponsor feels they want
that information communicated nonetheless.
So, the PI does need to review
and make sure that they understand
if the protocol will be amended or and
or the consent will need to be amended.
They will need to, you know, make those amendments.
They do need to inform the research team
and let the team know if the amendment is going to be needed,
refer to the IRB policy of, if it is a true SUSAR,
on how is that then reported to the IRB.
And then finally informing participants and documenting
their willingness to continue on the study.
It also could even impact enrollment.
Maybe enrollment will need to be halted.
So, it does -- we do need to as part of continuing,
you know, informed consent,
make sure that our participants are aware of that
even before there may be a new consent document
that the participant is required to sign
and that would all be related
to the nature of the IND safety report itself.
So, few reminders.
Expedited reporting of an adverse event
and for FDA regulated research
is very much driven by the regulations.
The time frames and what.
So, it's important to keep that in mind,
these are a subset of all adverse events.
All of the information captured about the expedited event
must be present in the source document
and be found in an adverse event case report form.
So, all of the SAE information grade attribution term
should be in the regular routine adverse event case report form.
And remember that some events that initially appear to meet
expedited reporting requirements may actually be excluded
from expedited reporting per the protocol.
So, remember to check your protocol to make sure
if you have exceptions to expedited reporting.
Because that -- the protocol will trump the regulations
in terms of the 24-hour reporting of an SAE
to the sponsor.
All expedited report forms and responses
do need to be placed in the regulatory file.
Again, I had already mentioned the investigator
sponsored studies that must follow both
the investigator reporting requirements
as well as the response or reporting requirements.
So, I did want to just, you know,
I talked about FDA and INDs, but I --
some of you may be wondering about devices.
The reporting requirements for the investigator and sponsor
for events
under the Investigational Device Exemption Regulations
includes reporting to the sponsor or the FDA
and to the IRB as well.
An investigator needs to submit to the IDE sponsor
and to the reviewing IRB or the IRB of record
of any unanticipated adverse device effect occurring
during the investigation as soon as possible,
but no later than 10 working days
after the investigator learns about the effect.
So again, refer to the sponsor as well as to the IRB
in terms of the submission formats.
And then the sponsor, who's conducting the evaluation
of the unanticipated adverse device effect,
will report the results of the evaluation to the FDA
and to all of the reviewing IRBs and participating investigators
within 10 working days after the sponsor
first received notice of the device effect.
The submission should include a cover letter
summarizing the sponsors analysis of the event
and the FDA's mandatory MedWatch form that 3500a.
The sponsor should submit additional reports, obviously,
concerning on the effect as appropriate
or as requested by the FDA.
So, in summary, adverse event reporting involves both routine
and expedited reporting by the PI
and Research team to the sponsor and the sponsor to the FDA.
It's important to know your sponsor’s expedited AE
reporting requirements,
including the timeliness, the format.
Remember the narrative summary is extremely important
and also be aware of any exclusions
to expedited reporting to the sponsor.
So, let's do a knowledge check here.
Per the FDA regulations,
and I'll say the IND regulations and investigator
is to report an SAE to the sponsor,
fill in the blank: immediately, 24 hours within seven days
or at the next monitoring visit.
And the correct answer is immediately.
The sponsor -- the regulations say immediately,
the sponsor may say that's 24 hours.
So, do refer to your protocol.
So, thank you for listening to part three of Adverse Events.