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>> Elizabeth Ness:
Welcome to Part 4 

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of Adverse Events, 
Adverse  Event Reporting to the IRB.

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My name is Liz Ness.

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I'm the director
of the Office of Education

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and Compliance
in the Center for Cancer

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Research at the 
National Cancer Institute.

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One of the most important
considerations for an IRB

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once a study
has been approved

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is whether there is
any new information

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that would alter the risk
for the participants.

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During this session,
this part,

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I will cover what adverse events
need to be reported to the IRB

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in an expedited manner,

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what a corrective
and preventive action plan is,

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and introduce
other new information

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that needs to be
reported to the IRB.

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So, an adverse event 
that meets the definition

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of an unanticipated problem
needs to be reported to the IRB.

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The phrase
"Unanticipated problems

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involving risk to subjects
and others" is found,

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but not defined in HHS
regulations at 45 CFR Part 46.

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OHRP considers
unanticipated problems

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in general to include
any incident experience

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or outcome that meets
all of the following criteria.

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It's unexpected in terms
of the nature, severity,

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or frequency given 
the research procedures

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that have been described
in the protocol

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and related documents,
such as the consent

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and the characteristics of the
study population being studied.

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They need to also meet the --
be related or possibly related

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to the participation
in the research.

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So, in the guidance document,
it states "possibly related,"

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meaning that there's
a reasonable possibility.

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Again, we hear that term
"reasonable possibility,"

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that the incident experience
or outcome may have been caused

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by the procedures
involved in the research.

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And that the event
or non-AE presents a --

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replaces the subjects or others
at greater risk of harm

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than was previously known.

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And harm here 
can include physical,

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psychological, economic,
or even social harm.

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So, in this Venn diagram,

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which is in the 
OHRP guidance document,

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you can see the relationship
between adverse events

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and unanticipated problems.

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The vast majority
of adverse events

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occurring in human 
subjects and research

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are not unanticipated problems

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as you can see in Area
A of the Venn diagram.

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A small portion
of adverse events

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are unanticipated 
problems as seen in Area B.

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Then there are also
unanticipated problems

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that are not 
adverse events at all

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that can be seen in Area C.

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So, the key question regarding
a particular adverse event

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is whether it meets
the three criteria

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of being unexpected, related,

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and putting subjects or others
at greater risk of harm

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as previously just described
in the slide before this one.

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I just wanted to give you
a couple of examples

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of a non-AE that 
could  also be a UP.

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These may be other 
incidences or experiences

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or outcomes that aren't 
related to an adverse event

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if they meet the three criteria.

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For example, an investigator
conducting behavioral research

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collects individually identifiable
sensitive information

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about illicit drug use
by surveying college students.

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The data was collected
and stored on a laptop

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that wasn't encrypted,
and the laptop was stolen.

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This is an example
of putting the subject

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at greater risk of harm.

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And harm here
may not be physical harm.

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It could be psychological harm
or even potentially social harm.

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There could be a dosing error.

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So, a larger dose of
the investigational product

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was given,
but the participant

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didn't actually
experience an adverse event.

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This is example meets
the three criteria, which --

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because it meets the criteria

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suggesting it could have
an increased harm.

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It doesn't say in the definition
of unanticipated problems

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that it did create harm.
And also -- and final example

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is some type of product
contamination was found

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and there weren't
any adverse events

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that subjects experienced.

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So, the FDA regulations
also support prompt reporting

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of an unanticipated problem
to the IRB.

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And you can see here listed
the IND regulations,

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the IDE regulations,
as well as the Part 56,

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which is the IRB 
regulations under title --

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all under Title 21 of the FDA.

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You can also see what I consider
a very helpful guidance

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for clinical investigators,
sponsors,

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and IRB when assessing adverse
event reporting to the IRB.

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That came out in 2009
and is still, you know,

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current and applicable today.

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So, the FDA believes that only
adverse events

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that meet the definition
of an unanticipated problem

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need to be reported to the IRB.

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This would include those events
that were described in Part 3

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as the IND safety reports
or the safety reports.

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Of note, not all safety reports
from sponsors, as I mentioned,

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in Part 3 actually 
meet the definition

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of unanticipated 
problem or a UP.

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So, the PI does need
to make that assessment.

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Also, as discussed in Part 3,

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unanticipated adverse
device effect

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should be reported by
the investigator to the sponsor

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and the sponsor to the FDA
no later than 10 working days.

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So, the HHS regulations require
written procedures be in place.

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So, this is under
Title 45 Part 46

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for ensuring prompt reporting
of unanticipated problems

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to the IRB, appropriate
institutional officials,

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any supporting department
or agency head,

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as well as OHRP, the Office
for Human Research Protection.

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The purpose of the prompt
reporting is to ensure

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that appropriate steps are being
taken in a timely manner

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to protect other subjects
from potentially avoidable harm.

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So, the regulations
don't define what prompt is.

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The appropriate timeframe
from satisfying

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that requirement of prompt
reporting will vary

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depending upon the nature
of the unanticipated problem,

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the nature of the research
associated with the problem,

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the entity to which reports
are to be submitted.

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For example,
an unanticipated problem

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that results
in a subject's death

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or was potentially
life-threatening, generally,

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should be reported to the IRB
within a shorter period of time

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than other
unanticipated problems

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that are not life-threatening.

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Therefore, as you can see
in this slide,

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OHRP recommends that the
following guidelines are used

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to satisfy the requirement
of prompt reporting.

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Unanticipated problems that
are serious should be reported

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to the IRB within one week
of the investigator,

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and I'll say,
slash research team

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becoming aware of the event.
And other unanticipated problems

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should be reported
within two weeks.

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However, please be aware
of your own institutions,

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Human Research Protection
Program policy,

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as well as the IRB
of records policies

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because they may have
shortened the timeframe.

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They can't make it longer,
but they can make it shorter.

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Typically, these reports are
submitted through some type

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of a reportable new information
form or database.

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OHRP recommends that
investigators include

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on the information
that you see here on the slide

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when reporting an adverse event

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or another incident
or experience

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or unanticipated problem
to the IRB.

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Appropriately identify
the information

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for the research protocol
such as the title,

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investigator's name,
the IRB project.

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A detailed description
of the adverse event,

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the incident, experience,
or outcome.

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An explanation of the basis

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for that determination
of the incident or outcome

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and how it represents
an unanticipated problem.

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And a description of any changes
to the protocol

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or other corrective actions
that have been taken

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or are proposed in response
to an unanticipated problem.

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And this is referred
to as a corrective

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and preventive action
or CAPA Plan.

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So, a CAPA Plan establishes
a process or sets up processes

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to identify, correct,
and prevent future occurrences

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that may impact safety and data,

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and ensures that the quality
of the research --

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the conduct of the study
is maintained.

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CAPAs actually started
in industries,

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specifically in manufacturing
as a process

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that is used in all steps of
the manufacturing for a company,

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so that they can
identify, correct,

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and prevent quality issues
from occurring.

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And this type of plan is similar

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to what's conducted
in a hospital

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setting for a sentinel event,
which may --

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which many of you
may already be familiar with.

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This is not at all uncommon
for institutions

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that are JCO accredited
or Joint Commission Accredited.

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So, just to briefly review
CAPA terminology,

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a root cause analysis
is a problem-solving method

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to identify the 
origin of the cause

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or causes of the 
problem or the issue.

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A corrective action plan
simply is the action

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that's taken to eliminate
the cause of the problem.

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And preventive action is to,
obviously,

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then prevent the potential
problem from occurring again.

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In crafting an effective plan,

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the investigator
and research team

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needs to really think about
why the event occurred.

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Is it a system problem?
Is it a problem with a procedure

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or something within
the protocol itself?

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Is it a training issue?

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The first step in creating the
plan is to identify the problem.

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This can be a potential
or an actual problem.

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You want to describe
how this issue

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was uncovered or discovered.

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Next, you want to 
analyze the problem.

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You want to determine
the root cause or causes

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and any contributing causes
of the problem or issue

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by conducting that root
cause analysis.

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You want to collect the evidence
for the causes

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and document them.

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And remember,
there may be several causes

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to one problem or issue.

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Once the root cause
and contributing causes

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have been identified,

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you can then begin
developing your plan to mitigate

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or prevent each identified
cause or contributing cause.

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You may need to do
some corrective action

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more immediately as you have
identified the cause and you --

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before you start
to do a deep analysis

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then of a prevention plan.

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But be specific when you're
listing each of the actions

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that need to be completed
or implemented,

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and who will be responsible
for those actions

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and the due date
for each of those actions.

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You'll then need to, obviously,
implement or complete

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the implementation
of the corrective action plan

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and to then implement
your preventive action plan.

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You'll need to look
at resources.

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Resources do need to be
allocated to implement

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each of those actions.

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Typically, when a, you know,
what I call a major CAPA Plan

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is truly needed,

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it's often not just the research
team, the PI themselves.

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There are other,
if not at least,

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contributing causes
that could be

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part of the preventive action
plan in particular.

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And then once you've implemented
your plan periodically,

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you want to evaluate the plan.

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You want to verify
that the actions

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that were outlined
have been completed.

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Were they effective?

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Did you need to do something
else as a result of that?

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You want to confirm 
and document those actions

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when they are completed.

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And this may be a six-month
process of evaluation.

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It could be a year process.

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It may even be
a little bit longer

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depending upon
what preventive actions

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make the most sense
for the identified problem.

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But you do want to make sure
that you, ultimately,

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document full closure
of a corrective

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and preventive action plan.

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Even if something may not ever
be able to be resolved

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that might be
an institutional issue,

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and you would need to,
at least, note that.

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And, you know, it would --
if your plan then,

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you weren't able
to close everything out,

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some view then that your CAPA

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Plan would be
considered ineffective

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and you would need
to actually revise it.

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So, doing an ongoing evaluation
is extremely helpful

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to having
a successful, corrective,

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and preventive action plan.

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Some types of correction
and preventive actions

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you can see here.

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There can be related
to the protocol in terms

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of potentially modifying
your eligibility criteria

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that may be needed to mitigate
a newly identified risk.

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Implement additional procedures
for participant's safety.

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Monitoring could be related to
modifying the informed consent

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as it relates to new information
about newly recognized risks

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to previously enrolled
subjects and --

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or informing enrolled subjects.

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It may need to suspend
enrollment of new subjects

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or put a hold,
at least,

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temporarily
until you have your corrective

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and preventive action
plans well underway.

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And then if that is part
of your preventive action

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or immediate corrective action,

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you'd want to note
what the criteria would be then

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to return to enrolling
new subjects.

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Any -- it could be a suspension
of the research project.

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Increase
in monitoring activities,

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providing some type
of training, retraining.

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And again, as I mentioned,
you want to work

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with your appropriate
institutional officials

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to correct the problem.

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Typically, this is not something
that just the PI

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or the research team
will be able to fix.

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There is often other information
that may need

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to be reported to the IRB
that are not adverse events

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or not even
unanticipated problems

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that don't overlap
with an adverse event.

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These may be referred
to by your IRB

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as Reportable New Information
or an RNI.

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Examples can include
non-compliance,

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which can be defined as failing
to follow applicable laws,

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regulations,
and institutional policies

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that govern human subjects,
protection research,

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or not following
the requirements

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or determinations of the IRB.

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A major protocol deviation that
has or may have a potential --

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to potential risk of impacting
negatively on the rights

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and welfare of the participants
or impact

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the scientific integrity
or validity of a study.

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Any new information that might
affect the participant's

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willingness to enroll
or remain on the study,

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such as results
from an interim analysis

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that indicate a new risk
or decrease effectiveness

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of the study intervention.

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Or maybe the intervention
in one --

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if it's a randomized study
and one arm of the study

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that might result in that arm
needing to be closed.

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It could be a withdrawal
or restriction

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of a marketing approval
even by the FDA.

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It can also include
a complaint of a subject

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that can't be resolved
by a research team,

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death of a subject that is,
at least,

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possibly related
to the research.

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And this may have a more quickly
reporting timeframe to your IRB.

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So, again, be aware
of what your IRB's policy

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is on reporting of
other reportable information.

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Any audit inspections
or inquiries by federal agencies

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may need to be reported,
breach of confidentiality.

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A change to a protocol
that was taken

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without prior IRB approval
that was done that

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didn't necessarily immediately
impact the harm for a subject.

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And incarceration
of a subject in a study

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that was not previously approved
by the IRB to include prisoners

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or even premature suspension

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00:19:26,960 --> 00:19:31,130
or termination of research
by the sponsor,

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00:19:31,130 --> 00:19:34,180
the investigator,
or the institution.

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So, the IRB is responsible
then for reviewing

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00:19:38,460 --> 00:19:40,270
these unanticipated problems,

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as well as other information
that is submitted to them.

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They may ask
for more information.

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They make a final determination
of sort of what needs to happen.

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For example, revise --
you need to make --

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you know, amend your protocol

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if you hadn't already
identified that.

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00:19:59,350 --> 00:20:03,290
More frequent monitoring
or increase the frequency

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00:20:03,290 --> 00:20:05,050
of the continuing review

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00:20:05,050 --> 00:20:08,550
or maybe even including
terminating the study.

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And if the UP
or the other type of serious

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or continuing non-compliance
is determined by the IRB,

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00:20:18,570 --> 00:20:22,030
then that does need
to be reported to OHRP.

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00:20:22,030 --> 00:20:23,300
And if applicable,

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00:20:23,300 --> 00:20:27,010
for an FDA regulated study
to the FDA as well.

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So, in summary,
UPs, by definition,

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are events
that are unanticipated

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00:20:34,580 --> 00:20:38,160
related to the research
and pose a new risk.

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00:20:38,160 --> 00:20:40,680
This applies to non-adverse
events,

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00:20:40,680 --> 00:20:43,470
as well as issues of
non-compliance.

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00:20:43,470 --> 00:20:46,630
And the IRB must review
this promptly to see

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00:20:46,630 --> 00:20:49,120
if the risk benefit ratio
is favorable

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00:20:49,840 --> 00:20:52,900
and what other actions
may need to be taken.

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00:20:53,420 --> 00:20:56,410
Then it is up to the IRB
to review this,

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00:20:56,410 --> 00:20:59,750
make a determination,
and report accordingly.

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So, for test your knowledge.

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The study coordinator
identified an adverse event

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00:21:07,870 --> 00:21:11,880
that they believe is unexpected,
not related to the research,

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00:21:11,880 --> 00:21:13,420
and not serious.

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00:21:13,420 --> 00:21:17,180
The coordinator should report it
to the IRB right away.

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00:21:17,760 --> 00:21:25,190
Is that true or false?
And the correct answer is false.

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00:21:25,190 --> 00:21:27,490
The study coordinator
identified it,

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00:21:28,010 --> 00:21:34,300
but the PI and the sponsor
did not necessarily.

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00:21:35,240 --> 00:21:38,020
And finally, one last test
your knowledge question.

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What is the process
for developing a CAPA Plan?

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00:21:41,940 --> 00:21:44,880
Describe the problem,
describe the desired situation.

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00:21:44,880 --> 00:21:48,780
List the steps to move
the problem to solution.

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00:21:48,780 --> 00:21:50,230
Assign a responsible party

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00:21:50,230 --> 00:21:53,820
and due date assigned
to each step.

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00:21:53,820 --> 00:21:55,280
Describe the problem,

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00:21:55,280 --> 00:21:57,910
explain who is responsible
for the problem and why.

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00:21:59,270 --> 00:22:02,470
Describe the problem,
describe the desired situation,

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00:22:02,470 --> 00:22:04,200
report back on the progress.

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00:22:04,800 --> 00:22:07,260
And finally, D,
describe the problem,

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00:22:07,260 --> 00:22:09,280
describe the desired situation,

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00:22:10,080 --> 00:22:13,250
list the steps to move
the problem to solution,

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00:22:13,250 --> 00:22:16,270
determine exactly
who caused the problem.

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00:22:17,400 --> 00:22:20,340
And the correct answer is A.

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You want to do
all of those steps,

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00:22:25,520 --> 00:22:30,870
not just subsets of those steps
as identified in B, C, and D.

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Thank you very much

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00:22:33,600 --> 00:22:36,610
for listening to Part 4
of Adverse Events.