>> Elizabeth Ness: Welcome to Part 4
of Adverse Events, Adverse Event Reporting to the IRB.
My name is Liz Ness.
I'm the director of the Office of Education
and Compliance in the Center for Cancer
Research at the National Cancer Institute.
One of the most important considerations for an IRB
once a study has been approved
is whether there is any new information
that would alter the risk for the participants.
During this session, this part,
I will cover what adverse events need to be reported to the IRB
in an expedited manner,
what a corrective and preventive action plan is,
and introduce other new information
that needs to be reported to the IRB.
So, an adverse event that meets the definition
of an unanticipated problem needs to be reported to the IRB.
The phrase "Unanticipated problems
involving risk to subjects and others" is found,
but not defined in HHS regulations at 45 CFR Part 46.
OHRP considers unanticipated problems
in general to include any incident experience
or outcome that meets all of the following criteria.
It's unexpected in terms of the nature, severity,
or frequency given the research procedures
that have been described in the protocol
and related documents, such as the consent
and the characteristics of the study population being studied.
They need to also meet the -- be related or possibly related
to the participation in the research.
So, in the guidance document, it states "possibly related,"
meaning that there's a reasonable possibility.
Again, we hear that term "reasonable possibility,"
that the incident experience or outcome may have been caused
by the procedures involved in the research.
And that the event or non-AE presents a --
replaces the subjects or others at greater risk of harm
than was previously known.
And harm here can include physical,
psychological, economic, or even social harm.
So, in this Venn diagram,
which is in the OHRP guidance document,
you can see the relationship between adverse events
and unanticipated problems.
The vast majority of adverse events
occurring in human subjects and research
are not unanticipated problems
as you can see in Area A of the Venn diagram.
A small portion of adverse events
are unanticipated problems as seen in Area B.
Then there are also unanticipated problems
that are not adverse events at all
that can be seen in Area C.
So, the key question regarding a particular adverse event
is whether it meets the three criteria
of being unexpected, related,
and putting subjects or others at greater risk of harm
as previously just described in the slide before this one.
I just wanted to give you a couple of examples
of a non-AE that could also be a UP.
These may be other incidences or experiences
or outcomes that aren't related to an adverse event
if they meet the three criteria.
For example, an investigator conducting behavioral research
collects individually identifiable sensitive information
about illicit drug use by surveying college students.
The data was collected and stored on a laptop
that wasn't encrypted, and the laptop was stolen.
This is an example of putting the subject
at greater risk of harm.
And harm here may not be physical harm.
It could be psychological harm or even potentially social harm.
There could be a dosing error.
So, a larger dose of the investigational product
was given, but the participant
didn't actually experience an adverse event.
This is example meets the three criteria, which --
because it meets the criteria
suggesting it could have an increased harm.
It doesn't say in the definition of unanticipated problems
that it did create harm. And also -- and final example
is some type of product contamination was found
and there weren't any adverse events
that subjects experienced.
So, the FDA regulations also support prompt reporting
of an unanticipated problem to the IRB.
And you can see here listed the IND regulations,
the IDE regulations, as well as the Part 56,
which is the IRB regulations under title --
all under Title 21 of the FDA.
You can also see what I consider a very helpful guidance
for clinical investigators, sponsors,
and IRB when assessing adverse event reporting to the IRB.
That came out in 2009 and is still, you know,
current and applicable today.
So, the FDA believes that only adverse events
that meet the definition of an unanticipated problem
need to be reported to the IRB.
This would include those events that were described in Part 3
as the IND safety reports or the safety reports.
Of note, not all safety reports from sponsors, as I mentioned,
in Part 3 actually meet the definition
of unanticipated problem or a UP.
So, the PI does need to make that assessment.
Also, as discussed in Part 3,
unanticipated adverse device effect
should be reported by the investigator to the sponsor
and the sponsor to the FDA no later than 10 working days.
So, the HHS regulations require written procedures be in place.
So, this is under Title 45 Part 46
for ensuring prompt reporting of unanticipated problems
to the IRB, appropriate institutional officials,
any supporting department or agency head,
as well as OHRP, the Office for Human Research Protection.
The purpose of the prompt reporting is to ensure
that appropriate steps are being taken in a timely manner
to protect other subjects from potentially avoidable harm.
So, the regulations don't define what prompt is.
The appropriate timeframe from satisfying
that requirement of prompt reporting will vary
depending upon the nature of the unanticipated problem,
the nature of the research associated with the problem,
the entity to which reports are to be submitted.
For example, an unanticipated problem
that results in a subject's death
or was potentially life-threatening, generally,
should be reported to the IRB within a shorter period of time
than other unanticipated problems
that are not life-threatening.
Therefore, as you can see in this slide,
OHRP recommends that the following guidelines are used
to satisfy the requirement of prompt reporting.
Unanticipated problems that are serious should be reported
to the IRB within one week of the investigator,
and I'll say, slash research team
becoming aware of the event. And other unanticipated problems
should be reported within two weeks.
However, please be aware of your own institutions,
Human Research Protection Program policy,
as well as the IRB of records policies
because they may have shortened the timeframe.
They can't make it longer, but they can make it shorter.
Typically, these reports are submitted through some type
of a reportable new information form or database.
OHRP recommends that investigators include
on the information that you see here on the slide
when reporting an adverse event
or another incident or experience
or unanticipated problem to the IRB.
Appropriately identify the information
for the research protocol such as the title,
investigator's name, the IRB project.
A detailed description of the adverse event,
the incident, experience, or outcome.
An explanation of the basis
for that determination of the incident or outcome
and how it represents an unanticipated problem.
And a description of any changes to the protocol
or other corrective actions that have been taken
or are proposed in response to an unanticipated problem.
And this is referred to as a corrective
and preventive action or CAPA Plan.
So, a CAPA Plan establishes a process or sets up processes
to identify, correct, and prevent future occurrences
that may impact safety and data,
and ensures that the quality of the research --
the conduct of the study is maintained.
CAPAs actually started in industries,
specifically in manufacturing as a process
that is used in all steps of the manufacturing for a company,
so that they can identify, correct,
and prevent quality issues from occurring.
And this type of plan is similar
to what's conducted in a hospital
setting for a sentinel event, which may --
which many of you may already be familiar with.
This is not at all uncommon for institutions
that are JCO accredited or Joint Commission Accredited.
So, just to briefly review CAPA terminology,
a root cause analysis is a problem-solving method
to identify the origin of the cause
or causes of the problem or the issue.
A corrective action plan simply is the action
that's taken to eliminate the cause of the problem.
And preventive action is to, obviously,
then prevent the potential problem from occurring again.
In crafting an effective plan,
the investigator and research team
needs to really think about why the event occurred.
Is it a system problem? Is it a problem with a procedure
or something within the protocol itself?
Is it a training issue?
The first step in creating the plan is to identify the problem.
This can be a potential or an actual problem.
You want to describe how this issue
was uncovered or discovered.
Next, you want to analyze the problem.
You want to determine the root cause or causes
and any contributing causes of the problem or issue
by conducting that root cause analysis.
You want to collect the evidence for the causes
and document them.
And remember, there may be several causes
to one problem or issue.
Once the root cause and contributing causes
have been identified,
you can then begin developing your plan to mitigate
or prevent each identified cause or contributing cause.
You may need to do some corrective action
more immediately as you have identified the cause and you --
before you start to do a deep analysis
then of a prevention plan.
But be specific when you're listing each of the actions
that need to be completed or implemented,
and who will be responsible for those actions
and the due date for each of those actions.
You'll then need to, obviously, implement or complete
the implementation of the corrective action plan
and to then implement your preventive action plan.
You'll need to look at resources.
Resources do need to be allocated to implement
each of those actions.
Typically, when a, you know, what I call a major CAPA Plan
is truly needed,
it's often not just the research team, the PI themselves.
There are other, if not at least,
contributing causes that could be
part of the preventive action plan in particular.
And then once you've implemented your plan periodically,
you want to evaluate the plan.
You want to verify that the actions
that were outlined have been completed.
Were they effective?
Did you need to do something else as a result of that?
You want to confirm and document those actions
when they are completed.
And this may be a six-month process of evaluation.
It could be a year process.
It may even be a little bit longer
depending upon what preventive actions
make the most sense for the identified problem.
But you do want to make sure that you, ultimately,
document full closure of a corrective
and preventive action plan.
Even if something may not ever be able to be resolved
that might be an institutional issue,
and you would need to, at least, note that.
And, you know, it would -- if your plan then,
you weren't able to close everything out,
some view then that your CAPA
Plan would be considered ineffective
and you would need to actually revise it.
So, doing an ongoing evaluation is extremely helpful
to having a successful, corrective,
and preventive action plan.
Some types of correction and preventive actions
you can see here.
There can be related to the protocol in terms
of potentially modifying your eligibility criteria
that may be needed to mitigate a newly identified risk.
Implement additional procedures for participant's safety.
Monitoring could be related to modifying the informed consent
as it relates to new information about newly recognized risks
to previously enrolled subjects and --
or informing enrolled subjects.
It may need to suspend enrollment of new subjects
or put a hold, at least,
temporarily until you have your corrective
and preventive action plans well underway.
And then if that is part of your preventive action
or immediate corrective action,
you'd want to note what the criteria would be then
to return to enrolling new subjects.
Any -- it could be a suspension of the research project.
Increase in monitoring activities,
providing some type of training, retraining.
And again, as I mentioned, you want to work
with your appropriate institutional officials
to correct the problem.
Typically, this is not something that just the PI
or the research team will be able to fix.
There is often other information that may need
to be reported to the IRB that are not adverse events
or not even unanticipated problems
that don't overlap with an adverse event.
These may be referred to by your IRB
as Reportable New Information or an RNI.
Examples can include non-compliance,
which can be defined as failing to follow applicable laws,
regulations, and institutional policies
that govern human subjects, protection research,
or not following the requirements
or determinations of the IRB.
A major protocol deviation that has or may have a potential --
to potential risk of impacting negatively on the rights
and welfare of the participants or impact
the scientific integrity or validity of a study.
Any new information that might affect the participant's
willingness to enroll or remain on the study,
such as results from an interim analysis
that indicate a new risk or decrease effectiveness
of the study intervention.
Or maybe the intervention in one --
if it's a randomized study and one arm of the study
that might result in that arm needing to be closed.
It could be a withdrawal or restriction
of a marketing approval even by the FDA.
It can also include a complaint of a subject
that can't be resolved by a research team,
death of a subject that is, at least,
possibly related to the research.
And this may have a more quickly reporting timeframe to your IRB.
So, again, be aware of what your IRB's policy
is on reporting of other reportable information.
Any audit inspections or inquiries by federal agencies
may need to be reported, breach of confidentiality.
A change to a protocol that was taken
without prior IRB approval that was done that
didn't necessarily immediately impact the harm for a subject.
And incarceration of a subject in a study
that was not previously approved by the IRB to include prisoners
or even premature suspension
or termination of research by the sponsor,
the investigator, or the institution.
So, the IRB is responsible then for reviewing
these unanticipated problems,
as well as other information that is submitted to them.
They may ask for more information.
They make a final determination of sort of what needs to happen.
For example, revise -- you need to make --
you know, amend your protocol
if you hadn't already identified that.
More frequent monitoring or increase the frequency
of the continuing review
or maybe even including terminating the study.
And if the UP or the other type of serious
or continuing non-compliance is determined by the IRB,
then that does need to be reported to OHRP.
And if applicable,
for an FDA regulated study to the FDA as well.
So, in summary, UPs, by definition,
are events that are unanticipated
related to the research and pose a new risk.
This applies to non-adverse events,
as well as issues of non-compliance.
And the IRB must review this promptly to see
if the risk benefit ratio is favorable
and what other actions may need to be taken.
Then it is up to the IRB to review this,
make a determination, and report accordingly.
So, for test your knowledge.
The study coordinator identified an adverse event
that they believe is unexpected, not related to the research,
and not serious.
The coordinator should report it to the IRB right away.
Is that true or false? And the correct answer is false.
The study coordinator identified it,
but the PI and the sponsor did not necessarily.
And finally, one last test your knowledge question.
What is the process for developing a CAPA Plan?
Describe the problem, describe the desired situation.
List the steps to move the problem to solution.
Assign a responsible party
and due date assigned to each step.
Describe the problem,
explain who is responsible for the problem and why.
Describe the problem, describe the desired situation,
report back on the progress.
And finally, D, describe the problem,
describe the desired situation,
list the steps to move the problem to solution,
determine exactly who caused the problem.
And the correct answer is A.
You want to do all of those steps,
not just subsets of those steps as identified in B, C, and D.
Thank you very much
for listening to Part 4 of Adverse Events.