I'm going to
spend our last, session for today.
Last lecture for today on a little more
on institutional review boards.
Here's my disclaimer again.
You'll see that again.
So there are,
in my opinion and the opinion of others,
at least two really important pillars
in the protection of human subjects
research.
One is the Institutional Review Board,
which we'll talk about.
And the second is informed consent.
The institutional review boards responsibility
is to make sure that the research
that they review is not too risky,
respects the participants recruit notes in a way
that's equitably, appropriate, etc..
So one can assume
or the system is set up so that one can assume
that if the Institutional Review Board
has reviewed and approved the research,
it's considered safe for an individual to
then provide informed consent.
If we
didn't have institutional review boards, right, investigators
could go directly to individuals and ask them to be in their
research.
We saw some examples of how that can go wrong.
But just a reminder that
when we talk about how the system protects
human subjects, we're going to talk
about the review board.
And then next week we have a whole day on informed
consent.
Doctor Grady will be back.
Doctor Scott Kim, also on our faculty will be
back,
and we'll have someone from the National
Institute of Mental Health
talking about how they assess capacity here at the clinical
center.
So here are the sort of key points
that I want you to get.
And, if you don't get anything else,
these are the important things.
So first, IRBs are responsible for their review
and oversight of all human subject
research conducted
in the United States at an academic medical center
that has
sought and gained a
federal wide assurance from the Office
of Human Research Protections.
That's the HHS level.
Office to review all research that happens at their
institution.
And I'll talk a little more about that.
But I wanted to just make the point that
outside of the United States,
these bodies are called ethical review boards,
independent ethics committees, research ethics committees,
etc..
So for those of you who are in places
other than the United States,
a lot of what I'm going to cover is similar to what
these boards do in other countries today.
Most countries that actively are engaged or
their investigators are actually engaged
in human subject research,
have some sort of review and oversight mechanism
to protect the citizens of their country or their region.
In the
United States, IRBs are guided in their
review
by those two federal regulations that doctor Grady mentioned.
There's one that covers all of HHS
and the key component of that of 4645
for a life road around 45 CFR 46 also applies to.
That's called the common rule because it
applies to 17 other federal departments.
So the Department of Energy,
the Department of
Housing and Urban Development, etc.,
so the key federal regulations
in the United States are the HHS ones.
And when it comes to the review and approval of drugs,
the FDA kicks in as well.
And they're very similar.
IRBs in the United States are local,
meaning that every academic medical
institute
that is conducting human subject research has a local IRB or
multiple IRBs.
I used to work at Johns Hopkins.
I sat on a medical school IRB.
There were seven IRBs to review
and approve all the research that was happening at the
institution,
and they were all local in the sense
that we needed
seven to keep up with the amount of
research that was going on.
Those local groups can
develop their own policy and practice
based on the federal regulations.
They can be more strict, but the set of regulations are the
baseline.
And outside of the US, IRBs are sometimes local, sometimes
regional.
So, in the UK it's done by regions.
In other countries there is a national IAB.
In Uganda, for example, there are both local committees,
attached to academic institutions
and a national IRB.
So all to say for those of you out there
who are not in the US,
you might want to find out how the system works in your
setting.
And the one thing I wanted to say is,
if you're doing research and you have a question and you
don't know
if it needs to be your research, it needs to be submitted to the
IRB
or how to think about the research
you're planning.
Ask them.
They are there to help investigators
navigate their research and to make sure
that it meets the ethical standards.
So when in doubt, go and find that institution,
whether it's local, regional, national
and ask them questions.
So this is just a reiteration
of that independent review ethical requirement.
And the IRB is meant to review the research.
And it's meant to be reviewed by individuals who are not
conducting the research.
The goal
is to assure some public and social accountability.
Right.
If you are thinking about enrolling in research,
you may have no idea what an IRB is.
But if you did know what an AI IRB
is, that would give you some sense
that a learned body has reviewed
the research and considered it safe.
The IRB is also there to minimize
the impact
of potential researcher conflict of interest.
And this is a just a great quote that I
really,
I use every time I talk about IRBs
from Edgar and Rosman back in 1995.
Unquestionably, their very existence
has tempered the inevitable propensity
of researchers to pursue investigations
without dispassionately weighing the risks
they are asking others to assume or fully informing their
subjects of them.
So another way to say this is just that
IRBs exist, hopefully in their mind.
Remind investigators that they have to think about
the subjects
and their research, and that there is a body that is going to
review.
So on one hand, you know, investigators
might think, oh my gosh, right.
This might be a cure.
They might overestimate the potential benefit.
That's why you have the Institutional
Review Board
to address that sort of inherent personal
conflict.
Right.
If I'm doing a research project, of course I think it's going to
work.
But we do the research in order to find out if it
works.
If we knew it worked, we wouldn't have to do research.
So the IRB says, hey, this is exciting.
Let's make
sure the plan is scientifically sound
and appropriately protect subjects.
So they're bit of a guardrail
for investigators when it comes to conflict of
interest.
I'm just going to touch on a
number of key components of what I IRBs do.
Happy to answer questions.
And as will always be the case, we have put readings on canvas.
For those of you who want to learn more about
IRBs,
there are articles about IRBs, so if you have questions about
them,
you can ask them today or ask them
as we move forward in the class.
So what is their role?
As I said, their role is to review
and oversee all the human subject research
that's happening at an individual institution
and in the United States, the IRB.
When I say institutional review board, I'm
referring to the group of individuals
who are brought together to review
a particular protocol or protocols
and decide whether or not they ought to be approved or
not.
Often in the United States, IRBs are just one component
of what's referred to as the Human Research Protection
Program.
So some institutions have IRBs, but there has to be
an administrative infrastructure for that IRB to be supported.
And so I may refer to today and moving forward,
the Human Research Protection Program
to convey
the sort of administrative body that's in charge in the United
States,
according to the federal regulations, IRBs
must have at least five members.
And the, there are requirements for those five members.
One of them has to be unaffiliated
with the institution, and one has to be a
non-scientist.
When I'm
not teaching, I do a lot of empirical
research,
about research ethics and worked on a study
a couple of years ago where most IRBs have only one
person
who is both unaffiliated and a non-scientist.
So that means there's only one person
who is probably is not a physician
or a PhD trained scientist.
That's hard.
I'm sorry to be the only person who's not a scientist in the
room.
Some countries, like New Zealand, for
example, have very different approaches.
Their equivalent institutional review
board has to have
one more member of the community than there are scientists.
So if there are four scientists, they have to have five community
members.
So different countries have, set up their systems in
different ways
to make sure that sort of voice is at the
table.
There are a number of challenges
in sort of essential to an institutional review
board.
One is the individual conflict of interest.
So we can sort of quickly deal with that
with IRBs if I'm doing research.
So I happen to be on the IRB here
at the Clinical Center
when I submit my research to the IRB,
I can't be on the IRB when my research is reviewed.
Right.
So that's a pretty clear way to remove
the conflict of interest that I would have
if I was sitting in the room.
Of course, I would say it's awesome
and it needs to be approved.
Or let's say my
supervisor, Doctor Grady, is my supervisor,
Christy.
I'm working with Christine on a project
and her project comes to my IRB.
I'm going to raise my hand and say,
everybody, this is my boss.
She has a supervisory role over me.
I don't feel like I'm the best person to review
there's
so I can self recuse myself from the deliberations.
Now the outside of the NIH,
almost all research conducted at academic
medical centers
is funded by the National Institutes of
Health.
And so imagine you are an IRB member
at Johns Hopkins as an example.
What happens is,
if your grant to the NIH is funded,
it is then reviewed by the Institute
review Board at your institution before it can be implemented.
If the IRB is the sort of,
only thing between the research
getting done and the, you know, getting the
funding,
then the IRB itself has a conflict of interest,
right?
That if the IRB doesn't approve it,
the institution doesn't get the money.
Now, that's not to say that therefore
all our views
are essentially conflicted and can't do their job.
Fortunately, that doesn't mean that.
But I make that point just because
there are conflicts of interest and tensions.
When we talk about ethics, when we talk
about the infrastructure developed
to sort of over, you know, overview
to oversee the ethics in,
any sort of, you know, any sort of system set
up.
So institutional review boards informed consent.
Right.
Again, really quick digression to informed consent.
I'm the investigator.
You're someone who I want to enroll in your study.
I might have the incentive to not tell you
about the really problematic risk,
even though it's in the form.
I'm not going to point it out because I really want you to
enroll.
So only to say, this will be a
theme as we move forward, that there are going to be
challenges
even when we set up systems to hopefully make the system
work.
And then group dynamic dynamics
is another issue that relates to IRB.
So I've served on many IRBs over the many years of my
career,
and they are
bodies that sometimes have been together
for ten, 15 more years.
Some IRBs don't have any term limits,
so you can sort of
encounter observer drift
or sort of everyone cedes to this person
when it comes to that,
or the chair has a lot of say or sway.
So there are things that any group
that's together for a long time may encounter.
Because of that, some IRBs do set term limits.
So when I was at the School of Public Health at Hopkins,
you could you would serve for three years
and then you would rotate off.
So the group was always had some carryover
or not
everybody sorry, not everybody's term
limit ended at the same time.
But that's a way to sort of address
both needing
the expertise and avoiding sort of groupthink
attitudes.
So why do we need this IRB?
I've already alluded to this.
The IRB needs to review
any research that is funded by the NIH.
Many other funders require ethics review.
And that federal wide assurance that I mentioned before,
when an academic medical center
sets up a federal right assurance with the federal
government,
they say in their documentation,
I will review all the research
at my institution, regardless of the source of
funding.
So that means that at an academic
medical center, all research, whether
NIH funded, gates funded, self-funded,
discretionary, fund funded, etc.
it is all reviewed.
So you can't escape quote unquote
the review,
by getting funding from a source other than the National
Institutes
of Health, when you're in the US and the FDA also requires IP
review.
So all pharmaceutical companies who hope to send a package of
materials
for marketing their drug in the future,
the FDA's going to say,
did you have an IRB review, all of these clinical protocols,
and you need to be able to say of course I did
this.
Is that federal wide assurance that I just mentioned and just
reiterates
this idea that it review, you agree to review all,
you review all research, regardless of
funding.
And two other things about this FHWa.
One is that institutions outside of the United States
can request a federal wide assurance.
It's kind of weird, but it happens.
And in that federal wide assurance,
you have to note
which regulation, which ethical code you're going
to follow.
In the United States.
It's almost always the Belmont Report.
And in international organizations, often
they'll say the Declaration of Helsinki,
because they don't have the Belmont Report
done.
The report is U.S. centric.
Declaration of Helsinki is meant to be international.
So you have to state at least what
standard you're using as your baseline.
So in terms of
responsibilities, Doctor Grady mentioned these really
quickly.
These are the review criteria in the federal regulations.
And I want you to notice that this
this is verbatim, okay.
This is all the direction that the IRB gets.
Risks must be minimized reasonable
when compared with benefit.
Right.
So there's a lot of discretion and a lot of responsibility
on behalf of the IRB to figure out
what are the risks.
Are they minimized?
How are we going to do that.
Are they reasonable.
What are the benefits. Are they in balance.
So the regulations just don't
give IRBs a lot of help, which means that most IRBs
develop policies for their investigators
and IRB members to follow.
These are the additional review criteria.
So most IRBs will obviously make sure
that they tick a box related to each one of these
things.
We have checked and made sure that each of these things is
true, but
checking the box that safety monitoring
provisions are in place
isn't the same as looking at the provisions and making
sure
that you're confident that those will,
in fact, be adequate for monitoring
safety.
There's additional criteria.
So in addition to the local policy,
NIH has guidelines.
So we have a bunch of guidelines,
for example, related to the inclusion
of women, minorities, children, people who are older.
So if a project is
funded by the NIH, the IRB ought to be making sure
that it is compliant with those NIH guidelines.
Some states have particular or laws for IRB.
So in Maryland, we would need to know
what the Maryland state laws are.
And Kristi mentioned the National
Commission
that was pulled together after the National Research Act.
They put out a lot of recommendations
and all subsequent
national commissions have been created.
Big reports,
many of them are on the shelf in my office
that add additional recommendations.
So it's up to the IRB to decide, are we going to follow
those recommendations?
Should we use those recommendations
to draft our local policy.
So plenty to incorporate now
what IRBs need to do is review research.
And this is how research is defined
in the regulations.
A systematic investigation, including research, development,
testing and evaluation design to contribute to generalizable
knowledge.
So that should remind you of scientific validity.
So the idea here is that
if you're doing this you have to go to the IRB.
Now this creates some concerns.
So I do a lot of qualitative research.
My intent is not to contribute to generalizable knowledge.
I'm exploring a phenomenon in order to identify themes
and patterns that might be transferable
to another setting.
Am I doing research?
Absolutely.
So this is what's written in the code.
But I IRBs need to be thinking about what
does that really mean for my institution?
If there's people like Holly, I don't want
her research not to be reviewed.
So we've got to make sure
that everyone knows we're reviewing qualitative work
as well.
So these are the potential categories
that the IRB is
going to, apply to your research.
One, they can say it's not human subject research and
therefore
you're not required to follow all of the rules and
regulations.
Some research is exempt from IRB review.
You still have to submit your research
to the IRB for them to determine that it's
exempt.
But one thing that all of the categories have
in common
is that it is no more than minimal risk,
and it meets one of those criteria,
the one that is most relevant to me,
and those of my colleagues here at the Department of
Bioethics,
is that it's data collected without identifiers.
So if I did a survey of all of you,
about what you eat for breakfast
this morning, social value quite low,
but I would say we're going to do this
and I'm not going to collect your names.
I just want you to answer the questions
that would qualify as exempt
from IAB review, though they shouldn't approve it because
there's no social value.
The next category is expedited.
Review expedited in this case doesn't mean faster,
but it means that the research you're
submitting is no more than a minimal risk,
and it can be reviewed by a chairperson
or experienced reviewer.
So technically, it could be faster.
It's not always faster.
And then the final and sort of most important category as it
comes
when it comes to IRB is, is research
that has more than minimal risk.
So if your research has more than minimal
risk and that's, you know, physical,
psychological, etc., it has to be reviewed by a full
committee.
And that initial protocol
that you submit goes through first
and initial administrative review.
This little diagram here is to just highlight
that the IRB is separate from the administrative staff
that are staffing the human research program.
They're reviewing the research plan.
And anything that's the potential subject
will see.
So that includes the consent the advertisements.
And they also coordinate other ancillary reviews.
So if there's a review of the pharmaceuticals
or review of radiation or a review of Conflict of
Interest,
this group is coordinating that review
and that'll be relevant in a second.
Then the research goes to the IRB.
They deliberate again.
That's this group of experts.
There's at least five of them.
And they can do a couple of things.
They can approve approve with stipulations
defer or disapprove.
In my experience,
IRBs almost never disapprove.
And part of that is because investigators
these days know that their research
has to sort of be at a particular standard
in order to even be considered.
Some research is deferred when there's sort
of a big problem, it's on its way to approval.
But they forgot to talk about how they're recruiting their
subjects,
or they forgot to include information
about the risks
that they're going to expose the subjects to
approve with stipulations might just be something
as as straightforward as you're approved,
but you have to accept the revisions
we made to your consent form.
Straight up approval is also
very seldom the case.
When so when I was at,
the School of Public Health at Johns
Hopkins,
you are all too young, probably to remember this, but
the School of Medicine at Johns Hopkins was closed.
Their IRB was shut down after a healthy
volunteer died in an asthma study.
One of the things that they said,
oh, HRP who closed it down said is you have to re review
all the research that you're conducting, thousands of
protocols.
A subset of those were,
being
conducted by School of Public Health
faculty.
I was on the group that had to that got to review all of that
research.
There were more than 50 protocols.
We approved one without stipulations.
All the others had some sort of stipulation that we wanted
changed.
So all to say that most research is going to be approved with
stipulations,
there's going to be something that the IRB is going to want
you to do.
The other things that IRBs do are
they're in charge of continuing review.
So for those protocols reviewed by a full committee, the
investigators
have to come back to the IRB and give an update
if you're going to change your study.
And the general rule is if you're going to change the
risk benefit
assessment for the
subjects, then you have to amend your
study.
So, for example, if you're doing imagine
you're doing a study where you have
your plan is to take one biopsy from a colon
during a clinically indicated colon. AP
but you've realized that's not enough,
and you need a second sample
that would clearly shift the risk
benefit balance for the participants.
So you would have to amend your study
and send that to the IRB.
They have to approve that before you could actually expose anyone
to that.
Second biopsy.
So I want to spend just one minute, 2
or 3 minutes
on a present policy issue.
So a number of years ago, both the NIH
and HHS put in a policy that said,
if you're conducting multi-site research
in the United States, you need or you can
and you need to identify a single IRB of record.
And so back to my little,
diagram here
for the single IRB policy, if you were conducting a
multicenter
trial here, I have five sites and a coordinating center.
This is sort of, you know,
like many trials, like an average oncology
trial or something, right?
You have a coordinating center and you have five sites
that are recruiting cancer patients
into the study.
That meant that you would have one IRB review by the
coordinating center,
and five IRB reviews each of those sites
would do one, which added up to six.
And investigators did not like this at all
because it created delays
that meant they couldn't do their research,
identify
the most appropriate effective intervention, etc.
so in response, NIH and HHS decided
that they would require
that there be a single IRB of record.
So now what this means is the core netting center, or
the IRB
or the institution designated conducts
one IRB review
and the five individual sites
say to that IRB, we will do whatever you say.
Your approval will be our approval.
Now, one challenge with that which I tried to
convey
with these little lines is that that doesn't
relieve that local institutions from doing all those other
reviews, conflict of interest, radiation, pharmaceuticals.
So the policy has been in place for a number of years now.
There are evaluations under way.
The outcomes are unclear whether it in fact
makes the system more efficient.
And there's been a lot of work in developing things
like the smart IRB, which is a way that individual
institutes
can learn about how to best coordinate
with other sites. So,
we'll see where it goes.
But that's a current issue in IRB policy.
And here's my summary slide.
When in doubt about your research,
ask your local committee
because they are the best situated
to answer any of your questions.