Good afternoon.
I am David
Wendler from the Department of Bioethics here at the NIH Clinical Center.
And today I'm going to talk and hopefully we're going
to have some time for discussion on the ethical issues
that are raised in connecting research with what are called vulnerable subjects.
And I'll talk minute on what I mean by that.
Just a couple of notes. I work at the NIH.
I work here in the clinical center, but I am emphatically not a spokesperson
for the NIH.
What I say are going to be my own views.
They're based on my own thoughts and, as you'll see in some cases, my own research.
I hope people here agree with me on some of this,
but if we're really lucky people will disagree on some,
which will give us a chance to have a good discussion.
All right. So research with vulnerable subjects.
Everybody who's here, everybody's who's watching
online, knows the importance of conducting clinical research.
It's not the only way, but it's certainly one of the best,
and one of the primary ways for identifying new treatments,
new interventions, new ways to keep people from getting sick, cure
people who are sick, and treat people who are chronically ill.
In order to preserve clinical research, continue to do it,
keep public trust in it, protect subjects, it's important that we have sufficient
protections in place for the people who participate in research.
And the point of today's lecture is this is especially important
with vulnerable subjects.
And this is a topic that's not new.
This is not a claim that's original to me.
Regulations, commentators, and guidelines for at least the last 40 years
or so have been emphasizing the importance of protecting vulnerable subjects
who participate in clinical research.
This is just one blurb, one example of that from the U.S.
regulations, which says that IRB.
So review committees should be aware of the special problems of research
involving vulnerable populations and then should try to develop
ways additional protections, additional safeguards to protect vulnerable subjects.
So that raises three obvious questions,
and I'm going to talk about a little bit today.
One, who's vulnerable or which subjects are vulnerable?
What are the challenges that are raised
when we try to conduct research with vulnerable subjects?
And what additional requirements, protections, or safeguards
can we put in place to try to address those concerns.
So I'm going try to briefly go through each of these questions.
I'll talk a little bit initially on some background
regarding the debate over who's a vulnerable subject,
how you define vulnerable subjects, and then I'm just going to hone in on one
I think a very important example, but one example of research
with a vulnerable population in order to provide some insight into what
those concerns that get raised and then what are some protections
that can be put in place to try to address those concerns.
So vulnerability.
If you just think about it very generally.
So Merriam Webster says that vulnerable individuals are those
who are capable of being wounded, they're open to damage,
or they're assailable, which I think is an absolutely wonderful word.
So a vulnerable individual is any individual who can be harmed,
who can be hurt, who can be damaged, who can be wounded.
So if you think about that for a second, it's not hard to think of examples
of individuals who can be harmed, hurt, or wounded, right.
That's easy to do.
What's actually hard is to think about who doesn't fit this definition?
What individual isn't capable of being wounded or open to damage?
And that raises one of the first challenges and one of
the debates that's going on right now in thinking about research
with vulnerable subjects, which is if you think of vulnerable subjects
as somebody who's capable of being harmed, damaged, or wounded,
and then you think about humans, presumably one of the fundamental
aspects of the human predicament is the fact that we're all capable
of being harmed, damaged, or wounded.
We can experience disease.
Someone can cause us to suffer pain, loneliness, rejection.
We can die. We can be killed.
There are just myriad ways in which all of us can be harmed or damaged.
So this seems to suggest then,
if we take the definition of vulnerability seriously, that everybody is vulnerable.
And if our human subjects are human, it follows,
according to some pretty basic logic, that all human subjects are vulnerable.
So if all human subjects are vulnerable, then what does it mean
or how does it make sense to think about extra protections
for vulnerable subjects if in fact everybody's vulnerable?
Here's one example of that.
One of the complaints people
have been making over the last decade or so in research ethics
is that lists of vulnerable subjects just keep growing longer and longer.
This is an example.
CIOMS is the Council of the International Organization of Medical Sciences.
It is a very prominent and influential set of guidelines
for human subjects research, particularly human subjects research
that's conducted in developing countries.
And here is a non-exhaustive list from them of subjects who are vulnerable.
And as you just think about it, you could look through
a couple of the examples, this is an awfully long list.
And this isn't even a complete list.
And then the question becomes obviously if all of these people
and even more are vulnerable, then how is it
that we can come up with protections and safeguards for vulnerable subjects?
So this is the concern.
What sense does it make to try to institute special protections
for vulnerable subjects if almost everybody's vulnerable?
This is a, excuse me, this is a quote from a review about ten years ago
on the issue of vulnerability in research by Carol Levine,
also Christine Grady, who talked here a couple of weeks ago, was on this paper.
And they point out that if everybody's vulnerable, then it seems
as though the concept becomes too nebulous to be meaningful.
So there's this problem.
It looks like if you look at things like standard
definitions of vulnerability, everybody's vulnerable.
But if then if everybody's vulnerable, how is it that you can implement
additional protections for vulnerable subjects.
Doesn't that just mean that everybody needs additional protections?
And if everybody's vulnerable, then it seems in a sense that nobody is.
So what do we make of this?
So here's one way for me that I try to explain this.
It's the thing about two different kinds of claims that we can make when we talk
about vulnerability, either in general or with respect to human subjects research.
And the first one is what I call categorical claims.
So it's a claim that all of the individuals
in some group, some set, some population are vulnerable.
That's a categorical claim.
And then a comparative claim, which is that some individuals within
a group, class, or set are more vulnerable than other individuals
within that group, class, or set.
So here's some just basic examples.
Categorical claim, all cars are at risk of being stolen.
That seems pretty clear.
Just about every car is at least in a position where somebody might steal it.
That talks about all cars, right.
Now here's a comparative claim.
At least according to data from last year, I assume this is still true,
that Hondas, at least in the U.S., are the most stolen car.
So it looks like Hondas are at an increased risk of being stolen.
And what this suggests that is whatever we're talking about vulnerability,
the first thing we need to know is whether or not we're talking about
a categorical claim, all individuals, like all human beings, are vulnerable.
Or are we talking about a comparative claim.
Some set of human beings, or say research subjects,
are more vulnerable than other set, or individuals, or research subjects.
So what do you with categorical claims?
So the fact that everybody's vulnerable, the fact that everybody can be harmed,
the fact that human subjects, all human subjects can be harmed,
isn't necessarily meaningless.
It makes the point that what we need is we need protections
for all research participants, no matter who they are, and no matter
where they participate in research.
This is a point that was made by Fred Grinnell
who is a -- works in research ethics from Texas.
And basically, what he argues, he argues is once you take
seriously the fact that all -- the fact that all human subjects
are vulnerable, what we need is we need a new framework
for thinking about how to protect subjects.
And in particular, he talks about a kind of precautionary principle,
which is a principle that gets derived from thinking
about protection of the environment, which is basically that you're trying
to be very careful in terms of the risks that you're willing
to accept in a particular activity, or an enterprise.
And Fred's thought is given the fact that everybody is vulnerable,
all human subjects are vulnerable, maybe this is the kind of approach
we should take to research ethics, as well.
So we can talk about it if people are interested.
I'm not necessarily advocating this view.
My point is just that the categorical claim
all subjects are vulnerable can make sense to the extent
that what you're trying to figure out is what should be the regulations
or the protections for everybody who participates in clinical research.
So that's all regulations as part of a categorical claim.
Now there is the comparative claim.
So what do the comparative claims do?
So as I mentioned, comparative claims are picking out specific groups
who are especially, or more vulnerable, or at an increased risk of
being vulnerable.
And here the suggestion is that once you've got general protections in place
for all subjects, then the question is are those protections
sufficient for all the different groups that might enroll in your research?
If the answer is yes, great, you're set.
But if not, then it suggests that there
comparatively vulnerable subjects who might need additional protections.
And that's where the call for additional protections comes in.
So one of the groups that's famously started
some of this was the National Commission, which was one of the first groups
in the U.S., at least, to think about regulations for human subjects research.
And they started out with some
recommendations for human subjects research in general.
And then once they developed those, they then stopped and said,
okay, are they good enough for all types of research?
Or are there some categories of research or categories of subjects
who need even greater or additional protections?
And their answer was yes in a couple of cases.
And one of the examples for them was children, where children
might need even more protections than we give to competent adults.
So that's the distinction
between comparative claims here and then the prior categorical claims.
So one example of this, this is a nice example,
this one of the most influential papers I think that's been written
vulnerability in human subjects research by Ken Kipnis, who's in Hawaii.
And basically, he says this.
He says when I'm talking about vulnerable subjects, what I mean is
I assume that the basic baseline, guidelines, regulations
protections are in place, and they're working.
And then what I'm going to ask is are there groups
or are there individuals
for whom that general set of guidelines or protections isn't sufficient
so that we need even extra added safeguards or protections?
Going beyond what he calls that baseline of regulations.
These are a couple of examples.
So DOH is the Declaration of Helsinki.
That's one of the most influential set of guidelines on human subjects research.
And here, they're giving a comparative claim.
Some research populations are particularly vulnerable.
So they're not talking about all human subjects.
Maybe their granting that all human subjects
are vulnerable to a certain extent.
Then they're saying, well, some populations are even more vulnerable
than that baseline, and they need extra or special protections.
Then a similar comment from CIOMS that I mentioned just a minute ago.
So here's a comparative example.
So the U.S.
regulations based on the suggestions made by the National Commission
that I mentioned a minute ago, the U.S.
regulations are based on the National Commission's recommendations.
And the U.S.
decided there's a couple of important populations
who need additional or special protections.
Prisoners is one of them.
Children, as I mentioned, is another.
And one of the extra protections here is there are stricter
limits on the risks to which you can expose children.
So the idea is while we need some protections for research with competent
adults, but as long as they're competent, as long as they understand,
as long as they give informed consent, then maybe we can allow them to accept
or be exposed to a higher level of risk in the context of clinical research.
But now we start talking about younger children or infants, given
that they can't give informed consent, those general protections
aren't going to be enough, and we want some additional limits
on the extent to which we can expose children to risks
in the context of clinical research.
So here's
a crucial point and hopefully somebody here will ask me
if this doesn't make sense, but when we're talking about these
comparative claims, more vulnerable, somebody more vulnerable than us,
children are more vulnerable than competent adults.
Hondas are more vulnerable than other cars of being stolen.
If you think about those claims for a minute, what you'll realize
is that they tend to be context dependent, meaning whether or not
some group, population, or set of individuals is more vulnerable
than others, is going to depend upon the context.
So when it comes to research, it's going to depend upon the type of research,
where it's conducted, and how it's conducted.
This is just one simple example based on my earlier case of cars.
It turns out that in certain towns in the west of the U.S.,
Hondas actually aren't very susceptible to being stolen at all.
People aren't interested in them.
They're interested in SUVs and trucks.
So if you've got a Honda, and you're driving in
Washington D.C., it's probably more likely to be stolen than other cars.
You might want to take more protections.
If you live in one of these towns in the West, you probably don't
need to be as concerned.
So the context affects whether or not that car is more likely to be stolen.
So I threaten people here that there are going to be a couple of quiz questions.
Here comes the first one.
Context dependent applied to clinical research.
Maki works in a lab at the NIH.
He's been working with clinical investigators
doing both translational science and basic science for at least 15 years.
One day she's walking through the halls here at the clinical center
where there're often ads up for clinical studies.
She sees an ad and she's interested in enrolling in a study.
Is Maki a vulnerable subject?
[inaudible commentary] According to CIOM she is?
How come?
[inaudible commentary] Because she's an employee.
So why would be an employee or why might being an employee
make her vulnerable, or more vulnerable, comparatively vulnerable?
[inaudible commentary] Yeah.
[inaudible commentary] Okay, so.
Sorry, so -- there's lots and lots of people listening online.
If you can come up to the microphone, that would be good.
Otherwise, I'll just repeat for people.
So basically, her point here is if you remember the list from CIOMS,
employees are one of the examples of vulnerable subjects,
or what I'm calling comparatively, or especially vulnerable subjects.
And then my question was, well, why would they be on that list?
And your nice response is, well,
it might be that given that she's an employee at the NIH,
Maki feels some compulsion to say yes and be in a study.
So take an obvious example,
imagine that this is a study that's being run by her lab chief.
Imagine her lab chief is the principal investigator
of this study and now you want to enroll Maki in that study.
You're going to be worried.
You might be worried -- is she able to say no given that
the person who's in charge, who wants to complete this study,
presumably, is somebody who has power over her.
And that is a very nice example, and it turns out at the clinical center
at least we have a very specific policy for doing research with employees
where there sometimes needs to be an independent assessment
just exactly to address that concern.
So on the one hand,
if for the PI is her boss, do you think she's going to be vulnerable.
But on the other hand,
imagine she doesn't know any of the people who are doing this research.
You might think in that case, she might be less vulnerable
than almost anybody else.
She really understands this stuff, right.
She's been doing and involved in clinical research for 15 years,
she might be better able to assess its value, its risks,
its potential benefits, than somebody who doesn't have that background.
So this is just a nice example, I think, of how whether or not a person
or a group of people, say in this case employees, whether vulnerable
is going to depend on the context that we're talking about.
So those lists aren't going to apply broadly.
It's going to depend on the case in question.
Okay.
So that's a discussion of who's vulnerable.
So the same question.
So what protections are appropriate for vulnerable subjects.
And, as I said, given that vulnerability's going to be context dependent
whether or not somebody needs protections, and moreover what
those protections need to be, is going to depend upon that context.
So this is exactly your point.
If the PI is her boss, then we need to make sure that Maki's
able to -- not necessarily an informed decision.
She probably understands, but we need to make sure she's able
to make a voluntary decision.
That her boss isn't coercing
her, manipulating her, or forcing her to be in this study.
Whereas, an infant. That's not what you're worried about.
You're worried that infants can't understand.
So there you're going to focus more on understanding
rather than the voluntariness of the decision the person makes.
So here's just a couple examples of applying the vulnerabilities
and the safeguards.
So employees, as I mentioned, what we do, so we do an independent assessment
to make sure the person understands and they're making their own decision
voluntarily.
In the case of children, you're worried they don't understand.
They can't look out for their best interest.
You want their parents typically to help them.
Or you have somebody who doesn't speak English.
Well, if they speak French and they're enrolling in a study in Paris,
they're in good shape.
If they're speaking only French and they're enrolling in a study
at the clinical center, that might be a problem.
They might not understand as well as other people.
You might need a translator.
So very different context.
Very different vulnerabilities and very different protections,
depending upon the context and the particular vulnerability.