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Good afternoon.

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I am David

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Wendler from the Department of Bioethics
here at the NIH Clinical Center.

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And today I'm going to talk
and hopefully we're going

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to have some time
for discussion on the ethical issues

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that are raised in connecting research
with what are called vulnerable subjects.

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And I'll talk minute on what I mean
by that.

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Just a couple of notes. I work at the NIH.

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I work here in the clinical center,
but I am emphatically not a spokesperson

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for the NIH.

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What I say are going to be my own views.

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They're based on my own thoughts and, as
you'll see in some cases, my own research.

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I hope people here agree
with me on some of this,

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but if we're really lucky
people will disagree on some,

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which will give us a chance
to have a good discussion.

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All right.
So research with vulnerable subjects.

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Everybody who's here,
everybody's who's watching

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online, knows the importance
of conducting clinical research.

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It's not the only way, but it's
certainly one of the best,

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and one of the primary ways
for identifying new treatments,

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new interventions, new ways
to keep people from getting sick, cure

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people who are sick, and treat people
who are chronically ill.

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In order to preserve clinical research,
continue to do it,

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keep public trust in it, protect subjects,
it's important that we have sufficient

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protections in place for the people
who participate in research.

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And the point of today's lecture is
this is especially important

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with vulnerable subjects.

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And this is a topic that's not new.

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This is not a claim that's original to me.

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Regulations, commentators, and guidelines
for at least the last 40 years

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or so have been emphasizing the importance
of protecting vulnerable subjects

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who participate in clinical research.

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This is just one blurb,
one example of that from the U.S.

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regulations, which says that IRB.

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So review committees should be aware
of the special problems of research

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involving vulnerable populations
and then should try to develop

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ways additional protections, additional
safeguards to protect vulnerable subjects.

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So that raises three obvious questions,

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and I'm going to talk about a little bit
today.

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One, who's vulnerable
or which subjects are vulnerable?

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What are the challenges that are raised

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when we try to conduct research
with vulnerable subjects?

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And what additional requirements,
protections, or safeguards

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can we put in place
to try to address those concerns.

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So I'm going try to briefly
go through each of these questions.

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I'll talk a little bit
initially on some background

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regarding the debate over
who's a vulnerable subject,

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how you define vulnerable subjects,
and then I'm just going to hone in on one

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I think a very important example,
but one example of research

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with a vulnerable population
in order to provide some insight into what

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those concerns that get raised
and then what are some protections

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that can be put in place
to try to address those concerns.

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So vulnerability.

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If you just think about it very generally.

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So Merriam Webster
says that vulnerable individuals are those

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who are capable of being wounded,
they're open to damage,

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or they're assailable, which I think
is an absolutely wonderful word.

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So a vulnerable individual
is any individual who can be harmed,

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who can be hurt,
who can be damaged, who can be wounded.

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So if you think about that for a second,
it's not hard to think of examples

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of individuals who can be harmed, hurt,
or wounded, right.

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That's easy to do.

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What's actually hard is to think about
who doesn't fit this definition?

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What individual isn't capable
of being wounded or open to damage?

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And that raises
one of the first challenges and one of

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the debates that's going on right now
in thinking about research

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with vulnerable subjects, which is
if you think of vulnerable subjects

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as somebody who's capable
of being harmed, damaged, or wounded,

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and then you think about humans,
presumably one of the fundamental

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aspects of the human predicament
is the fact that we're all capable

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of being harmed, damaged, or wounded.

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We can experience disease.

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Someone can cause us to suffer
pain, loneliness, rejection.

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We can die. We can be killed.

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There are just myriad ways in
which all of us can be harmed or damaged.

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So this seems to suggest then,

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if we take the definition of vulnerability
seriously, that everybody is vulnerable.

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And if our human subjects are human,
it follows,

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according to some pretty basic logic,
that all human subjects are vulnerable.

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So if all human subjects are vulnerable,
then what does it mean

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or how does it make sense
to think about extra protections

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for vulnerable subjects
if in fact everybody's vulnerable?

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Here's one example of that.

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One of the complaints people

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have been making over the last decade
or so in research ethics

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is that lists of vulnerable subjects
just keep growing longer and longer.

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This is an example.

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CIOMS is the Council of the International
Organization of Medical Sciences.

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It is a very prominent
and influential set of guidelines

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for human subjects research,
particularly human subjects research

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that's conducted in developing countries.

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And here is a non-exhaustive list
from them of subjects who are vulnerable.

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And as you just think about it,
you could look through

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a couple of the examples,
this is an awfully long list.

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And this isn't even a complete list.

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And then the question becomes obviously
if all of these people

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and even more are vulnerable,
then how is it

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that we can come up with protections
and safeguards for vulnerable subjects?

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So this is the concern.

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What sense does it make
to try to institute special protections

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for vulnerable subjects
if almost everybody's vulnerable?

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This is a, excuse me, this is a quote
from a review about ten years ago

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on the issue of vulnerability
in research by Carol Levine,

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also Christine Grady, who talked here
a couple of weeks ago, was on this paper.

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And they point out that
if everybody's vulnerable, then it seems

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as though the concept becomes
too nebulous to be meaningful.

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So there's this problem.

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It looks like if you look at things
like standard

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definitions of vulnerability,
everybody's vulnerable.

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But if then if everybody's vulnerable,
how is it that you can implement

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additional protections
for vulnerable subjects.

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Doesn't that just mean that
everybody needs additional protections?

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And if everybody's vulnerable,
then it seems in a sense that nobody is.

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So what do we make of this?

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So here's one way for me
that I try to explain this.

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It's the thing about two different kinds
of claims that we can make when we talk

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about vulnerability, either in general or
with respect to human subjects research.

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And the first one is what I call
categorical claims.

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So it's a claim
that all of the individuals

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in some group, some set,
some population are vulnerable.

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That's a categorical claim.

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And then a comparative claim,
which is that some individuals within

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a group, class, or set are more vulnerable
than other individuals

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within that group, class, or set.

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So here's some just basic examples.

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Categorical claim,
all cars are at risk of being stolen.

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That seems pretty clear.

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Just about every car is at least in
a position where somebody might steal it.

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That talks about all cars, right.

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Now here's a comparative claim.

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At least according to data from last year,
I assume this is still true,

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that Hondas, at least in the U.S.,
are the most stolen car.

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So it looks like Hondas
are at an increased risk of being stolen.

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And what this suggests that is whatever
we're talking about vulnerability,

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the first thing we need to know
is whether or not we're talking about

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a categorical claim, all individuals,
like all human beings, are vulnerable.

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Or are we talking about
a comparative claim.

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Some set of human beings, or say
research subjects,

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are more vulnerable than other set,
or individuals, or research subjects.

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So what do you with categorical claims?

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So the fact that everybody's vulnerable,
the fact that everybody can be harmed,

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the fact that human subjects,
all human subjects can be harmed,

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isn't necessarily meaningless.

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It makes the point that what we need
is we need protections

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for all research participants,
no matter who they are, and no matter

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where they participate in research.

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This is a point that was made
by Fred Grinnell

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who is a -- works
in research ethics from Texas.

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And basically,
what he argues, he argues is once you take

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seriously the fact that all -- the fact
that all human subjects

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are vulnerable,
what we need is we need a new framework

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for thinking about
how to protect subjects.

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And in particular, he talks
about a kind of precautionary principle,

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which is a principle
that gets derived from thinking

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about protection of the environment,
which is basically that you're trying

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to be very careful in terms of the risks
that you're willing

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to accept in a particular activity,
or an enterprise.

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And Fred's thought is given
the fact that everybody is vulnerable,

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all human subjects are vulnerable,
maybe this is the kind of approach

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we should take
to research ethics, as well.

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So we can talk about it
if people are interested.

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I'm not necessarily advocating this view.

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My point is
just that the categorical claim

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all subjects are vulnerable
can make sense to the extent

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that what you're trying to figure out is
what should be the regulations

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or the protections for everybody
who participates in clinical research.

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So that's all regulations
as part of a categorical claim.

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Now there is the comparative claim.

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So what do the comparative claims do?

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So as I mentioned, comparative
claims are picking out specific groups

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who are especially, or more vulnerable,
or at an increased risk of

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being vulnerable.

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And here the suggestion is that once
you've got general protections in place

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for all subjects,
then the question is are those protections

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sufficient for all the different groups
that might enroll in your research?

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If the answer is yes, great, you're set.

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But if not, then it suggests that there

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comparatively vulnerable subjects
who might need additional protections.

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And that's where the call
for additional protections comes in.

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So one of the groups
that's famously started

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some of this was the National Commission,
which was one of the first groups

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in the U.S., at least, to think about
regulations for human subjects research.

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And they started out with some

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recommendations
for human subjects research in general.

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And then once they developed those,
they then stopped and said,

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okay, are they good enough
for all types of research?

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Or are there some categories of research
or categories of subjects

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who need even greater
or additional protections?

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And their answer was yes
in a couple of cases.

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And one of the examples
for them was children, where children

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might need even more protections
than we give to competent adults.

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So that's the distinction

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between comparative claims here
and then the prior categorical claims.

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So one example of this,
this is a nice example,

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this one of the most influential papers
I think that's been written

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vulnerability in human subjects
research by Ken Kipnis, who's in Hawaii.

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And basically, he says this.

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He says when I'm talking
about vulnerable subjects, what I mean is

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I assume that the basic baseline,
guidelines, regulations

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protections are in place,
and they're working.

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And then what I'm going to ask
is are there groups

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or are there individuals

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for whom that general set of guidelines
or protections isn't sufficient

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so that we need even extra
added safeguards or protections?

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Going beyond what he calls that
baseline of regulations.

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These are a couple of examples.

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So DOH is the Declaration of Helsinki.

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That's one of the most influential set
of guidelines on human subjects research.

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And here,
they're giving a comparative claim.

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Some research
populations are particularly vulnerable.

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So they're not talking
about all human subjects.

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Maybe their granting
that all human subjects

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are vulnerable to a certain extent.

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Then they're saying, well,
some populations are even more vulnerable

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than that baseline, and they need extra
or special protections.

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Then a similar comment from CIOMS
that I mentioned just a minute ago.

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So here's a comparative example.

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So the U.S.

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regulations based on the suggestions
made by the National Commission

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that I mentioned a minute ago, the U.S.

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regulations are based on
the National Commission's recommendations.

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And the U.S.

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decided
there's a couple of important populations

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who need additional
or special protections.

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Prisoners is one of them.

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Children, as I mentioned, is another.

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And one of the extra protections here is
there are stricter

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limits on the risks
to which you can expose children.

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So the idea is while we need some
protections for research with competent

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adults, but as long as they're competent,
as long as they understand,

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as long as they give informed consent,
then maybe we can allow them to accept

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or be exposed to a higher level of risk
in the context of clinical research.

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But now we start talking about younger
children or infants, given

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that they can't give informed consent,
those general protections

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aren't going to be enough,
and we want some additional limits

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on the extent
to which we can expose children to risks

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in the context of clinical research.

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So here's

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a crucial point
and hopefully somebody here will ask me

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if this doesn't make sense,
but when we're talking about these

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comparative claims, more vulnerable,
somebody more vulnerable than us,

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children are more vulnerable
than competent adults.

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Hondas are more vulnerable
than other cars of being stolen.

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If you think about those claims
for a minute, what you'll realize

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is that they tend to be context dependent,
meaning whether or not

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some group, population,
or set of individuals is more vulnerable

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than others,
is going to depend upon the context.

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So when it comes to research, it's
going to depend upon the type of research,

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where it's conducted,
and how it's conducted.

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This is just one simple
example based on my earlier case of cars.

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It turns out that in certain towns
in the west of the U.S.,

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Hondas actually aren't very susceptible
to being stolen at all.

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People aren't interested in them.

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They're interested in SUVs and trucks.

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So if you've got a Honda,
and you're driving in

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Washington D.C., it's probably
more likely to be stolen than other cars.

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You might want to take more protections.

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If you live in one of these towns
in the West, you probably don't

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need to be as concerned.

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So the context affects whether or not
that car is more likely to be stolen.

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So I threaten people here that there are
going to be a couple of quiz questions.

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Here comes the first one.

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Context
dependent applied to clinical research.

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Maki works in a lab at the NIH.

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He's been working
with clinical investigators

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doing both translational science
and basic science for at least 15 years.

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One day she's walking through the halls
here at the clinical center

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where there're often ads up
for clinical studies.

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She sees an ad and she's interested
in enrolling in a study.

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Is Maki a vulnerable subject?

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[inaudible commentary]
According to CIOM she is?

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How come?

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[inaudible commentary] 
Because she's an employee.

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So why would be an employee
or why might being an employee

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make her vulnerable, or more vulnerable,
comparatively vulnerable?

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[inaudible commentary] Yeah.

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[inaudible commentary] Okay, so.

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Sorry, so -- there's lots
and lots of people listening online.

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If you can come up to the microphone,
that would be good.

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Otherwise, I'll just repeat for people.

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So basically, her point here
is if you remember the list from CIOMS,

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employees are one of the examples
of vulnerable subjects,

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or what I'm calling comparatively,
or especially vulnerable subjects.

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And then my question was, well,
why would they be on that list?

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And your nice response is, well,

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it might be that given
that she's an employee at the NIH,

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Maki feels some compulsion to say
yes and be in a study.

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So take an obvious example,

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imagine that this is a study
that's being run by her lab chief.

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Imagine her lab
chief is the principal investigator

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of this study and now you want to enroll
Maki in that study.

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You're going to be worried.

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You might be worried
-- is she able to say no given that

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the person who's in charge,
who wants to complete this study,

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presumably,
is somebody who has power over her.

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And that is a very nice example,
and it turns out at the clinical center

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at least we have a very specific policy
for doing research with employees

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where there sometimes needs to be
an independent assessment

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just exactly to address that concern.

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So on the one hand,

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if for the PI is her boss,
do you think she's going to be vulnerable.

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But on the other hand,

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imagine she doesn't know any of the people
who are doing this research.

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You might think in that case,
she might be less vulnerable

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than almost anybody else.

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She really understands this stuff, right.

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She's been doing and involved
in clinical research for 15 years,

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she might be better able to assess
its value, its risks,

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its potential benefits, than somebody
who doesn't have that background.

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So this is just a nice example,
I think, of how whether or not a person

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or a group of people, say in this case
employees, whether vulnerable

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is going to depend on the context
that we're talking about.

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So those lists aren't going to apply
broadly.

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It's going to depend on the case
in question.

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Okay.

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So that's a discussion
of who's vulnerable.

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So the same question.

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So what protections are appropriate
for vulnerable subjects.

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And, as I said, given that vulnerability's
going to be context dependent

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whether or not somebody needs protections,
and moreover what

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those protections need to be,
is going to depend upon that context.

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So this is exactly your point.

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If the PI is her boss,
then we need to make sure that Maki's

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able to -- not necessarily
an informed decision.

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She probably understands,
but we need to make sure she's able

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to make a voluntary decision.

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That her boss isn't coercing

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her, manipulating her,
or forcing her to be in this study.

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Whereas, an infant.
That's not what you're worried about.

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You're worried
that infants can't understand.

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So there you're going to focus
more on understanding

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rather than the voluntariness
of the decision the person makes.

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So here's just a couple examples
of applying the vulnerabilities

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and the safeguards.

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So employees, as I mentioned, what we do,
so we do an independent assessment

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to make sure the person understands
and they're making their own decision

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voluntarily.

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In the case of children, you're worried
they don't understand.

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They can't look out
for their best interest.

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You want their parents
typically to help them.

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Or you have somebody who doesn't
speak English.

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Well, if they speak French
and they're enrolling in a study in Paris,

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they're in good shape.

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If they're speaking only French
and they're enrolling in a study

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at the clinical center,
that might be a problem.

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They might not understand
as well as other people.

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You might need a translator.

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So very different context.

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Very different vulnerabilities
and very different protections,

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depending upon the context
and the particular vulnerability.