Glad to be back here
again to talk about this topic.
Oops.
All right.
So you've seen this. So
you know what it says.
Let's start in 1966.
How many people here have is very great.
Have heard of this article.
So you may recall, if you've read it, the
following,
almost half, not quite half, maybe a little over a third
of examples involved, at least some people
who probably had difficulty giving consent.
For instance,
they had some choice language
back then that we would like to use.
Those folks given hepatitis B drug biopsies taken, which
challenges?
Same drug.
Another study
in which they induced confusion and many people it's not clear
how if they were able
during the studies to say, look, I don't want to do this anymore.
Experiments on
unconscious patients was common without consent.
Study of, impending coma and sick people.
Very sick people with, failing a liver. So.
And there were quite invasive procedures,
as you can see.
And you may recall, Doctor Beecher went through a
comb
through the literature, and he he found these studies.
And then there, of course, several
examples involving children and infants.
So this has always been one of the central
issues that led to what we now,
accept as research
regulations, laws that regulate,
the ethical principles of, human subject research.
But ironically, it's also been the topic
that's had
just had the most kind of evolution,
because there is
some issues that were never really
fully resolved in the beginning.
So let me just go through some of the history very
quickly.
This is national Commission is the, Belmont
Commission.
You know, that's another term that people
use.
They published many, books or monograph
regarding very different topics.
And it's interesting all of them became the
foundation
for the regulation that we have now.
So if you read those and you read the regulations,
you'll see that except for one where this
this some other graph research involving
those institutionalized as mentally infirm
really that question that remained open.
So it was again debated in 1982.
In the broader context of how do you make health care
and research decisions in,
among people
who have trouble giving their own consent?
And then 1998 was a very active year
because there had been some, scandals,
controversies
that occurred, in several studies,
both East and West Coast.
And this was around the time that I was actually
getting into, doing work in this area.
So that 1998 was, kind of a watershed
in terms of these, publications or,
official publications.
There was one by the Maryland Attorney
General's Working Group.
The really famous one was the End back
report, National Bioethics Advisory
Commission,
in 1998.
New York Department of Health
also had a working group and issued a report, a year
after that.
And this
sort of percolated along with different,
a lot of debates and studies and so forth that we,
I sort of helped contribute to during the intervening years.
And in 2009,
there were some recommendations made by,
what's called SAC Corp Secretary's
Advisory committee and human
research protections, meaning advising the DHHS
secretary.
And in 2015,
we had another this is during, President Obama.
Sears.
And there was a,
Nprm maybe I'm just having a little it's
a know this for public.
What is that?
I mean, you know, I worked for the government
proposed rule.
There you go.
I knew Hollywood now because she's a
she knows all these technical terms.
So the common rule
had been in place for decades, and it it received a,
revision.
And one of the things that, addressed
was this, this topic.
And I'll tell you the change that took place.
Okay.
So throughout all this,
I would say the most significant insight or agreement
that the field among researchers,
regulators
and ethicists is this,
agreement, which is that if you're going to involve those
lacking
or at risk for lacking a decision
making capacity.
You need to specifically justify what it is that you're doing
by meeting these conditions.
That research can't be done without this population.
If you can more convenient more you do it with other
populations,
even if less conveniently.
You have no, because there's no intrinsic
justification for having to use that
population.
And that's related to this.
Second point, research must be focused on the disorder
causing the incapacity, which kind of makes sense,
right?
If you're going to involve them and if that population
will benefit in some broad sense,
because some research can benefit people
in our current generation, but also people
who have this disorder in the future.
Now, I want to emphasize the third point,
though
rarely, it is okay to involve persons
with decisional difficulties
for other reasons, for other disorders.
And these will be situations
where if you exclude them based on the first two bullet
points,
it could actually amount to a kind of discrimination.
This implies that there are some types of
research
that has more or less potential for benefit.
And we all recognize that.
So for example, if they're if they're testing
a very promising,
let's say a monoclonal antibody
for treatment of melanoma and a person with
developmental disability
such that they may not be able to give consent or even be at
risk
for giving consent, has the same,
the cancer to exclude them
merely based on distinct disability
in that case could be discrimination.
So this thinking becoming
more prominent in research ethics
is actually a sign of tremendous progress
in this area.
Because we now realize that the first
two bullet points here is widely accepted.
And we're trying.
And as any policy should, we should be sensitive
to developments of the context
so that are their unintended consequences.
And this third point, I want to emphasize
that along those lines okay.
So I'm going to talk about this is making
capacity impairment as a topic
talk.
And then to talk about,
this, you know, notion
that in theory, studies involving
people who can't consent is permissible.
Okay.
Now the question is how do you do it?
Who should give consent?
And should there be limits to risk?
Those are the two fundamental questions.
When you raise the when you say I should be okay,
but
so but has to at least two major bullet
points.
I'm going to actually
give you some, evidence that we've gathered.
When I was before I came to NIH at
Michigan,
we did a lot of studies on this topic.
And that, I think, really informs how
we might make policy and also how do we incorporate
the moral perspectives of the public
into these kinds of decision making.
And then I'll
close with some additional protections of
safeguards
that I or these and investigators
might consider, depending on the context.
All right.
So what is decision making capacity and impairment.
So I want to make a distinction between adjudicated.
In other words having gone to court
decision about whether the person
has capacity or not.
We often use the terms capacity and competence
interchangeably.
Its meaning is basically do they have the ability
sufficient to make a decision?
In this case, when I say adjudicated.
It's, it's the judge who makes that decision.
So it has a special legal force.
Notice that I don't distinguish between capacity incompetence
as somehow lying between clinical and
legal.
I just want to warn you that there are many people out
there
who will tell you that's
how the world is, and that's how you're supposed
to use it.
It just that, just outright not true.
So I we can talk about that if you want,
but, don't get misled by that distinction.
When we just ordinarily talk about the
terms
in clinical practice or in a research setting, it
just means
a clinician's approximation of what the courts might or
would say.
And usually this carries the day. Why?
Because there are special legal provisions
that give certain persons the authority
to make those decisions unless it's
challenged, in which case it goes to court
the abilities or the functional components.
If you have sufficient amount of it of the right kind,
then you would be deemed competent
or have sufficient, capacity to make your own decisions.
Now the abilities come in degrees
and that we they go
by the name of things like understanding,
appreciating, reasoning,
and communicating at stable choice.
These are psychometric concepts.
You know, I mean, you can have
well-trained people
who can operationalize these so that you can actually
develop tools to, measure them.
Of course, the caveat is because as you'll
see, the concept is decision specific.
You have to actually modify them for each context,
which kind of puts some pressure on.
What does it mean to have a validated instrument
as such?
Because you have to customize it to each situation.
However,
now the second component to this last
bullet is yes,
there are degrees that we can measure,
but the concept is dichotomous.
Decisions in life are dichotomous.
It's yes or no.
You know, so you you can decide
to bring back the astronauts back
using their vehicle or you're not sure how safe for
this.
So you have to make another decision.
You can't just sort of do it or not
do it at the same time.
Same thing.
So you have to you have to sort of use
all that information
and reduce it to yes, no.
It's decision making capacity is part
of the doctrine of informed consent,
which has to be components,
the ability or the capacity to make the decision.
Having receive proper information, relevant
information,
and to be able to make the decision without,
duress, coercion,
undue influence.
The modern
functional model of decision making capacity has several
components.
One is the presumption of capacity.
We usually say adults have the right to presume to be
capable,
unless you have a reason to suspend
that presumption.
It doesn't mean suspension, doesn't mean you say they're not
capable.
It just means you have no reason to investigate whether or not
we need to make a decision about whether this person has capacity
or not,
but the presumption is they do, unless
you have good reason to challenge it.
You. We no longer use
terms like senile, unsound mind.
So if you go back to the laws and writings
back in the early 20th century, we will also people.
Doctors often use terms like this to say,
you know,
that person can't make their own decision
because their mind is unsound,
that that's it.
Actual abilities
relevant to the decision must be assessed.
And the threshold. How?
You know, there are many ways in which you can do this.
Assessments.
You can do it in such a way that.
Let me give you an example.
If a person,
even with a mild dementia is in a hospital
because they have an infection and the
and somebody comes in and says, Mr.
Jones, we're going to draw some blood
for labs, okay.
And he just puts his arm out.
Now, are you going to use a full,
complicated assessment to make sure he's giving
consent?
Probably not.
Because in that context, mere assent
might be something that is appropriate.
On the other hand, if the same person is
asked to participate in the clinical trial
of neurosurgical implant of gene therapy,
you know, and and if he says, well, doc,
you know best,
I'm willing to try whatever you want
and articulates that that clearly.
I would think that we would hold that person to a much higher
standard.
Okay.
And as I
said, it's tasked with decision specific.
I want to spend a couple of minutes
on this slide because you will,
depending on where you're listening to me
at this moment, you will be more or less
familiar
with this convention, this UN convention,
very important.
2008 was a convention that outlined
the human rights based
I guess, rights of persons
with disabilities, very important.
There was a problem with it in that.
There was an article
among the, in the convention
that basically strongly implied
that regardless of your abilities,
what we what I just laid out as your decisional capacity
and the abilities functional abilities
you have legal capacity
regardless of your functional status.
And so it was directly challenging
the concept of functional capacity.
Consequently, it also said
we need to get rid of all surrogate decision
making regimes.
Now I'm not going to go into the complicated political
and other history of why this, came to be in the
convention.
There was a general comment explaining it in this sense
that I just talked to you about,
let's just say even countries
that have ratified this accepted this convention
almost always insert a
what in America would call signing statements.
You know, we think this is important.
Wonderful convention we agreed to.
However, insofar as article 12 is concerned, as it implies
such and such, we reserve the right to xyzzy
because.
So this is a very important topic.
But I'm going to put it aside
because we are using the concept
that the convention, at least the general comment
number
one of the convention says we can't,
we shouldn't be using, but we are.
And virtually every jurisdiction that I know
does.
Okay.
So some
disorders elevate the risk for incapacity,
usually a most obvious ones that are ones that affect your
cognition.
Right.
Neurodegenerative disorders Alzheimer's from the temporal
dementias.
Neurodevelopmental disorders. So,
you know, learning disabilities, intellectual disabilities,
related disorders, injuries
and injuries like strokes, traumatic brain
injury, people who suffer trauma
from car accidents, war, for instance, or infections,
and people who come into the hospital
with acute situations that have temporary,
loss of cognitive.
So cognitive function, what we call acute
confusion or states or delirium,
psychotic disorders including I consider
manic states a bipolar disorder
as falling under psychotic, situations,
mood disorders when severe eating disorders
when severe gets affect decision making capacity.
There are other areas of controversy.
For instance, people who have,
personality disorders who are under specific duress
or distress and are decompensated in perhaps
even though they don't have one of these
major,
severe like, psychotic disorders.
Okay.
The thing to take away from this slide
is that notice
that I'm saying these are risk factors
not defining,
not definitions of incapacity.
All right.
It's actually very common.
In clinical work.
So in general, hospital inpatients,
if you do a survey going from room to room
people, researchers
find about 30 to 40% can't give their own consent.
It's actually probably higher because a lot of these studies
are based on interviews of people
who are able to be interviewed.
So if you count all those people who can't even do interviews,
it'll be a little higher.
So nursing homes, much higher, psychiatric
inpatients, it really has to do with the
kind of unit
that you're, running, whether it's a you know, a
Beverly Hills,
you know,
privately funded or whatever you may not have.
They have a different severity of illness,
distressing, but different type of illness
versus
a state run hospital where you hospitalized
people who have no other resources
or who are,
putting themselves or others in danger, for
instance.
It will vary.
If you just look at people with chronic
psychoses, it varies quite a bit.
But notice that it's only about half at
maximum.
So I think people should be aware
that chronic psychoses by themselves
don't create the kind of, severe automatically create
severe decisional ability except under certain,
a subset, I should say.
I'll explain that in a bit.
Mild to might.
A moderate depression really doesn't affect capacity
given the type of assessments that we now standardly do,
because we generally
these assessments aren't,
as so demanding that we would, you know,
that you might think because we, we kind of build in the balance
that we live in a society that values autonomy.
And it's really wrong if you're overly
sensitive and finding people incapable.
Okay.
However, if you're very depressed,
a certain minority will have,
incapacity.
Let me just talk about two disorders.
Because they have their major, they're very common.
Both. And there's been a lot of research.
So this issue comes up a lot in research
ethics.
So Alzheimer's disease.
About 40% of patients
with even what used to be called mild cognitive impairment
where, you know, technically they might fall on
the border
within normal range of certain cognitive tests,
are found to lack capacity to give consent to a like a drug
asked.
In our study about,
you know, two thirds to three quarters of patients
with many mental scores, the minimal is a cognitive test
here.
The 3030 is perfect.
Zero is,
22, 23 is sort of on the border.
You would say a person has moderate dementia.
But you had moderate dementia
and most would lack it
ability to consent to a clinical trial.
On the other hand, in a study that I was,
I was part of, we're doing a
part of it in the sense of doing the ethics and the
capacity
assessment of the clinical trial,
which was called Kati study.
When you look at the distribution of
performance
and the understanding score on a tool
that was used,
you can see the vast majority are above the cutoff
that at least the experts who did the came
up with this cutoff thought
was a good cutoff
to decide whether the person could or did
or did not understand sufficient amount.
And same for the appreciation,
although, you see, it's a little bit less
that.
Just to give you an idea, to give you a contrast.
All right.
Now, if studies with people lacking
or at risk of lacking
DMC are permissible, who gives consent?
Right.
If you can't give consent, how are they going to
participate?
Somebody has to give permission, right?
Now federal regulations allow in theory
and pre 2018 a common rule said the
following.
You will often hear the term lawyer
legally authorized representative.
So this is a specific regulatory term
where they're referring
to people who would be authorized
within these regulations that give consent
for somebody else to be in research.
How do they define it?
They defined it as people who are authorized
under applicable law, meaning nonfederal law.
Specific or actually even law outside
the research ethics regulations.
If there were such a thing
under the federal laws, I as far as I know, there isn't.
However, there are state and local laws
that may be relevant
to consent on behalf of prospective subject to the
subjects.
Participate in the procedures involved in research.
Okay, so what, you might ask, what does applicable law look
like?
And they are local state laws.
And before the 2018, even now,
very few states have actually addressed
this and their state laws.
It's not really high on the agenda of legislators
because it's a very niche topic.
So California, new Jersey, Virginia
have had
enactment of what I call modern laws.
And you can if you can, just when you hear
modern, you can just assume whoever
wrote this understood that there were
federal research ethics laws, okay.
So they wrote with that
in their knowledge base,
whereas most other laws that could be invoked
generally were written
earlier for independent of considerations
of research ethics.
The revised common Rule, which
really sort of,
for most situations help resolve this uncertainty,
because the question was, if you don't live in new Jersey,
Virginia
or California or some of these southern,
places where
either the attorney general has issued
a statement or things like this.
Who's LR?
Right.
So that was always a debatable question.
Until, in 2018, the post 2018
comment revise common rule says this
if there is no applicable law,
then it
means an individual recognized by institutional policy.
So it actually gives authority to academic
institutions, research institutions,
and other settings within which the person, is
involved
in research.
All right.
So putting aside that special institutional,
not putting aside
what's the right word, even if, sorry,
the institutions have policies, they have to sort of appeal to
something.
Right.
So I'm just going to go through different
types of layer possibilities okay.
So one is obviously legal guardians,
legal guardians.
Are people appointed by judges.
So there's real legal clarity
as to why they have the authority
and who it is.
But sometimes these are people who are total strangers to
the person, the, the, who, who has lost capacity.
So there's no necessarily link that you would hope to have
if you think you want them to represent
that person's wishes.
Second type is health care proxies
or durable
power of attorneys, where the subject's own choice
picks out who should serve
to play that role.
But usually that's for, clinical decisions.
And it's extrapolated to research questions.
De facto family.
This is the most common because, as you'll see,
very few people actually make research
proxies.
It's a nice idea.
Research proxy is a great idea.
Everybody figured out, you know, if I get incapacitated
and I could be eligible for research,
I would like this to be done.
Virtually no one fills that out
unless they're asked to after diagnosis
in a special setting.
So but there is a
this possibility of a concurrent proxy directive,
meaning
if you're diagnosed with an illness
like Alzheimer's
but still able to make other types
of decisions,
one of those decisions could be to appoint
somebody or, you know,
that person might be fully capable
of thinking, following.
I can see that.
I can, you know, I'll be overwhelmed
by all that research information.
Maybe I can't get my own consent, but
my wife always helps me with these decisions.
I trust her, so I'm going to.
You can consult her.
Something like that.
Okay.
This is a list that saccade the secretary's advisory
committee, proposed, which I think is a good one.
So obviously you go with the state law
because that's what the law says.
Dpos for, for health care, they're you extrapolate
to the research context,
hoping that the ethical cover that the,
this provides for health care decisions
also kind of extends to research.
Not unreasonable, given that, you know, that
person
is supposed to represent your values and views or your
interests.
The legal
guardian notice that it's third not in the top.
And then the rest of it is,
hierarchy for de facto family members,
although eight is a if you don't have
family members, there's special, writing.
So this is very similar to what we have
in the clinical center at the NIH.
And I suspect this would be this is virtually identical
across states.
So virtually every state has a de facto
family surrogate law for clinical
situations.
And most of them recapitulate
an order very similar to this.
This is just to tell you, you should go read it,
because this is a horrifying,
exposé of how guardianship laws can be,
exploited.
And, I just mentioned this is because, you know,
it's important to realize how these things actually work,
right?
Guardianship laws, presumably, are supposed to protect people,
but
if you read this, you
will value the importance of actually understanding
how to play out and how to monitor it
and keep people safe.
So it's written by Rachel Aviv, who I arguably has written
in some of the most seminal New Yorker
article, said that has affected,
health care policy in many ways.
Actually.
Okay, so what proportion of adults
prepare the advanced directive I'm not going to go into this is
a meta.
This is a systematic review.
And basically the bottom line is about a third.
It doesn't matter how chronic your illness is or whether
you're healthy.
It's not something that people do.
So again, you're going to have to fall
back toward
in most situations, this act of family
surrogate decision making.
Okay, I'm going to speed up a little bit.
Just to recap this.
So it appears that the fact
that surrogates will have to be lawyers,
this usually means family members.
But is this acceptable?
So we did a lot of research on this question
and combining it with the risk benefit limits.
So let me just go through some of our data.
It's the most common approach about IRBs
probably is something like this.
Does it have prospect for direct benefit.
Right.
If there's no prospect of direct benefit,
how much risk minimal
so-called minor increase or a minimal risk
and greater than minor increase?
This should be familiar.
If you have or will have
some overview of the pediatric research
regulations.
This doesn't apply to adults actually.
But this.
With that, people have kind of imported
this from the pediatric into how to think
about this incapacitated person's
participation in the research.
Now. So how does the public view family
surrogate and research and what level of risk is
acceptable?
We did a survey.
This is a nationally representative
sample of U.S public who are 50 and older.
And we found that if you ask the question
if patients can't make their own decisions
about being in a study,
and then you see the scenarios and the four columns, should
their society
allow their families to make that decision
in their place, yes or no?
So I'm only giving you the yes, definitely a probably yes.
And it's interesting.
Majorities say yes.
So lumbar puncture, just a physiological study drug
asked.
I think we use something for Alzheimer's
that was kind of similar to something
as risky as taking Motrin and said
aspirin, you know, something like that
vaccine our city is there was an attempt
to try to develop that,
antibodies to your own,
pathologic materials in the brain so that
that is no longer a, the avenue that's pursued.
But in case you were wondering why I have the word vaccine
there,
and then gene therapy.
Okay, so this was a national sample.
Just your typical cross-sectional.
Not very.
You know, we're not asking them, you know, to think about it.
And.
And what about this? We don't do any of that.
However, we have done a study like that.
This is what I call my wedding banquet research
because we have it in hotel.
What wedding back banquet rooms essentially with, you know, 6 to
8, nine people, you know, room full of 60 people, maybe five,
six tables.
And we spent all day having experts talking on either
side.
I yeah.
Both sides.
And, you know, they kind of travel together in
the room.
So this is under the rubric of,
democratic deliberative methods of doing research.
It originates from political science.
I did a lot of this when I was in back in Michigan.
And it's interesting when you actually have people
debate
this here, people talk about that at the
table.
As people become more familiar, because most people don't know
that there is a oversight and regulation of research
by either of these, for instance.
And there are all these regulatory
components.
And you hear both things, the history
of the regulations and the need for this research.
This is what you find is that you'll see in every
case,
the pre-post, there's a shift to greater
acceptance
of family surrogate
consent for those types of research.
So I'm not going to go through each number.
Just notice the trend.
And comments
during deliberations were, really fascinating.
One thing I would say is that, you know,
these research ethics topics, we think,
oh, you know, we need experts to really,
you know, get their intuitions
and so forth.
Honestly, now that these questions
most people can readily understand
with dialog, and if people are quick
to see the dilemma, potential solutions
and so forth.
And that's one of the most impressive
things about when you engage the public
in this kind of the research.
So for example, comments during that
deliberation, participant assess.
But if the answer is no, you can't let families do this,
that surrogates can't give consent, then
there's no hope for ever getting anywhere
because they've seen all the data,
what likely needs are and so forth.
So the answer has to be no.
In my mind, yes, meaning they have to be allowed
participant versus vote by voting
no against surrogate in Parliament.
What you're essentially doing is voting
no to every other family.
You're putting yourself in a position of impacting every
family
who has an Alzheimer's patient.
I thought that's that's a particularly
interesting way
to articulate what a policy does.
This is he's saying, look, it's a policy,
and policy works this way, right?
It's not just about me.
However, they all
repeatedly came back to, comments like this.
So it seems as though we almost have no choice
but to have some form of surrogate dissent.
But the challenge is, how do we make it work?
How do we build protections for the,
you know, people with Alzheimer's
and their families?
And one of the interesting things was that
when we asked people,
should there be leeway,
you know, a person says to you, yeah,
I want to be in research or not.
After you say that to them, if you later became
incapacitated,
how much leeway do you think your family members should have
in going with what you said now, or maybe even going against it
based on what they know then versus now?
And you can see the vast majority think
there should be at least some leeway.
So I think most people understand
the complexity and the limited
complexity of the situation, the limitation of current
knowledge.
When you try to pin down the future of
I want this, I don't want that. So,
I think we often
underestimate the wisdom of,
you know, the public and a lot of these issues.
Okay, I'm just going to run down the list
of other potential protections depending on the situation.
And I just want you to I'm going to contrast two situations very
quickly.
Mr. A has Alzheimer's.
He can't give consent,
but he's a retired professor, financially stable lot of
resources.
Family are support involved.
He enrolls in a novel intervention
only minor adverse events.
Effects seen.
And it has a goal of slowing down the disease.
He really wants to be in the study.
He has an altruistic motive.
He and his desire for benefit, felt
to be a worthwhile gamble.
Now, to me,
this person obviously is vulnerable,
but the kind of vulnerability
experience is very different from the following person.
This person does have members.
This person is did not have consent
because he's quite impaired.
This person meets the threshold
for capacity, so in theory can consent for him or herself.
However is single, estranged from family,
unemployed,
isolated in a minority group or city of a compound
that's already marketed as being studied
a meeting drug.
And it's not a new paradigm,
you know, it's you could even say
there are strong marketing considerations
this study like this.
And he himself may not have a strong incentive
to enroll.
I think I would say that this person is,
is more much more vulnerable
than the previous person, even though this person has
capacity.
And I think this is really important
to remember other protections.
So you have to think about, depending
on the context or things like this,
how rigorous, how well
defined, how much, who is for what the capacity assessment.
Is there any way we can sort of work
with the presumed abilities?
Because that's a gradation to show.
We have subject advocates, study partners, consent or city
monitors
independent of the researchers assessment of appropriate
surrogates.
You know, sometimes surrogates may also be 95 years old, right.
And it's not the age that it makes you vulnerable
or incapacitated, but that puts you at an
increased risk.
So there may be a need to assess that and other.
So it should be tailored to context.