I'm happy to say that as far as I can tell,
if any of the thousands of people who watch this online have other examples,
I'd be very interested in hearing about them.
As far as I can tell, the clinical center was one of the very
first institutions in the U.S., and probably in the world, to develop
a policy on research with adults who can't give informed consent.
We call it 87-4.
It's what it started in 1987, 4, that's the number for it.
And that policy has been revised a number of times.
And basically, what that policy aims to do,
it aims to implement four important safeguards for research with individuals
like Miss P, adults who can't give informed consent.
First is what you might call the compelling reason, or the necessity
requirement.
And here are the ideas that if you can do your research just as well
with people who can give informed consent, then don't enroll people
who can't give informed consent.
If those investigators could have done their research equally well
with people who can consent, they shouldn't enroll Miss P.
Only enroll Miss P, only enroll a 3 year old, only enroll
somebody who's unconscious, when you have to enroll people
from that population in order to answer an important scientific question.
The way our policy puts that is the IRB has to document that there's
a compelling reason to enroll individuals who can't give informed
consent, adults in this case who can't give informed consent.
Surrogate decision maker.
If you're going to have somebody enroll them, you have a compelling reason
to enroll them
for an important scientific reason, and they can't make their own decisions
about whether or not to be in research, ou should have somebody else who decides
whether or not their research -- again, the buzz term for this in the U.S.
regulations is a legally authorized representative, or an LAR.
I'll just call them a surrogate decision maker for today.
So you want somebody else who decides for that person.
And the crucial point is that surrogates aren't supposed to be asking
whether or not I want, Mr. P -- sorry,
Miss P's husband's not supposed to say do I want her in the study.
Miss P's husband is supposed to say would she want to be in the study.
It's the test that I mentioned before.
If she were able to make her own decisions, what would she say?
And that's sometimes described as a substituted judgment standard.
If Miss P could make this decision for herself, what would she say?
And if we're confident she would say yes, then that provides us good reason
to think, again, we're not taking advantage of her,
exploiting her inability to understand herself.
If she would say no,
then that's a pretty compelling reason not to enroll her in the study.
Unfortunately, there will be a lot of cases
where you're not sure what the answer to that question is
and typically what we're supposed to do is the best interest standard,
just figure out what would be best for this particular person.
So here's the
way that our policy does it, it's to substitute judgment,
it says the surrogate who enrolls the -- compelling reason
and then it needs a surrogate, and the surrogate
should have sufficient reason to believe participation in this study
is consistent with the individuals preferences and values.
So you might ask things like have you talked to her about ever
being in research?
Do you think this is the kind of thing she would want to do?
Why do you think she would want to be in this study?
Why do you think she would be willing
to undergo, say, a lumbar puncture in order for investigators to collect data
that might help other patients with dementia?
So I mentioned task specificity before.
So one important thing about this -- that was task specificity
with respect to understanding a particular study.
Here the point is that it's possible that somebody can't get informed
consent for a study, but nonetheless, they retain the capacity
to assign a surrogate to make decisions for them.
So I think that probably was the case with Miss P.
She couldn't possibly understand that research study, but she recognized
her husband, she knew who her husband was, she trusted her husband,
she trusted her husband to make medical decisions for her,
she trusted her husband to decide how her life went.
This is another nice study by Scott Kim, that I mentioned.
And according to their data, about little more than one-third of people
who were deemed not able to consent for themselves were able to identify
and name a surrogate, somebody else to make decisions for them.
So again, the important point is the fact that somebody can't consent doesn't mean
that they can't make any decisions, and you just have to pick somebody for them.
It might be that they can pick a surrogate for themselves.
Okay, so this is the first two protections,
compelling reason and surrogate.
The third one, and this is taken from pediatric regulations, assent and dissent.
And basically, the idea here is that even if a person can't fully understand
to make an independent, autonomous decision, it doesn't mean
we should just ignore them, and not care about what they want to do,
and that's respected by the assent and dissent requirements.
The idea here is that you should still explain the study,
and what's going to happen, to the extent the person can understand it, and obtain,
solicit their affirmative agreement, their willingness to be in it.
And if somebody dissents, that should be respected.
This is a nice paper by Betty Black and some of her colleagues
at Hopkins on this a couple of years ago.
Here's one of the real challenges, particularly
when you start thinking about people who can't give informed consent.
They don't fully understand, and they don't always communicate clearly,
and it's not always obvious when they're doing something
whether what they're doing is an expression of dissent.
So you imagine
somebody who just pulls their arm away when you want to do a blood draw.
Does that mean they don't want the blood draw?
Or does that mean they don't want to be in research?
Or does that mean they don't understand what you're doing?
Or does that just mean they're worried, that they're scared,
and there's maybe something you could do to try to reassure them?
So what I try to tell people here in cases like this,
you get some maybe unclear sign is to stop, evaluate it.
See what's going on
and then see if there's something that you can do to address it.
So maybe just the person was surprised
that you grabbed their arm, so they just need to have it explained.
Maybe they just need a break.
Maybe their just nervous and you need to explain what's happening.
In a lot of cases, by working through it,
you can figure out what's going on, and address their concerns.
Okay.
Last, safeguard is a risk/benefit evaluation and here are the assumption is
-- well, here I'll give you the background to this is people can think about this,
this is a bonus quiz question is, at least in the U.S.
regulations, there are no risk limits on research studies
with adults who can give informed consent.
Now that doesn't mean these studies are going to be approved,
but at least in principle, the regulations don't block IRBs from approving studies
that offer no chance of benefit, and have relatively high risk
if the subjects are competent and give voluntary and informed consent.
Now when we talk about people who can't give informed consent,
there's almost unanimous agreement that even if that standard
is appropriate for competent adults, no upper threshold on risks,
when we go to people who can't give informed consent,
such as adults like Miss P, we shouldn't have that kind of allowance.
We should have much stricter limits on the level of risks
that these people can be exposed to.
Talk about this.
Basically, the way it's done right now is roughly the idea that either
the risks have to be low or their has to be a compensating potential
for benefit, so the risks are justified by a potential for benefit.
And then, of course, that raises the challenge here of what we need then,
and this is a further challenge for people who work in research
ethics, is develop a systematic framework to help people make these judgments,
to figure out what the risks are, what the potential benefits are,
to what extent do or don't the potential benefits justify the risks.
So to give you that example, remember the study
with Miss P, do people remember what the procedures were?
Does anybody's short-term memory functioning?
Do you remember? Female Speaker: MRI.
[inaudible commentary] Behavioral testing.
Computer testing.
So lumbar puncture.
All right. So here's the standard.
You should only do research
with somebody like Miss P -- it's not going to help her.
So either it has to help her, this research isn't going to help her.
Or the risks have to be sufficiently low.
And then the question, if I put you guys IRB hats on,
the question would be whether or not the risk of that study are sufficiently
low that it's acceptable to do in somebody who can't give informed consent.
Is it okay to have them do an MRI?
Okay to have them do an LP?
Okay to have them do blood draws?
And then, of course, is it okay to have them exposed to the risks
of all of those things in a context of a single study?
All right
The threatened part of the lecture.
Quizzes.
So I'm actually going to -- here's what we'll do.
You have to have to talk about one of them before
you guys are allowed to leave here.
So I'll give you three quiz questions, and we can see if there's one
that strikes anybody's fancy. I can pick one.
So here's number one.
So as I mentioned, remember the compelling justification.
The compelling justification says
you shouldn't enroll individuals
who can't give informed consent when you can conduct the research
equally well with people who can give informed consent.
That's the compelling justification requirement.
Now here's the question.
What counts as a compelling justification?
What if you're the IRB and the investigator says,
"I don't need to enroll this person who can't give informed consent.
I can do my study with people who can give informed consent,
but this is a very promising drug.
And this might help this person." So imagine
now you've got somebody who has cognitive impairment,
they can't give informed consent, they have diabetes,
and now here's a potentially very promising drug for diabetes.
What would you say in terms of enrolling them?
And I can tell you this is a very lively debate.
We actually debate this in our department.
It seems, at least on the face of it, you could say one of two things.
You could say, well, if it really has a chance to help her,
why would you exclude the person just because they can't give informed consent?
That almost seems like turning protection into a kind of discrimination.
If it really has potential benefit, we should let the person enroll.
And then they might say no. This is research.
We can never be sure. There's all these risks.
We can collect the data from people who can give informed consent.
Informed consent's a crucial safeguard.
We shouldn't enroll people who can't give informed consent
when we can do the research with people who can give informed consent.
And I can tell you those are both widely endorsed views
both in our department here and also in the literature.
That's quiz question number one.
Quiz question number two.
Imagine a
study -- I can give you a couple of examples of these.
We do conferences around the world on research ethics.
And we were in the Philippines about five or six years ago,
and I was giving a lecture very similar to this one.
And afterwards, an investigator came up to me
and told me about a kind of disease that they were studying.
They were studying this very rare neurological disease.
And they had this potential new treatment.
Very new, very experimental, hadn't been given to very many
people, might be helpful, but also could be very risky.
And here's the challenge.
You can give that drug and test it in
people who can't give consent, but it poses low risk.
So what the idea was in this case was this investigator had two populations.
He had people who had very early disease.
Disease hadn't progressed very far, and they were perfectly competent,
and able to understand.
And he said to me, "I could do the research in that group.
But their brains are basically fully intact,
and the risks of this study, of this drug, are cognitive effects,
so there's great risks in that population because their brains are intact,
and if this drug turns out to be harmful, it could harm their brains." But
they could understand, and give consent, and they could understand those risks.
That's the first population.
The second population is people who have advanced disease.
They have advanced disease, and the condition is already largely done
its damage to their brain.
So their brains have already been damaged in this way, and as a result,
the drug doesn't
have as many risks to those people because they've already suffered
most of the deficits that they're going to get.
So even if the drug is risky, it's
not going to hurt them much more than they've already been harmed.
So everybody has this setup?
So you've got this population can understand high risks,
this population can't understand relatively
low risks, and the question is which group should you do it in?
There's actually an historical example
we could talk about for this one that's very interesting.
But I'm going to give you the next one.
Quiz question three.
This is one I said there should be a surrogate,
there should be somebody, a legally authorized representative,
who is the one who makes decisions for people like
Miss P, adults who can't understand, or make their decisions.
And then the question is who is an appropriate surrogate in this regard?
And this is a very challenging question in the U.S.
What the U.S.
federal regulations say is you need a legally authorized representative.
And then you say, okay, well, let's look at the regulations.
Who's a legally authorized representative.
The answer is, according to the federal regulations, is you look to state law.
And state law determines who counts as a legally authorized representative.
The problem is that typically state laws, or most states
in the U.S., don't have laws with respect to research.
So what you have to do then, is you have to start
looking at the laws with respect to surrogates for clinical care.
And that raises some questions.
To what extent is a clinical surrogate appropriate
to enroll somebody in research?
Almost every state -- I think maybe, I'm not a lawyer,
but I think maybe every state has a next-of-kin hierarchy.
So if I don't fill out an advanced directive, if I don't name a surrogate
for myself, and I'm in a car accident, then there's the next-of-kin hierarchy.
Somebody's chosen on that to make clinical care decisions for me.
Is that an appropriate person to also make research decisions?
Should we just leave it to the next-of-kin to make decisions for them?
All right.
That was quiz question one, quiz question two, and quiz question three.
We've got six minutes, which means I'm not going to let you guys out too early.
So does somebody want to give me the answer,
so I can write up a paper on one of these three.
I don't have a clear answer to any of these questions.
Quiz question one, prospect to benefit when people can't consent.
You enroll them or exclude them?
Quiz question two, do you do the low risks,
people who can't consent, or high-risk people who can consent?
Or surrogates.
Anybody have thoughts?
Any of these are easier or harder?
More interesting?
Should I give you one more example?
You tell me if this is a mistake
or not? So I'll talk about this one.
This one's contentious because it ended up in court
and getting the facts isn't necessarily easy.
I know people know the case of Jesse Gelsinger,
who was an older teenager who enrolled in a study, and basically,
at least on one description of the case,
what was going on was there was an option,
this was a gene transfer study, very early gene transfer study.
And the option was they could do it, again,
it's all contentious, who knows if this is right.
One description, though, is could do the study in very young kids
who couldn't understand it because they were very young,
but because of their immune systems
and their disease condition, the research would likely not be terribly
risky for them.
Although, it still would be risky.
Or they could do it in older teenagers who according to most data can understand,
but they would face much higher risks from it.
So who do you do that study in?
First, early gene transfer study, you could do it in 3 year olds,
can't possibly understand,
but you could get the permission of their parents, relatively low risks.
Or you do it in 19 year olds who face much higher risks
but can agree to themselves, consent for themselves.
All right. Ready?
Show of hands, everybody's got the question?
All right, who says you do it in the 3 year olds?
Can't understand but risks -- let's call them relatively low.
All right.
How about you do it in the 19 year old?
Higher risks, but they can understand, and they're making the decision
for themselves.
Nobody else is making the decision for them?
So almost -- almost an even split.
Somebody want to give me -- somebody have an argument one way or the other?
Strong reason?
All right, I'll try to repeat it so we get it into the mic.
Yeah. Male Speaker: Are the benefits equal in these examples? Yep.
Benefits are equal.
Both scientifically -- let's just imagine, scientific benefits are equal.
So the researcher will tell you I'll learn as much from the 19 year
old as the 3 year old, in terms of whether this works and everything.
And also, to that person, similar benefits.
Now, of course, there is a slight difference that a 3 year
old gets the benefits,
they'll have them for longer in their life than a 19 year old.
I don't know if you want to take that into account.
Any other questions?
Any arguments?
So who was on the 3 year old side?
Somebody want to give the argument for the 3 year old side?
Anybody?
Anybody got a -- why are you doing the 3 year old?
You don't care about informed consent?
Female Speaker: It's just less risk. So less risk.
So the important thing is protecting the subject from being harmed.
Yeah. Female Speaker: They have a surrogate. And they have a surrogate.
They have a parent.
You figure, hopefully, the parent's pretty good decision-maker for them.
And we have a lot of experience
be a treatment like that.
Where.
and treatment like that where [inaudible]. Yeah, okay.
Are you guys convinced the ones who wanted the teenagers.
Everybody? I think you guys have -- I don't know.
Did they win?
Or did they jut cowed you guys into silence?
Anybody want to argue for doing it with a teenager?
[inaudible commentary]
It all sounds good as long as know what?
Female Speaker: That all the [inaudible] is correct. Yeah, yeah.
So good.
So one of the things that you might be worried about is
this is research and, well, we think these are the risks, and we think
these are the potential benefits, but we never can be sure, right.
And you might think to the extent
that you're not sure, maybe it shouldn't be us to us.
Maybe it shouldn't even be up to the parents, right, and maybe that's a reason
for letting people who can understand for themselves.
I was going to leave everybody with this one because why I think
this one is so great, and I don't know the answer to this question.
But I think what's crucial and what's fundamental about this thinking
about the ethics of clinical research,
thinking about vulnerable subjects is, I think what it does is it presses on
what I take to be two of the most important protections.
Informed consent is really important
and protecting people from risks and harm is really important.
And what's challenging about this is it doesn't let you have both, right.
It says, look, I'll give you informed consent,
or I'll give you low risks, but you don't get both.
And then what you have to decide, or what we have to decide is,
we have to decide which one we're going to go with.
And I'll give you an argument on both sides quickly before we end.
One is, you might think, and this is true with parents, we let parents --
we give parents a lot of leeway in making decisions for kids.
Or you might think in the case of Miss P and Mr.
P, they were married for 40 years.
You might think, okay, it's somebody else, but it's somebody
who really knows her, and probably knows what she wants.
Well, it turns out
unfortunately that there's at least a fair amount of empirical data
that we're not very good predictors of the preferences of other people,
including people
who are very close to us, people we've known for a really long time.
So it's hard to know how much we can rely on other people.
In the Jesse Gelsinger
-- so that's the consent worry about how much we rely on surrogates.
On the other hand, unfortunately in the Jesse Gelsinger
-- this is an actual case, Jesse Gelsinger died as a result of being in this study.
Now of course, that's not a clear reason why we should have done it
because maybe the 3 year olds would have died, we're never going to know that,
but it shows that these are really challenging, important questions
to try to think hard about, and get right that people are faced with, okay.
All right. Any last thoughts?
Things I should have said?
Questions we should have answered? Yes.
Female Speaker: So a lot of times when dealing with this topic,
people discussing informed consent,
and this is one of the most important [inaudible] --
Yep. Female Speaker: -- but I very rarely hear
all the protections are stacked up --
Yep. Female Speaker: -- at the beginning of the study.
Right. Female Speaker: This makes perfect sense.
But what happens when pregnant women
with children, with prisoners, once they're in the study and approved?
Are there still additional -- Yeah. Female Speaker: -- [inaudible] over
other subjects?
Or at that point is everybody equally considered? Good.
Great question.
So as you say, most -- as you pointed out here, most of the protections
that we talked about are at the point of enrollment, or before enrollment.
So IRB review, that happens before enrollment.
And then at the point of enrollment, a surrogate, or extra
-- for Maki, it was independent assessment of her voluntariness.
So a lot of this goes on before a person is enrolled and starts in a study.
So that's where I think typically most of the protections are.
So your question's but what about added protections as the study goes along.
So there are protections for everybody as the study goes along.
So for instance, typically in the U.S., each study has to be re-reviewed
at least once a year.
You have
to find out how things are going, whether or not
anybody's been hurt, whether or not there's any information on risks.
So there's ongoing evaluation of the study from the point of the IRB.
Also, as it's always said, informed consent
isn't just at the point of enrollment, it's ongoing.
So somebody can always say no.
Somebody can always withdraw.
That's true of a competent adult.
For a child it would be they could dissent.
Or with Miss P, they could say dissent.
They enroll, but a week later
they might want to say I want to go home, so there's that protection.
But that's also a protection that applies to competent adults, as well.
So typically,
I would say that most of the protections for vulnerable subjects happen early on.
What you could do -- there are possibilities for added ones
as the study goes along.
So for instance, in the U.S.,
which I know the best, there's provisions for things like independent monitors.
So what you could do is you could say, okay, we're worried about Miss P.
We're going to enroll her, but I'm going to have somebody check in
on her once every couple of days just to make sure she's okay.
There is a group actually called the Human Subjects Protection Unit
that's run out of the clinical director of the Mental Health
Institute here that's a very novel way of doing that.
And they do that for some studies.
Studies where they're people who are identified as vulnerable.
They are monitors, and they stay with the people throughout
their participation in the study, and they check in on them
every once in a while to make sure things are going okay.
So that is one case where there's, I think, a valuable added protection
for vulnerable subjects.
So there's things like that you can do.
I think without having any good data on it,
I think it's probably relatively rare that that happens.
Although, it's happening here in a number of studies.
Anything else? All right. Thank you.