From Kim,
she says regarding the informed clinician test.
It's slightly different, though, for the clinician
because we make the decision at the individual level,
whereas the IRB makes the decision
at the population level.
Yeah.
Yeah, I think that's right.
And so the way I think about the informed
clinicians has what the inform clinician
has to do is they have to ask the question
not of a specific individual.
What they have to ask is they have to ask
of the individuals who qualify for this study.
Given the way the inclusion exclusion criteria are currently
worded,
is it in their medical interest to be in the study
and the clinician obviously might give a couple different
answers.
They might say yes, they might say no,
or they might say, well, it depends.
For some subpopulations, this prospect of
benefit and for others it's really risky.
And if that's the answer, they give it,
I said Mrs.
Kim's worried.
That's really important information for
the IRB.
Then maybe what the IRB wants to do
is go back and rethink the inclusion
exclusion criteria and say, okay,
is there a way that what we can do
is rejigger them so that we exclude those
people who face the really high risk?
Now, of course, there's the fairness issue
I talked about for the background,
but bracketing that for a second,
they might want to think about redoing
the inclusion exclusion criteria.
I think there's some case where they can do that.
It's pretty clear if they can't do it.
I've actually has been on some IRBs
where we mandated
and I literally an individual which doesn't happen.
She's right very often.
But again
where you can build into the protocol
that we're not sure if this is going to be
appropriate
for individuals who satisfy the inclusion
exclusion criteria.
So rather than fiddling with them,
what we're gonna do is we're going to have
an individual clinician look at each
individual person and assess it for them.
Now that's something you could do.
A phase one trial with just rolling ten people.
It's not necessarily something you could do for
somebody
only 5000 in a big phase three trial.
But even that general assessment that you started with.
Right. No. Yes.
And it might depend it's more than what
the IRB might have at hand.
So that's information that they could use.
Absolutely. Daniel.
Yeah.
Thanks for that.
It's really interesting.
My question was about the,
the fallacy of the package deal. Yeah.
So I'm wondering why you can't
just appeal to whether or not,
highly beneficial, like, net beneficial,
interventions are contingent
upon a highly risky intervention.
Like with a biopsy.
You know, if there's only if the only way
you can do some very, like, beneficial
interventions was through something risky
like that, that seems relevant.
This is just, you know, nothing is contingent upon it,
and it's just highly risky.
If that's the case, it seems like we can just,
you know, justify eliminating it based on minimizing risk.
Like if you have a really, really,
beneficial intervention, it's not like
we can just, like, tack on a bunch of highly risky.
Yeah. Intervention rates, you know, acceptable.
Yeah. So I don't I don't see Daniel.
Let me let me give you let me give you
an example and see what think.
And I hope this is clear wrapping.
So. So Daniel this was I get to be fully topical for a
second.
I hope this is clear as
compare two different cases.
So when I, when I,
when I do this, we have these debates
of people who are clinicians in the clinical setting.
We don't see the fallacy of the package
deal is a fallacy.
That's why it's called the fallacy.
The poster, because people think it's a
fallacy.
Take the clinical setting.
There are lots of interventions that we give patients
that offer them specifically no benefit at all and are risky.
And the reason
why we give them those interventions is
they set them up for other interventions
that are beneficial.
So obvious example consistent with what you're saying that I'm
assuming
that we mean by sort of contingent on is
central lines.
Right.
So central lines is I've go straight in
to you basically smashing into people's
maybe I should say smash it into
you lovingly and gently inserted into the chest and then
centralized.
Getting a central line is risky.
You get hurt, you can get infections,
you can get bleeding, and it doesn't
do you any good to have this thing
sticking in your chest, per se.
The reason why we do it in a clinical setting all the
time is
because there are certain drugs that that's how you administer
them.
So getting the central line puts you
in position to get the experience.
Not sorry, put you in position to get
treated.
So nobody I've never heard a clinician
say you can't justify the benefits
to the rest of the central line
by the potential benefits of another intervention.
That's a fallacy of a package deal.
Nobody says that.
They say, of course you have to give the
central line in to administer the drug.
That's perfectly fine because. So that seems acceptable, right?
That's contingent, I assume, in the way you were talking
about it.
That's acceptable.
Okay. Now I'll take a different case.
Take the case of giving a drug
where this exact same benefit of that drug
we were just talking about
in the clinical case, the exact same thing.
And in order to figure out
whether or not this drug works,
you need to figure out whether it goes into the tumor
to find out whether or not the drug goes into the tumor,
you need to do a biopsy and take a little bit of the
kidney
or the liver or whatever, and put it in a lab,
and somebody tells you whether or not
the drug got in there or not.
So imagine that the risk benefits
exactly the same, right.
So the experimental intervention offers
the same benefits as that clinical drug
we were giving.
The risks of the research biopsy are exactly
the same as the rest of the central line.
Is that what do you think about that.
So so here's what I say.
I say look, isn't it the same the risks
I of course I made them the same,
but the risks are the same.
And in order to get the experimental drug,
we need to do this other thing.
What people who worry about the fallacy,
the package deal says no.
You could give them.
You could give them the the experiment
without doing the biopsy.
The reason why you're doing the biopsy is for your research
purposes.
So that's exploiting that for the purposes of research.
That's the fallacy of the package deal.
So the question for you and why I want you to stay there is you
think
ethically are those cases similar
or are they really different?
Who's right? Do you have a sense or is too hard to think?
I don't know.
I it's a good question.
I'm not sure I have the answers.
Yeah, yeah.
That's fair. Yeah.
I don't know if someone else does.
Yeah.
Or we don't have to really pursue that.
But I think diamond is hard.
But that's that's sort of the dilemma.
That's the dilemma.
And I think IRBs right now are working on the assumption
that it's always a fallacy in the research setting.
And I'm not so convinced.
I think it doesn't seem that different
in an ethically important way.
But oh, sorry, I don't have an answer to that
question.
I shan't flesh it out.
I want to ask you about something.
You said it much, much earlier as an open
question,
which is whether the IRB members just would have sometimes,
quote unquote, step in and recommend
improvements on a protocol.
Yeah.
So on the one hand, you may think, well,
people are putting all sorts of resources
into an investigation.
If there isn't, you know, if there are ways to improve it.
And if the IRB member spots or recognize
that there's a potential for improvement,
why not?
Perhaps you may think it's obligatory.
Right. Yeah.
On the on the other hand, I also feel like,
there is a question
about the division of labor and throwing improvements, ideas
for improvements, in case in some cases
can drastically change.
For instance, the risk benefit profile for protocol.
And that may delay, the reviewing
process, which then, you know, bring in,
will bring in the question of you
know, resources.
Right.
So I just I just want to hear more about
what you think about this particular.
Yeah. So,
so can I give your answer to my question,
which is I don't know.
Yeah. Sure. Sure. Yeah.
So I think I think
so here's what some people will say.
Some people will say IRB shouldn't
be doing that at all, because what
the job of an IRB is, is to evaluate
whatever protocol gets presented to them.
And as long as that's acceptable they shouldn't be doing
any of these comparisons within a study.
Different designs of the same study
or across different size.
They could do.
I think that's wrong.
I think that's just a mistake.
I think there's different ways to argue for it.
I mean, one way is to say that and it's
kind of be consequentialist it away
and to say, look, what you said they're supposed to be doing is
whether or not the thing that was proposed
to them is ethically acceptable.
But part of making that determination
is precisely asking the question
of what they could do otherwise.
And you don't ask what they could do
otherwise.
You can't say whether or not this is ethically proper.
That's at least one way to argue.
But I think something like that is right.
But so then the question is, I think the important hard one
is what you
were pointing to, which I think is it's
just a practical matter of who does it.
I think for some of these things,
like comparing across studies,
I just often aren't in a position to do that.
So I think what we need is we need somebody further
upstream.
Funding agencies, institutions making those determinations
and hopefully IRBs being able to rely on.
Collecting another
slight variation on that is that
a lot of research, that IRB review
had been reviewed by a group of scientists.
So if it's an NIH grant it's gone through a peer review
of hopefully scientists who know, you know that field
and have said this is a really great protocol.
We think it ought to be funded.
And by the time it gets to the IRB,
it has gone through that process.
And so some might say if there has been
a robust scientific review, that's a reason
maybe to only comment on the study design.
If it's like a real importance versus
an investigator proposing a study that he plans,
she plans to fund with discretionary funds
that maybe was reviewed
at the department level, but maybe not really strictly.
And now it's on the IRBs desk.
I would say, you know, that's a case
where the IRB really ought to pay attention to the study
design
and whether it's been well-designed,
whether it can actually
answer the research question, because no other group
has provided a robust scientific review.
Did you have a question?
We have time for one more.
First, first of all, thank you so much for the talk.
That was really fascinating.
And I think I'll take away a lot of questions after this
lecture.
One of the questions I had was, I guess, thinking
about like international studies and the concept of fairness.
So like internationally, there's a diversity of cultural, ethical
beliefs.
And some of them might involve, for example, taking on
more risk or net risk as like for example,
I could take a more individual risk of a benefit society.
And for example, what if you have like a Western
culture
who takes on less net risk because they are more aware,
a more individualistic versus a culture
who believes that it's okay to enroll
children for the benefit of society,
or is okay for adults, take on more risk.
It would benefit society.
Like what are your thoughts on that?
And do you feel like that's fair?
Because it
feels like we are all participating
and thinking it's ethical.
But at the same time, if I impart
my Western view, it doesn't seem ethical
for one group to take on more risk than
another.
Yeah, I love that question.
And I think it's I think it applies,
as you suggested, across the board,
but I think it's especially relevant
this in a practical sense, when you think about something
like kids.
And so a lot of these standards for minimal
risk are basically,
as I said, compare the risks of the research to the
risks
that are thought to be acceptable
for ordinary kids in that society.
And your point is right that, well, the risks that a
given culture
society thinks are acceptable for kids
might be very different in one society
or culture to another one.
And so does that mean if we're in a society where
we're not as willing to take on risk
for other people,
that then you can only have a tiny bit of pediatric research
risk.
But in other countries where we're willing to take
on more risks for others, you can have more.
That, I think is a really great question.
And it raises this. I say one more thing.
It raises question that I've thought about
for a while, which is that.
It has practical implications
because the regulations in certain
countries are very different.
So there are certain countries.
Last time I looked at this couple of years
ago, I think it's still true,
but a couple of years ago there were certain countries
that had laws
that said you cannot expose a kid
to any research risk
for the benefit of others, so an even minimal risk wasn't
allowed.
And the country next door allowed that.
So okay.
Do we just say, yeah, countries get to decide what they want to
do?
Now here's the worry.
Imagine then that we do all the pediatric
research in the one country.
We learn all these things,
and then the other countries just like,
yeah, this is great.
We don't have to expose our kids to any risks.
So we learned all this stuff that these guys are learning
over here.
When they expose their kids to risk.
That doesn't seem right. Right.
What do you do about that? Yeah.