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Good morning, everyone in the
room and

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everywhere else that you're
watching from.

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As Holly mentioned,
I'm going to talk about a

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framework

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for the ethical conduct
of clinical research.

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And as Holly already alluded to,

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this is a framework
that the course is sort of built

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on.

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So you so the things that I'm
going

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to talk about in the next 40
minutes,

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you're going to hear over and
over again

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throughout the rest of the
course,

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and I'll make some references to
those.

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Before I start, I want to thank
Holly

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for doing such a great job

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of organizing this course.

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And Alex, so thank you both.

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There's my disclaimer,
and I have no conflicts of

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interest.

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So I think when we think about
the ethics

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of clinical research,

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there are several questions

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that sort of big picture
questions

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we should ask ourselves.

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One is the first.

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Before I ask any of them,

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I want to make sure that we
understand

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what we're talking about

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when we're talking
about clinical research,

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because there are lots of kinds
of

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research that we might be
interested in.

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The ethics of clinical research
being research that's about the

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health

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and humans.

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And it's either research to,
to understand better the health

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of humans

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or illness in humans or to
intervene,

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in prevention or diagnosing or
treating.

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So that's the domain of research
we're talking about.

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So that precludes, for example,
basic

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research,

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pre-clinical research,
research with non-human animals,

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all other kinds of research
that's not related to human

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health.

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So three important questions.

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What's the value?

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Why do we do research at all?

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That's one question to ask.

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And then the second and subset
of

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that is okay, if we do research
at all

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to try to understand humans,
why do we have to include humans

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in it?

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Why do we have to involve
humans?

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Experiments on humans.

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And if the answer to both of
those is,

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well,

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it's important
and we need to involve humans,

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then how should we do it
in the most ethical manner.

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And so I'm going to try to cover
each of these very briefly

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with respect to

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the value.

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This is just one example.

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This is the NIH website that
talks

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about the impact of NIH
research.

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Now, NIH is one funder of
research,

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happens to be probably

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the largest funder,
public funder of research in the

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world.

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But it's just one funder.

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But you can see on
the the left hand side here,

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it talks about

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improving health,
revolutionizing science

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and serving society.

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So the value of research is to
understand

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and improve health.

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For sure. That's what
we're going to be talking about

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mostly.

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But there are a couple of other
things.

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You know,
we learn how to do science

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better.

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We learn new techniques that
will

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in the future help improve
health.

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And then there's a way in which,
research

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actually

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has a huge impact
on other aspects of society.

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So, for example, if you go to
that website

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on serving society,

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it'll talk about the economy
value

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of doing research.

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It's a boon to the economy.

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It raises, it in places

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where research is funded,
the economy is improved.

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And by helping people be
healthier,

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we improve the economy because

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people can work.

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So there's a lot of ways
in which research itself is

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valuable.

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And this is just,

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you know, when I age.

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But everywhere else that funds
research

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or does research

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has the same kind of goals.

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So what about including humans?

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So one thing that's probably
true

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is that the kinds of results
that we get from doing

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clinical research
have compelling societal health

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benefits.

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So these are new therapies,
diagnostic and preventive

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strategies
improvement and quality of life,

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etc..

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I think all of us can probably
recognize

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examples of people who have
survived

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from a devastating disease

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or not got a devastating disease
because of research discoveries.

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So, for example, treatments for
HIV

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have changed the trajectory of
HIV

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from a rapidly fatal disease
to a pretty people

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live a normal life
with a chronic controlled

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disease.

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Treatments for childhood
leukemia have changed from,

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again,

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rapid decline in death to 90
plus percent

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survival.

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Lipid lowering drugs constantly.

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I mean, many, many people are on
lipid

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lowering drugs that that's
improved.

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Morbidity

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and mortality from
cardiovascular disease,

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vaccines, vaccines
for measles, for polio, for,

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HPV for Covid, so many others.

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So you can

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you can sort of
think about the kinds of things

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that have been shown to work
through clinical research

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that have made a major impact
on the health of society, of

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people

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and saving lives
and improving the quality of

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health.

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Also,

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and this is sort of the same
idea,

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but in a sort of a more micro
level.

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When you go to a physician's
office

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to get treated for something,

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you hope that the physician
has some evidence upon which

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to make a suggestion about what
you have

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and what to do about it.

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And those kinds of that
evidence, again,

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comes from clinical research.

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So most of the, kinds of things
that we do

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when we go

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to a doctor's office is based on
research

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that have been done in the past.

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There's also

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a pretty clear understanding
that human participation is

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necessary

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in order to gain accurate
and relevant data for humans.

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So we do,

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the normal trajectory

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of research is basic in vivo.

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I mean, in vitro, sorry.

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Then preclinical in non-human
animals.

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But most of the non-human animal
models are not perfect models

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for humans.

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And so testing things in humans
or

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understanding humans as part of
research

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is, is really important to
understand

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how humans work and what works
in humans.

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And that's the reason we do it.

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So why is it challenging then?

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Okay, research is good.

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Humans are necessary.

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What's the problem? Right.

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The problem is that the primary
goal of

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doing research is to generate
knowledge,

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to generate useful knowledge
about human health and illness.

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It's not to benefit
the people that are part of the

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study.

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Now, that doesn't mean
that people in studies don't

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benefit.

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They often do, but that's not
the goal,

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and they often don't benefit.

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So we're really asking a

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small number of people
to accept risk and burden

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in order to answer important
questions

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that might be beneficial to
others.

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And therefore, the people who
are being

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enrolled in research
or participating in research are

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the means

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to developing useful knowledge
and therefore at risk

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of being exploited.

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There's lots of public

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sort of feeling about this
issue,

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and if you talk to people

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who don't know much about
research,

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they will say,

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oh my gosh,
you can't do research on humans.

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That's, you know, we're making
humans

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into human guinea pigs.

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And, you know, there's
a lot of misunderstanding about

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the

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the goals of research and the
reasons

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research is done and how it's
done.

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But there's a lot of feeling
about,

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not using people as a human.

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Guinea pigs.

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So the ethics of clinical
research

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is what I've said.

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Made sense
so far, really has two really

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important,

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parts to it or goals to it.

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One is that we want to promote
responsible

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and useful research

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that's going to benefit society
and future patients.

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That's a really important
ethical imperative of doing good

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clinical research.

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At the same time,
we want to minimize any harm

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and the possibility of
exploitation

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by protecting the rights

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and welfare of the participants,
protecting and respecting.

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So both of those are important.

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And sometimes they come into
tension.

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By the way, and the ethical
requirements

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that we are going to learn about

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are you're going to learn about
in this course.

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And some of you might already
know some

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about how provide guidance

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in order to allow this to
happen,

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to how to ethically conduct
research

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in order to promote responsible
research,

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seeking progress,

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minimizing exploitation and
harm,

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or the possibility of ensuring
that rights

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and welfare of participants are
respected

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and helping to maintain

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the trust of the public
in the research enterprise.

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So important pieces of it.

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So how do we how do we conduct
research

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ethically?

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How do we do that?

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How do we promote useful
research

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to protect the rights and
welfare

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and maintain public trust?

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Well, we've

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we've learned over the course of
history

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through many historical lessons,

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some of the things that are
important

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in terms of how to conduct
research

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and then we can also sort of
go through some ethical reasons.

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And I'm going to do a little bit
of each.

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I'm not going to spend
much time on history because

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later

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Susan Lederer is going to speak
to you.

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And she's a historian.

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She's a historian that's done

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a huge amount of work on the
history

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of the ethics of research.

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And so let her give you
the specific examples.

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And she's a wonderful lecturer
as well.

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But years ago, Dick
Emanuel and I wrote a paper,

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which is, which was rewritten
for the textbook Oxford Textbook

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of Clinical Research Ethics in
2008,

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which tried to divide the ethics

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of clinical research
historically into different eras

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and just briefly,
to give you a sense of how this

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went.

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You know, for a long time,
hundreds of years, there were no

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rules,

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there were no guidelines, there
were no,

268
00:10:11,078 --> 00:10:12,979
limits on what people could do.

269
00:10:12,979 --> 00:10:15,982
And in fact, there wasn't much
money or,

270
00:10:16,316 --> 00:10:19,152
there weren't many resources
for clinical research either.

271
00:10:19,152 --> 00:10:23,920
So research was often done
by individual scientists or

272
00:10:23,920 --> 00:10:24,891
clinicians

273
00:10:25,325 --> 00:10:27,802
who had some extra time or
money,

274
00:10:27,802 --> 00:10:29,829
but mostly with the motive

275
00:10:29,829 --> 00:10:32,020
of trying to benefit the
individuals

276
00:10:32,020 --> 00:10:33,967
that they were responsible for.

277
00:10:34,534 --> 00:10:37,309
And because there were so few
guidelines,

278
00:10:37,309 --> 00:10:39,339
there was a lot of, you know,

279
00:10:40,373 --> 00:10:42,625
sometimes the experiments were
worse

280
00:10:42,625 --> 00:10:43,877
than no experiment,

281
00:10:43,877 --> 00:10:47,213
and there was a lot of, negative
outcomes

282
00:10:47,213 --> 00:10:50,216
rather than only positive that

283
00:10:50,817 --> 00:10:53,371
when there was more money
and more resources and more

284
00:10:53,371 --> 00:10:53,853
attention

285
00:10:53,853 --> 00:10:56,328
to research, research,
excuse me, and the value of

286
00:10:56,328 --> 00:10:56,823
research,

287
00:10:57,190 --> 00:10:59,377
we went into what people have,
in

288
00:10:59,377 --> 00:11:02,161
retrospect, called a very
utilitarian era

289
00:11:02,562 --> 00:11:06,145
where people who were
marginalized,

290
00:11:06,145 --> 00:11:07,066
captive,

291
00:11:07,634 --> 00:11:11,377
unimportant to society
were asked to participate in

292
00:11:11,377 --> 00:11:12,038
research

293
00:11:12,038 --> 00:11:15,207
that was seen as good for the
common good,

294
00:11:15,207 --> 00:11:16,943
good for the majority.

295
00:11:17,477 --> 00:11:20,404
And you'll hear about
some of those examples from

296
00:11:20,404 --> 00:11:21,180
Susan later.

297
00:11:21,180 --> 00:11:23,077
And probably, you know, some of
them

298
00:11:23,077 --> 00:11:24,183
anyway, from history

299
00:11:24,584 --> 00:11:27,687
that led to an era of scrutiny,

300
00:11:27,687 --> 00:11:31,175
some of the exposure
of those kinds of experiments

301
00:11:31,175 --> 00:11:31,524
done

302
00:11:31,524 --> 00:11:34,019
with prisoners and orphans and
other

303
00:11:34,019 --> 00:11:36,930
very vulnerable people, people,
you know,

304
00:11:36,930 --> 00:11:39,257
the scientific and the way
communities

305
00:11:39,257 --> 00:11:41,401
started to say, what are we
doing?

306
00:11:41,401 --> 00:11:42,823
You know, what is what is
happening

307
00:11:42,823 --> 00:11:43,636
with this research?

308
00:11:43,636 --> 00:11:47,084
And so there was intense
scrutiny, driven

309
00:11:47,084 --> 00:11:49,943
by a couple of very, public
cases

310
00:11:50,577 --> 00:11:53,680
that led to questions about what
the limits

311
00:11:53,680 --> 00:11:55,973
and the scope of clinical
research

312
00:11:55,973 --> 00:11:56,849
ought to be.

313
00:11:56,849 --> 00:12:00,513
And from that scrutiny,
there were derived a number of

314
00:12:00,513 --> 00:12:00,920
rules

315
00:12:00,920 --> 00:12:06,059
and regulations which emphasized
and have focused on protection

316
00:12:06,059 --> 00:12:09,266
of the participants, protection
of human participants and

317
00:12:09,266 --> 00:12:09,829
research.

318
00:12:09,829 --> 00:12:12,932
And so you'll see, or maybe,
you know, a lot of the rules

319
00:12:12,932 --> 00:12:15,935
and regulations
have that as their primary

320
00:12:15,935 --> 00:12:16,436
focus,

321
00:12:17,737 --> 00:12:19,205
I'd say in the last

322
00:12:19,205 --> 00:12:22,175
now almost 30, 30 years,
I guess there's been

323
00:12:22,175 --> 00:12:25,478
a little bit of a pendulum
swing in the sense that,

324
00:12:26,045 --> 00:12:30,350
clinical research is recognized
as a benefit,

325
00:12:30,350 --> 00:12:32,518
that a benefit sometimes to
people

326
00:12:32,518 --> 00:12:34,687
who want to be in clinical
trials

327
00:12:34,687 --> 00:12:36,456
because it's a way for them to
access

328
00:12:36,456 --> 00:12:38,403
experimental drugs
that they couldn't get

329
00:12:38,403 --> 00:12:38,925
elsewhere.

330
00:12:38,925 --> 00:12:39,392
Elsewhere.

331
00:12:39,392 --> 00:12:42,048
Excuse me,
but also benefit for

332
00:12:42,048 --> 00:12:43,162
populations.

333
00:12:43,162 --> 00:12:45,625
So there's been, for example,
recognition

334
00:12:45,625 --> 00:12:47,066
that children have been

335
00:12:47,433 --> 00:12:49,914
what some people call
therapeutic orphans

336
00:12:49,914 --> 00:12:51,971
because there's been
insufficient

337
00:12:51,971 --> 00:12:54,507
amount of research to generate
evidence

338
00:12:54,507 --> 00:12:57,043
on how to treat children
appropriately

339
00:12:57,277 --> 00:13:00,913
and therefore including them in
research is a benefit,

340
00:13:00,913 --> 00:13:02,882
because then we learn
how to treat children.

341
00:13:02,882 --> 00:13:04,384
So that's been,

342
00:13:04,384 --> 00:13:06,614
a very important insight that's
happened

343
00:13:06,614 --> 00:13:08,287
over the last 30 or so years.

344
00:13:10,790 --> 00:13:14,160
During this time, and currently
there are

345
00:13:15,194 --> 00:13:18,398
there there were derived a
number of codes

346
00:13:18,398 --> 00:13:22,301
and guidelines and regulations
that guide clinical research.

347
00:13:22,602 --> 00:13:24,426
Some of these you've probably
heard from,

348
00:13:24,426 --> 00:13:25,672
I've heard about excuse me.

349
00:13:25,672 --> 00:13:28,675
And I'm just going to mention
a few of them just briefly.

350
00:13:29,075 --> 00:13:32,300
The Nuremberg Code was the code
that was written at the end of

351
00:13:32,300 --> 00:13:32,612
World

352
00:13:32,612 --> 00:13:36,114
War two, when there was a trial
of the Nazi doctors who did a

353
00:13:36,114 --> 00:13:36,516
number

354
00:13:36,516 --> 00:13:40,420
of experiments on prisoners,
Nazi prisoners of World War Two.

355
00:13:41,788 --> 00:13:44,023
The Declaration of Helsinki

356
00:13:44,023 --> 00:13:47,026
followed 15 years almost later

357
00:13:47,293 --> 00:13:49,512
by the World Medical
Association,

358
00:13:49,512 --> 00:13:51,731
because it began to realize that

359
00:13:52,365 --> 00:13:55,618
although the the sort of tenets
of the Nuremberg Code were

360
00:13:55,618 --> 00:13:56,235
important,

361
00:13:56,636 --> 00:13:58,104
they didn't apply.

362
00:13:58,104 --> 00:14:02,566
So obviously to research
that was done by doctors with

363
00:14:02,566 --> 00:14:03,309
patients

364
00:14:03,309 --> 00:14:05,826
to try to improve the
understanding

365
00:14:05,826 --> 00:14:07,480
of what patients need.

366
00:14:07,947 --> 00:14:10,917
And so the Declaration of
Helsinki in 64,

367
00:14:10,917 --> 00:14:14,353
started was by doctors for
doctors

368
00:14:14,353 --> 00:14:17,421
about how to do research
with patients and people who are

369
00:14:17,421 --> 00:14:17,690
ill.

370
00:14:18,858 --> 00:14:19,859
That declaration

371
00:14:19,859 --> 00:14:22,995
has been revised multiple times.

372
00:14:22,995 --> 00:14:25,798
The most recent published
version is 2013.

373
00:14:25,798 --> 00:14:27,673
But there is a they are in the
process

374
00:14:27,673 --> 00:14:29,202
of revising it at this moment.

375
00:14:29,202 --> 00:14:32,172
There's been a number of,
meetings around the world,

376
00:14:32,172 --> 00:14:32,972
actually, to,

377
00:14:33,539 --> 00:14:37,509
consultant consultancies
to try to get that, revised

378
00:14:37,509 --> 00:14:38,044
again.

379
00:14:38,044 --> 00:14:40,713
So we'll see
a new declaration of Helsinki.

380
00:14:40,713 --> 00:14:43,716
I'm assuming this year

381
00:14:43,716 --> 00:14:46,953
the Belmont Report was a report
from the Nash,

382
00:14:46,953 --> 00:14:49,047
the United States National
Commission

383
00:14:49,047 --> 00:14:50,123
for the Protection

384
00:14:50,123 --> 00:14:54,527
of Participants of Medical
and Behavioral Research, which

385
00:14:55,728 --> 00:14:58,231
which was a commission
that was put into place

386
00:14:58,231 --> 00:15:00,424
after the exposure of the
Tuskegee

387
00:15:00,424 --> 00:15:03,069
Public Health Service, syphilis
studies,

388
00:15:03,069 --> 00:15:03,603
which you're going

389
00:15:03,603 --> 00:15:06,032
to hear more about later
and you probably have already

390
00:15:06,032 --> 00:15:06,572
heard about

391
00:15:07,006 --> 00:15:08,641
the Belmont Report, is is a

392
00:15:09,642 --> 00:15:11,811
it's not a,

393
00:15:11,811 --> 00:15:12,845
set of rules.

394
00:15:12,845 --> 00:15:16,382
It's a explication
of the underlying principles

395
00:15:16,816 --> 00:15:18,351
for the ethics of clinical
research.

396
00:15:18,351 --> 00:15:21,387
And it's it's a very useful,
document.

397
00:15:21,387 --> 00:15:23,871
It's also short, it's easy to
read,

398
00:15:23,871 --> 00:15:25,291
and it is the basis

399
00:15:25,291 --> 00:15:28,261
on which our regulations have
been made.

400
00:15:29,362 --> 00:15:31,364
And I'll come to that in a
minute.

401
00:15:31,364 --> 00:15:33,384
The Sims is the Council of
International

402
00:15:33,384 --> 00:15:35,101
Organization of Medical
Sciences,

403
00:15:35,368 --> 00:15:37,254
which has collaborated over the
years

404
00:15:37,254 --> 00:15:39,038
with the World Health
Organization

405
00:15:39,505 --> 00:15:43,276
to provide international
guidelines.

406
00:15:43,276 --> 00:15:47,213
And those guidelines,
they originally took the

407
00:15:47,980 --> 00:15:50,650
the goal that they took
was to take the principles

408
00:15:50,650 --> 00:15:53,119
that were enunciated
in the Declaration of Helsinki

409
00:15:53,119 --> 00:15:56,222
and apply them specifically
to the kind of research

410
00:15:56,222 --> 00:16:00,059
that's sponsored by a resource
rich country and conducted

411
00:16:00,059 --> 00:16:02,279
in a research poorer country,
resource,

412
00:16:02,279 --> 00:16:03,930
poorer countries, excuse me.

413
00:16:04,397 --> 00:16:08,326
And they're one of the things
that I really like about the

414
00:16:08,326 --> 00:16:08,868
science

415
00:16:08,868 --> 00:16:12,338
guidelines is not only do they
have tenets

416
00:16:12,338 --> 00:16:15,341
which all these others do too,
but they explain them.

417
00:16:15,341 --> 00:16:17,877
They have many paragraphs of
explanation.

418
00:16:17,877 --> 00:16:19,440
Why do they think this is
important,

419
00:16:19,440 --> 00:16:21,047
how you would actually implement
it?

420
00:16:21,047 --> 00:16:23,159
So it's a useful document to
look at for

421
00:16:23,159 --> 00:16:25,218
more than just international
research.

422
00:16:26,285 --> 00:16:28,855
And then the OECD is

423
00:16:28,855 --> 00:16:30,763
International Conference on
Harmonization

424
00:16:30,763 --> 00:16:32,391
Good Clinical Practice
guidelines.

425
00:16:32,725 --> 00:16:35,962
So the International Conference
on Harmonization was a group

426
00:16:35,962 --> 00:16:41,267
that got together in the 1990s
to say,

427
00:16:42,001 --> 00:16:43,657
well, we're doing clinical
research

428
00:16:43,657 --> 00:16:45,171
all around the world when we do

429
00:16:45,171 --> 00:16:48,624
research in the United States,
and then we want to adopt the

430
00:16:48,624 --> 00:16:49,141
findings

431
00:16:49,141 --> 00:16:50,916
in the European Union, it has to
go

432
00:16:50,916 --> 00:16:53,045
through the whole process all
over again.

433
00:16:53,312 --> 00:16:56,415
So there was an effort
to harmonize those regulations.

434
00:16:56,415 --> 00:16:58,885
So that research that was done
in one

435
00:16:58,885 --> 00:17:00,953
jurisdiction could be accepted

436
00:17:00,953 --> 00:17:03,956
by another jurisdiction
by the regulatory authorities.

437
00:17:04,390 --> 00:17:06,392
And it

438
00:17:06,392 --> 00:17:09,262
documents has multiple, multiple
volumes

439
00:17:09,262 --> 00:17:12,163
about multiple things
related to how to do clinical

440
00:17:12,163 --> 00:17:12,732
research.

441
00:17:13,032 --> 00:17:17,536
One important guidance
from for how to do research

442
00:17:17,536 --> 00:17:19,909
ethically is the good clinical
practice

443
00:17:19,909 --> 00:17:20,640
guidelines.

444
00:17:20,640 --> 00:17:25,552
And that, that has become in
many jurisdictions around the

445
00:17:25,552 --> 00:17:26,145
world,

446
00:17:26,145 --> 00:17:28,304
the guiding regulatory framework
for

447
00:17:28,304 --> 00:17:30,883
how research is done in that
jurisdiction.

448
00:17:33,152 --> 00:17:35,278
So in addition to codes and
guidelines,

449
00:17:35,278 --> 00:17:36,422
we have regulations.

450
00:17:36,422 --> 00:17:40,026
So in the United States
we have the common rule

451
00:17:40,293 --> 00:17:45,865
which is a set of regulations
about how to protect

452
00:17:46,299 --> 00:17:49,302
participants in research that is

453
00:17:49,602 --> 00:17:52,071
adopted, has been adopted by

454
00:17:52,071 --> 00:17:55,074
the 17 US federal agencies,

455
00:17:55,741 --> 00:17:57,812
one of which is the Department
of Health

456
00:17:57,812 --> 00:17:59,779
and Human Services and the
Department

457
00:17:59,779 --> 00:18:03,594
of Health and Human Services,
which is the agency that NIH

458
00:18:03,594 --> 00:18:04,383
belongs to.

459
00:18:05,284 --> 00:18:08,287
Uses the common rule, which is
found at us

460
00:18:08,521 --> 00:18:11,807
at 45, Code of Federal
Regulations,

461
00:18:11,807 --> 00:18:12,558
not 46.

462
00:18:12,992 --> 00:18:14,661
And you know that you might say,
well,

463
00:18:14,661 --> 00:18:15,628
who cares about that?

464
00:18:15,628 --> 00:18:18,048
But you'll find around here, for
example,

465
00:18:18,048 --> 00:18:20,232
people say, well, what is 45 CFR
46?

466
00:18:20,232 --> 00:18:22,305
Say, and you have to know what
that means.

467
00:18:22,305 --> 00:18:22,601
Okay.

468
00:18:22,601 --> 00:18:24,036
That's that's the common rule.

469
00:18:25,004 --> 00:18:26,772
Interestingly,

470
00:18:26,772 --> 00:18:28,959
the FDA, Food and Drug
Administration

471
00:18:28,959 --> 00:18:30,910
has their own set of regulations

472
00:18:30,910 --> 00:18:33,773
that are not they don't
they don't fall under the common

473
00:18:33,773 --> 00:18:34,080
rule.

474
00:18:34,413 --> 00:18:36,026
And they have a set of
regulations,

475
00:18:36,026 --> 00:18:37,316
several sets of regulations

476
00:18:37,316 --> 00:18:40,353
which are relevant to the ethics
of doing research.

477
00:18:41,053 --> 00:18:43,756
Most relevant are probably

478
00:18:43,756 --> 00:18:46,826
the ones found at 21 CFR 50 and
56.

479
00:18:47,393 --> 00:18:49,962
And they're very similar to what

480
00:18:49,962 --> 00:18:52,965
you see in 45 CFR 46, but not
identical.

481
00:18:53,499 --> 00:18:56,734
And so it's important
to think about the differences

482
00:18:56,734 --> 00:18:57,169
there.

483
00:18:57,436 --> 00:19:00,001
And if somebody is developing a
product

484
00:19:00,001 --> 00:19:01,974
that will ultimately want to,

485
00:19:02,341 --> 00:19:05,344
apply for FDA approval,

486
00:19:05,644 --> 00:19:08,647
then they have to follow the FDA
regs

487
00:19:09,048 --> 00:19:12,351
in addition to the regulations
that govern the agencies.

488
00:19:12,685 --> 00:19:16,122
There are often or maybe usually

489
00:19:16,555 --> 00:19:20,126
institutional policies
that, people have to adhere to.

490
00:19:20,126 --> 00:19:23,229
So the NIH, for example,
has a number of policies about

491
00:19:23,229 --> 00:19:26,038
who to include
and how research ought to be

492
00:19:26,038 --> 00:19:26,365
done

493
00:19:26,365 --> 00:19:29,702
ethically that are, relevant to
research

494
00:19:29,702 --> 00:19:33,072
that's funded by or done within
the NIH.

495
00:19:33,572 --> 00:19:35,993
And, Holly mentioned earlier
that,

496
00:19:35,993 --> 00:19:38,911
you know, most of our focus is
domestic,

497
00:19:38,911 --> 00:19:41,685
but many research projects in
these

498
00:19:41,685 --> 00:19:44,617
in this day are done across
borders.

499
00:19:44,617 --> 00:19:46,852
And so there are laws and
jurisdiction

500
00:19:46,852 --> 00:19:50,105
regulations in many, many other
jurisdictions that are also

501
00:19:50,105 --> 00:19:50,656
relevant.

502
00:19:51,123 --> 00:19:54,226
If somebody is doing research
that's funded by the NIH,

503
00:19:54,493 --> 00:19:56,295
it doesn't matter where it's
being done.

504
00:19:56,295 --> 00:19:58,726
They still have to follow when I
rules,

505
00:19:58,726 --> 00:20:01,033
but they may also have to follow
the

506
00:20:01,300 --> 00:20:03,909
the laws and regulations
of the jurisdiction in which

507
00:20:03,909 --> 00:20:04,303
they're

508
00:20:04,837 --> 00:20:06,639
conducting their research.

509
00:20:06,639 --> 00:20:09,108
So lots of details.

510
00:20:09,108 --> 00:20:10,943
I went over that pretty fast.

511
00:20:10,943 --> 00:20:14,395
I do want to focus just a moment
on what the Belmont Report does

512
00:20:14,395 --> 00:20:14,880
include,

513
00:20:14,880 --> 00:20:17,053
because I think I mentioned it's
it's

514
00:20:17,053 --> 00:20:19,518
not a code in the same way as
the others,

515
00:20:19,518 --> 00:20:22,242
but it has ethical principles
underlying the conduct of

516
00:20:22,242 --> 00:20:22,688
research

517
00:20:22,688 --> 00:20:25,006
and explicates them what they
are

518
00:20:25,006 --> 00:20:28,027
and how they apply so respect
for persons.

519
00:20:28,027 --> 00:20:30,182
They apply to the process of
informed

520
00:20:30,182 --> 00:20:31,464
consent, beneficence,

521
00:20:31,464 --> 00:20:34,600
to the process of assessing
risks and benefits, and research

522
00:20:34,867 --> 00:20:38,164
and justice to the process
of selecting participants

523
00:20:38,164 --> 00:20:38,671
fairly.

524
00:20:38,971 --> 00:20:41,173
And you're going to hear
about all of those more.

525
00:20:41,173 --> 00:20:43,096
The other thing, important
thing,

526
00:20:43,096 --> 00:20:45,311
I think that the Belmont Report
does,

527
00:20:45,311 --> 00:20:48,173
and very few of these other
documents

528
00:20:48,173 --> 00:20:50,649
do, is describe the distinction

529
00:20:50,649 --> 00:20:54,595
and the boundaries between
clinical practice and clinical

530
00:20:54,595 --> 00:20:55,287
research.

531
00:20:55,955 --> 00:20:58,424
And interestingly,

532
00:20:58,424 --> 00:21:01,660
when you think about the kinds
of ethical issues

533
00:21:01,660 --> 00:21:04,300
or tensions that come up
in a clinical research

534
00:21:04,300 --> 00:21:05,030
environment,

535
00:21:05,397 --> 00:21:08,768
they often are because of
tension

536
00:21:08,768 --> 00:21:11,770
or confusion about these
boundaries.

537
00:21:12,438 --> 00:21:15,805
So I wanted to spend one minute
talking about what I mean by

538
00:21:15,805 --> 00:21:16,142
that.

539
00:21:17,042 --> 00:21:18,962
So the difference between
clinical

540
00:21:18,962 --> 00:21:20,713
research and clinical practice

541
00:21:20,713 --> 00:21:22,781
is multifold.

542
00:21:22,781 --> 00:21:24,283
First of all, there are
different goals.

543
00:21:24,283 --> 00:21:25,651
And I've already mentioned that

544
00:21:25,651 --> 00:21:28,024
the goal of clinical research is
to answer

545
00:21:28,024 --> 00:21:29,889
useful, generalizable questions.

546
00:21:30,289 --> 00:21:32,342
The goal of clinical practice is
to help

547
00:21:32,342 --> 00:21:34,293
the peop, the person or the
people in

548
00:21:34,293 --> 00:21:36,503
front of you based on evidence
that you've

549
00:21:36,503 --> 00:21:38,397
that somebody else collected
before

550
00:21:39,899 --> 00:21:41,467
and also use different methods.

551
00:21:41,467 --> 00:21:46,005
So in research you may be aware
and you will hear more about

552
00:21:46,705 --> 00:21:48,274
we randomized people.

553
00:21:48,274 --> 00:21:50,259
We randomized people to get this
drug

554
00:21:50,259 --> 00:21:51,010
or that drug.

555
00:21:51,010 --> 00:21:53,384
We blind them, meaning they're
not allowed

556
00:21:53,384 --> 00:21:55,080
to know what they're getting.

557
00:21:55,381 --> 00:21:57,524
Sometimes the investigator
doesn't know what they're

558
00:21:57,524 --> 00:21:58,184
getting either.

559
00:21:58,184 --> 00:21:59,852
That's a double blind.

560
00:21:59,852 --> 00:22:03,722
We offer placebos
as one part of a control group.

561
00:22:04,089 --> 00:22:06,692
That's very common in research.

562
00:22:06,692 --> 00:22:10,062
We do, dose escalation in
trials.

563
00:22:10,062 --> 00:22:12,187
So, you know,
these three people will get this

564
00:22:12,187 --> 00:22:12,464
dose.

565
00:22:12,464 --> 00:22:14,600
The next three people
will get a higher dose.

566
00:22:14,600 --> 00:22:17,603
So there's a number of really
important

567
00:22:18,204 --> 00:22:21,840
methodology in research
that are critical to,

568
00:22:23,209 --> 00:22:25,144
getting good unbiased data

569
00:22:25,144 --> 00:22:28,614
that you would find anathema
in clinical practice.

570
00:22:28,614 --> 00:22:30,813
So if you went to your doctor's
office

571
00:22:30,813 --> 00:22:33,185
with a sore throat and your
doctor said,

572
00:22:33,552 --> 00:22:34,653
I'm going to give you a drug,
but

573
00:22:35,821 --> 00:22:37,289
I'm not going to tell you what
it is.

574
00:22:37,289 --> 00:22:40,125
I don't even know what it is
you would be like,

575
00:22:40,125 --> 00:22:41,794
I think I need a new doctor.

576
00:22:41,794 --> 00:22:44,344
So I think there is really an
interesting

577
00:22:44,344 --> 00:22:45,464
dichotomy between

578
00:22:45,464 --> 00:22:48,927
the methods
that are common to each of those

579
00:22:48,927 --> 00:22:49,635
domains.

580
00:22:50,402 --> 00:22:52,549
There's
also different justification for

581
00:22:52,549 --> 00:22:52,871
risk.

582
00:22:52,871 --> 00:22:55,562
So in clinical practice,
certainly

583
00:22:55,562 --> 00:22:58,410
people absorb accept whatever
risk.

584
00:22:58,410 --> 00:23:01,413
There's risks
with interventions of all kinds.

585
00:23:01,880 --> 00:23:05,317
But those risks are justified
because they

586
00:23:06,452 --> 00:23:11,523
the, benefit
that is presumed to be happening

587
00:23:11,523 --> 00:23:14,793
by giving this intervention
outweighs the risk.

588
00:23:15,094 --> 00:23:17,663
And so the risk is worth it
for that individual.

589
00:23:17,663 --> 00:23:20,399
In research, we ask people
sometimes

590
00:23:20,399 --> 00:23:23,159
to do things
for which there are no benefits

591
00:23:23,159 --> 00:23:23,535
then.

592
00:23:23,535 --> 00:23:26,639
So we may ask them, for example,
to have an extra biopsy

593
00:23:26,639 --> 00:23:29,305
or an extra blood draw or an
extra X-ray,

594
00:23:29,305 --> 00:23:30,476
or to take a drug

595
00:23:30,809 --> 00:23:34,647
just to get a pharmacokinetic, 
reading on it.

596
00:23:35,114 --> 00:23:37,668
Those are things that are done
for no benefit to those

597
00:23:37,668 --> 00:23:38,284
individuals,

598
00:23:38,517 --> 00:23:40,720
and they accept those risks for
the

599
00:23:40,720 --> 00:23:41,287
for the,

600
00:23:41,287 --> 00:23:44,290
interests of science.

601
00:23:44,523 --> 00:23:47,126
There are also different levels
of uncertainty.

602
00:23:47,126 --> 00:23:49,128
Again, not everything in
clinical practice

603
00:23:49,128 --> 00:23:50,129
is certain for sure.

604
00:23:50,129 --> 00:23:53,024
People we we often have to say,
well,

605
00:23:53,024 --> 00:23:54,667
here's what we know.

606
00:23:54,667 --> 00:23:55,958
Here's what we don't know,
here's

607
00:23:55,958 --> 00:23:56,935
what we're going to try.

608
00:23:56,935 --> 00:24:00,072
But in but for the most part
in clinical practice,

609
00:24:00,406 --> 00:24:03,909
what is done is based on prior
evidence

610
00:24:03,909 --> 00:24:06,619
or prior experience
or the standards in the

611
00:24:06,619 --> 00:24:07,313
community.

612
00:24:08,047 --> 00:24:10,364
In research,
the starting point is

613
00:24:10,364 --> 00:24:11,250
uncertainty.

614
00:24:11,250 --> 00:24:14,453
In other words, we wouldn't
do a clinical trial if we knew,

615
00:24:15,020 --> 00:24:17,082
if we knew that if we're testing
A versus

616
00:24:17,082 --> 00:24:18,490
B and we knew A was better,

617
00:24:18,957 --> 00:24:20,759
why would we do the trial?

618
00:24:20,759 --> 00:24:23,128
So the starting point is we
don't know.

619
00:24:23,128 --> 00:24:24,431
We don't know which one is
better,

620
00:24:24,431 --> 00:24:25,197
which one is safer,

621
00:24:25,197 --> 00:24:26,899
which was more effective,
whatever.

622
00:24:26,899 --> 00:24:28,500
And that's the starting point.

623
00:24:28,500 --> 00:24:30,775
And because of all these
differences

624
00:24:30,775 --> 00:24:31,470
and goals,

625
00:24:31,470 --> 00:24:33,852
methods, justification
for risk and levels of

626
00:24:33,852 --> 00:24:34,540
uncertainty,

627
00:24:34,540 --> 00:24:37,255
we also have different
obligations of the

628
00:24:37,255 --> 00:24:38,977
the players, if you will.

629
00:24:39,211 --> 00:24:42,114
So clinicians have an obligation

630
00:24:42,114 --> 00:24:43,820
to competently offer care and
treatment

631
00:24:43,820 --> 00:24:45,351
in their patient's best
interests.

632
00:24:45,918 --> 00:24:48,087
That's their their obligation.

633
00:24:48,087 --> 00:24:50,949
Whereas researchers have an
obligation

634
00:24:50,949 --> 00:24:53,359
to competently conduct research

635
00:24:53,659 --> 00:24:55,544
while they're respecting the
rights

636
00:24:55,544 --> 00:24:57,429
and welfare of their
participants.

637
00:24:57,896 --> 00:25:00,232
So very different obligations as
well.

638
00:25:01,633 --> 00:25:02,568
So now you get to this

639
00:25:02,568 --> 00:25:04,665
point in my talk, and then we
say, whoa,

640
00:25:04,665 --> 00:25:05,871
that's a lot of stuff.

641
00:25:05,871 --> 00:25:08,107
And what doesn't make any sense.

642
00:25:08,107 --> 00:25:10,909
And I think oftentimes

643
00:25:10,909 --> 00:25:13,487
for investigators,
for people who are involved in

644
00:25:13,487 --> 00:25:14,012
research,

645
00:25:14,012 --> 00:25:18,866
for people who are on IRBs,
they're like, okay, so how do we

646
00:25:18,866 --> 00:25:19,351
know?

647
00:25:19,351 --> 00:25:21,854
How do we really know what to
do?

648
00:25:21,854 --> 00:25:25,663
Do we follow the common rule, or
do we follow the Declaration of

649
00:25:25,663 --> 00:25:26,258
Helsinki,

650
00:25:26,625 --> 00:25:28,537
or do we have to know both or,
you know,

651
00:25:28,537 --> 00:25:29,828
and what if they conflict?

652
00:25:29,828 --> 00:25:32,030
How do we figure out what to do?

653
00:25:32,030 --> 00:25:35,033
So there's a lot of unfortunate
confusion.

654
00:25:35,634 --> 00:25:38,036
And to add to that,

655
00:25:38,036 --> 00:25:41,073
a lot of the guidance
that I've mentioned, the rules

656
00:25:41,073 --> 00:25:43,558
and the regulations
and the codes of ethics were

657
00:25:43,558 --> 00:25:44,076
developed

658
00:25:44,076 --> 00:25:46,753
in response
to a particular historical

659
00:25:46,753 --> 00:25:47,246
event.

660
00:25:47,246 --> 00:25:49,960
So, as I mentioned,
Nuremberg was response to Nazi

661
00:25:49,960 --> 00:25:50,449
Germany.

662
00:25:50,883 --> 00:25:54,453
Helsinki was a response
to the Nuremberg Code.

663
00:25:54,887 --> 00:25:57,286
Belmont was a response to
Tuskegee,

664
00:25:57,286 --> 00:25:58,657
among other things.

665
00:25:58,657 --> 00:26:01,860
But, I mean, each of them
sort of came about historically

666
00:26:01,860 --> 00:26:04,363
because of something that had
happened

667
00:26:04,363 --> 00:26:06,865
and therefore their their main
focus,

668
00:26:06,865 --> 00:26:10,330
focus is often
in response to that historical

669
00:26:10,330 --> 00:26:10,869
event.

670
00:26:13,172 --> 00:26:13,972
The end

671
00:26:13,972 --> 00:26:16,445
result is that different
regulations

672
00:26:16,445 --> 00:26:17,476
and different,

673
00:26:17,876 --> 00:26:20,646
guidance sometimes come into not
conflict,

674
00:26:20,646 --> 00:26:22,426
but have different
interpretations

675
00:26:22,426 --> 00:26:24,049
or emphasize different things.

676
00:26:24,283 --> 00:26:27,286
And so understanding them,
there's some divergence.

677
00:26:27,686 --> 00:26:30,882
And I also mentioned already
that different, regulations

678
00:26:30,882 --> 00:26:31,623
might apply.

679
00:26:32,057 --> 00:26:34,447
So for example,
if you're a NIH funded

680
00:26:34,447 --> 00:26:35,327
investigator,

681
00:26:35,594 --> 00:26:39,375
you are you have to follow the
common rule

682
00:26:39,375 --> 00:26:40,365
45 CFR 46.

683
00:26:40,599 --> 00:26:44,369
If you're an NIH investigator
and you're developing a product

684
00:26:44,369 --> 00:26:46,738
that you want to ultimately
get approved by the FDA,

685
00:26:46,738 --> 00:26:49,374
you also have to follow
the FDA regulations.

686
00:26:49,374 --> 00:26:52,382
If you're an NIH investigator
following common rule and FDA

687
00:26:52,382 --> 00:26:53,045
regulations,

688
00:26:53,312 --> 00:26:56,982
and you want to get your paper
published in the journal,

689
00:26:57,616 --> 00:26:58,968
you have to follow the
Declaration

690
00:26:58,968 --> 00:26:59,485
of Helsinki.

691
00:26:59,485 --> 00:27:01,572
In fact, many journals ask you
to say

692
00:27:01,572 --> 00:27:02,588
you have followed

693
00:27:02,588 --> 00:27:05,023
the Declaration of Helsinki,
so you have to know what it is.

694
00:27:05,023 --> 00:27:07,143
So all of these things are
important

695
00:27:07,143 --> 00:27:08,026
to know about.

696
00:27:08,694 --> 00:27:12,637
But now I'm going to take you
to a different place because I

697
00:27:12,637 --> 00:27:13,031
think

698
00:27:13,732 --> 00:27:16,902
recognizing the number of
different,

699
00:27:16,902 --> 00:27:19,737
guidances and regulations
and the confusion that they

700
00:27:19,737 --> 00:27:20,539
might generate

701
00:27:20,973 --> 00:27:24,543
led us 20 some odd years ago to
develop a

702
00:27:24,877 --> 00:27:27,078
what we called a systematic,
coherent,

703
00:27:27,078 --> 00:27:29,047
universally applicable
framework.

704
00:27:29,047 --> 00:27:31,149
And this is the framework
that you're going to

705
00:27:31,149 --> 00:27:34,536
learn about now and hear
about repeatedly throughout the

706
00:27:34,536 --> 00:27:35,020
course.

707
00:27:35,521 --> 00:27:37,656
And this framework has eight
principles.

708
00:27:38,757 --> 00:27:39,057
You can

709
00:27:39,057 --> 00:27:41,885
see what they are collaborative
partnership, valuable scientific

710
00:27:41,885 --> 00:27:42,327
question,

711
00:27:42,828 --> 00:27:45,821
valid scientific methodology,
fair subject or participant

712
00:27:45,821 --> 00:27:46,398
selection,

713
00:27:46,398 --> 00:27:48,200
favorable risk benefit,

714
00:27:48,200 --> 00:27:49,743
independent review, informed
consent,

715
00:27:49,743 --> 00:27:51,203
and respect for enrolled
subjects.

716
00:27:51,537 --> 00:27:54,540
And I'm going to really briefly
say what each of those mean

717
00:27:54,940 --> 00:27:56,842
and why we think it's important.

718
00:27:56,842 --> 00:27:59,845
But also some of the challenges
with it.

719
00:28:00,112 --> 00:28:02,570
So collaborative partnership
basically,

720
00:28:02,570 --> 00:28:04,082
if the goal of research

721
00:28:04,082 --> 00:28:08,001
is to try to improve health,
then we have to realize that it

722
00:28:08,001 --> 00:28:08,654
should be

723
00:28:08,654 --> 00:28:11,614
a partnership with the relevant
partners,

724
00:28:11,614 --> 00:28:13,058
those, for example,

725
00:28:13,058 --> 00:28:15,050
who are responsible for
planning,

726
00:28:15,050 --> 00:28:17,162
conducting and overseeing
research

727
00:28:17,162 --> 00:28:19,274
and integrating the results of
research

728
00:28:19,274 --> 00:28:20,465
into a health system.

729
00:28:20,866 --> 00:28:23,218
The contribution of the various
partners

730
00:28:23,218 --> 00:28:24,336
that are involved,

731
00:28:24,703 --> 00:28:27,706
and collaboration
with existing systems of health.

732
00:28:28,373 --> 00:28:31,843
And this means collaborating
with policymakers,

733
00:28:31,843 --> 00:28:34,484
health systems, community
advisory boards

734
00:28:34,484 --> 00:28:35,514
or communities.

735
00:28:36,014 --> 00:28:39,017
Patient advocates
advocates for research funding,

736
00:28:39,251 --> 00:28:42,497
collaborating investigators,
practicing clinicians,

737
00:28:42,497 --> 00:28:43,388
participants.

738
00:28:43,388 --> 00:28:46,391
I mean, the list could go on,
but thinking about

739
00:28:46,592 --> 00:28:49,628
who are the important partners
in any research endeavor

740
00:28:49,861 --> 00:28:54,132
so that the, research is
responsive

741
00:28:54,132 --> 00:28:57,517
to what partners need
and respects the contributions

742
00:28:57,517 --> 00:28:58,103
of each.

743
00:28:59,071 --> 00:29:00,973
There's a lots of examples of

744
00:29:00,973 --> 00:29:03,887
collaborative partnership,
some probably more effective

745
00:29:03,887 --> 00:29:04,576
than others.

746
00:29:05,310 --> 00:29:08,313
Many studies have community
advisory boards.

747
00:29:08,513 --> 00:29:11,516
There are many advocacy groups.

748
00:29:11,950 --> 00:29:14,528
Like where advocacy for rare
diseases,

749
00:29:14,528 --> 00:29:16,088
the Friends of Cancer,

750
00:29:16,455 --> 00:29:17,940
the Clinical Center, for
example,

751
00:29:17,940 --> 00:29:19,291
has a patient advisory group.

752
00:29:19,291 --> 00:29:21,285
There's a lot of different
examples

753
00:29:21,285 --> 00:29:22,995
of the kinds of collaboration

754
00:29:22,995 --> 00:29:25,097
that, makes sense.

755
00:29:25,097 --> 00:29:27,532
But collaboration is also
complex.

756
00:29:27,532 --> 00:29:30,669
If you go, for example, to a

757
00:29:30,669 --> 00:29:33,173
recent issue of the New England
Journal

758
00:29:33,173 --> 00:29:34,072
and just look

759
00:29:34,072 --> 00:29:37,075
at some of the randomized trials
that might be reported in there.

760
00:29:37,309 --> 00:29:40,850
You know, sometimes you'll see a
study

761
00:29:40,850 --> 00:29:42,714
that has 40 authors

762
00:29:43,415 --> 00:29:46,618
and was done in 83 countries
with, you know,

763
00:29:47,686 --> 00:29:51,156
600 sites and 10,000 people.

764
00:29:51,757 --> 00:29:55,746
And that, you know, in one way,
they're all collaborators,

765
00:29:55,746 --> 00:29:56,228
right?

766
00:29:56,228 --> 00:29:59,911
But that's a huge, complex
mass of people to try to figure

767
00:29:59,911 --> 00:30:00,165
out

768
00:30:00,165 --> 00:30:02,934
how to collaborate with.
So it's challenging.

769
00:30:02,934 --> 00:30:04,756
So the challenges are
identifying

770
00:30:04,756 --> 00:30:05,971
who the partners are,

771
00:30:05,971 --> 00:30:10,008
who are the right partners are,
and then how to engage them.

772
00:30:11,076 --> 00:30:12,811
There's a lot of information,

773
00:30:12,811 --> 00:30:14,653
a lot of literature now on
patient

774
00:30:14,653 --> 00:30:16,982
engagement, engagement, public
engagement,

775
00:30:16,982 --> 00:30:20,619
community based engagement,
all really important concepts,

776
00:30:20,919 --> 00:30:23,236
but all over the map in terms of
what

777
00:30:23,236 --> 00:30:25,490
that mode of engagement looks
like.

778
00:30:27,459 --> 00:30:30,362
The second principle is valuable
scientific question.

779
00:30:30,362 --> 00:30:34,666
And this, we often talk about
in our world as social value.

780
00:30:35,000 --> 00:30:37,669
And basically this

781
00:30:37,669 --> 00:30:39,538
what this is, is that

782
00:30:39,538 --> 00:30:41,644
the question has to be worth
asking,

783
00:30:41,644 --> 00:30:43,809
how are we going to learn
something?

784
00:30:43,809 --> 00:30:46,044
Are we going to learn something
that's useful to somebody?

785
00:30:46,044 --> 00:30:48,490
If the goal is to find useful
information

786
00:30:48,490 --> 00:30:49,981
to understand or improve

787
00:30:49,981 --> 00:30:53,385
human health, is the question
that we're asking in this study

788
00:30:53,952 --> 00:30:56,955
or in this program of research
going to do that?

789
00:30:57,622 --> 00:31:00,201
So it should answer valuable
question,

790
00:31:00,201 --> 00:31:01,626
one that can or will

791
00:31:02,027 --> 00:31:04,536
generate new knowledge or
understanding

792
00:31:04,536 --> 00:31:06,531
about human health or illness.

793
00:31:06,898 --> 00:31:08,711
And that could be socially
valuable,

794
00:31:08,711 --> 00:31:09,768
clinically valuable,

795
00:31:09,768 --> 00:31:11,303
or scientifically valuable.

796
00:31:14,239 --> 00:31:15,841
We often ask,

797
00:31:15,841 --> 00:31:18,247
you know, then what is the value
of answering a specific

798
00:31:18,247 --> 00:31:18,677
question?

799
00:31:18,677 --> 00:31:20,927
It's not always so easy to
judge,

800
00:31:20,927 --> 00:31:21,813
but thinking

801
00:31:21,813 --> 00:31:23,468
carefully about what will we
learn

802
00:31:23,468 --> 00:31:24,783
and how useful will it be?

803
00:31:25,016 --> 00:31:27,753
How will we know if it's useful,

804
00:31:27,753 --> 00:31:30,756
and to whom will the knowledge
be useful?

805
00:31:30,756 --> 00:31:33,759
Is it to the participants in the
study?

806
00:31:34,025 --> 00:31:35,060
Sometimes it is.

807
00:31:35,060 --> 00:31:36,928
Is it to the community in which
they live?

808
00:31:36,928 --> 00:31:39,231
Is it to people with similar
conditions?

809
00:31:39,231 --> 00:31:42,901
Future people, society
in general, science sponsors?

810
00:31:42,901 --> 00:31:44,600
I mean, it could be lots of
answers

811
00:31:44,600 --> 00:31:46,638
to the question, but trying to
figure out

812
00:31:46,638 --> 00:31:49,641
what the value is of a specific
study,

813
00:31:50,142 --> 00:31:53,145
there is room for more.

814
00:31:54,312 --> 00:31:55,614
Work on this topic.

815
00:31:55,614 --> 00:31:57,883
And there was
a, I think, a very important,

816
00:31:59,684 --> 00:32:01,419
issue of bioethics

817
00:32:01,419 --> 00:32:04,368
of eight years ago
that tried to ask the question

818
00:32:04,368 --> 00:32:04,790
about,

819
00:32:05,190 --> 00:32:06,855
you know, what really is social
value

820
00:32:06,855 --> 00:32:08,160
and how do we understand it?

821
00:32:08,160 --> 00:32:10,428
And there were
a number of important questions.

822
00:32:10,428 --> 00:32:13,799
I mean, papers in that volume.

823
00:32:13,799 --> 00:32:16,802
This is one from people in our
group

824
00:32:16,802 --> 00:32:18,770
who were defending the social
value

825
00:32:18,770 --> 00:32:20,739
requirement, another from a
person

826
00:32:20,739 --> 00:32:23,975
in our group who was questioning
the social value requirement

827
00:32:24,209 --> 00:32:27,212
and thinking about the limits of
it.

828
00:32:27,479 --> 00:32:29,518
People have built on this, and
there was

829
00:32:29,518 --> 00:32:31,149
a, I think, a very useful paper

830
00:32:31,149 --> 00:32:35,594
in the Hastings Center, in 2018
by Danny Winter, who talked

831
00:32:35,594 --> 00:32:36,121
about,

832
00:32:36,121 --> 00:32:38,476
you know, how to think about
social value

833
00:32:38,476 --> 00:32:39,624
in a different way.

834
00:32:40,458 --> 00:32:43,188
And then there have been people
like one of my fellows and I

835
00:32:43,188 --> 00:32:43,461
wrote

836
00:32:43,461 --> 00:32:48,107
a, paper for a chapter
for a book recently which tried

837
00:32:48,107 --> 00:32:48,967
to select

838
00:32:48,967 --> 00:32:52,777
cases to try to exemplify
what value means in specific

839
00:32:52,777 --> 00:32:53,271
cases.

840
00:32:53,271 --> 00:32:55,810
And we picked what we called
high value

841
00:32:55,810 --> 00:32:58,610
cases or low value cases as a
exploration.

842
00:32:59,811 --> 00:33:02,210
So that's a lot more to be done
about what

843
00:33:02,210 --> 00:33:03,181
social value is.

844
00:33:03,181 --> 00:33:05,951
But you'll hear it throughout
this course.

845
00:33:05,951 --> 00:33:08,987
The third is valid scientific
methodology.

846
00:33:09,387 --> 00:33:10,956
So you've got partners in place.

847
00:33:10,956 --> 00:33:13,258
You've got a question. It's
worth asking.

848
00:33:13,258 --> 00:33:16,494
The next real important
ethical requirement

849
00:33:16,862 --> 00:33:20,003
is setting up the study so that
it's valid

850
00:33:20,003 --> 00:33:21,199
so that you get

851
00:33:21,800 --> 00:33:25,203
reliable, understandable
information

852
00:33:25,203 --> 00:33:27,744
that you can make sense out of,
that you can answer the

853
00:33:27,744 --> 00:33:28,206
question.

854
00:33:28,540 --> 00:33:31,810
That doesn't mean
it has to be a positive trial.

855
00:33:32,210 --> 00:33:34,520
It just means you have to be
able to know

856
00:33:34,520 --> 00:33:36,548
what the answer to the question
is.

857
00:33:37,649 --> 00:33:39,618
Excuse me when you're done.

858
00:33:39,618 --> 00:33:41,450
And that includes a bunch of
things

859
00:33:41,450 --> 00:33:43,021
like how to design the trial,

860
00:33:43,588 --> 00:33:46,607
what the methods are that you're
going to be using, what's the

861
00:33:46,607 --> 00:33:47,192
statistics,

862
00:33:47,192 --> 00:33:50,061
are you going to be using,
what kind of statistical power?

863
00:33:51,396 --> 00:33:53,832
The goal being

864
00:33:53,832 --> 00:33:56,868
valid, reliable, generalizable

865
00:33:56,868 --> 00:34:01,373
and interpretable
data is also an important part

866
00:34:01,373 --> 00:34:04,643
of valid scientific methodology,
and that is feasibility.

867
00:34:05,176 --> 00:34:08,747
There are some questions
that cannot be answered because

868
00:34:09,180 --> 00:34:10,869
you can't design the study in a
way

869
00:34:10,869 --> 00:34:12,751
that will ever come up with an
answer.

870
00:34:13,485 --> 00:34:17,489
And so making sure
that what you're asking

871
00:34:17,489 --> 00:34:20,659
and how you're designing it is
feasible is an important part

872
00:34:20,659 --> 00:34:24,262
of justifying
asking people to participate.

873
00:34:26,798 --> 00:34:28,839
Sometimes when we talk about
scientific

874
00:34:28,839 --> 00:34:29,467
methodology

875
00:34:29,467 --> 00:34:31,104
as an ethical requirement,
people say,

876
00:34:31,104 --> 00:34:32,871
well, that's science, that's not
ethics.

877
00:34:32,871 --> 00:34:35,265
And so my slide here is just to
tell you,

878
00:34:35,265 --> 00:34:36,841
you can't pull them apart.

879
00:34:37,208 --> 00:34:39,744
They are totally integrated.

880
00:34:39,744 --> 00:34:42,580
And only to make something

881
00:34:42,580 --> 00:34:45,103
ethically
okay has to be scientifically

882
00:34:45,103 --> 00:34:45,750
rigorous.

883
00:34:45,750 --> 00:34:47,346
And something that's
scientifically

884
00:34:47,346 --> 00:34:48,987
rigorous should be ethical as
well.

885
00:34:50,188 --> 00:34:51,530
There's
a number of different

886
00:34:51,530 --> 00:34:52,223
considerations

887
00:34:52,223 --> 00:34:55,660
in thinking about scientific,
validity.

888
00:34:56,127 --> 00:34:58,730
And these are just some
examples.

889
00:34:58,730 --> 00:35:01,132
Choosing the endpoints, you
know, as

890
00:35:01,132 --> 00:35:03,601
how do you measure a

891
00:35:03,601 --> 00:35:06,605
the effect of an anti viral or,

892
00:35:07,205 --> 00:35:10,021
or a vaccines antibodies
or is it infection or is it

893
00:35:10,021 --> 00:35:10,508
disease.

894
00:35:10,508 --> 00:35:12,777
And it matters
in terms of numbers of people.

895
00:35:12,777 --> 00:35:16,715
You would need certainty
at the end of the study etc.

896
00:35:17,582 --> 00:35:19,851
when these randomized

897
00:35:19,851 --> 00:35:22,554
double blind placebo controlled
trial

898
00:35:22,554 --> 00:35:24,920
and do you make trials
noninferiority

899
00:35:24,920 --> 00:35:26,391
or superiority trials?

900
00:35:26,825 --> 00:35:29,961
When do you use qualitative
and quantitative methods?

901
00:35:30,462 --> 00:35:32,197
How do you measure the outcome?

902
00:35:32,197 --> 00:35:33,447
What's the measure of the
outcome

903
00:35:33,447 --> 00:35:35,000
that you're going to build into
a study?

904
00:35:35,000 --> 00:35:36,601
How long do you follow people?

905
00:35:36,601 --> 00:35:37,802
What kind of power do you need?

906
00:35:37,802 --> 00:35:40,939
What kind of sample sizes,
what what other

907
00:35:40,939 --> 00:35:43,942
methods of statistical methods
do you need, etc..

908
00:35:43,942 --> 00:35:46,344
So those are all interesting,
important questions.

909
00:35:46,344 --> 00:35:48,513
And there's been some cartoons
out there.

910
00:35:48,513 --> 00:35:50,615
There's the control group
and the out of control group.

911
00:35:51,683 --> 00:35:53,952
The placebo

912
00:35:53,952 --> 00:35:56,955
member who died, member placebo
group.

913
00:35:57,455 --> 00:36:00,258
And this one I think is really
fun.

914
00:36:00,258 --> 00:36:03,395
You know, the the.

915
00:36:03,395 --> 00:36:05,463
Possible modes of statistics

916
00:36:05,463 --> 00:36:08,566
that can be mis, misused.

917
00:36:08,566 --> 00:36:10,402
So all of that's important.

918
00:36:10,402 --> 00:36:12,061
There's also a really
interesting

919
00:36:12,061 --> 00:36:13,772
challenge is right now that
we're

920
00:36:13,772 --> 00:36:17,008
sort of learning more
about decentralized trials,

921
00:36:17,776 --> 00:36:20,011
pragmatic trials, platform

922
00:36:20,011 --> 00:36:23,662
trials, and secondary
analysis of data specimens, all

923
00:36:23,662 --> 00:36:24,282
of which

924
00:36:24,282 --> 00:36:28,420
have methods that are different
from the sort of standard one,

925
00:36:28,787 --> 00:36:31,589
you know, in person,
randomized controlled trial.

926
00:36:31,589 --> 00:36:35,193
But require some very careful
thought

927
00:36:35,193 --> 00:36:38,630
about how to set it up
so that it's rigorous, valid,

928
00:36:38,997 --> 00:36:42,000
and you'll get interpretable
data and feasible.

929
00:36:43,134 --> 00:36:44,632
You'll hear about some of these,
but

930
00:36:44,632 --> 00:36:46,337
I don't have time to go over
them today.

931
00:36:47,138 --> 00:36:50,030
Fair subject selection
or participant selection is

932
00:36:50,030 --> 00:36:50,608
basically

933
00:36:51,376 --> 00:36:52,710
what it sounds like.

934
00:36:52,710 --> 00:36:56,938
And then the main issue
is that the scientific

935
00:36:56,938 --> 00:36:57,949
objectives

936
00:36:58,249 --> 00:37:01,352
should guide inclusion criteria,

937
00:37:01,352 --> 00:37:04,322
recruitment strategies and
selection.

938
00:37:04,322 --> 00:37:06,912
And this is based you know,
some of this is in the Belmont

939
00:37:06,912 --> 00:37:07,225
Report

940
00:37:07,225 --> 00:37:11,162
based on a response to previous
kinds of research that were done

941
00:37:11,529 --> 00:37:14,966
where privilege or easy
availability

942
00:37:14,966 --> 00:37:17,502
or vulnerability were used as
criteria

943
00:37:17,502 --> 00:37:19,170
for select participants.

944
00:37:19,170 --> 00:37:19,971
And those are all,

945
00:37:22,107 --> 00:37:24,542
wrong criteria.

946
00:37:24,542 --> 00:37:27,512
There is a Dave Wendler
who you're going to hear from

947
00:37:27,912 --> 00:37:29,876
the course, talks about flipping
it

948
00:37:29,876 --> 00:37:31,783
on a side and saying the best
way

949
00:37:31,783 --> 00:37:36,214
to think about fair participant
selection is to say there is no

950
00:37:36,214 --> 00:37:36,988
exclusion.

951
00:37:36,988 --> 00:37:39,924
Everybody's,

952
00:37:39,924 --> 00:37:42,961
eligible without justification.

953
00:37:43,294 --> 00:37:44,362
And so then you might say, well,

954
00:37:44,362 --> 00:37:46,856
what are the justifications that
sometimes could be used to

955
00:37:46,856 --> 00:37:47,532
exclude people?

956
00:37:47,832 --> 00:37:49,762
Sometimes it's that they're
scientifically

957
00:37:49,762 --> 00:37:51,002
inappropriate, can't study

958
00:37:51,236 --> 00:37:52,793
treatment of breast cancer and
people that

959
00:37:52,793 --> 00:37:54,239
don't have breast cancer, for
example.

960
00:37:54,806 --> 00:37:56,341
Now sometimes it's risk.

961
00:37:56,341 --> 00:37:59,310
And that's contentious,
but also very important

962
00:37:59,310 --> 00:38:01,805
if the risk is too high
for a certain group of people,

963
00:38:01,805 --> 00:38:02,313
maybe it's

964
00:38:02,580 --> 00:38:05,416
appropriate and justifiable
to exclude them

965
00:38:05,416 --> 00:38:08,253
little even more.

966
00:38:08,253 --> 00:38:10,455
Controversy about vulnerability.

967
00:38:10,455 --> 00:38:12,204
Some people say you should
exclude people

968
00:38:12,204 --> 00:38:13,057
who are vulnerable,

969
00:38:13,057 --> 00:38:14,592
and I'll talk about that again
in a minute.

970
00:38:14,592 --> 00:38:16,861
But, again, it's contentious.

971
00:38:18,096 --> 00:38:19,063
It's also a part of

972
00:38:19,063 --> 00:38:22,567
their participant selection
that, has us think about

973
00:38:22,567 --> 00:38:25,627
how do we fairly distribute
the harms and benefits of

974
00:38:25,627 --> 00:38:26,204
research.

975
00:38:26,204 --> 00:38:27,983
In other words, don't always
pick people

976
00:38:27,983 --> 00:38:29,808
with the same people over and
over again

977
00:38:29,808 --> 00:38:31,900
because they then accept all the
risks

978
00:38:31,900 --> 00:38:34,212
without necessarily getting the
benefits.

979
00:38:34,512 --> 00:38:35,613
Don't select a group

980
00:38:35,613 --> 00:38:37,119
that's always going to take
risks

981
00:38:37,119 --> 00:38:38,716
when benefits go to somebody
else.

982
00:38:39,517 --> 00:38:43,060
You know, those kinds of,
considerations are really

983
00:38:43,060 --> 00:38:43,755
important

984
00:38:43,755 --> 00:38:47,058
at the front end
in selecting participants.

985
00:38:47,358 --> 00:38:51,886
And I mentioned this earlier,
but there's a really interesting

986
00:38:51,886 --> 00:38:52,397
switch

987
00:38:52,397 --> 00:38:56,239
that's happened over time where
both of these end up being

988
00:38:56,239 --> 00:38:56,968
important.

989
00:38:56,968 --> 00:39:00,251
But they're but they really are,
historically situated in

990
00:39:00,251 --> 00:39:01,172
different ways.

991
00:39:01,172 --> 00:39:03,648
So research was seen for a long
time

992
00:39:03,648 --> 00:39:04,542
as a burden.

993
00:39:04,909 --> 00:39:08,889
And participants need protection
from that burden or from the

994
00:39:08,889 --> 00:39:09,280
risk.

995
00:39:09,814 --> 00:39:12,984
And as I mentioned earlier,
if it's seen as a benefit,

996
00:39:12,984 --> 00:39:14,919
then people will need access to
research.

997
00:39:14,919 --> 00:39:17,589
And so both of these are still
true.

998
00:39:17,589 --> 00:39:20,542
But the pendulum swings back
and forth a little bit between

999
00:39:20,542 --> 00:39:20,992
the two.

1000
00:39:21,960 --> 00:39:23,928
So I mentioned
protecting vulnerable groups.

1001
00:39:23,928 --> 00:39:25,096
There's a lot of question about

1002
00:39:25,096 --> 00:39:28,145
what does vulnerability
actually mean in the context of

1003
00:39:28,145 --> 00:39:28,700
research.

1004
00:39:29,200 --> 00:39:31,703
And if we protect people

1005
00:39:31,703 --> 00:39:34,706
too much, we keep them out of
and,

1006
00:39:35,106 --> 00:39:37,520
prevent them
from getting the benefits of

1007
00:39:37,520 --> 00:39:38,109
research?

1008
00:39:38,376 --> 00:39:39,410
I'm not sure.

1009
00:39:39,410 --> 00:39:41,923
Is there another session on
vulnerability

1010
00:39:41,923 --> 00:39:42,413
at all?

1011
00:39:43,081 --> 00:39:44,048
Not specifically.

1012
00:39:44,048 --> 00:39:47,318
When it comes up for children.

1013
00:39:47,619 --> 00:39:49,654
Yeah. Okay.

1014
00:39:49,654 --> 00:39:52,590
There's really some challenges
to selecting the appropriate

1015
00:39:52,590 --> 00:39:53,925
participants for a study.

1016
00:39:53,925 --> 00:39:55,919
For example,
this is one that comes up all

1017
00:39:55,919 --> 00:39:56,394
the time.

1018
00:39:56,394 --> 00:39:59,192
Is it preferable to test an
early,

1019
00:39:59,192 --> 00:40:01,332
potentially risky therapy

1020
00:40:01,733 --> 00:40:05,603
in healthy, affected adults
who can give their own consent?

1021
00:40:06,271 --> 00:40:09,274
Or in severely ill infants

1022
00:40:09,607 --> 00:40:12,017
who are otherwise likely to die
as infants

1023
00:40:12,017 --> 00:40:14,312
if they don't get something that
works.

1024
00:40:14,312 --> 00:40:17,448
That's a that's a real dilemma
that has happened in studies.

1025
00:40:17,849 --> 00:40:19,923
Another example of a challenge
is

1026
00:40:19,923 --> 00:40:22,186
when do you enroll pregnant
persons

1027
00:40:22,186 --> 00:40:22,687
in research?

1028
00:40:22,687 --> 00:40:26,424
This is another topic
that could take a whole lecture.

1029
00:40:26,424 --> 00:40:27,292
And sometimes that's

1030
00:40:28,626 --> 00:40:31,001
the next element is favorable
risk

1031
00:40:31,001 --> 00:40:31,629
benefit.

1032
00:40:32,130 --> 00:40:35,533
And the questions really to ask
are risks to subjects necessary

1033
00:40:36,301 --> 00:40:38,494
and are they
minimized to the extent

1034
00:40:38,494 --> 00:40:39,103
possible.

1035
00:40:39,103 --> 00:40:41,090
And then there's a judgment that
all of us

1036
00:40:41,090 --> 00:40:42,840
have to make, both as
investigators,

1037
00:40:42,840 --> 00:40:45,843
research teams, IRB members,
even participants

1038
00:40:46,077 --> 00:40:49,914
are the risks justified by
either

1039
00:40:49,914 --> 00:40:52,737
benefit to the individual
or the social value of the

1040
00:40:52,737 --> 00:40:53,117
study.

1041
00:40:53,785 --> 00:40:56,054
And that's a, you know,
incommensurate.

1042
00:40:56,054 --> 00:40:59,273
And people say evaluation,
but it's an important one to

1043
00:40:59,273 --> 00:40:59,624
make.

1044
00:40:59,957 --> 00:41:02,960
And then many,

1045
00:41:03,161 --> 00:41:06,164
many argue for the need
also to enhance benefits.

1046
00:41:07,031 --> 00:41:08,488
Importantly, as the Belmont
Report

1047
00:41:08,488 --> 00:41:10,201
points out, and as I've
mentioned, only

1048
00:41:10,201 --> 00:41:12,473
a couple of times, sometimes
interests

1049
00:41:12,473 --> 00:41:14,505
other than those of the
subjects.

1050
00:41:14,505 --> 00:41:18,409
In other words, the participants
in the study can justify risks

1051
00:41:18,409 --> 00:41:20,682
as long as the rights of the
participants

1052
00:41:20,682 --> 00:41:21,846
have been protected.

1053
00:41:24,148 --> 00:41:25,683
Lots of challenges.

1054
00:41:25,683 --> 00:41:29,821
One is how do you identify which
which risks and which benefits?

1055
00:41:29,821 --> 00:41:30,922
Account?

1056
00:41:30,922 --> 00:41:33,246
And there's been a lot of
interesting

1057
00:41:33,246 --> 00:41:34,125
debate about,

1058
00:41:34,125 --> 00:41:35,794
you know, in some of the
guidance

1059
00:41:35,794 --> 00:41:37,261
that says we should consider

1060
00:41:37,261 --> 00:41:41,457
physical, psychosocial,
and even economic and legal

1061
00:41:41,457 --> 00:41:42,033
risks,

1062
00:41:42,400 --> 00:41:46,411
but we don't consider physical,
psychosocial, economic and legal

1063
00:41:46,411 --> 00:41:47,038
benefits.

1064
00:41:47,038 --> 00:41:49,707
So how do we deal with that?

1065
00:41:49,707 --> 00:41:51,242
How do we minimize risks.

1066
00:41:51,242 --> 00:41:54,121
And you'll hear from some of
the,

1067
00:41:54,121 --> 00:41:57,348
others that in in protecting
certain

1068
00:41:57,348 --> 00:41:59,627
groups of people, one of them
strategy

1069
00:41:59,627 --> 00:42:01,786
strategies we use is by
regulation.

1070
00:42:01,786 --> 00:42:04,555
We limit the amount of risks
that people can be exposed to.

1071
00:42:04,555 --> 00:42:06,752
That's what happens with
children, with

1072
00:42:06,752 --> 00:42:08,893
pregnant persons and with,
prisoners.

1073
00:42:09,894 --> 00:42:12,611
There's a huge debate about
direct versus

1074
00:42:12,611 --> 00:42:14,532
indirect benefits, you know,

1075
00:42:14,532 --> 00:42:18,302
direct benefits
as the kind of benefit that can

1076
00:42:18,302 --> 00:42:19,926
justify a certain amount of
risks,

1077
00:42:19,926 --> 00:42:20,738
whereas indirect

1078
00:42:20,738 --> 00:42:24,075
benefits like money or access
to good clinicians or,

1079
00:42:24,609 --> 00:42:29,881
access to other kinds of care
may not be the kind of benefit

1080
00:42:29,881 --> 00:42:32,311
that you want to justify a risk
based on,

1081
00:42:32,311 --> 00:42:34,385
but they still happen in
research.

1082
00:42:35,353 --> 00:42:35,853
And then

1083
00:42:35,853 --> 00:42:38,823
determining that level is is a
challenge.

1084
00:42:39,123 --> 00:42:41,014
Just two more, three more, I
guess

1085
00:42:41,014 --> 00:42:42,126
independent review,

1086
00:42:42,593 --> 00:42:44,522
which is ensuring that the
regulatory and

1087
00:42:44,522 --> 00:42:46,497
ethical requirements have been
fulfilled,

1088
00:42:46,864 --> 00:42:51,156
that it's a process that checks
investigator biases and

1089
00:42:51,156 --> 00:42:51,936
conflicts

1090
00:42:52,403 --> 00:42:54,611
and ensures the public that the
research

1091
00:42:54,611 --> 00:42:56,874
is not exploiting individuals or
groups,

1092
00:42:56,874 --> 00:42:59,382
and you're going to learn more
about IRBs

1093
00:42:59,382 --> 00:43:00,178
later today.

1094
00:43:00,945 --> 00:43:03,217
I just wanted to put up the
regulatory

1095
00:43:03,217 --> 00:43:03,815
criteria,

1096
00:43:03,815 --> 00:43:07,952
both in 45 CFR and 21 CFR 56,

1097
00:43:08,252 --> 00:43:10,313
because you can see that they
mimic

1098
00:43:10,313 --> 00:43:12,256
a lot of what I've already said,

1099
00:43:12,790 --> 00:43:15,652
that risks or minimize
justified by anticipated

1100
00:43:15,652 --> 00:43:16,260
benefits,

1101
00:43:16,661 --> 00:43:19,530
even if there only to the
participants

1102
00:43:19,530 --> 00:43:22,989
fair subject selection
and then informed consent is

1103
00:43:22,989 --> 00:43:23,668
adequate.

1104
00:43:23,668 --> 00:43:26,971
And so our next oops forgot
about this.

1105
00:43:29,173 --> 00:43:31,402
Two regulatory bodies you should
know

1106
00:43:31,402 --> 00:43:33,511
about the Office of Human
Research

1107
00:43:33,511 --> 00:43:36,023
Protections, which is the
Department

1108
00:43:36,023 --> 00:43:38,116
of Health and Human Services,

1109
00:43:39,217 --> 00:43:40,118
office

1110
00:43:40,118 --> 00:43:43,688
that oversees research funded by
HHS.

1111
00:43:44,021 --> 00:43:45,776
And then we have an intramural
office

1112
00:43:45,776 --> 00:43:47,625
of Human Subjects research
protection,

1113
00:43:48,025 --> 00:43:51,395
which is the federal wide

1114
00:43:51,395 --> 00:43:54,398
assurance holder
for the intramural program.

1115
00:43:56,501 --> 00:43:57,568
Let me just get that.

1116
00:43:57,568 --> 00:44:00,571
So the next one is informed
consent.

1117
00:44:00,771 --> 00:44:04,075
And this basically is a process
that ensures that individuals

1118
00:44:04,075 --> 00:44:05,943
have the opportunity to decide

1119
00:44:05,943 --> 00:44:07,566
whether they want to participate
or

1120
00:44:07,566 --> 00:44:09,514
continue to participate, and
whether it's

1121
00:44:09,514 --> 00:44:12,517
compatible with their goals,
their interests, their values.

1122
00:44:13,618 --> 00:44:15,660
Many people, when we first put
out this

1123
00:44:15,660 --> 00:44:17,021
framework said, you know,

1124
00:44:17,021 --> 00:44:18,523
what is what makes clinical
research

1125
00:44:18,523 --> 00:44:20,191
ethical and said, oh, informed
consent.

1126
00:44:20,691 --> 00:44:22,928
Well, as you can see, this is
the seventh

1127
00:44:22,928 --> 00:44:24,729
on the list of eight principles.

1128
00:44:24,729 --> 00:44:28,397
So the point being that
you don't ask people to

1129
00:44:28,397 --> 00:44:29,333
participate

1130
00:44:29,700 --> 00:44:32,043
until then,
all of the other things are

1131
00:44:32,043 --> 00:44:32,703
satisfied.

1132
00:44:33,070 --> 00:44:34,472
You have to have a good
question.

1133
00:44:34,472 --> 00:44:37,074
A valid science, scientific
methodology,

1134
00:44:38,109 --> 00:44:39,727
make sure
you understand the risks and

1135
00:44:39,727 --> 00:44:40,111
benefits

1136
00:44:40,111 --> 00:44:43,518
and have an independent review
before you invite people to

1137
00:44:43,518 --> 00:44:44,282
participate.

1138
00:44:45,183 --> 00:44:47,552
And informed consent has a lot
of pieces.

1139
00:44:47,552 --> 00:44:48,753
I think I'm coming next week

1140
00:44:48,753 --> 00:44:50,679
to speak to you in more depth
about it,

1141
00:44:50,679 --> 00:44:52,456
so I'll probably skip this for
now.

1142
00:44:53,057 --> 00:44:55,693
A lot of interesting challenges
right now

1143
00:44:55,693 --> 00:44:58,696
in terms of informed consent,
focusing on

1144
00:45:00,431 --> 00:45:02,767
long, long standing problems,
the quality

1145
00:45:02,767 --> 00:45:05,905
of informed consent,
and how do we assess capacity

1146
00:45:05,905 --> 00:45:06,470
consent.

1147
00:45:06,837 --> 00:45:09,890
But there's also lots of changes
in how we obtain informed

1148
00:45:09,890 --> 00:45:10,575
consent now.

1149
00:45:10,975 --> 00:45:12,998
And some of that is based on
changes

1150
00:45:12,998 --> 00:45:14,178
in research methods.

1151
00:45:16,247 --> 00:45:19,016
The set the eighth of the
principles

1152
00:45:19,016 --> 00:45:21,852
is what's called respect
for enrolled participants.

1153
00:45:21,852 --> 00:45:25,189
And this is probably another one
that needs a lot of attention.

1154
00:45:25,456 --> 00:45:27,391
And here's what I mean by it.

1155
00:45:27,391 --> 00:45:29,353
Early
on, we just developed this

1156
00:45:29,353 --> 00:45:30,027
framework.

1157
00:45:30,027 --> 00:45:31,028
There was this idea,

1158
00:45:31,028 --> 00:45:32,657
as I just mentioned, that some
people say,

1159
00:45:32,657 --> 00:45:34,131
what makes clinical research
ethical?

1160
00:45:34,131 --> 00:45:35,466
When you get your IRB to review
it

1161
00:45:35,466 --> 00:45:36,133
and then you get

1162
00:45:36,133 --> 00:45:39,203
the person's informed consent
and you're done, ethics is done.

1163
00:45:40,004 --> 00:45:41,798
And that just makes no sense at
all,

1164
00:45:41,798 --> 00:45:43,741
because at the beginning of the
trial,

1165
00:45:43,741 --> 00:45:47,315
you're just beginning to engage
with the people that are in the

1166
00:45:47,315 --> 00:45:47,712
study,

1167
00:45:48,045 --> 00:45:51,271
and you have responsibilities,
ethical responsibilities to

1168
00:45:51,271 --> 00:45:52,049
those people.

1169
00:45:52,383 --> 00:45:54,964
And you have ethical
responsibilities

1170
00:45:54,964 --> 00:45:56,220
to the, you know,

1171
00:45:56,220 --> 00:45:58,698
the world in terms of reporting
your data

1172
00:45:58,698 --> 00:46:00,391
and reporting your science.

1173
00:46:00,391 --> 00:46:03,723
So there's a lot that happens
after informed consent is

1174
00:46:03,723 --> 00:46:04,328
obtained.

1175
00:46:04,862 --> 00:46:08,699
And this is just a partial list
protecting confidentiality,

1176
00:46:08,699 --> 00:46:12,213
monitoring welfare, right
to withdraw, providing

1177
00:46:12,213 --> 00:46:13,604
information, etc..

1178
00:46:14,805 --> 00:46:17,408
And there
are some interesting challenges.

1179
00:46:17,408 --> 00:46:18,809
We don't do a good job

1180
00:46:18,809 --> 00:46:20,642
of providing results or
information

1181
00:46:20,642 --> 00:46:22,580
to participants for the
communities.

1182
00:46:22,580 --> 00:46:25,583
After studies are done.

1183
00:46:25,883 --> 00:46:27,385
So this is our framework.

1184
00:46:27,385 --> 00:46:31,022
Systematic, sequential we argue
necessary.

1185
00:46:31,389 --> 00:46:33,363
Sometimes there are waivers of
certain

1186
00:46:33,363 --> 00:46:35,026
of the procedural requirements.

1187
00:46:35,326 --> 00:46:36,460
Universal.

1188
00:46:36,460 --> 00:46:39,697
Although it has to be adapted
to the context,

1189
00:46:40,264 --> 00:46:42,900
it does require balancing
specification

1190
00:46:42,900 --> 00:46:44,807
and judgment, and you'll hear
about that

1191
00:46:44,807 --> 00:46:45,903
throughout the course.

1192
00:46:45,903 --> 00:46:49,810
And we need people informed
investigators, IRB members,

1193
00:46:49,810 --> 00:46:50,307
others

1194
00:46:50,307 --> 00:46:52,091
interested in research to be
able

1195
00:46:52,091 --> 00:46:54,145
to understand what the
principles are

1196
00:46:54,145 --> 00:46:54,945
and how to apply them.