Good morning, everyone in the room and
everywhere else that you're watching from.
As Holly mentioned, I'm going to talk about a
framework
for the ethical conduct of clinical research.
And as Holly already alluded to,
this is a framework that the course is sort of built
on.
So you so the things that I'm going
to talk about in the next 40 minutes,
you're going to hear over and over again
throughout the rest of the course,
and I'll make some references to those.
Before I start, I want to thank Holly
for doing such a great job
of organizing this course.
And Alex, so thank you both.
There's my disclaimer, and I have no conflicts of
interest.
So I think when we think about the ethics
of clinical research,
there are several questions
that sort of big picture questions
we should ask ourselves.
One is the first.
Before I ask any of them,
I want to make sure that we understand
what we're talking about
when we're talking about clinical research,
because there are lots of kinds of
research that we might be interested in.
The ethics of clinical research being research that's about the
health
and humans.
And it's either research to, to understand better the health
of humans
or illness in humans or to intervene,
in prevention or diagnosing or treating.
So that's the domain of research we're talking about.
So that precludes, for example, basic
research,
pre-clinical research, research with non-human animals,
all other kinds of research that's not related to human
health.
So three important questions.
What's the value?
Why do we do research at all?
That's one question to ask.
And then the second and subset of
that is okay, if we do research at all
to try to understand humans, why do we have to include humans
in it?
Why do we have to involve humans?
Experiments on humans.
And if the answer to both of those is,
well,
it's important and we need to involve humans,
then how should we do it in the most ethical manner.
And so I'm going to try to cover each of these very briefly
with respect to
the value.
This is just one example.
This is the NIH website that talks
about the impact of NIH research.
Now, NIH is one funder of research,
happens to be probably
the largest funder, public funder of research in the
world.
But it's just one funder.
But you can see on the the left hand side here,
it talks about
improving health, revolutionizing science
and serving society.
So the value of research is to understand
and improve health.
For sure. That's what we're going to be talking about
mostly.
But there are a couple of other things.
You know, we learn how to do science
better.
We learn new techniques that will
in the future help improve health.
And then there's a way in which, research
actually
has a huge impact on other aspects of society.
So, for example, if you go to that website
on serving society,
it'll talk about the economy value
of doing research.
It's a boon to the economy.
It raises, it in places
where research is funded, the economy is improved.
And by helping people be healthier,
we improve the economy because
people can work.
So there's a lot of ways in which research itself is
valuable.
And this is just,
you know, when I age.
But everywhere else that funds research
or does research
has the same kind of goals.
So what about including humans?
So one thing that's probably true
is that the kinds of results that we get from doing
clinical research have compelling societal health
benefits.
So these are new therapies, diagnostic and preventive
strategies improvement and quality of life,
etc..
I think all of us can probably recognize
examples of people who have survived
from a devastating disease
or not got a devastating disease because of research discoveries.
So, for example, treatments for HIV
have changed the trajectory of HIV
from a rapidly fatal disease to a pretty people
live a normal life with a chronic controlled
disease.
Treatments for childhood leukemia have changed from,
again,
rapid decline in death to 90 plus percent
survival.
Lipid lowering drugs constantly.
I mean, many, many people are on lipid
lowering drugs that that's improved.
Morbidity
and mortality from cardiovascular disease,
vaccines, vaccines for measles, for polio, for,
HPV for Covid, so many others.
So you can
you can sort of think about the kinds of things
that have been shown to work through clinical research
that have made a major impact on the health of society, of
people
and saving lives and improving the quality of
health.
Also,
and this is sort of the same idea,
but in a sort of a more micro level.
When you go to a physician's office
to get treated for something,
you hope that the physician has some evidence upon which
to make a suggestion about what you have
and what to do about it.
And those kinds of that evidence, again,
comes from clinical research.
So most of the, kinds of things that we do
when we go
to a doctor's office is based on research
that have been done in the past.
There's also
a pretty clear understanding that human participation is
necessary
in order to gain accurate and relevant data for humans.
So we do,
the normal trajectory
of research is basic in vivo.
I mean, in vitro, sorry.
Then preclinical in non-human animals.
But most of the non-human animal models are not perfect models
for humans.
And so testing things in humans or
understanding humans as part of research
is, is really important to understand
how humans work and what works in humans.
And that's the reason we do it.
So why is it challenging then?
Okay, research is good.
Humans are necessary.
What's the problem? Right.
The problem is that the primary goal of
doing research is to generate knowledge,
to generate useful knowledge about human health and illness.
It's not to benefit the people that are part of the
study.
Now, that doesn't mean that people in studies don't
benefit.
They often do, but that's not the goal,
and they often don't benefit.
So we're really asking a
small number of people to accept risk and burden
in order to answer important questions
that might be beneficial to others.
And therefore, the people who are being
enrolled in research or participating in research are
the means
to developing useful knowledge and therefore at risk
of being exploited.
There's lots of public
sort of feeling about this issue,
and if you talk to people
who don't know much about research,
they will say,
oh my gosh, you can't do research on humans.
That's, you know, we're making humans
into human guinea pigs.
And, you know, there's a lot of misunderstanding about
the
the goals of research and the reasons
research is done and how it's done.
But there's a lot of feeling about,
not using people as a human.
Guinea pigs.
So the ethics of clinical research
is what I've said.
Made sense so far, really has two really
important,
parts to it or goals to it.
One is that we want to promote responsible
and useful research
that's going to benefit society and future patients.
That's a really important ethical imperative of doing good
clinical research.
At the same time, we want to minimize any harm
and the possibility of exploitation
by protecting the rights
and welfare of the participants, protecting and respecting.
So both of those are important.
And sometimes they come into tension.
By the way, and the ethical requirements
that we are going to learn about
are you're going to learn about in this course.
And some of you might already know some
about how provide guidance
in order to allow this to happen,
to how to ethically conduct research
in order to promote responsible research,
seeking progress,
minimizing exploitation and harm,
or the possibility of ensuring that rights
and welfare of participants are respected
and helping to maintain
the trust of the public in the research enterprise.
So important pieces of it.
So how do we how do we conduct research
ethically?
How do we do that?
How do we promote useful research
to protect the rights and welfare
and maintain public trust?
Well, we've
we've learned over the course of history
through many historical lessons,
some of the things that are important
in terms of how to conduct research
and then we can also sort of go through some ethical reasons.
And I'm going to do a little bit of each.
I'm not going to spend much time on history because
later
Susan Lederer is going to speak to you.
And she's a historian.
She's a historian that's done
a huge amount of work on the history
of the ethics of research.
And so let her give you the specific examples.
And she's a wonderful lecturer as well.
But years ago, Dick Emanuel and I wrote a paper,
which is, which was rewritten for the textbook Oxford Textbook
of Clinical Research Ethics in 2008,
which tried to divide the ethics
of clinical research historically into different eras
and just briefly, to give you a sense of how this
went.
You know, for a long time, hundreds of years, there were no
rules,
there were no guidelines, there were no,
limits on what people could do.
And in fact, there wasn't much money or,
there weren't many resources for clinical research either.
So research was often done by individual scientists or
clinicians
who had some extra time or money,
but mostly with the motive
of trying to benefit the individuals
that they were responsible for.
And because there were so few guidelines,
there was a lot of, you know,
sometimes the experiments were worse
than no experiment,
and there was a lot of, negative outcomes
rather than only positive that
when there was more money and more resources and more
attention
to research, research, excuse me, and the value of
research,
we went into what people have, in
retrospect, called a very utilitarian era
where people who were marginalized,
captive,
unimportant to society were asked to participate in
research
that was seen as good for the common good,
good for the majority.
And you'll hear about some of those examples from
Susan later.
And probably, you know, some of them
anyway, from history
that led to an era of scrutiny,
some of the exposure of those kinds of experiments
done
with prisoners and orphans and other
very vulnerable people, people, you know,
the scientific and the way communities
started to say, what are we doing?
You know, what is what is happening
with this research?
And so there was intense scrutiny, driven
by a couple of very, public cases
that led to questions about what the limits
and the scope of clinical research
ought to be.
And from that scrutiny, there were derived a number of
rules
and regulations which emphasized and have focused on protection
of the participants, protection of human participants and
research.
And so you'll see, or maybe, you know, a lot of the rules
and regulations have that as their primary
focus,
I'd say in the last
now almost 30, 30 years, I guess there's been
a little bit of a pendulum swing in the sense that,
clinical research is recognized as a benefit,
that a benefit sometimes to people
who want to be in clinical trials
because it's a way for them to access
experimental drugs that they couldn't get
elsewhere.
Elsewhere.
Excuse me, but also benefit for
populations.
So there's been, for example, recognition
that children have been
what some people call therapeutic orphans
because there's been insufficient
amount of research to generate evidence
on how to treat children appropriately
and therefore including them in research is a benefit,
because then we learn how to treat children.
So that's been,
a very important insight that's happened
over the last 30 or so years.
During this time, and currently there are
there there were derived a number of codes
and guidelines and regulations that guide clinical research.
Some of these you've probably heard from,
I've heard about excuse me.
And I'm just going to mention a few of them just briefly.
The Nuremberg Code was the code that was written at the end of
World
War two, when there was a trial of the Nazi doctors who did a
number
of experiments on prisoners, Nazi prisoners of World War Two.
The Declaration of Helsinki
followed 15 years almost later
by the World Medical Association,
because it began to realize that
although the the sort of tenets of the Nuremberg Code were
important,
they didn't apply.
So obviously to research that was done by doctors with
patients
to try to improve the understanding
of what patients need.
And so the Declaration of Helsinki in 64,
started was by doctors for doctors
about how to do research with patients and people who are
ill.
That declaration
has been revised multiple times.
The most recent published version is 2013.
But there is a they are in the process
of revising it at this moment.
There's been a number of, meetings around the world,
actually, to,
consultant consultancies to try to get that, revised
again.
So we'll see a new declaration of Helsinki.
I'm assuming this year
the Belmont Report was a report from the Nash,
the United States National Commission
for the Protection
of Participants of Medical and Behavioral Research, which
which was a commission that was put into place
after the exposure of the Tuskegee
Public Health Service, syphilis studies,
which you're going
to hear more about later and you probably have already
heard about
the Belmont Report, is is a
it's not a,
set of rules.
It's a explication of the underlying principles
for the ethics of clinical research.
And it's it's a very useful, document.
It's also short, it's easy to read,
and it is the basis
on which our regulations have been made.
And I'll come to that in a minute.
The Sims is the Council of International
Organization of Medical Sciences,
which has collaborated over the years
with the World Health Organization
to provide international guidelines.
And those guidelines, they originally took the
the goal that they took was to take the principles
that were enunciated in the Declaration of Helsinki
and apply them specifically to the kind of research
that's sponsored by a resource rich country and conducted
in a research poorer country, resource,
poorer countries, excuse me.
And they're one of the things that I really like about the
science
guidelines is not only do they have tenets
which all these others do too, but they explain them.
They have many paragraphs of explanation.
Why do they think this is important,
how you would actually implement it?
So it's a useful document to look at for
more than just international research.
And then the OECD is
International Conference on Harmonization
Good Clinical Practice guidelines.
So the International Conference on Harmonization was a group
that got together in the 1990s to say,
well, we're doing clinical research
all around the world when we do
research in the United States, and then we want to adopt the
findings
in the European Union, it has to go
through the whole process all over again.
So there was an effort to harmonize those regulations.
So that research that was done in one
jurisdiction could be accepted
by another jurisdiction by the regulatory authorities.
And it
documents has multiple, multiple volumes
about multiple things related to how to do clinical
research.
One important guidance from for how to do research
ethically is the good clinical practice
guidelines.
And that, that has become in many jurisdictions around the
world,
the guiding regulatory framework for
how research is done in that jurisdiction.
So in addition to codes and guidelines,
we have regulations.
So in the United States we have the common rule
which is a set of regulations about how to protect
participants in research that is
adopted, has been adopted by
the 17 US federal agencies,
one of which is the Department of Health
and Human Services and the Department
of Health and Human Services, which is the agency that NIH
belongs to.
Uses the common rule, which is found at us
at 45, Code of Federal Regulations,
not 46.
And you know that you might say, well,
who cares about that?
But you'll find around here, for example,
people say, well, what is 45 CFR 46?
Say, and you have to know what that means.
Okay.
That's that's the common rule.
Interestingly,
the FDA, Food and Drug Administration
has their own set of regulations
that are not they don't they don't fall under the common
rule.
And they have a set of regulations,
several sets of regulations
which are relevant to the ethics of doing research.
Most relevant are probably
the ones found at 21 CFR 50 and 56.
And they're very similar to what
you see in 45 CFR 46, but not identical.
And so it's important to think about the differences
there.
And if somebody is developing a product
that will ultimately want to,
apply for FDA approval,
then they have to follow the FDA regs
in addition to the regulations that govern the agencies.
There are often or maybe usually
institutional policies that, people have to adhere to.
So the NIH, for example, has a number of policies about
who to include and how research ought to be
done
ethically that are, relevant to research
that's funded by or done within the NIH.
And, Holly mentioned earlier that,
you know, most of our focus is domestic,
but many research projects in these
in this day are done across borders.
And so there are laws and jurisdiction
regulations in many, many other jurisdictions that are also
relevant.
If somebody is doing research that's funded by the NIH,
it doesn't matter where it's being done.
They still have to follow when I rules,
but they may also have to follow the
the laws and regulations of the jurisdiction in which
they're
conducting their research.
So lots of details.
I went over that pretty fast.
I do want to focus just a moment on what the Belmont Report does
include,
because I think I mentioned it's it's
not a code in the same way as the others,
but it has ethical principles underlying the conduct of
research
and explicates them what they are
and how they apply so respect for persons.
They apply to the process of informed
consent, beneficence,
to the process of assessing risks and benefits, and research
and justice to the process of selecting participants
fairly.
And you're going to hear about all of those more.
The other thing, important thing,
I think that the Belmont Report does,
and very few of these other documents
do, is describe the distinction
and the boundaries between clinical practice and clinical
research.
And interestingly,
when you think about the kinds of ethical issues
or tensions that come up in a clinical research
environment,
they often are because of tension
or confusion about these boundaries.
So I wanted to spend one minute talking about what I mean by
that.
So the difference between clinical
research and clinical practice
is multifold.
First of all, there are different goals.
And I've already mentioned that
the goal of clinical research is to answer
useful, generalizable questions.
The goal of clinical practice is to help
the peop, the person or the people in
front of you based on evidence that you've
that somebody else collected before
and also use different methods.
So in research you may be aware and you will hear more about
we randomized people.
We randomized people to get this drug
or that drug.
We blind them, meaning they're not allowed
to know what they're getting.
Sometimes the investigator doesn't know what they're
getting either.
That's a double blind.
We offer placebos as one part of a control group.
That's very common in research.
We do, dose escalation in trials.
So, you know, these three people will get this
dose.
The next three people will get a higher dose.
So there's a number of really important
methodology in research that are critical to,
getting good unbiased data
that you would find anathema in clinical practice.
So if you went to your doctor's office
with a sore throat and your doctor said,
I'm going to give you a drug, but
I'm not going to tell you what it is.
I don't even know what it is you would be like,
I think I need a new doctor.
So I think there is really an interesting
dichotomy between
the methods that are common to each of those
domains.
There's also different justification for
risk.
So in clinical practice, certainly
people absorb accept whatever risk.
There's risks with interventions of all kinds.
But those risks are justified because they
the, benefit that is presumed to be happening
by giving this intervention outweighs the risk.
And so the risk is worth it for that individual.
In research, we ask people sometimes
to do things for which there are no benefits
then.
So we may ask them, for example, to have an extra biopsy
or an extra blood draw or an extra X-ray,
or to take a drug
just to get a pharmacokinetic, reading on it.
Those are things that are done for no benefit to those
individuals,
and they accept those risks for the
for the,
interests of science.
There are also different levels of uncertainty.
Again, not everything in clinical practice
is certain for sure.
People we we often have to say, well,
here's what we know.
Here's what we don't know, here's
what we're going to try.
But in but for the most part in clinical practice,
what is done is based on prior evidence
or prior experience or the standards in the
community.
In research, the starting point is
uncertainty.
In other words, we wouldn't do a clinical trial if we knew,
if we knew that if we're testing A versus
B and we knew A was better,
why would we do the trial?
So the starting point is we don't know.
We don't know which one is better,
which one is safer,
which was more effective, whatever.
And that's the starting point.
And because of all these differences
and goals,
methods, justification for risk and levels of
uncertainty,
we also have different obligations of the
the players, if you will.
So clinicians have an obligation
to competently offer care and treatment
in their patient's best interests.
That's their their obligation.
Whereas researchers have an obligation
to competently conduct research
while they're respecting the rights
and welfare of their participants.
So very different obligations as well.
So now you get to this
point in my talk, and then we say, whoa,
that's a lot of stuff.
And what doesn't make any sense.
And I think oftentimes
for investigators, for people who are involved in
research,
for people who are on IRBs, they're like, okay, so how do we
know?
How do we really know what to do?
Do we follow the common rule, or do we follow the Declaration of
Helsinki,
or do we have to know both or, you know,
and what if they conflict?
How do we figure out what to do?
So there's a lot of unfortunate confusion.
And to add to that,
a lot of the guidance that I've mentioned, the rules
and the regulations and the codes of ethics were
developed
in response to a particular historical
event.
So, as I mentioned, Nuremberg was response to Nazi
Germany.
Helsinki was a response to the Nuremberg Code.
Belmont was a response to Tuskegee,
among other things.
But, I mean, each of them sort of came about historically
because of something that had happened
and therefore their their main focus,
focus is often in response to that historical
event.
The end
result is that different regulations
and different,
guidance sometimes come into not conflict,
but have different interpretations
or emphasize different things.
And so understanding them, there's some divergence.
And I also mentioned already that different, regulations
might apply.
So for example, if you're a NIH funded
investigator,
you are you have to follow the common rule
45 CFR 46.
If you're an NIH investigator and you're developing a product
that you want to ultimately get approved by the FDA,
you also have to follow the FDA regulations.
If you're an NIH investigator following common rule and FDA
regulations,
and you want to get your paper published in the journal,
you have to follow the Declaration
of Helsinki.
In fact, many journals ask you to say
you have followed
the Declaration of Helsinki, so you have to know what it is.
So all of these things are important
to know about.
But now I'm going to take you to a different place because I
think
recognizing the number of different,
guidances and regulations and the confusion that they
might generate
led us 20 some odd years ago to develop a
what we called a systematic, coherent,
universally applicable framework.
And this is the framework that you're going to
learn about now and hear about repeatedly throughout the
course.
And this framework has eight principles.
You can
see what they are collaborative partnership, valuable scientific
question,
valid scientific methodology, fair subject or participant
selection,
favorable risk benefit,
independent review, informed consent,
and respect for enrolled subjects.
And I'm going to really briefly say what each of those mean
and why we think it's important.
But also some of the challenges with it.
So collaborative partnership basically,
if the goal of research
is to try to improve health, then we have to realize that it
should be
a partnership with the relevant partners,
those, for example,
who are responsible for planning,
conducting and overseeing research
and integrating the results of research
into a health system.
The contribution of the various partners
that are involved,
and collaboration with existing systems of health.
And this means collaborating with policymakers,
health systems, community advisory boards
or communities.
Patient advocates advocates for research funding,
collaborating investigators, practicing clinicians,
participants.
I mean, the list could go on, but thinking about
who are the important partners in any research endeavor
so that the, research is responsive
to what partners need and respects the contributions
of each.
There's a lots of examples of
collaborative partnership, some probably more effective
than others.
Many studies have community advisory boards.
There are many advocacy groups.
Like where advocacy for rare diseases,
the Friends of Cancer,
the Clinical Center, for example,
has a patient advisory group.
There's a lot of different examples
of the kinds of collaboration
that, makes sense.
But collaboration is also complex.
If you go, for example, to a
recent issue of the New England Journal
and just look
at some of the randomized trials that might be reported in there.
You know, sometimes you'll see a study
that has 40 authors
and was done in 83 countries with, you know,
600 sites and 10,000 people.
And that, you know, in one way, they're all collaborators,
right?
But that's a huge, complex mass of people to try to figure
out
how to collaborate with. So it's challenging.
So the challenges are identifying
who the partners are,
who are the right partners are, and then how to engage them.
There's a lot of information,
a lot of literature now on patient
engagement, engagement, public engagement,
community based engagement, all really important concepts,
but all over the map in terms of what
that mode of engagement looks like.
The second principle is valuable scientific question.
And this, we often talk about in our world as social value.
And basically this
what this is, is that
the question has to be worth asking,
how are we going to learn something?
Are we going to learn something that's useful to somebody?
If the goal is to find useful information
to understand or improve
human health, is the question that we're asking in this study
or in this program of research going to do that?
So it should answer valuable question,
one that can or will
generate new knowledge or understanding
about human health or illness.
And that could be socially valuable,
clinically valuable,
or scientifically valuable.
We often ask,
you know, then what is the value of answering a specific
question?
It's not always so easy to judge,
but thinking
carefully about what will we learn
and how useful will it be?
How will we know if it's useful,
and to whom will the knowledge be useful?
Is it to the participants in the study?
Sometimes it is.
Is it to the community in which they live?
Is it to people with similar conditions?
Future people, society in general, science sponsors?
I mean, it could be lots of answers
to the question, but trying to figure out
what the value is of a specific study,
there is room for more.
Work on this topic.
And there was a, I think, a very important,
issue of bioethics
of eight years ago that tried to ask the question
about,
you know, what really is social value
and how do we understand it?
And there were a number of important questions.
I mean, papers in that volume.
This is one from people in our group
who were defending the social value
requirement, another from a person
in our group who was questioning the social value requirement
and thinking about the limits of it.
People have built on this, and there was
a, I think, a very useful paper
in the Hastings Center, in 2018 by Danny Winter, who talked
about,
you know, how to think about social value
in a different way.
And then there have been people like one of my fellows and I
wrote
a, paper for a chapter for a book recently which tried
to select
cases to try to exemplify what value means in specific
cases.
And we picked what we called high value
cases or low value cases as a exploration.
So that's a lot more to be done about what
social value is.
But you'll hear it throughout this course.
The third is valid scientific methodology.
So you've got partners in place.
You've got a question. It's worth asking.
The next real important ethical requirement
is setting up the study so that it's valid
so that you get
reliable, understandable information
that you can make sense out of, that you can answer the
question.
That doesn't mean it has to be a positive trial.
It just means you have to be able to know
what the answer to the question is.
Excuse me when you're done.
And that includes a bunch of things
like how to design the trial,
what the methods are that you're going to be using, what's the
statistics,
are you going to be using, what kind of statistical power?
The goal being
valid, reliable, generalizable
and interpretable data is also an important part
of valid scientific methodology, and that is feasibility.
There are some questions that cannot be answered because
you can't design the study in a way
that will ever come up with an answer.
And so making sure that what you're asking
and how you're designing it is feasible is an important part
of justifying asking people to participate.
Sometimes when we talk about scientific
methodology
as an ethical requirement, people say,
well, that's science, that's not ethics.
And so my slide here is just to tell you,
you can't pull them apart.
They are totally integrated.
And only to make something
ethically okay has to be scientifically
rigorous.
And something that's scientifically
rigorous should be ethical as well.
There's a number of different
considerations
in thinking about scientific, validity.
And these are just some examples.
Choosing the endpoints, you know, as
how do you measure a
the effect of an anti viral or,
or a vaccines antibodies or is it infection or is it
disease.
And it matters in terms of numbers of people.
You would need certainty at the end of the study etc.
when these randomized
double blind placebo controlled trial
and do you make trials noninferiority
or superiority trials?
When do you use qualitative and quantitative methods?
How do you measure the outcome?
What's the measure of the outcome
that you're going to build into a study?
How long do you follow people?
What kind of power do you need?
What kind of sample sizes, what what other
methods of statistical methods do you need, etc..
So those are all interesting, important questions.
And there's been some cartoons out there.
There's the control group and the out of control group.
The placebo
member who died, member placebo group.
And this one I think is really fun.
You know, the the.
Possible modes of statistics
that can be mis, misused.
So all of that's important.
There's also a really interesting
challenge is right now that we're
sort of learning more about decentralized trials,
pragmatic trials, platform
trials, and secondary analysis of data specimens, all
of which
have methods that are different from the sort of standard one,
you know, in person, randomized controlled trial.
But require some very careful thought
about how to set it up so that it's rigorous, valid,
and you'll get interpretable data and feasible.
You'll hear about some of these, but
I don't have time to go over them today.
Fair subject selection or participant selection is
basically
what it sounds like.
And then the main issue is that the scientific
objectives
should guide inclusion criteria,
recruitment strategies and selection.
And this is based you know, some of this is in the Belmont
Report
based on a response to previous kinds of research that were done
where privilege or easy availability
or vulnerability were used as criteria
for select participants.
And those are all,
wrong criteria.
There is a Dave Wendler who you're going to hear from
the course, talks about flipping it
on a side and saying the best way
to think about fair participant selection is to say there is no
exclusion.
Everybody's,
eligible without justification.
And so then you might say, well,
what are the justifications that sometimes could be used to
exclude people?
Sometimes it's that they're scientifically
inappropriate, can't study
treatment of breast cancer and people that
don't have breast cancer, for example.
Now sometimes it's risk.
And that's contentious, but also very important
if the risk is too high for a certain group of people,
maybe it's
appropriate and justifiable to exclude them
little even more.
Controversy about vulnerability.
Some people say you should exclude people
who are vulnerable,
and I'll talk about that again in a minute.
But, again, it's contentious.
It's also a part of
their participant selection that, has us think about
how do we fairly distribute the harms and benefits of
research.
In other words, don't always pick people
with the same people over and over again
because they then accept all the risks
without necessarily getting the benefits.
Don't select a group
that's always going to take risks
when benefits go to somebody else.
You know, those kinds of, considerations are really
important
at the front end in selecting participants.
And I mentioned this earlier, but there's a really interesting
switch
that's happened over time where both of these end up being
important.
But they're but they really are, historically situated in
different ways.
So research was seen for a long time
as a burden.
And participants need protection from that burden or from the
risk.
And as I mentioned earlier, if it's seen as a benefit,
then people will need access to research.
And so both of these are still true.
But the pendulum swings back and forth a little bit between
the two.
So I mentioned protecting vulnerable groups.
There's a lot of question about
what does vulnerability actually mean in the context of
research.
And if we protect people
too much, we keep them out of and,
prevent them from getting the benefits of
research?
I'm not sure.
Is there another session on vulnerability
at all?
Not specifically.
When it comes up for children.
Yeah. Okay.
There's really some challenges to selecting the appropriate
participants for a study.
For example, this is one that comes up all
the time.
Is it preferable to test an early,
potentially risky therapy
in healthy, affected adults who can give their own consent?
Or in severely ill infants
who are otherwise likely to die as infants
if they don't get something that works.
That's a that's a real dilemma that has happened in studies.
Another example of a challenge is
when do you enroll pregnant persons
in research?
This is another topic that could take a whole lecture.
And sometimes that's
the next element is favorable risk
benefit.
And the questions really to ask are risks to subjects necessary
and are they minimized to the extent
possible.
And then there's a judgment that all of us
have to make, both as investigators,
research teams, IRB members, even participants
are the risks justified by either
benefit to the individual or the social value of the
study.
And that's a, you know, incommensurate.
And people say evaluation, but it's an important one to
make.
And then many,
many argue for the need also to enhance benefits.
Importantly, as the Belmont Report
points out, and as I've mentioned, only
a couple of times, sometimes interests
other than those of the subjects.
In other words, the participants in the study can justify risks
as long as the rights of the participants
have been protected.
Lots of challenges.
One is how do you identify which which risks and which benefits?
Account?
And there's been a lot of interesting
debate about,
you know, in some of the guidance
that says we should consider
physical, psychosocial, and even economic and legal
risks,
but we don't consider physical, psychosocial, economic and legal
benefits.
So how do we deal with that?
How do we minimize risks.
And you'll hear from some of the,
others that in in protecting certain
groups of people, one of them strategy
strategies we use is by regulation.
We limit the amount of risks that people can be exposed to.
That's what happens with children, with
pregnant persons and with, prisoners.
There's a huge debate about direct versus
indirect benefits, you know,
direct benefits as the kind of benefit that can
justify a certain amount of risks,
whereas indirect
benefits like money or access to good clinicians or,
access to other kinds of care may not be the kind of benefit
that you want to justify a risk based on,
but they still happen in research.
And then
determining that level is is a challenge.
Just two more, three more, I guess
independent review,
which is ensuring that the regulatory and
ethical requirements have been fulfilled,
that it's a process that checks investigator biases and
conflicts
and ensures the public that the research
is not exploiting individuals or groups,
and you're going to learn more about IRBs
later today.
I just wanted to put up the regulatory
criteria,
both in 45 CFR and 21 CFR 56,
because you can see that they mimic
a lot of what I've already said,
that risks or minimize justified by anticipated
benefits,
even if there only to the participants
fair subject selection and then informed consent is
adequate.
And so our next oops forgot about this.
Two regulatory bodies you should know
about the Office of Human Research
Protections, which is the Department
of Health and Human Services,
office
that oversees research funded by HHS.
And then we have an intramural office
of Human Subjects research protection,
which is the federal wide
assurance holder for the intramural program.
Let me just get that.
So the next one is informed consent.
And this basically is a process that ensures that individuals
have the opportunity to decide
whether they want to participate or
continue to participate, and whether it's
compatible with their goals, their interests, their values.
Many people, when we first put out this
framework said, you know,
what is what makes clinical research
ethical and said, oh, informed consent.
Well, as you can see, this is the seventh
on the list of eight principles.
So the point being that you don't ask people to
participate
until then, all of the other things are
satisfied.
You have to have a good question.
A valid science, scientific methodology,
make sure you understand the risks and
benefits
and have an independent review before you invite people to
participate.
And informed consent has a lot of pieces.
I think I'm coming next week
to speak to you in more depth about it,
so I'll probably skip this for now.
A lot of interesting challenges right now
in terms of informed consent, focusing on
long, long standing problems, the quality
of informed consent, and how do we assess capacity
consent.
But there's also lots of changes in how we obtain informed
consent now.
And some of that is based on changes
in research methods.
The set the eighth of the principles
is what's called respect for enrolled participants.
And this is probably another one that needs a lot of attention.
And here's what I mean by it.
Early on, we just developed this
framework.
There was this idea,
as I just mentioned, that some people say,
what makes clinical research ethical?
When you get your IRB to review it
and then you get
the person's informed consent and you're done, ethics is done.
And that just makes no sense at all,
because at the beginning of the trial,
you're just beginning to engage with the people that are in the
study,
and you have responsibilities, ethical responsibilities to
those people.
And you have ethical responsibilities
to the, you know,
the world in terms of reporting your data
and reporting your science.
So there's a lot that happens after informed consent is
obtained.
And this is just a partial list protecting confidentiality,
monitoring welfare, right to withdraw, providing
information, etc..
And there are some interesting challenges.
We don't do a good job
of providing results or information
to participants for the communities.
After studies are done.
So this is our framework.
Systematic, sequential we argue necessary.
Sometimes there are waivers of certain
of the procedural requirements.
Universal.
Although it has to be adapted to the context,
it does require balancing specification
and judgment, and you'll hear about that
throughout the course.
And we need people informed investigators, IRB members,
others
interested in research to be able
to understand what the principles are
and how to apply them.