That's a whirlwind through a little bit of history
and a little bit of the rules and regulations that exist.
What I want to spend the rest of the time talking with you about
are some sort of conceptual ideas about how you think about research
in a way that helps you answer the questions of, "Is
this research ethical?" And I want to preface it by saying that,
you know, in our department some 15 or so years ago now,
we realized that a lot of the guidance that's found in the codes
and the regulations were developed in response to specific problems.
So, they were developed historically at a time
that they were responding to some events that happened in history.
And so, they understandably kind of focused on what
the sort of details of that event that initiated their implementation.
In addition to -- or for the same reason, perhaps, some issues
are probably incompletely addressed in some of these guidances,
and some of the guidances and regulations are at least interpreted
to have divergent recommendations to not agree on specific things.
So, we thought that there was a need for investigators, for people
who are interested in understanding the ethics of research,
for people who review research, IRB members and others,
to have a systematic, coherent, and universally applicable framework
that they could use to make decisions about or make judgments about whether
or not a particular research that they were writing or reviewing was ethical.
And so, we proposed a seven-principle framework.
And the seven principles -- and it's published in a couple of different places.
The first paper was in 2000 in JAMA.
It's also in a textbook.
There are some additions to this in the international context.
So, there's a number of references that I could provide for you
if you want that explicate that -- this pretty in some detail,
but I'm going to go through it today.
So, there are seven principles.
They include valuable scientific question, valid scientific methodology, fair
subject selection, favorable risk-benefit evaluation,
independent review, informed consent, and respect for enrolled subjects.
One thing before I go into each one of them
I want to say is we didn't make any of these up.
So, if you look at the various guidelines
and codes, you will find vestiges of each of these.
Maybe not exact words, these exact words, but the concepts and the ideas are there.
We've just put them together in a way that seemed more systematic to us.
And what I mean by that is that it
seems right that you have to start at the top.
You have to answer the question, "Is this a valuable scientific question?"
before you go down the list.
And so, you know, the question of informed consent, informed consent is on there.
It's a very important part of doing research.
But you don't even get near it until you've gone
through lots of other considerations in terms of a project.
So, what does it mean to have a valuable scientific question?
So, basically, what this means is that it has to be worth doing,
if that's the sort of shorthand for it.
An ethical clinical research should answer a valuable question, one
that will generate new knowledge or understanding about human health
or illness that's socially, clinically, or scientifically useful.
So, a good example of this is an article that was written by a very prolific writer
in research ethics, Benjamin Friedman, who wrote an article about --
in this article, he was writing about social value in a certain way.
And what he said was he had a nightmare where he was walking down the hall,
and he ran into one of his colleagues who excitedly came to him
and said, "I just successfully transplanted an appendix."
And in the article, Benji says he's -- he kind of scratched his head,
and he said, "Well, was that ethical?" And his colleague responded, "Well,
I got the guy's informed consent." And he uses that
as an example of how informed consent doesn't solve the problem.
If there wasn't a good reason, a good question to answer
by transplanting an appendix,
something that you might learn, something that you might use to do
some important work with, then it wasn't ethical to do it.
And it's an interesting concept, because it seems like
it is the most important
first question to ask, "Is this research worth doing?" Now, importantly,
it doesn't mean that the answer to the question has to be positive.
You can have negative -- you know, ask a question,
get negative answers, and that's still socially valuable.
It still gives you information that can be very useful and in many cases is.
But if you can't answer --
if you can't say why this question is worth asking,
then you probably have to re-ask yourself, "Is this research ethical?"
There are many reasons that social value is important.
It promotes benefit to society.
So, the sort of one side of the balance that I showed you before.
And it also minimizes exploitation.
You're asking people to do things for a good reason,
not just wasting their time for nothing.
Therefore, it justifies asking them to accept some risk and burden.
And it's also a responsible way to use resources.
The second principle in the framework is scientific --
valid scientific methodology.
And this basically says, "Ethical research should be designed
in a methodologically rigorous manner, the design, the methods,
the statistical power, et cetera, that will yield
valid, reliable, generalizable, and interpretable data."
So, the shorthand here is, you have a question that's worth asking.
The second ethical requirement is to design it in a way
that you'd get an answer that you can interpret, that you know
what you found, that you have data that's, you know, reasonably understandable.
Again, it doesn't have to be positive.
It just has to be understandable.
And it has to be designed in a way that's feasible as well.
Now, this requires lots of
details in terms of choices of endpoints, choices
of designs, choices of procedures, statistical methods, et cetera.
And you look at this list, and some of you might say, "Well,
those are all scientific considerations." And in
fact, they are scientific considerations.
But every scientific choice that you make has ethical implications.
And so, designing your study, picking the right outcomes,
picking the right design to give you the best and most rigorous
answer to your question, choosing the procedures that will be used
to measure outcomes or data points or whatever.
And not only planning your statistical methods, but managing your data,
well, are all ethical requirements in terms of good clinical research.
There's lots of controversies about this.
Not so much about the idea that things need to be designed in a way
that give you a rigorous answer, but how do you balance the best design,
the most rigorous design
with some of the other things that you need to care about, like the fact
that you don't want to exploit people or expose them to excessive risk.
So, some of you may have followed the debates
that occurred over clinical trials related to Ebola in the last year.
And there were a lot of discussions about, you know,
what's the right kind of design that both gives us an answer
to the questions that are so urgently needed to be answered and respects
the rights and the welfare of the participants that are in these trials.
There's also a lot
of really important ethical weight that goes into feasibility.
So, if you're -- for example, imagine designing a trial where you know
you're not going to be able to get the participants that you need to answer it.
That's sort of ethically a non-starter, because you can't ask some people
to accept risk and burden to answer a question that you know
you're not going to be able to answer, because it's not feasible
to get all the people that you need or to get the equipment that you need
or do you have the right freezer capabilities or whatever.
There could be lots of details in terms of feasibility.
The third is fair subject selection.
So, you have an -- a question that's worth answering, a design and methodology
that's rigorous,
and it's going to give you an answer that you can make sense out of.
Now, you have to ask the question, "Who do I include?
Who do I go after to be part of this study?"
And I think critically, especially looking historically,
the first guide should be scientific objectives.
That the scientific objectives of the study guide the inclusion
criteria, the recruitment strategies, and the selection of subjects.
And not the fact that people are easily
available, or vulnerable, or marginable -- marginal, excuse me,
or that they're privileged either, you know, that
there needs to be a fairness in terms of scientific objectives.
Scientific objectives is where you start.
And then you -- when you're thinking about fair subject selection,
there's also a consideration of fairly distributing the harms and benefits.
So, let me give you an example.
Let's imagine you think you're doing a study to test a treatment for
breast cancer.
You know, scientifically, you're going to need people in that study
who have breast cancer and maybe it's a very specific type of breast cancer.
When you're thinking
about fairly distributing the harms and the benefits, you may want to --
you may think about, well, which subgroups within the population of people
who have breast cancer are more susceptible
to the kinds of risks that this intervention might have?
Maybe kidney disease or liver disease or some kinds of things that might need
to be used as exclusion criteria in order
to reduce the risks and protect some of the subgroups.
One of my colleagues talks about the best way to think
about fair subject selection is to flip it on its head.
In other words, not start with who scientifically should you include
in the study, but start with the idea that everybody should be included,
unless there's a reason to exclude them, a justification for excluding them.
And so, then the question becomes, "What are acceptable justifications
for excluding people?" Well, one might be that they can't help answer the question.
They don't meet the scientific objectives.
Another might be that they are at higher risk
than everybody else who could meet these scientific objectives.
And a third and a very important one is that they may be more vulnerable
than other populations, and therefore we should think about
how to -- whether we need to include them at the front end.
I understand there will be another lecture -- a whole lecture on vulnerability.
So, I won't say more about that.
But if you have questions, we can talk about them.
I think it's important to go back to something I've already alluded to,
and that is,
in thinking about distributing or fair distribution of the risks and benefits,
it's important to keep in mind
this sort of pendulum swing that's been occurring between
thinking of research as always a burden and always subjects -- excuse me,
as always in need of protection, and the sort of opposite swing
of the pendulum where research can be or is in many cases
a benefit, and subjects need and want access to participation.
And so, thinking about the risks and the benefits,
you need to keep in mind those different polls
and where any particular project might fall in that spectrum.
So, you've got a question worth asking, a design
that's rigorous, selected the appropriate population given,
scientific objectives, and risk and benefit and vulnerability.
And now, the question is, "What's the risk-benefit look like
for the participants in the study?" So, this is a sort of different kind of risk
benefit analysis than the first one, which is, "Is the study worth
doing?" In a study that's worth doing, there are still ways
that one can make sure that the risks to the individuals
in the study are minimized and necessary.
So, you may see a proposal, for example, that asks to do,
you know, 10 MRIs over the course of six months.
And so, an interesting question to ask is, "Are 10 necessary?" Or could
the question be answered by doing six or five or,
you know, spreading them out over a further amount of time?
Are there other ways to minimize the burden of those procedures
to the participants?
Are the risks to the individuals in the study justified
by either benefit to them -- or potential benefit to them or
-- and/or the importance of the knowledge, the social value?
And are benefits enhanced?
Are there ways to enhance benefits in the process of doing research?
And these are -- these -- you might say, "Well,
these are pretty normal and understandable questions,
no big deal." But the process of doing that is not so straightforward.
I mean, just thinking about risks, for example.
There's a very interesting challenge in terms of defining what is a risk
in research. What counts as a research risk?
How do we know how bad this risk is or
how to think about this risk on some kind of a scale?
And there are certainly lots of reasons to think about
both probability and magnitude of risk and different types of risk.
So, one of the things that the
regulations talk about is physical, psychological, social, financial risks.
It's interesting to think about how often in research
we consider financial risks as an example.
Some people talk about -- or I've had questions
raised that fall in the following sort of category.
If somebody has to travel through a very tough neighborhood
or a park really far away from the clinic and walk to the clinic
and there are some hazards in that walk, are those risks of research,
or are those separate from the risks of research?
How do we take those things into account
when we're making an assessment of what the risks are?
And I think importantly, in all cases of research,
there is some uncertainty about risks.
And if there wasn't
some uncertainty about risks, we probably wouldn't be doing the research
because part of doing researches is helping to identify either
what the risks are, the magnitude of the risks,
the comparative risks, or some other nuance about the risks.
So, defining risks and measuring risks are -- is a very important part
of figuring this out, but it's not easy in many cases.
Minimizing risks is also something that we need
to pay attention to and some things are very straightforward.
I mentioned already, you know, reducing the
number of procedures if you can and still get an answer.
Other things that people talk about are, you know, doing procedures
that are clinically required and -- in other words,
instead of asking for additional blood for research purposes,
have it drawn at the time when clinical bloods are being drawn.
Making sure that the
people who are doing procedures have the right kind of training.
That's a way to minimize risk.
So, there are lots of really important sometimes very obvious ways
to minimize risk.
And limiting risk really gets down to how we protect certain groups of people.
So, one of the ways, for example, that the regulations regarding research
with children work is that it limits the amount of risk that can --
that children can be exposed to in research.
Minimal risk procedures and research for children is --
basically are generally fine.
More risk can be accepted when there is a prospect of benefit
for the children in the study.
And then the rules for anything more than a minimal risk
without a prospect of benefit in children are much more stringent.
And in some cases, research cannot be done.
There are also similar challenges in terms of defining benefits.
What is a prospect of benefit in research?
If you're -- if you have a certain kind of serious illness,
and there are a few interventions available to treat that illness,
and you are entering a study in which there's an intervention
being offered, is that by definition a prospect of benefit?
Is it only a prospect of benefit if we already know something about the drug?
If it's in Phase III versus Phase I, for example?
How do we decide what's the prospect of benefit in certain cases?
And a lot of discussion about distinguishing what are called
direct benefits versus secondary or sometimes ancillary benefits.
So, the direct benefits are, you know, maybe the therapeutic -- possible
therapeutic benefits that one might derive from an intervention.
The secondary benefits might be other medical care that you might receive
as part of the study, payment that you might receive
as part of the study, feeling like you're contributing to society
that might be psychologically beneficial as part of the study.
Those are generally considered secondary benefits.
So, importantly, and going back to my original balancing scale,
the most guidance recognizes that interests other than the subject
those of the subjects may on some occasions
be sufficient by themselves to justify risks.
What this basically means is that research in which we know in advance
the individuals who are participating will not benefit, there's no
prospect of benefit, can sometimes be ethically acceptable
as long as the rights of the individuals who are participants
have been adequately protected.
So, a question worth
asking, a design that's rigorous, the right population
chosen, efforts made to minimize risks, and enhance benefits.
Now, the next thing on that list is independent review.
And so, this is a process which allows an investigator
or a research team who has investments in research
to have somebody else say, "Is this acceptable
to ensure that the ethical requirements have been fulfilled,
check any biases that the investigator might bring,
and assure the public that research is not exploiting individuals or groups?"
And so, most research in the United States
is independently reviewed by Institutional Review Boards or IRBs.
There is research that's exempt from IRB review
and expedited through IRB review, so there are other methods of reviewing.
Most countries around the world have an equivalent kind of Ethics Research
Review Committee that does
looks at research before it starts, research with humans.
And the criteria that are found in both the Common Rule
and in the FDA regulations that the IRB is supposed to use in order
to determine whether a particular study is approvable include these.
And the -- and you'll see flavors of things that I've already talked about.
That risks are minimized.
There's more to that statement than I put on this slide.
That risks are justified by any anticipated
benefits to the subjects or the importance of the knowledge.
That subjects will be selected and treated fairly.
And that informed consent is adequate.
There are lots of interesting and sort of
in the news challenges right now with IRB review.
One is lots of -- many IRBs
have huge volume of protocols to review.
So, how many of you have ever been to an IRB meeting?
Anybody? Only one. Okay, two.
Okay.
So, oftentimes, IRB meetings can last four hours,
but you have, you know, maybe 10 protocols to review.
Some of them protocols sometimes are, you know, 300 pages
long and dense in terms of their scientific background, et cetera.
So, the challenge is not trivial in terms of understanding when it's about,
having a process of asking questions often of the investigator,
and then applying these principles and thinking about, "Well, is this something
that's approvable in its current form, or does it need to be changed?"
Consequently, there's
been data -- plenty of evidence to show that IRBs are --
tend to be inconsistent in terms of how they make their judgments.
And this has created problems in particular for multicenter studies
or multi-site studies.
So, if you have a study that has 100 different
sites, oftentimes 100 different IRBs have to review it.
And they may have either grossly different decisions or sometimes
just mildly different decisions but that impact the
entire spectrum of sites that are conducting the study.
So, this is a problem that a lot of people have talked about
and lots of attention right now to using
single IRB review for multi-site studies.
This year in September of 2015, the Department of Health
and Human Services published what's called the Notice of Proposed Rulemaking.
That's NPRM stands for.
Maybe some of you have heard from -- about it.
And basically, it's a proposal for changing the Common Rule.
And there are some very interesting, some minor,
and some huge changes in terms of what they're proposing.
One of them is this, that for multicenter studies
that are domestic, non-international, a single IRB review will be required.
They won't be able to have different institutions
doing IRBs that -- I mean, reviewing different institutions IRB
is reviewing the study, but only one will be able to do it.
And there's a lot of consternation about how this is going to look
and whether it will work and whether it will be adequately protective
and how you'll make arrangements between institutions, and lots of details.
So, the sixth of the seven on our list is informed consent.
And as someone in the audience said, a lot of people
when they think about, you know, sort of abstractly, what is it
that makes informed -- sorry, research ethical -- clinical research ethical?
The answer often is informed consent.
And certainly, in most cases, informed
consent is an important part of doing ethical research.
But what's interesting about it is if you think about it, until you have a proposal
that's worth doing and well designed and you've minimized risks
and had somebody else review it, there is no reason to ask
anybody for their informed consent.
You don't even get there until you've gone through those other steps.
But informed consent, once you're there, has a goal of making sure
that the people that you're offering participation
to have an opportunity to decide whether they want to participate
or continue to participate and whether or not participating
is compatible with their goals and their interests and their values.
So, it's a really important concept.
Most of the documents, the codes, guidelines, regulations,
have something related to informed consent in them.
And some of them are very strong.
So, Nuremberg Code is famously quoted as saying, "The voluntary consent of
human subjects is absolutely essential." CIOMS says, "For all biomedical research
involving human subjects, the investigator must obtain the informed
consent of the prospective subject or an authorized representative."
And the regulations have pretty much --
language is very similar to this as well.
There are some exceptions.
There are some ways to waive informed consent.
Emergencies are one example.
So, the study I showed you at the beginning,
where you're encountering and doing an intervention on people
in the emergency room who have traumatic brain injury.
There is a process that's regulatorily described
that one needs to go through in order to do that,
but those kinds of research can sometimes be done
without getting the consent of the individuals who are in a position
for the most part to not be able to give informed consent.
So, I will choose -- skip that one.
So, what does informed consent involve?
It involves a number of steps, disclosure of information
to people, often -- usually written and oral,
some sense
that they understand the information well enough to be able to make a decision,
a choice that they can make which is hopefully voluntary,
in other words not coerced or unduly influenced by others or other factors.
And then they authorize it.
And I don't know if you can see my picture.
But it's a cartoon, which is not really that funny.
They're people standing around the table
looking at the guy who's being asked to sign a consent.
And you can see them with their trench coats and their hats
and putting a lot of pressure on this poor guy who's sweating.
Unfortunately, sometimes informed consent in clinical research
does look like that or feels like that to people.
In other times, it's done, you know, in a very open and trance
-- iterative way so that people really can engage
with the information, ask questions, understand it, and make a decision.
There are lots of challenges to this.
You can tell I spend a lot of time thinking about it for me
and said I did some of my researches on informed consent.
But just, for example, think about, how many of you have seen
consent forms that are used in the intramural program?
Many of you have seen them? Okay.
And so, the -- oftentimes, not always, but oftentimes, the consent
form of the intramural program is, you know, 15, 18 pages long.
Those are long documents for people to read.
Choices about what to put in those consent documents
and how to say things are really very ethically important
and very difficult in order to be able to give people
the information they need without making it so long
and so cumbersome that they can't read it or they can't absorb it.
And then the
IRB has an important role in reviewing consent, both the plan
for informing participants about the various aspects of the study,
how they're -- how investigators or the research team is going to know
whether or not somebody understands and whether their choice is voluntary.
So, the seventh of our seven-principle framework is what we called respect
for enrolled subjects.
And this is a --
an element or a principle that I think really needs some more work.
And the reason I -- let me say where I -- where it came from first
and then say why I think it needs more work.
So, in reviewing the documents, the codes of ethics, the literature
on research ethics, the regulations, they all talk about what you do upfront.
You know, you get review, you make sure
the risks and benefits are justified and risks are minimized,
and get the person's informed consent, and then the study begins.
And much of the guidance -- not all of it, but
much of the guidance doesn't say much else about what happens.
And that doesn't make any sense, right?
Your ethical obligations to people that you're enrolling in research
can't end the minute you get their informed consent, right?
You still have obligations to people.
And so, these obligations include at least things like protecting
their confidentiality, monitoring their welfare, recognizing
that they have a right to withdraw, providing them new information
as it becomes available that might affect their decision to participate,
informing them of new findings, planning for what happens at the end of the trial.
There are other things that are not on the
-- this list, compensation for research related injury.
I mean, there are a lot of things that people do talk about that
are sort of in this -- under this rubric of what happens after the study begins.
And so, I think both -- hopefully, you can see why
this is an important element, but also you can see why there needs to be
more work on this
because some of these things are sort of done without a lot of guidance.
There is some guidance.
So for example, in the Nuremberg Code, it says,
"During the course of the experiment, the subject should be at liberty
to bring the experiment to an end." So, you can withdraw at any time.
And Helsinki talks about privacy and confidentiality, and minimizing
the impact of the study on a person's physical
and mental integrity.
So, those are the seven.
Hopefully, they made some sense.
I think importantly, again I've said this,
but you know, we think of them as systematic and sequential.
So, you start at the top and work your way down, and that they're necessary.
So that when you're thinking about a study, whether you're writing it
or reviewing it or thinking about entering it as a participant, it's worth
thinking them through one at a time and saying, okay, does this study have value?
Is it well designed?
Are the right people being asked to participate?
Are the inclusion criteria right?
It -- are the risks minimized?
Has it been reviewed by an IRB?
Is there a good process in place for informed consent?
And are all the things that happen to people once a study starts?
The monitoring, the confidentiality, the plans
for what happens at the end, are those all adequate?
And you can ask those questions
for every single study that you consider in any way.
It also seems important to recognize that these can be universal.
In other words, they apply to all studies everywhere across time.
What's important, however, is thinking about how they're actually manifested.
So, risks, for example, might vary from -- over time
from one time point to another, or from one geographic location to another.
The method by which you disclose information
and the process of informed consent might vary by population appropriately so.
It doesn't mean informed consent the principle of giving people information
that they can use to make a decision changes.
It's how you implement it that changes from study to study.
And, of course, they're going to require some balancing and specifying.
So, the idea of, you know, having an adequate justification
for the risks requires a lot of specification
in terms of determining what are the risks that count in this case.
How do we balance them with the benefits?
What are the benefits that that count in this case?
How do we weigh them?
How do we balance them against the rigor of the study?
And there are a lot of interesting examples of challenges,
for example, in randomized control trials.
People worry about things like randomizing people, especially if we
one of the arms to which people might be randomized is the placebo arm.
People worry about that from an ethical perspective.
And yet, if the question is worth asking and the design is rigorous,
it might be that placebo is the best way to answer the question.
And not only the best way
to answer the question, but the fairest thing for the individuals.
Because if you know upfront that the drug is much
better than placebo, then maybe you shouldn't be doing the study.
So, it's that kind of balancing that needs to be done.