And our topic today,
international research ethics specifically.
I'm going to be offering a brief introduction and then a
more
in-depth discussion of standards of care.
And while I am a faculty member in the
Clinical Center Department of Bioethics,
nonetheless, none of the views that are
expressed
in this talk are anyone else's but my own.
I'm not representing my ass.
That's not not even the department itself.
I'm just speaking for me here.
So another note on terminology.
I'm going to be using the term
the terms low and middle income countries
and high income countries.
Lmics and HIV Aids.
But in using those terms, I don't mean to imply that
there's
a hierarchy of countries based on their economic status.
There's more to well-being than wealth, both at the
individual
and at the social levels.
And I also don't mean to imply the individual countries that
fall within
these designations are just interchangeable with
each other.
Obviously, there's a great deal of
variation
between countries at any income level.
Nonetheless, even acknowledging that generalizations are never
perfectly accurate.
It is helpful to be able to speak broadly,
and these are
the terms that match current NIH terminology and program
announcements.
So those are going to be the ones
that I'm going to use in this talk.
Okay.
So let's start off with the big question.
What are researchers and sponsors
ethical obligations in international collaborative
research.
Specifically, what are researchers
and sponsors ethical obligations
when it comes to research, which is sponsored by
institutions
in high income countries
and carried out in low and middle
income countries with limited resources.
I mean, of course,
there's no principled reason that an institution in a lower
middle
income country cannot sponsor research
to take place in a high income country.
But the reality of where current money
and resources are concentrated
means that the vast majority of international collaborations
do rely on
high income country funding to conduct
trials in low and middle income countries.
So it makes sense to ask about the ethical considerations that
arise
in that kind of partnership.
Specifically.
Okay.
In thinking through those issues,
it's helpful
to take a step back and think about the context.
So what is that context first?
There are cultural differences that include different habits
and systems of value and meaning.
For instance, moral, political and
economic understandings of human activity
that shape people's ideas about what research should be
conducted
and how that research should be conducted.
These differences can exist between the research
team
and the study population, but importantly
also within the research team itself
and also within the study population,
which is not a homogeneous
okay.
So there are also power differentials,
which are differences in the ability
to direct or influence
the behavior of others or courses of events.
These kind of create and include differences in the
ability
to negotiate collaborative projects
due to differences in
funding,
sorry, the differences in funding,
access to facilities, education, and so on.
Again, these can exist between the research team and study
population,
but also within each of the research team
and study populations
themselves.
And finally, they're also background
injustices.
These can include injustices due to colonial history,
to the current global order and political failures at the
local level.
These injustices mean that
there are cases where the institutions
and society do not function in a way
that allows study participants and host
communities to meet their basic needs.
For example, some host community communities may not have access
to sanitation, good quality health care, or universal
education.
And as a result, people living in those
communities can be especially vulnerable.
Researchers and sponsors typically have no personal
responsibility for these preexisting
injustices.
And their primary professional responsibility is to conduct
research.
But nonetheless, background injustices form part
of the non-ideal conditions under
which they need to conduct their studies,
and attempting to address, or at least attempting to not
exploit
or exacerbate those vulnerabilities
will place some obligations on them.
So what sort of challenges are created
by the context I've just described?
I list some out.
For me,
I list some out here.
Got lost on my slides for a second.
My apologies. Okay.
I list them out here.
So start with,
cultural differences and informed consent.
What should informed consent looks like when cultural or
social norms
around decision making differ
from what the standard view of informed
consent presumes?
Like, for instance, if those norms are less
individualistic,
or think about how those norms might have,
or think about how power differentials
might affect collaborative partnership,
how can researchers achieve collaborative partnership?
And there are big differences in power
between research teams and research teams
and communities in terms of education,
skills, funding and the like.
How might they affect independent review?
How can the independence of ethical review
be ensured when research projects
could bring in, for example,
enormous investments in research or health
infrastructure,
prestigious collaboration and other
extremely scarce and important goods?
Or consider background injustices
in conditions
where health needs can be very different
between the sponsoring and host country.
Must research always address and attempt to directly correct
the needs of the host country, as opposed to the sponsoring
country.
Or in other words, does research
need to be responsive to the local health needs?
In particular?
Or could it be reasonable to conduct
research that provides other benefits
to host communities, for instance, through
investing in health infrastructure?
Even when the study question itself
is not directly relevant,
related and important questions
concerning appropriate standards of care.
What is the appropriate standard of care in research
when there are large differences in the level of care that's
provided
in low and middle income countries,
in high income countries?
Relatedly, what are
researchers and ancillary care obligations?
Do researchers have an obligation
to address
health problems of participants that are unrelated to research?
And if so, like when and which kinds?
Finally, whether researchers to study
obligations.
Once the study is over to researchers and
or sponsors have an obligation to continue
to provide treatment for participants
or to make any of the proven effective study interventions
available to the wider community.
You'll note that on this slide, some of this is highlighted in
pink.
That's because we're going to be focusing on them in
today's session.
So I'm going to transition tonight
into examining
what standard of care researchers are ethically
required
to provide to study participants in international collective
research.
I Joe, we'll talk to you shortly about post-trial obligations,
and you'll also hear later from Da
fiscal year about community engagement,
which can be helpful with navigating background
injustices,
as I'll mention later,
but is especially essential in responding to cultural
differences
and power differentials, which is why it's
highlighted in both of those categories.
Okay, so that's our background.
As I mentioned,
I will be,
sorry, I just realized it takes several clicks to advance
the slide.
That's what's been going on on my side.
There's with the way it's set up on the side.
Okay. So.
As I mentioned, I'm going to be discussing
standards of care.
What sorts of ethical questions does this raise
and why is it an important topic?
It's quite helpful to start by discussing a particular,
very prominent controversy that erupted about 20 years ago
about standard of care and international research,
which will help clarify both what's the issue and why it
matters.
So that controversy was over short course AZT trials.
And here's the context.
When untreated, pregnant people who live with HIV
transmit it to 15 to 45% of their
newborns.
AZT AZT
is a particular type of antiretroviral,
and in the early 1990s,
a placebo controlled trial conducted in the United States
showed that the so-called 076 regimen,
which was named after the clinical
trial number of the trial, reduced
perinatal transmission to less than 5%.
This regimen involved oral AZT in the second trimester
IV, especially during delivery.
Oral AZT for six weeks after birth
and volunteering for six months.
While this quickly became
the standard of care in the US and other high income countries,
it was not implementable in many low and middle income
countries,
which were also the countries suffering the greatest burden of
HIV
and the highest rates of perinatal transmission.
Long course AZT cost $800 for a treatment,
while the per person expenditure per year in on health
was less than $100 in most pharmacies
and less than 20 or $30 in many.
There was also a lack of personnel
and infrastructure to implement
such a complex and long term regimen.
Finally, bottle feeding infants in settings
without access to clean water poses risks of serious
infection and death.
Okay, so
against this backdrop, I learned, in fact, a strategy
to test simpler and cheaper regimens
against placebo or no intervention.
16 trials were conducted in total, 15 against placebo
and one against a 76 as an active control.
These were expected to be less effective than a 76,
but it was hoped they'd be effective
enough and cheap and simple enough
to be worth implementing in low and middle
income countries.
So the decision
to run these trials left controversy
with two high profile articles in the New England Journal of
Medicine
criticizing the medicine and unethical one.
The first one you see here
was written by Peter Lurie and Sidney Wolfe from Public
Citizen,
a nonprofit consumer advocacy organization
founded in 1971 that,
in its own words, champions the public interest in the halls
of power
and defends democracy, resists corporate power, and works
to ensure the government works for the
people, not big corporations.
The other was written by Marcia Angel,
the New England
Journal of the Journal of Medicine
editor at the time.
The journal also ran a response piece
defending the trials from Harold Varmus,
who was NIH director, and David Satcher,
who was CDC director
and who had funded the placebo controlled studies.
In this exchange,
the key claim that critics of the Salk
course trials made
was that they were unethical because they did not provide
the control group with the global
best standard of care,
which at the time would have been the 076 regimen.
But while I think that providing the global
best standard of care is required,
they offer several reasons.
Okay, so first, researchers have an
obligation
of beneficence, which requires them
to avoid preventable harm.
As they point out,
giving given a control group of seven six
rather than placebo
would result in fewer perinatal transmissions and
fewer deaths.
So, of course, fewer transmissions
and fewer deaths are good things.
So they also have an obligation to avoid treating participants
merely as a means to answering their scientific
questions.
Now it's it's less clear what's meant by this,
since the authors don't explain and philosophers don't actually
all agree
on, what it means to treat someone as a mere means.
Since it's not clear, I'm not going to focus on it
now, but I will come back to it and address it at the end,
okay?
They also have an obligation to treat participants equally
and relatedly, to adhere to universal ethical
standards.
So they say that
given that an act of control would have been required for a
short
course AZT trial in a high income country
where 0761 standard care,
the same standard should apply in the low
and middle income country.
Otherwise, pregnant people and infants
in low and middle income countries
are being treated equally, which is morally wrong.
Is that true?
So it is true
that requiring active controls in high income countries,
and that low and middle income countries
would involve treating people differently?
But does being treated differently
mean being treated unequally?
And does it imply violating universal standards?
As philosophers will tell you, these questions can be pretty
tricky.
So here's just a quick sort of cute.
Some might even say facile argument
that treating people differently
doesn't necessarily mean treating them
unequally in a morally problematic way.
So my mom received a cesarean section.
Difficult labor. Sorry, mom. My fault.
My dad never did.
So doctors treated them differently.
Does that mean they were treated unequally?
And was that unequal treatment wrong?
Well, of course not.
My mom had a difficult labor and needed a C-section.
My dad was never pregnant. He didn't.
So they were treated equally in a moral sense.
Both were able to access the medical care
that they needed in their lives.
But they were also treated differently
because that was different.
Care for each of them.
So the top line point here
is just that moral equality requires
that we not treat people differently
on the basis of morally irrelevant differences between
them.
For instance, treating one person from a
favored race,
religion, or gender better than another.
But it does allow for treating people
differently
when there are relevant differences between them.
So the important question here
is just whether, for the purposes
of deciding
whether to offer the seven six regimen
as an act of control,
the fact that it's locally available
in some places
and not in others is a morally relevant
difference.
Is it or is it not?
That's what we need to investigate.
Now, in saying the equal treatment
requires offering under 76
as an act of control everywhere in the world
whose officials were asserting that local availability.
It's not a relative difference.
It's an irrelevant difference.
But what justifies that claim?
They lean heavily on the Declaration
of Helsinki to substantiate it.
So the Declaration of Helsinki is a World
Medical Association statement putting forth
ethical principles for medical research
involving human participants.
It was originally formulated in the wake of medical
atrocities
during the Second World War, and was first published in 1964.
It's been controversial and subject
to multiple revisions,
many of which did address standard of care, specifically.
So what I quoted here is the 1996 version
that was getting referenced in this debate.
It states in any medical study, every patient,
including those of a control group,
if any, should be assured
of the best proven diagnostic and therapeutic method.
Note that this actually implies that it
or may imply that it would be wonderful
to test short course AZT, even against 076
as an active control, as short course was expected to be
inferior,
and hence it wouldn't be the case
even in a trial with an active control
that every patient was getting the best proven therapeutic
method.
And indeed, some commenters did in fact argue for that.
You just can't touch short course at all,
because we should be getting everyone
long course in all contexts.
The bracketing at issue.
This declaration does support the more limited claim
that local availability is not a relevant difference,
as it appears to assert a universal ethical principle
which states
the best proven care must be offered
everywhere.
Okay,
as mentioned, this element of the Declaration of Helsinki
has been controversial.
Are still, the current stance from 2024
is not substantially updated from the last tradition, and
it's
only slightly more permissive than the 1996 version.
Per the updates,
it is permissible for researchers
to offer some participants less
than the global best standard of care
only when there's no proven intervention,
or there are compelling methodological reasons
for using less than the global standard of care
and providing less than global best poses
no risk of serious and irreversible harm.
Even with that requirement, the document
also says
extreme care must be taken to avoid the abuse of this
option.
So the Declaration of Helsinki is generally
opposed to the placebo controls, where
active control controls
exists, and endorses trials which offer
some participants less than the global
best standard of care only under quite select
circumstances.
Okay, so it says these things
and also the claim that research
should generally and to compare against some standard of care,
even if not the global best, does have plausible reasons
supporting it.
It's often socially valuable to know how a new intervention
performs
against what's already available,
and offering standard care, rather than placebo,
can help minimize risk to participants,
as it does increase the number who receive
effective interventions.
But as we will
see, there are also some challenges.
One I'll just note is that the requirement
that deviations from the global
best must pose no risk of serious and
irreversible harm
is a version of a minimal risk requirement,
but in this case, it's being applied
to trials enrolling competent adults
rather than, as is typical, being applied to trials
in which participants cannot consent for themselves.
So like that's curious.
And that could use an explanation.
But rather than dwell on that future,
I'm going to focus instead
focus on the challenges involved in determining what
baseline
researchers should be comparing against as the standard of care.
Okay, so the organizing question here
is whether it is permissible
to provide less than the global best standard of care.
You know, the critics we've just summarized said no
and leaned heavily on the Declaration
of Helsinki in making their case.
But I'm going to give some reasons
to think yes, and also discuss
some potential alternatives to the global test as the relevant
standard.
Okay, here's the first proposal.
The baseline that researchers can compare
against is what participants otherwise would have gotten,
which can also be referred to as the de facto standard of
care.
After all, if everyone who participates in
a trial
gets at least as good as what they would
have gotten outside of the trial,
possibly some people get something
that's better
than some people were made better off,
and nobody was made worse off.
So on this view, there's no loss to participants from trials
taking place under those conditions,
and perhaps some gain,
of course, in some places.
What participants are able to get outside
of the trial is not very much
as was true in the short course AZT trials,
but for this view, the consequence
of not getting very much outside the trial
is that researchers also don't need to offer that
much
in order to get participants a better deal than what they
would
have otherwise gotten.
So this
view denies that what is locally available is an irrelevant
difference.
Instead, it maintains that what is locally
available is irrelevant difference
because in areas where the global best standard
is available, offering less than that can harm
participants
by preventing them from receiving it,
since they would have.
But in areas where very little is
available, offering less than the global
best may not harm anyone as they weren't
going to get the global best anyway.
This view maintains that this difference,
namely the difference between
whether you might be harming people or not, is not morally
irrelevant.
Okay.
But while this view has a simple and compelling argument
in its favor, it's also subject to powerful
criticisms.
The most serious is that the de facto
standard of care can be unacceptable.
It is, as in this quote, just a description of what
happens,
even as what happens is highly morally objectionable.
So there
may be cases where treatment is known
to be effective in a given population.
It's cheap and feasible to implement.
And so it really should be widely available,
but it just isn't.
For instance, basic childhood vaccines
might be the kind of intervention
where that could be true.
The point is even more forceful when we consider limitations
on available care that are grounded
in extreme social injustice.
For instance, while there are many, many,
many things wrong with Tuskegee,
one was that it withheld syphilis treatments even once,
once were developed that were safe,
highly effective, and easy to implement.
Penicillin.
The no loss view apparently suggests
that this could be acceptable
if it were known that participants
would not be tested
or treated for syphilis outside of the trial,
even if the reasons they wouldn't be tested or
treated
are injustice in the form of extreme
racial discrimination
and economic marginalization.
But many people believe it would be a form of
wrongful
compounding of this injustice to allow,
as the no last few apparently does, for it
to be used to justify offering less
care to these individuals
than would be offered to other individuals
who have better options
outside of a trial.
Okay,
so a second proposal addresses that problem
by maintaining that baseline research
as you compare against
should be what participants should receive
rather than what
they actually would receive outside of the
trial.
This is the discovery or by rights
standard,
as opposed to the de facto or by fact
standard.
Those two standards come apart when the actually existing
situation
violates someone's legal, and more likely, their moral
rights,
as for instance, when extreme racial
discrimination
and economic marginalization meant that many black men in the
South
were not going to be diagnosed or treated, was treated for
syphilis
despite testing and treatment being cheap and easily
implementable.
So in those kinds of cases,
the appropriate local care view maintains
that we should not identify the standard
of care with white individuals or actually getting,
but instead with what they should be
getting.
This view, like the no last view,
also denies that where research conducted
is an irrelevant feature when it comes to the standard of
care,
but it says that it's relevant not because it affects
what people actually are getting outside of trials,
but because it affects what people should get outside
of a trial.
It's reasonable for different areas
to adopt different tertiary
standards of care based on their populations
needs, their resources, their priorities for instance,
health
against other socially valuable improvements and projects.
It can be at least can be reasonable
for more resource constrained contexts
to prioritize and decline
to offer the most expensive health
interventions, including some of those
that are among the global best
per the local appropriate care of you.
Whether the global best is something
that should be offered locally
is the morally relevant difference.
Okay,
of course, applying any of you like this requires
some method of determining
what people should be
getting outside of research, if that's
what we're going to be comparing against.
And that's very difficult.
So I'll briefly sketch some suggestions
for how to do it,
aiming mostly just to demonstrate the
complexity.
Okay, so first the Nuffield Council proposed
that
that minimum standard of care should be
whatever a country endeavors to provide
nationally e.g.
what is made available in the formulary
of the public health system.
In many circumstances, they maintain
it will be appropriate to offer an even higher level of care
than that.
And exceptionally, it may be okay to offer a lower
one.
But nonetheless, what the nation commits itself
to providing is the relevant standard to compare against.
Okay, so that's one proposal.
It's also UNAids in a report
from 2000, offers a somewhat more demanding
conception,
saying that the ideal is to provide
the best proven therapy.
So that's the ideal.
But at minimum, researchers must offer
the highest level
of care attainable in a country.
And that's going to depend on facts
about the sponsor and the host,
the availability of infrastructure
to provide care and treatment,
the potential duration and sustainability
of the care and treatment, and so on.
Both this and the Nuffield suggestion,
though,
do suffer from a problem similar to the no loss sphere.
Which is that it may be that what a nation
endeavors
to supply, or the highest level of that is
in fact available,
are poor for what are just actually bad
reasons.
So a nation might lack political
will to supply things that it really could and should,
and then
that would not be something that the nation endeavor to
provide itself
or a level of care attainable, but arguably is something
that should still be provided regardless.
So another UNAids report from 2021 offers
a more explicitly normative justification
to help with this problem.
This one recommends that researchers adopt
the standards recommended by W.H.O..
Those standards are based on available
evidence using a transparent framework,
and take into account values and preferences of end users
and providers, as well as equity costs and
feasibility.
So in this case, even if some countries lack
the political will to supply an intervention, if
W.H.O.
had recommended it, researchers would be obligated to supply the
trials.
A practical difficulty with this suggestion, though, is
that
global standards don't always reflect
local differences, and it may be hard
to distinguish whether countries departing from recommendations
due
to sort of political failures, as suggested above,
or whether it's actually a reasonable decision based on
the unique
features and challenges of that specific
country.
After all, as I pointed out at the beginning,
countries are very heterogeneous,
and even when recommendations are
specifically targeted at home, I see this
clinic might be importantly different.
Okay, so a final proposal,
this one from a colleague, which I also like.
Is that a fair priority setting process on the path to
universal
health coverage should be what defines local, appropriate
care.
This thought takes
as a starting point that universal health care is a
good goal,
and that any universal health care
system will need to make determinations
regarding what it covers, and also that making
this determinations will require some kind of fair
process.
So ideally, all around the world,
there will eventually be universal health
care and along with it, independent,
fair priority setting processes
aimed at determining what services should be included
in that country's basic health care package.
This standard from the health system could
then be used as a standard
of care and research.
Of course, we don't live in the future.
We live in the now.
And not all countries actually do have
universal health care or any priority
setting process, let alone a fair and transparent one like
this.
Nonetheless, even more such a process doesn't
exist.
We can still use it as a hypothetical ideal, which
can help us
think about what standard of care
there should be in different countries.
What are the sorts of interventions
that universal health
care in that country should cover?
Whatever those are, those are the interventions
which participants in research should also be entitled to.
Okay.
Let's apply the specific appropriate
care of you to AZT trials
since again, few like us, let alone
HIV Aids,
had fair priority setting processes
for health care coverage in the 90s.
We can't ask about what the actual results
of those processes were.
Still, we can imagine what they might have covered.
And really, given the basic fact that the
oh 76 regimen cost $800 per treatment
when the per person per year budgets were often less
than 100
or even less than 20 or $30,
makes it reasonable to expect that a fair priority setting
process
would not have selected 076 for provision
through a national health system.
So on this view, 76
would not count as part of appropriate
local care in those places,
and it wouldn't be wrong to test short
course against short course AZT
against placebo in those places.
Okay.
You've seen that there are ways of understanding a standard of
care
that's different from the global test
and also plausibly is morally relevant
because it matters whether participants
would or would not be harmed
on the de facto standard.
And it matters whether participants
are not deprived of something
they should be getting on the jury standard.
But considering the other objection,
this objection just maintains that,
look, even if local appropriate care
weren't to include an intervention,
if that intervention really does work
and researchers could provide it,
they need some justification not to.
After all, why not provide the best
treatment?
And wouldn't that just prevent more harm?
And isn't that a good thing?
Again, coming back to the obligations of
beneficence.
So the answer
which defenders of the short course
trials leaned on is that not providing
the best treatments is sometimes necessary
for doing socially valuable science.
In particular, testing against less
than the global best can be essential
for the ability of researchers to answer the questions
most pressing to local communities.
Setting this rationale and adding it on as another
requirement,
we get the view.
That testing against less than the global
best is permissible
when it doesn't undercut the local standard of care,
and it's also scientifically necessary
to test against the lesser
standard in order to conduct research
which is responsive to local health needs.
So again,
this is something that defenders of the short course trials
emphasized.
The point of the whole trial was to gain knowledge that would
be most
useful in the lmics, where they were being
contracted.
So Varmus and Satcher say the most compelling reasons
to use a placebo controlled study
is that it provides definitive
answers to questions about the safety
and value of the intervention
and the setting in which the study is performed.
And these are.
These answers are the point of the research without clear
and firm answers to whether and if so, how well an
intervention works.
It is impossible for a country to make
a sound judgment about the appropriateness
and financial feasibility of offering that intervention.
So the act,
of course, trials, in addition to not undercutting appropriate
local care, seem to meet this responsiveness
requirement.
The point was to develop knowledge
of a regimen that would be feasible
to implement in Olympics, and testing costs against
placebo
helped answer for policymakers how much better it was then.
Nothing.
Which in turn could tell them
whether it was worth investing scarce
resources in providing it.
Furthermore, in this case,
Furthermore, in this case, the placebo
control was particularly scientifically
important given the variability in perinatal transmission rates
and the fact that enabled the trials
to be conducted at a manageable size.
Okay, this yes.
Okay.
How do critics of the trials respond to the point
that they were responding to important local health needs,
and it was necessary to test against placebo to do
this?
Do they say that these important healthy
is simply cannot ever be met,
because the research necessary to do
so is unethical? No.
Instead, they say that these needs
should be in other ways.
For instance, Laurie and Wolfe argue
we shouldn't aim to develop inferior regimens for illnesses.
We should aim to develop equivalent ones.
So here they are saying
the researchers conducting the placebo
controlled trials assert that such trials
represent the only appropriate research
design, implying
that the answer to the question is this
sort of regimen better than nothing?
We take the more optimistic view that, given the findings
of A-76 and other clinical information,
researchers are quite capable
of designing a sort of regimen that's approximately as
effective as 076.
The proposal
for the Harvard study in Thailand states
the research question clearly.
Can we reduce the duration of the prophylactic?
This is another name for AZT, by the way, in the brackets
treatment without increasing the risk
of perinatal transmission of HIV.
That is, without compromising the demonstrated efficacy of
076.
We believe that such equivalency studies
of alternative antiretroviral regimens
will provide even more useful results
than placebo controlled trials,
without the deaths of hundreds of newborns
that are inevitable.
If placebo groups are used.
In a similar,
in a similar yet different vein.
Others argue that instead of developed
aiming to develop inferior regimens
for areas where resource scarcity
complicates provision of the global
best care, research should target those inequalities
in cells,
for instance, lowering drug prices
for existing drugs so that unaffordable
drugs become more affordable, or building health
infrastructure
so that impracticable regimens become practicable.
So here's
Rochelle Blank arguing as much, saying
wanting to develop a treatment regime
that is easier to administer
in the developing world context is not a scientific
reason.
It is an economic reason.
If we really want to improve medical care
for the world's poor,
perhaps we should spend more time thinking
about ensuring access to existing drugs,
as opposed to using this as a rationale for developing
new ones.
Okay, so what can be said
in response to these critiques?
Of course, we should agree immediately
that it's a great thing
to develop interventions for illnesses
there as good or better than those
in high income countries,
and also that researchers should try to conduct research
which can ameliorate the underlying inequalities
that drive differences in standard of care around the
world.
But the problem is that these suggestions
just might not be feasible.
It's difficult to make simpler or cheaper
and equally good interventions.
Otherwise, we would do it all the time.
If you could just ask for that and get it,
it would be great.
And demonstrating non-inferiority
against an active control
does typically require larger and more expensive trials.
And it is, if anything, even harder
to intervene on incorrect resource
inequalities and social systems.
That research is important and will hopefully be fruitful.
I don't think anyone could, with a straight face,
maintain that the results are just around the corner,
so we're not going to be able to respond
to local health needs, at least
in the short and medium term, effectively,
by using these strategies exclusively.
In fact, Surface Act was found to reduce
perinatal transmission by about half,
which was worse than the other
seven six regimen, but substantially better than
nothing.
And many babies were prevented
from carrying HIV through the administration of short
course,
insisting that development, insisting that instead of
developing it
through testing against placebo,
we should have waited for much more
difficult and far off research to finish.
We'd be saying that those babies in the here
and now need
to go unprotected, and so we should avoid,
in cases like these,
making the perfect the enemy of the good.
Okay,
so we should work to improve health
and like in a number of ways,
but developing new interventions,
including second test ones,
can be an important way of doing that. In the short
term.
And different efforts can't go in tandem.
We can research better interventions,
health system improvements, and also
feasible interventions that could make
a big difference in the here and now.
Okay,
wrapping things up
or transitioning into that.
So in this talk so far, we looked at three potential
standards
for defining the care that researchers
out of their trial participants.
The de facto standard or in their last view, the jury
standard
for local appropriate care review
and the global best view,
notably the Tertiary Standard and Local Appropriate Care of
you, admit
of many different possible specifications
depending on what you think.
Locally appropriate care is.
Along the lines of those proposals,
I was canvasing earlier.
We also added on one refinement responsiveness to local health
needs.
And then what I'm going to offer you
now is a limited conclusion,
which is that
the local appropriate care
review, together with the responsiveness
requirement, is superior
to the view that the global test is always
the required standard of care.
So here, just for reference, is the view
I'm referring to.
Again, it says contrary to global
best view, it's sometimes permissible
to provide less than the global best standard, specifically,
when participants still receive the appropriate local standard
and offering that instead of the global
best, it's also scientifically
necessary to respond to local health
needs.
Also, though I haven't discussed it prior,
you know that it is actually responsive
and provides appropriate care
is something that ideally should be ensured
through
meaningful engagement with local communities.
And I am adding that on.
Yeah.
Okay.
So often earlier at the reasons for embracing the global best
with respect to treating people equally
and applying universal ethical standards,
the appropriate
local care view with the responsiveness
requirement arguably does so.
The equal treatment and the universal standard
is that everyone in clinical research
should receive
at least locally appropriate care,
and that if they're receiving less than the global best, this
is because
it is scientifically necessary to respond to local health
needs.
Insistence on local appropriate care
also avoids much of the preventable
harm that allowing de facto standards of care to prevail
might allow.
Granted, it still does allow more harm
to befall participants
than insisting on the global best standard would,
because it will allow, for instance,
placebo groups.
When there is a global best intervention
that does work.
Nonetheless, although it does allow more of
that harm,
it does also prevent more harm to populations
through enabling the answering of what we've been arguing
are extremely important research questions.
So overall, I would say it does better
on the standard of preventing harm.
It prevents more harm.
Nor does it treat
participants merely as a means, at least not on a rating.
That makes much sense to me.
As I mentioned at the beginning, it's
often quite obscure what this term means.
People don't agree on a simple
definition, but
it's important here that
the reason that the global best is being
withheld is to respond to local health needs that participants
presumably also care about and want to see corrected,
and also that they have meaningful
opportunity to participate
in the governance of those decisions
through meaningful community engagement.
So under those conditions, it's hard to see them
being used merely as a means.
Okay.
And at the same time,
that responsive research is able to accommodate these
concerns.
It's also allows for researchers to answer questions that, in the
short
medium term, maybe the only realistic way,
as we have, of preventing
large amounts of suffering and death,
where the global best for you doesn't.
So my own view anyhow, and I'm going to repeat
for the umpteenth time, it's mine.
And it's not NIH is it's not the department's.
I'm not speaking for anyone else.
My view is that working through this controversy over
standards
of care reveals that there are just better
alternatives to the global best view.
And this, in particular strikes me
as a promising option.
Of course, I'm happy to hear if you disagree with me in the
Q&A.
Finally, the last slide.
We have some meetings for those interested
in following up more deeply.