So what I'm going to talk
about, this morning is what I'll call
a scandalously short history of research
ethics.
There's so much more I could say.
Hopefully.
What I, speak to you about this morning
will give you some appreciation
of the role of the past in shaping the rules for
research
that governed, the use of human subjects
in research, you know, for decades.
And as Doctor Grady so eloquently described.
Require,
vigilance because research changes,
society changes.
And, it's important to keep the fact that
these are changeable in mind.
So what I want to
focus on today is why we have the particular kinds of rules
that we had
and the role of scandals, tragedies, revelations of
abuses,
shaped the particular, regulations.
And I want to also make a broader
historical point
that US policy, health policy in general,
over the course of the 20th century
also was responsive to,
to scandal and to tragedy.
And I'm just going to go through,
very briefly, a series of,
examples to help put this in mind.
Some of you may know that the first food
and drug,
regulation, occurred in 1906.
There were concerns about the safety
of patent medicines, for example,
and the lack of safety.
You could see cocaine, tooth products
and the the wine is endorsed by the Pope.
It actually contains, cocaine in small
doses.
But it was really the concern over the safety of the food
supply.
Some of you may have read, Upton Sinclair's searing
indictment of the meatpacking industry
in Chicago, The Jungle.
And, as he famously said, he aim for the nation's heart.
And he reached the stomach.
But that pushed the U.S.
Congress to pass the Food and Drug Act in
1906,
which was the first sort of regulatory
venture
to ensure the safety of food and drugs, used by American
consumers.
The major revision, a major revision of the Food and
Drug Act,
occurred in 1938 following this terrible tragedy.
The Elixir of Self, an Elamite tragedy
in which a chemist used as a solvent
for the new sulfa drugs, diethylene glycol, which is also
used
in antifreeze, led to the deaths of more than 100 children.
There was nothing the Food and Drug
Administration could actually do to pull the drugs off the
market.
There were also concerns about the safety of cosmetics,
you know, mascara that would blind women reducing
drugs
that would make you lose weight but also kill you.
And it led to the first sort of major
revisions
of the, of the food and,
Drug and Cosmetic Act for the first time,
that drugs and cosmetics actually had to be tested for
toxicity
before marketing, that there had to be
corrections,
on the package, and that some drugs
were too dangerous to be dispensed
just over the counter, but had to be dispensed by
prescription only.
Children born with unusual birth defects,
eventually connected to the prenatal use of
thalidomide,
which led to, amendments to the food,
drug and,
act in the Father Harris amendments
that the FDA, for the first time
could demand scientific data to,
to determine that the Drug Act worked
in a very different realm.
Talking about, the regulation of animal
experimentation
for something like seven decades,
Congress had been, revisiting
potential legislation to protect animals,
used in research after this photo essay
that appeared in life magazine in 1966.
Congress received more mail, about this.
You know, the theft of dogs, organized
pet theft,
the treatment of animals before they got to the
laboratory.
Congress got more mail than they did
about the,
than it did about the Vietnam War
and passed the Animal Welfare Act,
which, like the National Research Act,
has been amended over
the years as animal experimentation itself
has also changed.
And finally, sort of the National Research
Act, which,
well, we'll be talking about today
that was shaped by revelations, particularly in the 1960s, of
abuses
of human subjects, in American medical research.
So even before the Tuskegee
syphilis study, which I would argue
was the tipping point for Congress to pass
that legislation in 1974, there were Nazi medical
experiments.
And there was also, experimentation
in the United States.
Both the, history of human experimentation
and and history of controversy and concern about the moral
problems
raised by human experimentation are much older.
And I'm going to give you a very brief example.
In 1900, the United States Congress
actually entertained,
legislation
that would have, a Senate bill 3424
that would have regulated
human experimentation in the District of Columbia,
that in 1900
it would have required investigators
to disclose in advance, you know, the purpose and
procedures
of any non therapeutic experiments
involving human beings.
And it also called for an,
an explicit ban on using, people in studies,
people who were deemed unable to and unable
to consent to participation.
This included children under the age
of 21, infants and even pregnant women
who were deemed unable to exercise
sort of adult decision making capacity.
That's another story.
So then these bills did not pass,
but it's it exhibits sort of a concern
that people had about the direction
in which medical research was developing.
But I don't want to give you the idea
that responsible
medical experimentation was, in fact,
not occurring at this time.
And one of the best examples of this
is the experiments that were conducted
under the auspices of the U.S.
Army, the Yellow Fever Board experiments
in Cuba in 1900 and 1901.
Some of you may know the name of Walter
Reed.
Walter Reed led a commission.
They were interested in, establishing how yellow
fever spread.
Yellow fever was a, was a real threat,
in the southern United States
and Central America and South America
in this time period.
And they, were determined to establish
sort of the vector
of yellow fever, which they eventually did
for that research.
They had to expose human beings to considerable risk.
They needed,
they needed, people who were new to the
island.
Many of these people were newly arrived
Spanish people.
And but they needed naive subjects
in order to see if they could
spread the disease through various means,
including mosquitoes.
And Reed introduced a written permission form
that was available in both English and Spanish.
It, you know, it did not would not meet
our standards of informed consent.
But it was extraordinary for its time,
warning of dangers
to life and experiments with infected clothing and
mosquitoes.
It promised good medical care, and it also identified
a considerable compensation ration
that the men would receive if they signed
and were selected for the study.
Subjects who were selected actually
receive $100 in American gold, which was a considerable sum at
the time,
and they promised to give $200
to the surviving family if death occurs.
Now, Frank,
fortunately, none of the participants
in the study died,
although one of the investigators
actually succumbed
to yellow fever during the course of the study.
So I want to begin with or I want to shift,
if you will, to World War two, which does represent an
important moment
in the history of research in the United States
and also in the history of research
ethics.
In 1941, President Roosevelt's Office
for Scientific and Research was, was
established.
And importantly for medical research
was the advent of unprecedented
federal funding for medical research
related to the war effort.
And this was something that would continue
after the war
and was an important moment, sort of
in the growing recognition of the importance of medical
research
not only to U.S., society, but, to our place in the world as
well.
Now, I also
mentioned, if you will, sort of Nazi
medical experimentation and again,
in as in the United States, high ranking Nazi
officials believed that medical research
would help Germany win the war.
And they undertook an ambitious.
And if frightening, program of research
in order to advance sort of their medical interests.
Some of these may be familiar to you,
but I also think it's it's useful
just to briefly,
briefly revisit them.
Among the first that were undertaken were
those at the Dachau concentration camp.
They were interested in studying the effects of
immersion
and freezing water and and techniques of rewarming.
These often ended with the, death of the,
participant.
Sort of.
How long would it take to die
if you were, you know, in the freezing water of wood
equipment,
for example, help you to survive longer
so that you might be rescued and so forth.
Also, at concentration camp, with death as an endpoint,
there were studies of the effects
of high altitude and low oxygen
concentration and death as an endpoint was
important
because they wanted to study postmortem changes in the brain.
As in the
United States, the Nazis were interested
in seawater studies
how to quickly desalinate sea water
to promote
survival at sea against so that fliers,
for example, could be rescued or Navy personnel.
Here you see a victim of a Roma victim
of Nazi medical experiments
that also involved, among other things,
you know, giving people,
to see how long you'd survive with absolutely no water,
forcing
seawater on people, giving seawater
flavored with a tomato extract,
all involving great suffering, if not death to the
participants.
So the study of burns and wounds
was also of great interest in the United States.
A standard burn and wound was developed on
animal subjects, chiefly pigs and dogs.
The Nazis used Polish women at the Ravensbrück concentration
camp,
where they deliberately infect, you know, cut open
to create a wound, infected it with bacteria, dirt, slivers of
glass
in order to study, sort of the natural history of
the wound.
Various ways to, to promote its healing.
After the war,
after the trials of the major Nazi war
criminals, the U.S.
military tribunal took on various groups
in the first prosecution of various groups for war
crimes.
And the first group was the Nazi doctors.
In 1946, the trial of United States
versus Carl Brandt and all began.
This was an action brought against 23
high ranking Nazi medical personnel,
22 men and one woman, a woman doctor who had presided
over
some of those burn and wound studies
at Ravensbrück.
There's much that can be said.
And there are entire books written about the Nazi doctors
trial.
And what I'll just say here
is that what among the issues for the tribunal, for the
tribunal
was how to judge these were these normal medical
research?
Were there rules about research, how to assess the guilt
or innocence of the Nazi doctors on trial?
And in so doing, they
actually formulated, a list of principles
that constituted permissible or acceptable human
experimentation.
I will say that, there was some squirming on the
part
of some of the American doctors who were
called in to advise about the trial.
The defense attorneys representing
Karl Brandt, for example, sort of made a comparison.
Well, what was so different with Nazi
concentration camp experiments
involving prisoners and the kinds of experiments,
that were being conducted in American persons at the same
time,
experiments that involved deliberate infection with
disease
and experiments in which sometimes
prisoners didn't fact die.
One of the things that was actually,
brought into evidence by the Nazi,
excuse me, by the German, defense attorney
was this issue of life
magazine from June 4th, 1945 that featured malaria research
at the Stateville prison in Illinois, where,
some, 40
or 50 inmates actually underwent infection
with, loaded mosquitoes in order to study
malaria and its treatment.
So, as I already mentioned,
when they delivered their verdict
in the Nazi doctors trial, they,
the judges, with the advice of several
physicians,
put together a set of of ten principles
called permissible medical experiments,
which we've come to know and it seems to
be universally called the Nuremberg Code.
Usually in discussions about the Nuremberg Code,
it's the first principle that gets the,
the attention and deservedly so.
It sets an extraordinarily high standard
that the voluntary consent of the human
subject is absolutely essential.
It does not permit proxy consent.
It means, for example, that children are not legitimate
subjects according to the Nuremberg Code.
And it also excludes, you know, people in institutions
and so forth, depending on one's
interpretation.
There were, of course, others.
I'm not going to go through them,
but just some that were seen as extremely
important,
to American physicians who wanted to defend medical
research.
That research had been based on prior
animal studies.
It was intended at the outset to avoid unnecessary suffering,
should not have death as an endpoint.
Studies risk should not exceed benefit,
and that only scientifically
qualified personnel were to conduct the studies.
So it's in case you're interested,
let me just tell you that seven of
the Nazi doctors were actually acquitted
on insufficient evidence.
Seven received death sentences and nine received
prison sentences ranging from ten years
to life imprisonment.
And I will say it was surprising to me
that almost all of the nine
who received prison sentences had their sentences, seriously,
commuted to like one year or, only a few years.
And they were back in medical practice.
In fact, in Germany, Carl Brandt was among
those sentenced to death.
He actually offered his body for experimentation to the U.S.
Army, which rejected his offer.
And and he was, hanged at Landsberg Prison.
So there is a real debate among my colleagues and
interested
in the history of research ethics
and and the history of research
in the 1950s and 60s and 70s in the United States, about
what does the Nuremberg Code actually mean to medical
researchers?
And, you know, there are arguments
sort of on on both sides.
Some people have have made the claim that, you know, most
American
medical researchers did not even know
that the Nuremberg Code existed.
I do not support this.
In 1953, for example, the journal science, the,
you know, the scientific journal with the largest circulation
actually published the code in a big article.
They published the results of a symposium
discussing this.
It seems to me that that that's reaching a broad
audience.
I will also say that, in 1953,
the secretary of defense, Charlie Wilson, actually,
signed,
you know, a memorandum requiring the code
for all research conducted by the U.S.
Armed forces.
Curiously, and perhaps ironically,
the document was also classified
as top secret.
So it seems to be something of an implement implementation,
failure.
But nonetheless, it came to the attention of many
people.
On the other hand,
a number of, you know, commentators have
argued
that most American researchers kind of dismiss the Nuremberg
Code
as something that Germans and barbarians
Nazis would need,
but that American researchers did not need
because they were already careful
and concerned about both the safety
and welfare of their subjects.
I think
it's important to keep in mind, though,
that if you were to ask,
what American researchers have, investigators have met the
Nuremberg Code
and its requirements in research that was
going on both during the war and after.
Absolutely not.
Because, again, it's set an extra ordinarily
high standard.
So if I want to make the point here
that in the 1950s,
there was tremendous social support
for the medical research enterprise
and great,
admiration for medical researchers
themselves.
And in part, it's because,
medical research at this time was associated with volunteers.
It was a voluntary action.
There was actually sort of a society
created for both these human guinea pigs
in which they were honored for their willingness
to risk their welfare and, and lives to advance medical
research.
There was
also a long tradition of self-experimentation,
which many, people in the public and I think some researchers
saw as kind of the gold standard.
If an investigator was willing to risk his
or or her own body,
then, you know, that was a test of how much they were invested
in it.
Today, of course, Self-Experimentation is not,
recommended.
And I'm sure you'll hear more about that,
in, in the rest of the course.
I also say the 1950s, there had been
so many great advances in medicine
associated
with the wartime experience, primarily things like
antibiotics,
the importance of blood transfusion,
that many people were confident
that only great things were also going to come.
And so, in part, I think it's important to keep
in mind
that the kind of the social, response
to, to research and even research
tragedy was very different than it would be only a decade
later.
I've always been surprised when I found this article.
This is from the New York Times.
As you can see, it's reporting the death
in research of an 18 year
old freshman at Seattle University
in, he was
he had had volunteered to take part
in a blood substitute
study, and, died,
and his father was asked by reporters,
was he going to sue the university or,
you know, or sue the authorities?
And his father said, of course not.
This was a, you know, a project,
a project that was intended to advance
medical knowledge.
He was going to treasure his son's,
you know, heroic participation
in such a study.
And you could imagine it would be
a very different response today if,
you know, a freshman died in a research
project.
And that may also explain sort of the willingness to have large
numbers
of children participate in trials of the new
polio vaccine in 1954.
I'll remind you, polio, reversed
the usual trend of infectious disease
death in the 19.
In the 20th century.
Epidemic polio got only worse.
It was it's, you know, terrified American parents and
children.
And 1952 was the worst, polio epidemic on
record.
Two years later,
Jonas Salk and developed with
with funding from the National Foundation
for Infantile Paralysis, a vaccine.
2000 American children participated in trials of the
vaccine.
So here you see a picture of those polio,
pioneer years.
And here you see, it's not an informed consent
form,
and it's actually a parental request form
for a child
to participate in this poliomyelitis
vaccination field trial.
But it represents sort of an early attempt
to, at least in,
in some ways not as advanced as Walter
Reed's from 1900, but
an early attempt to inform, you know, the,
at least the parent of the child,
the conditions of participation, the risks involved,
and for the parent to authorize their
participation.
And, of course, it led to the successful,
demonstration of an effective and
mostly safe vaccine that,
that was responsible for the eradication
of polio in the United States.
And, and again, sort of assumed the world,
or at least that's the hope
now for the
medical research community, who are not unaware of
some of the moral problems of medical experimentation in
this period.
They were concerned
that the Nuremberg Code represented, too.
It was an unworkable guide
for their medical research.
And again, as I've already said, it
would not allow experiments on children.
It would not allow experiments on people
who were institutionalized,
the dying and the mentally ill.
And there were efforts.
I'm most familiar with the efforts of the World
Medical Association, which Doctor Grady already
referred to.
And it's a ten year effort from 1954
to 1964 to create a kind of workable
code of ethics.
And again, this is the challenge.
That is a perennial one.
How do you protect human subjects
and at the same time,
enable medical research to advance,
from which presumably all would benefit?
So it was
largely the Committee on Ethics of the
LeMay
and its American representatives,
French representatives
and British representatives who struggled over what would be
an effective set of recommendations
for clinical researchers.
Well, this culminated and you've
already heard
in the 1964 Declaration of Helsinki, in
which,
physicians from all over the world
unanimously recommended
not a code of ethics, but recommendations guiding,
guiding, clinical research.
So this is refers to the original
declaration of Helsinki in 1964.
And as you know, it's undergone, significant revisions.
And perhaps there's one under, happening
even as we speak.
But what was perhaps most important difference for
researchers
from the earlier Nuremberg Code was that it permitted proxy
consent
and it and,
and so, for example, children could, could participate in
trials
of new vaccines, a number of new vaccines
that are coming online,
that,
prisoner populations, which, could participate
in trials of new drugs and sort of there's
an explosion in the number of drugs
that become available, in the 1950s, 60s and 70s.
And I'll just remind you, sort of prisoner
experimentation was not permitted,
in, in countries like, the UK and France,
but in the United States,
every major pharmaceutical company
had a major prison ward,
facility for testing new drugs
and other, interventions.
This is just to show sort of, again,
sort of,
research and research ethics
are, you know, are not stagnant.
They change over time, both the way research is
conducted
and how it's understood and the context
in which it's being, experienced,
as well as, sort of
the challenges, ethical challenges
that confront us.
So that's being done on the international
level back in the United States.
I want to return now to the,
to the United
States in its response to scandal and tragedy.
What will precipitate the National Research Act
in 1974?
Well, as I've already indicated, by
the 1960s,
there's no longer sort of faith in the medical research
enterprise.
This is a time of challenge to all institutions.
And physicians are no exception.
And two things I think are largely responsible for
propelling,
Congress to act.
One is the release of Doctor Henry Beecher's
bombshell article in the New England
Journal of Medicine.
And again, sort of what represents the
tipping
point, the revelation in 1972
of a 40 year study of untreated syphilis
in Tuskegee, Alabama.
So for those of you who have not read
this article are not familiar.
Henry Beecher is a very important,
figure in the history of bioethics.
He was a professor of anesthesia research
at Harvard Medical School.
He would go on and other, arenas as a convener of the Harvard ad
hoc,
Committee on Brain Death.
But in
in 1966, he published this article,
which I encourage you to read.
It's very short.
And this article, Ethics in Clinical Research
actually discusses, without naming names
or naming the journals, talks
about 22 examples of what he called
questionable research practices.
And they were questionable in that
they were, insofar as they were being
conducted without concern for the safety
and welfare of the participants.
And the overriding point the feature wanted to
communicate
was that this wasn't sort of from fringe or,
researchers, but from people at the very
heart
of the medical research enterprises
that the U.S.
mainstream researchers at major institutions.
And another point that Beecher wanted to make
is that it involved populations that would certainly read,
I think most people's definitions of vulnerable,
who were the subjects mentally defective children?
That's the term that was used at the time,
quote, mentally
retarded people and quote, juvenile
delinquents.
The very elderly, senile and demented
soldiers in the armed forces,
charity patients, the terminally ill.
A group that we don't often see.
Alcoholics, children and newborns
and patients at the NIH Clinical Center.
Now, two of his 22 examples,
would have been well known to readers
of the New York Times and other major
newspapers in the US, and perhaps known to you as
well,
example 16, which was not identified
as the, you know, the studies on hepatitis
at the Willowbrook State School, but nonetheless involves them.
Willowbrook was a large
and underfunded a state institution on Staten
Island.
It was intended for mentally defective
children.
It, it was a terrible place by all.
By all observers.
At the institution, hepatitis was rife.
And Saul Krugman, a,
a pediatrician at NYU, proposed
to use newly admitted children
with their parents consent and actually give them
hepatitis.
Study them in a special ward
at, Willowbrook for, to understand
the natural history of hepatitis
A, and also ways in which the disease
might be effectively treated
if they were using, for example, infusions of gamma globulin at
the time.
But it was the idea that testers are using, you
know,
the most vulnerable children actually
giving them disease that disturbed many.
So, again, here's
Krugman is also, again, the idea was to work
toward an effective vaccine and prevent the spread of this
disease.
Krugman through I mean, throughout his
career, continued to defend the studies.
I already mentioned parental concern, parental
consent,
which in
some ways was sort of a, you know, he was in the
vanguard.
But critics have emphasized that it was group consent.
He'd bring parents together and, you know, tell them about
the study,
have them sign sort of a brief, you know, brief
form.
And many people have found that problematic.
And also issues about, you know, withholding gamma globulin from
infected
children, once they had established
that would have a beneficial effect.
The other the other one that's, would have been known to
readers
of the New York Times and again, other papers was the experiments
conducted
at the Jewish Chronic Disease Hospital,
in which they were interested in studying
sort of what live cancer cells do in the bodies of elderly
patients.
It was funded by the U.S.
Public Health Service and the American Cancer Society.
It, they did not get the consent of these elderly people.
Some are, you know, identified as senile and demented.
And the reason being that they didn't wish to
stir up
any, unnecessary anxieties.
And the patients who had phobia and ignorance
about cancer.
Chester Southam was the principal
investigator.
He was at Memorial Sloan Kettering.
He did not do his his case.
Any favor when he gave and,
he gave an interview to science again,
the magazine of the triple A s,
and the reporter asked,
Doctor Southam, what would he have experimented
on himself with these injections of live
cancer cells?
I'm not going to read the long quote.
He basically said I would not have hesitated
if it would have served a useful purpose.
And then he goes on, he said, I did not regard the experiment
as dangerous, but his the last sentence
I'll call your attention to.
But let's face it, there are relatively
few skilled cancer researchers,
and it seems stupid to take even the little risk, that did not
win him.
Friends at admirers.
But again,
perhaps the the singular most important moment,
capping more than a decade of
discussions about legislation to protect human subjects
was the revelation of the Tuskegee
Syphilis Study on
July 25th, 1972.
I think that many of you are familiar
with the Tuskegee syphilis study.
And so I just have a very a few very brief slides.
You know, that the study actually,
began in 1932.
It was, intended to be a six month study.
It was then extended and until it was formally ended
by the Department of Health, education
and Welfare in 1972,
it was overseen by the Public Health
Service.
Surgeon General Thomas Perron.
In the, you know, after, in 1936 to 1948,
Perron was a crusader against this,
syphilis and,
other sexually transmitted diseases
and intent on vanquishing,
these diseases from the United States
and sort of
openly discussing sort of that the toll that this disease
exerted.
So, it turns out they did it,
a study at six counties of the incidence of
syphilis.
They found Macon County had an
extraordinarily high,
incidence.
And it was selected because there was a,
veterans hospital for African American, servicemen
in Tuskegee for the initial six month study.
From the start.
It involved deception of the participants.
Doctor Raven Von Miller, who played an important role in
the study,
wrote letters to the men offering
what he called
last chance for special free treatment
for their bad blood.
And it turns out that, what he was
offering was lumbar puncture, which was,
undertaken to obtain spinal fluid for diagnosis.
For diagnosis.
It's a completely diagnostic procedure.
There's nothing curative about it.
The men found it very painful.
And actually, one of the things I think
is interesting and suggests
that there's even some limited agency
on the part of participants is that they,
it was done one time only because the researchers
realized
if they wanted to do more spinal punctures
in the future, their research population
would completely absent itself from further participation
in some to at.
Sometimes Tuskegee was talked about a study of nature.
These were men who were were very poor.
They didn't have medical care.
They weren't going to see a doctor.
They weren't going to get treatment.
But the public health service
also took steps to ensure that they would not get
treatment when,
at least 254 of the men were called up
for military service in World War two,
and the Public Health Service intervened with the draft board
and said,
do not take these men because we they're in our study
and we want to follow their untreated syphilis.
If they had been inducted into the Army,
or even if they hadn't found if once
they were identified as syphilitic,
they would have received free treatment
for their disease, from the Army.
Crucial to the success of the
society of the study was Nurse Eunice Rivers.
She was a trained nurse.
She graduated from Bristol University,
and she was crucial
in bridging sort of the large cultural gap
between these, unlettered farmers
and, the Public Health Service
researchers who came at irregular
intervals over, over the 40 years.
It was Nurse Rivers, for example,
who was given the job
of obtaining permission for postmortem,
participation.
It's always interesting to me
that the one thing they asked them
for was permission for autopsy.
All right.
And their families, her job became much easier when the
Milbank Fund
offered a burial stipend, initially $50, later raised to
$100.
And as she reported in public health
reports in a 1953 article,
she had only one refusal in 140 requests,
so the study was not a secret.
There were 13 publications between 1936 and 1974,
in the open medical literature, but it's a 1954
after things like the publication
and science of the Nuremberg Code,
that for the first time men in the study
were identified as, quote, volunteers
with social incentives.
In an effort to kind of promote the,
the knowledge that they were in a medical research study.
In 1957, the Public Health Service,
rewarded the men
with a with a certificate signed by the surgeon general.
And each man in the study received a dollar for every year
they had participated. So they received $25.
And this certificate that says,
active participation
in the Tuskegee Medical Research Study.
Now, that did not translate necessarily
to the men who who still may
not have known that they were actively
participating in medical research.
So it's in 1972 that the,
study is revealed, 1974.
Oh, there were hearings,
presided by,
Senator Ted Kennedy, among others.
And the creation of the National Commission
to study the moral issues posed by human experimentation.
And, this is the organization that also sponsors,
the publication of the Belmont Report
about what you've heard so much.
One of the things that I will say
is that I, I certainly hope that I've
whetted your appetite for, an interest
in the history of human experimentation.