So, I now want to just say
a few comments in the remaining time
about some statistical approaches.
And we'll start with blind studies.
You may not realize that the first person
to use a blind study was Benjamin Franklin.
In 1784, King Louis XVI of France
asked Franklin to study a problem
he had, where his people in Paris
were hugging the trees in Versailles.
And they were convinced it may them better, it cured all
their ills.
And so, the king didn't like that.
So, he asked Franklin to appoint a committee,
and he did.
And on that committee were all sorts of famous people,
such as Guillotine of the Knife [spelled phonetically] and
others.
And they went to the Versailles and they hugged the trees, this
committee,
and they couldn't decide whether it made any difference.
So, they decided to bring in volunteers,
blindfold them, and give them objects
to hold, some of which were tree limbs and pieces of the
Versailles' trees.
And they concluded that it didn't work and --
but Franklin was phenomenally observant,
and he identified the placebo effect.
And this was also the discovery of the placebo effect.
So, the first paper using blinded approach
to do clinical research
and identifying a placebo effect was done by Franklin in the
paper --
I have a copy of it if anybody's interested
-- is shown here on the right.
Probably didn't know that about Franklin.
Now, placebo or blinding was sort of ignored
them,
but a few hundred years later, Torald Sollman, who was a great
statistician,
suggested a placebo control
and blinded observer might be a solution to
investigator bias.
And that was about 1930.
And then, of course, blindfold tests
were widely used by advertisers'
and consumers' groups in the 1930s and 1940s.
The first use of statistics was a borrowed
idea,
borrowed from Sir Ronald Aylmer Fisher,
who applied statistics for agriculture use
and introduced the application of statistics
in experimental design.
And for farming and plant fertility,
the concept of randomizations
and analysis of variance were developed by him.
And then, it was later applied to medicine.
The first modern example of a controlled
clinical trial was done by Sir
Austin Bradford in 1948, who did a study to show
that streptomycin was an effective drug
for pulmonary tuberculosis.
This was a beautiful study and clearly showed the
importance
of a randomized control group to prove that
streptomycin was an effective therapy for TB.
Okay, medical ethics.
There's a -- you probably heard of Gerhard
Hansen,
who discovered the cause of leprosy in 1874.
But this claim was not well-received at the
time.
And he became desperate to prove that it really was the cause of
leprosy.
So, without telling some nurses, he inoculated them
with live leprosy bacillus, and he gave them leprosy.
And he was sued, and he lost.
And he was removed from his position,
but for reasons that aren't completely clear,
he was so well-recognized in his institution
that he was allowed to still work.
But he committed what would be considered
a grave violation of ethical principles.
In 1898, William Osler, at a meeting,
said to Giuseppe Sanarelli,
who had discovered the etiologic agent
for yellow fever, and did somewhat similar to
what Hansen did: he injected this agent into
volunteers
without telling them and gave them yellow fever.
He said, "To deliberately inject a poison of known high-degree of
virulence
into a human being, unless you obtain
a man's consent, is criminal."
And that was the end of Sanarelli's career,
unlike Hansen.
So, that was sort of the beginning
of informed consent.
And I'm going to jump ahead to 1953, the day
shortly
-- within days of the Clinical Center
opening here at NIH, when the medical board,
in their very first meeting under Luther Terry, who was
chair
of that board, said that, "They had to provide each
patient
with a reasonable understanding of his role in a study project
and the means of obtaining evidence
for such understand and consent."
And this policy at the Clinical Center
had a big effect.
It had a big effect on Congress.
And the Harris -- Kefauver-Harris
amendment to the FDA's law stipulated
that subjects must be told whether a drug
is being used for investigational purposes.
And the United States Surgeon General issued a policy
saying that
any federal money used to support research
using drug development required
review by an institutional review board
to make sure that it was ethical.
And that was on all public health service
grants.
In 1967, relatively recently, the FDA required all new drug
sponsor obtain informed consent for use of investigational drugs
in humans.
And you're going to hear about ethics
and the history of ethics from Christine
Grady and others, and you'll learn more
about the background and current policies.
So, this is my last slide.
And I wanted to leave you with the message
-- if you haven't figured it out --
that the business of clinical research
has been an international business
with great people literally in every culture
and we're all the beneficiaries of that.
And what we do today, I think, is just capitalizing
on what an awful lot of people have done before
us.
In 1995,
Doctor John Gallin created a curriculum
and clinical research
that started as a seminar with 25 students
at the National Institutes of Health
in Bethesda, Maryland.
Since then, Doctor Gallin and his team
expanded and modernized
the introduction to the Principles
of Practice, a clinical research course
which now enrolls thousands of participants
from over 150 countries around the world.
Doctor Gallin's remarkable career
at the NIH
and infectious disease research, and the role of inflammation
has spanned over half a century, a testament to his unwavering
dedication.
For 23 years, he led the NIH Clinical Center,
which is the hospital at the NIH,
as its director.
He fondly referred to the clinical center
as the House of Hope for its patient
centric approach to improving health
through clinical research.
We are sorry to share that
since the filming of this presentation
Doctor Gallin has passed away.
However, his legacy lives on, inspiring
and shaping
the future of clinical research training for generations to
come.