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So, I now want to just say

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a few comments in the remaining
time

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about some statistical
approaches.

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And we'll start with blind
studies.

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You may not realize that the
first person

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to use a blind study was
Benjamin Franklin.

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In 1784, King Louis XVI of
France

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asked Franklin to study a
problem

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he had, where his people in
Paris

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were hugging the trees in
Versailles.

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And they were convinced it
may them better, it cured all

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their ills.

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And so, the king didn't like
that.

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So, he asked Franklin to appoint
a committee,

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and he did.

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And on that committee
were all sorts of famous people,

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such as Guillotine of the Knife
[spelled phonetically] and

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others.

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And they went to the Versailles
and they hugged the trees, this

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committee,

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and they couldn't decide
whether it made any difference.

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So, they decided to bring in
volunteers,

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blindfold them, and give them
objects

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to hold, some of which were tree
limbs and pieces of the

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Versailles' trees.

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And they concluded that it
didn't work and --

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but Franklin was phenomenally
observant,

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and he identified the placebo
effect.

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And this was also the discovery
of the placebo effect.

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So, the first paper using
blinded approach

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to do clinical research

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and identifying a placebo effect
was done by Franklin in the

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paper --

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I have a copy of it if anybody's
interested

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-- is shown here on the right.

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Probably didn't know that about
Franklin.

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Now, placebo
or blinding was sort of ignored

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them,

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but a few hundred years later,
Torald Sollman, who was a great

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statistician,

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suggested a placebo control

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and blinded observer
might be a solution to

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investigator bias.

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And that was about 1930.

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And then, of course, blindfold
tests

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were widely used by advertisers'

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and consumers' groups in the
1930s and 1940s.

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The first use of statistics was
a borrowed

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idea,

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borrowed from Sir Ronald Aylmer
Fisher,

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who applied statistics for
agriculture use

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and introduced the application
of statistics

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in experimental design.

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And for farming and plant
fertility,

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the concept of randomizations

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and analysis of variance
were developed by him.

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And then, it was later applied
to medicine.

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The first modern example of a
controlled

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clinical trial was done by Sir

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Austin Bradford in 1948,
who did a study to show

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that streptomycin was an
effective drug

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for pulmonary tuberculosis.

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This was a beautiful study
and clearly showed the

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importance

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of a randomized control group to
prove that

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streptomycin was an effective
therapy for TB.

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Okay, medical ethics.

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There's a --
you probably heard of Gerhard

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Hansen,

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who discovered the cause of
leprosy in 1874.

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But this claim
was not well-received at the

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time.

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And he became desperate to prove
that it really was the cause of

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leprosy.

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So, without telling some nurses,
he inoculated them

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with live leprosy bacillus,
and he gave them leprosy.

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And he was sued, and he lost.

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And he was removed from his
position,

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but for reasons that aren't
completely clear,

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he was so well-recognized in his
institution

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that he was allowed to still
work.

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But he committed what would be
considered

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a grave violation of ethical
principles.

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In 1898, William Osler, at a
meeting,

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said to Giuseppe Sanarelli,

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who had discovered the etiologic
agent

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for yellow fever, and did
somewhat similar to

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what Hansen did:
he injected this agent into

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volunteers

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without telling them
and gave them yellow fever.

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He said, "To deliberately inject
a poison of known high-degree of

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virulence

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into a human being, unless you
obtain

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a man's consent, is criminal."

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And that was the end of
Sanarelli's career,

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unlike Hansen.

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So, that was sort of the
beginning

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of informed consent.

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And I'm going to jump ahead to
1953, the day

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shortly

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-- within days of the Clinical
Center

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opening here at NIH, when the
medical board,

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in their very first meeting
under Luther Terry, who was

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chair

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of that board, said
that, "They had to provide each

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patient

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with a reasonable understanding
of his role in a study project

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and the means of obtaining
evidence

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for such understand and
consent."

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And this policy at the Clinical
Center

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had a big effect.

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It had a big effect on Congress.

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And the Harris --
Kefauver-Harris

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amendment to the FDA's law
stipulated

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that subjects must be told
whether a drug

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is being used for
investigational purposes.

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And the United States
Surgeon General issued a policy

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saying that

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any federal money used to
support research

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using drug development required

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review by an institutional
review board

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to make sure that it was
ethical.

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And that was on all public
health service

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grants.

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In 1967, relatively recently,
the FDA required all new drug

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sponsor obtain informed consent
for use of investigational drugs

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in humans.

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And you're going to hear about
ethics

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and the history of ethics from
Christine

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Grady and others, and you'll
learn more

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about the background and current
policies.

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So, this is my last slide.

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And I wanted to leave you with
the message

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-- if you haven't figured it out
--

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that the business of clinical
research

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has been an international
business

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with great people literally in
every culture

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and we're all the beneficiaries
of that.

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And what we do today,
I think, is just capitalizing

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on what an awful
lot of people have done before

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us.

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In 1995,

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Doctor John Gallin created a
curriculum

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and clinical research

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that started as a seminar with
25 students

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at the National Institutes of
Health

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in Bethesda, Maryland.

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Since then, Doctor Gallin and
his team

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expanded and modernized

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the introduction to the
Principles

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of Practice, a clinical research
course

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which now enrolls
thousands of participants

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from over 150 countries around
the world.

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Doctor Gallin's remarkable
career

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at the NIH

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and infectious disease research,
and the role of inflammation

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has spanned over half a century,
a testament to his unwavering

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dedication.

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For 23 years,
he led the NIH Clinical Center,

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which is the hospital at the
NIH,

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as its director.

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He fondly referred to the
clinical center

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as the House of Hope for its
patient

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centric approach to improving
health

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through clinical research.

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We are sorry to share that

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since the filming of this
presentation

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Doctor Gallin has passed away.

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However, his legacy lives on,
inspiring

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and shaping

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the future of clinical research
training for generations to

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come.