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So, I now want to just say

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a few comments in the remaining time
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
to use a blind study was Benjamin Franklin.

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In 1784, King Louis XVI of France
asked Franklin to study a problem

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he had, where his people in Paris
were hugging the trees in Versailles.

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

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And they went to the Versailles
and they hugged the trees, this 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,
blindfold them, and give them objects

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to hold, some of which were tree
limbs and pieces of the Versailles' trees.

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

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but Franklin was phenomenally observant,
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
to do clinical research

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and identifying a placebo effect
was done by Franklin in the paper --

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I have a copy of it if anybody's interested
-- 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 them,

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

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suggested a placebo control

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and blinded observer
might be a solution to investigator bias.

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And that was about 1930.

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And then, of course, blindfold tests
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
idea,

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borrowed from Sir Ronald Aylmer Fisher,
who applied statistics for agriculture use

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and introduced the application of statistics
in experimental design.

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And for farming and plant fertility,
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
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
for pulmonary tuberculosis.

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This was a beautiful study
and clearly showed the importance

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of a randomized control group to prove that
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 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 time.

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And he became desperate to prove
that it really was the cause of 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,
but for reasons that aren't completely clear,

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he was so well-recognized in his institution
that he was allowed to still work.

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But he committed what would be considered
a grave violation of ethical principles.

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In 1898, William Osler, at a meeting,
said to Giuseppe Sanarelli,

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who had discovered the etiologic agent
for yellow fever, and did somewhat similar to

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what Hansen did:
he injected this agent into 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 virulence

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into a human being, unless you obtain
a man's consent, is criminal."

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And that was the end of Sanarelli's career,
unlike Hansen.

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So, that was sort of the beginning
of informed consent.

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

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-- within days of the Clinical Center
opening here at NIH, when the medical board,

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in their very first meeting
under Luther Terry, who was chair

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of that board, said
that, "They had to provide each 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
for such understand and consent."

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And this policy at the Clinical Center
had a big effect.

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It had a big effect on Congress.

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And the Harris -- Kefauver-Harris
amendment to the FDA's law stipulated

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that subjects must be told whether a drug
is being used for investigational purposes.

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And the United States
Surgeon General issued a policy saying that

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any federal money used to support research
using drug development required

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review by an institutional review board
to make sure that it was ethical.

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And that was on all public health service
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 in humans.

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And you're going to hear about ethics
and the history of ethics from Christine

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Grady and others, and you'll learn more
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
-- if you haven't figured it out --

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that the business of clinical research
has been an international business

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with great people literally in every culture
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 us.