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.