WEBVTT

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Prof: Okay,
let's start up.

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So remember we were talking
about configuration,

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about handedness,
which was introduced - the idea

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was introduced - in the context
of a tetrahedral carbon.

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But you don't need a
tetrahedral carbon in order to

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have handedness.

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And an example is shown by the
oxidation of a sulfide to a

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sulfoxide.

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So let's first talk about the
mechanism.

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What makes the sulfide reactive
in this case?

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What do you see for an orbital
that would make the compound on

00:36.340 --> 00:37.190
the top left?

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Russell?

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Student:  High HOMO.

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Prof: Pardon me?

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Student:  High HOMO.

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Prof: High HOMO,
the unshared pair on sulfur.

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And how about the peroxy?

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Notice that's not a normal
benzoic acid.

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It's got two oxygens in a row.

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What reactivity does that
confer on it?

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Devin, you got an idea,
two oxygens in a row?

00:55.500 --> 01:01.450
What's going to be unusual in
terms of an orbital?

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We're looking,
obviously, for a low LUMO.

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Student:  It's probably
going to be a higher HOMO.

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Prof: Yeah,
it'll have -- it has unshared

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pairs, no doubt.

01:09.599 --> 01:12.579
But we want it to react with
the sulfur that has unshared

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pairs.

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So we're looking for a low LUMO.

01:14.379 --> 01:15.489
Anybody got an idea?

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Russell?

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Student:
σ*,

01:19.366 --> 01:20.856
between --
Prof: σ* of

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the oxygens, because oxygen's
got a big nuclear charge,

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right?

01:22.959 --> 01:24.129
So its orbitals are low.

01:24.129 --> 01:26.549
Okay, so we have the unshared
pair on sulfur,

01:26.549 --> 01:29.739
σ* on the oxygen,
and we get one of these where

01:29.738 --> 01:32.108
we make a bond and break a bond
at the same time,

01:32.110 --> 01:34.360
which puts on oxygen onto the
sulfur.

01:34.360 --> 01:37.820
And notice that,
as you said Devin,

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the oxygen has unshared pairs,
the n electrons there.

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But those won't give
stabilization by mixing with an

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unshared pair on sulfur.

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But sulfur's in the next row of
the periodic table.

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So it has a vacant d
orbital that can overlap with

01:56.510 --> 01:56.980
that.

01:56.980 --> 01:59.510
So you can get partial
stabilization there,

01:59.506 --> 02:02.876
of the unshared pair on oxygen,
which you could denote by

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drawing a double bond.

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Right?

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So we sometimes draw a double
bond to sulfur.

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And we can lose the proton from
that, and we get what's called a

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sulfoxide.

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So there's the mechanism of
making a sulfoxide.

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And notice that it's not planar
at the sulfur.

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Even though the sulfur has only
three substituents,

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it's not planar.

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So it's asymmetric.

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It's hande;, it's chiral.

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Right?

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And obviously you could easily
well have reacted the top

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unshared pair of the starting
material, as well as the bottom

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one.

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So when you do the reaction you
get a racemate,

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a 50:50 mixture of the
sulfoxides.

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Okay, now we mentioned
omeprazole last time.

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Here's the chemical structure
of omeprazole.

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What will make it reactive?

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Anybody got a hint for what
might make it reactive?

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Elizabeth?

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Student:  A lone pair on
nitrogen.

02:58.210 --> 02:59.720
Prof: It's got a lone
pair on two nitrogens.

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Student:  Right.

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Prof: Right? Okay.

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Now one way to discriminate
between them is to protonate one

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of them.

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Right?

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Because when you do that,
you now have this

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carbon-nitrogen double bond.

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Right?

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And the π* will be
unusually low because of the

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positive charge that came from
the proton.

03:20.080 --> 03:23.250
So acid is the stuff that's
going to activate this.

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So now you've got a low LUMO
and also the high HOMO,

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from the other unshared pair on
nitrogen.

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So bingo, you can add,
just as the nitrogen would add

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to a C=O double bond,
like that.

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Then you get this thing with
now four bonds to that central

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carbon.

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Protonate again,
and now this compound has two

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positive charges.

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That's not so great,
to have a dication.

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So you get rid of it.

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You can get rid of it by losing
that original proton.

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But there's another proton you
can lose, just as easily,

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in this way.

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Right?

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So lose the proton on the
nitrogen and then have those

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electrons re-form the double
bond to carbon,

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and the electrons go out on
sulfur,

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and you get this thing.

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Now, that happens -- remember
it's the acid coming along;

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the H+^( )is what caused this
to happen to omeprazole.

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So if you have a pH,
an acid pH between one and

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three, omeprazole will undergo
this acid-catalyzed

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rearrangement,
with a half-life of two

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minutes.

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So in no time at all it's
converted to this form,

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which is the active form.

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Now active to what?

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Well suppose you have an enzyme
that has a sulfur on it,

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that's got an unshared pair of
electrons, that will make it

04:43.870 --> 04:44.620
reactive.

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What will make the drug,
in this form,

04:46.846 --> 04:47.506
reactive?

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Anybody got an idea?

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Russell, I'm going to go to you
again, because you answered the

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same question before.

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We just made this group here.

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Student:  Yes,
that's right.

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Prof: What's going to
make it reactive?

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Student:  π*
makes it --

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Prof: Not π*,
no.

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Student:
>.

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Prof: It's the same as
O-O, right?

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Sulfur is right below oxygen.

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Student:  I meant to say
σ*,

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Prof: Can you see that?

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So it's σ*.

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Oh, that's what you meant to
say.

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Student:  Yeah..

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Prof: σ*
S-O.

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Okay, so we got that low LUMO
and the high HOMO on the sulfur

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coming in.

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So we can do exactly the same
reaction as before,

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right?

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Make a bond, break a bond.

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OH- goes away.

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Right?

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And we have this thing where
we've now formed a covalent bond

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with the enzyme.

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So the enzyme can't do its
stuff anymore,

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right?

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Because it's tied up.

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Okay?

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So the pump,
the pump which takes acid

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that's made in the cells that
line the stomach and transports

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the acid into the stomach,
doesn't work anymore,

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because that enzyme is what did
the trick.

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So the pump enzyme is
inactivated and the flow of HCl

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to the stomach is stopped.

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Okay?

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And, in fact,
this is an interesting problem

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in the design of the drug,
because it's acid that causes

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this to happen,
in two minutes,

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to become the active form.

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But you don't want it to happen
until it gets into the cells

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that line the stomach.

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So you take the pill orally,
it goes into the stomach.

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What problem are you suffering
from, when you put the -- when

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you take this pill?

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Student: Acid.

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Prof: Acid,
in your stomach.

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So bingo, it's going to happen
in the stomach,

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not in the cells in the wall of
the stomach.

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So they have to coat it with
something that'll make it get

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through the stomach first
without doing its reaction,

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and so they say don't grind the
pill up --

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right?

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-- before you take it.

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Let it get through.

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Then it gets through the liver,
into the bloodstream,

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and comes back to the wall of
these cells in the stomach,

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and then it gets activated by
acid and does this trick and

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stops the acid from pumping into
the stomach.

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So that's the idea.

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Okay, now should a chiral
switch, to a single enantiomer

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-- omeprazole,
Prilosec, is a racemate,

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it's a 50:50 mixture of the
enantiomers;

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enantiomers,
remember, at sulfur,

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not at carbon.

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Okay?

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Now, if you go to a single
enantiomer, will the drug be

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twice as good,
or at least better?

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Can anybody see a problem that
you would have?

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Right?

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When something interacts with
an enzyme, the enzyme is a

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single hand.

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So the complex,
the reacting complex,

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between the enzyme and the
stuff that you're reacting,

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is diastereomeric if that stuff
is handed;

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if it's right or left-handed.

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The enzyme say is all
right-handed.

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So you have right-right,
or right-left.

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One of them will be better than
the other.

07:49.490 --> 07:50.910
Right?

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So is that going to be
something that'll be important

07:53.589 --> 07:53.949
here?

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If we make a single enantiomer
of omeprazole -- remember,

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we talked about thalidomide,
ibuprofen before.

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Will a single enantiomer likely
help?

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There's an interesting
observation about this compound,

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the active form,
that makes it different from

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the original omeprazole.

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Do you see what it is?

08:11.209 --> 08:14.789


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Incidentally,
notice, that's the original

08:17.423 --> 08:18.283
omeprazole.

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All that that mechanism I
showed you did was to change

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that bond from there to there,
and the proton from nitrogen to

08:25.548 --> 08:26.248
sulfur.

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Let's go back again.

08:27.410 --> 08:30.590
That's all that happened during
the activation.

08:30.589 --> 08:34.149
But it did something crucial
with respect to stereochemistry.

08:34.149 --> 08:36.049
How about that original form?

08:36.049 --> 08:36.949
Was it chiral?

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Student:  Yes.

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Prof: Why? Angela?

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What made it chiral? Yeah?

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Student:  The bond is
going -- like it can either go

08:48.655 --> 08:50.505
inside or outside.

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Prof: Right.

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The bond -- the oxygen on the
sulfur could be either going in

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or out;
the sulfur is pyramidal.

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What happened when we activated
it?

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Student:  It gets bigger.

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Prof: Now it's not
chiral anymore.

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So this thing is not going to
discriminate between anything,

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because it's not chiral
anymore.

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Okay?

09:08.480 --> 09:11.970
So this thing is achiral.

09:11.970 --> 09:12.260
Okay?

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So it shouldn't make any
difference which hand you're

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using at this stage.

09:16.678 --> 09:20.058
Now, so there's no difference
after omeprazole has been

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activated by acid.

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Notice it's not activated by an
enzyme,

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because if it were activated by
an enzyme,

09:26.460 --> 09:29.540
then it could discriminate
between the two hands and one

09:29.535 --> 09:31.825
would be more activated than the
other.

09:31.830 --> 09:32.140
Right?

09:32.138 --> 09:33.728
So that could be a difference.

09:33.730 --> 09:35.050
But that's not true.

09:35.048 --> 09:38.908
It's just acid that does the
activation and makes it achiral.

09:38.908 --> 09:41.408
So at first glance one would
think it'd make no difference at

09:41.408 --> 09:41.658
all.

09:41.658 --> 09:45.108
Still, it could be that one
enantiomer is better at getting

09:45.111 --> 09:48.681
through the digestive system and
getting back to the stomach,

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in order to do the trick.

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So it's still possible.

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How could you tell whether it's
better or not?

09:55.250 --> 09:59.230
This is getting pretty
complicated -- right?

09:59.230 --> 10:01.630
-- all the different things it
would go through to get from

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here to there.

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How would you find out whether
it's worth using a single

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enantiomer?

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What would you do?

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Student:  Test it.

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Prof: Test it. How?

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Student:  Clinical trial.

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Prof: You'd do a
clinical trial.

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Okay.

10:14.308 --> 10:17.878
So you need -- but in order to
do that, you need a single

10:17.876 --> 10:21.446
enantiomer in order to do the
laboratory and the clinical

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testing.

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And we're going to talk about
that in just a second.

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But first let's talk just a bit
about the economics of this.

10:28.570 --> 10:32.570
These things called proton pump
inhibitors are the newest

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generation of things to treat
acid reflux.

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And here's data from Wellmark,
which is the Blue Cross/Blue

10:40.380 --> 10:44.900
Shield of Iowa and South Dakota;
so a pretty small population

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area.

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And this is how many
prescriptions they wrote for

10:48.976 --> 10:52.286
Prilosec in the period from 1999
to 2003;

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just went up by 250% to a
quarter of a million.

10:56.389 --> 11:00.829
And if you go world -- so 15%
of the members of Wellmark got

11:00.828 --> 11:07.788
this stuff, as of 2003;
and 600 million worldwide.

11:07.789 --> 11:10.209
That's a big market. Right?

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So now here's cost comparison
for things that treat acid

11:14.220 --> 11:14.950
stomach.

11:14.950 --> 11:18.860
So the first stuff is Tums and
Rolaids and so on.

11:18.860 --> 11:20.550
Those cost three or four cents
apiece.

11:20.548 --> 11:24.328
Okay, then there are these
over-the-counter H_2 blockers,

11:24.330 --> 11:27.030
like Zantac,
which are now very cheap;

11:27.029 --> 11:28.259
like thirty-seven cents.

11:28.259 --> 11:31.509
But they didn't used to be,
because they used to be covered

11:31.508 --> 11:33.628
by patent, and were prescription
drugs.

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Okay.

11:34.139 --> 11:37.639
Then there are prescription
versions you see of these H_2

11:37.640 --> 11:40.640
blockers, and Zantac,
when it's for prescription,

11:40.642 --> 11:42.082
costs $4.27 apiece.

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Okay, but now these proton pump
inhibitors come along.

11:45.639 --> 11:52.379
And in 1988 Prilosec came on
the market at $4.61 a pop.

11:52.379 --> 11:56.119
You take one every day. Okay?

11:56.120 --> 12:00.910
But in 2002 the patent ran out.

12:00.908 --> 12:04.918
So now generic people started
selling the generic version of

12:04.918 --> 12:07.408
omeprazole for $2.76,
and AstraZeneca,

12:07.407 --> 12:10.367
the manufacturer of Prilosec,
said we can do better than that;

12:10.370 --> 12:13.350
we've been making this stuff
for years, so we'll make an OTC

12:13.352 --> 12:15.782
version and have Proctor &
Gamble sell it.

12:15.778 --> 12:19.448
And so in 2003 they introduced
Prilosec OTC;

12:19.450 --> 12:22.210
which was actually exactly the
same stuff but seventy-nine

12:22.206 --> 12:22.826
cents a pill.

12:22.833 --> 12:23.273
Right?

12:23.269 --> 12:25.929
But you can still get the
prescription form,

12:25.926 --> 12:28.826
if you want the real thing,
for $4.61 a pill.

12:28.830 --> 12:32.820
Okay, but so now you're losing
a big market.

12:32.820 --> 12:36.490
If your pills are costing only
something like what?;

12:36.490 --> 12:39.570
1/6th or 1/7th of what they
originally cost.

12:39.570 --> 12:43.830
So in 2000, AstraZeneca
introduced Nexium,

12:43.827 --> 12:46.837
which is a single enantiomer.

12:46.839 --> 12:47.669
Okay?

12:47.668 --> 12:50.548
And now that's $4.87 a pill.

12:50.548 --> 12:51.268
Right?

12:51.269 --> 12:53.459
And that process,
to go from the R/S to

12:53.460 --> 12:55.480
the S,
to go from the racemate to a

12:55.476 --> 12:57.406
single enantiomer,
is called a "chiral

12:57.405 --> 12:59.505
switch",
in the industry;

12:59.509 --> 13:03.309
to go from a racemate to a
single enantiomer.

13:03.313 --> 13:03.923
Okay.

13:03.918 --> 13:07.378
Now this was touted,
within AstraZeneca,

13:07.380 --> 13:09.780
as the most successful U.S.

13:09.778 --> 13:11.108
launch ever.

13:11.110 --> 13:14.430
And here you can see the graph
of how much better it is than

13:14.427 --> 13:16.957
Viagra, Vioxx,
Lipitor, Celebrex and so on.

13:16.960 --> 13:20.740
Over this little more than
three-year period it went up to

13:20.741 --> 13:22.801
eight billion dollars in sales.

13:22.798 --> 13:23.328
Okay?

13:23.330 --> 13:28.030
And you can see that there's
been a lot of integration of

13:28.032 --> 13:32.402
clinical and commercial
enterprise at AstraZeneca.

13:32.399 --> 13:35.549
This is from a website that you
can see there.

13:35.549 --> 13:38.599
In December 2003 they say:
"…the executive

13:38.596 --> 13:41.476
director and development brand
leader" (at AstraZeneca)

13:41.475 --> 13:44.105
"adds the clinical and
scientific proficiency as a

13:44.110 --> 13:45.720
research gastroenterologist.

13:45.720 --> 13:48.670
As Levine and his staff put
together clinical development

13:48.674 --> 13:51.104
plans,
such as additional indications

13:51.096 --> 13:53.986
or line extensions,
they get commercial input at

13:53.985 --> 13:55.015
every stage."

13:55.019 --> 13:58.909
Well I don't know if you
noticed I drink water every once

13:58.913 --> 14:01.213
awhile because my mouth is dry.

14:01.210 --> 14:04.510
And just before -- when I
learned that the class was going

14:04.513 --> 14:07.323
to be filmed this year,
I realized that I'd been

14:07.322 --> 14:09.822
suffering from hoarseness since
last spring,

14:09.820 --> 14:12.720
and I figured that wouldn't be
good for the recording.

14:12.720 --> 14:15.470
So I went to see a doctor to
find out if I could do anything

14:15.469 --> 14:17.659
about this, whether there was
anything wrong.

14:17.658 --> 14:23.598
Now there's something you can
do for this, and Nexium has been

14:23.604 --> 14:27.994
the most intensively advertised
stuff ever.

14:27.990 --> 14:29.580
Right? That was for the public.

14:29.580 --> 14:31.970
This is for doctors.

14:31.970 --> 14:32.860
Okay?

14:32.860 --> 14:37.470
So if you go to that website,
you can see a seven-part,

14:37.471 --> 14:42.511
seven-scene description of why
Nexium is so much better than

14:42.511 --> 14:44.051
anything else.

14:44.048 --> 14:48.658
And what I'd like you to do for
a homework problem for Wednesday

14:48.662 --> 14:52.912
is to go through that show and
evaluate whether this series

14:52.908 --> 14:55.908
shows that Nexium is superior or
not.

14:55.908 --> 14:58.928
Is it worth paying five times
as much for a pill,

14:58.929 --> 15:01.069
or six times as much for a
pill?

15:01.070 --> 15:10.090
Now, this is the FDA-approved
label for Nexium.

15:10.090 --> 15:13.210
And so they did clinical
trials, just as we said they

15:13.210 --> 15:13.930
should do.

15:13.928 --> 15:18.968
Okay, so here they tried to
heal erosive esophagitis.

15:18.970 --> 15:20.840
So what they tested,
you can see,

15:20.841 --> 15:23.301
is the healing rate for this
condition,

15:23.298 --> 15:27.548
from 40 mg of Nexium,
20 mg of Nexium --

15:27.548 --> 15:29.858
so that's the single enantiomer
in two different doses --

15:29.860 --> 15:33.730
or the traditional omeprazole,
the racemic stuff.

15:33.730 --> 15:37.430
So, "These were evaluated
in patients with endoscopically

15:37.432 --> 15:40.652
diagnosed erosive esophagitis in
four multicenter,

15:40.649 --> 15:42.799
double-blind,
randomized studies.

15:42.798 --> 15:45.678
The healing rates after 4 and 8
weeks were evaluated and shown

15:45.682 --> 15:46.962
in the table below."

15:46.960 --> 15:50.860
Now suppose you were in charge
of designing this test.

15:50.860 --> 15:54.340
How much of the racemate,
omeprazole --

15:54.340 --> 15:59.670
so 40 mg and 20 mg of Nexium --
but compared to omeprazole,

15:59.668 --> 16:03.368
how much would you have
administered to compare with --

16:03.370 --> 16:05.530
so there are the single
enantiomer,

16:05.529 --> 16:07.329
40 mg or 20 mg.

16:07.330 --> 16:09.770
How much omeprazole would you
use?

16:09.769 --> 16:11.419
Student:  Forty and
twenty.

16:11.419 --> 16:13.749
Prof: And why?

16:13.750 --> 16:16.630
Lucas, what do you say?

16:16.629 --> 16:19.109
Student:  20 mg,
as little as possible.

16:19.110 --> 16:20.580
Prof:
>

16:20.580 --> 16:20.840
Why?

16:20.840 --> 16:23.090
Student:  To show the
best distinction between the new

16:23.086 --> 16:24.056
stuff and the old stuff.

16:24.058 --> 16:25.918
Prof: Okay.

16:25.918 --> 16:29.328
Does everybody agree with
Lucas?

16:29.330 --> 16:30.810
Kate, what would you choose?

16:30.808 --> 16:36.108
Student:  Well I'd want
to do both twenty and forty.

16:36.110 --> 16:38.830
But it looks like there's only
one omeprazole.

16:38.830 --> 16:40.750
Prof: Okay,
but if you were designing the

16:40.750 --> 16:42.140
test, you'd do twenty and forty.

16:42.139 --> 16:45.059
We'll have an auction here.

16:45.059 --> 16:46.659
Do I hear eighty from anyone?

16:46.659 --> 16:49.069
Rick you --
Student:  I would do

16:49.072 --> 16:49.752
eighty and forty.

16:49.750 --> 16:51.130
Prof: eighty and forty.

16:51.129 --> 16:51.359
Why?

16:51.360 --> 16:54.110
Student:  Because that
way -- because so omeprazole is

16:54.105 --> 16:54.695
a racemate.

16:54.700 --> 16:57.550
If you do eighty and forty of
those, you would get forty and

16:57.548 --> 16:58.898
twenty of the active form.

16:58.899 --> 16:59.759
Prof: Okay.

16:59.758 --> 17:01.618
Does everybody see what Rick's
saying?

17:01.620 --> 17:04.470
If you want the same amount of
what is ostensibly the active

17:04.468 --> 17:07.218
stuff, you should have double
the amount of omeprazole.

17:07.220 --> 17:09.600
Now this is what the label
says, what was actually used;

17:09.599 --> 17:10.869
20 mg.

17:10.869 --> 17:12.149
You win Lucas.

17:12.150 --> 17:15.260
Okay? Now why?

17:15.259 --> 17:19.639
It's because that's the
approved dose for that disease.

17:19.640 --> 17:20.090
Right?

17:20.086 --> 17:22.836
That's what the FDA approved,
right?

17:22.838 --> 17:27.078
But we'll give twice or four
times as much of what we think

17:27.077 --> 17:31.607
to be the active ingredient to
the other people in the test.

17:31.609 --> 17:32.749
Okay, so that's the test.

17:32.750 --> 17:35.370
There were four different
tests, and this shows it.

17:35.368 --> 17:38.208
But let's summarize it with a
graph that'll show it I think

17:38.213 --> 17:38.953
more clearly.

17:38.950 --> 17:43.420
So after four weeks and after
eight weeks, these are what

17:43.424 --> 17:47.184
fraction of healing there was
with the racemate,

17:47.182 --> 17:49.982
which is shown in open figures.

17:49.980 --> 17:52.150
And the shapes are different
studies;

17:52.150 --> 17:53.750
remember, there were four
different studies.

17:53.750 --> 17:57.350
And this is what you get if you
use the single enantiomer,

17:57.346 --> 17:59.986
is 20 mg;
which remember is twice the

17:59.987 --> 18:02.437
dose, if that one form is
active.

18:02.440 --> 18:05.370
What would you conclude from
this?

18:05.368 --> 18:09.228
Is it worth paying seven times
as much, or six times as much?

18:09.230 --> 18:10.210
Student:  No.

18:10.210 --> 18:13.860
Prof: Okay now -- or you
could use 40 mg.

18:13.858 --> 18:16.738
Now I think we would probably
agree that it's better,

18:16.741 --> 18:19.181
just eyeballing this thing,
even if we aren't

18:19.182 --> 18:20.182
statisticians.

18:20.180 --> 18:20.730
Okay?

18:20.726 --> 18:25.316
So four times the dose does a
better job.

18:25.318 --> 18:27.548
Now, then this was heavily
advertised.

18:27.548 --> 18:29.988
You may have seen these things
for the purple pill.

18:29.990 --> 18:36.530
So you get this grey-haired guy
here who says,

18:36.529 --> 18:39.319
"If I told you
prescription Nexium heals acid

18:39.317 --> 18:41.647
reflux damage better,
you'd want proof.

18:41.650 --> 18:44.990
And now your doctor has that
proof.

18:44.990 --> 18:48.090
Recent medical studies prove
Nexium heals better than the

18:48.086 --> 18:50.516
other leading prescription
medicine."

18:50.519 --> 18:52.799
(Now notice,
he says prescription medicine.

18:52.798 --> 18:55.858
The OTC stuff isn't a
prescription medicine.

18:55.859 --> 18:58.299
So this is a different test.)

18:58.298 --> 19:01.138
"No wonder they call
Nexium the healing purple pill.

19:01.140 --> 19:04.390
So call your doctor today,
because if left untreated the

19:04.394 --> 19:06.234
damage could get worse."

19:06.230 --> 19:09.450
So you can get a purple pill
there.

19:09.450 --> 19:12.240
Okay, this is the test he was
referring to,

19:12.243 --> 19:15.043
which compared esomeprazole,
that's Nexium,

19:15.038 --> 19:16.368
to lansoprazole.

19:16.368 --> 19:19.398
But again it's 40 mg versus 30
mg.

19:19.400 --> 19:21.610
I don't know anything about
lansoprazole,

19:21.606 --> 19:23.646
but that's what they tested
anyhow.

19:23.650 --> 19:26.190
But notice incidentally,
in the acknowledgements,

19:26.189 --> 19:28.939
this study was supported by a
grant from AstraZeneca,

19:28.940 --> 19:30.210
Wayne, Pennsylvania.

19:30.210 --> 19:32.960
So these are not completely
disinterested people,

19:32.964 --> 19:36.184
at least some of them,
who are involved in this study.

19:36.180 --> 19:38.250
And it says,
"So call your doctor today

19:38.250 --> 19:39.600
to learn about this."

19:39.598 --> 19:44.048
And fortunately we have my
doctor here, Dr. Duffey.

19:44.048 --> 19:45.518
So she's going to give you her
perspective

19:45.523 --> 19:46.463
>

19:46.460 --> 19:48.440
on Nexium and omeprazole.

19:48.440 --> 19:49.720
Thank you for coming.

19:49.720 --> 19:51.360
Dr. Dianne Duffey:
My pleasure Professor

19:51.358 --> 19:51.638
McBride.

19:51.637 --> 19:52.647
Thank you for having me.

19:52.650 --> 19:57.450
<<Technical
adjustments>>

19:57.450 --> 19:59.430
Dr. Dianne Duffey:
Well I can remember

19:59.428 --> 20:01.538
sitting in organic chemistry
classe as a pre-med,

20:01.538 --> 20:04.308
wondering why it was I needed
to learn how to make paint.

20:04.308 --> 20:07.198
So this is a real treat for me
to be here today,

20:07.200 --> 20:10.240
to be able to talk to you about
some clinical aspects of why

20:10.238 --> 20:13.168
it's important to study and do
well in Professor McBride's

20:13.173 --> 20:13.693
class.

20:13.690 --> 20:15.430
Sorry.

20:15.430 --> 20:18.360
All right, so I'm a
otolaryngologist,

20:18.355 --> 20:22.905
I'm an ear, nose and throat
physician, and I work here at

20:22.907 --> 20:23.637
Yale.

20:23.640 --> 20:26.200
Some of you may recognize me
from the health plan.

20:26.200 --> 20:29.110
And Professor McBride did give
me permission today to talk a

20:29.108 --> 20:30.488
little bit about his case.

20:30.490 --> 20:34.060
So I'm not going to show you
any confidential pictures,

20:34.064 --> 20:36.914
but I may allude to him here in
the talk.

20:36.910 --> 20:38.690
So first of all the disclosure.

20:38.690 --> 20:41.080
I don't have any financial
interest in any of the drugs or

20:41.077 --> 20:42.247
companies discussed today.

20:42.250 --> 20:43.860
I'm not on any speakers'
bureaus.

20:43.858 --> 20:46.368
So, in a word,
I don't really have a vested

20:46.374 --> 20:48.774
interest in anything shown here
today.

20:48.769 --> 20:51.529
But I will discuss some
off-label or experimental uses

20:51.534 --> 20:52.634
of these compounds.

20:52.630 --> 20:56.800
And the opinions presented by
me are mine and no one else's.

20:56.798 --> 21:00.658
So as you've heard testified
here today, Professor McBride

21:00.655 --> 21:03.425
took Prilosec and actually did
improve.

21:03.430 --> 21:06.430
So he sent me an email and was
very excited that I could come

21:06.434 --> 21:09.344
and speak to you all today,
and said, "By the way,

21:09.339 --> 21:11.299
my symptoms were improved."

21:11.298 --> 21:16.458
So Prilosec fixes symptoms of
GE reflux disease,

21:16.460 --> 21:19.970
gastroesophageal reflux
disease, and laryngopharyngeal

21:19.968 --> 21:22.588
reflux disease,
which is the entity that I

21:22.593 --> 21:22.983
treat.

21:22.980 --> 21:25.910
GE reflux disease is in the
domain primarily of the

21:25.909 --> 21:27.139
gastroenterologist.

21:27.140 --> 21:31.560
So I'm going to refer mostly to
LPR today, laryngopharyngeal

21:31.556 --> 21:32.226
reflux.

21:32.230 --> 21:35.930
So we've heard that Prilosec
works.

21:35.930 --> 21:37.130
Or does it?

21:37.130 --> 21:38.560
We really need to know.

21:38.558 --> 21:40.618
How is it we know these drugs
work?

21:40.618 --> 21:42.938
Someone talked about clinical
trials today,

21:42.940 --> 21:44.940
and I'm going to focus a little
bit more closely on that,

21:44.940 --> 21:47.460
because that's -- we rely on
these,

21:47.460 --> 21:49.090
and they come primarily from
pharma.

21:49.088 --> 21:52.038
Yale University,
my clinic, doesn't really have

21:52.036 --> 21:55.876
the money to run extensive
clinical trials on my patients.

21:55.880 --> 21:59.460
Sometimes some centers are able
to do it, or you may have a

21:59.461 --> 22:02.241
grant to do something that looks
at a drug.

22:02.240 --> 22:04.720
But primarily we're relying on
what the pharmaceutical

22:04.719 --> 22:06.449
companies tell us in terms of
data.

22:06.450 --> 22:10.380
So about Prilosec working in
him, all we know is that his

22:10.375 --> 22:14.445
symptoms are improved --
they were in his body -- eating

22:14.451 --> 22:16.411
his diet,
and living his life,

22:16.414 --> 22:18.984
and taking the drug at the
prescribed dose.

22:18.980 --> 22:22.130
But there are a lot of
variables that we may not know

22:22.134 --> 22:24.054
about,
and some of these variables are

22:24.054 --> 22:26.454
what the pharma companies need
to take into account,

22:26.450 --> 22:27.940
when they're doing these
clinical trials,

22:27.940 --> 22:28.900
when they're designing them.

22:28.900 --> 22:32.190
Are we taking other patient
variables into account?

22:32.190 --> 22:35.040
For example, diet;
does he take a large number of

22:35.037 --> 22:37.397
herbal supplements we don't know
about, for example?

22:37.400 --> 22:40.170
This could affect the
pharmacodynamics.

22:40.170 --> 22:43.040
It could affect the
pharmacokinetics of the drug in

22:43.038 --> 22:43.668
his body.

22:43.670 --> 22:47.000
Did he take the prescribed
medication on an empty stomach,

22:47.000 --> 22:50.450
as it's supposed to be taken,
so that the acid will activate

22:50.450 --> 22:51.210
it early?

22:51.210 --> 22:53.490
In other words,
was he compliant?

22:53.490 --> 22:56.340
And these are all things that I
need to be taking into account

22:56.337 --> 22:58.157
when I prescribe a drug to a
patient.

22:58.160 --> 22:59.830
For example,
these studies were done in

22:59.829 --> 23:02.029
patient populations,
but they may have been done on

23:02.028 --> 23:03.828
the West Coast,
they may have been done in

23:03.832 --> 23:04.362
China.

23:04.358 --> 23:07.558
Is that patient population
representative of my patient

23:07.558 --> 23:08.328
population?

23:08.328 --> 23:11.838
So when they're designing these
trials, they try to control for

23:11.840 --> 23:14.730
as many patient individual
variables as possible.

23:14.730 --> 23:16.740
In addition,
these studies have to be

23:16.737 --> 23:19.777
statistically sound,
because biostatistics drive

23:19.775 --> 23:22.435
these clinical trials and their
design,

23:22.440 --> 23:25.820
so that if differences are
actually observed between

23:25.824 --> 23:28.694
Prilosec and a placebo,
or Prilosec versus

23:28.685 --> 23:31.455
esomeprazole,
we have to be able to determine

23:31.462 --> 23:35.252
with reasonable certainty if
these differences are real or if

23:35.250 --> 23:37.650
they're due to just chance
alone.

23:37.650 --> 23:39.360
So that's where biostatistics
comes in.

23:39.358 --> 23:43.728
And I submit -- and I think
Professor McBride,

23:43.730 --> 23:45.600
who helped write some of these
slides,

23:45.598 --> 23:48.838
probably also feels -- that
there is some duty on the part,

23:48.838 --> 23:52.578
not only of the manufacturers,
but of academic institutions,

23:52.578 --> 23:54.348
who are also running their own
clinical trials,

23:54.348 --> 23:58.678
to actually design the studies
so that it's easy to understand;

23:58.680 --> 24:01.920
the data are there and they're
very clear, so that they can

24:01.915 --> 24:04.535
make also very legitimate
head-to-head marketing

24:04.538 --> 24:07.048
comparisons between competitor
compounds.

24:07.048 --> 24:09.458
So I think this is very
important.

24:09.460 --> 24:12.010
As a physician,
I feel that I have a duty to

24:12.009 --> 24:14.619
really evaluate the literature
critically.

24:14.618 --> 24:16.888
Sometimes I actually need to go
back and pull the studies.

24:16.890 --> 24:19.230
I can look at the package
insert, for these drugs,

24:19.229 --> 24:21.759
but how do I know -- how can I
actually believe it?

24:21.759 --> 24:25.329
So sometimes I actually go back
and I'll pull the study off

24:25.334 --> 24:26.694
PubMed, and read it.

24:26.690 --> 24:29.690
And we have to be able to
ascertain the validity of the

24:29.688 --> 24:32.518
research that supports our
choices as clinicians.

24:32.519 --> 24:34.449
There's a lot of marketing out
there;

24:34.450 --> 24:36.430
as we heard,
there's a lot of money to be

24:36.425 --> 24:37.755
made off these compounds.

24:37.759 --> 24:41.769
And I think I'm going to also
propose today that we as a

24:41.768 --> 24:43.568
society,
we as patients,

24:43.567 --> 24:47.507
we as members of the society,
perhaps a society who may one

24:47.505 --> 24:50.345
day have a single-payer
healthcare system,

24:50.349 --> 24:52.119
we need to be educated also.

24:52.118 --> 24:54.308
And this information's
available.

24:54.309 --> 24:55.349
It's available on the web.

24:55.348 --> 24:57.768
You've already seen some of it
from Professor McBride this

24:57.766 --> 24:58.186
morning.

24:58.190 --> 25:00.570
This website is a fantastic
resource.

25:00.568 --> 25:02.588
If you have a question about
any medication you're taking,

25:02.588 --> 25:05.138
you want to look at the
chemical compound of it,

25:05.140 --> 25:08.450
the chemical structure and how
they designed it,

25:08.450 --> 25:10.610
how they make it,
how it's marketed,

25:10.608 --> 25:13.788
how it's distributed,
all this is available on the

25:13.789 --> 25:14.439
website.

25:14.440 --> 25:16.470
So you can just plug in the
drug that you're taking,

25:16.465 --> 25:18.445
or the drug of interest,
and that information's all

25:18.452 --> 25:18.852
there.

25:18.849 --> 25:19.849
It's public domain.

25:19.849 --> 25:22.189
So use that as a resource.

25:22.190 --> 25:26.870
But direct-to-patient marketing
can be really effective.

25:26.868 --> 25:30.538
And this is also referred to as
direct-to-consumer marketing.

25:30.538 --> 25:32.808
You saw some of it in the
earlier slides,

25:32.805 --> 25:35.635
but all you have to do is turn
on the evening news,

25:35.636 --> 25:37.616
and these ads are there,
right?

25:37.618 --> 25:40.628
Every time there's a commercial
break, you see some happy person

25:40.632 --> 25:42.642
walking around,
talking about this drug.

25:42.640 --> 25:44.480
And you just hear the drug name.

25:44.480 --> 25:45.930
You don't hear anything more
about it.

25:45.930 --> 25:47.800
You may not hear anything about
the studies.

25:47.799 --> 25:50.929
But it can be very effective.

25:50.930 --> 25:53.740
So I think we need to look
critically at some of the

25:53.736 --> 25:56.816
claims, and we need to think,
is this really actually the

25:56.817 --> 25:58.797
right thing for me to be taking?

25:58.798 --> 26:02.578
So my specialty -- so back to
our clinical model -- my

26:02.579 --> 26:04.719
specialty is otolaryngology.

26:04.720 --> 26:08.600
I'm focusing on the larynx with
laryngopharangeal reflux.

26:08.599 --> 26:10.719
The larynx is the voice box.

26:10.720 --> 26:12.630
It's where your vocal cords are.

26:12.630 --> 26:14.220
It's what we use when we're
speaking.

26:14.220 --> 26:17.010
Ear, nose and throat is another
name for my specialty.

26:17.009 --> 26:19.869
But we're talking about
laryngopharangeal reflux,

26:19.868 --> 26:21.538
which is reflux,
acid reflux,

26:21.537 --> 26:23.977
that primarily affects the
voice box.

26:23.980 --> 26:25.460
It's under-diagnosed.

26:25.460 --> 26:28.750
It's also a significant source
of morbidity and decreased

26:28.752 --> 26:31.642
quality of life --
hoarseness, feeling like you

26:31.644 --> 26:34.934
have a frog in your throat,
sore throat -- and it's

26:34.931 --> 26:38.811
frequently associated with other
forms of reflux disease,

26:38.808 --> 26:41.528
like GE reflux disease,
gastroesophageal reflux

26:41.528 --> 26:42.118
disease.

26:42.118 --> 26:44.518
So it's a significant public
health problem.

26:44.519 --> 26:48.889
And this is a very busy slide,
but just to point out some

26:48.892 --> 26:53.582
statistics: that up to 10% of
patients who present to the ENT

26:53.576 --> 26:55.656
practice,
for any reason,

26:55.660 --> 26:59.360
may actually have symptoms or
findings related to LPR,

26:59.359 --> 27:00.749
laryngopharyngeal reflux.

27:00.750 --> 27:04.090
It's also increasingly
recognized as a problem that can

27:04.090 --> 27:06.690
be associated with non-allergic
asthma,

27:06.690 --> 27:10.130
and a great number of these
patients also present with a

27:10.125 --> 27:12.495
history of acid reflux from
other --

27:12.500 --> 27:16.590
where their symptoms are coming
from other sources,

27:16.588 --> 27:18.538
such as the esophagus,
for example.

27:18.539 --> 27:20.569
So reflux is a very big problem.

27:20.569 --> 27:22.179
I see a lot of patients.

27:22.180 --> 27:25.520
It's estimated that up to 40%
of the adult population in this

27:25.520 --> 27:28.790
country may have reflux;
and some studies say even more.

27:28.788 --> 27:31.008
So there's a lot of money to be
made.

27:31.009 --> 27:33.479
What is its treatment?

27:33.480 --> 27:35.840
In the year 2008,
what we're doing is we're

27:35.837 --> 27:38.307
treating this with proton pump
inhibitors.

27:38.308 --> 27:41.568
But I have to also put in a
disclaimer that there was a

27:41.569 --> 27:44.089
recent meta-analysis,
within the last couple of

27:44.089 --> 27:46.059
years, looking critically at the
literature,

27:46.058 --> 27:48.678
and at a number of different
studies.

27:48.680 --> 27:50.420
It evaluated about ten
different studies,

27:50.423 --> 27:52.783
and there is also a significant
placebo effect here.

27:52.779 --> 27:56.089
So the jury's not completely
out, but there are plenty of

27:56.085 --> 27:59.385
studies, in my literature,
that support it to use for the

27:59.390 --> 28:00.630
treatment of LPR.

28:00.630 --> 28:02.220
I'm not going to go into all
that today.

28:02.220 --> 28:05.990
But the reality is that PPIs
are FDA approved.

28:05.990 --> 28:06.930
They're out there.

28:06.925 --> 28:08.015
They're easy to get.

28:08.019 --> 28:10.889
All you have to do practically
is ask your physician for a

28:10.893 --> 28:11.653
prescription.

28:11.650 --> 28:13.580
So what are we trying to target?

28:13.578 --> 28:16.478
Here is a reasonably
good-looking larynx.

28:16.480 --> 28:17.990
So these are the vocal cords.

28:17.990 --> 28:20.050
This is the anterior portion.

28:20.048 --> 28:22.688
This is the posterior portion,
back where your esophagus is,

28:22.691 --> 28:23.991
and there's left and right.

28:23.990 --> 28:27.240
So this is what I see when I'm
looking with a scope.

28:27.240 --> 28:29.570
I pass it very carefully
through the nose and we get a

28:29.574 --> 28:30.944
very nice look at the larynx.

28:30.940 --> 28:32.850
And this is a patient with
moderately severe

28:32.849 --> 28:34.049
laryngopharyngeal reflux.

28:34.048 --> 28:36.408
You can see that there's a lot
of swelling here,

28:36.411 --> 28:38.171
compared to these other
pictures.

28:38.170 --> 28:41.070
This area back here is all
beefed up, and this area down

28:41.068 --> 28:42.808
here also looks quite reddened.

28:42.808 --> 28:45.398
So this is what we're treating
with these proton pump

28:45.402 --> 28:46.052
inhibitors.

28:46.048 --> 28:48.338
And we're hoping to take a
patient that looks like this,

28:48.344 --> 28:50.684
and turn their larynx into
something more that looks like

28:50.680 --> 28:51.640
this normal larynx.

28:51.640 --> 28:53.470
You can see the sharpened edges
here.

28:53.470 --> 28:55.310
So data is out there.

28:55.308 --> 28:58.428
We can follow this clinically,
and that's usually what we do.

28:58.430 --> 29:02.290
So another reality,
when you're considering these

29:02.287 --> 29:06.627
drugs that are being developed,
as we're hearing about today,

29:06.625 --> 29:09.495
and being prescribed,
is that really only about one

29:09.497 --> 29:12.687
in a 1000 of these compounds
that enter preclinical testing

29:12.691 --> 29:15.061
will actually make it to human
testing,

29:15.059 --> 29:16.389
what we call clinical trials.

29:16.390 --> 29:20.390
And out of these only about a
fifth may actually be deemed

29:20.394 --> 29:24.614
safe and effective enough by the
FDA to gain FDA approval.

29:24.608 --> 29:28.658
FDA approval is the Holy Grail
for a pharmaceutical company

29:28.664 --> 29:32.864
interested in developing drugs
and getting these drugs on the

29:32.859 --> 29:33.629
market.

29:33.630 --> 29:36.030
Without FDA approval they can't
market the drug.

29:36.029 --> 29:39.249
Without FDA approval they can't
put out ads on the evening news.

29:39.250 --> 29:43.200
So this is an example of one of
those documents that's available

29:43.196 --> 29:45.386
on the website that I showed
you.

29:45.390 --> 29:48.220
And this is the approval letter
for Prilosec OTC,

29:48.222 --> 29:49.702
which came out in 2003.

29:49.700 --> 29:52.120
It was written to Proctor and
Gamble by the FDA.

29:52.118 --> 29:54.878
And I just want to point out
this area down here.

29:54.880 --> 30:00.020
This is an approval letter for
this drug, given at this dose,

30:00.023 --> 30:02.343
used for this indication.

30:02.339 --> 30:03.539
So they're very, very specific.

30:03.538 --> 30:07.078
The drug companies can't --
they're not allowed to market

30:07.077 --> 30:09.097
its use for other indications.

30:09.098 --> 30:11.618
But this is really,
really important information

30:11.615 --> 30:14.495
for the company in order to be
able to put this out and

30:14.503 --> 30:17.503
actually start to see some
return on their investment for

30:17.500 --> 30:19.160
research and development.

30:19.160 --> 30:22.580
So again I just want to point
out, this is for omeprazole

30:22.576 --> 30:25.806
twenty mg, for the treatment of
frequent heartburn.

30:25.808 --> 30:29.318
Now here's some information
that -- you saw a different form

30:29.318 --> 30:30.388
of this earlier.

30:30.390 --> 30:33.970
Esomeprazole also has approval
by the FDA for a number of

30:33.967 --> 30:37.217
different indications,
but also for the treatment of

30:37.223 --> 30:38.633
GE reflux disease.

30:38.630 --> 30:42.540
And what I want to point out
here is that in the design of

30:42.539 --> 30:45.969
these clinical trials they look
very carefully,

30:45.970 --> 30:48.120
strategically,
at how can we show that our

30:48.116 --> 30:50.156
drug is better than the
competitor's?

30:50.160 --> 30:53.400
So clinical trials,
when they're designing these,

30:53.404 --> 30:56.384
are generally broken down into
three phrases:

30:56.376 --> 30:57.996
phase I, II and III.

30:58.000 --> 31:01.940
We have phase IV,
which usually occurs after the

31:01.942 --> 31:05.302
FDA has given approval for a
compound.

31:05.298 --> 31:07.968
Phase I is used in healthy
volunteers.

31:07.970 --> 31:09.500
The endpoint is really safety.

31:09.500 --> 31:11.350
They want to know what are the
side-effects.

31:11.348 --> 31:13.638
Is this a drug that we can
actually give to the public?

31:13.640 --> 31:16.910
And they also use a lot of
studies to determine metabolism

31:16.910 --> 31:20.180
and excretion of the drug at
this point in development.

31:20.180 --> 31:22.790
And these are usually smaller
studies, and they usually only

31:22.789 --> 31:25.179
need anywhere from twenty to 100
patients for these.

31:25.180 --> 31:28.260
And then once they pass into
phase I -- oh sorry,

31:28.262 --> 31:31.092
let me say just a little bit
about safety.

31:31.088 --> 31:36.098
Some of the side-effects -- in
the industry they call these

31:36.101 --> 31:37.571
adverse events.

31:37.568 --> 31:39.798
This is a terminology that the
FDA uses as well,

31:39.800 --> 31:42.460
and it really is just something
to mean a side-effect.

31:42.460 --> 31:45.430
Somebody had something that was
out of the ordinary and they

31:45.434 --> 31:47.104
happened to be taking the drug.

31:47.098 --> 31:49.438
So you have to at least
consider that it may have been

31:49.442 --> 31:52.052
considered by the -- it may have
been caused by the drug.

31:52.048 --> 31:55.088
A serious adverse event
would've led to some sort of

31:55.086 --> 31:57.826
damage to the patient,
or extended care such as

31:57.825 --> 31:59.785
hospitalization or a surgery.

31:59.788 --> 32:01.578
And these AEs,
adverse events,

32:01.582 --> 32:05.292
need to be reported to the FDA
during the clinical trials.

32:05.288 --> 32:07.638
So they're watched very
carefully, and they can't

32:07.644 --> 32:10.344
proceed through to the next
phase of clinical studies if

32:10.340 --> 32:12.740
there are too many adverse
events or, for example,

32:12.743 --> 32:15.843
if they have deaths;
those usually tend to raise

32:15.837 --> 32:17.317
really big red flags.

32:17.318 --> 32:19.888
And again, all this
information's available on that

32:19.890 --> 32:20.610
FDA website.

32:20.608 --> 32:23.368
So if you want to see how a
drug was developed and what

32:23.372 --> 32:25.732
adverse events occurred during
its development,

32:25.726 --> 32:28.076
you can see that there,
for the most part.

32:28.078 --> 32:30.548
There's a lot of internal stuff
that's not going to be on there,

32:30.548 --> 32:33.658
but for the most part they have
to report these AEs to the FDA

32:33.655 --> 32:34.925
as they're going along.

32:34.930 --> 32:38.540
In phase II they're looking for
effectiveness or efficacy.

32:38.538 --> 32:42.168
The preliminary data generated
generally is for effectiveness

32:42.174 --> 32:45.694
of the compound for a particular
disease or a condition.

32:45.690 --> 32:48.790
So this is where we start to
get into specifics about which

32:48.786 --> 32:52.096
dose of omeprazole am I going to
choose if I'm going to compare

32:52.095 --> 32:53.425
this to esomeprazole?

32:53.430 --> 32:56.420
They can compare it also to
placebo.

32:56.420 --> 32:58.330
They can compare it to a
different drug.

32:58.328 --> 33:00.218
And again they're looking at
adverse events,

33:00.221 --> 33:02.601
they're looking at safety,
but they're also starting to

33:02.598 --> 33:04.798
now look, am I actually
targeting the disease?

33:04.798 --> 33:06.508
The study sizes are usually
bigger.

33:06.509 --> 33:09.099
And then finally,
if it gets past phase II,

33:09.103 --> 33:10.773
you can get to phase III.

33:10.769 --> 33:13.449
And if anybody watches the
stock market,

33:13.451 --> 33:16.621
looking at drug companies or
biotech companies,

33:16.615 --> 33:20.185
phase III is where things
really -- you'll hear about

33:20.192 --> 33:20.952
this.

33:20.950 --> 33:23.290
When Wall Street hears a
whisper that a drug's not going

33:23.288 --> 33:24.988
to make it through phase III
studies,

33:24.990 --> 33:28.330
or it may not get FDA approval,
you can tank the price of the

33:28.325 --> 33:28.765
stock.

33:28.769 --> 33:31.659
It's really quite remarkable to
watch, as a clinician.

33:31.660 --> 33:35.870
Because again I don't really
have any vested interest in any

33:35.869 --> 33:39.449
particular company,
but I just find it fascinating

33:39.446 --> 33:43.056
that even just a suggestion will
actually impact things

33:43.061 --> 33:45.641
economically,
so importantly.

33:45.640 --> 33:48.470
So here again we continue to
look at safety and

33:48.473 --> 33:49.463
effectiveness.

33:49.460 --> 33:52.340
We may study different patient
populations.

33:52.338 --> 33:55.058
They may look abroad to do some
of these studies.

33:55.058 --> 33:58.398
India is a place where a lot of
studies are being done these

33:58.404 --> 34:00.224
days - Eastern Europe as well.

34:00.220 --> 34:02.820
They may look at different
dosages, and they may combine

34:02.823 --> 34:03.963
this with other drugs.

34:03.960 --> 34:06.150
These are usually very large
studies.

34:06.150 --> 34:08.880
By this time they've gotten to
-- they want to see clinical

34:08.880 --> 34:11.560
differences that are so subtle
that they have to have very

34:11.563 --> 34:14.533
large numbers of patients to
make this statistically sound.

34:14.530 --> 34:17.810
So they cost -- these studies
cost millions and millions of

34:17.807 --> 34:18.597
dollars too.

34:18.599 --> 34:20.459
So these companies are very,
very invested.

34:20.460 --> 34:22.320
They want to make sure that
they get return on their

34:22.324 --> 34:22.804
investment.

34:22.800 --> 34:27.620
And then phase IV occurs after
the FDA has approved a drug.

34:27.619 --> 34:30.249
These are post-marketing study
commitments,

34:30.250 --> 34:32.450
and these are commitments by
the sponsor,

34:32.449 --> 34:35.479
the person actually doing the
studies and marketing the drug

34:35.483 --> 34:37.563
and selling it,
that they will provide

34:37.559 --> 34:40.749
additional information to the
FDA about the product safety,

34:40.750 --> 34:43.090
efficacy or perhaps its optimal
use.

34:43.090 --> 34:46.230
And more recently we're hearing
about phase zero trials in the

34:46.226 --> 34:49.366
cancer research literature --
my area of research is in

34:49.369 --> 34:52.089
cancer --
and phase zero trials are

34:52.088 --> 34:55.108
exploratory, first-in-human
trials.

34:55.110 --> 34:58.260
So these are designed to speed
up development of promising

34:58.262 --> 34:58.762
agents.

34:58.760 --> 35:01.840
As we know, cancer is a very
big problem in this country,

35:01.836 --> 35:04.966
especially with the population
aging, and it can kill very

35:04.969 --> 35:05.629
quickly.

35:05.630 --> 35:09.080
So these trials are designed to
establish very early on whether

35:09.081 --> 35:12.261
an agent behaves in human
subjects differently than it was

35:12.255 --> 35:14.645
expected from the pre-clinical
studies.

35:14.650 --> 35:15.900
And that does happen sometimes.

35:15.900 --> 35:18.720
So you can imagine if you spent
months and months planning a

35:18.724 --> 35:20.444
phase I trial,
only to find out,

35:20.443 --> 35:23.423
when you put it into humans,
that it reacts -- it doesn't

35:23.420 --> 35:26.580
behave the way you expected,
based on how it looked in mice,

35:26.579 --> 35:29.829
you can lose a lot of money and
you lose a lot of momentum.

35:29.829 --> 35:33.749
So these phase zero trials are
being put more and more into

35:33.746 --> 35:34.216
play.

35:34.219 --> 35:36.579
So back to our clinical model.

35:36.579 --> 35:39.339
So some of the studies that we
already heard about from

35:39.336 --> 35:42.086
Professor McBride were to
determine whether these drugs

35:42.094 --> 35:44.704
actually worked in patients with
reflux or not.

35:44.699 --> 35:48.049
So, and I'm not showing all the
studies, by the way.

35:48.050 --> 35:49.390
I just have to disclose that.

35:49.389 --> 35:51.239
I'm only showing you a few
studies,

35:51.239 --> 35:54.529
just to demonstrate what type
of data I have to actually take

35:54.525 --> 35:56.445
into consideration,
as a clinician,

35:56.452 --> 35:59.252
when I'm looking critically at
how the studies were done;

35:59.250 --> 36:02.050
whether I think the drug's
actually going to be helpful for

36:02.045 --> 36:03.005
my patient or not.

36:03.010 --> 36:06.660
So this was in a group of
patients, a particular patient

36:06.657 --> 36:10.567
population, with already
established erosive esophagitis;

36:10.570 --> 36:12.890
sounds pretty bad.

36:12.889 --> 36:14.079
It's pretty uncomfortable.

36:14.079 --> 36:17.119
They studied these patients
with esomeprazole and

36:17.123 --> 36:20.423
omeprazole, at similar doses,
with similar numbers of

36:20.420 --> 36:22.070
patients in both arms.

36:22.070 --> 36:25.650
They found no statistically
significant difference in the

36:25.650 --> 36:28.530
symptoms of heartburn,
sustained resolution of

36:28.527 --> 36:31.657
heartburn symptoms in this group
of patients.

36:31.659 --> 36:35.379
Now if you read the
esomeprazole package insert,

36:35.380 --> 36:38.230
they state that they chose
omeprazole twenty as the

36:38.226 --> 36:40.716
competitor dose,
because it's the FDA approved

36:40.722 --> 36:42.762
dose for this indication;
which it is.

36:42.760 --> 36:45.950
So then I went to the Prilosec
package insert to find that they

36:45.949 --> 36:48.879
did look at 40 mg when they were
looking at these types of

36:48.880 --> 36:49.550
symptoms.

36:49.550 --> 36:52.740
They found that there was
really no improve -- no benefit

36:52.740 --> 36:54.280
to using the higher dose.

36:54.280 --> 36:57.330
So they went with the lower
dose when they went for FDA

36:57.327 --> 36:57.947
approval.

36:57.949 --> 37:00.759
So that's, I think,
partly why they chose 20 mg.

37:00.760 --> 37:03.060
And then also,
if you look more closely,

37:03.059 --> 37:06.619
there's also they lose some
linearity between plasma

37:06.623 --> 37:09.843
concentration versus areas under
the curve,

37:09.840 --> 37:12.610
which is plasma concentration
in the patient over time.

37:12.610 --> 37:16.280
So it becomes less and less
predictable, as you go up on the

37:16.280 --> 37:20.070
dose, how much drug is actually
being seen physiologically for

37:20.074 --> 37:21.074
the patient.

37:21.070 --> 37:23.820
So once they get out of that
predictable linearity,

37:23.815 --> 37:26.945
things become a little bit
iffy, and you could potentially

37:26.947 --> 37:28.537
get into adverse effects.

37:28.539 --> 37:31.289
So I think that's part of the
logic for why they chose that.

37:31.289 --> 37:35.219
But again, I'm not trying to
make an exhaustive argument for

37:35.222 --> 37:38.692
what should've been done or
against what was done;

37:38.690 --> 37:42.310
just to give you some idea for
what we have to deal with as

37:42.307 --> 37:43.117
clinicians.

37:43.119 --> 37:45.789
So then finally these are some
of the three studies that

37:45.793 --> 37:48.663
Professor McBride has already
alluded to, showing that there

37:48.664 --> 37:49.884
are variable results.

37:49.880 --> 37:53.140
This one showed a definite
statistically significant

37:53.143 --> 37:56.213
improvement in healing of
erosive esophagitis for

37:56.213 --> 37:59.673
esomeprazole over --
any dose of esomeprazole over

37:59.666 --> 38:00.456
omeprazole.

38:00.460 --> 38:03.540
But two other studies actually
showed that there was no

38:03.538 --> 38:04.278
difference.

38:04.280 --> 38:07.750
So there's another bigger study
as well that's not included

38:07.751 --> 38:08.171
here.

38:08.170 --> 38:10.590
Prof: Actually it's the
next one.

38:10.590 --> 38:11.580
Dr. Dianne Duffey:
Oh I'm sorry,

38:11.581 --> 38:12.271
yeah there it is,
okay.

38:12.268 --> 38:16.178
Yeah, so again you just kind of
have to look at the literature

38:16.184 --> 38:18.564
and say okay,
I'm convinced or I'm not

38:18.561 --> 38:19.461
convinced.

38:19.460 --> 38:21.520
I don't know that there's any
right or wrong.

38:21.518 --> 38:23.578
But the FDA also has a role to
play here,

38:23.579 --> 38:27.549
and they really vet these
studies quite well,

38:27.550 --> 38:29.680
and they're not allowed to
market if they don't feel that

38:29.677 --> 38:31.247
--
if the FDA doesn't feel that

38:31.251 --> 38:33.741
there's sufficient evidence
there to support it.

38:33.739 --> 38:37.519
So in my patient population,
who have LPR,

38:37.519 --> 38:42.129
a large number of these
patients have heartburn.

38:42.130 --> 38:44.510
They may or may not be treated
for the heartburn already.

38:44.510 --> 38:47.090
I may be the first physician
they see, and I may say,

38:47.090 --> 38:49.820
"Well do you also have
heartburn symptoms?"

38:49.820 --> 38:52.720
Those would be GE reflux type
of symptoms.

38:52.719 --> 38:56.599
So I can end up treating both
of those if I put my patient on

38:56.599 --> 38:59.769
one of these PPIs for
laryngopharyngeal reflux.

38:59.768 --> 39:03.028
So if I've just told you that
these drugs are approved for a

39:03.028 --> 39:05.798
specific indication,
maybe at a specific dose,

39:05.800 --> 39:09.100
how is it I'm able to use it
for something that it's not

39:09.099 --> 39:10.779
really even approved for?

39:10.780 --> 39:14.000
And this is where we get into
off-label use of drugs.

39:14.000 --> 39:17.270
So once a drug is approved by
the FDA for any indication,

39:17.269 --> 39:20.069
I as a clinician can write it,
as a prescription,

39:20.072 --> 39:21.652
for another indication.

39:21.650 --> 39:24.990
But the FDA has put out these
guidelines,

39:24.989 --> 39:28.029
such that good medical practice
and the best interests of the

39:28.028 --> 39:31.258
patient should prevail here,
so that we're using legally

39:31.260 --> 39:33.800
available drugs --
it's an important term --

39:33.795 --> 39:36.565
according to the --
and devices -- according to my

39:36.572 --> 39:39.042
best knowledge and judgment as a
clinician.

39:39.039 --> 39:41.779
If we use a product for an
indication that's not in the

39:41.782 --> 39:44.282
approved labeling,
I have the responsibility to be

39:44.275 --> 39:47.255
well-informed about the product,
to base its use on firm

39:47.264 --> 39:50.354
scientific rationale,
and on sound medical evidence.

39:50.349 --> 39:53.679
Now in my literature there's a
lot of sound medical evidence

39:53.682 --> 39:56.962
supporting the use for PPIs in
laryngopharyngeal reflux.

39:56.960 --> 39:58.370
But I just also --
Prof: Can I ask you a

39:58.371 --> 39:58.771
question about that?

39:58.768 --> 39:59.418
Dr. Dianne Duffey:
Yeah.

39:59.420 --> 40:01.270
Prof: You say you have a
--

40:01.268 --> 40:04.128
it's not underlined there but
you say there's a responsibility

40:04.125 --> 40:06.695
to maintain records of the
product's use and effects.

40:06.699 --> 40:07.069
Dr. Dianne Duffey:
Uh-hum.

40:07.070 --> 40:09.690
Prof: Does anyone come
around and collect those records

40:09.686 --> 40:11.226
and try to make something of
them?

40:11.230 --> 40:12.780
Dr. Dianne Duffey:
I've never been contacted

40:12.775 --> 40:13.225
by anybody.

40:13.230 --> 40:17.280
Prof: Are people pretty
conscientious about doing that?

40:17.280 --> 40:19.900
Dr. Dianne Duffey:
I think that we're

40:19.898 --> 40:22.878
conscientious about recording
whether there've been

40:22.876 --> 40:25.076
side-effects at the given dose.

40:25.079 --> 40:27.799
We're conscientious about
recording whether there's been

40:27.797 --> 40:29.277
improvement in the symptoms.

40:29.280 --> 40:32.300
But I don't have a detailed
questionnaire,

40:32.297 --> 40:33.107
in general.

40:33.106 --> 40:34.686
So --
Prof: Yeah.

40:34.688 --> 40:37.548
Because one would think that
this would be sort of like a

40:37.550 --> 40:39.530
wiki,
that even though you can't

40:39.534 --> 40:42.544
afford to do a big study,
that if you collect enough

40:42.541 --> 40:46.061
observations from enough people,
you could make something out of

40:46.056 --> 40:46.266
it.

40:46.268 --> 40:47.748
Dr. Dianne Duffey:
We could,

40:47.750 --> 40:48.300
we could.

40:48.300 --> 40:50.070
But then you're in to
experimenting,

40:50.070 --> 40:53.050
if you're doing it with the
intention of actually showing or

40:53.052 --> 40:54.472
disproving a hypothesis.

40:54.469 --> 40:56.389
Prof: Well but you said
you have a responsibility to

40:56.385 --> 40:57.075
maintain the records.

40:57.079 --> 40:57.209
Why?

40:57.210 --> 40:58.070
>

40:58.070 --> 40:59.050
Dr. Dianne Duffey:
We do.

40:59.048 --> 40:59.718
No, I agree with that.

40:59.722 --> 41:00.122
I agree.

41:00.119 --> 41:03.979
But we're not really obligated
to submit it to an IRB.

41:03.980 --> 41:06.770
If we were doing it with the
intention of definitely showing

41:06.771 --> 41:09.661
a difference one way or another,
then that would be considered

41:09.657 --> 41:10.507
an experiment.

41:10.510 --> 41:13.430
So I would be obligated to run
that through the institutional

41:13.431 --> 41:15.191
review board,
which is there for the

41:15.193 --> 41:18.033
protection of human subjects,
and to make sure that any

41:18.030 --> 41:20.700
studies that we're designing are
legitimate,

41:20.699 --> 41:23.679
that they're ethical,
that the patient has been given

41:23.675 --> 41:25.675
the opportunity to ask
questions.

41:25.679 --> 41:28.449
They can refuse,
they can drop out of the study.

41:28.449 --> 41:31.719
So, but they're all important
issues that I think would be in

41:31.719 --> 41:33.189
the realm of,
at that point,

41:33.190 --> 41:34.990
doing actual experimentation.

41:34.989 --> 41:38.339
But it's a really important --
it's an important point.

41:38.340 --> 41:41.820
But we can use these drugs for
off-label marketed uses.

41:41.820 --> 41:44.720
Now the drug companies
importantly are not allowed to

41:44.717 --> 41:46.547
market;
they're not allowed to

41:46.550 --> 41:49.150
advertise for off-label uses of
compounds.

41:49.150 --> 41:53.250
So again I have a duty,
as a physician,

41:53.250 --> 41:56.710
to evaluate this literature
critically and to really be able

41:56.713 --> 42:00.063
to validate or ascertain the
validity of the research that

42:00.059 --> 42:01.469
supports my choices.

42:01.469 --> 42:03.499
So just a very quick word about
marketing.

42:03.500 --> 42:05.570
As I mentioned,
my research area is in

42:05.572 --> 42:06.192
oncology.

42:06.190 --> 42:09.050
I've been involved in some
clinical trials with oncologic

42:09.052 --> 42:10.742
drugs for head and neck cancer.

42:10.739 --> 42:13.169
And I get these emails all the
time.

42:13.170 --> 42:16.260
Marketing is a really big deal
when it comes to these

42:16.257 --> 42:16.967
compounds.

42:16.969 --> 42:21.799
Just to give you an idea,
this one in particular is about

42:21.800 --> 42:25.510
how do you market your oncology
products?

42:25.510 --> 42:28.960
And this is an actual meeting,
to which I was invited.

42:28.960 --> 42:31.990
And one of the teasers here is
that "in such a crowded and

42:31.992 --> 42:34.632
competitive market,
the ability to differentiate

42:34.630 --> 42:37.420
your product has never been more
important."

42:37.420 --> 42:40.840
So this just gives you some
idea of what the thought process

42:40.836 --> 42:42.976
is and what the general culture
is.

42:42.980 --> 42:46.210
And this is again a wordy
slide, but just to point out --

42:46.206 --> 42:48.566
and this comes from Nature
News;

42:48.570 --> 42:51.400
it's fairly recent -- that
industry is really starting

42:51.402 --> 42:53.382
shift attention now to other
areas.

42:53.380 --> 42:57.200
So cardiovascular drugs,
which cardiovascular disease is

42:57.195 --> 43:01.005
really the foremost killer in
our country right now,

43:01.010 --> 43:04.110
but they're really shifting
their attention now to drugs

43:04.114 --> 43:07.224
where perhaps they can make
another blockbuster drug;

43:07.219 --> 43:09.699
and that's usually always what
the impetus is,

43:09.701 --> 43:10.971
return on investment.

43:10.969 --> 43:14.129
So oncology drugs;
immunology, which would be

43:14.126 --> 43:17.096
something for rheumatoid
arthritis, for example;

43:17.099 --> 43:20.579
and neurology are going to be a
very, very big focus of

43:20.581 --> 43:22.581
attention of pharma industry.

43:22.579 --> 43:25.529
So as you watch the evening
news, or whichever channel you

43:25.527 --> 43:28.287
might be tuning into,
you'll be hearing a lot more

43:28.286 --> 43:30.686
about this,
and I think a lot more direct

43:30.693 --> 43:33.343
to patient marketing is going to
take place.

43:33.340 --> 43:36.920
So again, this has been a lot
of fun for me to participate,

43:36.920 --> 43:40.380
and I thank Professor McBride
also for stimulating me to think

43:40.382 --> 43:43.902
a little bit more deeply about
proton pump inhibitors and how I

43:43.902 --> 43:44.642
use them.

43:44.639 --> 43:46.649
Prof: Great. Thank you.

43:46.650 --> 43:49.470
>

43:49.469 --> 43:52.029
Prof: Leave it on,
there might be some questions.

43:52.030 --> 43:55.010
Are there some questions for
Dr. Duffey?

43:55.010 --> 43:56.510
Dr. Dianne Duffey:
I'd be happy to try to

43:56.514 --> 43:57.954
field any questions,
as long as they're not too

43:57.954 --> 43:58.304
hard.

43:58.300 --> 44:01.430
Yeah?

44:01.429 --> 44:04.169
Student:  I am an
international student,

44:04.170 --> 44:08.190
and I have noticed in the
marketing for drugs that they

44:08.190 --> 44:12.510
have on television here that
they always give the full,

44:12.510 --> 44:15.510
like two paragraphs about the
side-effects of the drugs,

44:15.507 --> 44:16.377
on television.

44:16.380 --> 44:18.210
Is that required, and why?

44:18.210 --> 44:20.050
How is that regulated?

44:20.050 --> 44:22.320
Prof: Right,
so the question is from -- you

44:22.315 --> 44:24.115
said you're an international
student?

44:24.119 --> 44:24.879
Student:  Yeah.

44:24.880 --> 44:24.920
Prof: She's from
Australia.

44:24.920 --> 44:26.190
Student:  I'm not used
to that at all.

44:26.190 --> 44:27.000
So it's sort of like whoa.

44:27.000 --> 44:28.570
Dr. Dianne Duffey:
Right.

44:28.567 --> 44:31.457
So she's noted when these ads
come on TV that there's a very

44:31.456 --> 44:34.196
long disclaimer afterwards about
the side-effects.

44:34.199 --> 44:37.799
And I'm not actually an expert
on how the marketing of these

44:37.802 --> 44:38.782
drugs is done.

44:38.780 --> 44:42.000
I'm going to speculate here,
but I'm pretty confident that

44:41.998 --> 44:44.648
this is correct,
that the FDA mandates that they

44:44.650 --> 44:45.950
put that out there.

44:45.949 --> 44:49.339
So if you're going to make a
claim about a compound and how

44:49.338 --> 44:52.488
great it is, you also better
tell the other side of the

44:52.494 --> 44:53.084
story.

44:53.079 --> 44:54.369
You better tell them,
"Listen,

44:54.371 --> 44:56.161
we might fix your reflux but
you're going to get

44:56.157 --> 44:56.877
diarrhea."

44:56.880 --> 44:57.300
You know?

44:57.300 --> 44:59.830
And it's kind of funny
actually, because if you look at

44:59.829 --> 45:02.209
these and you say,
"Okay, I'm going to take

45:02.206 --> 45:05.026
that drug to fix my runny nose,
but I'm going to get diarrhea

45:05.034 --> 45:07.314
and muscle pains and all these
other things."

45:07.309 --> 45:11.959
So it really -- I think it's
probably mandated by the FDA,

45:11.961 --> 45:16.371
and the FCC also may have
something to do with that.

45:16.369 --> 45:20.299
But that would be my
speculation.

45:20.300 --> 45:21.410
Yes?

45:21.409 --> 45:24.009
Prof: Sam?

45:24.010 --> 45:27.170
Student:  I was
wondering what your opinion is

45:27.168 --> 45:30.748
about -- I know recently one of
the big things was like that

45:30.753 --> 45:32.033
Vioxx isn't safe.

45:32.030 --> 45:35.350
Do you think that clinical
trials, they should do longer

45:35.353 --> 45:36.263
term studies?

45:36.260 --> 45:39.700
Because I think -- I don't know
of other specific examples,

45:39.695 --> 45:43.125
but a lot of drugs like it
comes through after a long time,

45:43.132 --> 45:45.762
long-term use problems --
Dr. Dianne Duffey:

45:45.762 --> 45:47.512
Right, and then we wonder
as consumers,

45:47.509 --> 45:48.239
is this safe?

45:48.239 --> 45:51.079
If I'm going to keep taking
this drug for years and years,

45:51.079 --> 45:53.469
am I safe, or are my progeny
going to be safe?

45:53.469 --> 45:54.529
It's a good question.

45:54.530 --> 45:57.200
And that's where some of these
phase IV studies -- they're

45:57.197 --> 45:59.207
called post-marketing studies --
come in.

45:59.210 --> 46:02.480
I was involved with one
clinical trial where a phase IV

46:02.481 --> 46:04.301
study actually was mandated.

46:04.300 --> 46:07.490
And so for years afterwards
that drug company had to

46:07.489 --> 46:11.119
continue to pour resources into
contacting patients who had

46:11.115 --> 46:13.685
taken the drug --
"Are you still taking it?

46:13.690 --> 46:15.570
If you're still taking it,
what side-effects are you

46:15.567 --> 46:16.117
having?"

46:16.119 --> 46:19.179
So those are mandated on some
level.

46:19.179 --> 46:21.829
And the FDA really plays the
key role there.

46:21.829 --> 46:25.939
And that's been my experience.

46:25.940 --> 46:27.640
But it definitely raises
questions.

46:27.639 --> 46:30.939
And the Vioxx trial just was
devastating for Merck.

46:30.940 --> 46:33.780
And I think a lot -- they
didn't see a lot of that coming.

46:33.780 --> 46:36.950
So I think for the pharma
companies -- correct me if I'm

46:36.949 --> 46:38.689
wrong;
you may have more insights --

46:38.688 --> 46:40.628
it's probably,
it's a decision that they have

46:40.630 --> 46:41.160
to weigh.

46:41.159 --> 46:44.629
How much resources are they
going to continue to pour in?

46:44.630 --> 46:46.830
And that would,
on paper, it would take away

46:46.833 --> 46:47.913
from their profits.

46:47.909 --> 46:52.059
So I'm sure there's a lot of
internal debate about it.

46:52.059 --> 46:55.939
But yeah, that's where we're
thankful that we have the FDA

46:55.936 --> 46:56.886
looking out.

46:56.889 --> 47:00.099
A lot of countries don't have
an organization such as the FDA.

47:00.099 --> 47:03.319
You can market anything you
want, for almost any indication,

47:03.315 --> 47:04.675
and whatever dose goes.

47:04.679 --> 47:07.789
So I think we're very fortunate
in that respect.

47:07.789 --> 47:10.139
I'm going to turn the mike over.

47:10.139 --> 47:11.259
Prof: Well Dana's got a
question.

47:11.257 --> 47:12.257
Dr. Dianne Duffey:
Oh sorry,

47:12.260 --> 47:12.720
I'm sorry.

47:12.719 --> 47:15.169
Student:  I've heard
there can be cases where a drug

47:15.168 --> 47:17.828
was actually more effective for
a certain off-label use than the

47:17.829 --> 47:19.729
use that it's actually FDA
approved for,

47:19.730 --> 47:23.190
but it's been FDA approved for
something that has a bigger

47:23.186 --> 47:25.786
patient population,
so you can potentially make

47:25.793 --> 47:26.363
more money.

47:26.360 --> 47:29.150
If off-label uses can't be
advertised, how do you as

47:29.152 --> 47:31.782
doctors find out about that and
evaluate that?

47:31.780 --> 47:34.940
Dr. Dianne Duffey:
So the question is if an

47:34.940 --> 47:38.670
off-label use for a drug can't
be advertised by the company,

47:38.668 --> 47:41.448
how do I as a physician hear
about it?

47:41.449 --> 47:45.399
I would hear about it from
other clinical trials that were

47:45.396 --> 47:49.616
done, maybe have -- may have
been supported by the company;

47:49.619 --> 47:53.199
so as we saw an example of
earlier.

47:53.199 --> 47:56.179
But I look for literature
within my field.

47:56.179 --> 47:59.169
So laryngopharyngeal reflux is
a perfect example of that.

47:59.170 --> 48:01.620
It works pretty well,
for this drug,

48:01.619 --> 48:03.369
but you do have to take it for
a longer time period,

48:03.369 --> 48:06.249
and sometimes you actually have
to take it for higher doses than

48:06.248 --> 48:07.938
is recommended for GE reflux
alone.

48:07.940 --> 48:10.940
But it works pretty well,
and I hear patients all the

48:10.938 --> 48:12.378
time say that it works.

48:12.380 --> 48:14.780
I have other patients who say
it doesn't work.

48:14.780 --> 48:19.840
So yeah, we just have to look
at our own literature.

48:19.840 --> 48:22.230
And there are smaller studies;
they may have fifty,

48:22.233 --> 48:23.283
seventy patients.

48:23.280 --> 48:27.300
But in an academic institution,
somebody who,

48:27.300 --> 48:29.130
with an interest in that
particular area,

48:29.130 --> 48:31.240
may run their own study,
because they want that

48:31.242 --> 48:33.542
information and the
information's not out there.

48:33.539 --> 48:38.349
So we look for good solid data
to help guide our choices that

48:38.349 --> 48:38.829
way.

48:38.829 --> 48:41.969


48:41.969 --> 48:42.539
Prof: Kevin?

48:42.539 --> 48:45.909
Student:  As a
physician, about off-label use,

48:45.909 --> 48:50.999
do you ever use drugs in an
off-label use and take advantage

48:51.001 --> 48:55.111
of their side-effects,
in that sense?

48:55.110 --> 48:56.910
Dr. Dianne Duffey:
Okay.

48:56.914 --> 48:59.304
I'll give you -- well yeah
there was.

48:59.300 --> 49:02.690
So when -- I don't,
I don't really have any drugs

49:02.686 --> 49:04.236
that I use that for.

49:04.239 --> 49:08.929
But there's one drug in my
field;

49:08.929 --> 49:10.659
Botox, for example.

49:10.659 --> 49:16.979
Botox was being used to help
weaken the vocal cords.

49:16.980 --> 49:18.240
Okay?

49:18.239 --> 49:21.469
It's been used for that for
years, in patients who have

49:21.467 --> 49:24.987
speech problems and don't have
good control over their vocal

49:24.994 --> 49:26.614
cords and the function.

49:26.610 --> 49:28.660
So you can use Botox injections.

49:28.659 --> 49:31.979
Then Botox injections came
along for use in the face,

49:31.976 --> 49:35.036
and you read about this on page
six all the time;

49:35.038 --> 49:36.248
it's hilarious.

49:36.250 --> 49:41.840
But what they've also noticed
was that migraine headaches got

49:41.842 --> 49:43.242
a lot better.

49:43.239 --> 49:46.139
So you can use that,
you can use Botox to treat

49:46.137 --> 49:47.457
migraine headaches.

49:47.460 --> 49:51.110
And there actually are phase
III trials going on right now by

49:51.108 --> 49:54.508
a colleague of mine down in
Manhattan, looking at exactly

49:54.514 --> 49:55.614
that question.

49:55.610 --> 49:59.260
So yeah, you can use them for
-- and you can take advantage of

49:59.255 --> 50:00.985
some of these side-effects.

50:00.989 --> 50:04.799
But I don't know of any
specific negative side-effects

50:04.797 --> 50:06.017
that were used.

50:06.018 --> 50:07.118
But that just happened.

50:07.117 --> 50:09.837
You may see some beneficial
positive side-effects that the

50:09.840 --> 50:11.990
pharma companies didn't even
know existed;

50:11.989 --> 50:13.239
they didn't even target that.

50:13.239 --> 50:16.299
So we continue -- so that's
where it's important to do

50:16.297 --> 50:18.257
clinical trials,
as a clinician.

50:18.260 --> 50:20.020
So I'm involved in clinical
trials as well.

50:20.018 --> 50:22.628
And that's sort of an ongoing
duty I think,

50:22.630 --> 50:26.050
certainly being an academic
institution, that we need to

50:26.050 --> 50:28.040
also play an important role.

50:28.039 --> 50:30.539
Okay? Thanks.

50:30.539 --> 50:32.629
Prof: So if you have a
few more questions,

50:32.625 --> 50:33.185
come on up.

50:33.190 --> 50:33.580
Dr. Dianne Duffey:
Yeah.

50:33.579 --> 50:35.699
Prof: I'm sure you have
to get back to your practice.

50:35.699 --> 50:38.339
But the time's up now,
and thanks again Dr. Duffey.

50:38.340 --> 50:38.890
Dr. Dianne Duffey:
My pleasure.

50:38.894 --> 50:39.104
Thank you.

50:39.099 --> 50:41.799
>

50:41.800 --> 50:47.000