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T H E

P 1 P B L I N B

Operator Israel Gonzalez and production leader Betsy Galarza of the dry products plant in
Puerto Rico inspect a granulator used in the manufacture of validation lots for olanzapine.

Lilly is redefining the way it brings

products to market.
And olanzapine, the company's
antipsychotic drug in development for the
treatment of schizophrenia and other
psychotic disorders, is forging new
ground-from process definition to
clinical trial studies to global marketing
strategies.
"We are blazing a new trail in how
we develop products at Lilly," said Beth S.
Morris, manager of development projects
management.
In fact, Morris describes the
changes in chemistry, manufacturing, and
control CM&C as a "quantum leap" for
the company. CM&C is the part of the
drug development process that includes
the process development and character
ization of a new drug substance and the
development of analytical methods,
dosage formulations, and supporting
stability data for registration and market
ing requirements.

Early validation
A key strategy recently introduced

in chemistry, manufacturing, and control

is the early validation of bulk and product
processes. Historically, the company has
manufactured separate lots for stability
studies and full-scale validation. In the
past, stability lots were manufactured at
pilot scale to ensure that when the process
or product was taken to full-scale
production, it would remain stable i.e.,
potency of bulk drug substance or tablet,
shelf life, etc.. The data generated from
these lots were used for regulatory
submission. Full-scale validation lots at
the manufacturing site were not com
pleted until after regulatory submission
and often right before product launch.
"Under the previous system, we
didn't know if the process parameters
used for stability studies and regulatory
submission would reflect what the process
or product would do when it went to fullscale production," Morris said. "With that
kind of system, it's possible to find yourself
living with a suboptimal process that was
locked in at the time of submission."
Employing the new strategy with
olanzapine as the pioneer, Lilly completed

Zyprexa MDL 1596

validation of the bulk drug substance at

Kinsale, Ireland, in late 1993. The
company recently completed validation of
full-scale tablet lots in Puerto Rico. See
related story on page 8. In addition, fullscale production of granules was com
pleted at Basingstoke, England, in
September.
The greatest advantage of early
validation is that the process for full-scale
manufacturing is fully defined and
optimized at the time of regulatory
submission. According to Morris, it's a
significant strategic investment that
contributes to the company's quality
speed initiative.

Dedicated core team

Morris is one of eight members of
the olanzapine dedicated core team, a
pilot effort in which the central-nervoussystem CNS compound is serving as a
model for other Lilly products. While the
core team concept is not new at Lilly,
previous core team members worked on
several projects simultaneously. The
concept of the dedicated core team is to

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focus all team members' efforts on only

one compound.
"1 think the dedicated core team is
the first step in an interesting evolution in
the project team structure at UIly," said
Jeffrey S. Kasher, Ph.D., manager of
pharmaceutical projects. "If you look at
companies outside the pharmaceutical
industry you'll see that this is how they're
getting things done."
Representing pharmaceutical
projects management, central-nervoussystem global business unit, medical, and
development projects management, the
olanzapine core team has project respon
sibility solely for this compound.
"While there are others working on
olarizapine, the core team is looking at the
overall strategy and focusing exclusively
on this one compound," Kasher said.
"That focus allows the team to anticipate
possible issues and to react more quickly.
The team is in a better position to keep
the project on track. And olarizapine is a
project which can't afford delays of weeks
or months."

tions are perhaps the most debilitating

and most difficult to treat.
Antipsychotic drug therapy for
treating schizophrenia has been available
for decades. The conventional
antipsychotics, however; treat only the
positive symptoms. And the tradeoff for
controlling the hallucinations and
delusions often includes severe side
effects, such as a Parkinson's disease-like
syndrome and tardive dyskinesia, an
involuntary writhing of the muscles. Such
side effects, along with persisting negative

If anything,
market

v !aas been
too long

A drug in demand
If anything, the market already has
been waiting too long for a drug like
olanzapine. A central-nervous-system
disorder whose causes are not completely
understood, schizophrenia afflicts more
than 5 million people worldwide. In the
United States, schizophrenia is the
number one mental illness in terms of
patients who are hospitalized. And
experts estimate that one-third of the
nation's homeless suffer from schizophre
nia. The disease severely impairs a
person's ability to reason and to feel
emotion, leading the individual down a
spiral of devastating despair.
"Schizophrenia is truly a malignant
disease whose signs and symptoms are far
from everyday human experience," said
Charles M. Beasley,Jr., M.D., a senior
clinical research physician.
Symptoms include hallucinations
and delusions, called positive symptoms,
as well as social withdrawal, apathy, and
an emotionless demeanor. Referred to as
negative symptoms, these latter manifesta
Ocro9ffR

symptoms, make it almost impossible for

a person with schizophrenia to resume a
normal life.
In past years, the focus of therapy
has moved to a new class of medicines
called atypical antipsychotics. These drugs
not only suppress the positive and
negative symptoms of schizophrenia, but
do so with a relative reduction in the
severe side effects of traditional
antipsychotics. Currently, the "goldstandard" among atypical antipsychotics
for the treatment of schizophrenia is
clozapine, which, like olanzapine,
interacts at a diverse array of neurotrans
mitter receptors, including receptors for
dopamine, serotonin, and acetylcholine.
Marketed by Sandoz Pharmaceuticals,
clozapine is the only approved drug
believed to control both the positive and
negative symptoms of schizophrenia
without the extrapyramidal side effects of

other neuroleptics. But treatment is not

without a cost.
Clozapine is an older compound
that initially was removed from develop
ment because it was linked to a potentially
fatal condition called agranulocytosis, a
precipitous loss of white blood cells that
can lead to a fatal infection. Today, patients
who use clozapine must have their blood
tested regularly to monitor their white
blood cell count, a test that is both timeconsuming and expensive. For this reason
alone, clozapine will probably never be a
first-line treatment for schizophrenia.
Although the drug boasts a high success
rate in treating both positive and negative
symptoms, its potentially fatal side effect,
along with other less serious but uncom
fortable side effects, has made clozapine a
treatment of last resort, especially for
patients who haven't responded adequately
to other antipsychotics.
The market is looking for a safe
clozapine, and Lilly's drug candidate
olanzapine looks like it might "fit the bill."
"Preliminary study data are highly
encouraging regarding the safety profile of
olanzapirie," said Gary D. Tollefson, M.D.,
Ph.D., executive director of clinical
investigation and regulatory affairs. "[The
datal suggest that the compound may
successfully differentiate itself from
clozapine."
Targeted for worldwide regulatory
submission in 1995, olanzapine has been
shown to suppress both the positive and
negative symptoms of the disease. In
addition, more than 2,500 patients have
been given the investigational drug in
clinical trials, and no cases of
agranulocytosis have been reported.
A Phase II placebo-controlled study,
using haloperidol a common neuroleptic
as an active comparator, showed olanza
pine to be statistically superior to both
placebo and haloperidol. Data from addi
tional Phase II studies will be presented to
the European and American Colleges of
Neuropsychopharmacology by year-end.
Enrollment in a 2,000-patient
international Phase III trial was completed
in August, reflecting another innovative
step in the development of olanzapine.

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"From a clinical perspective, the manner

in which our trials have been conducted
is one remarkable aspect about this
project," Beasley said.
In the past, Lilly has waited for
complete results from one phase of clinical
trial studies before proceeding to the next
phase. However, with olanzapine, instead
of waiting for data from the completed
Phase II trials, the company launched
Phase III trials based on the interim
analysis of the Phase II trials.
The overlapping trials, in which the
company moved from a 10-patient study
at a single center to hundreds and then to
thousands of patients at multiple sites
around the world, are a significant
contributor to the speed-to-market goal.
"Careful planning and protocol design
and implementation were employed to
ensure patient safety while expediting the
developmental process to the anticipated
benefit of our patients," Tollefson said.
Beyond the core clinical trials
required for regulatory submission
worldwide, a number of studies are in
development to further expand scientists'
knowledge of the compound. For
example, a U.S. safety and efficacy study
will look at more than 200 geriatric
patients with psychoses in the context of
Alzheirner's disease. Enrollment in the
geriatric study is expected to be com
pleted inJanuary 1995.
Also scheduled for next year is a
large comparative study with risperidone,
an antipsychotic drug made by Janssen
Pharmaceutica Inc., a subsidiary of
Johnson & Johnson.
Risperidone was launched in the
U.S. in March 1994. Recent figures show
the drug's share of the U.S. market to be
around 29 percent. However, according to
Tollefson, "risperidone has not unequivo
cally demonstrated negative symptom
efficacy or benefit in resistant patients."
Nor has it been free of some of the side
effects seen with typical antipsychotic
drugs. Consequently in a number of
major markets, risperidone has not
received regulatory approval as an atypical
antipsychotic.

Early validation marks milestone

for Puerto Rico
The Carolina manufacturing site in Puerto
Rico celebrated a milestone event in June.
One month previously, in May, the Puerto
Rico dry products plant PRO1 had completed
the manufacture of validation lots for
olanzapine, the company's compound
currently in development for the treatment of
schizophrenia.
So why the cause for celebration? Olanzapine
is the first compound in the company's history
for which stability data for regulatory
submission were generated by the
manufacture of full-scale validation lots at the
site of manufacturing. And Puerto Rico
played a pivotal role in this milestone
achievement. The validation lots completed at
the plant site in Puerto Rico will provide the
stability data that are required for worldwide
regulatory submission of olanzapine. In the
past, stability data were generated by smallscale stability lots manufactured in
Indianapolis.

David E Long, Ph.D. left, head of pharma

ceutical research and development and
Tommy C. Morris Ph.D., senior pharma
ceutical chemist commend the efforts of
the Carolina manufacturing site during
Olanzapine Day in June.

"The key to our success has been the

teamwork approach taken by all the different
areas," said Lourdes M. Tejada, Puerto Rico project leader. The areas involved at the Puerto
Rico site included production, quality control, technical services, validation, materials, and
others. "We had very close communication with the development group, manufacturing kit
"When we look at our data, we're
incredibly excited about our opportunity
in this market," Rasher said.

Treatment beyond a pill

Schizophrenia strikes most often in
early adolescence, a time when its victims
should be exploring life-not withdraw
ing from it. "Instead of developing
relationships or pursuing careers, people
with schizophrenia are just trying to get
the voices out of their heads," said John R.
Richards, manager of global pharmaceuti
cal marketing for olanzapine. Conse
quently, when patients with schizophrenia
are prescribed clozapine as a last resort,
most have lived through a painful pattern
of multiple drug therapy, relapse, and

hospitalization-a cycle that literally has

stolen years from their lives.
What happens when these patients
are prescribed a drug that gives them back
some semblance of a normal life? What
happens when they "wake up" after
having lost years of social development
and interaction?
"These patients get a jolt when they
reenter society" Richards said. "Drug
therapy alone doesn't help someone hold
down a full-time job. A drug like
olanzapine has the opportunity to give
patients back some type of a productive
life, but it won't do it by itself. Drug
therapy has to be coordinated with
educational, residential, vocational, and
social services and programs."

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LILLY

DEAR

group, and development projects management [in Indianapolis]. Once we drew the plan, we
stuck to our commitments. All of us were focused on the same specific goal and driven by the
same motivation. This is just a start in a series of speed-to-market projcts in which PRO1 is
currently participating and committed to continuously improve."
The eady site validation required the plant to implement a number of modifications to prepare
the site for full-scale manufacturing. The group responsible for the facility modification
worked extra hours during the winter holiday in order to have the plant ready by the
beginning of the year. Modifications were made to the granulation suite and the finishing
lines to meet the specific requirements for fulI.scale production of olnzapine in five different
tablet formulations.
Scale-up at the site began in August 1993, with manufacturing of the validation lots
beginning in March 1994. Among the specific goals of the first speed-to-market initiative for
the Puerto Rico plant site were a commitment to the project timetable, use of the 1996 u.s.
Food and Drug Administration standards for new product approval, quality and customer
satisfaction.
V

Even with a few Iurdles to clear Iong the path, the site met its stated goals and completed
the validation lots according to schedule.
To recognize this significant achievement and the roughly 60 employees who were a part of
the effort, the Puerto Rico site announced June 22 as Olanzapine Day and hosted a number
of activities to recnize the important contribution of the manufacturing site to the early
validation project
.

"This was just an utstanding effort between development and manufacturing to bring new
products on-line irjirecord time," said Beth S. Morris, manager of dveIopment projects
management
,.,

According to TereCok5n plant manager for the dry products plant in Carolina, this
achievement has st the standard for the Puerto Rico plant. "Wa ae foised on rufts and
doing it better evy time," she said. "Our utmost intrest is fo#stisfy the customer and
contribute to the mpany's speed-to-market goal."
V

As Ully becomes a provider of

outcomes, and not just pharmaceuticals, it
becomes evident that providing the
market with an atypical antipsychotic is
the first step in giving people with
schizophrenia optimal results.
Educating the public and
destigmatizing the disease is one area
where Lilly is making a difference. Lilly
has funded educational grants through
the National Alliance for Mental Illness, a
key advocacy group in the United States,
to help educate consumer groups about
the disease. In fact, Lilly was the only
pharmaceutical company to host an
exhibit at the organization's annual
convention in July. The exhibit included a
bank of six computers used to collect
information about patients, caregivers,
OCrOBER

disease therapies, and compliance issues.

"With this kind of market data,
we're trying to get behind the eyes of our
customers in onier to find answers that
will help Lilly better market olanzapine
and integrate patients back into society,"
Richards said. "We are looking at ways in
which we as a company can work with
organizations that offer services such as
job training and social development
programs."
As a company, Lilly has a major
focus in CNS. "And clearly we see
olanzapine as the next pharmaceutical
product we're going to add to our CNS
portfolio," Kasher said, "giving us great
opportunity to deliver optimal results to
patients with psychoses."
-by Laura Stailman

The following is excerpted from

a letter written to two Lilly
.researchers at En Wood by a
physician who is participating
in clinical trials for olanzapine.
I want to thank yoltpersonally
for allowing me, through your
research, the enormously
gratfying experience ofwatching
this 35-year-old woman,
diagnosed with schizophrenia in
,2dolescence,find a placefor
herselfin herfamily and society
Before olanzapin she had been
unable to leave her house except
to drive with her inother to
doctor's appozntnr.ents or the
rocery stoVr, where she would
cower in the car She blasted acid
rock nzusicto "dmw,outth&
voices "Size experzencei delusions
and command auditory
hallucinations to jail herself; and
the had acted on the coiiunanxfr
. .

On olanzapine wve slowly seen

this woman emeigefrom
debilitatingpsychos4c She has
much more abilityto"connect"
with people than we had ever
suspectecL She has much to do
in "sortrng through"izfe events
6utisabletoworkeffecuvelyin
psychotherapy
Thank you.

-<

Nora Heflin WUlzams MD

1994

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BARBA8 J RING
O2 MC909

28/2

MR17

Medca Mracles
Delivering on a Promise
People have urgent medical needs that continue
to go unmet. The rapid advance of science and
technology is breathtaking. Indeed, modern science
has become a manufacturer of miracles. However, the
unmet medical needs of people-life-threatening
diseases that medical science cannot successfully treat
or cure-present a sobering challenge. At Eli Lilly and
Company, our goal is to meet these needs.
Lilly research focuses on diseases that de' current
treatments. We're targeting the central nervous
system for diseases such as depression, Alzheimer's
disease, and schizophrenia. Endocrine diseases, such
as diabetes and osteoporosis. Infectious diseases.
Cancer, Cardiovascular diseases.
We're focusing on all the elements involved in
dealing with each of these categoiies. We want
people to achieve the best results in preventing and
managing disease. So we're innovating-in information
services, in educational programs, and in more
convenient ways for people to take medicines. Were
seeking breakthrough drugs using our expanding
knowledge and the most sophisticated technology in
the wod. We're accelerating the search for cures.
At LiIIy we're optimistic about the future.

We're excited about our opportunities to meet the

needs of people. And we're committed to doing what
it takes to further the hope and healing of patients who
wa for new medical miracles.

-<
Co
0

Eli Lilly and Company

Delivering hope and healing

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