PAGE 1

On the Same Page Personalized Medicine June 17 2011 Yesterday we announc ed the funding of three grants totaling $1.25 million from the National Institutes of Health to develop a personalized medicine program, expand community based clin ical research in Florida, and improve clinical tri al design. These three projects, which represent supplements to our Clinical and Translational Science Award, involve researchers from multiple colleges at UF as well as at Florida State University, Stanford University a nd the University of Iowa. Nearly half a million dollars of these funds will jump start the creation of a personalized medicine program at UF, which will be replicated at Stanford University Lead investigator Julie A. Johnson, Pharm.D., the V. Ravi Chandran professor and chair of pharmacotherapy and translational research in the College of Pharmacy, will head a multidisciplinar y team to develop personalized medicine at UF. To begin, the grant will fund creation of a system that uses gen etic information to create alerts in a p inform s treatment decisions about a drug used to prevent strokes and heart attacks. The Wall Street Jou rnal Targeting Drugs for Each Unique Genetic Profile." (A few months later, the same article was published in The Oncologist 1999;4:426 27). This article, by Robert Langreth and Michae l Waldholz, described a consortium of 10 major pharmaceutical companies, the Wellcome Trust, and five academic research centers that aimed to develop a comprehensive map of the human genome. The central concept was to develop drugs specifically designed to A dozen years later, the field is exploding. Many journals, conferences, research institutes, drug companies and people are now devoted to personalized medicine. The hope is to improve health and reduce co st while minimizing adverse reactions and avoiding ineffective therapies. Has this hope materialized? And what role are we playing at the University of Florida? The UF Program in Personalized Medicine is being created under the CTSI to integrate our new system of electronic medical records with data from our evolving tissue repository, as well as data on other genetic and molecular markers, to determine disease ri sk and guide treatment decisions. In addition to the CTSA supplement, there is more good news. We have recently learned that Dr. Johnson will receive an additional grant for $351,600 over four years, strengthening support for the Personalized Medicine Program. This grant comes from the N IH Pharmacogenomics Research Network, where UF and five other institutions will gather data on the collective experiences of launching personalized medicine programs.

PAGE 2

[Note: The two other CTSA supplements to UF, funded in an extremely competitive review p rocess, were: (1) A program to based research infrastructure by facilitating pilot projects focused on concussion assessment and health risk assessment in Daytona Beach, Orlando and Tallahassee. (Co lead investigators: Russell Bauer, Ph.D., a professor and chair of clinical and health psychology in the College of Public Health and Health Professions, and Elizabeth Shenkman, Ph.D ., a professor and chair of the Department of Health Outcomes and Policy in the College of Medicine). of Public Health and Health P rofessions and College of Medicine, to assess the use of adaptive trial de sign methods in comparative effectiveness research and to develop and disseminate guidelines for gathering evidence efficie ntly and cost effectively The work will be done in conjunction with biostatisticians and clinical scientists at the University of Io wa. ( L ead investigator: John A. Kairalla, Ph.D., assistant professor of B iostatistics.) ] Many investigators at UF are involved in different aspects of biomarker and risk identification research that are broadly subsumed under the personalized medicine umbrella, but Dr. Johnson will lead the charge along with Michael Clare Salzler, M.D., chair, Department of Pathology, College of Medicine, and David Nelson, M.D., professor of medicine and director of the Clinical and Translational Science Institute (CTSI ). The Program in Personalized Medicine will be designed to incorporate genetic data in a and potentially influence team also will create a genetic data repository linked with clinical records to support additional genetics research The new grant will implement a specific example of how this linkage between genetic data and electronic medical records improves patient care. In particular, the investigators will use pharmacogenetic information to guide treatment decisions involving clopidogrel, a drug used to prevent strokes and heart attacks. Clopidogrel recently had an FDA black box warning added to its label to alert clinicians to the clinical differences in treatment related outcomes based on genotype. The initial research program, which represents a collaboration with the Stanford CTSA that integrates genotype, biorepository and electronic health record data, lays t he groundwork for developing a system that enables a much broader integration of genetic and pharmacogenetic information into patient care. Why was clopidogrel chosen as the test case? Dr. Johnson explains it this way: Clopidogrel is an example of a drug for which pharmacogenomics biomarkers were discovered after its approval. A n antiplatelet agent, it is administered as a "prodrug" that requires a two step enzymatic activation. A genetic polymorphism in one of these enzymes leads t o higher rates of adverse cardiovascular events during treatment in certain high risk patients On the basis of these data, the Food and Drug Admi nistration added the boxed warning noted above to the clopidogrel product label in March 2010, informing clini cians of the potential for reduced efficacy of clopidogrel in patients with certain genotypes related to the enzyme Thus, it was thought that an excellent way to launch PPM is to determine whether these genetic polymorphisms are present among high risk pa tients in the cardiac catheterization laboratory who are likely to have clopidogrel prescribed. Their physician will then receive an alert in the

PAGE 3

electronic medical record about their specific enzyme genotype and potential options if their genotype suggest s the potential for reduced clopidogrel efficacy. If this personalized medicine system works with clopidogrel on the immediate horizon would be other drugs for which the FDA has revised the label to include pharmacogenetic information, including warfarin beta blockers, antidepressants, thiopurines, codeine and statins. Warfarin (Coumadin), for example, is one of our oldest drugs, in use for well over 50 years as an anticoagulant. While extremely effective in preventing clot formation, it has a narrow the rapeutic window, below which it has limited ability to prevent clot formation and above wh ich bleeding risk is elevated. Warfar use is made even more challenging by the fact that the dose required to get within that therapeutic window can range by 10 t o 20 times among different patients. Recent studies have provided clear evidence for genetic and clinical factors (like age and body size) that influence warfarin dose requirements, and dosing algorithms have been developed to lead to personalized dosing strategies. Under Dr. Johnson's leadership, UF is currently one of 12 sites nationally undertaking an NIH funded clinical trial to test whether a genetic guided personalized dosing strategy is superior. Dr. Johnson's colleagues on this grant include Drs. William Allen (ethics), R. David Anderson (cardiovascular medicine), Anthony Bavry (cardiovascular medicine), Michael Conlon (biomedical informatics), Michael Clare Salzler (pathology), and Taimour Langaee (pharmacotherapy) Beyond pharmacogenetics, UF is developing a tissue repository to be incorporated into the Program in Personalized Medicine under the CTSI and the leadership of Dr. Clare Salzler. This repository will create a process for obtaining and storing patient tissue, with appropriate informed c onsent, and for ensuring that tissues, particularly tumors, are collected and stored in a manner that will provide accurate information about the tissue examined. For example, the quality of tissues used for gene expression studies are highly dependent upo n collection procedures, and these will be standardized under state of the art repository protocols. Disease related tissues are likely to become the cornerstone for personalized medicine in oncology or organ specific disease, as they will allow tumor or t issue specific analysis that may not be present in other non affected tissues, such as peripheral blood. We believe that UF's program represents a measured, step wise approach to our involvement in personalized medicine. Demonstrated value in improved health and reduced cost will be needed for personalized medicine to be fully embraced and reimbursed. Payers are challenged by the lack of information on cost effectiveness as well as patient movement across time; patients typically average only 3 4 years in a given payer plan, so long term benefit is of less importance to payers. Moreover, providers show variable interest, since reimbursement is activity/procedure based and billing is not standardized and scalable at this time. (Of course, this may change with an increased trend towards capitated payments and self insurance.) Demonstrating clear value in terms of improved levels of patient quality and safety and a lower total cost of treatment is critical to enabling reimbursements and driving large scale a doption of personalized medicine.

PAGE 4

One believer is Dr. Johnson. Due to her passion for the potential of personalized medicine and her desire to focus on this field, she is stepping down from her position as c hair of the Department of Pharmacotherapy and Tr anslational Rese arch in the College of Pharmacy. As of July 1, she will be the distinguished professor of Pharmacy and the director of the Personalized Medicine Program. It is often of interest to readers of this newsletter to learn a little more about the people responsible for the amazing things that go on at the Health Science Center. Starting with an initial desire in high school to become a pharmacist and run her own drug store, Julie Johnson unexpectedly became hooked on research during a 10 week elective in her final quarter of her undergraduate pharmacy training at Ohio State. She decided to pursue advanced training and obtained her Pharm.D. from the University of Texas Health Science Center in San Antonio and the University of Texas at Austin, r eturning to Ohio State for postdoctoral research training in clinical pharmacology, with a focus on cardiovascular drugs. Her research interest has always been focused on understanding why patients respond differently to a given medication, and seeking ways to use that knowledge to improve drug therapy in patients. Pharmacogenomics was not a term that existed when she undertook her research training, but as evidence emerged regarding the role of genetics on variability in drug response, a transition to t his area only seemed logical given her in terests. Dr. Johnson's first faculty position was at the University o f Tennessee in Memphis, and she then joined the faculty at UF in 1998. It was around this time that she made a significant shift in her research p rogram to pharmacogenomics, and since coming to UF she has been awarded over $30 million in research funding for work in this field, mostly from the NIH. She was recently renewed in her grant application to lead the hypertension pharmacogenomics group that is Dr. Johnson and her husband, Dr. John Lima, have two daughters who keep them busy: Sarah (16) and Elizabeth (12). In her spare time Dr. Johnson likes to run, play tennis, read and scuba dive. The things two marathons. Given Dr. Johnson's record of achievement whenever she puts her mind to something, and given the expertise and commitment of her coll eagues in implementing personalized medicine at UF&Shands, I have no doubt that we will be successful, and that many patients here and around the world will benefit from this work. Forward Together, David S. Guzick, M D Ph D Senior Vice President, H ealth Affairs President, UF&Shands Health System


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On the Same Page


Personalized Medicine
June 17, 2011


Yesterday, we announced the funding of three grants totaling $1.25 million from the National
Institutes of Health to develop a personalized medicine program, expand community-based
clinical research in Florida, and improve clinical trial design. These three projects, which
represent supplements to our Clinical and Translational Science Award, involve researchers
from multiple colleges at UF as well as at Florida State University, Stanford University and
the University of Iowa.

Nearly half a million dollars of these funds will jump-start the creation of a personalized
medicine program at UF, which will be replicated at Stanford University. Lead investigator
Julie A. Johnson, Pharm.D., the V. Ravi Chandran professor and chair of pharmacotherapy
and translational research in the College of Pharmacy, will head a multidisciplinary team to
develop personalized medicine at UF. To begin, the grant will fund creation of a system that
uses genetic information to create alerts in a patient's medical record that informs treatment
decisions about a drug used to prevent strokes and heart attacks.

The term "Personalized Medicine" was introduced not in a scientific journal but in The Wall
Street Journal, in an April 16, 1999 article titled "New Era of Personalized Medicine-
Targeting Drugs for Each Unique Genetic Profile." (A few months later, the same article was
published in The Oncologist 1999;4:426-27).

This article, by Robert Langreth and Michael Waldholz, described a consortium of 10 major
pharmaceutical companies, the Wellcome Trust, and five academic research centers that
aimed to develop a comprehensive map of the human genome. The central concept was to
develop drugs specifically designed to target an individual patient's genetic profile.

A dozen years later, the field is exploding. Many journals, conferences, research institutes,
drug companies and people are now devoted to personalized medicine. The hope is to
improve health and reduce cost while minimizing adverse reactions and avoiding ineffective
therapies. Has this hope materialized? And what role are we playing at the University of
Florida?

The UF Program in Personalized Medicine is being created under the CTSI to integrate our
new system of electronic medical records with data from our evolving tissue repository, as
well as data on other genetic and molecular markers, to determine disease risk and guide
treatment decisions. In addition to the CTSA supplement, there is more good news. We
have recently learned that Dr. Johnson will receive an additional grant for $351,600 over four
years, strengthening support for the Personalized Medicine Program. This grant comes from
the NIH Pharmacogenomics Research Network, where UF and five other institutions will
gather data on the collective experiences of launching personalized medicine programs.









[Note: The two other CTSA supplements to UF, funded in an extremely competitive review process,
were: (1) A program to enhance Florida's community-based research infrastructure by facilitating
research partnerships with physician practices in FSU's clinical network. The program will conduct two
pilot projects focused on concussion assessment and health risk assessment in Daytona Beach,
Orlando and Tallahassee. (Co-lead investigators: Russell Bauer, Ph.D., a professor and chair of
clinical and health psychology in the College of Public Health and Health Professions, and Elizabeth
Shenkman, Ph.D., a professor and chair of the Department of Health Outcomes and Policy in the
College of Medicine). (2) Collaboration by scientists from UF's College of Public Health and Health
Professions and College of Medicine, to assess the use of adaptive trial design methods in
comparative effectiveness research and to develop and disseminate guidelines for gathering evidence
efficiently and cost-effectively. The work will be done in conjunction with biostatisticians and clinical
scientists at the University of Iowa. (Lead investigator: John A. Kairalla, Ph.D., assistant professor of
Biostatistics.)]

Many investigators at UF are involved in different aspects of biomarker and risk identification
research that are broadly subsumed under the personalized medicine umbrella, but Dr.
Johnson will lead the charge along with Michael Clare-Salzler, M.D., chair, Department of
Pathology, College of Medicine, and David Nelson, M.D., professor of medicine and director
of the Clinical and Translational Science Institute (CTSI).

The Program in Personalized Medicine will be designed to incorporate genetic data in a
patient's electronic medical record that could generate alerts to inform and potentially
influence a doctor's treatment decisions. In developing the program, the team also will
create a genetic data repository linked with clinical records to support additional genetics
research.

The new grant will implement a specific example of how this linkage between genetic data
and electronic medical records improves patient care. In particular, the investigators will use
pharmacogenetic information to guide treatment decisions involving clopidogrel, a drug used
to prevent strokes and heart attacks. Clopidogrel recently had an FDA black box warning
added to its label to alert clinicians to the clinical differences in treatment-related outcomes
based on genotype. The initial research program, which represents a collaboration with the
Stanford CTSA that integrates genotype, biorepository and electronic health record data, lays
the groundwork for developing a system that enables a much broader integration of genetic
and pharmacogenetic information into patient care.

Why was clopidogrel chosen as the test case? Dr. Johnson explains it this way: Clopidogrel
is an example of a drug for which pharmacogenomics biomarkers were discovered after its
approval. An antiplatelet agent, it is administered as a "prodrug" that requires a two-step
enzymatic activation. A genetic polymorphism in one of these enzymes leads to higher rates
of adverse cardiovascular events during treatment in certain high-risk patients. On the basis
of these data, the Food and Drug Administration added the boxed warning noted above to the
clopidogrel product label in March 2010, informing clinicians of the potential for reduced
efficacy of clopidogrel in patients with certain genotypes related to the enzyme. Thus, it was
thought that an excellent way to launch PPM is to determine whether these genetic
polymorphisms are present among high-risk patients in the cardiac catheterization laboratory
who are likely to have clopidogrel prescribed. Their physician will then receive an alert in the









electronic medical record about their specific enzyme genotype and potential options if their
genotype suggests the potential for reduced clopidogrel efficacy.

If this personalized medicine system works with clopidogrel, on the immediate horizon would
be other drugs for which the FDA has revised the label to include pharmacogenetic
information, including warfarin, beta blockers, antidepressants, thiopurines, codeine and
stations. Warfarin (Coumadin), for example, is one of our oldest drugs, in use for well over 50
years as an anticoagulant. While extremely effective in preventing clot formation, it has a
narrow therapeutic window, below which it has limited ability to prevent clot formation and
above which bleeding risk is elevated. Warfarin's use is made even more challenging by the
fact that the dose required to get within that therapeutic window can range by 10 to 20 times
among different patients. Recent studies have provided clear evidence for genetic and clinical
factors (like age and body size) that influence warfarin dose requirements, and dosing
algorithms have been developed to lead to personalized dosing strategies. Under Dr.
Johnson's leadership, UF is currently one of 12 sites nationally undertaking an NIH-funded
clinical trial to test whether a genetic-guided personalized dosing strategy is superior.

Dr. Johnson's colleagues on this grant include Drs. William Allen (ethics), R. David Anderson
(cardiovascular medicine), Anthony Bavry (cardiovascular medicine), Michael Conlon
(biomedical informatics), Michael Clare-Salzler (pathology), and Taimour Langaee
pharmacotherapyy)

Beyond pharmacogenetics, UF is developing a tissue repository to be incorporated into the
Program in Personalized Medicine, under the CTSI and the leadership of Dr. Clare-Salzler.
This repository will create a process for obtaining and storing patient tissue, with appropriate
informed consent, and for ensuring that tissues, particularly tumors, are collected and stored
in a manner that will provide accurate information about the tissue examined. For example,
the quality of tissues used for gene expression studies are highly dependent upon collection
procedures, and these will be standardized under state-of-the-art repository protocols.
Disease-related tissues are likely to become the cornerstone for personalized medicine in
oncology or organ-specific disease, as they will allow tumor or tissue-specific analysis that
may not be present in other non-affected tissues, such as peripheral blood.

We believe that UF's program represents a measured, step-wise approach to our
involvement in personalized medicine. Demonstrated value in improved health and reduced
cost will be needed for personalized medicine to be fully embraced and reimbursed. Payers
are challenged by the lack of information on cost-effectiveness as well as patient movement
across time; patients typically average only 3-4 years in a given payer plan, so long-term
benefit is of less importance to payers. Moreover, providers show variable interest, since
reimbursement is activity/procedure based and billing is not standardized and scalable at this
time. (Of course, this may change with an increased trend towards capitated payments and
self-insurance.) Demonstrating clear value in terms of improved levels of patient quality and
safety and a lower total cost of treatment is critical to enabling reimbursements and driving
large-scale adoption of personalized medicine.









One believer is Dr. Johnson. Due to her passion for the potential of personalized medicine
and her desire to focus on this field, she is stepping down from her position as chair of the
Department of Pharmacotherapy and Translational Research in the College of Pharmacy. As
of July 1, she will be the distinguished professor of Pharmacy and the director of the
Personalized Medicine Program.

It is often of interest to readers of this newsletter to learn a little more about the people
responsible for the amazing things that go on at the Health Science Center. Starting with an
initial desire in high school to become a pharmacist and run her own drug store, Julie
Johnson unexpectedly became hooked on research during a 10-week elective in her final
quarter of her undergraduate pharmacy training at Ohio State. She decided to pursue
advanced training and obtained her Pharm.D. from the University of Texas Health Science
Center in San Antonio and the University of Texas at Austin, returning to Ohio State for
postdoctoral research training in clinical pharmacology, with a focus on cardiovascular drugs.

Her research interest has always been focused on understanding why patients respond
differently to a given medication, and seeking ways to use that knowledge to improve drug
therapy in patients. Pharmacogenomics was not a term that existed when she undertook her
research training, but as evidence emerged regarding the role of genetics on variability in
drug response, a transition to this area only seemed logical given her interests. Dr. Johnson's
first faculty position was at the University of Tennessee in Memphis, and she then joined the
faculty at UF in 1998. It was around this time that she made a significant shift in her research
program to pharmacogenomics, and since coming to UF she has been awarded over $30
million in research funding for work in this field, mostly from the NIH. She was recently
renewed in her grant application to lead the hypertension pharmacogenomics group that is
funded as part of NIH's Pharmacogenomics Research Network. Dr. Johnson and her
husband, Dr. John Lima, have two daughters who keep them busy: Sarah (16) and Elizabeth
(12). In her spare time, Dr. Johnson likes to run, play tennis, read and scuba dive. The things
that most surprise people about her are that she showed cattle growing up, and that she's run
two marathons.

Given Dr. Johnson's record of achievement whenever she puts her mind to something, and
given the expertise and commitment of her colleagues in implementing personalized
medicine at UF&Shands, I have no doubt that we will be successful, and that many patients
here and around the world will benefit from this work.

Forward Together,

David S. Guzick, M.D., Ph.D.
Senior Vice President, Health Affairs
President, UF&Shands Health System




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