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Personalized Medicine

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 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 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 (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 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