1. Pharmacogenetics & Your Medical Practice Presenters: Tom Ashlock, MD Morris Burgess, PharmD Luis Martinez, MD Phil Tagariello, PharmD

2. What Your Patients are starting to see MAYO CLINIC INTRODUCTION to PHARMACOGENOMICS 3. As Seen On TV What Your Patients See 4. There is a new potential threat on the horizon for Physicians and the UCLA Journal of Law and Business has already published an extensive article about it Pharmacogenetic testing is a tool currently available to assist you in your practice. Not using it proactively can and likely will have an adverse effect on your practice in the form of LIABILITY Eliminate trial and error: Right Drug, Right Dose, Right Indication, Right Patient, Right Time Eliminate One Size Fits All medication management Enhance Patient Care Enhance Patient Satisfaction Enhance Compliance Enhance Patient Confidence. Risk Management: Reduce liability to physician Why Should Physicians Test their Patients? 5. FDA has posted 130 Black Box Warnings where manufacturers recommend pharmacogenomics testing prior to or soon after initiation of therapy. Of those, over 100 drugs require pharmacogenetic testing prior to prescribing, or it is highly recommended.. http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm 6. Pharmacogenetic Testing: A Reality TODAY Pharmacogenetic testing eventually can lead to an overall decrease in the cost of health care Physicians should consider pharmacogenomics information an additional piece of information when selecting drug therapy. We should also encourage health care systems and interested providers to be early adopters Some would argue that, once we have the information, we have an obligation to use it, just as we use other information in our clinical decision- making. Overcoming Barriers to Using Pharmacogenomics in Practice Kathryn Teng, MD Department of Internal Medicine, Cleveland Clinic From the website of the American Medical Association http://www.ama-assn.org/ama/pub/physician-resources/medical-science/genetics-molecular-medicine/current- topics/pharmacogenomics.page? In 2013 the following institutions implemented PGx testing: Cornell, Columbia, Georgetown, Harvard, Mayo Clinic, Scripps, Stanford, Vanderbilt to name a few. 7. Why Should We Care about Pharmacogenetics Testing? There are over 2.2 million+ avoidable ADR hospitalizations per year There are over 106,000 avoidable ADR deaths per year. That equates to 1 avoidable death every 5 minutes! FDA report states in excess of $136+ billion in avoidable annual cost for ADRs Additionally over 350,000 Nursing Home ADRs per year Study concluded of 3695 hospitalized patient episodes for ADRs, over half of them were definitely avoidable The more drugs a patient is taking, the more chance of an ADR The average Medicare patient takes 5-8 drugs with some as high as 20+ drugs per day Over 50% of Nursing Home patients take 5+ drugs and placed on at least one psychiatric drug within 2 weeks Patients taking over 11 drugs have a 96% chance of and ADR Pharmacogenetics Testing can significantly reduce these statistics, yet we are unnecessarily subjecting our patients to avoidable ADRs and even deaths 8. Drug Metabolizing Phenotype Ultra Rapid Metabolizers (UM) Increased enzyme Extensive Metabolizers (EM) Normal Intermediate Metabolizers (IM) Impaired Poor Metabolizers (PM) Non functional 9. Major CYP450 Isoforms 1. A2 6. 2D6 2. 2B6 7. 2E1 3. 2C8 8. 3A4 4. 2C19 9. 3A5 5. 2C9 10. 3A7 10. Inhibitor A substrate(drug) that slows down or inhibits the metabolism of other substrates Inducer A substrate that increases the elimination of other substrates Prodrug A substrate that is biologically inactive in its original (parent) form. These drugs must be metabolized (activated)before they work in the body and produce their desired effect Definition of Terms Used Regarding Drug Properties 11. Pharmacogenomic testing: Relevance in medical practice Why drugs work in some patients but not in others Cleveland Clinic Journal of Medicine, Volume 78, Number 4, April 2011 12. Case Study 1: Codeine 30 year old woman gave birth; post episiotomy was given codeine for pain. Breast fed healthy infant; at 13 days infant died. Post mortem autopsy revealed morphine overdose of infant. How would genetic testing help patient and physician? Genotyping of patients CYP2D6 gene prior to prescribing codeine would have revealed patient was an ultra-rapid metabolizer. Armed with this knowledge, patients physician would have prescribed a different analgesic; and saved patients infants life Pain Medicine News: Genetic Testing in Pain Medicine April 2013 In the classic nature versus nurture scenario, investigators use twin pairslooked at pain conditions and concluded that migraines have a 39% to 58% genetic contribution, low back pain carries a 21% to 67% contribution. In that same article they state patients taking 8 drugsthey calculated a potential of 476 drug interactions in 63% of the patients. 10% Caucasians are ultra-rapid metabolizers of codeine. Another 5% of African Americans, Asians and Hispanics are ultra-rapid metabolizers. Only 1% of patients were aware of the potential for drug-drug, or drug-gene interactions. Only 58% of patients receive relief from pain medications with the first attempt at getting it right. (Peter D. Hart Research Associates) 13. Case Study 2: Clopidogrel JM, a 58 year-old man recently had an acute MI. To prevent ischemic events, JMs physician recommends antiplatelet therapy and prescribes Clopidogrel. Six months later, JM suffered another acute MI, and his physician suspects that patient has been non-adherent, or alternatively, that Clopidogrel therapy may have been ineffective. How would genetic testing help JM and his physician? Determining JMs CYP2C19 genotype may reveal that he carries a variant that diminishes the antiplatelet effect on Clopidogrel. If this were the case, alternative anti-platelet therapies may have been considered, reducing the chance that JM would suffer a second cardiac event. Patients with reduced function alleles have a 3.5 8 times greater risk for major adverse cardiovascular events, with greater risk in poor metaboloizers (Tobassome, MD Genetic Determinants of Response to Clopidogrel and Cardiovascular Events). NOTE: FDA has posted a warning that diminished effectiveness in poor metabolizers may cause lack of efficacy and place patient at great risk. 14. Case Study 3: Warfarin ML, a 65 year-old woman diagnosed with atrial fibrillation. To reduce the risk of stroke and other thrombotic events, MLs physician recommends Warfarin therapy. To estimate the initial dose, MLs clinical characteristics were considered (age, sex, weight, diet). However, ML will need to return to the clinic every day for INR monitoring until a stable dose is determined, and then every few weeks thereafter for maintenance monitoring. How would genetic testing help ML and her physician? Determination of MLs CYP2C9 and VKORC1 genotype would reveal whether she carries any variations that alter her ability to metabolize and respond to Warfarin. Knowing about any gene variations before initiating therapy allows for more accurate initial dosing and faster INR stabilization, and can reduce the risk of bleeding or clotting events. NOTE: JACC Journal: Warfarin Genotyping Reduces Hospitalization Rates June 2010 (Medco-Mayo Warfarin Effectiveness Study) Reveals that there was a 43% lower risk of hospitalization for bleeding or thromboembolism in patients who were genotyped. Pharmacogenetics testing is applicable to 70-75% of patients not in controlled anticoagulation centers. Testing reduced between 4,500 and 22,000 serious bleeding events annually. Pharmacogenetic testing is now required by FDA 15. Case Study 4: Clonidine and Fluoxetine 9 year old boy with ADHD placed on Clonidine and Fluoxetine develops symptoms of low- grade fever, in-co-ordination and seizures. Boy went into status epilepticus and died. The boy could not metabolize Prozac, and he had built up very toxic levels before anyone recognized it. Mrazek in Psychiatric Times states that some patients still die even when medication is stopped because some patients have limited metabolic capacity. How would pharmacogenetic testing help this patient and physician? Physician would have known that patient was a poor metabolizer of CYP2C19 and chosen another therapeutic regimen that was not metabolized through that pathway NOTE: FDA reports 30 approved drugs psychiatric drugs with pharmacogenetic testing information on their labels. Mrazek, in Psychiatric Times, recommended increased clinician educationand translation of laboratory test results into actionable prescribing decisions for specific drugs including pharmacogenetic information on electronic medical records. In their JAMA article, Mrazek predicted that it wont be too long before diagnostic and treatment guidelines for psychiatric disorders recommend pharmacogenomics testing as part of the initial workup. 16. Liability is likely to be a major driver for the future direction and implementation of personalized medicine, spurring the adoption of genetic tests and other pharmacogenomic technologies liability will often be both unpredictable and influential in changing medical practice. It is critical to anticipate and attempt to prevent such liability risks in a proactive manner so to minimize the disruptive impact that liability can cause. Physician Liability: The Next Big Thing for Personalized Medicine? Gary E Marchant, Doug E Campos-Outcalt, Rachel A Lindor Personalized Medicine. 2011;8(4):457-467. Risk Management: Reduce liability to physician 17. Medical Malpractice: Physicians could face liability for failure to test patients only 13% of the more than 10,000 physicians surveyed had ever prescribed a pharmacogenomic test. Pharmacogenomics will alter the way physicians practice medicine. As physicians incorporate pharmacogenomic techniques in their practice, patients will likely suffer fewer ADRs however, pharmacogenomics will likely be accompanied by (if not spurred on by) medical malpractice suits based on a number of claims. Lack of Informed Consent: injured patients could sue under a theory of informed consent physician failed to disclose all pertinent information, including risks, benefits, and alternatives, they would have chosen a different avenue of treatment. UCLA Journal of Law and Technology: Legal Issues Stemming from the Advancement of Pharmagenomics 18. Simple, Non invasive Buccal Swab Pediatrics: no diagnosis required (base-line for future drugs), OB: Medical Necessity Black Box Warning Medical Necessity only requires patient be on 2 meds (OTC or Script) Medicare fully covers PGx testing with no deductible and no copay. Most Third Party cover PGx testing subject to deductible/copay. Cash payors charged same as Medicare currently about $1,000. One-time, lifetime test that will benefit the patient for life unlike routine tests such as CBCs etc. that are often ordered throughout a patients lifetime equating to much more than the one-time test. Lab offers Friendly Billing Policy - Lab DOES NOT call patient or send patient bill to collection or credit bureau in the event Lab does not receive patient portion of the test. Billing questions handled by Lab. Lab assists patients in financial need. Physician may be eligible to bill at a higher level of complexity for an office visit. Eg: If physician normally bills 99212 or 99213, he may choose to bill 99214 and increase reimbursement to his practice by an average of $50. PGx testing qualifies for one of the requirements to be eligible for the higher rate of billing. Physician should properly annotate patient office visit notes. . Physician may bill for interpretation of PGx test with G0452, reimbursement to practice of approx. $20. Some physicians successfully bill individually for each one of the 9 panels. Ease of Testing, CPT Codes, Billing and Reimbursement 19. Physicians use science to diagnose, but have had to use trial and error in prescribing for therapeutic treatment. NOW, prescribers have science to assist them in getting the right med for the right patient at the right dosage the first time. Enhance patient care, Enhance patient satisfaction, Enhance patient compliance, Enhance patient confidence, Enhance patient outcome Receive Private Consult with PharmD on your patients before prescribing Risk Management: Reduce liability to physician One Question Remains: Now that you have reviewed the risks and benefits of implementing Pharmacogenetics Testing into your Medical Practice: Why Wouldnt You Begin Testing Your Patients Now? Why Should Physicians Test their Patients? 20. Cardiovascular pharmacogenomics: current status, future prospects Anderson JL, Carlquist JF, Horne BD, Muhlestein JB J Cardiovasc Pharmacol Ther 2003;8(1):71-83 Pharmacogenomics Drug disposition, drug targets, and side effects Evans, WE, and McLeod, HL New England Journal of Medicine 2003; 348:538-549 Cancer pharmacogenomics: current and future applications Watters JW, McLeod HL Biochim Biophys Acta 2003 Mar 17;1603(2):99-111 Pharmacogenomics study of statin therapy and cholesterol reduction Chasman DI, et al. Journal of the American Medical Association 2004; 291(23) 2821-2827. Role of pharmacogenomics in individualizing treatment with SSRIs Mancama D, Kerwin RW CNS Drugs 2003;17(3):143-51 Partial List of References for Clinical Applications