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Promulgating Uptake of Personalized Medicine Robert Epstein, MD, MS April 17, 2011 Foundation.cap.org v. # Outline of Discussion • Who sees the benefit? • Notes from the field. • What does the near-term future hold? Legal disclaimer “Change is inevitable, except from vending machines.” –Woody Allen Source: Peter Pitts. www.pacificresearch.org, April 13, 2005. 4 Focus of talk: Pharmacogenomics Predisposition, Dx Using an individual’s genetic information to identify diseases or predict their future risk of developing other medical conditions Risk Assessment Prevention Pharmacogenomics A science that examines the inherited variations in genes that dictate drug response (whether a drug will be effective or safe) Targeted Monitoring Diagnosis Early Detection Testing Source: Personalized Medicine Coalition: Personalized Medicine 101. Available at http://www.personalizedmedicinecoalition.org/sciencepolicy/personalmed-101_overview.php Therapy Response Monitoring What we fear will be patient reactions My DNA? Are you trying to clone me? Patient perspective “Knowing your molecular identity is irresistible”* Anita Cosgrove, 23andme, personal communication Patients want to know - • Experience with women on tamoxifen who want 2d6 test o 83% say “YES” 700 Payers Vote – This Topic Tied for #2 Topic of Interest! 0 1 2 3 4 3.51 New benefit design strategies Pharmacogenomics 3.40 Consumerism 3.40 Drug pipeline 3.35 Emerging trends in science 3.33 Specialty cost reduction strategies Member communications Generic opportunities 3.13 3.10 3.03 Why do payers care? 1 in 4 Medco patients take a drug with pharmacogenomic considerations 36.1 million patients with ≥1 Rx fill in 2006 8.7 million (24%) with Rx for a drug with human PGx info in label Source: Frueh et al. Pharmacotherapy. 2008;28(8):992-998. How fast this has changed medical care - Oncology 20th Century Cancer care • Cut it • Burn it • Kill it 21st century is about targeted therapy for oncology In 2006, the molecular targeted therapies overtook the cytotoxic therapies for the first time, with sales of $10.7 billion and $8.9 billion, respectively 40,000 35,000 Sales ($M) 30,000 25,000 20,000 15,000 10,000 5,000 0 2006 2007 2008 2009 Antihormonal Therapies 2010 2011 2012 Cytotoxic Therapies 2013 2014 2015 2016 Molecular Targeted Therapies Source: Datamonitor forecasts and MIDAS Sales Data, IMS Health, April 2007. 12 Newer cancer drugs that target pathways Drug Pathway Condition Test Gleevec, Sprycel, Tasigna BCR-ABL kinase Chronic Myelogenous Leukemia BCR-ABL copies Herceptin HER-2 receptor Breast cancer HER-2 status Rituxan CD-20 protein Lymphoma FCGR3A gene Avastin VEGF Colon cancer VEGFA? Tamoxifen Estrogen receptor Breast cancer CYP 2D6 Tarceva, Iressa EGFR kinase Lung, pancreatic cancer EGFR Sutent Tyrosine kinases GI cancer KIT mutations Erbitux, Vectibix EGFR Colon, head/neck cancer KRAS mutations Anticancer Drugs Approved by the Food and Drug Administration (FDA) with Labeling Regarding Pharmacogenomic Biomarkers. Wang L et al. N Engl J Med 2011;364:1144-1153. Challenges of Promulgating Pharmacogenomics (Pgx) Case of Warfarin Background • Warfarin exhibits large inter-individual dosing requirements • Warfarin is a leading cause of morbidity and mortality • Two genes account for ~33% of variance in dosing o Cytochrome P450 2C9 (CYP2C9) – pharmacokinetics o VKORC1 – pharmacodynamics • Meta-analysis of 3 clinical trials of warfarin genotyping showed a 32% decrease in major bleeding (RR 0.68, CI 0.222.06)* *Eckman MH, Rosand J, Geenberg SM, Gage BF: Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation. Ann Int Med 2009;150(2):73-83. Variability in warfarin dosing Pharmacogenomics. 2009, 10 (12) :1955-1965 Expected warfarin dosing by genotype - FDA Source: FDA approved product label, viewed Feb 1, 2011 Does Incorporation Of Pharmacogenomics with Warfarin Therapy Lead to Better Outcomes? US Clinical Trials of Genetic Testing for Warfarin (Clinical Utility) GIFT Trial COAG WARFARIN MM-WES Design Prospective RCT; 2x2 factorial Prospective RCT Prospective RCT Quasi-experiment CER Population Medicare At least 1 mo warfarin for hip/knee arthroplasty No prior genotype info Outpatient in AC clinic At least 3 mos warfarin Target INR 2-3 ≥65 years old New to warfarin for longterm AC, INR >2.0 Adults 40-75 years old New to warfarin Tx Arms PGx vs. clinical dosing Target INR <2.0 versus 2.5 Active Comparator PGx vs clinical dosing PGx vs clinical dosing (www.warfarindosing.org) Matched historical controls; Parallel concurrent external controls. Setting WUSTL, UUtah, Intermountain Medical Center, HSS (NY) 12 academic medical ctrs 50 clinical sites Any community-based prescriber; (49 states) ~25% cardiologists Sample size 1600 1238 >7000 896 tested subjects 2688 historical and concurrent controls Follow-up 4-6 weeks 4 weeks 4 weeks 6 months % time in therapeutic INR range in first 4 wks All-cause hosp. and Non-fatal VTE 4-6 wks 1° outcomes All-cause hospitalization Major hemorrhage and hosp. for and hospitalization for thromboembolic events atherothrombotic or NF major bleeding 4-6 wks Vascular death atherothrombotic or bleeding events bleeding events Status Ongoing Ongoing Ongoing Completed/published Comparative Effectiveness Research (CER) • Study characteristics o Real world comparators o Typical practice settings o Real world patients o Relevant outcomes (including resource use and costs often) • Does not necessarily have to be a RCT – could be observational, quasi-experiment 23 But – here we are in 2000s……….. • Leeches inject hirudin that inhibits platelet aggregation and the coagulation cascade • This relieves venous congestion • Clinical studies in the 2000s showed 70-80% success rate in salvaging tissue (skin grafts, reattachment surgery) • Leeches gained 510K FDA clearance in 2004 – Recarimpex SAS was the company involved. 24 And a National Payer (Aetna) covers leeches • Clinical Policy Bulletin: Bio-Surgery: Medicinal Leech Therapy and Medical Maggots • Number: 0556 Aetna considers medicinal leech (Hirudo medicinalis) therapy medically necessary for any of the following conditions: o Poor venous drainage (venous congestion/venous outflow obstruction); or o Salvage of vascularly compromised flaps (muscle, skin, and fat tissue surgically removed from one part of body to another); or o Salvage of vascularly compromised replants (limbs or other body parts re-attached after traumatic amputation). 25 Actual Origin of CER may be… • Also may be the origin of the expression – • Blowing smoke up one’s a** 26 Participants from 49 US states 28 Actionable information Translation into clinical practice – can we? Physician Adoption of Pgx Testing Medco/AMA Partnership: Nationwide Survey of >10,000 Physicians (2008) 98% 100% 90% 80% 70% 57% 60% 50% 40% 26% 23% 30% 20% 10% 12% 10% 0% Believe Genetics Prior Education Affects Drug On PGx Response Stanek et al. ASHG meeting, October 2009 Feel Informed About PGx Testing Ordered PGx Test for Patient in Last 6 Mos Anticipate Test Not Ordered Ordering Test Due to Inadequate in Next 6 Mos Info Warfarin Pgx testing is rarely done National Benchmark for Pgx Testing Rates in Patients New to Warfarin Therapy 2007 2008 2,267 52 16% 54% 2,264 53 17% 52% PGx testing within 2 months before to 3 months after new warfarin Rx claim 1724 1730 Warfarin PGx testing rate 1.70% 1.84% Background PGx testing rate (in patients not on warfarin) 0.12% 0.13% Apparent warfarin genetic testing rate 1.58% 1.71% 14 (5-60) 12 (4-53) 30 (5-107) 31 (5-107) PGx testing within 12 months before and after new warfarin Rx claim N Median age, yrs ≥65 years Female Median number of days from index warfarin claim date and genetic testing (IQ range) Before index warfarin claim On or after index warfarin claim Stanek et al. Clin Pharmacol Ther 2010;87(Supplement 1):S44. New Pgx Testing Program Process Creating a Teachable Moment Identify patients who are eligible for a test (prescriptions; eligibility) Contact physician to provide information about the test; ordering information Contact patients to inform about test and how it can help him/her with the therapy the doctor prescribed Facilitate the delivery and management of the test, ensures that test is performed and results are delivered A teachable moment has been created to inform a physician and a patient about the use of a genetic test to help guide therapy 35 Physician consent for testing WARFARIN Physicians Testing potentially appropriate in 32,192 patients Testing agreed to in 15,827 patients 49.2% Stanek E et al. ASHG 2010 36 New discoveries - all about partnership and collaboration What’s around the corner? • With new knowledge – specific individual Pgx tests will become important to promulgate o ALK for NSCLC o BRAF for metastatic melanoma o DNA repair markers for triple negative breast cancers What’s around the corner? • Movement from individual tests • To panels of Pgx tests • To whole genome sequencing − Esp. relevant in oncology What’s around the corner? • Circulating tumor cells o Enumeration o Characterization What’s around the corner? • Infrastructure related to the data o Storing, managing billions of data o Interrogating the data to find specific gene variants? o Intelligence to create action-able information from the test? What’s around the corner? • Gene therapy – and who to give this to? Corey Haas, 9 year old boy from Hadley, NY • Was in gene therapy trial at CHOP, Philadelphia • Single subretinal injection of RPE65 gene for congenital amaurosis • Was able to “see stars” in the night sky for first time • “I’m going into Little League” to play baseball • First approval projected to be 3 years from now — for hereditary blindness Source: Maguire AM, High KA et al: Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet. 2009 Nov 7;374(9701):1597-605. Epub 2009 Oct 23. 43 43 Concluding Thoughts 44 44 Many thanks • Advocacy position – trusted 3rd party endorsements o CAP support of warfarin Pgx testing – really mattered • Education and outreach and support of innovation • Humanitarian efforts All of us can make a difference • "If you think you're too small to have an impact, try going to bed with a mosquito in the room." - Dame Anita Roddick, 1942-2007, British businesswoman, humanitarian, founder of The Body Shop