Dec 31, 2015
Foundation.cap.org v. #
Promulgating Uptake of Personalized Medicine
Robert Epstein, MD, MSApril 17, 2011
Outline of Discussion
• Who sees the benefit?
• Notes from the field.
• What does the near-term future hold?
Legal disclaimer
Source: Peter Pitts. www.pacificresearch.org, April 13, 2005.
““Change is inevitable, except Change is inevitable, except from vending machines.” from vending machines.”
––Woody AllenWoody Allen
4
Therapy ResponseMonitoring
Focus of talk: Pharmacogenomics
Source: Personalized Medicine Coalition: Personalized Medicine 101. Available at http://www.personalizedmedicinecoalition.org/sciencepolicy/personalmed-101_overview.php
Predisposition, DxPredisposition, Dx PharmacogenomicsPharmacogenomics
Using an individual’s genetic information to identify diseases or predict their future risk of developing other medical conditions
A science that examines the inherited variations in genes that dictate drug response (whether a drug will be effective or safe)
RiskAssessment Prevention Targeted
Monitoring
Early Detection Testing
Diagnosis
What we fear will be patient reactions
My DNA? Are you trying to clone me?My DNA? Are you
trying to clone me?
Isn’t that going a little
too far?
Isn’t that going a little
too far?
You need
my spit? You need
my spit?
That’s crazy talk
That’s crazy talk
Ew…that’s grossEw…that’s gross
Really? Mail you the wet Q-tip?
Really? Mail you the wet Q-tip?
What do you mean
What do you mean
you want to get into
you want to get into
my genes?!?
my genes?!?What do you mean
What do you mean
you want to get into
you want to get into
my genes?!?
my genes?!?
Pharmaco-what?
Pharmaco-what?
Patient perspective
“Knowing your molecular identity is irresistible”*
Anita Cosgrove, 23andme, personal communication
700 Payers Vote – This Topic Tied for #2 Topic of Interest!
3.03
3.10
3.51
3.40
3.40
3.35
3.33
3.13
0 1 2 3 4
New benefit design strategies
Pharmacogenomics
Consumerism
Drug pipeline
Emerging trends in science
Specialty cost reductionstrategies
Member communications
Generic opportunities
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
Why do payers care? 1 in 4 Medco patients take a drug with pharmacogenomic considerations
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
0
5,000
10,000
15,000
20,000
25,000
30,000
35,000
40,000
2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Sal
es (
$M)
Antihormonal Therapies Cytotoxic Therapies Molecular Targeted Therapies
21st century is about targeted therapy for oncology
Source: Datamonitor forecasts and MIDAS Sales Data, IMS Health, April 2007.
In 2006, the molecular targeted therapies overtook the cytotoxic therapies for the first time, with sales of $10.7 billion and $8.9 billion, respectivelyIn 2006, the molecular targeted therapies overtook the cytotoxic therapies for the first time, with sales of $10.7 billion and $8.9 billion, respectively
12
Newer cancer drugs that target pathways
DrugDrug PathwayPathway ConditionCondition TestTest
Gleevec, Sprycel, Tasigna
BCR-ABL kinase
Chronic Myelogenous Leukemia
BCR-ABL copies
HerceptinHER-2
receptorBreast cancer HER-2 status
Rituxan CD-20 protein Lymphoma FCGR3A gene
Avastin VEGF Colon cancer VEGFA?
TamoxifenEstrogen receptor
Breast cancer CYP 2D6
Tarceva, Iressa
EGFR kinase Lung, pancreatic cancer EGFR
SutentTyrosine
kinasesGI cancer KIT mutations
Erbitux, Vectibix
EGFR Colon, head/neck cancerKRAS
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.
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 0.22-2.06)*
*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.
US Clinical Trials of Genetic Testing for Warfarin (Clinical Utility)
Trial GIFT COAG WARFARIN MM-WES
Design Prospective RCT; 2x2 factorial Prospective RCT Prospective RCT Quasi-experiment CER
Population
MedicareAt least 1 mo warfarin for hip/knee arthroplastyNo prior genotype info
Outpatient in AC clinicAt least 3 mos warfarin Target INR 2-3
≥65 years oldNew to warfarin for long-term AC, INR >2.0
Adults 40-75 years old New to warfarin Tx
ArmsPGx vs. clinical dosingTarget INR <2.0 versus 2.5 Active Comparator
PGx vs clinical dosingPGx vs clinical dosing(www.warfarindosing.org)
Matched historical controls; Parallel concurrent external controls.
SettingWUSTL, 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 >7000896 tested subjects2688 historical and concurrent controls
Follow-up 4-6 weeks 4 weeks 4 weeks 6 months
1° outcomes
Non-fatal VTE 4-6 wks
NF major bleeding 4-6 wks
Vascular death
% time in therapeutic INR
range in first 4 wks
All-cause hospitalization
and hospitalization for
atherothrombotic or
bleeding events
Major hemorrhage and
thromboembolic events
All-cause hosp. and
hosp. for
atherothrombotic or
bleeding events
Status Ongoing Ongoing Ongoing Completed/published
Comparative Effectiveness Research (CER)
• Study characteristicsoReal world comparatorsoTypical practice settingsoReal world patientsoRelevant outcomes (including resource use
and costs often)
• Does not necessarily have to be a RCT – could be observational, quasi-experiment
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.
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And a National Payer (Aetna) covers
leeches
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• 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); oro 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).
Actual Origin of CER may be…
• Also may be the origin of the expression – • Blowing smoke up one’s a**
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Physician Adoption of Pgx Testing
Medco/AMA Partnership: Nationwide Survey of >10,000 Physicians (2008)
98%
23%
10% 12%
26%
57%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Believe GeneticsAffects Drug
Response
Prior Education On PGx
Feel InformedAbout PGx
Testing
Ordered PGxTest for Patientin Last 6 Mos
Anticipate Ordering Testin Next 6 Mos
Test Not OrderedDue to Inadequate
Info
Stanek et al. ASHG meeting, October 2009
Warfarin Pgx testing is rarely done
National Benchmark for Pgx Testing Rates in Patients New to Warfarin Therapy
2007 2008
PGx testing within 12 months before and after new warfarin Rx claimNMedian age, yrs≥65 years
Female
2,26752
16%54%
2,26453
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%
Median number of days from index warfarin claim date and genetic testing (IQ range)
Before index warfarin claim
On or after index warfarin claim
14 (5-60)
30 (5-107)
12 (4-53)
31 (5-107)
Stanek et al. Clin Pharmacol Ther 2010;87(Supplement 1):S44.
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New Pgx Testing Program ProcessCreating a Teachable Moment
Identify patients who are eligible
for a test(prescriptions;
eligibility)
Contact patients to inform about test and how it
can help him/her with the therapy
the doctor prescribed
Contact physician to
provide information
about the test; ordering
information
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
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Physician consent for testing
Testing potentially appropriate in 32,192 patients
Testing agreed to in 15,827 patients
49.2%
WARFARINPhysicians
Stanek E et al. ASHG 2010
What’s around the corner?
• With new knowledge – specific individual Pgx tests will become important to promulgate
oALK for NSCLCoBRAF for metastatic melanomaoDNA 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?
• Infrastructure related to the dataoStoring, managing billions of
dataoInterrogating the data to find
specific gene variants?oIntelligence to create action-
able information from the test?
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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
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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.
Many thanks
• Advocacy position – trusted 3rd party endorsementsoCAP 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