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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.
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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.
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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).
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Actual Origin of CER may be…
• Also may be the origin of the expression –
• Blowing smoke up one’s a**
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Participants from 49 US states
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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
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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%
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(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
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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.
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Concluding Thoughts
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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