The Case For Pharmacy

The Case for
Personalized
Medicine
3rd Edition
Today:
A patient has late-stage non-small cell lung cancer (NSCLC). She has gone through a number
of treatments, but none were able to arrest the cancers spread. The mother of four has
progressive disease and precious little time to waste on treatments that do not work. Her
physician read reports of a newly approved drug called Xalkori (crizotinib) that might offer
hope. However, only about five percent of NSCLC patients whose tumors have the anaplastic
lymphoma kinase (ALK) gene rearrangement can potentially benefit. A newly approved
diagnostic test determines that the patient has the gene rearrangement and that the drug is a
treatment option for her. After starting to take Xalkori , the tumors begin to respond.
The Future:
Imagine a physician sitting down with his laptop and a morning cup of coffee. On a website that
he uses to help manage his practice, an alert pops up. It tells him that a series of studies have
demonstrated a connection between multiple rare mutations found in 10 percent of people and the
likelihood that they might convert to type 2 diabetes. Nearly all of his patients have had their entire
genome sequenced and entered into their electronic medical record a process that takes only a
week, costs a few hundred dollars, and is reimbursed by insurance companies because of the many
benefits it provides to lifelong health management. He conducts a quick search of his 2,000 patient
database and finds about 80 who are at risk. To half of those patients, he sends a strong reminder
and advice on diet and lifestyle choices they can take to avoid the disease. To the other half, whose
medical records reveal pre-diabetic symptoms, he sets up appointments to consider more proactive
treatment with drugs that can prevent the onset of disease.
Introduction
For more than two millennia, medicine has never wavered from its aspiration of being
personalized. In ancient times, Hippocrates would combine an assessment of the four
humours blood, phlegm, yellow bile and black bile to determine what was then considered
the best course of treatment for each patient. Today, the sequence of four chemical building
blocks of DNA in the genome, together with telltale proteins in the blood, enable more
accurate predictions of whether an individual will develop an illness many years in the future
or is developing it now, will respond positively to treatment, or will suffer a serious reaction
to a drug. What is different about medicine today, and the reason the word personalized
has been added for emphasis, is that technology has brought us much closer to exquisite
precision in disease diagnosis and treatment.
Patients with melanoma, metastatic

lung, breast, or brain cancers, and
leukemia are now being routinely
We face significant challenges in
offered a molecular diagnosis in
accelerating growth in this field
some clinical centers, allowing their
physicians to select tailored treatments
scientific, business, regulatory and
that can greatly improve their chances
of survival. Melanoma is no longer
policy challenges. Together we must
just melanoma, but can now be subbreak down the barriers and move
classified by its genetics (e.g., BRAF
positive). Nonsmall cell lung cancer
personalized medicine forward.
can be EGFR positive or ALK positive.
Treatments targeting BRAF, ALK and
John Castellani
other gene mutations are remarkable
President and Chief Executive Officer, Pharmaceutical Research
improvements over standard therapies
and Manufacturers of America (PhRMA)
and the point at which most cancer cases
are given a targeted course of treatment
based on their molecular designation
Thousands of patients have already hospital, clinic and medical practice,
will not be far off (Figure 1).1
seen dramatic benefits, yet examples of supported by electronic health records,
The genotyping of drug-metabolizing personalized medicine in action remain a clinical decision support system,
enzymes has led to improved dosing of sporadic, occurring mostly at well- tailored blood and tissue tests aimed at
drugs for conditions as wide-ranging as funded academic medical centers, or very early and precise diagnosis, and a
depression and anxiety, coronary and prompted by a well-informed patient or personal genomic sequence linked to
every patients medical record. It is a
peripheral artery disease, inflammatory a technologically-savvy physician.
scenario that seems all the more plausible
bowel disease and cancer, thereby helping
patients avoid harmful side effects, drug In the future, personalized medicine with the plunging costs of genomic
interactions or ineffective treatment. will become embedded in every sequencing, emerging epigenetic and
The Case for Personalized Medicine, 3rd Edition
FIGURE 1. Forging a Path to Personalized Cancer Care
TACKLING TUMORS
Percentage of patients whose tumors were driven by certain genetic mutations
that could be targets for specific drugs, by type of cancer
73%
Melanoma
Thyroid
56%
Colorectal
51%
43%
Endometrial
Lung
41%
Pancreatic
41%
32%
Breast
31%
Other gynecological
29%
Genitourinary
Other gastrointestinal
25%
Ovarian
21%
Head and neck
21%
Source: Wall Street Journal Copyright 2011 by DOW JONES & COMPANY, INC. Reproduced with permission of DOW JONES
& COMPANY, INC.
proteomic technologies and a strong

commitment by the federal government
to support full implementation of
electronic health records.
based on their genetic makeup; new

systems of insurance payment must
account for future disease risks as well
as present conditions; and payment
systems must provide flexibility for
With such rapid developments, it is clinicians to tailor care to individuals
imperative for the health care system and based on genetics and other factors.
society to co-evolve with the technology.
Regulatory guidelines must adapt
Additional laws must be enacted to to the coupling of diagnostics and
protect citizens from discrimination drugs that target genetically defined
populations and professional education

must be modernized to prepare the
next generation of doctors and other
health care professionals to administer
personalized medicine.
There is momentum toward these goals,
but much remains to be done to stay
ahead of a very steep technology curve.
Building a Track Record

In 1902, Sir Archibald Garrod made the first connection between genetic inheritance and susceptibility
to a disease alkaptonuria;2 and in 1956, the first discovery of a genetic basis for selective toxicity was
made for the antimalarial drug primaquine.3 In 1977, the discovery of cytochrome P450 metabolic
enzymes and their role in chemically altering drugs so they can be eliminated from the bloodstream led
to the realization that variation in these enzymes can have a significant influence on the effective dose
of a drug. Yet it is perhaps only in the few years since the complete sequencing of the human genome
in 2003 that personalized medicine has begun in earnest and is now moving beyond the genome into
the entire spectrum of molecular medicine, including the proteome, metabolome and epigenome.
The historical precedents for modern

personalized medicine stretch back several
decades, but clearly momentum is building
now for a more rapid transformation.
Segmenting populations into groups of
patients who have a greater likelihood
of responding to a particular treatment
or avoiding side effects is changing
the dynamic of drug development and
the practice of medicine, and creating
opportunities to introduce new business
and health care economic models. These
changes are beginning to take place
as the field builds a solid track record,
demonstrating that it can:
Shift emphasis in medicine from
reaction to prevention;
Select optimal therapy and reduce trialand-error prescribing;
Make drugs safer by avoiding adverse
drug reactions;
Increase patient adherence to treatment;
Improve quality of life;
Revive drugs that failed in clinical trials
or were withdrawn from the market;
Help control the overall cost of
health care.
markers that signal disease risk or presence

before clinical signs and symptoms appear,
and it offers the opportunity to focus on
prevention and early intervention rather
than on reaction at advanced stages
of disease. In many areas, the clinical
interventions can be life-saving.
diagnosis often permits targeted prevention

or mitigation strategies. A patient with
inherited cardiomyopathy, for example,
can be identified and lifestyle changes and
disease monitoring implemented to avoid
the risk of sudden death.8
Select optimal therapy and reduce trial-anderror prescribing. Many patients do not
benefit from the first drug they are offered
in treatment. For example, 38 percent of
depression patients, 50 percent of arthritis
patients, 40 percent of asthma patients,
and 43 percent of diabetic patients will not
respond to initial treatment (Figure 2).9
Studies have linked differences in response to
the differences in genes that code for the drugmetabolizing enzymes, drug transporters, or
drug targets.10,11,12 The use of genetic and
other forms of molecular screening allows
the physician to select an optimal therapy
the first time and to avoid the frustrating and
More than 1,600 genetic tests exist costly practice of trial-and-error prescribing.
that signal inherited susceptibility to
conditions ranging from hearing loss to One of the most common applications
sudden cardiac arrest.7 A subset of these has been for women with breast cancer.
tests that offer a predictive capability, About 30 percent of breast cancer cases are
spotting the potential disease before characterized by over-expression of a cell
Shift emphasis in medicine from reaction symptoms appear, may be considered to surface protein called human epidermal
to prevention. Personalized medicine be personalized. While not every test is growth factor receptor 2 (HER2). For these
introduces the ability to use molecular linked to a therapeutic option, a genetic women, standard therapy is not effective,
For example, women with certain BRCA1

or BRCA2 gene variations have a 36 to
85 percent lifetime chance of developing
breast cancer, compared with a 13
percent chance among the general female
population,4,5,6 and a 16 to 60 percent
chance of developing ovarian cancer,
compared with a 1.7 percent chance
among the general female population. The
BRCA1 and BRCA2 genetic test can guide
preventive measures, such as increased
frequency of mammography, prophylactic
surgery, and chemoprevention.
The power in tailored therapeutics is for us to say more clearly to

payers, providers, and patientsthis drug is not for everyone, but
it is for you. That is exceedingly powerful.
John C. Lechleiter, Ph.D.
President and Chief Executive Officer, Eli Lilly and Company
but an antibody drug called Herceptin

(trastuzumab) can reduce the recurrence
of a tumor by 52 percent when used in
combination with chemotherapy, compared
to chemotherapy alone.13,14 Molecular
diagnostic tests for HER2 are used to
identify the patients who will benefit from
receiving Herceptin and other drugs that
target HER2, such as Tykerb (lapatinib).
Two complex diagnostic tests, Oncotype
DX and MammaPrint, use genetic
information to help physicians chart the
best course of treatment for breast cancer
patients. Oncotype DX can determine
whether women with certain types of
breast cancer are likely to benefit from
chemotherapy.15,16,17 MammaPrint can
determine which early-stage breast cancer
patients are at risk of distant recurrence
following surgery.18 Both tests place patients
into risk categories that inform physicians
and patients whether their cancer may be
treated successfully with hormone therapy
alone, avoiding the expense and toxic
effects of chemotherapy, or whether a more
aggressive treatment is needed.
A growing number of drugs have become
available for the treatment of colon cancer,
some of which are best selected using a
genetic test. For example, approximately 40
percent of patients with metastatic colon
cancer are unlikely to respond to Erbitux
(cetuximab) and Vectibix (panitumumab)
because their tumors have a mutated form
of the KRAS gene.19 Current practice
guidelines recommend that only patients
with the normal (wild-type) form of the
KRAS gene should be treated with these
drugs in conjunction with chemotherapy.20
Meanwhile, new targeted therapies, paired

with genetic tests, are providing hope to
late-stage cancer patients and their families.
Approved in August 2011, Zelboraf
(vemurafenib) treats melanoma that cannot
be surgically removed in patients who have
the BRAF V600E gene mutation. Xalkori
(crizotinib), indicated for the treatment of
non-small cell lung cancer, is only effective
for patients who express the abnormal
anaplastic lymphoma kinase (ALK ) gene.
Both BRAF and ALK mutations can be
detected by commercially available tests,
cobas 4800 BRAF V600 Mutation Test and
Vysis ALK Break Apart FISH Probe Kit.
Outside oncology, the blood clot-preventing

drug Plavix (clopidogrel) presents another
case for using genetic testing to select the
best course of treatment. Plavix can have
a very different impact on protecting stent
patients from thrombosis, depending
on patients genetic variance within
CYP2C19, which encodes an enzyme that
converts the drug from an inactive to an
active state. About 25 to 30 percent of
stent patients have a three-fold risk of stent
thrombosis when using Plavix, relative to
other patients.21 A genetic test costing a
few hundred dollars can reveal the risk and
allow physicians to craft an alternate course
FIGURE 2. One Size Does Not Fit All

PERCENTAGE OF THE PATIENT POPULATION FOR WHICH
A PARTICULAR DRUG IS INEFFECTIVE, ON AVERAGE
ANTI-DEPRESSANTS
(SSRIs)
38%
ASTHMA DRUGS
40%
DIABETES DRUGS
43%
ARTHRITIS DRUGS
50%
ALZHEIMERS DRUGS
70%
CANCER DRUGS
75%
Source of data: Brian B. Spear, Margo Heath-Chiozzi, Jeffery Huff, Clinical

Trends in Molecular Medicine, Volume 7, Issue 5, 1 May 2001, Pages 201-204.
Building a Track Record Continued

of treatment, such as administration of the Administration of the drug warfarin, used
drug Effiant (prasugrel).
to prevent blood clots, is complicated by
genetic variations in a drug-metabolizing
Many more treatments that use molecular enzyme (CYP2C9) and an enzyme that
markers to aid in clinical decision-making are activates vitamin K (VKORC1). Dosing
in development. A 2010 survey conducted is typically adjusted for the individual
by the Tufts Center for the Study of Drug patient through multiple rounds of trial
Development (Tufts CSDD) found that and error, during which the patient may
50 percent of clinical trials are collecting be at risk of excessive bleeding or further
DNA from study participants to aid in blood clots. The need to get warfarin
the discovery of drug-related safety and dosing right the first time to avoid serious
efficacy biomarkers, and 30 percent of the and possibly fatal adverse effects led the
companies surveyed require all compounds FDA to recommend genotyping for all
in development to have a biomarker.22
patients before warfarin treatment.27
the drug are tested for the gene, significantly

improving the safety of its administration.
Make drugs safer by avoiding adverse drug

reactions. According to several studies,
about 5.3 percent of all hospital admissions
are associated with adverse drug reactions
(ADRs).23 Many ADRs are the result of
variations in genes that code for the family
of cytochrome P450 (CYP450) enzymes and
other drug-metabolizing enzymes.24,25 These
variants cause a drug to be metabolized
either faster or slower than is true in the
general population. As a result, some
individuals have trouble inactivating a drug
and eliminating it from their bodies, leading
to overdose toxicity, while others eliminate
the drug too rapidly, before it has had a
chance to work. The consequences range
from unpleasant to fatal if these genetic
variations are not considered when dosing.
Inherited forms of hypercholesterolemia

(high cholesterol) can increase the risk of
myocardial infarction before the age of
40 more than 50-fold in men and 125fold in women. Knowledge of a genetic
predisposition for hypercholesterolemia
provides patients with a powerful incentive
to make lifestyle changes and manage their
condition. Patients with a genetic diagnosis
have shown more than 86 percent adherence
to their treatment program after two years,
compared to 38 percent prior to testing.29
The use of genetic markers to facilitate safer

and more effective drug dosing and selection
takes on added significance at the population
level. For example, adverse reactions to the
HIV drugs Stocrin and Sustiva (efavirenz)
can occur at standard dosing due to the
presence of the CYP2B6*6 allele, which
metabolizes the drug more slowly and is
found significantly more often in Africanthan in European-based populations.28
Lowering drug dose in individuals with this
allele can help reduce adverse effects and
increase treatment compliance.
Increase patient adherence to treatment.

Patient non-compliance with treatment
leads to adverse health effects and increased
overall health care costs. When personalized
therapies prove more effective or present
fewer side effects, patients will be more
likely to comply with their treatments. The
greatest impact could be for the treatment
of chronic diseases such as asthma and
diabetes, in which non-compliance
commonly exacerbates the condition.
Improve quality of life. A molecular

diagnostic test that simply requires a
blood sample can replace invasive and
uncomfortable tissue biopsies. Allomap
is a multi-gene expression test that can
detect whether the immune system of a
heart transplant recipient is rejecting the
new organ.30 Approximately 25 percent
About five to eight percent of HIV patients

treated with Ziagen (abacavir) can experience
multi-organ system hypersensitivity to the
drug, which in some cases can be fatal. This
adverse reaction is strongly associated with the
The U.S. Food and Drug Administration HLA-B*5701 gene, easily identified through
(FDA) has approved the Amplichip genetic testing. Nearly all patients receiving
CYP450 test, a microarray device that
can detect 29 variations in two important
CYP450 genes, CYP2D6 and CYP2C19.
These genes are linked to the metabolism of
We are on the tipping point of a whole
about 25 percent of all drugs prescribed.26
new game in how we develop drugs
Follow-on multiplex assays from
Autogenomics (CYP2C19) and Luminex
[for cancer].
(CYP2D6 ) have also been approved by the
FDA. These tests are especially useful for
Janet Woodcock, M.D.
comprehensive polypharmacy management,
Director, Center for Drug Evaluation and Research, U.S. Food and
Drug Administration
prevalent in the elderly and seriously ill.
As the field advances, we expect to see more efficient clinical

trials based on a more thorough understanding of the genetic
basis of disease. We also anticipate that some previously
failed medications will be recognized as safe and effective
and will be approved for subgroups of patients with specific
genetic markers.
Margaret Hamburg, M.D.
Commissioner, U.S. Food and Drug Administration
of heart transplant patients experience a

rejection, which can prove fatal. To monitor
for rejection, endomyocardial biopsies are
performed as frequently as once a week after
the transplant, and then every few months
for several years. This invasive procedure
requires inserting a tube into a vein in the
neck which is then threaded to the heart to
obtain the biopsy. Allomap, FDA-approved
in 2008, requires only a blood sample to
measure the expression level of 11 genes
data that can determine the likelihood that
the patient is experiencing a rejection. A
recent study suggests that outcomes may be
equivalent for patients who are monitored
using Allomap and those who receive
endomyocardial biopsies, which several
major health insurance companies deem
medically necessary.31
Revive drugs that failed in clinical trials or
were withdrawn from the market. A failing
drug or drug candidate can be revived
by limiting its use to genetically-defined
patient populations. The lung cancer drug
Iressa (gefitinib) did not demonstrate a
survival advantage in a general population of
patients in clinical trials, and was withdrawn
from the market after initially being granted
accelerated approval. The sponsoring
company has been using pharmacogenetics
to demonstrate benefit in about 10 percent
of patients who test positive for epidermal
Francis Collins, M.D., Ph.D.

Director, National Institutes of Health
growth factor mutations, and has won Organizations set up under the Affordable
approval as a first line treatment for that Care Act to coordinate patient care and
patient population in the United Kingdom. reduce costs. One model estimated that
genetic testing to target dosing of the blood
Bucindolol is a beta-blocker that was being thinner drug warfarin could prevent 17,000
tested for the treatment of heart disease, strokes in the U.S. and could avoid as many
but was dropped by its maker several as 43,000 visits to the emergency room.35
years ago after it failed to demonstrate
effectiveness over placebo.32 Since then, Mayo Clinic and the pharmacy benefits
scientists have developed a diagnostic manager Medco put the warfarin model
test, called the Beta-blocker Evaluation of to the test in a 3,600-subject prospective
Survival Test (BEST), which can predict study. Hospitalization rates for heart
which patients will benefit from the drug. patients were reduced by about 30 percent
A study using BEST provided much clearer when genetic information was available
evidence of bucindolols effectiveness in a to doctors prescribing the drug.36
subpopulation (about 50 percent) of heart
patients; the drug reduced heart disease An economic analysis of the Oncotype
deaths by 48 percent and hospitalizations Dx test looked at the real costs of treating
for heart failure by 44 percent.33 As a women with breast cancer in a two million
result, bucindolol may be resurrected to member health plan. If one-half of the 773
treat patients for whom it will work.
eligible patients received the test, then the
savings in terms of adjuvant chemotherapy,
Help control the overall cost of health care. supportive care and management of adverse
The cost of health care in the United States events would be about $1,930 per patient
is on an unsustainable upward climb. tested (based on a 34 percent reduction
Incorporating personalized medicine into in chemotherapy use).37 Another study
the fabric of the health care system can help found that $604 million could be saved
resolve many embedded inefficiencies, such annually among all patients if Vectibix
as trial-and-error dosing, hospitalizations (panitumumab) or Erbitux (cetuximab)
due to adverse drug reactions, late were limited to those patients with metastatic
diagnoses, and reactive treatments. As colorectal cancer whose KRAS gene is not
such, it can also play an important role in mutated, because those are the only patients
the implementation of Accountable Care who benefit from the drugs.38
Technology
Technological developments have enabled advances in our understanding of human genetics
and its influence on disease and treatment, but the technology that launched the biomedical
revolution genomic DNA sequencing has accelerated so rapidly that it is once again poised
to transform biomedical research and clinical care.
It took $3 billion and 13 years to

sequence the first draft of the human
Today, one of our biggest goals is to cut
genome. During that time, sequencing
technology evolved from the manual
the cost of sequencing an entire human
Sanger method using radioactive labels to
automated sequencing using color-coded
genome to $1,000 or less. This advance
fluorescent dyes. As a result, the cost of
will pave the way for each persons
sequencing an entire genome declined
at a rate described by Moores Law, the
genome to be sequenced as part of the
same rule that has predicted reliably
the exponential increase in performance
standard of care, leading to a revolution
of computer technology for the past 40
years; whole-genome sequencing costs
in the practice of medicine.
fell from $100-300 million in 2001
Francis S. Collins, M.D., Ph.D.
to about $10 million in 2007, a price
Director, National Institutes of Health
that still confined such sequencing
within the purview of only well-funded
The National Human Genome benchmark because it is comparable
laboratories or government initiatives.
Research Institute (NHGRI) has to costs of existing medical tests and
funded a number of projects aimed at procedures, and could begin to attract a
By 2008, as second-generation DNA
developing technology to sequence an consumer market of patients.42 Costs
sequencing instruments were taken up
entire genome for less than $1,000, and of full genomic sequencing have already
broadly by the research market, Moores
has tracked the performance for those fallen to the point that such sequencing
Law was no longer relevant the ability
projects over time. The results reflect has been employed in certain cases to
to sequence entire genomes accelerated at
a general trend in the industry and resolve difficult diagnoses, with insurers
a rate far exceeding that ever experienced
an important transition around mid- determining that the approach was costby the semiconductor and computer
2007 brought on by next-generation effective enough to be reimbursed.43,44
industries. By 2009, the cost and
sequencing technology (Figure 3).
duration of sequencing an entire genome
Capturing individual genomes of entire
decreased significantly, to $50,000 in
As the cost and duration of genomic populations will be a tremendous boon to
two months.39 In May 2011, Illumina
sequencing continues on a sharp research. When thousands and ultimately
announced that it had lowered the price
downward curve, many scientists believe millions of complete (de-identified)
for sequencing whole human genomes to
that, with the help of private and genome sequences are made available to
$5,000 per genome.40 Additional costs
public investment, the $1,000 genome researchers, a tremendous gap in human
and time may be added for analysis and
will arrive within a few years.41 This genetic variation data will be filled. It
annotation in a clinical setting.
price point is considered a critical is thought that many common human
off. They represent an area of intense

study, and have already been linked to
heart disease, diabetes, and cancer. The
National Institutes of Health (NIH)
Roadmap Epigenomics Program and the
Epigenetics Consortium were set up to
identify this supplemental parts list of
the human genome.
FIGURE 3. The Rapidly Decreasing Cost of

Sequencing Complete Genomes
COST PER GENOME
$100,000,000
$10,000,000
Moores Law
$1,000,000
$100,000
$1,000
Jul-01
Oct-01
Jan-02
Apr-02
Jul-02
Oct-02
Jan-03
Apr-03
Jul-03
Oct-03
Jan-04
Apr-04
Jul-04
Oct-04
Jan-05
Apr-05
Jul-05
Oct-05
Jan-06
Apr-06
Jul-06
Oct-06
Jan-07
Apr-07
Jul-07
Oct-07
Jan-08
Apr-08
Jul-08
Oct-08
Jan-09
Apr-09
Jul-09
Oct-09
Jan-10
Apr-10
Jul-10
Oct-10
Jan-11
genome.gov/sequencingcosts
Average cost of sequencing a genome for NHGRI-funded sequencing technology

projects over time. This graph captures the dramatic decline in sequencing costs
through January 2011, which have since reached $5,000 per genome.
ailments, such as heart disease, diabetes,

and cancer, are actually the result of
numerous rare genetic variations, and
that even for the same disease, one
person might not carry the same set of
variants as another. Personal genomes
will provide both a powerful tool for
identifying those rare genetic variants as
well as more accurate means to predict
disease susceptibility and response to
treatment. These rare variants are, as
National Institutes of Health Director
Francis Collins termed them, the dark
matter of genetic patterns that remain
undiscovered, even after extensive
mapping by the SNP Consortium,
the International HapMap Project,
and numerous genome-wide disease
association studies.
In addition, efforts by the National

Cancer Institute to standardize existing
proteomic technologies such as mass
spectrometry are leading to more robust
identification of protein biomarkers,
which indicate the presence or absence of
disease apart from the risk prediction of
genetic analysis. Entirely new approaches
to protein biomarker detection are
promising to make proteomics as
simple as genetic analysis, ushering in
an era when diseases can be diagnosed
and treated in their earliest stages.
Proponents of personalized medicine
envision a future in which all individuals
will have their full genomic sequence
linked to their medical record.
The information from a personal
genome, with an overlay of clinical
interpretation, would allow physicians
to develop a more holistic, proactive
health care strategy based on the patients
susceptibility to different diseases and
responses to different types of medicine.
These budding technologies include

reading off base pairs of DNA strands
as they thread through nanopores,45
identifying nucleotides as they are
synthesized onto templates attached to
beads, using microfluidic glass wafers to
drastically reduce reagent usage and cost,
and using atomic force microscopy or
electron microscopy to visually identify
individual nucleotides along the length
At present, our ability to collect data
of DNA fragments.46
outpaces the medical communitys ability
Advances are occurring not only in to understand and act on it. But, over
sequencing technology. There is a time, as researchers identify additional
growing understanding of the changes genetic variations that correlate to disease
that occur to the genome that alter its and treatment response and as they
chemistry and structure without altering develop decision-support tools to aid
its sequence, through modifications such health care professionals in managing
as adding single-carbon methyl groups patients with specific genetic and other
to the DNA chain. These epigenetic characteristics, genomic sequencing
As mass sequencing efforts are underway, changes can occur in response to the and health information technology will
a third generation of sequencing environment and lifestyle, and influence transform the practice of medicine.
technologies is preparing for its debut. whether certain genes are turned on or
Regulatory Policy
Clear and appropriate regulation of personalized medicine products and services can enable
the development of personalized medicine by providing innovators with a stable, predictable
means for bringing new technologies to market, and providing a foundation for fair coverage and
payment decisions that ultimately allow research and development costs to be recouped.
Personalized Medicine Tests. The

emergence of personalized medicine
tests to inform clinical decisionmaking, along with tests to guide drug
selection and dose, has led the FDA to
publish guidance documents related
to the regulation of these products.
Traditionally, diagnostic tests have fallen
into two main categories, diagnostic kits
and laboratory-developed tests (LDTs).
The former are products containing all
the reagents and materials needed to run
the test, and are regulated by the FDA as
medical devices. Very few personalized
medicine diagnostics fall under this
category; most are considered LDTs. Use
of LDTs often requires more extensive
sample and reagent preparation than is
required for the diagnostic kits, as well
as specialized laboratory equipment and
the services of skilled technicians. Both
the Centers for Medicare and Medicaid

Services (CMS) and FDA claim
jurisdiction over LDTs, but the FDA has
taken a hands-off approach, leaving the
laboratories that perform these tests to
be regulated by CMSs authority under
the Clinical Laboratory Improvement
Amendment (CLIA) rules.
Recent developments in personalized
medicine, in particular the proliferation
of complex diagnostic tests and services
linked to major health decisions and
targeted directly to consumers, have
prompted concerns in some sectors about
the safety of these new products. The
concept of test safety comes into play
when one considers the consequences
of misinterpretation: an ineffective
therapy, an unnecessary preventive
surgery, or any number of suboptimal,
Promoting personalized medicine

means making sure the FDA medical
product centers work together as a
team to get safe and effective new
treatments to patients as quickly
as possible.
FDA Innovation Report, October 5, 2011
10
and sometimes irreversible, medical

decisions. Many have argued that the
FDA should assume a more active
role in regulating certain molecular
diagnostic tests used in the selection,
dosing or exclusion of treatments.
Although landmark FDA approvals
have been conferred upon LDTs used in
personalized medicine (e.g. Mammaprint
and AlloMap), the vast majority of
molecular tests have not been submitted
for FDA regulatory approval. Due to the
sheer volume and long-term outcomes of
many of these tests, the FDA has declared
its intention to take a tiered approach to
their regulation. Tests linked to riskier
clinical decisions will be more rigorously
studied and reviewed for clinical outcomes
and safety, while CLIA certification
might suffice for laboratories performing
most LDTs. In addition, to provide
some transparency around the quality
and regulation of hundreds of molecular
tests offered by clinical laboratories, the
National Institutes of Health is launching
a voluntary national registry to catalog
available tests.
In general, the protean state of molecular
testing regulation has created uncertainty
for companies, which have no way of
knowing how much they will need to
invest, in terms of clinical, economic, or
comparative studies, to get their products
on the market and to keep them there.
Recently, the development of therapeutic products that depend

on the use of a diagnostic test to meet their labeled safety
and effectiveness claims has become more commonThese
technologies are making it increasingly possible to individualize,
or personalize, medical therapy by identifying patients who are
most likely to respond, or who are at lower or higher risk for a
particular side effect.
Draft Guidance for Industry and FDA Staff In Vitro Companion Diagnostic Devices, July 14, 2011
Pharmaceuticals. While the clinical

regulation of genetic testing is debated,
the FDAs Voluntary Exploratory
Data Submissions (VXDS) program
(introduced in 2004 as the Voluntary
Genomic Data Submission program)
continues to have a positive impact on
drug and biologic development. The
program enables companies and the FDA
to work together to better understand
pharmacogenomics before issuing
regulatory standards. The informal
communication and the agencys
policy of supporting adaptive clinical
trials that can genetically enrich a
study population helps companies to
integrate genomics into their product
development. 47 As a result, most
development projects are accompanied
by data on the effects of genetic variation
or other biomarkers on the safety and
efficacy of the treatment. The molecular
information has found its way onto about
10 percent of product labels that inform
or recommend molecular or genetic
testing for optimal treatment.48 At least 13
of those labels require the use of a genetic
or protein marker-based diagnostic test had either mandated or recommended

to guide appropriate selection and dosing in several cases that biomarker testing be
performed prior to prescribing certain
of the drug (Table).49
drugs. Recognizing that the class of
Companion Diagnostics. The need for companion therapeutics/diagnostics is
a clear regulatory path for companion likely to grow, the FDA began publishing
diagnostics has been a great concern a table of genomic biomarkers that it
ever since the first therapeutic/ considers valid in guiding the clinical
diagnostic product pair (Herceptin / use of approved drugs.51
HercepTest ) was approved six
months apart in 1998. Definitive There remain many logistical difficulties
guidelines have not been published, in the coordinated development of
but regulatory agencies, including the drugs and diagnostic tests, and a
FDA and European Medicines Agency defined path for the regulatory approval
(EMA), have shown signs of addressing of such product combinations would
the issues. In 2011, the FDA released its be a significant step forward. The
Draft Guidance for In Vitro Companion FDAs renewed focus on personalized
Diagnostic Devices, which has helped medicine, signaled by the creation
to clarify the agencys intention to of a new position for Director for
conduct simultaneous reviews of a Personalized Medicine in the Office
drug and its corresponding companion of In Vitro Diagnostic Evaluation and
diagnostic. 50 The guidance suggests Safety, as well as its partnership with
conditions under which a targeted Medco to mine data on prescriptions,
drug might be approved ahead of a genetic tests, and clinical outcomes,
corresponding diagnostic test. While may ultimately lead to more definitive
these guidelines were in development, regulatory guidelines.
the FDA, Health Canada and the EMA
11
Payment
Regulatory approval of personalized medicine products and services is only half the battle on
the road to adoption; coverage and payment by CMS or a patients insurance policy is also
needed. Both public and private insurers recognize the benefits of molecular testing in patient
management but payers also require evidence of its clinical, if not economic, value.
Payers stress that to justify coverage,

prognostic tests will have to be subjected
to a more rigorous assessment of their
cost-effectiveness and impact on health
outcomes than is currently the case.52
However, if the tests are not reimbursed
and not widely used in practice, it is
difficult to gather sufficient evidence to
supply proof of cost-effectiveness. To date,
the scarcity of clinical data on personalized
medicine products able to satisfy these
assessments has kept payers from fully
embracing them. This conundrum was
perhaps most clearly illustrated by the
rejection of genetically-guided warfarin
dosing by Medicare (due to studies that
cast some doubt on benefit claims),53
despite the fact that the genetic tests were
recommended by the FDA.54
Pharmacy benefit managers (PBMs) have

stepped in to provide what might be a more
viable business model for adoption. Because
they are responsible for processing and
paying prescription drug claims, developing
formularies and managing drug benefits for
more than 210 million Americans, PBMs
have a significant interest in getting the best
economic value from prescribing practices.
Along with their clients (private insurers,
employers and Medicare), they also have
extensive access to data on patient outcomes
and the use of drugs and diagnostics.
Rather than conduct expensive randomized
controlled trials, PBMs offer clinicallyvalidated diagnostic tests to patients and then
use real-world observational data from
actual clinical encounters, not a controlled
trial to establish the clinical utility and cost
effectiveness of the test. With these data,
molecular tests can then be introduced to
insurers with a greater chance of reimbursement
and adoption. The use of observational data
avoids the Catch 22 of having to establish
proof of utility before most people can even
use the tests. By partnering with PBMs, the
costs to the diagnostic company to obtain
the required evidence for reimbursement are
much lower than if they conducted studies
on their own, although questions about
the significance of observational studies
compared with randomized, controlled
clinical trials remain.
Clinical trials for personalized drugs and

companion diagnostics have been funded
under government grants and programs.
Examples include the TAILORx study of
Oncotype DX funded by the National
Cancer Institute, the Warfarin Adverse
Event Reduction for Adults Receiving
Genetic Testing at Therapy Initiation
(WARFARIN) Study approved by
CMS, and the Clarification of Optimal
Anticoagulation through Genetics (COAG)
trial.55 Although these multi-million dollar
studies complement industry-funded
efforts, they do not provide a sustainable
solution to closing the evidence gap for
supporting reimbursement and adoption Two of the largest PBMs, CVS Caremark
of personalized medicine.
and Medco, have launched initiatives to
12
assess the contribution of genetic testing

toward patient outcomes and health care
savings. Medco has presented data from a
real-world observational study of warfarin,
recruiting more than 900 patients for
genotyping and comparing geneticallyguided dosing of the anticoagulant to
patients dosed without the benefit of a
genetic test.56 The study established clinical
utility and cost-effectiveness of genotyping at
a significantly lower cost than the traditional
approach of conducting clinical trials. CVS
Caremark is evaluating a number of other
pharmacogenomic drug/test combinations,
including Pegasys (peginterferon alfa-2a)
and Copegus (ribavirin) for hepatitis C;
Gleevec (imatinib mesylate), Tasigna
(nilotinib) and Sprycel (dasatinib) for
chronic myeloid leukemia; Tarceva
(erlotinib) for non-small cell lung cancer;
and Tykerb (lapatinib) for breast cancer.
The model also works for diagnostic tests that
guide therapy with generic drugs, and there are
ongoing studies through Medcos Genetics
for Generics program to assess azathioprine
(an immunosuppressant), tamoxifen for breast
cancer, carbamezepine for epilepsy, abacavir
for HIV, and clopidogrel for preventing
stroke and heart attack.
PBM involvement in promoting personalized
medicine for both branded and generic drugs
is a natural fit: since anywhere from 20 to
80 percent of initially prescribed treatments
fail, the payer community has an incentive
to ensure that medicines are prescribed
Comparative effectiveness should complement the trend in medicine

to develop personalized medicine the ability to customize a drug and
dose based on individual patient and disease characteristics. One of the
advantages of large comparative effectiveness studies is the power to
investigate effects at the sub-level that often cannot be determined in
a randomized trial. This power needs to be harnessed so personalized
medicine and comparative effectiveness complement each other.
Federal Coordinating Council for Comparative Effectiveness Research, June 30, 2009
correctly the first time so that money is not policies of government and private insurers
wasted by trial and error.
will still have to be modified to make full
use of personalized medicine diagnostics.
As diagnostic and drug developers struggle Specifically, CMS policies, often replicated
with establishing evidence for safety and throughout the insurance industry, need to
efficacy for regulatory approval, as well as be updated to permit screening when it is
clinical utility and cost effectiveness for cost-effective.
reimbursement, insurers and policymakers
have raised the bar further by calling for For a new era of medicine that relies on
studies that establish the comparative predicting and preventing disease before
effectiveness of the new products and services it occurs, the CMS rules for Medicare are
against established standards of care.
outmoded. They state tests for screening
purposes that are performed in the
In 2010, the newly enacted health care absence of signs, symptoms, complaints,
reform law established the independent or personal history of disease or injury are
Patient-Centered Outcomes Research not covered except as explicitly authorized
Institute (PCORI), tasked with conducting by statute. Such a policy has placed
studies on the comparative risks and benefits significant limits on the adoption of
of marketed drugs and devices. The law personalized medicine practices that offer
specifically directs the institute to conduct value by predicting disease risk precisely in
comparative effectiveness research (CER) the absence of signs or symptoms. Although
in subpopulations differentiated by race, Medicare generally does not cover tests
ethnicity, gender, and age, as well as that are prognostic or predictive, there
genetic and molecular subtypes, an approach are some notable exceptions, including
advocated by the Personalized Medicine Pap tests, colorectal cancer screening tests,
Coalition. This shift would be the first time mammograms, and PSA screening.
such studies are conducted with a focus
on subpopulations. As such, it will require Even if CMS covers a predictive test, the
consideration of how to conduct them in way it is paid for can hinder its adoption.
a way that facilitates rather than inhibits New molecular tests are typically
development of personalized medicine categorized under the current procedural
tests and drugs.
terminology (CPT) codes, which often do
not account for the technical complexity of
Even if the economics and evidence the tests and their interpretation. Many of
requirements for personalized medicine the services provided by genetics specialists
studies can be demonstrated, reimbursement required to interpret the tests are not
reimbursed, or are undervalued by current

payment policies. Although research and
development costs for molecular diagnostic
tests are significantly higher than those
for conventional laboratory tests, due to
extensive genomic research and clinical
validation, CMS generally pays for the
innovative molecular tests based mostly on
materials cost and performance steps, and
at the same level as older laboratory tests.
There are indications, however, that the
payment policies of both public and
private insurers are beginning to move
toward supporting personalized medicine:
The American Medical Association CPT
Editorial Board is developing a multitiered set of CPT codes for molecular
diagnostics that will identify and describe
the technology and services of these tests.57
CMS announced that it was
considering opening a National
Coverage Determination (NCD) process
for pharmacogenetic testing in 2009,
allowing payment for investigational
products (such as genotyping for
warfarin) in order to facilitate a path to
reimbursement and adoption.54
Several large private insurers, including
Aetna, United Healthcare, and Kaiser
Permanente, have instituted progressive
coverage policies that pay for molecular
tests identifying pre-symptomatic highrisk populations (e.g., BRCA1/2 for
breast cancer) or that guide optimal
therapy (e.g., Oncotype Dx).
13
Health Information Technology

Health information technology (Health IT) helps power personalized medicine, but personalized
medicine will not reach its full potential or widespread adoption until nearly every hospital, clinic
and physicians office incorporates Health IT into its organization and practice. It will be difficult
to manage the large volume of information generated from tens of thousands of human genes
and proteins to understand their relationship with disease risk and treatment response. It will
be hard to create an instantand molecular data to better understand disease correlations and
allow health care providers to make timely, sound clinical decisions based on a body of scientific
knowledge that may be beyond the training, experience or memory of a single practitioner.
Nevertheless, these are the features that will be required to enable personalized medicine
in the new Health IT infrastructure.
Government support for Health IT

is strong. The Obama administration
has made implementation of Health
IT a top priority by including $44
billion in funding as part of the Health
Information Technology for Economic
and Clinical Health Act, or HITECH
Act. A section of the American Recovery
and Reinvestment Act of 2009 (ARRA),
HITECH formalized the Office of
the National Coordinator for Health
Information Technology and offers
funding for infrastructure and incentive
payments to providers who adopt and use
Health IT at an evolving standard of
implementation termed meaningful
use. It is important to note that after
2015, hospitals and physicians face
penalties for not using Health IT, such as
electronic health records (EHRs), in a
meaningful way, which should include
molecular information.
Many hurdles to implementing an
interoperable system of EHRs nationwide
remain, but many are being overcome not
only by the pressing need for change, but
also by the commitment from the federal
14
[W]e must ensure that new

systems are capable of handling,
sharing and analyzing the
genetic and outcomes data
needed to promote the
continued development of
Darrell M. West, Ph.D.
Vice President, Governance Studies, The Brookings Institution
government to complete the transition to

EHRs as an essential part of health care
reform. While the driving force may be to
use Health IT to reduce medical errors and
costs, the more substantive and long-term
value will be its use as a central component
of personalized medicine: creating a
learning health care system that links
clinical outcomes to new research on
genetic and other molecular variation,
encourages a team-based approach to

health care, provides the physician with
clinical decision support, engages patients
in their own health maintenance and
provides data on personalized diagnostics
and treatments to support a rational basis
for insurance coverage. Health IT will
thereby become a powerful enabler in the
realization of personalized medicine.
Genetic Non-Discrimination
As the role of genetics in medicine becomes more prominent, genetic privacy has also
come into sharper focus. The knowledge of a persons susceptibility to disease, even before
he or she shows signs or symptoms, can be either a powerful tool in improving health and
quality of life, or a means to discriminate in the workplace, and limit access to insurance and
other resources. To the extent that laws can confine genetic and other predictive medical
information to decisions benefiting patients and their medical care, those laws will enable
rather than inhibit the adoption of personalized medicine.
We are in a new era of the life sciences...but in no area

of research is the promise greater than in the field of
Senator Edward M. Kennedy
Remarks on the Senates Consideration of the Genetic Information Nondiscrimination Act, April 24, 2008
Although there existed at the time only a

patchwork of protections against genetic
discrimination, the Health Insurance
Portability and Accountability Act
(HIPAA) of 1996 attempted to limit
misuse of medical and genetic information
by controlling its access. However, the
rules only applied to federally-funded
institutions and gaps remained in privacy
protections with respect to employers and
insurance providers.
In 2008, the Genetic Information
Nondiscrimination Act (GINA) was signed
into law, explicitly prohibiting employers
and health insurers from discriminating
against individuals on the basis of their
genetic risk factors. The federal law
remains to be tested but it has established
a foundation for genetic privacy and
non-discrimination that is building
confidence among the public that genetic

information will not be used against them.
Such confidence may open the door to
greater participation in research as well as
acceptance of genetic information as part
of medical records. In November 2010,
the Equal Employment Opportunity
Commission stepped in to provide greater
clarification on its interpretation of
GINA, generally strengthening its
provisions (although some employers, such
as the military, are exempt).
Recognizing that GINA does not sufficiently
protect against genetic discrimination
outside employment and health insurance,
several states have sought to improve
protections against genetic discrimination
in other areas. In September 2011, for
example, California Governor Jerry Brown
signed the California Genetic Information
Nondiscrimination Act, which protects

citizens against genetic-based discrimination
in housing, employment, education, public
accommodations, health insurance, life
insurance, mortgage lending and elections.58
Similar legislation has been introduced in
Massachusetts and Vermont. The growing
prevalence of genetic and genomic data in
the medical record is likely to prompt more
states to follow suit in closing these gaps.
While laws on genetic privacy evolve to
meet the needs of patients, current law,
HIPAA in particular, can also make it
harder to collect and analyze aggregated
clinical data for the development of new
personalized treatments and diagnostics.
The publics expectation of protecting
privacy and the need to encourage research
must be properly balanced so that medical
care can continue to improve.
15
Medical Education
As personalized medicine becomes a reality in mainstream medical practice, physicians and other
health care providers will have to administer or advise on the application of growing numbers of
molecular and genetic tests and pharmacogenomically-guided drugs, make treatment decisions
based on more predictive evidence and estimations of risk, use information systems for managing
patient care, and deal with new ethical and legal issues that arise from molecular and genetic
testing. The adoption of personalized medicine technology and approaches will depend heavily on
the degree to which the provider community is educated in the field and is prepared to engage in
medical practice focused on risk assessment and predictive/prognostic modeling.
Many studies have documented the deficit

in genetics education for the health care
professions and the barriers it presents to full
integration of genetics into medical practice.59
Such studies have uncovered several reasons
for the continuing absence in medical
educational programs: crowded curricula
that leave little room for the introduction
of new topics; prevalent misconceptions
of genetics as being relevant mostly to rare
Mendelian-inherited disorders rather than
to common chronic diseases; medical school
faculty who are not trained or prepared to
teach the topic; and little or no representation
of genomic issues on medical certification
exams. Even when integrated into basic
science curricula, genetics instruction is
usually left out of clinical training.
The lack of genetics curricula has prevented
new genetic knowledge from widespread
clinical adoption. A recent survey of
physicians regarding hereditary breast,
ovarian and colorectal cancer revealed
limited knowledge and a lack of confidence
in incorporating key genetic concepts
into their practice.60 For example, only
37.5 percent of respondents understood
correctly that hereditary breast cancer
linked to BRCA1 and BRCA2 genes could
be transmitted through fathers. A survey
16
of psychiatrists found that although 83

percent believed it was their responsibility
to discuss genetics with patients, only
58 percent actually did so, and only 25
percent felt able to do so competently.61
Other studies pointed to physicians lack
of awareness of the newly passed genetic
anti-discrimination law,62 inappropriate
referrals to genetic testing and counseling,63
and shortcomings in their ability to pass
on key genetic information relevant to
their patients conditions.64 A recent survey
by Medco and the American Medical
Association found that 98 percent of
physicians are aware that patient genetic
profiles can and will influence therapy,
but only 10 percent believe they have
the knowledge required to use genetic
information in practice.65
Harvard Medical School has one of the

longest standing programs, in which a twoto-three year course of training with 12month clinical rotations is offered at Brigham
and Womens Hospital, Childrens Hospital
of Boston, and Massachusetts General
Hospital. Brigham and Womens Hospital
offers a five-year clinical genetics training
program that explores the diagnosis and
management of monogenic and genomic
diseases, as well as clinical laboratory rotations
and specialty clinics in cardiovascular, cancer,
renal, pulmonary and endocrine genetics. A
number of other leading medical education
institutions including, but not limited to,
Duke University School of Medicine, Ohio
State University and Stanford University
have made significant commitments to
combine classroom and clinical training
in genomic approaches for internal and
Taking genomics training from the classroom pediatric medicine.
to the clinic will be an essential feature
of a new approach to medical education. Allied health care specialists, including
Although the current state of medical nurses, genetic counselors, and pharmacists
education is far from adequate in preparing continue to play a more prominent role in
the next generation of physicians, nurses, providing care and advice to patients and
pharmacists and other health care workers will also require better genomic education in
for the coming wave of genomic medicine, their training curricula. Genomic education
several specific programs have emerged has been formalized in nursing through the
to provide an example for what medical Genetic Nursing Credentialing Commission
education could look like in the future.
(GNCC) and in colleges of pharmacy.66
The Emergence of
Participatory Medicine
The expanding use of Health IT in the clinical setting, as well as the potential to connect
patients to their own medical records from their homes and smartphones, creates an entirely
new scenario where patients can become active participants in their own medical care. Such
participation will become an essential component of personalized medicine, completing the
loop between doctor, patient and medical research. There are several ways in which patient
participation enables and magnifies the benefits of personalized medicine.
First, the scale of studies required to

pinpoint multiple rare genetic mutations
that may be responsible for common
chronic conditions will make such
studies prohibitively expensive unless
the data are collected nationwide from
real-life clinical encounters. These
observational data will become major
currency for the discovery of gene-disease
associations and the variable response to
drugs and treatment. Patients willingness
to contribute data from their medical
records, including entire genomic
sequences, will drive both observational
and formal clinical studies.
Second, environment, lifestyle, diet, family
history, and the patients observations
of their own symptoms will need to be
combined with molecular data to provide
a comprehensive view of the factors that
influence disease risk, progression and
treatment outcomes. The personal health
record, essentially a patient-owned portal
into his/her electronic health record,
will enable patients not only to record
observations of their own health or
conditions into their record, but to manage
their treatment and make appropriate
lifestyle changes to slow progression or
prevent onset of disease.
to take on the practice of personalized

medicine, the engaged patient will play
an important role in driving adoption of
A survey of 1,000 U.S. residents in
2010 found that public support for
personalized medicine remains strong.
About 58 percent of respondents saw
the value in using genetic information to
help identify which drugs would work
best for them during treatment, and 65

percent would like to use genetic data
to determine whether they might suffer
unwanted adverse reactions to a drug.67

As patients continue to accept and even
demand personalized medicine products
that yield better health outcomes, their
active participation in contributing data
to research will accelerate the discovery
of new diagnostics and treatments.
Health care today is in crisis as it

is expensive, reactive, inefficient,
and focused largely on one size
fits all treatments for events of
late stage disease. An answer is
personalized, predictive, preventive
and participatory medicine.
Ralph Snyderman, M.D.
Chancellor Emeritus, Duke University
Founder and Chairman, Proventys
Third, in an environment where the

medical establishment has been slow
17
Conclusion
The long arc of medical history has been one in which diagnostic capability has evolved from the
metaphysical, to the anatomical, to the cellular, and ultimately to the molecular level. Now that
diseases can be sub-classified using evidence well beyond what is visibly obvious into categories
that presage the course of disease and its likely response to treatment, there is an obligation to
act on that information.
Technology continues to lead, with

genomic
sequencing
and
other
molecular measurements likely to join
other democratized technologies a
computer on every desk, a cell phone in
every pocket, and some day a genomic
sequence in every medical record. The
implications of this transition are that we
will have significantly more information
than we are prepared to act upon. To
keep up with the technology, serious
effort will be required from every corner
of the health care spectrum.
Regulatory authorities must establish a

clear set of guidelines for evaluating and
approving personalized drugs and the
diagnostics that identify patients who
can benefit from them.
Personalized medicine is our chance

to revolutionize health care, but it
will require a team effort by the
innovators, entrepreneurs, regulators,
payers, and policymakers.
Brook Byers
Partner, Kleiner Perkins Caufield & Byers
Educational institutions must now

prepare the next generation of physicians
for the inevitable arrival of personalized
medicine, and hospitals and physician
practices must adopt electronic health
The enabling technologies of personalized records.
medicine, in particular genomic
sequencing and its interpretation, will Finally, health information systems
have to be further developed and must incorporate features that support
standardized for routine clinical practice. 21st century medicine, providing the
ability to collect and analyze data
Medicare and private insurers must from everyday clinical encounters, and
establish a path toward evaluating helping physicians make decisions based
the clinical and economic utility of on the vast amount of information
personalized medicines in order to linking genetic patterns to diseases and
their treatment. A diagram illustrating
facilitate their reimbursement.
18
the degree to which each of these sectors

has progressed is presented in Figure 4.
Hippocrates warned us over 2,400 years
ago that the art is long, life is short,
opportunity is fleeting, experiment is
fallible, and judgment is difficult. Much
work remains to be done in building the
infrastructure for personalized medicine,
but the resources we invest in completing
the task now will enable us to seize
opportunity from a wave of data headed
our wayand to realize the full health
and economic benefits of matching the
right treatment or prevention to each
and every patient.
FIGURE 4. The Personalized Medicine Adoption Diagram
D
AN
CY S
IVA ON
PR CTI
TIC OTE
NE PR
GE GAL
LE
ON
I
AT
UC
IC
Recognition
of value
D
LE
ED
Enactment of
policy or legislation
Pilots and
precedent
Full
Implementation
And
Standardization
HEALTH CARE
INFORMATION TECHNOLOGY
RE
GU
LA
TI
ON
TE
CH
NO
LO
GY
AN
DT
OO
LS
INSURANCE COVERAGE
AND REIMBURSEMENT
The implementation of personalized medicine requires a confluence of several sectors (represented by wedges in the diagram). Concentric
circles represent stages of implementation. Full implementation of personalized medicine can only be achieved when all sectors converge
toward the center.
19
Table:
Selected Personalized Medicine Drugs, Treatments and

Diagnostics as of September 2011*
Indications in quotes and otherwise unattributed, are cited from the therapeutic or diagnostic product label.
Therapeutic product labels contain pharmacogenomic information as:
Information only
Recommended
Required
Unhighlighted products have no pharmacogenomic information, recommendations or requirements in the label.
THERAPY
BIOMARKER/TEST
Mivacron (mivacurium) Cholinesterase gene
INDICATION
Anesthesia adjunct: Mivacron is metabolized by plasma cholinesterase and
should be used with great caution, if at all, in patients known to be or suspected
of being homozygous for the atypical plasma cholinesterase gene.
Ansaid (flurbiprofen)
CYP2C9
Arthritis: In vitro studies have demonstrated that cytochrome P450 2C9 plays
an important role in the metabolism of flurbiprofen to its major metabolite,
4-hydroxy-flurbiprofen.
Depakote (divalproex)
UCD (NAGS; CPS; ASS;

OTC; ASL; ARG)
Bipolar disorder: Hyperammonemic encephalopathy, sometimes fatal, has been

reported following initiation of valproate therapy in patients with urea cycle disorders
[UCDs]...particularly ornithine transcarbamylase deficiency [OTC].
Aromasin (exemestane)
Arimidex (anastrozole)
Nolvaldex (tamoxifen)
Estrogen Receptor (ER)
Breast cancer: Exemestane is indicated for adjuvant treatment of postmenopausal women with ER-positive early breast cancer. Anastrozole is for
treatment of breast cancer after surgery and for metastases in post-menopausal
women. Tamoxifen is the standard therapy for estrogen receptor-positive early
breast cancer in pre-menopausal women.
Chemotherapy
Mammostrat
Breast cancer: Prognostic immunohistochemistry (IHC) test used for

postmenopausal, node negative, estrogen receptor expressing breast cancer patients
who will receive hormonal therapy and are considering adjuvant chemotherapy.
Chemotherapy
MammaPrint
Breast cancer: Assesses risk of distant metastasis in a 70-gene expression profile.
Chemotherapy
Oncotype DX 16-gene
signature
Breast cancer: A 16-gene signature (plus five reference genes) indicates whether a
patient has a low, intermediate, or high risk of having a tumor return within 10
years. Low-risk patients may be treated successfully with hormone therapy alone.
High-risk patients may require more aggressive treatment with chemotherapy.
Chemotherapy
CompanDx 31-gene
signature
Breast cancer: The test predicts time to event for metastasis of breast cancer,
following surgery or biopsy.
Faslodex (fulvestrant)
Hormone Receptor (HR)
Breast cancer: Fulvestrant is indicated for the treatment of hormone receptor

positive metastatic breast cancer in post-menopausal women with disease
progression following anti-estrogen therapy.
Herceptin
(trastuzumab)
Tykerb (lapatinib)
HER-2/neu receptor
Breast cancer: for the treatment of patients with metastatic breast cancer
whose tumors overexpress the HER-2 [Human Epidermal growth factor
Receptor 2] protein and who have received one or more chemotherapy
regimens for their metastatic disease. High levels of HER-2 expression have
been associated with increased disease recurrence in breast cancer, but show a
better response to trastuzumab.
Pharmaceutical and
surgical prevention
options and surveillance
BRCA 1/2
Breast cancer: Guides surveillance and preventive treatment based on

susceptibility risk for breast and ovarian cancer.
Nolvadex (tamoxifen)
Breast Cancer Index

(HOXB13, IL17BR)
20
SM
Breast cancer: Calculates a combined risk analysis for recurrence after tamoxifen
treatment for ER-positive, node-negative breast cancer.
THERAPY
BIOMARKER/TEST
INDICATION
Bidil (isosorbide and

hydralazine)
NAT1; NAT2
Cardiovascular disease: Prescribed for heart failure, the mean absolute

bioavailability of a single oral dose of hydralazine 75 mg varies from 10 to
26%, with the higher percentages in slow acetylators.
Coumadin (warfarin)
CYP2C9
Cardiovascular disease: Detects an increased bleeding risk for patients

carrying either the CYP2C9*2 or CYP2C9*3 alleles. The lower initiation
doses should be considered for patients with certain genetic variations in
CYP2C9 and VKORC1 enzymes.
Coumadin (warfarin)
VKORC1
Cardiovascular disease: Certain single nucleotide polymorphisms in the

VKORC1 gene (especially the 1639G>A allele) have been associated with lower
dose requirements for warfarin.
Coumadin (warfarin)
PGx Predict: Warfarin
Cardiovascular disease: Determines CYP2C9 and VKORC1 genotypes to

predict likelihood of adverse events with warfarin therapy.
Coumadin (warfarin)
Protein C deficiencies
Cardiovascular disease: Hereditary or acquired deficiencies of protein C

or its cofactor, protein S, has been associated with tissue necrosis following
warfarin administration.
Lipitor (atorvastatin)
LDLR
Cardiovascular disease: Doses should be individualized according to the

recommended goal of therapy. Homozygous Familial Hypercholesterolemia
(10-80mg/day) and heterozygous (10-20mg/day).
Pharmaceutical and
lifestyle prevention
options
Familion 5-gene profile
Cardiovascular disease: Guides prevention and drug selection for patients with
inherited cardiac channelopathies such as Long QT Syndrome (LQTS), which
can lead to cardiac rhythm abnormalities.
Plavix (clopidogrel)
CYP2C19
Cardiovascular disease: CYP2C19 poor metabolizer status is associated with

diminished response to clopidogrelPharmacogenetic testing can identify
genotypes associated with variability in CYP2C19 activity.
Statins
SINM PhyzioType
Cardiovascular disease: Predicts risk of statin-induced neuro-myopathy, based

on a patients combinatorial genotype for 50 genes.
Camptosar (irinotecan)
UGTIA1
Colon cancer: Individuals who are homozygous for the UGT1A1*28 allele
are at increased risk for neutropenia following initiation of Camptosar
treatment...A reduction in the starting doseshould be considered for patients
known to be homozygous for the UGT1A1*28 allele.
Chemotherapy
Oncotype DX 7-gene
signature
Colon cancer: The seven-gene signature (plus five reference genes) provides a risk
score that indicates whether a patient is likely to have a tumor recurrence with stage
II colon cancer. Risk levels guide treatment with adjuvant chemotherapy.
BRAF
Erbitux (cetuximab)
Vectibix (panitumumab)
Colon cancer: A mutation in BRAF identifies 12-15 percent of metastatic

colorectal cancer patients who fail to respond to TKIs. Non-mutated forms of
BRAF and KRAS genes are required for response.
Erbitux (cetuximab)
EGFR expression
Colon cancer: Patients enrolled in the clinical studies were required to have
evidence of positive EGFR expression using the DakoCytomation EGFR
pharmDx test kit. EGFR positive individuals (high expression) are more
likely to respond to the drug than those with reduced EGFR expression.
KRAS
Erbitux (cetuximab)
Iressa (gefitinib)
Tarceva (erlotinib)
Colon cancer: KRAS mutations are associated with poor response to the
anti-EGFR antibody cetuximab. The FDA suggests use of cetuximab and
panitumumab is not recommended for the treatment of colorectal cancer
patients with KRAS mutations.Retrospective analyses of metastatic colorectal
cancer trials have not shown a treatment benefit for the EGFR inhibitors in
patients whose tumors had KRAS mutations in codon 12 or 13.
Erbitux (cetuximab)
Target GI
5-fluorouracil (5-FU)
Colon cancer: Provides information of the expression of key molecular

targetsKRAS, TS, and TOPO1to guide therapy.
21
THERAPY
BIOMARKER/TEST
INDICATION
Platinum therapies
5-FU
Gemzar (gemcitabine)
Alimta (pemetrexed)
Erbitux (cetuximab)
ResponseDx:Colon
Tegretol
(carbamazepine)
HLA-B*1502
Epilepsy and bipolar disorder: Serious dermatologic reactions are associated

with the HLA-B*1502 allele in patients treated with carbamazepine. Patients with
ancestry in genetically at-risk populations should be screened for the presence of
HLA-B*1502 prior to initiating treatment with Tegretol. Patients testing positive
for the allele should not be treated with Tegretol unless the benefit clearly
outweighs the risk.
Immunosuppressive
drugs
AlloMap gene signature
Heart transplantation: Monitors patients immune response to heart transplant

to guide immunosuppressive therapy.
Pegasys (peginterferon
alfa-2a)
IL28B
Hepatitis C: A single nucleotide polymorphism near the gene encoding

interferon-lambda-3 (IL28B) was associated with variable SVR [sustained
virological response] rates.
Selzentry (maraviroc)
CCR5 receptor
HIV: Selzentry, in combination with other antiretroviral agents, is indicated for

treatment experienced adult patients infected with only CCR5-tropic HIV-1...
Ziagen (abacavir)
HLA-B*5701
HIV: Patients who carry the HLA-B*5701 allele are at high risk for
experiencing a hypersensitivity reaction to abacavir. Prior to initiating therapy
with abacavir, screening for the HLA-B*5701 allele is recommended.
Entocort (budesonide)
Prometheus IBD
Serology 7
Inflammatory bowel disease: Identifies subset of patients who will benefit

from budesonide.
Busulfex and Myleran

(busulfan)
Philadelphia
Chromosome/BCR-ABL
Leukemia: Busulfan is clearly less effective in patients with chronic

myelogenous leukemia who lack the Philadelphia (Ph1) chromosome.
Gleevec (imatinib)
Philadelphia
Chromosome/BCR-ABL
Leukemia: Gleevec (imatinib mesylate) is indicated for the treatment of newly

diagnosed adult and pediatric patients with Philadelphia chromosome positive [indicated
by presence of BCR-ABL] chronic myeloid leukemia (CML) in chronic phase.
Purinethol
(mercaptopurine)
Tabloid (thioguanine)
Imuran (azathioprine)
TPMT
Leukemia: Guides adjustment of dose in treatment of acute lymphoblastic

leukemia: Patients with inherited little or no thiopurine S-methyltransferase
(TPMT) activity are at increased risk for severe Purinethol toxicity from
conventional dosesIt is recommended that consideration be given to either
genotype or phenotype patients for TPMT.
Sprycel (dasatinib)
Philadelphia
Chromosome/BCR-ABL
Leukemia: Dasatinib is indicated for the treatment of adults with Philadelphia

chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance
or intolerance to prior therapy.
Tasigna (nilotinib)
UGT1A1, Ph+
Leukemia: Tasigna isindicated for the treatment of chronic phase and

accelerated phase Philadelphia chromosome positive chronic myelogenous
leukemia (CML) in adults resistant to imitinab. UGT1A1*28 patients have
a high risk of hyperbilirubinemia.
Trisenox
(arsenic trioxide)
Vesanoid (tretinoin)
PML/RAR
Leukemia: for induction of remission and consolidation in patients with acute

promyelocytic leukemia (APL)...whose APL is characterized by the presence of
the t(15;17) translocation or PML/RAR-alpha gene expression.
Bexxar (tositumomab)
CD20
Lymphoma: Bexxar...is indicated for the treatment of patients with CD20

antigen expressing...non-Hodgkins lymphoma.
Ontak (denileukin
diftitox)
CD25
Lymphoma: Ontak is indicated for the treatment of patients with persistent

or recurrent cutaneous T-cell lymphoma whose malignant cells express the
CD25 component of the IL-2 receptor.
22
Colon cancer: Expression profiles and mutations in ERCC1, TS, EGFR, BRAF,
KRAS provide information for the selection of various therapies.
THERAPY
BIOMARKER/TEST
5-fluorouracil (5-FU)
ResponseDx:Lung
Gemzar (gemcitabine)/
carboplatin
Erbitux (cetuximab)
Iressa (gefitinib)
Tarceva (erlotinib)
INDICATION
Lung cancer: Expression profiles and mutations in ERCC1, TS, EGFR,
RRM1, KRAS, and EML4-ALK provide information for the selection of
various therapies.
Daraplatin
(carboplatin)
RRM1
Lung cancer: Gemcitabine interferes with the DNA synthesis function of

ribonucleotide reductase through its active subunit (RRM1). Low levels of
RRM1 gene expression are associated with improved response to gemcitabine/
platin therapy.
Iressa (gefitinib)
Tarceva (erlotinib)
KRAS
Lung cancer: KRAS is mutated in about 30 percent of lung cancers,

which exhibit resistance to EGFR-directed drugs used in NSCLC therapy.
However recent evidence suggests the role of KRAS mutation status in
choosing EGFR TKI or anti-EGFR monoclonal antibodies is unclear.
Tarceva (erlotinib)
EGFR expression and

activating mutations
Lung cancer: EGFR activating mutations occur in approximately 10 percent of

Caucasian patients with NSCLC and up to 50 percent of Asian patients. Data
from multiple studies indicate a predictive role for EGFR activating mutations
with respect to response rate and progression-free survival with TKI therapy,
particularly in the first-line setting.
Xalkori (crizotinib)
ALK
Lung cancer: Xalkori is indicated for the treatment of patients with

locally advanced or metastatic non-small cell lung cancer (NSCLC) that
is anaplastic lymphoma kinase (ALK)-positive as detected by an FDAapproved test. The ALK abnormality occurs in 1-7% of NSCLC patients.
Xalkori (crizotinib)
Vysis ALK Break Apart

FISH Probe Kit
Lung cancer: The Vysis ALK Break Apart FISH Probe Kit is a qualitative
test to detect rearrangements involving the ALK gene via fluorescence in
situ hybridization (FISH)in non-small cell lung cancer (NSCLC) tissue
specimens to aid in identifying those patients eligible for treatment with
Xalkori (crizotinib).
Aralen (chloroquine)
G6PD
Malaria: The drug should be administered with caution to patients having

G-6-PD (glucose-6 phosphate dehydrogenase) deficiency.
Monitoring and
prevention strategies
p16
Melanoma: Anyone with the inherited gene mutation in p16 is at higher than
average risk for melanomaup to 50 percent by age 50, or 50 times the risk of
non-mutation individuals.
Zelboraf
(vemurafenib)
BRAF V600E
Melanoma: Zelboraf is a kinase inhibitor indicated for the treatment of

patients with unresectable or metastatic melanoma with BRAF V600E mutation
as detected by an FDA-approved test. The BRAF V600E mutation is found in
about half of melanoma patients.
Zelboraf
(vemurafenib)
cobas 4800 BRAF V600 Melanoma: The cobas 4800 BRAF V600 Mutation Test detects the BRAF
Mutation Test
V600E mutation in formalin-fixed, paraffin-embedded (FFPET) human
melanoma tissue. It is designed to help select patients for treatment with
vemurafenib, an oral medicine designed to treat patients whose melanoma
tumors harbor a mutated form of the BRAF gene.
Chemotherapy
CupPrint
Multiple cancers: Determines cancer classification for tumors of unknown

primary origin.
Chemotherapy
CancerTYPE ID
Multiple cancers: Classifies 39 tumor types from tumors of unknown primary

origin, using a gene expression profile.
23
THERAPY
BIOMARKER/TEST
INDICATION
5-FU
Alimta (pemetrexed)
TS
Multiple cancers:
Colon cancer: High levels of TS gene expression correlate with colorectal
tumor resistance to 5-FU.
Gastric cancer: TS gene expression in primary adenocarcinoma of the stomach
has an inverse relationship to response (e.g., high expression, low response) for
patients treated with 5-FU.
Lung cancer: Patients with high levels of thymidylate synthetase (TS), a
DNA synthesis enzyme, in their tumors tend to respond less favorably to TS
inhibitors such as 5-FU.
Elitek (rasburicase)
G6PD
Multiple cancers: Rasburicase administered to patients with glucosephosphate dehydrogenase (G6PD) deficiency can cause severe hemolysis. Do
not administer ELITEK to patients with glucose-6-phosphate dehydrogenase
(G6PD) deficiencyScreen patients at higher risk for G6PD deficiency (e.g.,
patients of African or Mediterranean ancestry) prior to starting ELITEK.
Pharmaceutical and
surgical treatment
options and surveillance
MLH1, MSH2, MSH6
Multiple cancers: Guides surveillance and preventive treatment based on

susceptibility risk for colon and other cancers.
Platinum therapies
Camptosar
(irinotecan)
ERCC1
Multiple cancers:
Colon cancer: In a study of advanced colorectal cancer treated with
5-fluorouracil/oxaliplatin, low ERCC1 expression is associated with longer
survival. High expression of ERCC1 is associated with response to
irinotecan therapy.
Gastric cancer: Patients treated with FOLFOX (5-fluorouracil/leucovorin/
oxaliplatin) regimen or first-line cisplatin-based regimens respond significantly
better if they show lower levels of ERCC1 expression.
Lung cancer: Enzyme excision repair complementing factor 1 (ERCC1) helps
repair DNA damage caused by platinum-based therapy. Low ERCC1 is a
favorable indicator for response to platinum therapy.
Xeloda (Capecitabine)
DPD
Multiple cancers: Rarely, unexpected severe toxicity (e.g., stomatitis, diarrhea,

neutropenia and neurotoxicity) associated with 5-fluorouracil has been
attributed to a deficiency of dihydropyrimidine dehydrogenase (DPD) activity.
XELODA is contraindicated in patients with known [DPD] deficiency.
Drugs metabolized by
Cytochrome P450
Amplichip CYP2D6/
CYP2C19
Multiple diseases: FDA classification 21 CFR 862.3360: This device is used

as an aid in determining treatment choice and individualizing treatment dose
for therapeutics that are metabolized primarily by the specific enzyme about
which the system provides genotypic information.
2C19: carisoprodol, clopidogrel,

dexlansoprazole, diazepam,
drospirenone & ethinyl estradiol,
esomeprazole, modafinil, nelfinavir,
pantoprazole, prasugrel, rabeprazole,
ticagrelor, voriconazole
2D6: aripiprazole, atomoxetine,
carvedilol, cevimeline,
chlordiazepoxide & amitriptyline,
citalopram, clomipramine, clozapine,
codeine, desipramine, desloratadine
& pseudoephedrine, dextromorphan
& quinidine, doxepin, fluoxetine,
fluoxetine & olanzapine,
fluvoxamine, galantamine, gefitinib,
iloperidone, imipramine, metoprolol,
modafinil, nefazodone, nortriptyline,
paroxetine, perphenazine,
pimozide, propranolol,
propafenone, protriptyline,
quinidine, risperidone, terbinafine,
tetrabemazine, thioridazine, timolol,
tiotropium, tolterodine, tramadol
& acetomenophen, trimipramine,
venlafaxine
24
THERAPY
BIOMARKER/TEST
INDICATION
Gleevec (imatinib)
PDGFR
Myelodysplastic syndrome: Imatinib is indicated for Adult patients with

myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with PDGFR
(platelet-derived growth factor receptor) gene re-arrangements.
Revlimid
(lenalidomide)
5q deletion
Myelodysplastic syndrome: For patients with transfusion-dependent anemia due

to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a
deletion 5q abnormality with or without additional cytogenetic abnormalities.
Celebrex (celecoxib)
CYP2C9
Pain: Patients who are known or suspected to be P450 2C9 poor metabolizers
based on a previous history should be administered celecoxib with caution as they
may have abnormally high plasma levels due to reduced metabolic clearance.
Immunosuppressant
Therapies
ImmuKnow
Post-Transplant Immune Status: ImmuKnow is an immune cell function assay

that detects cell-mediated immunity in an immunosuppressed population.
Enbrel (etanercept)
Remicade (infliximab)
PsoriasisDx
Psoriatic arthritis: This sequencing-based assay detects the presence of gene variant
MICA-A9, indicative of an increased risk of psoriatic arthritis. Identification of risk
could guide monitoring and early treatment with TNF-alpha antagonists.
Psychiatric drugs
GeneSightRx
Psychiatric disorders: Genetic variants (CYP1A2, CYP2D6, CYP2C19, serotonin

transporter gene SLC6A4, serotonin 2A receptor gene 5HTR2A) in this test may affect a
patients ability to metabolize, tolerate or respond to 26 psychotropic medications.
Risperdal (resperidone)
Zyprexa (olanzapine)
PhyzioType PIMS
Psychiatric disorders: Predicts risk of psychotropic-induced metabolic

syndrome, based on a patients combinatorial genotype for 50 genes.
Efudex (5-FU)
DPD
Skin cancer: Efudex should not be used in patients with dyhydropyrimidine

dehydrogenase (DPD) deficiency.
Gleevec (imatinib)
c-KIT
Stomach cancer: Gleevec is also indicated for the treatment of patients with
Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal
stromal tumors (GIST).
Herceptin (trastuzumab)
Tykerb (lapatinib)
HER-2/neu receptor
Stomach cancer: Patient survival was significantly improved with Herceptin+

chemotherapy versus chemotherapy alone in the treatment of gastric cancer.
Herceptin (trastuzumab)
Platinum therapies
5-FU
ResponseDx:Gastric
Stomach cancer: Expression profiles and mutations in ERCC1, TS, and HER2
provide information for the selection of various therapies.
Rifadin (rifampin)
Nydrazid (isoniazid)
Pyrazinamide
NAT
Tuberculosis: Slow acetylation may lead to higher blood levels of the drug,
and thus, an increase in toxic reactions.
* This list is not intended to be comprehensive but reflects commonly used or available products as of September 2011. Some
products, for which the FDA recommends or requires pharmacogenomic testing or which have pharmacogenomic information
in their label, are listed at the FDAs website (http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/
ucm083378.htm). Other listed products that are novel, and/or that address large populations, have been identified via websites
and public announcements.
25
References
Note: all websites were accessed as of September 8, 2011.
26
Winslow R. Major shift in war on cancer. Wall Street Journal. June 6, 2011.
Garrod AE. Incidence of alkaptonuria: a study in chemical individuality. Lancet. 1902; 2:6536.
Carson PE, Flanagan CL, Ickes CE, Alvong AS. Enzymatic deficiency in primaquine sensitive erythrocytes. Science. 1956;
124:4845.
National Cancer Institute BRCA1 and BRCA2 fact sheet. NCI website. (Available at: http://www.cancer.gov/cancertopics/
factsheet/risk/brca).
Struewing JP, Hartge P, Wacholder S, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among
Ashkenazi Jews. N Engl J Med. 1997; 336(20):1401-8.
Ries LAG, Harkins D, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2003. National Cancer Institute. (Available
online at: http://www.seer.cancer.gov/csr/1975_2003/).
Couzin-Frankel J. NIH Wants to Hear About Genetic Tests. Science Insider. March 2010.
Wordsworth S, Leal J, Blair E. DNA testing for hypertrophic cardiomyopathy: a cost-effectiveness model. Eur Heart J. 2010;
31(8):926-35.
Spear BB, Heath-Chiozzi M, Huff J. Clinical application of pharmacogenetics. Trends Mol Med. 2001; 7(5):201-4.
10
Mangravite LM, Thorn CF, Krauss RM. Clinical implications of pharmacogenomics of statin treatment. Pharmacogenomics J.
2006; 6(6):360-74.
11
Rieder MJ, Reiner AP, Gage BF, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J
Med. 2005; 352:2285-93.
12
Terra SG, Hamilton KK, Pauly DF, et al. Beta1-adrenergic receptor polymorphisms and left ventricular remodeling changes in
response to beta-blocker therapy. Pharmacogenet Genomics. 2005; 15(4):227-34.
13
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast
cancer. N Engl J Med. 2005; 353:1659-72.
14
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N
Engl J Med. 2005; 353:1673-84.
15
Hornberger J, Cosler LE, Lyman GH. Economic analysis of targeting chemotherapy using a 21-gene RT-PCR assay in lymphnode-negative, estrogen-receptor-positive, early-stage breast cancer. Am J Manag Care. 2005; 11:313-24.
16
Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor
positive breast cancer. J Clin Oncol. 2006; 24:3726-34.
17
Cronin M, Pho M, Dutta D, et al. Measurement of gene expression in archival paraffin-embedded tissues. Am J Pathol. 2004;
164(1):35-42.
18
Mammaprint website. (Available at: http://www.agendia.com/pages/mammaprint/21.php).
19
Livre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer.
Cancer Res. 2006; 66(8):3992-5.
20
National Comprehensive Cancer Network. Guidelines in Oncology: Colon Cancer. v.2.2009. NCCN website. (Available at:
http://www.nccn.org/professionals/physician_gls/PDF/colon.pdf ).
21
Shah, SH. Clopidogrel Dosing and CYP2C19. Medscape. July 1, 2011. Medscape website. (Available at: http://emedicine.
medscape.com/article/1733280-overview).
22
Pollack A. Drug companies pursue personalized medicine approach. New York Times. November 16, 2010.
References Continued
23
Kongkaew C, Noyce PR, Ashcroft DM. Hospital admissions associated with adverse drug reactions: a systematic review of
prospective observational studies. Ann Pharmacother. 2008; 42(7):1017-25.
24
Phillips KA, Veenstra DL, Oren E, et al. Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic
review. JAMA. 2001; 286:2270-9.
25
Blue Cross Blue Shield Technology Evaluation Center. Special Report: Genotyping For Cytochrome P450 Polymorphisms
To Determine Drug-Metabolizer Status. Assessment Program. 2004; 19(9):1-34.
26
Jain KK. Applications of AmpliChip CYP450. Mol Diag. 2005; 9(3):119-27.
27
U.S. Food and Drug Administration. FDA approves updated warfarin (Coumadin) prescribing information. August 16,
2007. (Available at: http://www.fda.gov/bbs/topics/news/2007/new01684.html)
28
Nyakutira C, Roshammar D, Chiqutsa E, et al. High prevalence of the CYP2B6 516G->T(*6) variant and effect on the
population pharmacokinetics of efavirenz HIV/AIDS outpatients in Zimbabwe. Eur J Clin Pharmacol. 2008; 64(4):357-65.
29
Umans-Eckenhausen MA, Defesche JC, van Dam MJ, et al. Long-term compliance with lipid-lowering medication after
genetic screening for familial hypercholesterolemia. Arch Intern Med. 2003; 163(1):65-8.
30
Allomap molecular expression testing website. (Available at: http://allomap.com/).
31
Pham MX, Teuteberg JJ, Kfoury AG, et al. Gene-expression profiling for rejection surveillance after cardiac transplantation.
N Engl J Med. 2010; 362(20):1890-900.
32
Kolata G. A tale of two drugs hints at promise for genetic testing. New York Times. July 11, 2006.
33
Tate CW, Roberton AD, Zolty R et al. Quality of life and prognosis in heart failure: results of the Beta-Blocker Evaluation
of Survival Trial (BEST). J Cardiac Failure. 2007; 13(9):732-7.
34
Hamburg MA, Collins FS. The path to personalized medicine. N Engl J Med. 2010; 363(4):301-4.
35
McWilliam A, Lutter R, Nardinelli C. Health care savings from personalizing medicine using genetic testing: the case of
warfarin. AEI-Brookings Joint Center for Regulatory Studies. 2006.
36
Epstein RS, Moyer TP, Aubert RE, et al. Warfarin genotyping reduces hospitalization rates. Results from the MM-WES
(Medco-Mayo Warfarin Effectiveness Study). J Am Coll Cardiol. 2010; 55:2804-12.
37
Genomic Health. Economic validity website. (Available at: http://www.genomichealth.com/en-US/sitecore/content/Home/

Breast/ManagedCareOrgs/EconomicValidity.aspx).
38
Shankaran V. Conference presentation at the Gastrointestinal Cancers Symposium. January 2009. (As reported online at:
http://www.medscape.com/viewarticle/586946).
39
Wade N. Cost of decoding a genome is lowered. New York Times. August 10, 2009.
40
Bio-IT World Staff. Illumina announces $5,000 genome pricing. Bio IT News. May 9, 2011.
41
National Institutes of Healths Office of Extramural Research. Revolutionary Genome Sequencing Technologies, RFA-HG08-009. NIH website. (Available at: http://grants1.nih.gov/grants/guide/rfa-files/RFA-HG-08-009.html).
42
Wolinsky H. The thousand-dollar genome: Genetic brinksmanship or personalized medicine? EMBO Reports. 2007;
8(10):900-3.
43
Worthey EA. Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with
intractable inflammatory bowel disease. Genet Med. 2011; 13(3):255-62.
44
Goh V, Helbling D, Biank V, et al. Next generation sequencing facilitates the diagnosis in a child with twinkle mutations
causing cholestatic liver failure. J Pediatr Gastroenterol Nutr. 2011. (E-pub ahead of print).
45
Clarke J, Wu HC, Jayasinghe L, Patel A, Reid S, Bayley H. Continuous base identification for single-molecule nanopore
DNA sequencing. Nat Nanotech. 2009; 4:265-70.
46
US patent 20060029957, ZS Genetics. Systems and methods of analyzing nucleic acid polymers and related components.
Issued July 2006.
47
Vastag B. New clinical trials policy at FDA. Nat Biotech. 2006; 24(9):1043.
27
References Continued
48
Frueh FW, Amur S, Mummaneni P, et al. Pharmacogenomic biomarker information in drug labels approved by the United
States Food and Drug Administration: prevalence of related drug use. Pharmacogen. 2008; 28:992-998.
49
Carver, KH. Companion diagnostics: Evolving FDA regulation and issues for resolution. (Available at: http://www.cov.com/
files/Publication/e5c4b3dc-1832-4742-9937-84f965052b44/Presentation/PublicationAttachment/7795d260-621d-4d13bd29-863acac00254/Companion%20Diagnostics%20-%20Evolving%20FDA%20Regulation%20and%20Issues%20
for%20Resolution.pdf ).
50
US Food and Drug Administration. Draft guidance for industry and Food and Drug Administration staff: In vitro
companion diagnostic devices. FDA website. July 2011. (Available at: http://www.fda.gov/downloads/MedicalDevices/
DeviceRegulationandGuidance/GuidanceDocuments/UCM262327.pdf ).
51
U.S. Food and Drug Administration. Table of pharmacogenomic biomarkers in drug labels. FDA website. (Available at:
http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm).
52
Ramsey SD, Veenstra DL, Garrison LP Jr, et al. Toward evidence-based assessment for coverage and reimbursement of
laboratory-based diagnostic and genetic tests. Am J Manag Care. 2006; 4:197-202.
53
Gandara E, Wells PS. Will there be a role for genotyping in warfarin therapy? Curr Opin Hematol. 2010; 17(5):439-43.
54
Centers for Medicare and Medicaid Services. Decision memo for pharmacogenomic testing for warfarin response (CAG00400N). August 3, 2009.
55
Ray T. NIH launches large randomized trial to determine utility of PGx-based warfarin dosing. Pharmacogen Rep. February
18, 2009.
56
Epstein RS, Moyer TP, Aubert RE, et al. Warfarin genotyping reduces hospitalization rates: results rrom the MM-WES
(Medco-Mayo Warfarin Effectiveness Study). J Am Coll Cardiol. 2010; 55:2804-12.
57
American Medical Association. Molecular Pathology Coding Workgroup. AMA website. (Available at: http://www.amaassn.org/resources/doc/cpt/molecular-pathology-coding-workgroup.pdf ).
58
Gotten, V. California Governor Signs Padilla Bill to Prevent Genetic Discrimination Unruh Civil Rights Act Modernized
to Reflect 21st Century. Cal Newswire. September 7, 2011.
59
Guttmacher AE, Porteous ME, McInerney JD. Educating health-care professionals about genetics and genomics. Nat Rev.
2007; 8:151-7.
60
Wideroff L, Vadaparampil ST, Greene MH, et al. Hereditary breast/ovarian and colorectal cancer genetics knowledge in a
national sample of US physicians. J Med Genet. 2005; 42(10):749-755.
61
Finn CT, Wilcox MA, Korf BR, et al. Psychiatric Genetics: a survey of psychiatric knowledge, opinions, and practice
patterns. J Clin Psych. 2005; 66:821-830.
62
Lowstuter KJ, Sand S, Blazer KR, et al. Influence of genetic discrimination perceptions and knowledge on cancer genetics
referral practice among clinicians. Genet in Med. 2008; 10(9):691-698.
63
White DB, Bonham VL, Jenkins J, et al. Too many referrals of low-risk women for BRCA1/2 genetic services by family
physicians. Cancer, Epidem, Biomar & Prev. 2008; 17(11):2980-2986.
64
Burke W, Emery J. Genetics education for primary-care providers. Nat Rev Genet. 2002; 3:56166.
Medco. National Pharmacogenomics Physician Survey 2008. Medco website. (Available at: http://www.medcoresearchinstitute.
com/pharmacogenomics/physician-survey).
65
66
Springer JA, Iannotti NV, Kane MD et al. Pharmacogenomics training using an instructional software system. Am J Pharm
Educ. 2011; 75(2):32.
67
Cogent Research Attitudes & Trends (CGAT) Study 2010.
The Personalized Medicine Coalition (PMC) gratefully acknowledges Feinstein Kean

Healthcare and Mike Silver, Ph.D., for the research, writing and design of this document
and the contributions of our many members who offered insights and suggestions.
28
Membership List
CLINICAL LABORATORY
TESTING SERVICES
HEALTH INSURANCE
COMPANIES
DIAGNOSTIC COMPANIES
INDUSTRY & TRADE

ASSOCIATIONS
Genelex Corporation
Iverson Genetic Diagnostics, Inc.
Laboratory Corporation of America
(LabCorp)
Quest Diagnostics
AdvanDx
Agendia BV
Allegro Diagnostics
Almac Diagnostics
AltheaDx, Inc.
Aperio
ArcticDx Inc.
AssureRx Health, Inc.
ASURAGEN, Inc.
Axial Biotech, Inc.
Biodesix
BioMarker Strategies
bioMrieux
BioStat Solutions, Inc.
Brain Resource Company Limited
CardioDx, Inc.
Caris Life Sciences
Clarient, a GE Healthcare Company
Crescendo Bioscience, Inc.
Cylex Inc.
Dako Denmark A/S
DiagCor Bioscience Incorporation
Limited
Expression Analysis, Inc.
Foundation Medicine, Inc.
Gen-Probe Incorporated
Genomic Health, Inc.
HistoRx
Integrated Diagnostics
Intervention Insights
Lineagen, Inc.
Luminex Corporation
MolecularMD
Nodality
On-Q-ity
PrimeraDx
Prognomix Inc.
Proventys
QIAGEN, Inc.
Saladax Biomedical, Inc.
Siemens Medical Solutions
Silicon Valley Biosystems
SomaLogic, Inc.
SureGene, LLC
SurExam
TcLand Expression
Telome Health, Inc. (THI)
Tethys Bioscience
Verinata Health, Inc.
VitaPath Genetics, Inc.
XDx, Inc.
EMERGING BIOTECH/
PHARMACEUTICAL
COMPANIES
Alper Biotech, LLC

ARCA biopharma
Asterand
BIOCRATES Life Sciences AG
Cabernet Pharmaceuticals, Inc.
Debiopharm Group
Genomind, LLC
KineMed, Inc.
Neogenix Oncology, Inc.
Pamlab, LLC
Selventa
Aetna
CVS Caremark
Generation Health, Inc.
Humana Inc.
Medco Health Solutions, Inc.
AdvaMed (Advanced Medical

Technology Association)
American Clinical Laboratory
Association
BIO (Biotechnology Industry
Organization)
PhRMA
IT/INFORMATICS
COMPANIES
5AM Solutions, Inc.

CTIS, Inc.
Cytolon AG
GenomeQuest, Inc.
HP Health and Life Sciences
Lead Horse Technologies, Inc.
McKesson
Molecular Health
NextBio
Oracle Health Sciences
SAIC Health Solutions
UNIConnect
XIFIN, Inc.
LARGE BIOTECH/
PHARMACEUTICAL
COMPANIES
Abbott
Amgen, Inc.
Astellas Pharma Global Development
Boehringer-Ingelheim
Pharmaceticals, Inc.
Bristol-Myers Squibb Company
Eli Lilly and Company
Endo Pharmaceuticals
GE Healthcare
GlaxoSmithKline
Johnson & Johnson
Merck
Millennium: The Takeda Oncology
Company
Novartis
Pfizer Inc
PATIENT ADVOCACY
GROUPS
Accelerated Cure Project for

Multiple Sclerosis
Alliance for Aging Research
Genomix Canada
Hoosier Oncology Group
International Cancer Advocacy
Network (ICAN)
Malignant Hyperthermia
Association of the US
Multiple Myeloma Research
Foundation
National Alliance for Hispanic
Health
National Brain Tumor Society
PERSONALIZED MEDICINE
SERVICE PROVIDERS
23andMe
DNA Direct, Inc.
Informed Medical Decisions, Inc.
Michael J. Bauer, MD &
Associates, Inc.
Navigenics, Inc.
Pathway Genomics Corporation
RESEARCH & EDUCATIONAL

INSTITUTIONS
American Association for Cancer

Research
American Institute for Medical &
Biological Engineering (AIMBE)
American Medical Association
American Society of Human
Genetics (ASHG)
Association for Molecular
Pathology (AMP)
Brown University
Cardiovascular Research Center /
Mount Sinai School of Medicine
Catholic Health Initiatives Center
for Translational Research
Cepmed
Childrens Hospital & Research
Center Oakland
Childrens Mercy Hospitals
and Clinics
Cleveland Clinic Genomic
Medicine Institute
College of American Pathologists
Coriell Institute for Medical
Research
The Critical Path Institute (C-Path)
Duke University
El Camino Hospital
Fairbanks Institute for Healthy
Communities
FasterCures
Genome British Columbia
The George Washington
University Medical Center
H. Lee Moffitt Cancer Center &
Research Institute, Inc.
Indiana Institute of Personalized
Medicine
Institute for Individualized Health
(IGNITE)
Institute for Systems Biology
Institute for Translational
Oncology Research (ITOR)
Instituto Cartuja Hospital
Molecular
The Jackson Laboratory
The Dr. John T. Macdonald
Foundation Department of
Human Genetics, University
of Miami
Marshfield Clinic
Mayo Clinic
MIT Center for Biomedical
Innovation (CBI)
National Foundation for Cancer
Research
National Jewish Health
National Pharmaceutical Council
NorthShore University
HealthSystem
The Ohio State University
Medical Center
Partners HealthCare Center for
Personalized Genetic Medicine
Poliambulatorio Euganea Medica

Raabe College of Pharmacy, Ohio
Northern University
RTI International
Stanford University School
of Medicine
Translational Genomics Research
Institute (TGen)
United States Diagnostic
Standards (USDS)
University of Pittsburgh Medical
Center (UPMC)
University of Rochester
University of Utah
Vanderbilt University Medical
Center
VCU Health System
RESEARCH TOOL
COMPANIES
Affymetrix, Inc.
DNA Genotek Inc.
Genia Technologies
Illumina, Inc.
Life Technologies Corporation
Pacific Biosciences
STRATEGIC PARTNERS
AB&C Life Sciences, (a division of

Aloysius Butler & Clark)
Archon Genomics X PRIZE
Ascel Bio
Beaufort, LLC
Bionest Partners
Bioscience Valuation BSV GmbH
Boston Healthcare
Bridgehead International
CAHG
Cambridge Healthtech Institute
CryerHealth
Defined Health
Ernst & Young Global Life
Sciences Center
Feinstein Kean Healthcare
Foley & Lardner LLP
Genomic Healthcare Strategies
Growing Company Solutions, Inc.
Health Advances, LLC
HealthFutures, LLC
Hogan Lovells LLP
Kilpatrick Townsend & Stockton LLP
L.E.K. Consulting
McDermott Will & Emery LLP
Medivo, Inc.
Nixon Peabody LLP
PAREXEL International
Pendergast Consulting
Personalized Medicine Partners, LLC
PricewaterhouseCoopers LLP
PRTM
Robinson, Bradshaw & Hinson
Russell Reynolds Associates
Scientia Advisors
Slone Partners
Valerie August & Associates, LLC
Biotechnology Recruiter
William Blair & Company
Wilson Sonsini Goodrich & Rosati
VENTURE CAPITAL
Burrill & Company

Kleiner Perkins Caufield & Byers
Mohr Davidow
Pappas Ventures
Third Rock Ventures, LLC
Personalized Medicine Coalition

1225 New York Avenue, NW, Suite 450
Washington, DC 20005
Phone 202-589-1770 | Fax 202-589-1778
Email info@personalizedmedicinecoalition.org
www.PersonalizedMedicineCoalition.org

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The Case for

Patients with melanoma, metastatic

The Case for Personalized Medicine, 3rd Edition

FIGURE 1. Forging a Path to Personalized Cancer Care

Head and neck

proteomic technologies and a strong

based on their genetic makeup; new

populations and professional education

The Case for Personalized Medicine, 3rd Edition

Building a Track Record

The historical precedents for modern

markers that signal disease risk or presence

diagnosis often permits targeted prevention

For example, women with certain BRCA1

The Case for Personalized Medicine, 3rd Edition

The power in tailored therapeutics is for us to say more clearly to

but an antibody drug called Herceptin

Meanwhile, new targeted therapies, paired

Outside oncology, the blood clot-preventing

FIGURE 2. One Size Does Not Fit All

Source of data: Brian B. Spear, Margo Heath-Chiozzi, Jeffery Huff, Clinical

The Case for Personalized Medicine, 3rd Edition

Building a Track Record Continued

the drug are tested for the gene, significantly

Make drugs safer by avoiding adverse drug

Inherited forms of hypercholesterolemia

The use of genetic markers to facilitate safer

Increase patient adherence to treatment.

Improve quality of life. A molecular

About five to eight percent of HIV patients

The Case for Personalized Medicine, 3rd Edition

As the field advances, we expect to see more efficient clinical

of heart transplant patients experience a

Francis Collins, M.D., Ph.D.

The Case for Personalized Medicine, 3rd Edition

It took $3 billion and 13 years to

The Case for Personalized Medicine, 3rd Edition

off. They represent an area of intense

FIGURE 3. The Rapidly Decreasing Cost of

Average cost of sequencing a genome for NHGRI-funded sequencing technology

ailments, such as heart disease, diabetes,

In addition, efforts by the National

These budding technologies include

Personalized Medicine Tests. The

the Centers for Medicare and Medicaid

Promoting personalized medicine

The Case for Personalized Medicine, 3rd Edition

and sometimes irreversible, medical

Recently, the development of therapeutic products that depend

Pharmaceuticals. While the clinical

or protein marker-based diagnostic test had either mandated or recommended

The Case for Personalized Medicine, 3rd Edition

Payers stress that to justify coverage,

Pharmacy benefit managers (PBMs) have

Clinical trials for personalized drugs and

The Case for Personalized Medicine, 3rd Edition

assess the contribution of genetic testing

Comparative effectiveness should complement the trend in medicine

reimbursed, or are undervalued by current