THE PERSONALIZED MEDICINE REPORT - 2017 Opportunity, Challenges, and the Future
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THE PERSONALIZED MEDICINE REPORT 2017 · Opportunity, Challenges, and the Future
The Personalized Medicine Coalition gratefully acknowledges graduate students at Manchester University in North Manchester, Indiana, and at the University of Florida, who updated the appendix of this report under the guidance of David Kisor, Pharm.D., Director, Pharmacogenomics Education, Manchester University, and Stephan Schmidt, Ph.D., Associate Director, Pharmaceutics, University of Florida. The Coalition also acknowledges the contributions of its many members who offered insights and suggestions for the content in the report.
CONTENTS INTRODUCTION 5 THE OPPORTUNITY 7 Benefits 9 Scientific Advancement 17 THE CHALLENGES 27 Regulatory Policy 29 Coverage and Payment Policy 35 Clinical Adoption 39 Health Information Technology 45 THE FUTURE 49 Conclusion 51 REFERENCES 53 APPENDIX 57 Selected Personalized Medicine Drugs and Relevant Biomarkers 57
HISTORICAL PRECEDENT For more than two millennia, medicine has maintained its aspiration of being personalized. In ancient times, Hippocrates combined an assessment of the four humors — blood, phlegm, yellow bile, and black bile — to determine the best course of treatment for each patient. Today, the sequence of the four chemical building blocks that comprise DNA, coupled with telltale proteins in the blood, enable more accurate medical predictions.
The Personalized Medicine Report 5
INTRODUCTION
When it comes to medicine, one size does not fit all. Treatments that help some patients
are ineffective for others (Figure 1),1 and the same medicine may cause side effects in
only certain patients.
Yet, bound by the constructs of traditional disease, and, at the same time, increase the
care delivery models, many of today’s doctors still efficiency of the health care system by improving
prescribe therapies based on population averages. quality, accessibility, and affordability.
As a result, health care systems around the world Health care is in the midst of a transformation
continue to deliver inefficient care that fails to away from one-size-fits-all, trial-and-error
help significant portions of the patient population. medicine and toward this new, targeted approach
Enter personalized medicine. Personalized that utilizes patients’ molecular information to
medicine, also called precision or individualized inform health care decisions. Completing that
medicine, is an evolving field in which physicians transformation, however, will require a collabora-
use diagnostic tests to identify specific biological tive effort in the U.S. and abroad to keep up with
markers, often genetic, that help determine which the pace of progress in science and technology.
medical treatments and procedures will work best A myriad of nuanced regulatory and reimburse-
for each patient. By combining this information ment challenges as well as complexities regarding
with an individual’s medical records, circumstances, the clinical adoption of new medical norms and
and values, personalized medicine allows doctors standards, in particular, continue to make it
and patients to develop targeted treatment difficult for health care systems around the world
and prevention plans. Personalized health care has to capitalize on innovative science and a growing
the capacity to detect the onset of disease body of knowledge pointing to a new era in the
at its earliest stages, pre-empt the progression of history of medicine.6 Introduction
FIGURE 1: ONE SIZE DOES NOT FIT ALL
Percentage of the patient population for which a particular drug in a class is
ineffective, on average.
ANTI-DEPRESSANTS 38%
SSRIs
ASTHMA DRUGS 40%
DIABETES DRUGS 43%
ARTHRITIS DRUGS 50%
ALZHEIMER’S DRUGS 70%
CANCER DRUGS 75%
Reproduced with permission from: Spear, BB, Heath-Chiozzi, M, Huff, J. Clinical application
of pharmacogenetics. Trends in Molecular Medicine. 2001;7(5): 201-204.The Personalized Medicine Report 7 THE OPPORTUNITY
8 The Opportunity
“The power in tailored therapeutics is
for us to say more clearly to payers,
providers, and patients: ‘this drug is not
for everyone, but it is for you.’ That is
exceedingly powerful.”
— John C. Lechleiter, Ph.D.
former Chairman, President, and CEO, Eli Lilly
and CompanyThe Personalized Medicine Report 9
BENEFITS
Personalized medicine benefits patients and the In some areas, early genetic testing can save
health system by: lives. For example, women with certain BRCA1
• Shifting the emphasis in medicine from reaction or BRCA2 gene variations have up to an 85
to prevention percent lifetime chance of developing breast
• Directing targeted therapy and reducing trial- cancer, compared to a 13 percent chance among
and-error prescribing the general female population.2, 3, 4 Women with
• Reducing adverse drug reactions harmful BRCA1 and BRCA2 mutations also have
up to a 39 and 17 percent chance, respectively,
• Revealing additional targeted uses for medicines
of developing ovarian cancer, compared with a
and drug candidates
1.3 percent chance among the general female
• Increasing patient adherence to treatment
population.2 The BRCA1 and BRCA2 genetic
• Reducing high-risk invasive testing procedures
tests can guide preventive measures, such as
• Helping to control the overall cost of health care prophylactic surgery, chemoprevention, and
more frequent mammography.
Shifting the Emphasis in Medicine from Personalized medicine also opens the door
Reaction to Prevention to early intervention for patients with familial
hypercholesterolemia, which is characterized
Personalized medicine introduces the ability to
by a mutation in the LDL receptor gene. These
uncover molecular markers that signal disease risk
patients can take drugs that block the PCSK9
or presence before clinical signs and symptoms
gene (known as PCSK9 inhibitors) to reduce
appear, offering an opportunity to focus on
their cholesterol levels and potentially decrease
prevention and early intervention rather than on
their risk of developing coronary artery disease.
reaction at advanced stages of disease.10 The Opportunity
Directing Targeted Therapy and Reducing Other personalized medicine tests measure
Trial-and-Error Prescribing prognostic markers that help indicate how
a disease may develop in an individual when a
In many disease areas, diagnostic tests enable
disorder is already diagnosed. Two complex tests,
physicians to identify the most effective treat-
Oncotype DX® and MammaPrint®, for example,
ment for a patient immediately by testing
use prognostic markers to help physicians target
for specific molecular characteristics, thus
the best course of treatment for breast cancer
avoiding the frustrating and costly practice of
patients. Oncotype DX® can determine whether
trial-and-error medicine. Medicines that target
women with certain types of breast cancer
those molecular characteristics often improve
are likely to benefit from chemotherapy.8, 9, 10
outcomes and reduce side effects. One of the
MammaPrint® can detect which early-stage breast
most common applications of this practice has
cancer patients are at risk of distant recurrence
been for women with breast cancer. About
following surgery.11 Both tests place patients into
30 percent of breast cancer cases are character-
risk categories that inform physicians and patients
ized by over-expression of a cell-surface protein
of whether the cancer may be treated success-
called human epidermal growth factor receptor 2
fully with hormone therapy alone, as opposed
(HER2). For breast cancer patients who express
to some combination of hormone therapy and
this molecule, adding an antibody drug like
chemotherapy, which is associated with an addi-
trastuzumab (Herceptin®) to their chemotherapy
tional financial burden and toxic effects. Similar
regimen can reduce their recurrence risk by
prognostic tests for prostate and colon cancer
52 percent.5, 6 Molecular diagnostic tests for HER2
patients have also been developed.12, 13, 14
are used to identify the patients who will benefit
from receiving Herceptin® and other drugs that
target HER2, such as lapatinib (Tykerb®). Reducing Adverse Drug Reactions
Treatments targeting genetic variants involved in Another category of personalized medicine tests,
the molecular pathway of disease, such as BRAF called pharmacogenomic tests, help predict what
in melanoma and ALK and EGFR in non-small medications at what doses will be safest for indi-
cell lung cancer, represent a remarkable improve- viduals based on their genetic makeup. Doing so is
ment over trial-and-error medicine, and we are important. According to several studies, about 5.3
moving toward an era in which we treat all cancer percent of all hospital admissions are associated
cases with a targeted course of treatment with adverse drug reactions (ADRs).15 Many ADRs
(Figure 2).7 are attributed to variations in genes that code forThe Personalized Medicine Report 11
FIGURE 2: F
ORGING A PATH TO PERSONALIZED CANCER CARE
TACKLING TUMORS: Percentage of patients whose tumors are driven by certain
genetic mutations that could be targets for specific drugs, by types of cancer.
73%
Melanoma
56%
Thyroid
51%
Colorectal
43%
Endometrial
41%
Lung
41%
Pancreatic
32%
Breast
31%
Other gynecological
29%
Genitourinary
25%
Other gastrointestinal
21%
Ovarian
21%
Head and neck
Reproduced with permission from: Winslow, R. Major shift in war on cancer. Wall Street Journal.
June 5, 2011. Accessed September 13, 2016 at http://www.wsj.com/articles/SB10001424052702304
432304576367802580935000.12 The Opportunity
drug-metabolizing enzymes, such as cytochrome The use of genetic markers to facilitate safer
P450 (CYP450).16, 17 These variants cause drugs and more effective drug dosing and selection
to be metabolized either faster or slower than takes on added significance at the population
normal. As a result, some individuals have trouble level. For example, adverse reactions to the HIV
inactivating a drug and eliminating it from their drug efavirenz (Stocrin®/Sustiva®) can occur at
bodies, leading to systemic overexposure to the standard dosing due to the presence of a genetic
drug, while others eliminate the drug too rapidly mutation (the CYP2B6*6 allele) in an enzyme that
before it has had a chance to work. Thus, these metabolizes the medicine. This results in slower
genetic variations should be considered when metabolism of the drug and is found significantly
determining dose. more often in patients of African heritage than
Pharmacogenomic testing can help guide those of European heritage.22 Lowering the
the safe application of medicines in many health drug dose in individuals with this allele can help
areas, including heart disease, hematologic reduce adverse effects and increase treatment
disorders, HIV and other infectious diseases, compliance. Similarly, the HLA-B*5701 mutation is
cancer adjunct therapy, anesthesiology, derma- associated with severe and life-threatening hyper-
tology, gastroenterology, neurology, psychiatry, sensitivity to the HIV drug abacavir (Ziagen®/
and rheumatology. One of the first applications Epzicom®).23 The HLA-B*5701 mutation is present
of pharmacogenomics was for patients that in approximately five percent of HIV patients in
had been prescribed the drug warfarin, used the U.S.
to prevent blood clots. Genetic variations in
a drug-metabolizing enzyme (CYP2C9) and Revealing Additional Targeted Uses for
an enzyme that activates vitamin K (VKORC1)
Medicines and Drug Candidates
complicate the safe use of warfarin.18, 19 Dosing
is typically adjusted for the individual patient Molecular testing can also help identify the most
through multiple rounds of trial-and-error, during appropriate uses for therapies that were initially
which the patient may be at risk for excessive targeted to the general population. The lung
bleeding or further blood clots. FDA now recom- cancer drug gefitinib (Iressa®), for example, did
mends genotyping for all patients before warfarin not demonstrate a survival advantage in a general
treatment, which allows for more precise dosing. population of lung cancer patients in clinical trials,
Although the data are still evolving, early evidence and was withdrawn from the market in 2005
suggests that genetic testing in advance of after initially being granted accelerated approval
prescribing warfarin helps patients avoid serious in 2003. However, continued clinical research
and possibly fatal adverse effects.20, 21The Personalized Medicine Report 13
revealed benefits in patients who test positive toma and anaplastic large cell lymphoma.33, 34
for epidermal growth factor mutations. FDA FDA has fast-tracked regulatory review for these
approved Iressa® as a first-line treatment for this expanded indications, which some observers
subset of patients in 2015. believe is a precursor to an era in which the agency
Gene and protein analyses have also led to an approves all personalized medicines faster based
evolution in the way tumors are evaluated and on the increased likelihood that a molecularly
classified. With an increasing body of knowledge targeted drug will be safe and effective.
about the underlying genomic alterations and the
expression of relevant biomarkers, tumor clas- Increasing Patient Adherence
sification is shifting away from tissue of origin and
to Treatment
toward molecular taxonomy, which is having a
profound effect on the way that oncology treat- Patient non-adherence with treatment leads to
ment decisions are made. For example, trial results adverse health effects and increased overall health
suggest that expression of the PD-L1 biomarker, care costs. When personalized therapies prove
which has been widely observed in cancers from more effective or present fewer side effects,
multiple tissues of origin, can help doctors make patients may be more likely to comply with their
more informed decisions about the use of some treatment regimens. The greatest impact could be
novel immune checkpoint inhibitors.24 This has led in the treatment of chronic diseases, for which non-
to expanded approvals for immune checkpoint adherence commonly exacerbates the condition.
inhibitors like pembrolizumab (Keytruda®), which For example, inherited forms of hypercholes-
was initially approved in 2014 for melanoma.25 terolemia (high cholesterol) can increase the risk
FDA revised Keytruda’s label in 2015 for use in of myocardial infarction before the age of 40 by
non-small cell lung cancer and has fast-tracked more than 50-fold in men and 125-fold in women.
review for its use in other indications.26, 27 Similarly, Knowledge of a genetic predisposition for hyper-
FDA has also approved the use of nivolumab cholesterolemia provides patients with a powerful
(Opdivo®) for multiple indications.28, 29, 30, 31, 32 incentive to make lifestyle changes and manage
Likewise, early studies indicate that crizotinib their condition with drugs. Patients with a genetic
(Xalkori®), already approved to treat specific forms diagnosis have shown more than 86 percent
of non–small cell lung cancers, including those that adherence to their treatment program after two
are EML4-ALK-positive, is also effective against years, compared to 38 percent prior to testing.35
other types of tumors containing ALK alterations,
such as aggressive forms of pediatric neuroblas-14 The Opportunity
FIGURE 3: A NEW TREATMENT PARADIGM
Without Personalized Medicine: Some Benefit, Some Do Not
Patients
Therapy
Some patients benefit, some patients do not benefit, and
some patients experience adverse effects
With Personalized Medicine: Each Patient Receives the Right Medicine
Patients
Biomarker
Diagnostics
Therapy
Each patient benefits from individualized treatment
Adapted with permission from: PhRMA. A New Treatment Paradigm. Accessed September 13, 2016
at http://chartpack.phrma.org/personal-medicines-in-development-chartpack/a-new-treatment-
paradigm/personalized-medicine-can-improve-efficiencies-within-the-health-care-system.The Personalized Medicine Report 15
Avoiding Invasive Testing Procedures system can help decrease costs associated with
many embedded inefficiencies, such as trial-and-
Molecular tests that simply require a blood sample
error dosing, hospitalizations due to adverse drug
can also sometimes replace invasive and uncom-
reactions, late-stage health condition diagnoses,
fortable tissue biopsies. For example, Allomap®,
and reactive treatment. Personalized medicine can
a multi-gene expression test, detects whether
also play an important role in the implementation
the immune system of heart transplant recipients
of value-based payment and delivery models, which
is rejecting the new organ.36 Approximately 25
can help coordinate patient care and reduce costs.
percent of heart transplant patients experience
As an example, data suggest that pharmacoge-
a rejection, which can prove fatal. To monitor for
nomic testing associated with the management
rejection, heart tissue biopsies are performed as
of dosing of the blood thinning drug warfarin can
frequently as once a week after the transplant,
eliminate costs associated with hospitalizations
and then every few months thereafter for several
for bleeding or thromboembolism. The Mayo
years. This invasive procedure requires inserting a
Clinic and the pharmacy benefits manager Medco
tube into a vein in the neck and threading it to the
put the model to the test in a 3,600-subject
heart to obtain the biopsy, which is uncomfortable
prospective study. Hospitalization rates for heart
for patients and has risks associated with injury to
patients were reduced by about 30 percent when
the vein and heart. Patients who are monitored for
genetic information was available to doctors
rejection using Allomap® have equivalent outcomes
prescribing the drug.39 Additionally, breast cancer
as those who receive heart tissue biopsies, but
therapy guided by the Oncotype DX® test has
without the associated risks and complications.37, 38
been estimated to provide a net cost savings of
$2,256 per patient tested, based on a reduction
Helping to Control the Overall in chemotherapy use with an incremental cost-
Cost of Health Care effectiveness ratio of $1,944 per life year saved.40
By introducing innovative science that can create Another study found a $604 million annual
efficiencies and sustainability, personalized medi- savings among all patients when treatment with
cine also has the potential to reduce health care panitumumab (Vectibix®) or cetuximab (Erbitux®)
costs worldwide. As noted, incorporating personal- was limited to patients with metastatic colorectal
ized medicine into the fabric of the health care cancer whose KRAS gene was not mutated.4116 The Opportunity
“It’s not really ‘should we do this.’ We have
to do this. We don’t get to decide what
the biology of these diseases are, we just
have to work with it.”
— Barbara Weber, M.D.
Interim Chief Medical Officer, Neon TherapeuticsThe Personalized Medicine Report 17
SCIENTIFIC
ADVANCEMENT
The scientific tools necessary to realize the for the Study of Drug Development showed that
benefits of personalized medicine are already at 42 percent of the drugs in the development pipe-
our disposal. line now include biomarkers in their research and
PMC counts 132 personalized medicines, that development design. The survey also suggested
is, drugs that point to specific biomarker(s) in that biopharmaceutical manufacturers have nearly
their labels to direct use, currently on the market doubled their investment in personalized medicine
(Figure 4; Appendix), and recent estimates by the over the past five years, and that these companies
genetic testing data company Concert Genetics expect investment to increase by another 33
indicate that there are now no fewer than 65,000 percent over the next five years (Figure 7).
genetic tests available (Figure 5). Analysts peg the Scientific developments in genomic
market value for drugs reliant on companion diag- sequencing, how an individual’s biology impacts
nostics (CDx) at over $25 billion in 2015 (Figure 6). disease susceptibility, immunotherapy, gene
These numbers are likely to continue growing. therapy, and CRISPR-Cas9 gene editing are laying
A recent survey conducted by the Tufts Center the groundwork for a new era in medical discovery.18 The Opportunity
FIGURE 4: COMING OF AGE
Number of Personalized Medicines Has Increased Steadily Since 2008*
132
106
81
36
5
2008 2010 2012 2014 2016
Personalized Medicine Coalition. The Case for Personalized Medicine (eds. 1–4). 2008–2014; Personalized
Medicine Coalition. Applications: Therapies. Accessed October 31, 2016 at http://www.personalizedmedi-
cinecoalition.org/Education/Therapies.
*Methodological notes: The number of personalized medicines was calculated by combining informa-
tion from former editions of PMC’s Case for Personalized Medicine (2008–2014) with 2016 data
from FDA’s Table of Pharmacogenomic Biomarkers in Drug Labeling, accessed October 31, 2016 at
http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.
htm and CPIC’s Genes-Drugs tables, accessed October 31, 2016 at https://cpicpgx.org/genes-drugs/.
A complete list of the 132 drugs counted as of October 2016 is available at http://www.personalized-
medicinecoalition.org/Education/Therapies and in the Appendix of this report.The Personalized Medicine Report 19
Genomic Sequencing Human Biology and Disease Susceptibility:
It took $1 billion and 13 years to sequence the first The Role of DNA, RNA, Epigenetics,
draft of the human genome. Since then, sequencing and Proteins
technology has evolved from the manual Sanger Understanding the role of genetic variation in
method using radioactive labels to automated disease has also become a central part of medical
sequencing that employs color-coded fluores- research. Most scientists believe that many
cent dyes. As a result, the cost of sequencing an common human ailments, such as heart disease,
entire genome has declined at a rate that exceeds diabetes, and cancer, are significantly influenced
Moore’s law (Figure 8). The results reflect a general by numerous rare genetic variations present within
trend in the industry and an important transition a single genome. Thus, one person might not carry
around mid-2007 brought on by next-generation the same set of variants as another, even if both
sequencing technology. have the same disease. These rare variants are, as
The cost to sequence a human genome today, National Institutes of Health (NIH) Director Francis
at approximately $1,000,42 is comparable to the Collins termed them, the “dark matter” in genetic
cost of other medical tests and procedures, and patterns that remain undiscovered.
new innovations may continue to drive sequencing Thanks to the Human Genome Project and
costs down. Current estimates suggest that in subsequent advancements in sequencing tech-
ten years the cost will be $100.43 Additional costs nology, the scientific community is now more
and time are necessary, however, for analysis and equipped than ever to make sense of this “dark
annotation in a clinical setting. matter.” It is now possible to simultaneously
interrogate hundreds of thousands of sites in20 The Opportunity
FIGURE 5: PROGRESS BY THE THOUSANDS
65,839 Total
Singles
Panels
Genetic Testing Products Now on the Market
(as of September 2016)
(Cumulative growth)
65,839
APR MAY JUN JUL AUG SEP OCT NOV DEC JAN FEB MAR APR MAY JUN JUL AUG SEP
More Than 5,500 New Genetic Testing Products Came to Market Between
April 2015 and September 2016*
Data provided by: Concert Genetics. Available at concertgenetics.com.
*Methodological notes: Concert Genetics began publishing the first reliable data on the number of
genetic testing products available in January of 2016. PMC has published a list of 127 genetic tests com-
monly associated with the 132 personalized medicines listed in the Appendix of this document at http://
www.personalizedmedicinecoalition.org/Education/Tests.The Personalized Medicine Report 21
an individual’s DNA to find associations between There is also a growing understanding of
a given disease and genetic variation. In 2015, genomic changes that can alter the chemistry and
U.S. President Barack Obama launched the structure of DNA without altering its sequence.
Precision Medicine Initiative (PMI), an effort to These “epigenetic” changes can occur in response
build a national research cohort of one million to environmental factors, and influence whether
or more Americans who volunteer their genetic certain genes are turned “on” or “off.” Epigenetic
information for research aimed at finding more factors have been linked to a number of health
effective ways to improve health and treat disease. conditions, including heart disease, diabetes, and
The project is poised to fill a tremendous gap cancer. The NIH has developed the Roadmap
in our understanding of human genetic variation Epigenomics Project to study the role of epi-
by making thousands and ultimately a million genetics in human diseases.46
genome sequences securely available for scientific In addition, scientists are working to standardize
interrogation. existing proteomic technologies such as mass
But advances in personalized medicine are not spectrometry, leading to more robust identification
confined to analysis of DNA. In fact, analyzing of protein biomarkers, which indicate the presence
messenger RNA transcripts, the immediate or absence of disease apart from the risk predic-
downstream mediator of the genome, can some- tion of genetic analysis. Entirely new approaches
times detect gene expression in ways that DNA to protein biomarker detection47 are promising to
analysis cannot. RNA sequencing analysis repre- make proteomics as “simple” as genetic analysis,
sents an expanding share of the next-generation ushering in an era when diseases can be diagnosed —
sequencing marketplace.44, 45 and treated — in their earliest stages.22 The Opportunity
Immunotherapy Gene Therapy
Researchers and pharmaceutical companies are Medical researchers are also developing ways
also developing highly personalized treatment to introduce genetic material directly into cells
approaches that use the patient’s own immune to treat or prevent disease. Gene therapy, for
system to help fight cancer. These “immuno- example, may allow scientists to “knock out” or
therapies” work in different ways. Some provide replace a mutated gene that causes illness, or to
a general boost to the body’s immune system. introduce a healthy copy of a gene to restore the
Others help train the immune system to attack function of a needed protein. The European Union
specific cancer cells by inhibiting a tumor’s ability has approved the first gene therapy, alipogene
to use a substance called PD-L1 to put the “brakes” tiparvovec (Glybera®),50 and several gene thera-
on immune cells. Novel immune checkpoint pies have advanced to phase III trials in the U.S.51
inhibitors like Keytruda® and Opdivo®, for example, Although the clinical efficacy of these treatments
block the ability of PD-L1 to bind with its receptor, has not yet been established,52 proponents believe
PD-1, which normally acts as a type of “off-switch” the therapies will begin to carve out a niche as the
that helps keep a patient’s immune system from number of potential targets for these treatments
attacking cancer cells. These therapies have been continues to increase.
approved for the treatment of melanoma, non-
small cell lung cancer, kidney cancer, and Hodgkin
lymphoma.48, 49 They are also being studied for use
against many other types of cancer.The Personalized Medicine Report 23
FIGURE 6: MARKETED THERAPEUTICS RELIANT ON A CDx
GENERATED ~$25 BILLION IN THERAPEUTIC REVENUES IN 2015
Biopharma worldwide marketed CDx drug revenue segmentation (2015)*
Percent of revenues
~$25B ~$25B ~$25B
100
Other****
Other***
Therapy selection/
80 monitoring
Opdivo (BMS)
Tarceva (Roche)**
Perjeta (Roche)
Erbitux (BMS)
60
Sprycel (BMS)
Tasigna (Novartis) Oncology
40 Therapy selection
Gleevec (Novartis)
20
Herceptin (Roche)
0
Drug (Company) Therapeutic area Test purpose
* 2015 revenues are actual or analyst estimates; PHC products include those with labels that require/recommend
CDx tests for candidacy
** Includes all Tarceva revenues, not just those from first-line treatment for EGFR+ non-small cell lung cancer patients
*** Other includes Alecensa, Aristada, Blincyto, Bosulif, Cholbam, Cotellic, Gilotrif, Ibrance, Iressa, Kadcyla, Lonsurf,
Lynparza, Mekinist, Nucala, Orkambi, Praluent, Repatha, Rexulti, Selzentry, Tafinlar, Tagrisso, Tykerb/Tyverb, Vectibix,
Victrelis, Xalkori, Zelboraf, and Zykadia drug revenues
**** Other includes infectious disease, neurology, cardiology, pediatrics, respiratory, and gastroenterology
therapeutic areas
Republished with permission from: L.E.K. Consulting. “Marketed Therapeutics Reliant on a CDx Generated
~$25B in Therapeutic Revenues in 2015,” PowerPoint presentation, updated January 27, 2016.24 The Opportunity
FIGURE 7: THE BIOPHARMACEUTICAL INDUSTRY
IS COMMITTED TO PERSONALIZED MEDICINE
Drug development pipelines are full of targeted treatments that offer
new hope for patients.
42% 73%
of all drugs in of oncology drugs
development are in development are
personalized medicines personalized medicines
Personalized Medicines
• 2% of all compounds and 73% of oncology compounds in the pipeline have
4
the potential to be personalized medicines
• Biopharmaceutical companies nearly doubled their R&D investment in
personalized medicines over the past five years, and expect to increase their
investment by an additional 33 percent in the next five years
• iopharmaceutical researchers also predict a 69% increase in the number of
B
personalized medicines in development over the next five years
Tufts Center for the Study of Drug Development. Personalized medicine gains traction but still
faces multiple challenges. Impact Report. 2015;17(3).The Personalized Medicine Report 25
CRISPR/Cas9 Gene Editing The potential of germ-line genetic modifica-
tion, however, has raised ethical concerns about
A new tool called CRISPR/Cas9 gene editing is
the appropriate use of the technology. These
also generating excitement in personalized medi-
concerns are sure to lead to ethical debates going
cine. The discovery of CRISPR (clustered regularly
forward. Nonetheless, CRISPR/Cas9’s application
interspaced short palindromic repeats) and
to treatment of diseases targeting somatic cells in
CRISPR-associated (Cas) genes has allowed for
adult patients will likely have a significant impact
the development of efficient and reliable ways to
on medical technology, as will many of the other
make precise changes to the genomes of living cells.
trends described here.
Gene editing using the CRISPR/Cas9 technology
may allow for the correction of disease-causing
mutations in humans.53 The potential application of
this technology for personalized treatment strate-
gies spans a wide spectrum of health conditions,
from congenital blindness to cancer.
“[B]etween 2012 and 2016 we have invented technologies
that allow us to change human genomes intentionally and
permanently … We can now ‘read’ human genomes, and we
can ‘write’ human genomes in a manner inconceivable just
three or four years ago.”
—S
iddhartha Mukherjee, M.D., D.Phil.
author, The Gene: An Intimate History26 The Opportunity
FIGURE 8: THE RAPIDLY DECREASING COST OF
SEQUENCING HUMAN GENOMES
This graph shows the average cost of sequencing a genome for sequencing
technology projects funded by the National Human Genome Research Institute
over time. The data capture the dramatic decline in sequencing costs through
2015, and the cost has continued to drop.
$100M
$10M
Moore’s Law
COST PER GENOME
$1M
$100K
$10K
$1K
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
National Human Genome Research Institute. The Cost of Sequencing a Human Genome. Accessed
September 13, 2016 at http://www.genome.gov/sequencingcosts.The Personalized Medicine Report 27 THE CHALLENGES
28 The Challenges
“We are pleased to see substantial
progress and look forward to continuing
our efforts to advance biomarkers, which
will help bring additional, important new
therapies to patients in need.”
— Janet Woodcock, M.D.
Director, Center for Drug Evaluation and Research, FDAThe Personalized Medicine Report 29
REGULATORY
POLICY
Scientific progress is driving an increase in the The landscape for regulation of personalized
number of personalized medicine products and medicine, however, is still emerging, and the lack
services subject to regulatory review. In fact, of a clear regulatory pathway for personalized
nearly one of every four drugs FDA approved medicine diagnostics continues to discourage
from 2014 – 2016 was a personalized medicine, investment in the field. Among the topics under
and personalized medicines accounted for 27 continued discussion are FDA’s proposed over-
percent of new drug approvals in 2016. Those sight policies related to laboratory-developed
numbers are a sharp increase from 2005, when tests (LDTs) and next-generation sequencing
personalized medicines accounted for just 5 technologies. In contrast, the agency’s well-
percent of new drug approvals (Figure 9). The developed position on the codevelopment of
agency has responded to the growing demand for personalized medicine products has removed an
regulatory clarity by issuing draft guidance docu- obstacle to the field’s progress.
ments (Figure 10). The 21st Century Cures Act,
which Congress passed in 2016, encourages the Regulatory Oversight of LDTs
agency to modernize its paradigm for considering
The emergence of personalized medicine tests
“real-world evidence,” the patient experience,
that inform clinical decision-making and guide
and molecular pathways as they relate to clinical
drug selection and dosage has led FDA to
trial designs. The year 2017 will also mark the fifth
re-examine its approach to regulating diagnostics.
reauthorization of the Prescription Drug User Fee
Traditionally, diagnostic tests have fallen into two
Act (PDUFA), which includes several provisions
main categories: diagnostic kits and LDTs. The
that will offer clarity in areas such as biomarker
former are products containing all the reagents
qualification, patient-focused drug development,
and materials needed to run the test, and are
and the use of innovative clinical trial designs.30 The Challenges
FIGURE 9: PERSONALIZED MEDICINE AT FDA: THEN AND NOW
Personalized medicines accounted for just 5 percent of the new molecular entities
FDA approved in 2005. In 2016, they accounted for more than 25 percent.
2005 2016
5% 27%
of the new molecular of the new molecular
entities approved by FDA entities approved by FDA
were personalized were personalizedThe Personalized Medicine Report 31
regulated by FDA as medical devices. Only a small surrounding the future of the regulatory landscape
portion of personalized medicine diagnostics falls for LDTs continues to discourage investment in
under this category; most are LDTs, only a handful innovative molecular diagnostics.
of which are FDA-approved.
The clinical laboratories that perform LDTs are Regulatory Oversight of NGS-Based
subject to the Clinical Laboratory Improvement
Diagnostic Tests
Amendment (CLIA) rules administered and
implemented by the Centers for Medicare and FDA is also working to understand how to regulate
Medicaid Services (CMS).54 Clinical laboratories diagnostics that incorporate next-generation
can obtain CLIA certification directly from CMS, sequencing (NGS) technology, which yield insights
typically through state agencies that survey labs from entire sets of genes. While current regula-
for compliance with CLIA requirements. A lab tory concepts are applicable for the regulation of
can also seek accreditation by one of the inde- conventional diagnostics that measure a limited
pendent accreditation organizations approved number of endpoints associated with a disease
by CMS, which include the College of American or condition, diagnostic tests that use NGS
Pathologists (CAP), among others. Although FDA technology can examine millions of DNA variants
has historically claimed jurisdiction to regulate at a time, and therefore require a more flexible
LDTs, the agency has also historically refrained oversight approach.
from actively regulating these tests, under a policy FDA is developing a new approach to regulat-
it describes as “enforcement discretion.” ing NGS tests that the agency says will allow
In July of 2014, however, FDA outlined a draft timely access to tools that have adequate analyti-
framework for the agency’s oversight of LDTs. cal and clinical performance. Through 2016, only
Following publication, many organizations one NGS instrument (Illumina MiSeqDx™) and
concluded that a legislative solution would be two accompanying assays for the diagnosis of
required to adequately address concerns raised by cystic fibrosis (Illumina MiSeqDx,™ Cystic Fibrosis
the different sectors of the laboratory community. 139 Variant and Clinical Sequencing Assays) have
FDA’s efforts to finalize its own guidance docu- been FDA-approved. Because it was impractical
ment culminated only in a non-binding discussion to detect every possible variant that might exist in
paper published in January 2017. The uncertainty a genomic sequence, analytical test performance32 The Challenges
FIGURE 10: POLICY AND GUIDANCE DOCUMENTS FROM THE U.S. FDA
2005 Pharmacogenomic Data Submissions (final guidance)
2007 Pharmacogenomic Tests and Genetic Tests for Heritable Markers (final guidance)
2007 In Vitro Diagnostic Multivariate Index Assays (draft guidance)
2008 E15 Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics,
Genomic Data, and Sample Coding Categories (final guidance)
2011 E16 Guidance on Biomarkers Related to Drug or Biotechnology Product Development:
Context, Structure, and Format of Qualifications Submissions (final guidance)
2012 Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and
Biological Products (draft guidance)
2013 Clinical Pharmacogenomics: Premarket Evaluation in Early-Phase Clinical Studies
and Recommendations for Labeling (final guidance)
2013 Clinical Pharmacogenomics: Premarket Evaluation in Early-Phase Clinical Studies
and Recommendations for Labeling (final guidance)
2014 Qualification Process for Drug Development Tools (final guidance)
2014 In Vitro Companion Diagnostic Devices (final guidance)
2014 Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs)
(draft guidance)
2014 FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs)
(draft guidance)
2016 Use of Standards in FDA Regulatory Oversight of Next Generation Sequencing
(NGS)-Based In Vitro Diagnostics (IVDs) Used for Diagnosing Germline Diseases
(draft guidance)
2016 Use of Public Human Genetic Variant Databases to Support Clinical Validity for
Next Generation Sequencing (NGS)-Based In Vitro Diagnostics (draft guidance)
2016 Principles for Codevelopment of an In Vitro Companion Diagnostic Device with a
Therapeutic Product (draft guidance)
2017 Discussion Paper on Laboratory Developed Tests (LDTs) (discussion paper)
U.S. Food and Drug Administration. Search for FDA Guidance Documents. Accessed January 31, 2017 at
http://www.fda.gov/RegulatoryInformation/Guidances/default.htm.The Personalized Medicine Report 33
for the MiSeqDx™ system was demonstrated (Herceptin®) was approved six months apart from
for a representative number of subsets of types the diagnostic test (HercepTest™) in 1998. In 2014,
of variants in multiple sequencing contexts. The FDA released its final In Vitro Companion Diagnostic
agency is considering extending this subset-based Devices Guidance, which helped clarify its method
approach for other NGS platforms alongside other for conducting simultaneous reviews of a drug and
approaches for the establishment of analytic valid- its companion diagnostic.56 The guidance describes
ity and clinical significance. conditions under which a targeted drug might
In 2014, FDA issued a discussion document be approved ahead of a corresponding diagnostic
seeking public input on these novel regulatory test. While these guidelines were in develop-
approaches, and in 2016 the agency released two ment, FDA, Health Canada, and the European
draft guidance documents describing potential Medicines Agency had, in several cases, either
processes for analytic standards development and mandated or recommended that biomarker testing
FDA-recognized public genome database develop- be performed prior to prescribing certain drugs.
ment. Although the landscape remains ambiguous, Recognizing that the class of companion thera-
many members of the personalized medicine peutics/diagnostics is likely to grow, FDA has also
community now believe the processes outlined in begun publishing a table of genomic biomarkers
the documents reflect FDA’s willingness to adapt that it considers valid in guiding the clinical use of
to the changing landscape of medicine. approved drugs.57
In mid-2016, FDA published an additional
Codevelopment draft guidance document on codevelopment
called Principles for Codevelopment of an In Vitro
According to FDA, “a companion diagnostic is
Companion Diagnostic Device with a Therapeutic
an in vitro diagnostic or an imaging tool that
Product. The document explains how therapeutic
provides information that is essential for the safe
and diagnostic partners should engage with the
and effective use of a corresponding therapeutic
agency when codeveloping products, removing
product.”55 The need for a clear regulatory path for
one regulatory hurdle to the parallel regulation
companion diagnostics has been a great concern
of targeted therapeutics and their companion
for personalized medicine since the first thera-
diagnostic tests.
peutic product with an accompanying diagnostic34 The Challenges
“[The top challenges facing personalized
medicine are] reimbursement,
reimbursement, and reimbursement.”
— Alexis Borisy
Partner, Third Rock VenturesThe Personalized Medicine Report 35
COVERAGE AND
PAYMENT POLICY
Regulatory approval of personalized medicine cuts. In addition to limiting patient access, these
products and services is critically important for decisions may inadvertently discourage continued
advancing the field. However, it is only part of the research and development in personalized
story. Coverage and payment policies — both in medicine. Bringing personalized medicine to
the public and private sectors — play an equally patients will depend on policymakers appreciating
important role in ensuring patient access and the value of this new paradigm as they consider
encouraging continued innovation. health technology and value assessment frame-
Health care policy leaders have contended works, procedural changes to the reimbursement
that in order “to stimulate the development of a landscape, and value-based payment models.
more robust diagnostics pipeline and to harness
the benefits of personalized medicine in patient- Evidence Requirements
centered care delivery, policymakers must create
As discussed, personalized medicine offers many
an environment that encourages increased
benefits to patients, including an improved
investment in diagnostics, enables new advances
capacity to prevent disease, more effective treat-
in patient care that are safe, accurate and reliable,
ments, improved side-effect profiles, and reduced
and establishes a viable pathway toward patient
use of invasive testing procedures. By ensuring
access.”58 However, under pressure to address
that only patients who will benefit from a partic-
rising health care costs, policymakers and payers
ular intervention receive it, personalized medicine
are increasingly considering policies that may
can also make the health care system more
result in across-the-board coverage and payment36 The Challenges
efficient. In assessing the value of personalized decision support tools, have the potential to
medicine products and services, however, payers encourage the use of personalized medicine if they
look for convincing evidence of their clinical and incorporate explicit mechanisms for capturing
economic impact.59 There is significant ambiguity the value of the field. Many of the frameworks,
regarding how that evidence should be developed however, have been criticized for failing to account
and disseminated. Widespread insurance coverage for the heterogeneity of treatment effects. For
of diagnostic tests, for example, will likely require example, in 2016, the Institute for Clinical and
practice-based evidence demonstrating value. Economic Review (ICER), a nonprofit organization
Obtaining the real-world data necessary for gener- that uses available evidence to examine the value
ating this evidence, however, is difficult unless the of therapeutics based on a conceptual framework
products and services in question are covered by that combines its estimation of the clinical and
insurance policies. These realities have led to a economic value of a particular drug with several
challenging conundrum in demonstrating the value other factors, issued a value assessment deter-
proposition for personalized medicine. A solution is mination on drugs for multiple myeloma that was
not yet apparent. largely based on population averages.60 Patient
groups responded negatively to the report, noting
Value Assessment Frameworks a lack of consideration of the clinical benefit
of a drug to certain patients. As the Multiple
Over the past several years, “value assessment
Myeloma Research Foundation pointed out in its
frameworks” have emerged as tools for supporting
letter to ICER, “the promise of precision medicine
health care decision-making by quantifying the
is that each patient is unique and will consequently
value of treatments, and these frameworks have
respond to treatment differently based on
begun to influence coverage and payment deci-
their particular genetic profile and further under-
sions. The frameworks, like other evidence-based
standing of the biology of their disease.”61The Personalized Medicine Report 37
The Changing Reimbursement Landscape Medicare Clinical Diagnostic Laboratory Tests
for Diagnostics Payment System,” which was part of the Protecting
Access to Medicare Act (PAMA), implemented
Significant challenges also exist in establishing
re-pricing and reporting requirements62 that
payment rates for diagnostic tests that appro-
further exacerbated the downward pressure on
priately reflect the value they bring to care. Until
utilization of these technologies. The rule lacks
recently, payments for diagnostic and molecular
mechanisms that capture the value of targeted
tests, the backbone of personalized medicine,
treatment, and may therefore threaten progress.
were predictable and standardized, relying on
payments based on “stacked codes.” However,
recently, a number of coding and payment Value-Based Payment Models
policy changes have led to significant changes CMS and private payers are also proposing new,
in reimbursement for molecular diagnostic tests. “value-based” payment models, also known
CMS’ decision, for example, to use “gapfill” as “alternative payment models” (APMs), that
methodology, which allows regional contractors seek to drive improvements in care quality and
to set prices for laboratory and molecular efficiency. Understanding the changes and
diagnostic tests, coupled with other payment potential consequences these APMs will have on
decisions, has resulted in decreased payment personalized medicine tests, pharmaceuticals,
rates for many personalized medicine tests. This, and companion diagnostics is essential to ensure
in turn, has placed a consistent downward pres- continued progress in personalized medicine
sure on physicians and laboratories interested in and improvements to patient care. APMs should
using novel, high-value molecular diagnostics encourage physicians to tailor care based on an
to inform treatment decisions. individual’s genetics and other factors.
The 2016 Clinical Laboratory Fee Schedule
(CLFS) final rule entitled “Medicare Program:38 The Challenges
“I always tell my patients that genetic
knowledge is power. It is not about
good news or bad news, it is about
understanding the underlying cause of
disease and using it to tailor a road map
of prevention.”
— Charis Eng, M.D., Ph.D.
Founding Chair, Genomic Medicine Institute,
Cleveland ClinicThe Personalized Medicine Report 39
CLINICAL ADOPTION
Despite rapid scientific and technological genomic-based research to health care.67, 68, 69
advancement, the health care system has been The Personalized Medicine Coalition (PMC)
relatively slow to integrate personalized medicine also assembled a Health Care Working Group to
into clinical practice.63 Survey data shows, for develop a road map for integration of personalized
example, that only four out of 10 consumers medicine into health care,70 and the Interna-
are aware of personalized medicine, and only 11 tional Consortium on Personalized Medicine (IC
percent of patients say their doctor has discussed PerMed) has identified an index of barriers for
or recommended personalized medicine treat- clinical adoption.71
ment options to them.64 Recent surveys have also Integrating personalized medicine into health
shown that most health care organizations do care requires: increasing awareness and under-
not have formalized plans to leverage advances standing of personalized medicine concepts
in genomics and data analytics to personalize amongst the public and health care workforce;
patient care, and are unprepared to implement placing a greater emphasis on patient perspec-
personalized medicine programs.65, 66 Behind this tives; recognizing the value of molecular pathways
lag in clinical adoption are novel challenges that in guiding care; building new infrastructure
health care delivery systems are encountering as and information management processes; and
they adapt to the new requirements, practices, reshaping health care delivery to ensure access to
and standards associated with the field. personalized medicine technologies and services.
Recently, a number of efforts to understand To successfully integrate personalized medicine
how to best encourage the efficient clinical into health care, providers will need to implement
adoption of personalized medicine have been a range of programs and processes (Figure 11) in
launched. The National Academy of Medicine, for each of these areas.
example, has issued several reports on translating40 The Challenges
Education and Awareness Pharmacists have also taken a proac-
tive approach to education and awareness.
Perhaps the greatest challenge to integrating
Pharmacogenomics is now a required element
personalized medicine into health care is a lack
of every doctor of pharmacy curriculum in the
of education and awareness among patients and
U.S.,79 graduate programs in pharmacogenomics
throughout the health care delivery community.
and precision medicine are now common,80, 81 and
Freely available educational resources are being
certification programs are available regionally
developed by a number of organizations72, 73, 74, 75, 76
and nationally.82, 83, 84, 85
that are presented in multiple formats based on
the needs of different stakeholders. However, they
must be accurate, trusted, and updated regularly. Patient Empowerment
PMC, which represents all sectors of the health care The involvement of patients in their own treat-
community, continues to work with personalized ment decisions and protection of their molecular
medicine’s stakeholders to develop a content-rich information from being used in ways that would
website that can serve as the most reliable source cause them concern, and, perhaps, long-term
for personalized medicine knowledge.77 repercussions, such as discrimination, job loss, or
Although many community education strategies loss of health insurance coverage, are also critical
are clear, building awareness and knowledge will for the clinical adoption of personalized medicine.
not be easy, especially among physicians and other Many health and research organizations in
health care providers. In recognition of this reality, the public and private sectors are reconsidering
the Genomic Medicine Institute at Cleveland Clinic current policies related to patient privacy and
and others host accredited genetics education consent for the use of molecular information.86, 87
symposia for practicing health care providers. The Programs are being developed that will establish
Mayo Clinic’s Center for Individualized Medicine the necessary partnerships among industry
educates members of the health care team suppliers, providers, and patients and their families
and patients about personalized medicine and to ensure that patient data are presented in ways
its implications in practice through professional that are meaningful to each of these groups while
development courses, conferences, and ongoing ensuring privacy. For example, biopharmaceu-
education that is integrated into practice.78 These tical development and commercial outsourcing
programs, however, reach only a fraction of the services company Quintiles has initiated a Global
available population. Data Protection Program, which has issued globalThe Personalized Medicine Report 41 FIGURE 11: PRINCIPLES FOR INTEGRATING PERSONALIZED MEDICINE INTO HEALTH CARE 1. Health care providers, payers, employers, and policymakers, as well as patients and their families, need to have a better understanding of personalized medicine concepts and technologies. 2. Policies and practices related to patient engagement, privacy, data pro- tections, and other ethical, legal, and societal issues regarding the use of individual molecular information must ensure appropriate consent and be acceptable to patients. 3. Best practices must be established for the collection and dissemination of evidence needed to demonstrate clinical utility of personalized medicine and ensure the recognition of its value to care. 4. Effective health care delivery infrastructure and data management systems should be developed and applied so that individual patient and clinical support information is comprehensive, useful, and user-friendly, and so that it can be used to guide clinical decisions. 5. Best practices for health care delivery approaches, processes, and program operations that ensure access to personalized medicine must be established and implemented.
42 The Challenges
corporate policies for the “protection of personal Payers also need to understand financial
information” and “data confidentiality” related and risk reduction endpoints within the body of
to patient and proprietary information exchange evidence, along with patient survival and disease
between industry and providers.88 progression information. Strategies for addressing
Perhaps most importantly, practitioners are these challenges have begun to emerge. Forums
recognizing that they need to regularly involve between payers and product developers, for
patients in health care decision-making.89 Some example, may facilitate a better understanding of
providers are developing genetic counseling the evidence requirements necessary for positive
service policies to ensure that patients, early in coverage determinations. In 2015, the Molecular
their care, are able to understand their individual Evidence Development Consortium (MED-C) was
molecular information and its implications, so that launched to help bridge the gap between payers,
they can make informed decisions regarding its providers, and industry in demonstrating the value
disclosure and use before problems arise.90, 91, 92 of personalized treatment strategies by providing
These developments are encouraging. a forum to discuss and develop plans to gather
molecular data on individual patients along with
Value Recognition thorough information about their treatments and
clinical outcomes.95
While many stakeholders believe that personalized
medicine provides benefits to patients and the
health care system, payers and providers are still Infrastructure and
often reluctant to change policies and practices Information Management
without having convincing evidence of its clinical Effectively managing the massive amount of
and economic value.93 To help build the evidence information associated with personalized medicine
base for personalized medicine, regional Medicare and coordinating programmatic processes and
contractor Palmetto GBA initiated the MolDx services related to its use are also major areas of
Program in 2011 to establish unique identifiers need. Health care providers emphasize the need
for molecular diagnostic tests to help facilitate for data management processes that are straight-
claims processing and track utilization, as well forward, user-friendly, and save time for the health
as to establish clinical utility expectations and to care workforce. Institutional personalized medicine
complete technical assessments of published test program policies and processes also need to be
data to determine clinical utility and coverage.94 coordinated across research and clinical programs.You can also read
