May 2017

Upholding the Clinical

Promise of Precision Medicine
Current Position and Outlook
Table of contents
Introduction 3

A systems approach to medicine 4

Systems therapeutics 4

Benefits of precision medicine 6

Characteristics of stratified and personalized medicines 7

Trends in the use of stratified medicines 12

Health system spending on stratified medicines 15

Novel therapies 20

Optimal use of systems therapeutics 22

Elements of an effective system for delivering full value from systems therapeutics 22

Use of big data and real world insights 26

Stakeholder roles 28

Challenges to improve the value of systems therapeutics for patients 31

Disparities in patient value 31

Variability of health outcomes 39

Recommendations for future applications of systems therapeutics 40

Multi-panel testing and increased use of next generation sequencing techniques 40

Sharing of healthcare data 41

Helping physicians make simpler decisions 41

Protecting patient privacy and data security 41

Evidence generation through increased collaboration 42

Notes on sources 43

References 44

Footnotes 50

Methodology 53

About the authors 58

About the Institute 59

2
Introduction
Recent advances in genomics, imaging and biomarkers are translating into the
development and use of systems therapeutics — medicines which target specific
pathways to modify the course of disease, and are intended for personalized or
stratified use in specific patient populations. Precision medicines are a subset within
systems therapeutics and have seen a period of rapid growth and acceptance
within healthcare systems, bringing the benefit of more effective treatments to
patients along with reduced adverse effects. This paradigm shift in medicine
will have resounding impacts on patients, while also transforming all aspects of
healthcare systems.

Challenges remain for health systems to maximize The study was produced independently by the IQVIA
positive health outcomes for patients from systems Institute for Human Data Science Institute as a public
therapeutics. Healthcare systems need to adapt to service, without industry or government funding. The
move efficiently from scientific breakthroughs to contributions to this report of Winfred Shaw, Terri
optimal patient care. As such, there is a growing Wallace, Amir Forouzan, Laura Mitrofan and others at
need to understand the requirements for systems IQVIA are gratefully acknowledged.
therapeutics to successfully reach patients and be
Find Out More
used to greatest effect.
If you wish to receive future reports from the IQVIA
This report introduces a framework for understanding Institute for Human Data Science or join our mailing list,
the unique challenges associated with systems visit iqviainstitute.org.
therapeutics including cost, clinical decision making,
MURRAY AITKEN
patient privacy, and the sometimes competing roles
Executive Director
of multiple stakeholders. In addition, case studies of
IQVIA Institute for Human Data Science
systems therapeutics provide insights into the lessons
learned on obtaining the optimal value of these
medicines. Finally, the report offers recommendations
for how systems therapeutics may achieve their full
potential for patient care in the future.

All analyses and conclusions are retained from this report previously published as the QuintilesIMS Institute. All references and citations to QuintilesIMS,
IMS Health or IMS data have also been retained to preserve the integrity of the report and analyses herein.

3
A systems approach
to medicine
• Systems therapeutics are changing the medical
landscape by directly targeting the biological systems
behind disease.
• Precision medicine, a subset of stratified and
personalized therapies within systems therapeutics
add significant value for patients and health systems by
offering improvements in response rate and tolerability.
• Eighty stratified therapies require the use of predictive
biomarkers to identify patient response to therapies
and they make up the bulk of systems therapeutics.
• Spending and volume of stratified medicines in
oncology has increased dramatically over the past five
years with spending on stratified oncology medicines
growing at a CAGR of 9.1% from 2011-2016.
• The clinical trial landscape is increasingly including
the use of predictive biomarkers for patient selection
with 350 studies selecting patients with predictive
biomarkers in 2016.
The introduction of biologic
treatments for multiple sclerosis
and immune-mediated
disorders led for the first time
to development of drugs that
more specifically interfered
with the disease process.
4
SYSTEMS THERAPEUTICS
Systems therapeutics represent a paradigm shift in
drug development. Historically in medicine, drugs
primarily addressed disease symptoms, even if a
molecular mechanism action was well understood.
However, the introduction of biologic treatments for
multiple sclerosis and immune-mediated disorders in
the late 1990’s led for the first time to development of
drugs that more specifically interfered with the disease
process. The increasing application of systems biology
in drug development led to further insights into the
mechanisms of diseases which in turn allowed for the
discovery of additional novel drug targets to interfere
with and slow or halt the process of disease. In addition,
new insights into the mechanisms of disease led to
further differentiation in diagnosis and treatments,
with significant advances in targeting patients with
specific pharmacogenomic profiles for stratification
of drug treatment. At the same time, novel insights
into the mechanisms of inter-individual variation in
pharmacokinetics and pharmacodynamics have led to
personalized drug treatments.
Systems therapeutics are interventions which are:
• Personalized with respect to the selection of
medicines and dosing
• Directly or indirectly impact disease progression
• Complex (incorporating patient status,
comorbidities, etc.)1
An understanding of systems biology has allowed
greater insight into the processes that govern disease
and has helped to usher in the era of precision
medicine, where the right patient gets the right therapy
at the right dose and benefits from the right response.
Systems therapeutics go hand in hand with precision
medicine in that they both include patient stratification
for drug response and personalization of medicines for
individual patients.
Predictive biomarkers are essential components in
identifying those patients who can be stratified in
regards to response and risk. Along with predictive
biomarkers, pharmacodynamic/pharmacokinetic
profiles of individuals are used to understand a
patient’s drug metabolism profile, anticipate drug–
drug interactions, and will be necessary to track
response to treatment. As a result, it will be necessary
to work with rational combinations of drugs and
diagnostics to induce a change in disease processes,
disease progression, and ultimately cure. In an ideal
future, each patient may receive a unique treatment
plan designed for them.
Systems therapeutics can be broken into two
broad categories: stratified and personalized. Both
stratification and personalization are components of
precision medicine (see Exhibit 1, boxed area). Stratified
medicines provide differential treatments tailored
to specific groups of patients with individuals within
the group receiving identical treatment. Stratified
therapies for this report were selected for analysis
based on the following criteria: the medicines came
with a recommendation or requirement on their label
EXHIBIT 1: Systems Therapeutics
Pharmacologic Therapies
Disease Modifying Therapies
Stratified
Precision Medicines
Personalized
Source: IQVIA Institute for Human Data Science, Apr 2017
for testing of a specific gene, protein, or hormone
prior to use in either the United States, Canada, Japan
or Europe. Products where testing of viral genotype
was required prior to use were also included within
the analysis. The 80 unique, stratified therapies in the
analysis span over eight broad therapy areas including
oncology, central nervous system (CNS), antivirals,
genetic disorders, inborn errors of metabolism,
respiratory, immunology and rheumatology.
Personalized medicine takes stratified medicine one
step further as differential treatments tailored to
individual patients based on their specific genome as
well as their status (e.g., pediatric, elderly, gender).
The goal of personalized medicine is to treat the
underlying cause of the disease in the individual
patient (e.g., by altering the genetic code of the
individual), but, in addition, would include the use of
pharmacogenetic screening to aid in predicting clinical
outcomes for diseases with associated comorbidities,
pharmacogenetic screening for drug–drug interactions
in patients receiving multiple drugs, and identification
of a patient’s unique pharmacokinetic profile to aid in
drug selection and optimal dosing.
• All symptomatic and disease modifying treatment
• Disease modifying therapies have an effect that modifies a disease t hrough an
interaction with a specific target in the biological network u nderlying the disease
with the result being to directly or indirectly i mpact disease progression
• Differential treatments that are tailored to specific groups of patients based on
predictive biomarkers
• Individual patients in the patient group receive identical treatment
• Not all stratified medicines are disease-modifying
-- Medicines stratified for dosing or adverse events recommendations d
 o not have
to be disease-modifying therapies
• Differential treatments that are tailored to individual patients based o n specific
genotypes as well as status (e.g., pediatric, elderly) or dose adjustments
• Can include cell-based or gene-based therapies
• Not all personalized medicines are stratified
5
BENEFITS OF PRECISION MEDICINE
Precision medicines – medical treatment that is
personalized to the characteristics of each patient by
stratifying individuals into subpopulations that differ
in their susceptibility to a particular disease or their
response to a specific treatment – have the potential
to provide significant value to patient outcomes. Prior
to the advent of precision medicines, all patients with
a diagnosed disorder would receive similar treatment,
with some individuals experiencing benefit and others
harm and added expense. The availability of precision
medicine now allows for personalized diagnosis
and treatment, with patients selected for treatment
based on individual traits and medicines developed
to specifically target the biological processes behind
diseases. A selection of the benefits of precision
medicines is shown in Exhibit 2.
EXHIBIT 2: Examples of Success in Precision Medicine
• Chronic myeloid leukemia (CML)
patients who have the typical
BCR-ABL1 fusion gene are treated
with a tyrosine kinase inhibitor (TKI)
such as imatinib, dasatinib or nilotinib 
• Prior to the use of these Infectious
therapies, allogenic stem cell
Diseases
transplantation was the only
treatment for long-term control
• In one eight year follow up
study, the estimated overall survival of
all patients randomized to receive
imatinib was 85%
• The overall survival of metastatic
melanoma patients was less than 1 Oncology
year and long-term survivors were
rare prior to the introduction of
BRAF inhibitors
• 57% of metastatic melanomas carry a mutation in the
BRAF gene allowing targeted therapy with BRAF
inhibitor such as vemurafenib or dabrafenib
• Response rates for treatment with BRAF inhibitors in
patients with specific BRAF mutations ranged from
48-59% in Phase II and Phase III clinical trials
Sources: Blood 2009 114:1126; Immunotargets Ther. 2017 Feb 13;6:1-10; Ther Adv Med Oncol. 2016 Jan;8(1):48-56; Lancet. 2015 Mar 21; 385(9973): 1124–1135. For
full references see 5-8
6
Overall, precision medicine can add significant
value for patients and health systems by offering
improvements in response rate and tolerability, dosing
guidelines, potential drug–drug interactions, and
effective management of complex diseases. In addition
to assessing treatment effect, pharmacogenomic
testing can also identify those patients at greater risk
for adverse events.2 Use and adoption of precision
medicine rely on the availability of predictive
biomarkers to identify patients who are susceptible
to a particular drug effect, be it beneficial or harmful.
Response to historical, first-line therapies across a
number of therapeutic areas are currently suboptimal,
and the ability to specifically target pathways in a
disease has the capability to offer improved efficacy to
certain individuals who harbor specific genotypes.i,3,4
• A paradigm shift in the treatment of hepatitis C occurred through the use of
direct acting antivirals (e.g., sofosbuvir, daclatasvir)
• Success rates for the treatment of hepatitis C with DAAs reach more than 90%;
previously, success rates were approximately 50%
• Duchenne muscular dystrophy (DMD) is a rare, fatal
neuromuscular disorder
• 14% of patients with DMD have a confirmed mutation
of the DMD gene that is amenable to exon 51 skipping
• A recently approved therapy, eteplirsen, acts
by restoring the translational reading frame
Rare
of DMD through specific skipping of exon 51
Diseases
• Prior to the approval of eteplirsen, treatments of DMD
was symptomatic
• Cystic fibrosis is caused by mutations of the cystic fibrosis
transmembrane conductance regulator (CFTR) gene
• CTFR modulators (e.g., ivacaftor and ivacaftor/lumacaftor) target
patients with specific mutations, such as G551D mutation or
F508del mutation
• Treatment was previously limited to symptomatic therapies
• Prior to the approval of CTFR modulators, treatments of cystic
fibrosis was symptomatic
The use of pharmacogenomic data to aid in treatment
decisions can also have a beneficial effect for other
healthcare stakeholders. A study (n=110) conducted in
a hospital-based home health agency investigated the
effect of using pharmacogenetic profiling along with
guidance from a clinical decision support tool (CDST) to
aid in treatment decisions for patients receiving more
than three therapies with the goal being to reduce the
risk of dangerous drug–drug interactions. The results
of the study indicate that hospital readmissions and
emergency department visits were decreased by 52%
and 42%, respectively, 60 days post-discharge in the
pharmacogenetic tested group.9 The economic benefits
from the use of precision medicine can therefore be
consequential; the case study above lead to health care
savings of $4,382 per patient over 60 days.9
The use of prognostic and predictive biomarkers to
facilitate disease prevention also has significant potential.
Cancer prevention programs can use pharmacogenetic
screening for early detection. Many neurological disorders
are challenging to treat, and early identification remains
critical for optimal patient care and development of potential
disease modifying treatments. In the future, it may be
possible to identify risk of Alzheimer’s disease with predictive
biomarkers, and at present, biomarkers are increasingly
used in clinical trials for Alzheimer’s disease to support
proof of efficacy. Research is also ongoing for prognostic
10
biomarkers to predict a risk for epilepsy and to improve
multiple sclerosis diagnosis and disease progression. 11,12,13
Predictive biomarkers also provide an opportunity to identify
and stratify asthma patients, and in future, will help to predict
patient response to medication.14,15
CHARACTERISTICS OF STRATIFIED AND
PERSONALIZED MEDICINES
Advances in the study of systems biology have
transformed healthcare by moving the treatment
paradigm away from symptomatic therapies to targeted
disease pathways in specific individuals. In addition,
improvements in speed, access and affordability of
personalized genomic testing since the realization
of the Human Genome Project have allowed for the
development of methods to ensure drug response,
precise dosing, and minimize adverse drug reactions in
individual patients.16
Predictive biomarkers allow the stratification of
patient populations based on their predicted
response to a therapy. For example:
• Diagnostic tests identifying EGFR and ALK mutations
in non-small cell lung cancer, KRAS status in colorectal
cancers, and BRAF mutations in melanoma can help
stratify patient populations into those who will have a
more effective response to treatment.
• 57% of patients with metastatic melanomas carry a
mutation in the BRAF gene allowing targeted therapy
with BRAF inhibitor such as vemurafenib (Zelboraf)
or dabrafenib (Tafinlar); response rates for treatment
with BRAF inhibitors in patients with specific BRAF
mutations ranged from 48–59% in Phase II and Phase
III clinical trials.17,18
Other predictive biomarkers can stratify patients
according to risk. For example:
• The availability of diagnostic tests to identify genetic
variants of the cytochrome P450 (CYP450) enzymes,
enzymes crucial for drug metabolism are significant
tools to identify optimal drug dosing, inform risk of
adverse events, and predict drug–drug interactions.
• Of the over 200 drugs on the FDA’s Pharmacogenomic
Biomarkers in Drug Labeling list, 35% of the
biomarkers listed are for variations of a cytochrome
P450 enzyme, and of those, 61% are for Cytochrome
P450 2D6 (CYP2D6).19 For the purpose of the analysis
for this report, we included those medicines that
required or recommended testing for the variant
on the label; however, labeling for CYP2D6 can be
informative and not require testing.ii,20
7
Characteristics of stratified therapies
As of 2016, over 230 therapies across the United States,
Canada, Europe and Japan include pharmacogenetic
information on their labels and the FDA’s list of
therapies with pharmacogenomic biomarkers in
drug labeling totals over 200 medicines. 19,21
Stratified
medicines included in the analysis in this report came
with a recommendation or requirement on their label
or based on regulatory professional society testing of a
specific gene, protein, or hormone prior to use in either
the United States, Canada, Japan or Europe. Products
where testing of viral genotype was required prior to
use were also included within the analysis and these
included the direct acting hepatitis C therapies (e.g.,
sofosbuvir, daclatasvir).
A total of 80 therapies have been approved
with labeling that requires or recommends
pharmacogenomic testing (see Exhibit 3). Thirty of
the stratified medicines in our analysis received a
pharmacogenomic biomarker that directed patient
stratification post-approval, and 40 have received
regulatory approval since 2011. The increasing
availability of therapies with pharmacogenetic
information enables healthcare stakeholders to take
actions to optimize the healthcare system to better
meet the needs of patients.
Oncology contributed the greatest number of
molecules and represented 58% of the total number of
stratified therapies (see Exhibit 4).
• The increasing use of prognostic and predictive
biomarkers to enable improvements in disease outcome,
effect of treatment, and reduction in risk of toxicity is a
positive shift in the treatment of many cancers.

EXHIBIT 3: Number of Stratified Medicines

80 Total Number of Stratified Medicines Number of Stratified Medicines

by Biomarker Approval Date by Approval Type
70
9

60

50 7

40

5
30

20
2
10

0 0
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6

6
7
0
5
7
9
200
200
200
200
200
200
200
200
200
200
201
201
201
201
201
201
201

201

201

201

201

201

201
197
199
199
199
199

Biomarker Post Approval Biomarker At Approval

Notes: Divalproex sodium and atazanavir were not included in the analysis; these drugs received regulatory approval in 1983 and 2003, respectively, but date of
biomarker approval could not be identified
Sources: https://www.pharmgkb.org/view/drug-labels.do; https://www.accessdata.fda.gov/scripts/cder/daf/;http://www.personalizedmedicinecoalition.org/
Resources/Personalized_Medicine_at_FDA; IQVIA Institute for Human Data Science, Apr 2017

8
EXHIBIT 4: Characteristics of Stratified Medicines

Therapy Area Year of Regulatory Approval Biomarker Function Black Box Status

6%
13% 18%

25%
45%
16%
58% 55%
69%
9%
83%

Oncology Genetic Disorders <1990 Efficacy BBW

CNS Immunology 1990-2005 Dosing, ADR or Both No BBW
Antiviral Rheumatology 2006-2016

100 Review Priority and Orphan Status

50 Priority
Standard

0 Orphan

Notes: ADR = Adverse drug reaction; BBW = black box warning; values may not add up to 100% due to rounding
Sources: https://www.pharmgkb.org/view/drug-labels.do; https://www.accessdata.fda.gov/scripts/cder/daf/; http://www.personalizedmedicinecoalition.org/
Resources/Personalized_Medicine_at_FDA; IQVIA Institute for Human Data Science, Apr 2017

• Targeted cancer therapies, including those therapies
with predictive biomarkers as well as molecules that
interrupt cell processes, such as angiogenesis (blood
vessel growth), represented 82% of all novel oncology
therapies launched from 2010 through 2014.22
Sixteen percent of the stratified molecules consist
of antiviral therapies from the HIV and hepatitis C
drug classes.
antiepileptic therapy drug class and biomarker testing
is recommended or required based on the potential
for adverse drug reactions.
Genetic disorders, which include inborn errors of
metabolism (e.g., hyperammonemia, Gaucher disease)
and other genetic disorders (e.g., cystic fibrosis,
Duchenne muscular dystrophy), make up 13% of the
number of stratified therapies.

• Globally, hepatitis C is associated with six main
genotypes, each with different approved therapies
and response rates.
• Direct acting hepatitis C medicines are a success story
for stratified medicines and provide high cure rates
for hepatitis C.
• Patient populations of these therapies tends
to be minimal.
• For example, there are approximately 30,000
cystic fibrosis patients in the United States and
approximately 25,000 patients in Europe, while the
disorder is rare and under-reported in Asia.23,24

CNS therapies made up 9% of stratified medicines. • Even fewer patients have Gaucher Disease; in the United
States there are approximately 6,000 patients.25
• The bulk of these molecules belong to the

9
EXHIBIT 5: Components of Personalized Medicines

Therapies alter genetic information

in specific cells in individual patients
Individual Cell Line
Diagnostic testing can Therapies
ascertain the pharmacokinetic
profile of the patient to
aid in drug selection Dosing and
and dosing PK Effects Comorbidities Use of pharmacogenetic
screening can aid in
predicting clinical
outcomes in patients
with comorbid disease
Polypharmacy
Pharmacogenetic screening can help
identify drug-gene based interactions
in patients taking multiple therapies

Sources: PLoS One. 2017 Feb 2;12(2); IQVIA Institute for Human Data Science, Apr 2017

A singular characteristic of stratified medicines is that The regulatory characteristics of stratified medicines
there are a significant number of older, small molecules show that the majority of the therapies were approved
alongside more recently launched therapies and biologics. as new molecular or biological entities and 73%

• 80% of stratified medicines are small molecules. received priority regulatory review.

• 45% of stratified therapies are accompanied by a

• The greatest number of stratified therapies have been
approved or received biomarker designation post-
approval since 2006, yet 31% of stratified therapies
were approved before 2005 (see Exhibit 4).
Diagnostic testing most often stratifies therapies based on
predictive effect with fewer therapies requiring diagnostic
black box warning.
• More non-orphan drug applications were associated
with a black box warning than orphan drug
applications (see Exhibit 4).
• Stratified therapies tend to treat serious, degenerative

testing to inform dosing and risk of adverse events. diseases (e.g., cancers) where providers and patients
are prepared to accept risks in order to slow or halt
• 83% of stratified medicines predict efficacy; within
disease progression.
this group there were four stratified medicines that
were associated with both efficacy as well as dosing • Patient outcomes will hinge, however, on safety as
and/or adverse reaction (see Exhibit 4). well as efficacy, and patient monitoring and support
during therapy is a key component of realizing the
• 18% of stratified therapies require testing
value of these therapies.
due to the prospect of adverse event or
dosing recommendations.

10
EXHIBIT 6: Stratified Therapies by Volume across the Developed Markets

Number of Number of Total Volume Growth 2006-2016 Growth 2011-2016

molecules molecules (Mn) 2016 %
2006 2016

All Stratified
Therapies 37 80 4,502 100% -7% -3%

CNS 6 7 2,698 60% -23% -12%

Oncology (total) 21 45 1,150 26% 40% 21%

Oncology
(excluding hormonal 14 38 216 5% 94% 32%
therapies)
Immunology/
Rheumatology 3 4 512 11% 37% 14%

Antivirals 4 14 139 3% -18% -10%

Genetic Disorders 3 10 4 0.1% 128% 87%

Sources: IQAVIA, MIDAS, Q4 2016; IQVIA Institute for Human Data Science, Apr 2017
Notes: Developed markets = United States, France, Germany, Italy, Spain, United Kingdom, Japan, Canada, South Korea, Australia; Oncology (excluding
hormonal therapies) does not include the following molecules: anastrozole, buserelin, exemestane, fulvestrant, letrozole, tamoxifen, toremifene; Count
includes Tositumomab iodine-131 and denileukin diftitox but no volume was available in 2016

Components of personalized medicines Gene therapies that treat non-oncology

Currently available personalized medicines are gene
therapies that can alter genetic information in specific
cells in individual patients to treat or prevent disease.
Components of personalized medicine are shown in
Exhibit 5.
Existing personalized gene therapies can be segmented
into oncology and non-oncology products. Examples
within oncology include:
• Talimogene laherparepvec (Imlygic, formerly
OncoVex) a genetically engineered viral therapy for
the local treatment of recurrent melanoma.
• Recombinant adenovirus–p53 (Gendicine), a viral
therapy for patients with a mutated p53 gene for the
indications include:
• Alipogene tiparvovec (Glybera), an adeno-associated
virus (AAV)-based gene therapy for the treatment of
lipoprotein lipase deficiency (LPLD).
• Strimvelis, a stem cell gene therapy for the treatment
of severe combined immunodeficiency due to
adenosine deaminase deficiency (ADA-SCID).
• Neovasculgen, a vascular endothelial growth factor
(VEGF)-based gene therapy for the treatment of
atherosclerotic peripheral arterial disease (PAD),
including critical limb ischemia (CLI).
Though not a gene therapy, sipuleucel-T (Provenge) is a cell

treatment of head and neck squamous cell carcinoma. based immunotherapy for advanced prostate cancer that
modifies a patient’s personal immune cells with genetically
engineered fusion proteins which results in an increased
ability of the immune system to fight prostate cancer.

11
EXHIBIT 7: Oncology Stratified Therapies by Volume 2006–2016, Standard Units Mn

Oncology Units by Region Stratified Oncology Medicines Approved

1,200 10% 2011-2016

60
1,000
8%
50
800
6% 40
600
30
4%
400
20
2%
200 10

0 0% 0
6 7 8 9 0 1 2 3 4 5 6 1 2 3 4 5 6
200 200 200 200 201 201 201 201 201 201 201 201 201 201 201 201 201
ROW EU5 US % Unit Growth

Notes: ROW = Japan, Canada, South Korea, Australia

Sources: IQVIA, MIDAS, Q4 2016; IQVIA Institute for Human Data Science, Apr 2017

TRENDS IN THE USE OF STRATIFIED MEDICINES
Total use of stratified medicines in the developed
markets, measured in standard units, has remained
relatively flat since 2006. This is primarily due to the
higher representation of small molecule therapies
within the group, many of which experienced generic
competition within the study period, balanced against
the launch of novel oncology and antiviral therapies
with low volumes (see Exhibit 6).
• 4.5 billion standard units were used by patients in the
10 major developed markets in 2016, out of 4 trillion
units for global medicines.26
Use of molecules approved within the past five years
has grown through 2016 and has begun to level off
(see Exhibit 6).
• Among the molecules with the highest volume since
their approval in 2011 are therapies from the oncology
and antiviral therapy areas, in particular, hepatitis C
and chronic lymphocytic leukemia (CLL).
Oncology
Use of stratified oncology therapies across the
developed markets has been growing since 2006 with a
year over year growth rate of 4% in 2016 (see Exhibit 7).

• The top 10 oncology therapies make up 94% of the

• Within stratified medicines, older small molecules,
volume of stratified oncology therapies; all are small
particularly those in CNS and breast cancer, account
molecule therapies.
for over 75% of the volume.
• Tamoxifen, anastrozole and letrozole contribute the
• The perception that precision medicines are primarily
greatest share of volume and all are approved for
biologic, disease modifying therapies is balanced by
estrogen receptor (ER) positive breast cancer.iii,iv,27
the reality that there is also significant use of older,
Among the top ten molecules by volume, year over
small molecule medicines.
year growth rate of breast cancer was 4.2% in 2016.

12
• The oral chronic myeloid leukemia (CML) tyrosine • Overall volume of stratified antiviral therapies has
kinase inhibitors imatinib, ibrutinib and nilotinib also declined since 2006, due to the decline of the
contribute a significant amount to the volume of stratified HIV therapies as more patients move on to
stratified oncology therapies, although growth has newer medicines, such as dolutegravir, which is not
declined since 2010. Among the top ten molecules stratified (see Exhibit 8).
by volume, year over year growth rate of leukemia
• In 2016, direct acting hepatitis C therapies accounted
therapies was only 0.5% in 2016.v,28
for 32% of stratified antivirals.
• 48% of stratified oncology medicines received
• Hepatitis C therapies saw significant volume growth
regulatory approval since since 2011, and the CAGR
at time of launch, but uptake has since leveled off and
was 80% in the period from 2012-2016.
will no longer drive significant growth in this therapy
• Non-small cell lung cancer (NSCLC) was the only area in developed countries.
other therapy area represented in the top 10 oncology
molecules by volume due to use of erlotinib.
Antiviral therapies include those
Antivirals
HIV therapies stratified by risk
Antiviral therapies include those HIV therapies stratified
by risk of adverse events and the direct acting hepatitis of adverse events and the direct
C therapies that are stratified by viral genotype. acting hepatitis C therapies that
are stratified by viral genotype.

EXHIBIT 8: Antiviral Stratified Therapies by Volume 2006–2016, Standard Units Mn

Antiviral Units by Region Total Units, HIV and HCV, 2016

180 15.0%

160
10.0%
140
5.0%
120
32%
100 0.0%

80 -5.0%
60
-10.0%
40
68%
-15.0%
20

0 -20.0%
6 7 8 9 0 1 2 3 4 5 6
200 200 200 200 201 201 201 201 201 201 201
ROW EU5 US % HIV Unit Growth HIV HCV

Notes: ROW = Japan, Canada, South Korea, Australia

Sources: IQVIA, MIDAS Dec 2016; IQVIA Institute for Human Data Science, Apr 2017

13
EXHIBIT 9: CNS Stratified Therapies by Volume 2006–2016, Standard Units Mn

CNS Units by Region Total Units, CNS Drug Class 2016

4,000 10%

3,500 8%

6%
3,000
4%
2,500
2%
2,000
0%
1,500
-2%
1,000
-4%
500 -6%

-8% 98%
6 7 8 9 0 1 2 3 4 5 6
200 200 200 200 201 201 201 201 201 201 201

ROW EU5 US Spending Growth AED Other

Notes: ROW = Japan, Canada, South Korea, Australia

Sources: IQVIA, MIDAS Dec 2016; IQVIA Institute for Human Data Science, Apr 2017

CNS • The use of other CNS medications have declined in

Current therapies for CNS are stratified by risk of
adverse events, in particular, for therapies where
cytochrome P450 testing is recommended or required.
As a whole, these molecules are older, genericized and
less tolerable therapies.
large part due to the launch and continued uptake
of more tolerable therapies, that, in turn, do not have
labeling requirements for pharmacogenomic testing.
Though effective, the risk of adverse events and side
effects lead these older, stratified medicines to be

• Total units have been declining since 2006; the year prescribed less often.

over year growth rate for 2016 was -2.3% (see Exhibit 9).

• Antiepileptic drugs (AEDs) make up 98% of stratified

CNS therapies.
Current therapies for CNS are
• Sodium valproate (divalproex semisodium; Depakote)
has the largest volume among the stratified CNS stratified by risk of adverse
therapies. The medicine has been launched globally events. As a whole, these
with multiple formulations and has approvals across
mood disorders, migraine and epilepsy. As such, the
molecules are older, genericized
volume of sodium valproate has remained relatively and less tolerable therapies.
stable since 2006.

14
EXHIBIT 10: Stratified Therapies by Value across the Developed Markets, 2006–2016

70

60

50
Spending US$Bn

40

30

20

10

0
2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

ROW EU5 United States

Notes: ROW = Japan, Canada, South Korea, Australia

Sources: IQVIA, MIDAS Dec 2016; IQVIA Institute for Human Data Science, Apr 2017

HEALTH SYSTEM SPENDING ON • Spending on stratified medicines in the EU5 reached

STRATIFIED MEDICINES $14.4Bn in 2016. EU5 countries experienced significant
Spending on stratified therapies in the 10 developed growth in the past five years, with a CAGR of 11.3%
markets totaled over $62.8Bn in 2016 (see Exhibit 10). over the period of 2011 through 2016. However, growth

• Spending across the developed markets increased at a declined from 2015–2016 by -8.1%. This decline was

CAGR of 20.5% from 2011–2016, driven primarily from due in part to the end of hepatitis C therapy uptake, as

growth outside of the United States and EU5; however, well as policymaker responses to unexpectedly high

growth slowed to 3% in 2016. This change in growth new drug spending in 2014 and 2015.

rate is largely driven by a reversal in hepatitis C-driven • Although overall spending was dwarfed by the United
therapy growth seen during the 2013-2015 period. States and the EU5, sharp growth was seen in the

• In the United States, spending on stratified therapies rest of the developed countries under study (Japan,

was $38.2Bn in 2016. Growth in the United States over Canada, South Korea and Australia) with a combined

the 2011–2016 period was also due to historically high CAGR of 19.3% over the 2011–2016 period.

price increases for branded and generic products

on an invoice price basis, in particular, the high
price points of oncology and hepatitis C medicines.
Spending on a net price basis – reflecting off-invoice
discounts, rebates and other manufacturer price
concessions – is estimated to be $30.5Bn.

15
Oncology and antiviral therapies made up the top five • Spending on biologics has increased from $10Bn in
stratified therapies by spending. 2011 to $14.9Bn in 2016. The greatest growth was

• The top five medicines by spending in the developed seen in small molecules, which accounted for $48Bn

markets included the oncology products imatinib, in spending in 2016.

rituximab, trastuzumab and the hepatitis C therapies • Overall, combined spending for stratified oncology
ledipasvir/sofosbuvir (Harvoni) and sofosbuvir products declined from a high of 77% of the total
(Solvadi) (see Exhibit 11). spending on stratified medicines in 2011 to 47% in

• Spending on breast and blood cancers remained 2016 due to the rapid uptake of hepatitis C medicines.

relatively flat from 2011–2016. Most notable are Antiviral agents accounted for 44% of spending on

the launch and uptake of ledipasvir/sofosbuvir and stratified medicines in 2016.

sofosbuvir, which offer essentially an effective cure for

hepatitis C. By 2016, these two medicines accounted
for 33% of total stratified medicines spending.

EXHIBIT 11: Trends in Stratified Medicine Spending across Developed Markets

Top 5 Product Spending by Disease Area

70
60 8.8
Spending US$Bn

9.2
50 4.5 4.4 Therapy Area, 2011 Therapy Area, 2016
40 9.4 20.6
4.4 23.7
30 10.7
20 8.3 8.5 8.9 3%
3.9 4.0 4.2 5%
10 6% 4%
0
2011 2012 2013 2014 2015 2016 11%
47%
Biologic and Small Molecule Spending
70
60 44%
Spending US$Bn

13.4 14.9
50 77%
40 12.6
30
11.3 47.5 48.0 100% = $24.7Bn 100% = $62.8Bn
20 10.0 10.5
32.5
10 14.8 15.0 16.6
0 Oncology Antiviral Immune/Rheumatology
2011 2012 2013 2014 2015 2016 CNS Genetic Disorders

Leukemias Breast Cancer HCV

All Others Biologics Small Molecules

Sources: IQVIA, MIDAS Dec 2016; IQVIA Institute for Human Data Science, Apr 2017

16
EXHIBIT 12: Oncology Stratified Therapies by Value 2006–2016

30 35%

25 30%

25%
20
Spending US$Bn

20%
15
15%
10
10%

5 5%

0 0%
2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

ROW EU5 US % Spending Growth

Notes: ROW = Japan, Canada, South Korea, Australia

Sources: IQVIA, MIDAS Dec 2016; IQVIA Institute for Human Data Science, Apr 2017

Oncology • Half of the top ten stratified oncology therapies are

Spending on stratified oncology products in the used to treat types of leukemia, four treat breast
developed markets grew at a CAGR of 9.1% from cancer and one treats lung cancer.
2011–2016 with growth rate of 12.7% from 2015 to 2016
• The greatest spending was on the biologic therapies
(see Exhibit 12).
rituximab and trastuzumab; however, small molecule
• Cancer remains among the leading causes of therapies imatinib and palbociclib (Ibrance) also
morbidity and mortality globally with over 14 million contributed significantly to spending.
new cases each year and 8 million resultant deaths
each year, projected to rise by about 70% through
2022 to 22 million.29

• Stratified medicines have had a significant impact on

the treatment of cancer as treatments options and
regimens are being tailored to individual patients by
targeting specific molecular pathways and harnessing
a patient’s immune system.

17
EXHIBIT 13: Antiviral Stratified Therapies by Value 2006–2016

30

25

20
Spending US$Bn

15

10

0
2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

ROW EU5 United States

Notes: ROW = Japan, Canada, South Korea, Australia

Sources: IQVIA, MIDAS Dec 2016; IQVIA Institute for Human Data Science, Apr 2017

Antivirals • In 2016, the spending on the top five antiviral

Spending on stratified HIV and hepatitis C medicines medicines was approximately 90% of the total
totaled $27.6Bn in 2016 with a CAGR of 58% from spending on stratified anti-invectives in the
2011–2016 (see Exhibit 13). developed world, due in large part to price. The cost

• Spending on stratified antiviral therapies spiked of stratified hepatitis C products is on par with some

in 2014 following the launch of stratified hepatitis oncology products.vi,30

C products in the developed markets. Previously,

growth of spending on stratified HIV medicines was
relatively flat.

18
EXHIBIT 14: CNS Stratified Therapies by Value 2006–2016

Spending by Region Spending by Therapeutic Class

3 30% 3

20% 2.5
2.5
10%
Spending US$Bn

Spending US$Bn
2 2
0%
1.5 1.5
-10%
1 1
-20%

0.5 -30%
0.5

0 -40% 0
06 07 08 09 10 11 12 13 14 15 16 06 07 08 09 10 11 12 13 14 15 16
20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20

ROW EU5 US % Spending Growth Antiepileptic Antipsychotic Other

Notes: ROW = Japan, Canada, South Korea, Australia

Sources: IQVIA, MIDAS Dec 2016; IQVIA Institute for Human Data Science, Apr 2017

CNS
Spending on stratified CNS therapies totaled just
Spending on stratified CNS
under $2Bn in 2016 with an 8.6% CAGR since 2011
(see Exhibit 14). therapies totaled just
• Overall, the launch of generic competitors to under $2Bn in 2016 with an
extended release valproate semisodium (divalproex) 8.6% CAGR since 2011.
led to a sharp decline in spending since 2008.

• The antiepileptic drug class accounts for the greatest

spending within CNS while the antipsychotic class has
remained relative static.

• The other CNS class, which includes

dextromethorphan/quinidine (Nuedexta
and tetrabenazine, has driven growth since
dextromethorphan/quinidine’s launch 2011 in
the United States for the treatment of
pseudobulbar affect.

19
EXHIBIT 15: Clinical Development with Biomarkers by Indication and Phase

Clinical Trials including Biomarkers Phase 0-Phase IV

Other Biomarker Trials
Predictive Biomarker Trials
1,200 1,091 40% % Trials with Predictive Biomarkers
1,027 957
1,000
30%
800
600 20%
400
10%
200
0 0%
2014 2015 2016

Clinical Trials Involving Predictive Biomarker Patient Selection, by Therapy Area, 2016 7%
Phase 1 Phase 2 Phase 3 Phase 4

150 134 19%

36%
100 79

50 38
20 15 14 11 10 9 7 6 6
0
gy ease logy CNS y r y y r r y
colo tor une Othe olog tolog scula sorde rolog
is
On us D ocrin
o
es pira y/Imm a lm rma iova ic Di ep h
R rg hth De Card enet
ctio End Alle Op
N 37%
Infe G

Notes: Other includes- Women’s health/sexual health, transplantation, gastrointestinal, orthopedics

Sources: Clarivate Analytics Cortellis, Feb 2017; IQVIA Institute for Human Data Science, Apr 2017

NOVEL THERAPIES Patient selection (or stratification) by a means of a

The late-stage pipeline for novel medicines is robust.
As of November 2016 there were 2,240 total active
therapies in late-stage development and an average
of 40-45 new active substances are forecasted to be
launched per year through 2021. These medicines
26
will address significant unmet needs across therapy
areas which include cancer, autoimmune diseases and
diseases of the CNS. Although the new medicines
will include conventional mechanisms of action, they
will also include novel, precise targeting of biological
processes within complex diseases.
predictive biomarker is the defining criterion for a
precision medicine or systems therapeutics. Predictive
biomarkers are related to therapeutic response in that
they identify patients who are susceptible to a particular
drug effect, be it a response in terms of efficacy or in
terms of adverse events. Other types of biomarkers
include prognostic, diagnostic and pharmacodynamic.
Among clinical trials with start dates in 2016, 350
studies selected patients using predictive biomarkers
out of a total of 957 studies that included biomarkers
(see Exhibit 15).

20
EXHIBIT 16: Emerging Therapies in Clinical Development in Trials Associated with Predictive Biomarkers

Number of Unique Molecules Emerging Therapies by Therapy Area, 2016

164
147 10%
3%
116 4%
4%

6%
55%
7%

11%

2014 2015 2016

Oncology Infectious Diseases Endocrinology CNS
Immunology Respiratory Dermatology Other

Note: Other includes- Women’s health/sexual Health, transplantation, gastrointestinal, orthopedics, ophthalmology, cardiovascular,
nephrology, genetic disorder Sources: Clarivate Analytics Cortellis, Feb 2017; IQVIA Institute for Human Data Science, Apr 2017

• In 2016, 4,726 clinical trials were started. Of these,
49% included some form of clinical biomarker. Of
the total trials that included biomarkers, an analysis
was conducted on those trials with biomarkers that
measured a therapeutic effect or toxic effect in
patients, not healthy volunteers. In total, 957 trials
were analyzed to determine which studies selected
patients using predictive biomarkers.
• The greatest number of trials that include predictive
biomarkers is within oncology, followed by infectious
disease and endocrinology.
Overall, there were 164 unique molecules being
investigated among the clinical trials that used
predictive biomarkers to stratify patient population in
2016 (see Exhibit 16).

• The number of emerging agents has been increasing

• The percentage of biomarker trials that selected
since 2014.
patients using a predictive biomarker has increased
from 18% in 2014 to 37% in 2016. • The greatest number of emerging agents is in
oncology (55%) followed by infectious disease (11%).
• In predictive biomarker trials with a start date in
2016, the greatest percentage was in early stage • Endocrinology and CNS made up 6 and 7% of unique
development, with 36% and 37% of trials belonging to molecules, respectively.
Phase I or Phase II development, respectively.

21
Optimal use of systems
therapeutics
• Systems therapeutics have unique traits that the current
healthcare framework does not adequately address,
such as access to and coverage of diagnostics.
• The use of systems therapeutics will generate large
quantities of data. Data standardizing, sharing and
analysis among stakeholders while protecting patient
privacy and confidentiality would support greater
patient value.
• There are a number of key stakeholders in regards
to the use of systems therapeutics. Key roles for
stakeholders include coordinating a patient’s
care and pharmacovigilance.
ELEMENTS OF AN EFFECTIVE SYSTEM FOR
DELIVERING FULL VALUE FROM SYSTEMS
THERAPEUTICS
The increasing number of stratified and personalized
medicines realized in the past few years is expected to
continue based on the number of quality molecules in
late-stage clinical development (see Exhibit 16). This has
important implications for patients, providers, payers
and pharmaceutical and diagnostic manufacturers alike.
The current healthcare framework will need to adapt to
support the increasing number of systems therapeutics
to help select the best treatment option for a particular
patient. The current healthcare system and how it
supports systems therapeutics is described in Exhibit 17.

EXHIBIT 17: How Healthcare Systems Support Systems Therapeutics

Patients eligible for treatment enter

the healthcare system

A subset of patients are identified via

predictive biomarkers

Multiple stakeholders coordinate to + +

enable patient access to the medicine

Stakeholders establish and implement

appropriate use for individual patients + +

RWE of patient outcomes is fed back

into the healthcare system
Source: IQVIA Institute for Human Data Science, Apr 2017

22
EXHIBIT 18: Systems Therapeutics Present Added Challenges to Health Systems

Predictive Timely Access Intricate and Evolving Big Data

Biomarkers to Therapies Treatment Protocols
• Patient identification • Timely access to • Protocols need to keep • RWE is more complex
via a predictive systems therapies up with scientific and includes large data
biomarker is required after diagnostic testing breakthroughs sets (e.g., genomics,
is necessary proteomics)
• Smaller patient pools • Intricate treatment
• For many cases, there decisions
• Diagnostic
is a greater emphasis
reimbursement can • Individualized
on cost, reimbursement
present challenges protocols are needed
and delivery
for each patient

Source: IQVIA, Apr 2017

Payers, providers and manufacturers alike have an
interest in optimizing the healthcare framework to
realize full value for patients from systems therapeutics.
Unlike “one size fits all” therapies, systems therapeutics
have unique traits that the current healthcare framework
does not adequately support (see Exhibit 18).
Identification of patients
The use of predictive biomarkers is the first critical
step for the identification of patients for a systems
therapeutic medicine and a biomarker is considered
• Use of a companion diagnostic is stipulated in the
label of the associated therapeutic product and is
intended to identify patients who are most likely to
receive benefit or harm from that product.32,33
• Although diagnostic tests can be developed in
parallel with a systems therapeutics medicine they can
also be developed post-approval or re-purposed for
additional indications.
Coverage of diagnostic tests by payers is a bottle

predictive should the effect of treatment show a difference neck in terms of adequate patient value from systems

between those patients screened positive for a biomarker therapeutics since payer coverage of diagnostic tests

compared with those who show a negative screen.31 varies. Without full access to appropriate screening, the
full value of systems therapeutics cannot be realized, as
• A predictive biomarker may be available as a specific
inappropriate patients may receive these therapies or
diagnostic test (e.g., a companion diagnostic) which
eligible patients could be missed. vi,vii,34,35
provides diagnostic information for use with a
specific, corresponding therapeutic product.

• Types of predictive biomarker assays,

including companion diagnostics, consist of
immunohistochemistry assays, next generation
sequencing (NGS) techniques, and molecular
diagnostics, such as PCR or Sanger sequencing.

23
Accuracy of diagnostic testing is important for optimal
use of systems therapeutics because incorrect
interpretation of test results can lead to the wrong
treatment for patients or could expose patients to
greater risk.ix,36
The smaller population size of patients eligible for
systems therapeutics can also lead to missed screening
opportunities, should there be a lack of awareness or
support of the testing among healthcare stakeholders.
Additional hurdles for diagnostics include:
• Insufficient sample size and quality
• Geographic availability for testing
• Timely access to test results
• Appropriate use and interpretation of test results
by physicians
Availability to patients
Optimal use of systems therapeutics will depend
in part on patient access to more complicated
medicines. Importantly, timely access to systems
therapeutics are critical, particularly for oncology
medicines, and there needs to be coordination among
stakeholders to move smoothly from companion
diagnostic testing and interpretation of results to
efficient access to these medicines.
Factors influencing patient access include:
• Physical availability of the therapy in the
location required
• Payer coverage
• Cost
• Reimbursement
Payer coverage and reimbursement is an important
component for access of the initial companion
diagnostic screen and also remains an important
step for patient access to the system therapeutic.
24
Payers are increasingly requiring demonstration of
cost-effectiveness or additional clinical benefit when
approving novel therapies. This underscores the
importance of stakeholders coordinating at each step
for expectations for use by the patient, especially
for therapies that require diagnostic testing and
are associated with greater, up-front cost. Although
payers cover a substantial number of rare diseases and
oncology products, coverage in not universal across all
health care systems.x
The cost of systems therapeutics, particularly for
oncology or rare diseases, can be a significant hurdle for
stakeholders. In particular, orphan drugs, for serious or
life-shortening or life-threatening diseases, can achieve
significant prices per year. For example, Glybera is one of
the most expensive medicines ever launched, with a list
price of €900,000 per treatment. There are a number of
factors that drive orphan drug prices which include:
• Impact on patient lives
• The value proposition of the medicine
• Disease severity
• Competition within the indication
• Prevalence of the indication (with higher drug costs
typically associated with lower prevalence)
Although the high cost of systems therapeutics are
shared across stakeholders, inevitably there is greater
shifting of cost to patients. Branded therapies are
getting more expensive on a list price basis, and
although this can be mitigated by patient assistance
programs or insurance design, when patient costs are
too high, patients may choose to not use the medicine.37
Distribution of systems therapeutics is also an integral
part of systems therapeutics reaching patients.
Wholesale distributors work closely with hospitals and
pharmacies to ensure timely availability after diagnosis
and can help mitigate cost of therapies by allowing

There is a need to simplify
treatment decisions for providers
in order to provide the greatest
value to patients.
hospitals and pharmacies to receive therapies at a
discount to manufacturer list prices and to allow these
facilities to keep a more modest on-hand inventory.
Distribution may also come with additional handling
requirements, more so than typical small molecules, or
involve additional steps, such as compounding prior to
patient use.
Appropriate use by physicians
The complexity of systems therapeutics requires
that protocols for use of systems therapeutics
be consistently updated with the latest scientific
information and tailored to individual patients to ease
treatment decisions for physicians. There is a need to
simplify treatment decisions for providers in order to
provide the greatest value to patients.
The use of stratified oncology medicines is particularly
complex. Predictive biomarkers are essential for
treatment in many oncology areas, and a personalized
protocol for each individual patient is becoming the
norm. This increased complexity can lead to difficult
treatment decisions by physicians who must draw from
clinical experience, disease area guidelines, academic
research and payer prescription guidelines.
• One example of the complexity of treatment
decisions can be taken from advanced melanoma
cancer.xi, 38 A physician with a BRAF positive patient
has a number of options to consider including:
immunotherapy, monotherapy BRAF inhibitor,
combination of BRAF/MEK inhibitor, combination of
BRAF/MEK with another targeted inhibitor (such as
CDK, PI3K, ERK or AKT inhibitors) and/or combining
BRAF inhibitors with an immunotherapy.39,40
In addition, coordinated care between all providers
and the patient has the potential to improve adherence
and compliance to treatment regimens. The full
value of human capital within the healthcare system
must be utilized in order to provide patients with the
coordinated care, education and support needed for
better patient outcomes.
Monitoring use and measuring outcomes
among patients
Adequate systems for pharmacovigilance are required
to ensure patient value and to feed information back into
the healthcare system to support cost-effectiveness and
clinical benefit assessments of systems therapeutics.
Patients should be monitored during and after
treatment to ensure adequate safety and avoidance
of adverse events of systems therapeutics and/or to
ascertain disease progression and clinical outcomes.xii,41
• To reach the full potential for patient value for systems
therapeutics, side effects of the medications must
also be monitored and managed to ensure patient
satisfaction and adherence for optimal effect.
• Even patients receiving oral oncology medicines,
though associated with high rates of adherence, may still
benefit from provider or other stakeholder follow up to
monitor adverse events, side effects and to make sure
medicines are taken as prescribed; many of the current
tools for adverse event reporting and adherence are
patient-reported which can introduce errors.42
• In addition, patients receiving medications outside
the hospital setting may “over-adhere” to their
regimen, continuing to take medications even in the
presence of significant adverse events, thus lowering
the value of the medicine to the patient.42
25
Analyzing patient outcomes helps to provide essential
information on the use of systems therapeutics that
can be used to influence future treatments. However,
the volume of data from patients receiving systems
therapeutics is often larger, and more complex, than
traditional medicines.
• The use of systems therapeutics will generate large
quantities of electronic medical and health records
including health information related to disease
diagnosis, diagnostic testing and results, treatments,
outcomes, provider visits, and, potentially personal
genomic, or even proteomic profiles.
• These large data sets will need to be effectively
protected and shared between stakeholders in order
to provide the feedback necessary to support the use
of these therapies in future patients.
USE OF BIG DATA AND REAL WORLD INSIGHTS
In healthcare, transactional data is now more typically
being collected digitally. More data is being captured
through Electronic Health Records (EHRs) than in the past,
as physicians move away from paper-based systems.
• A study in the United States in 2014 showed that EHRs
were being used by 76% of non-federal hospitals and,
in 2013, over 78% of office based physician practices
recorded health information in real time on patient
health conditions, vital signs, medicine use and
laboratory testing results.43,44
• A study in Japan in 2011 showed that 62.5% of major
hospitals had adopted EHRs and 62% of practitioners
in Canada had adopted EHRs by 2013.45,46
Systems therapeutics are unique in healthcare given the
scale of information accompanying their use. Big data
analytics within large, complex health care databases
can provide crucial knowledge and insights. Analysis
of the big data associated with systems therapeutics
will improve the understanding of how these therapies
26
Real-world data provides
researchers with a robust
pool of information and can
help to reveal when optimal
and suboptimal patient care
has occurred.
are working or not working within the current
healthcare system, and will enable steps to be taken for
stakeholders to best meet the needs of patients.
• For example, next generation sequencing technologies
allow for timely and low cost sequencing of a
patient’s genome although this is accompanied by
a large volume of data (~100 gigabytes); analysis
of this large dataset in conjunction with EHRs can
pin-point diseases or predict drug interactions for
individualized diagnosis and therapy.47
“Real-world data” provides insights into the efficacy
and safety of medical treatments in everyday practice,
and across much larger populations, it can be used
to improve the health system’s ability to save lives by
getting the right care to the right patient at the right time
and identify and address major healthcare gaps (see
Exhibit 19).48 Real-world data provides researchers with
a robust pool of information and can help to reveal when
optimal and suboptimal patient care has occurred.
While clinical studies are generally not large enough to
provide information to tailor treatment to specific patients
or narrow subpopulations, as is the case for patients
receiving systems therapeutics, the analysis of real-
world sources allows for clinical decision support (CDS)
by providing an analysis of smaller populations across
various settings.49 Analysis of real-world data can provide
information within subpopulations to aid in choosing
the right treatments based on diagnosis, comorbidities, • Identifying and assessing sources and causes
current medications, genomic profile, diagnostic test of suboptimal use of medicines – by healthcare
results and any additional completed procedures. professionals and patients.

Big Data’s Role in Healthcare • Predicting disease, drug interactions or adverse

Big data can shape healthcare by: events based on genomic and/or proteomic profile

• Predicting demand and budgetary impact.

• Assessing value in terms of patient outcomes, total
system costs, satisfaction.
• Supporting pharmacists in demonstrating their role
in supporting patient care, including appropriate
use of medicines.
• Identifying responders/non-responders in real world
settings to tailor clinical treatment approaches.
There are a number of challenges to applying big data
analytics to real world data to generate the greatest
value for healthcare (see Exhibit 20). Those particularly
relevant to systems therapeutics include:
• Accessing, analyzing, standardizing, sharing and
storing genomic data in conjunction with EHRs.
• Protecting patient privacy and confidentiality; this can
be accomplished via de-identifying patient data.

EXHIBIT 19: Twelve Main Sources of Real World Patient Data

Clinical Outcome Assessments

Lab/Biomarkers Data
Wearables
Mortality Data
Consumer Data
Social Media Data
Registries

Pharmacy Data

Electronic Medical
and Health Records
Hospital Data

Prospective and Enriched Studies Claims Data

Source: Quintiles and IMS Serving RWI Together: IQVIA Institute for Human Data Science 2016

27
EXHIBIT 20: Approaches to Maximize the Value of Big Data in Healthcare

Increasing the availability and accessibility of high-quality non-identified patient-level data sources
Standardization of data and interoperability to allow meaningful analyses
Dara sharing and infrastructure projects to create larger or richer pools of data for research, i.e., view the health system in its entirety,
or all aspects of a given disease
Continued processing of patient health data into non- identifiable forms for research by health information owners
Ensuring availability of unique and new types of health information to contribute to healthcare understanding

Increasing the use of non-identified patient-level data sources to conduct research

Broaden use of non-identified patient data for research where possible, including at facilities that use patient identifiable information
for other purposes

Universally applying best-practice privacy and security standards

Acceptance of best-practice de-identification frameworks across the industry
Broad adoption of these frameworks by all stakeholders
Adherence to these best-practice frameworks to ensure patient privacy
Greater transparency and accountability by data processors about the frameworks they use and how they handle non-identified data

Strengthening the impact of evidence through increased collaboration

Connect healthcare stakeholders through data to speed consensus and remove barriers to action
Multi-stakeholder alignment (commercial/academic/government/provider) as partners contributing to medical, scientific and
statistical healthcare research

Creative and tangible ways to ensure the output from this data has greater effects downstream on patient treatment

Source: Aitken M, Nass D. Closing the Healthcare Gap: the critical role of non-identified information, IQVIA Institute for Human Data Science, 2015 Oct

STAKEHOLDER ROLES challenges with reimbursement and coordination with

Stakeholders within the healthcare system are those
persons or groups that have an interest in clinical
decision making with different view-points on how
best to generate value within the healthcare system
(see Exhibit 21). Each stakeholder has a unique role
and set of needs for managing and dispensing
systems therapeutics.
Patient
Patients, family, caregivers, advocacy groups and other
support networks seek straightforward, affordable
access to medicines and clinical care. Patients receiving
systems therapeutics may require additional support
to ensure proper use of the medicine, given the
complexity of treatment decisions as well as navigating
multiple clinicians (e.g., a cancer patient may be under
the care of an oncologist, general practitioner, pain
specialist). Patients may also need support from other
stakeholders regarding tolerability concerns, side
effects, and the potential for drug–drug interactions.
Payer
Payers, which include both commercial and public
insurers, play a substantial role in how the patient and
other stakeholders (e.g., clinicians) make decisions
about diagnostic testing and treatment choices. As
the bulk of systems therapeutics are costly oncology
medications, payers increasingly require evidence
of cost effectiveness and clinical benefits to ensure
placement on formulary and have an interest in ensuring

28
EXHIBIT 21: Key Healthcare Stakeholders Providing Clinical Care Decisions for Systems Therapeutics
Pharmacist
Regulator
Hospital
Source: IQVIA, Apr 2017
that treatment guidelines are followed. Payers’ role in
systems therapeutics also extends to the diagnostic
testing associated with these medicines. Payers also
seek to obtain the best prices for medicines and
diagnostics in their negotiations with manufacturers.
Clinician
Clinicians, which in the context of systems therapeutics
includes not only doctors, nurses but other health
professionals, such as pathologists or radiologists
who interpret diagnostic test results, are at the center
of clinical decision making on behalf of the patient.
Clinicians are involved in developing treatment protocols
based on clinical experience and academic research
and guiding treatment decisions to comply with payer
prescription guidelines. Clinicians seek to strike a
balance between satisfying and supporting patients with
the need to optimize the time spent per patient.
Regulator
Regulatory approval bodies and policy makers seek
to ensure that treatment decisions are based on the
best available clinical evidence for efficacy and safety.
Clinicians Therapeutic
& Diagnostic
Manufacturer
Patient
Wholesaler
Payer
Research into comparative efficacy or patient-centered
outcomes can help to guide the decisions of public
health programs, payer coverage, or public programs
that aim to present the most accurate treatment
information for different diseases.50 Regulators also
provide a framework for pharmacovigilance that is
essential in monitoring current patients receiving
systems therapeutics and helping to determine
cost-effectiveness and clinical efficacy of current
medications and diagnostics.
Therapeutic and diagnostic manufacturer
Both therapeutic and diagnostic manufacturers
contribute to clinical decisions by being the entities
most familiar with their medicine or diagnostic. Both
types of manufacturers sustain education and support
for healthcare professionals and patients. Manufacturers
also provide critical information on usage issues and
health outcomes. Manufacturers also set list prices;
medicines which cure a disease or dramatically prolong
life are not necessarily expensive, but increasingly their
cost is coming under scrutiny by other stakeholders.
29
Novel, branded specialty products, (which include
oncologic, rare disease and hepatitis medicines) are on
average 15–20 times more expensive than new, non-
specialty brands.26 Manufactures are responding to
these high list prices by providing off-invoice discounts
and rebates at approximately 30% in the United States
and roughly 17% in Europe and lower in the rest of the
world.26 Manufacturers must coordinate closely with
other healthcare stakeholders, such as payers and
pharmacy benefit managers, in regards to pricing.
Wholesaler
The wholesaler and wholesale distributors play a large
role in the safe and timely physical flow of systems
therapeutics. Wholesalers leverage the capabilities
and infrastructure of a complex supply chain to provide
access to these complex medicines. Wholesalers will
purchase medicines directly from manufacturers and
store them at distribution centers throughout a region;
clinicians than work with wholesalers to order and
receive the medicines they need for their patients.
Wholesale distribution provides value to manufacturers
who do not have to devote financial resources to deliver
medicines directly to providers. Wholesaler distribution
also helps to provide value to pharmacies and hospital
systems by ensuring quality and timely product
availability, so that hospitals and pharmacies do not
Manufacturers set list prices;
medicines which cure a disease
or dramatically prolong life
are not necessarily expensive,
but increasingly their cost
is coming under scrutiny by
other stakeholders.
30
need store large quantities of specialty medicines for
immediate use.
Hospital
Hospitals, which include, community health
centers, community hospitals and their professional
associations, provide a structure around which health
care decisions are made. Hospitals manage the impact
of systems therapeutics on the budget of the institution
and also manage the workloads and cost of hospital
pharmacies and nursing support. Systems therapeutics
are often involved in complex treatment regimens and
may require access to specialists, diagnostic testing
and interpretation, and non-oral delivery methods
(e.g., infusions), all of which are supported within a
hospital system. In addition, coordination and sharing
of EHRs and other data can be organized within hospital
systems, and analysis of this data plays a significant
role around systems therapeutics, which can include a
significant volume of data from diagnostic screening
(i.e., genomic sequencing) as well as monitoring
drug interactions of current treatments and planning
coordinated care within the system.
Pharmacist
Pharmacists, which include both professional
pharmacists who work in local and mail pharmacies,
compounding centers and hospital pharmacies, provide
value to clinical decisions for systems therapeutics
by understanding and managing the patient’s total
drug profile. Pharmacists are also point of care
references for dosing and administration and can warn
of potential side effects. Systems therapeutics may
also be distributed by pharmacists through specialty
pharmacies, which can provide assistance to patients
navigating reimbursement issues or have insight into
manufacturer rebate or patient assistance programs.
Challenges to improve the
value of systems therapeutics
for patients
• Appropriate use and access to diagnostic testing
remain hurdles for systems therapeutics. For example,
results from a U.S. survey show that approximately
13% and 18% of NSCLC patients in did not receive
an EGFR test or ALK biomarker tests, respectively,
despite guideline recommendations.
• Systems therapeutics in the developing world also
face a number of challenges, including the availability
of diagnostic testing and access, particularly those
medicines associated with higher costs.
• Availability of systems therapeutics to patients is
varied across the world. 43% of countries included
in the analysis did not have access to a systems
therapeutics treating genetic disorders, which include
disease areas such as cystic fibrosis and Duchenne
muscular dystrophy.
• Cost can influence patient access to systems
therapeutics. Results from a U.S. survey covering
ten systems therapeutics indicate that 17–23% of
oncologists were not aware of their patients’ insurance
coverage when prescribing the therapy, which can
lead to a greater burden on patients to navigate
insurance coverage and payments and potentially
restrict access.
• Hurdles around pharmacovigilance in the developing
world put the value of systems therapeutics at risk. Taken
as a whole, these drugs are associated with a higher risk
of black box warnings and adverse events, which could
lead to lower patient value if not properly monitored.
There has been significant progress made around
development and use of systems therapeutics, with
multiple stakeholders within healthcare systems actively
supporting and promoting their use. However, there are
still a number of challenges faced by health systems to
deliver the full value of systems therapeutics to patients.
The framework within the healthcare system set up to
deliver systems therapeutics to patients includes patient
identification, pharmacotherapy availability, appropriate
use, and monitoring use and measuring outcomes. At
this time, the full value of use of systems therapeutics
has not been fully realized by patients. Exhibit 22
illustrates the case studies presented in each section.
DISPARITIES IN PATIENT VALUE
Patient identification with predictive biomarkers
The role of stratifying patients with predictive
biomarkers is fundamental for the use of systems
therapeutics but significant gaps remain around their
use. In developing countries, access to predictive
diagnostic testing may be impossible, given limited
resources and lack of infrastructure needed to support
testing and results interpretation.51 Even in developed
countries, the limited availability of genomic sequencing
centers provides a ceiling to the amount of genomic
testing that can be easily and quickly carried out.xiii
Demonstrating value to payers sufficiently to result in
their coverage of diagnostic testing and to physicians
to result in routine screening of patients remains an
obstacle to patient access. Healthcare stakeholders
need to address the issue of patients not receiving the
recommended diagnostic tests.
In oncology, although the uptake of diagnostic testing
with predictive biomarkers has increased over the past
five years, there appear to be disease-specific barriers
to receiving diagnostic testing (see Exhibit 23).
• Survey results are from a pool of approximately 425
oncologists and show the highest rates of non-
testing in PD-L1 and KRAS testing for lung cancer,
at 55 and 52%, respectively. However, PD-L1 has not
yet been incorporated into guidelines and KRAS
testing recommendations are mixed without also
testing of EGFR. 52
31
EXHIBIT 22: Case Studies Demonstrating the Challenges to Provide Full Value of Systems Therapeutics

CASE STUDIES

Identification of Patients Patient identification with predictive biomarkers

Next generation sequencing availability

Availability to Patients Global availability of systems therapeutics

Variability in access and health outcomes

Payer coverage of branded systems therapeutics

Appropriate Use by Physicians Use of pharmacogenomic testing recommendations: oncology

Use of pharmacogenomic testing recommendations: CNS

Monitoring Use and Measuring Challenges in pharmacovigilance: HIV

Outcomes Among Patients Challenges in pharmacovigilance: hepatitis

EXHIBIT 23: Patients Who Did Not Receive Diagnostic Testing by Oncology Area and Type, 2016

PD-L1
KRAS
FISH
ROS-1
NRAS
ALK
EGFR
IHC
KRAS
17p
BRAF
ER
PR
0% 10% 20% 30% 40% 50% 60%

Lung Breast Colorectal Melanoma CLL

Notes: Number of patients covered in the survey: Lung = 19,793; Breast = 12,534; Melanoma = 2,885; Colorectal = 11,224; CLL = 8,056
Source: IQVIA BrandImpact, 2016; IQVIA Institute for Human Data Science, Apr 2017

32
• Guidelines recommend diagnostic testing of NSCLC
patients with predictive biomarkers, in particular,
EGFR and ALK. 53
However, survey results show
that approximately 13% and 18% of patients in the
survey did not receive an EGFR biomarker test or
ALK test, respectively.
• Of interest is that while the rate of testing patients for
KRAS, EGFR and ALK have increased since 2014, the
rate of positive tests has not increased substantially,
indicating that oncologists may be overtesting in
certain patient groups.
• Survey results show that for melanoma, where systems
therapeutics are the gold standard treatment for
patients with BRAF mutations, only 1.4% of patients
do not receive BRAF testing.
• Overall, breast cancer had the lowest rate of non-
testing, with the exception of the FISH test for
determining HER2 status of the tumor. Although
FISH test is more accurate than IHC, it is less widely
available for routine screening.
Next Generation Sequencing Global Availability
Next generation sequencing (NGS) enables the
sequencing of a human genome, or specific areas of
interest, quickly and accurately, compared to historical
sequencing that takes significantly longer and can only
analyze smaller segments of DNA. One reason that
NGS has not been incorporated into routine clinical
care is restrictions around access. NGS often takes
place at larger institutions with significant infrastructure
investments; smaller health centers have to send out
samples for sequencing and analysis. In the developing
world this becomes more problematic as access to
NGS facilities are limited. The table below illustrates a
sample of countries by regions with access to genomic
sequencing centers mapped against GDP/capita. Many
developing countries, such as India and Brazil, have
made significant advances in supporting genomic
sequencing due to greater spending on research and
development, but many other countries, especially
those in Africa, will need increased support in order to
provide services to their populations.

160,000

Nigeria
Population/center (000)

Egypt
Iran China
India
Kenya
8,000
Peru Saudi Arabia
Kazakhstan Colombia
Senegal Russia
Tunisia Brazil
Philippines Malaysia
South Africa
Argentina
South Korea US
Germany
UK
400
0 5,000 10,000 15,000 20,000 25,000 30,000 35,000 40,000 45,000 50,000

GDP/Capita USD

Note: The average number of sequencing centers is an approximate value and includes academic centers. The average number of sequencing centers is based
on an analysis from: Helmy M, Awad M, Mosa KA. Appl Transl Genom. 2016 Mar 10;9:15-9. The number of available high throughput sequencing centers was also
considered as a bottom limit in certain countries and used to estimate the availability in the United States. Country populations were taken from UN estimates.
GDP estimates were based on the World Band Open Data source. A full list of sources is listed in the references.51,54,55,56,57

33
EXHIBIT 24: Global Availability of Systems Therapeutics, 2015–2016

46 Oncology 14 Antiviral 13 Genetic Disorders 7 Central Nervous System 4 Immunology/Rheumatology

Canada
Russia
40 13 0 6 2
32 8 2 3 2

Kazakhstan
United States 19 5 0 1 1 South Korea Japan
44 13 8 7 4 33 6 4 5 3
China 36 9 4 3 3
Taiwan
India 19 2 1 2 2
Mexico 30 9 2 6 3
20 7 0 6 3
31 9 0 5 2 Malaysia Hong Kong
Thailand
27 5 0 3 3 32 9 1 4 3
24 6 0 4 2
Vietnam Philippines
Singapore
Brazil 16 6 0 2 1 24 0 0 4 1
30 8 0 2 3
30 7 0 5 2 Indonesia
15 0 0 4 1
South Africa
20 5 0 4 2 Australia
32 11 2 4 3

Note: Cholic acid and carglumic acid were not included in the U.S. country analysis
Source: IQVIA, MIDAS, 2016; IQVIA Institute for Human Data Science, Apr 2017

Availability of system therapeutics medicines that are found primarily in Europe (e.g.,
Global availability of systems therapeutics Glybera). 43% of countries included in the analysis
did not have access to a systems therapeutic within
The availability of systems therapeutics (stratified and
this category.
personalized medicines) in 2016 across 47 countries is
shown in Exhibit 24 and 25 revealing: • CNS therapies as a group were more readily available
than antiviral and oncology medicines, likely due to
• Developing countries had less access to systems
their generic availability.
therapeutics as a whole than developed countries,
particularly within more costly oncologic and antiviral • Western European countries are more likely to have
groups (which includes hepatitis C therapies). access to systems therapeutics than Eastern European
countries, particularly around the category of inborn
• Significant variability was seen among access to
errors of metabolism, respiratory and genetic disorders.
oncology medicines when considering developed
versus developing countries, likely due to cost of the • Fewer antiviral systems therapeutics are found in the
agents and infrastructure requirements. former Eastern Bloc countries: on average, patients
in the former Eastern Bloc countries have access to
• Inborn errors of metabolism, respiratory and genetic
seven antiviral systems therapeutics compared to an
disorders were included in a single category (genetic
average of 12 in western European countries.
disorders) and represent the most at risk group
of therapies outside of the developed world; this
category also includes the rare disease personalized

34
EXHIBIT 25: Availability of Systems Therapeutics within the EU and Eastern Europe, 2015–2016

46 Oncology 14 Antiviral 13 Genetic Disorders 7 Central Nervous System 4 Immunology/Rheumatology

Finland Netherlands Poland Serbia

35 12 1 3 3 37 10 5 5 3 29 7 1 5 2 22 3 0 2 1
Sweden Belgium Lithuania Croatia
39 12 5 4 3 35 10 4 5 3 25 9 1 3 2 31 4 1 2 3
Norway France Slovakia Bosnia
37 11 6 7 3 41 10 5 6 3 35 7 2 4 3 18 2 0 2 2
Denmark Portugal Hungary Czech Republic
35 12 4 4 3 38 10 4 5 3 32 9 3 4 3 31 6 1 4 3
Germany Spain Romania Slovenia
42 12 8 5 3 33 11 3 5 3 25 6 0 3 1 34 8 2 2 3
UK Switzerland Bulgaria Austria
40 12 6 7 3 34 11 0 3 3 31 6 0 3 1 39 12 5 4 3
Ireland Italy Turkey
32 12 0 6 3 35 10 6 5 3 34 6 0 4 3

Source: IQVIA Institute for Human Data Science, Apr 2017

Variability in access and health outcomes • When the authors considered a lower limit for the
Lack of access to cancer medications is a significant potential number of HER2 positive patients, the
barrier to improved health outcomes. The use and United States was the first country to reach optimal
procurement of trastuzumab provides a strong example level of procurement of trastuzumab for HER2 positive
of how limited access to systems therapeutics can be patients, while only two out of nine Eastern European
associated with negative health outcomes. Trastuzumab countries reached the optimal level of procurement of
is a highly effective and relatively safe therapy indicated trastuzumab by 2013.
for patients with HER2 positive breast cancer and is the
• The authors of the study point out that although rates
gold standard therapy in HER2 positive patients. Results
of cancer survival have improved in Europe since
from one study investigating the number of patients
1999, there is a survival gap between Eastern Europe
in need of treatment with trastuzumab and the level of
and Western Europe in a number of cancers, including
procurement of trastuzumab from 2001–2013 showed
breast cancer, due in part to lack of public funding for
a significant difference in the uptake of trastuzumab
more costly therapies, such as trastuzumab, screening
across the United States and Europe.
programs and delayed diagnosis.58,59
• Most Western European countries and the United
States procured sufficient amounts of trastuzumab
necessary to treat appropriate patients while in
Eastern European countries, there was significant
underuse until the end of the study period.58

35
EXHIBIT 26: Impact of Insurance on Oncologist Choice of Systems Therapeutic
Aware and patient’s insurance coverage
allowed me to prescribe my first choice
Not aware of patient’s insurance coverage
Aware but did not consider
patient’s insurance coverage
Aware and patient’s insurance coverage led me to
prescribe something other than my first choice
0%
CLL Brands
CLL brands included:
Imbruvica, Venclexta
Source: IQVIA BrandImpact, 2016; IQVIA Institute for Human Data Science, Apr 2017
Payer coverage of branded systems therapeutics
Exhibit 26 shows results from a survey conducted in
approximately 400 oncologists in the United States
that demonstrates brand coverage for ten systems
therapeutics in NSCLC and CLL.
• On average, oncologists indicate that in 69–75%
of their patients receiving a systems therapeutics
medicine for NSCLC and CLL, they were aware of their
patients’ insurance coverage and allowed to prescribe
their first choice of therapy.
• However, 17–23% of oncologists were not aware of
their patients’ insurance coverage, which can lead to
a greater burden on patients to navigate insurance
coverage and payments.
Pharmacogenomic testing recommendations are not
always followed: oncology
Appropriate use of systems therapeutics will depend
on continued physician education on newly approved
treatments and emerging mechanisms of action as
well as consistent updates to guidelines and hospital
protocols. Guidelines are at times behind the latest
36
20% 40% 60% 80%
NSCLC Brands
NSCLC Brands included:
Tarceva, Xalkori, Gilotrif, Iressa, Zykadia,
Keytruda, Tagrisso, Alecensa
scientific findings. An example would be the use of
Programmed Death receptor 1 (PD-L1) testing for the
treatment of NSCLC.
• Two systems therapeutics have regulatory approval
that target PD-L1, nivolumab (FDA approval 2015; EMA
approval 2016) and pembrolizumab (FDA approval
2015; EMA approval 2016).
• Guidelines do not fully support PD-L1 testing, despite
the approval of PD-L1 targeting therapies for NSCLC, in
part due to the mixed clinical trial results in this patient
population and a lack of physician consensus.60,61
• Survey results from a pool of 406 oncologists covering
approximately 20,000 NSCLC patients indicate that
only 38% of their patients received a predictive
biomarker test for PD-L1 in 2016 (see Exhibit 23).
• In a separate survey conducted in Q4 2016, when
asked why they did not order PD-L1 biomarker testing
for NSCLC patients, 36% noted that it was because the
testing was not recommended in the guidelines and
24% of physicians noted the lack of consensus on PD-
L1 testing.
EXHIBIT 27: PD-L1Testing for NSLC, 2016

2016 Testing for PD-L1 in NSCLC Top reasons for Not Testing PD-L1 for NSCLC, Percent of Physicians

Lack of reimbursement from payers

12% 12%
Insufficient tissue sample

PD-L1 testing is not available as part

21% of the standard panel of biomarker
tests for this tumor type

Lack of a requirement for PD-L1 testing in

the product prescribing information

55% Lack of consensus on whether or not

PD-1/PD-L1 inhibitors are more efficacious in
patients who over-express PD-L1

PD-L1 testing is not currently

recommended in major clinical guidelines
that I follow (e.g., ASCO, ASH, NCCN)
Positive Negative No Test Other 0% 20% 40%

Notes: Patients = 2,000; other contains results pending, inconclusive, and unknown
Sources: IQVIA BrandImpact, 2016; IQVIA Institute for Human Data Science Apr 2017

Pharmacogenomic testing recommendations are not serious adverse events at the expense of a more
always followed: CNS efficacious outcome.2
Inappropriate use of systems therapeutics can lead to
• Thus there is a gap between patients’ approval
adverse events.
and value for a more tolerable therapy and how
• Carbamazepine is a first-line anticonvulsant agent stakeholders are using these therapies in routine
with global regulatory approval for epilepsy clinical care.
and mood disorders but use of the therapy is
complicated by a risk of serious adverse, immune- Monitoring use and measuring outcomes
mediated, drug reactions. Patient-centered value of care is related to a number
of factors, including the side effect profile and risk of
• Although pharmacogenetic testing is available to
adverse events associated with the use of medicines.
stratify patients into high risk groups, uptake of
Healthcare stakeholders benefit by setting up systems
the test has not been widely adopted in certain
to ensure patientcentered, pharmacovigilance to
European populations. 2
improve adherence and to monitor for adverse events.xiv
• A survey conducted with epilepsy patients and
Pharmacovigilance is a necessary aspect of a healthcare
neurologists sought to determine the preferences of
system to understand and prevent future deaths
patients and neurologist to inform carbamazepine
from ADRs, and in terms of systems therapeutics,
pharmacogenetic testing and results showed that
pharmacovigilance is of even greater importance.xv,62
both patients and neurologists were in favor of the
test; in particular, patients valued a lower risk of

37
Monitoring for ADRs associated with these drugs closely In order to effectively treat HIV/AIDS in developing
is an integral part of providing full patient value for all countries, pharmacovigilance to monitor adverse drug
medicines, particularly systems therapeutics. reactions are critical. Patients who experience ADRs

• When including both personalized and stratified may under-dose medication, or fail to take medication,

systems therapeutics, 41% are associated with black leading to poorer health outcomes. However,

box warnings for serious adverse events and can pharmacovigilance in African countries remains poor

require specialized monitoring by trained clinicians. when compared to pharmacovigilance methods in

developed countries:
• 18% of systems therapeutics are stratified by risk of
• According to a study on pharmacovigilance in Uganda
adverse events.
and South Africa, both countries have the burdens of
limited funding, limited trained staff, and inadequate
Challenges in pharmacovigilance: HIV
training programs with the authors concluding that
A number of systems therapeutics are associated
there was not adequate capacity to monitor medicines
with adverse events in certain patient populations.
according to minimal WHO standards.66
This has real world consequences when applying
the use of these medicines in countries with • Only 7 and 8 staff members, respectively, are
suboptimal infrastructure for diagnostic testing and assigned in South Africa’s National Adverse Drug
disease monitoring. Event Monitoring Centre and Uganda’s National
Pharmacovigilance Center.
In developing countries, the rate of mortality for
communicable infectious diseases is high, and in
Challenges in pharmacovigilance: hepatitis
particular, for HIV/AIDS, 70% of worldwide cases
Globally, approximately two billion people are infected
occur in sub-Saharan Africa.63 ADRs in developing
with hepatitis B. The viral infection is associated with
countries can be exacerbated by higher prevalences
approximately 620,000 related deaths per year. In areas
of malnutrition, tuberculosis, and in the case of HIV
where the infection is highly endemic, the prevalence
patients, anemia. Approved treatments for HIV include
can range from 8–15%, in developing regions such as
the use of antiretroviral therapies, such as abacavir;
Sub-Saharan Africa, the Amazon Basin and Central
individuals with the HLA-B*5701 allele receiving
and Southeast Asia.67,68 The prevalence of hepatitis
abacavir are at a higher risk of hypersensitivity
C is lower; approximately 170–180 million patients
reactions.xvi,64
worldwide are infected with the bulk of infections
occurring in Asia and Africa.67 Co-infection of the
Data on adverse events from HIV therapies in Africa points
viruses is common, particularly in regions where there
to high numbers of ADRs compared to less than 10% of
is a high endemic prevalence of hepatitis B.xvii,69 Many
antiretroviral therapy patients enrolled in randomized trials
patients are unaware they are co-infected, as patients
having treatment-limiting adverse events.62,65
may have an inactive hepatitis infection where the
• 18% of patients from a study conducted in
individual may not experience symptoms and may not
Botswana experienced adverse events that required
know they are carrying the disease.
treatment modification.64
A paradigm shift in the treatment of hepatitis C
• 65% of patients from a study conducted in Kenya
occurred through the use of direct acting antivirals
experienced adverse events.64

38
(DAA; e.g., sofosbuvir, daclatasvir) which essentially
offer a cure for hepatitis C. The therapies are approved
for use worldwide and are stratified according to
viral genotype. However, the use of DAA hepatitis C
therapies is associated with a small but very real risk
of hepatitis B reactivation, enough that the FDA and
the EMA have added warnings that direct health care
professionals to screen and monitor for hepatitis B in all
patients receiving direct acting treatments.xviii,70,71
Assuming a 90% cure rate, 275,000 people living in low-
and middle-income countries have avoided cirrhosis
and liver cancer based on access treatment in 2015.71
Although daclatasvir will soon be available as a generic
option in some countries, stakeholders will assess
value of these more expensive therapies based on
safety as well as efficacy. In developing countries with
limited access to resources for pharmacovigilance and
diagnostic testing, stakeholders may restrict access to
DAA treatments for hepatitis C due to fear of ADRs from
co-infection with hepatitis B, which would lead to fewer
cures and a higher rate of complications and death.
VARIABILITY OF HEALTH OUTCOMES
Management of cancers, viral infections and rare
diseases can lead to significant disparity in the
developing world compared to developed countries.
Sub-optimal patient selection, availability, appropriate
use and monitoring patient outcomes can compound
healthcare disparity around the systems therapeutics
that offer effective treatments in these therapy areas.
Breast cancer is an area with the availability of multiple
systems therapeutics, including the gold standard
treatment, trastuzumab, which has caused a significant
shift in survival rates in developed countries. There is
a high necessity to screen patients who would best
benefit from systems therapeutics, but a lack of access
to diagnostics to aid in selecting the optimal treatment
in developing countries.
Although the incidence of breast cancer is higher in
developed countries, the mortality rate is higher in
developing countries; the WHO estimates that 324,000
deaths from breast cancer occur in developing countries
compared to 198,000 deaths in developed countries.72
Hurdles to treatment include:
• Later presentation (tumors diagnosed at more
advanced stages)
• Lack of access to specialists
• Lack of access to radiography
• Higher prevalence of hormone receptor negative and
triple-negative cancers
• High cost
• Poor patient monitoring and follow upxix
The overall result is poor outcomes for breast cancer
patients in developing countries, and in particular,
Africa. One study suggests that the five year survival
rate for breast cancer patients in Africa does not exceed
60% for any low and middle-income country on the
continent compared to a survival rate of 80–90% for
patients in the United States, Europe and Japan.73,74,75
Recommendations for future
applications of systems
therapeutics
Healthcare systems need to adapt their existing
approaches to ensure that the maximum clinical and
economic value of systems therapeutics is delivered.
There has been growing recognition that systems
therapeutics, and indeed, precision medicines, offer
improvements to the status quo by targeting treatment
to the right patients and preventing waste on patients
39
who would otherwise not benefit or be harmed.
However, to maximize the value of systems therapeutics,
further progress by stakeholders will need to come
through the following approaches:
• Multi-panel testing and increased access to next
generation sequencing techniques.
• Sharing of healthcare data.
• Helping physicians make simpler decisions around
complex diseases.
• Protecting patient privacy and data security.
• Evidence generation through increased collaboration.
coverage and payments and potentially restrict access.
MULTI-PANEL TESTING AND INCREASED USE OF
NEXT GENERATION SEQUENCING TECHNIQUES
The movement from single panel, diagnostic tests
to multi-panel, diagnostic tests is an ongoing trend.
There is the potential that multi-panel testing, at
least in oncology, could exceed the use of single
panel, diagnostic tests within the next five years.76
In addition, although the use of NGS techniques
are on the rise, routine clinical practice remains an
important milestone. NGS enables the sequencing of
a human genome, or specific areas of interest, quickly
and accurately, compared to historical sequencing
that takes significantly longer and can only analyze
smaller segments of DNA. At this time, limitations
around access to NGS centers, challenges around
reimbursement in certain countries, privacy, consent
and handling the amount of data associated with these
techniques remain a bottleneck for increased use and
value of systems therapeutics.
The continued trend of multi-panel diagnostic testing
can be encouraged in order to obtain greater cost-
savings for stakeholders and also sample-sparing
for patients. Within the next ten years, to improve
40
access and acceptance of NGS among stakeholders,
policymakers must invest and prioritize genome
wide studies. Already a number of countries have
invested in precision medicine initiatives that
involve the widespread genetic screening of large
populations, such as the All of Us precision medicine
initiative in the United States, which seeks to recruit
one million participants to share their genomic and
other personal health data, and the United Kingdom’s
100,000 Genomes Project. Evidence of the utility
and cost savings of NGS by allowing the fast and
accurate selection of an appropriate systems medicine
must also be demonstrated to payers and other
reimbursement authorities in order to increase the use
of NGS in routine clinical care.
SHARING OF HEALTHCARE DATA
The full value of systems therapeutics will require
that a patient’s genomic information is analyzed
along with other real-world health care data. This
requires significant IT oversight, particularly over the
standardization of data so that it can be linked across
databases and analyzed. Currently, policy makers and
health information management (HIM) companies have
stepped up to help to regulate and provide solutions for
healthcare stakeholders and the use of HIM companies
will only expand over the next five years.
The complexity and size of genomic and healthcare
data associated with patients receiving systems
therapeutics presents an even greater challenge
around the infrastructure needed to store and analyze
the associated data as well and how to share the
data with multiple stakeholders. Within the next ten
years, policy makers and the healthcare industry will
need to make efforts to ensure that standards around
oversight of data storage and data sharing occurs and
that technology to deliver information simply to key
stakeholders exists.
 Healthcare systems need to adapt their existing approaches to ensure
that the maximum clinical and economic value of systems therapeutics
is delivered.
HELPING PHYSICIANS MAKE SIMPLER DECISIONS
Systems therapeutics invariably are used within complex
disease areas, such as oncology, or in areas with smaller,
highly specialized patient populations, such as rare
diseases. Multiple interacting factors such as age,
gender, comorbidities, polypharmacy, management of
side effects and evolving scientific literature must be
incorporated to provide holistic care for the patient.
Improved access by physicians to educational material
(e.g., free CME courses, online videos) that provides
basic scientific background, summaries of recent
research findings, and supported protocols from
professional societies for specific diseases around the
use of systems therapeutics, could increase awareness
and reduce physician frustration around the use of these
medicines. The goal being that by 2021, physicians
using systems medicines will be able to make faster,
accurate and well-informed decisions around these
complex therapies.
Improved communication between hospitals,
professional societies and academic researchers is also
necessary to provide protocols to physicians for systems
medicines that reflect the latest science, available
treatments and management of potential side effects.
Communication with diagnostic companies around
the use and interpretation of diagnostic tests will also
reduce the burden on physicians to understand and
interpret complex test results.
PROTECTING PATIENT PRIVACY AND DATA SECURITY
In order to reach individualized medical treatments
for each patient, there needs to be acceptance and
trust from the general public around the concept of
sharing genomic information for use in research studies.
Policy makers can encourage and normalize the use of
genomic research through government initiatives, but
in order to gain support from the public, individuals
must not only consent to the use of their genomic
data, but must be assured that their personal genomic
information is private and secure.
Of note, the public is increasingly demanding access
to their personal genomic data, as the success of direct
to consumer (DTC) companies, such as 23andMe,
shows. Policymakers are also responding; in 2017 the
FDA approved the first DTC genetic test to estimate a
patient’s risk of disease. However, if increased used of
genetic testing is to approach the majority of patients in
developed countries by 2021, patient consent, privacy
and data security will have to be more adequately
addressed. Although patient data can be de-identified
to increase anonymity, multiple data bases are used
when analyzing health care data, and this can allow
for third-parties to potentially re-identify patients,
thus necessitating strong data security. Physicians and
researchers must also obtain informed consent from
patients and explain how their data will and will not be
used. In a recent case between Google’s DeepMind and
the UK’s NHS, more than half a million patients in the
41
U.K. did not know their information was being shared
with Google to build an app.77 Lack of public support
for wide-scale genomic studies could significantly affect Healthcare stakeholders,
how future systems medicines are developed and used including policy makers, will
in routine clinical care.
need to coordinate at all stages
EVIDENCE GENERATION THROUGH INCREASED
of systems medicine, from
COLLABORATION
Fully incorporating new information into clinical practice development and approval,
from the use of systems medicine, such as improved through clinical protocols,
survival rates, long-term safety and adverse events, can
pharmacovigilance and post-
take decades. In addition, even when evidence comes
from randomized controlled trials or real-world data, marketing studies in order to
research findings may be ignored or simply fail to be ensure that criteria collected
recognized and have downstream impact. At this time,
there is limited evidence that precision medicine and as
and analyzed is sufficient to
such, systems therapeutics, have dramatically improved demonstrate value to all parties.
clinical outcomes.78 Economic assessments around the
cost savings of these medicines is also mixed, in part
due to the complexities around diagnostic testing.76 parties. A first step towards this type of engagement is
Another confounding factor in demonstrating the true occurring at present, as policy makers and commercial
value around systems medicines is that the gold standard companies (e.g., Verily/Google’s Project: Baseline) are
for evidence generation is the randomized-controlled investing in precision medicine and genome study
trial; for evidence generation, these trials would likely initiatives. However, other health care stakeholders,
be larger, costly, post-marketing studies that would be such as payers, therapeutic and diagnostic
challenging to enroll due to the inherent nature of the manufacturers, and physicians, will also need to be
smaller patient populations associated with systems engaged to ensure that evidence on how they define
medicines. Evidence generation for systems medicines value is also generated.
will likely require the use of novel trial designs, such as
the N-of-1 trials, that in aggregate can offer information
on how to better treat patient sub-populations.79

Healthcare stakeholders, including policy makers, will

need to coordinate at all stages of systems medicine,
from development and approval, through clinical
protocols, pharmacovigilance and post-marketing
studies in order to ensure that criteria collected and
analyzed is sufficient to demonstrate value to all

42
Notes on sources
This report is based on the IQVIA services detailed below. Analyses exclude OTC products and focus on
prescription-bound products. Spending is reported at wholesaler invoice prices and does not reflect off-invoice
discounts and rebates.

IQVIA MIDAS™ is a unique data platform for assessing worldwide healthcare markets. It integrates IQVIA National
audits into a globally consistent view of the pharmaceutical market, tracking virtually every product in hundreds
of therapeutic classes and providing estimated product volumes, trends and market share through retail and non-
retail channels. MIDAS data is updated monthly and retains 12 years of history.

IQVIA BrandImpact™ oncology data is based on a proprietary mobile research model and longitudinal
network of more than 400 i-enabled oncologists and is the only source of continuously-captured physician
treatment decisions for the biopharmaceutical industry. The real-time data generated by its information panel
of oncologists enables BrandImpact to provide unique insight into physician behavior and the influences on
that behavior. The combination of its network-generated syndicated data with its custom research and analytics
expertise enables BrandImpact to deliver more informed and actionable solutions to its customers’ critical
business issues.

43
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39. Manzano JL, Layos L, Bugés C, de Los Llanos Gil M, Vila L, Martínez-Balibrea E, et al. Resistant mechanisms
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49
 Footnotes
i. For example, in ALK positive NSCLC patients who previously were treated with chemotherapy, crizotinib
(Xalkori) demonstrated an overall response rate of (ORR) of 65% and a median progression free survival
rate of 7.7 months compared to chemotherapy, alone (20% and 3.0 months, respectively).3 In another
example, the use of two systems therapeutics, pertuzumab (Perjeta) and trastuzumab (Herceptin),
combined with the chemotherapy agent docetaxel, demonstrated an overall response rate (ORR) of 80.2%
for the treatment of HER2 positive breast cancer patients compared to an ORR of 69.3% in the same patient
population with trastuzumab and docetaxel. In the same trial, the median duration of response was nearly
double at 20.2 months versus 12.5 months.4

ii. For example, the prescribing information for paroxetine notes that paroxetine is metabolized by CYP2D6
and suggests to avoid co-prescribing with known CYP2D6 inhibitors, because and co-prescribing could
lead to adverse events such as prolonged QTC levels. However, the label does not specifically state
patients should be tested for pharmacokinetic profile prior to receiving the therapy. Genetic variations
of CYP2D6 are widespread, causing some individuals to be ultra-rapid, intermediate, or poor enzyme
metabolizers. CYP2D6 metabolizes a significant number of commonly used drug classes such as
antidepressants, antipsychotics, and opioids and so plays a significant role in drugdiscovery as well as
current treatment paradigms.

iii. Breast cancer is one of the leading cancers globally (1.7 million cases in 2012), and ER positive breast
cancers are a common variant (70–80%), which leads to high volume for breast cancer medicines.26

iv. Tamoxifen, anastrozole, and letrozole are all available as generic options and have a greater use in EU5 than in
the United States, which is reflected in this high volume of stratified oncology therapies in this region.

v. These medicines are a success story for personalized oncology as they helped to revolutionize the
treatment of patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML). Over
90% of patients with typical CML have this genotype, and it is part of the diagnostic criteria to test for the
status of this variant. Another leukemia therapy, ibrutinib, is the only therapy among the top 10 highest
volume oncology products to have been launched within the last five years. Ibrutinib is an oral, Burton’s
tyrosine kinase inhibitor with regulatory approval across the developed countries for chronic lymphocytic
leukemia (CLL)/small lymphocytic lymphoma that (SLL) with 17p deletion. Ibrutinib is recommended for
use in high risk CLL (those patients harboring a 17p deletion). Historically, patients with the 17p deletion
genotype had poor outcomes with conventional oncology regimens.27

vi. In the United States in 2016, Harvoni’s list price was $94,500 per 12-week course of treatment and Sovaldi
was $84,000, although in practice most US payers received these therapies at a discounted gross price.29

vii. An analysis of Medicare reimbursement in the United States of ten drug-diagnostic combinations found
that although the therapies themselves were reimbursed, there was “limited and variable reimbursement
of companion diagnostics for all new patients being prescribed the companion drug.” 32

50
 vii. In the EU5, although patients have access to companion diagnostics, the scope and timing of patient
access to diagnostics varies between countries; for example, funding of companion diagnostic testing is
mandatory if required by the drug label in Germany, while in in France, the National Institute of Cancer
(Institut National du Cancer; INCa) covers the cost of molecular testing of an associated oncology
medicine at the time of the corresponding drug launch but only on a temporary basis.33

ix. A 2015 statistical analysis assessed the impact of companion diagnostic measurement on treatment effects
and sample sizes for the clinical trials.36 The results support the idea that wrongly stratifying patients based
on inaccurate measurements of companion diagnostic tests leads to lower perceived efficacy in clinical
trials and that there is a direct relationship between dilution of efficacy in a clinical trial and increasing
inaccuracy of a companion diagnostic

x. Taking another example from oncology, although close to 100% of new cancer medicines were reimbursed
in the United States and Germany from 2014–2015, less than half of these medicines were reimbursed in
other countries, including the UK, Australia, Sweden, and Italy.22

xi. About half of cutaneous melanoma patients can be stratified by BRAF mutation to be eligible for treatment
with BRAF inhibitors such as vemurafenib, trametinib, or dabrafenib; monotherapy with these agent
has shown improved progression-free survival (PFS) and overall survival (OS) compared to traditional
chemotherapy, alone. However, disease progression can occur within 6 to 8 months due to development of
resistance mechanisms. Combination of a BRAF inhibitor with a MEK inhibitor (the current gold standard)
has shown benefits in PFS, but can still lead to resistance and each combination of therapies has slightly
different toxicity profiles.

xii. Regulatory bodies are responsible for post marketing safety monitoring for all medicines. According to
the world health organization, “while spontaneous reporting remains a cornerstone of pharmacovigilance
in the regulatory environment… the need for more active surveillance has also become increasingly clear.
Without information on utilization and on the extent of consumption, spontaneous reports do not make it
possible to determine the frequency of an adverse drug events attributable to a product, or its safety in
relation to a comparator. More systematic and robust epidemiological methods that take into account the
limitations of spontaneous reporting are required to address these important safety questions. They need
to be incorporated into post-marketing surveillance programs.”41

xiii. In developed countries, governments have taken initiatives to support precision medicine and genomic
initiatives, such as the United Kingdom’s 100,000 Genomes Project and the United States’ Precision Medicine
initiative; despite this, the right patients for a specific systems therapeutic may not receive testing.

xiv. In the United States, the FDA sets regulations for pharmacovigilance along with the divisions of the Center
for Drug Evaluation and Research and the Center for Biologics Evaluation and Research, within the FDA.
Post-marketing ADRs are reported to the FDA through MEDWatch, either voluntarily by stake holders or
through mandatory reporting, and are assessed by the divisions mentioned, previously.

51
 Footnotes
xv. In United States, a 1994 study estimated 100,000 annual hospital deaths from adverse drug reactions
(ADRs); this number was subsequently extrapolated to the population of the European Union to account
for 197,000 annual hospital deaths from ADRs in 2006.

xvi. Known adverse events to HIV antiviral therapies include neutropenia, which is one of the most
predominant adverse events in Africa which suggests that patients are experience a high rate of ADRs that
can be attributed to antiretroviral therapies.64

xvii. For the cases reported, two patients died and another patient required a liver transplant. According to the
World Health Organization, 275,000 people living in low- and middle-income countries have received DAA
hepatitis C treatment in 2015.70 71

xviii. According to one study, the lack of support services to manage the toxicity and adverse events associated
with treatment can be a reason to withhold treatment even when it is available.74

52
Methodology
IDENTIFICATION OF STRATIFIED MEDICINES
To identify stratified medicines, we examined information on the PharmGKB (https://www.pharmgkb.org/), FDA
(Drugs@FDA and the FDA’s Table of Pharmacogenomic Biomarkers in Drug Labeling), European Medicines
Agency (EMA), Health Canada and Pharmaceuticals and Medical Devices Agency (PMDA), Japan, through 2016.
We included those therapies whose labels require or recommend testing; we excluded therapies where biomarker
information was included but was informational. In addition, we included therapies which were stratified according
to viral genotype, such as sofosbuvir for HCV-1, HCv-2, HCV-3 and HCV-4. Two of the therapies were included
that were outside this definition. Buserelin, which is available in Canada and Europe, is indicated for hormone
dependent prostate cancer and so hormone status testing is necessary prior to use. Tamoxifen does not have a
labeling requirement for hormonal testing prior to use, but guidelines suggest testing prior to use.

DATA ON UTILIZATION OF STRATIFIED MEDICINES

To assure consistent geographic and intertemporal measurement of stratified medicine utilization, we used the
IQVIA MIDAS database, which reports standard units (SUs) and dollar expenditures (evaluated at manufacturers’
prices using annual exchange rates) for marketed therapeutics in the ten developed countries. This database
accounts for approximately 97% of global therapeutic usage, and utilizes standardized definitions and collection
processes. For eight medicines having both biomarker requirements and indications that do not have biomarker
requirements prior to use — rituximab (Rituxan), nivolumab (Opdivo), ibrutinib (Imbruvica), erolotinib (Tarceva),
pembrolizumab (Keytruda), cetuximab (Erbitux), atezolizumab (Tecentriq), everolimus (Afinitor) — we allocated
stratified medicine sales and volume by indication using indication-specific analyses based on IQVIA anonymized
patient level data.

These methods have some limitations. For example, existing global data sources do not link diagnostic testing
to therapeutic use. Thus we were unable to determine whether personalized medicines are actually utilized in
accordance with their labelling and treatment guidelines. Although we were able to measure use of personalized
medicines reasonably accurately, we were not able to estimate appropriate use.

53
 STRATIFIED MEDICINES

SAMPLE APPROVAL BIOMARKER THERAPEUTIC

MOLECULE BIOMARKER DX TEST PURPOSE
BRAND YEAR APPROVAL AREA

Adverse Drug
abacavir HLA-B Ziagen 1998 2008 Antiviral
Reaction

abacavir/ Adverse Drug

HLA-B Epzicom 2004 2008 Antiviral
lamivudine Reaction

abacavir/
Adverse Drug
lamivudine/ HLA-B Trizivir 2000 2008 Antiviral
Reaction
zidovudine

ado-trastuzumab
HER2+ Kadcyla 2013 2013 Oncology Efficacy
emtansine

Gilotrif
afatinib EGFR 2013 2013 Oncology Efficacy
GiIlotrif

alectinib ALK+ Alecensa 2015 2015 Oncology Efficacy

anastrozole ER+ Arimidex 1995 2000 Oncology Efficacy

t(15;17) translocation
arsenic trioxide and/or PML/RAR Trisenox 2000 2000 Oncology Efficacy
fusion gene

Adverse Drug
atazanavir CYP2C19 Reyataz 2003 n/a Antiviral
Reaction

atezolizumab PD-L1 Tecentriq 2016 2016 Oncology Efficacy

Adverse Drug
azathioprine TPMT Imuran 1968 2005 Immunology
Reaction

bosutinib BCR-ABL1 Bosulif 2012 2012 Oncology Efficacy

hormone-dependent
buserelin Suprefact 2003 2009 Oncology Efficacy
prostate cancer

Adverse Drug
carbamazepine HLA-B*1502 Tegretol 1968 2007 CNS
Reaction

CARBAGLU- Inborn Errors of

carglumic acid NAGS 2010 2010 Efficacy
Carbaglu Metabolism

ceritinib ALK Zykadia 2014 2014 Oncology Efficacy

cetuximab EGFR+/KRASwt Erbitux 2004 2006 Oncology Efficacy

AKR1D1, HSD3B7,
Inborn Errors of
cholic acid CYP27A1, AMACR, Cholbam 2015 2015 Efficacy
Metabolism
CYP7A1

cobimetinib BRAF Cotellic 2015 2015 Oncology Efficacy

crizotinib ALK/ROS1 Xalkori 2011 2015 Oncology Efficacy

dabrafenib BRAF Tafinlar 2013 2013 Oncology Efficacy

daclatasvir HCV 3 Daklinza 2015 2015 Antiviral Efficacy

54
 STRATIFIED MEDICINES

SAMPLE APPROVAL BIOMARKER THERAPEUTIC

MOLECULE BIOMARKER DX TEST PURPOSE
BRAND YEAR APPROVAL AREA

BCR-ABL1
(Philadelphia
dasatinib Sprycel 2006 2006 Oncology Efficacy
chromosome-positive
(Ph+))

denileukin diftitox CD25+ Ontak 1999 1999 Oncology Efficacy

dextromethorphan/ Adverse Drug

CYP2D6 Nuedexta 2010 2010 CNS
quinidine Reaction

Adverse Drug
divalproex sodium POLG Depakote 1983 n/a CNS
Reaction

elbasvir/grazoprevir HCV 1, 4 Zepatier 2016 2016 Antiviral Efficacy

Inborn Errors of Dosing and

eliglustat CYP2D6 Cerdelga 2014 2014
Metabolism Efficacy

Inborn Errors of
elosulfase alfa GALNS- Vimizim 2014 2014 Efficacy
Metabolism

erlotinib EGFR Tarceva 2004 2016 Oncology Efficacy

gene that is amenable

eteplirsen Exondys 51 2016 2016 Genetic Disorder Efficacy
to exon 51 skipping

everolimus ER+, HER2- Afinitor 2009 2012 Oncology Efficacy

exemestane ER+ Aromasin 1999 2005 Oncology Efficacy

fulvestrant HR+ Faslodex 2002 2002 Oncology Efficacy

EGFR-TK activating
gefitinib Iressa 2003 2009 Oncology Efficacy
mutations

gemtuzumab
CD33+ Mylotarg 2000 2000 Oncology Efficacy
ozogamicin

ibrutinib del (17p) Imbruvica 2013 2014 Oncology Efficacy

c-Kit+ or CD117+(Kit),
Dosing and
imatinib BCRABL1, PDGFRB, Gleevec 2001 2002 Oncology
Efficacy
FIP1L1-PDGFRA

ivacaftor CFTR Kalydeco 2012 2013 Respiratory Efficacy

ivacaftor /
CFTR Orkambi 2015 2015 Respiratory Efficacy
lumacaftor

lapatinib HER2+ Tykerb 2007 2012 Oncology Efficacy

ledipasvir/
HCV 1,4, 5,6 Harvoni 2014 2014 Antiviral Efficacy
sofosbuvir

lenalidomide 5q deletion Revlimid 2005 2005 Immunology Efficacy

letrozole ER+ Femara 1997 2001 Oncology Efficacy

maraviroc CCR5 tropic HIV-1 Selzentry 2007 2007 Antiviral Efficacy

55
 STRATIFIED MEDICINES

SAMPLE APPROVAL BIOMARKER THERAPEUTIC

MOLECULE BIOMARKER DX TEST PURPOSE
BRAND YEAR APPROVAL AREA

Dosing, Efficacy
mercaptopurine TPMT Purinethol 1953 2004 Oncology and Adverse Drug
Reaction

BCR-ABL
Efficacy and
(Philadelphia
nilotinib Tasigna 2007 2007 Oncology Adverse Drug
chromosome-positive
Reaction
(Ph+)); UGT1A1

nivolumab BRAF Opdivo 2014 2014 Oncology Efficacy

olaparib BRCA1-2 Lynparza 2014 2014 Oncology Efficacy

ombitasvir/
paritapre-vir/ HCV 4 Technivie 2015 2015 Antiviral Efficacy
ritonavir

ombitasvir/
paritaprevir/
HCV 1 Viekira Pak 2014 2014 Antiviral Efficacy
ritonavir/dasabuvir
sodium

osimertinib EGFR Tagrisso 2014 2016 Oncology Efficacy

oxcarbazepine
HLA-B*1502 Oxtellar XR 1999 2006 CNS Adverse Drug
Reaction

palbociclib ESR1, ERBB2 Ibrance 2015 2015 Oncology Efficacy

panitumumab EGFR+, KRASwt Vectibix 2006 2006 Oncology Efficacy

pegloticase
G6PD Krystexxa 2010 2010 Rheumatology Adverse Drug
Reaction

pembrolizumab CD274/PD-L1 Keytruda 2014 2015 Oncology Efficacy

pertuzumab ERBB2 Perjeta 2012 2012 Oncology Efficacy

deficiencies in CPS, BUPHENYL- Inborn Errors of

phenylbutyrate 1996 2009
OTC, or AS Buphenyl Metabolism

Dosing and
phenytoin CYP2C9,HLA-B Dilantin 1953 2008 CNS Adverse Drug
Reaction

pimozide CYP2D6 Orap 1984 2011 CNS Dosing

ponatinib BCR-ABL1 Iclusig 2012 2012 Oncology Efficacy

rasburicase
G6PD deficiency Elitek/ 2002 2002 Rheumatology Adverse Drug
Reaction

Oncology &
rituximab CD20+subset Rituxan 1997 1997 Efficacy
Immunology

rucaparib BRCA Rubraca 2016 2016 Oncology Efficacy

56
 STRATIFIED MEDICINES

SAMPLE APPROVAL BIOMARKER THERAPEUTIC

MOLECULE BIOMARKER DX TEST PURPOSE
BRAND YEAR APPROVAL AREA

simeprevir HCV 1 Olysio 2013 2013 Antiviral Efficacy

sodium
NAGS, CPS1, OTC, Efficacy of
phenylacetate and Ammonul 2005 2005 Inborn Errors
ASS1, ASL and ARG1 Metabolism
sodium benzoate

Solvadi/
sofosbuvir HCV 1,2,3,4 2013 2013 Antiviral Efficacy
Sovaldi

sofosbuvir/
HCV 1,2,3,4,5,6 Epclusa 2016 2016 Antiviral Efficacy
velpatasvir

tamoxifen ER+ Nolvadex 1977 1977 Oncology Efficacy

XENAZINE
tetrabenazine CYP2D6 Xenazine, 1950 2008 CNS Dosing
Nitoman

toremifene ER+ Fareston 1997 1997 Oncology Efficacy

tositumomab
CD20+ Bexxar 2003 2003 Oncology Efficacy
iodine-131

trametinib BRAF Mekinist 2013 2013 Oncology Efficacy

trastuzumab HER2 + Herceptin 1998 2004 Oncology Efficacy

t(15;17) translocation
tretinoin and/ or PML/RAR Vesanoid 1995 1995 Oncology Efficacy
fusion gene

vandetanib RET Caprelsa 2011 2011 Oncology Efficacy

Inborn Errors of
velaglucerase alfa GBA Vpriv 2010 2010 Efficacy
Metabolism

vemurafenib BRAF/NRAS Zelboraf 2011 2014 Oncology Efficacy

venetoclax 17p deletion Venclexta 2016 2016 Oncology Efficacy

57
About the authors
MURRAY AITKEN
Executive Director, IQVIA Institute
for Human Data Science
Murray Aitken is a Senior Vice
President at IQVIA and the executive
director of the IQVIA Institute for Human Data Science.
Murray is a renowned healthcare expert on addressing
the challenges facing the global healthcare industry
and prospects for improving patient outcomes,
managing costs and maximizing access through better
use of healthcare data and information. Established
in 2011, the IQVIA Institute for Human Data Science
provides global policy setters and decision makers
with objective, transformational insights into healthcare
dynamics derived from granular analysis of information.
58
ALANA SIMORELLIS, PH.D.
Publications Manager, IQVIA
Institute for Human Data Science
Alana is Publications Manager for
the IQVIA Institute for Human Data
Science and helps manage aspects of IQVIA Institute for
Human Data Science research projects and publications
as well as conducting research and analysis within
global healthcare. Alana came to IQVIA in 2016 having
previously worked at Decision Resources Group for
over six years as a Principal Business Insights Analyst.
At Decision Resources group, Alana authored a number
of publications within multiple disease areas that
included Alzheimer’s disease, pain, bipolar disorder,
schizophrenia and major depression. Alana has a Ph.D.
in Chemistry from the University of Utah and completed
a post-doctoral fellowship at Brandeis University, where
part of her research involved structural investigation of
a protein associated with Parkinson’s disease.
About the Institute
The IQVIA Institute for Human Data Science contributes
to the advancement of human health globally through
timely research, insightful analysis and scientific
expertise applied to granular non-identified patient-
level data.
Fulfilling an essential need within healthcare, the
Institute delivers objective, relevant insights and
research that accelerate understanding and innovation
critical to sound decision making and improved
human outcomes. With access to IQVIA’s institutional
knowledge, advanced analytics, technology and
unparalleled data the Institute works in tandem with a
broad set of healthcare stakeholders to drive a research
agenda focused on Human Data Science including,
including government agencies, academic institutions,
the life sciences industry and payers.
Research Agenda
The research agenda for the Institute centers on 5 areas
considered vital to contributing to the advancement of
human health globally:
• Improving decision-making across health systems
through the effective use of advanced analytics and
methodologies applied to timely, relevant data.
• Addressing opportunities to improve clinical
development productivity focused on innovative
treatments that advance healthcare globally.
• Optimizing the performance of health systems by
focusing on patient centricity, precision medicine
and better understanding disease causes, treatment
consequences and measures to improve quality and
cost of healthcare delivered to patients.
• Understanding the future role for biopharmaceuticals
in human health, market dynamics, and implications
for manufacturers, public and private payers,
providers, patients, pharmacists and distributors.
• Researching the role of technology in health system
products, processes and delivery systems and the
business and policy systems that drive innovation.
Guiding Principles
The Institute operates from a set of Guiding Principles:
• Healthcare solutions of the future require fact based
scientific evidence, expert analysis of information,
technology, ingenuity and a focus on individuals.
• Rigorous analysis must be applied to vast amounts of
timely, high quality and relevant data to provide value
and move healthcare forward.
• Collaboration across all stakeholders in the
public and private sectors is critical to advancing
healthcare solutions.
• Insights gained from information and analysis should
be made widely available to healthcare stakeholders.
• Protecting individual privacy is essential, so research will
be based on the use of non-identified patient information
and provider information will be aggregated.
• Information will be used responsibly to advance
research, inform discourse, achieve better healthcare
and improve the health of all people.
59
 CONTACT US
iqvia.com/contactus

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