oncology-marketplace

EXECUTIVE BRIEFING
While oral oncolytics are lauded by patients and oncologists for their convenience and ease of administration
compared to traditional IV chemotherapies, manufacturers need to be mindful of the challenges associated with
those agents in terms of drug adherence, side-effects management, off-label use, pricing and reimbursement.
• Understand the realities and trade-offs for oral
therapeutics in today’s site-of-care market and
review key risk management strategies involving hub
services, patient assistance, financial and tactical
patient support
• Hear strategic perspectives and pharma case examples
from Gilead, Celgene, Genentech and Taiho Oncology,
as well as stakeholders representing Lash Group/
AmerisourceBergen, Onco360, Association of Value-
Based Cancer Care and American Cancer Society
• Beyond orals: Learn about the next frontier of new
agents, infused immunotherapies and antibody-drug
conjugates
ORAL THERAPIES
IN THE ONCOLOGY
MARKETPLACE
Growth Potential, Challenges and Trade-offs
www.eyeforpharma.com/oncology

Oral Therapies in the Oncology Marketplace
AUTHOR
Suzanne Shelley, MS
EDITOR
Ulrich Neumann, MSc
DISCLAIMER
The information and opinions in this paper were prepared by eyeforpharma (a division of FC Business Intelligence) and its partners. FC Business
Intelligence has no obligation to tell you when opinions or information in this report change. FC Business Intelligence makes every effort to use
reliable, comprehensive information, but we make no representation that it is accurate or complete. In no event shall FC Business Intelligence
and its partners be liable for any damages, losses, expenses, loss of data, loss of opportunity or profit caused by the use of the material or
contents of this paper.
No part of this document may be distributed, resold, copied, or adapted without our prior written permission. FC Business Intelligence Ltd © 2014.
Contents
Executive Summary 3
Advances in Cancer Treatment 3
The Rise of Oral Oncology Agents 6
Self-administration and Its Risks 7
The Challenge of Adherence 9
Managing Reimbursement 9
Eliminating Financial Barriers 12
Investing in Hub Support Services 13
Using Tactical Support Services 15
Off-label Use and Oral Oncolytics 16
The Tipping Point 17
ABOUT THE AUTHOR
Suzanne Shelley, MS, Contributing Editor to eyeforpharma,
Pharmaceutical Commerce and Chemical Engineering, where she
previously served as Managing Editor.
Acknowledgements
eyeforpharma would like to thank the experts who generously
contributed their ideas and provided comments on the draft:
Loreen Brown, MSW
Senior Vice President
Lash Group, an AmerisourceBergen Company
Manuel Duenas, MBA
Director, Global Oncology Pricing and Market Access
Gilead Sciences
Scott Dulitz, MBA
Director, Market Access Programs & Professional Relations
Taiho Oncology
Dana Evans, MD
Director, Quality of Care and Patient Access
US Medical Affairs, Genentech, Inc.
Michael Kolodziej, MD, FACP
National Medical Director for Oncology Solutions
Aetna
Burt Zweigenhaft
Vice Chairman, Onco360 Oncology Pharmacy
Vice President, National Association of Specialty Pharmacy
Co-Chair, Association of Value-Based Cancer Care

3
www.eyeforpharma.com/oncology CONTENTS / PRINT
Oral Therapies in the Oncology Marketplace EXECUTIVE BRIEFING
Executive Summary
Advances in Cancer Treatment
Milestones and Continuing Needs
Receiving a cancer diagnosis is a life-changing event, but
in recent years, steadily declining per-capita incidence and
progressively growing survival rates have brought some
encouragement for patients. Longer-term survival rates,
coupled with ongoing breakthroughs in several classes
of oncology drugs, continue to provide strong market-
growth opportunities for drug developers. Oral oncolytics
are giving patients the freedom to receive cancer treatments
at home – in pill or capsule form, as opposed to via
traditional intravenous infusion in a clinical setting.
That offers welcome relief, but it also opens the door for a
variety of challenges.
Self-administration of powerful toxic therapies in an
unsupervised home setting can lead to sub-optimal
drug adherence and poor management of side effects,
and potential adverse reactions and unintended drug-
drug interactions. In addition, different reimbursement
considerations associated with oral oncolytics often
create significant additional out-of-pocket cost burdens
for patients. This leads to early drug abandonment, which
has a direct impact on health outcomes. Based on in-depth
interviews with executives in the industry and stakeholders
in managed care, the briefing explains the magnitude,
implications of and potential solutions to these challenges.
According to the most-recent annual cancer statistics
released by the American Cancer Society in January 2014,1
cancer death rates in the US have declined steadily for the
past two decades, resulting in a 20% drop in the overall
risk of dying from cancer over that time period. Specifically,
the combined cancer death rate in the US has continuously
declined from a peak of 215.1 per 100,000 in 1991, to 171.8
per 100,000 in 2010 (Figure 1). This 20% decline translates
to the avoidance of approximately 1,340,400 cancer deaths
during this time period (Figure 2).
f From 2006 to 2010, the death rate for all cancers
combined decreased by 1.8% per year in men and by 1.4%
per year in women. Compared to the peak rates – in 1990
for men and 1991 for women – the cancer death rate for all
sites combined in 2010 was 25% lower in men, 17% lower
in women, and 20% lower overall (age-adjusted to the 2000
US Standard population. Source: National Center for Health
Statistics, Centers for Disease Control and Prevention, 2013.
FIGURE 1: Trends in Cancer Deaths by Sex
Men
RatePer100,000
300
250
200
150
100
50
0
1975 1980 1985 1990 1995 2000 2005 2010
Both Sexes
Women

4
Advances in Cancer Treatment – Milestones and Continuing Needs
FIGURE 2: Cancer Deaths Averted in Men and Women in 2 Decades
n Almost 1.3 million cancer deaths were averted as a result of almost two decades of consistent declines in cancer deaths
rates, total numbers for men (1991-2010) and women (1992-2010). The blue line represents the actual number of cancer
deaths recorded in each year, and the red line represents the number of cancer deaths that would have been expected if cancer
death rates had remained at their peak. Source: American Cancer Society, 2014.
NumberofDeaths
Year of Deaths
Men450,000
400,000
350,000
300,000
952,700
Cancer Deaths Averted
387,700
Cancer Deaths Averted
250,000
200,000
150,000
100,000
50,000
0
1975
1980
1985
1990
1995
2000
2005
2010
Year of Deaths
Women450,000
400,000
350,000
300,000
250,000
200,000
150,000
100,000
50,000
0
1975
1980
1985
1990
1995
2000
2005
2010

5
Advances in Cancer Treatment – Milestones and Continuing Needs
Despite these gains, there’s still plenty of work to be done.
Projections show that by the end of 2014, nearly 1.7 million
new cases of cancer will have been diagnosed in the US,
and nearly 586,000 cancer-related deaths will have occurred
– a rate of 1,600 deaths per day. “The progress we are
seeing is good – even remarkable – but we can and must do
even better,” said John R. Seffirin, chief executive officer of
the ACS, when the 2014 report was released.
Ongoing improvements in long-term survival rates among
cancer patients are shaping the oncology marketplace in
many ways. Today, an estimated 14.5 million Americans
are living with cancer, and this number is projected to grow
to almost 19 million by 2024.2,3
While per capita cancer-
incidence rates continue to fall, the actual number of
cancer diagnoses has increased in recent years which is
due in part to ongoing improvements in early cancer-
detection methods.
As a result, the number of survivors who are managing their
cancer as a chronic condition – sustaining the need for long-
term drug therapies – continues to grow. In fact, reflecting in
part the ongoing effectiveness of today’s treatment options,
recent data from the ACS shows that the majority [64%]
of cancer survivors in the US were diagnosed five or more
years previously, and 15% were diagnosed 20 or more years
ago (Figure 3).
FIGURE 3: Trends in Five-Year Relative Cancer
Survival Rates (%)
Site 1975-1977 1987-1997 2003-2009
All Sites 49 55 68
Breast (Female) 75 84 90
Colon 51 60 65
Leukemia 34 43 59
Lung & Bronchus 12 13 18
Melanoma of the Skin 82 88 93
Non-Hodgkin Lymphoma 47 51 71
Ovary 36 38 44
Pancreas 2 4 6
Prostate 68 83 100*
Rectum 48 58 68
Urinary Bladder 72 79 80
n From data covering 10% of the US population, survival
rates for all cancers presented have improved significantly
since the 1970s, due largely to earlier detection and/
or advances in treatment. Survival rates have markedly
increased for cancers of the prostate, breast, colon, and
rectum, and for leukemia. Progress has been slower for
cancers of the pancreas and lung and bronchus. Sources:
American Cancer Society, 2014, SEER Program, National
Cancer Institute, 2013.
Taken together, all of these trends have continued to create
strong demand for – and spur ongoing growth in – the
development of novel oncology therapies and strategies
to better manage side effects that threaten to undermine
adherence efforts. Today, oncology products make up
roughly one quarter of the 2,000 new drugs that are
currently in late-stage clinical development.4
On a global
basis, spending on all oncology drugs is projected to reach
$100 billion in 2018, up from $65 billion in 2013.

6
The Rise of Oral Oncology Agents
The vast majority of chemotherapy agents are still
administered intravenously today, but over the past decade,
the floodgates have opened in terms of the development
and approval of oral oncology agents. Not surprisingly, the
ability to receive cancer treatment in tablet or capsule form
in the comfort of one’s own home provides a desirable
alternative to traditional chemotherapy drugs that are
administered using intravenous infusion.
The first wave of concerted development effort related to
oral oncology drugs took place in the 1990s, and the pace
has quickened. Since 2010 alone, roughly 30 new oral
oncolytics (or new indications for existing oral oncolytics)
have been approved.
As of early December 2014, 58 oral anticancer medications
had been approved by FDA for cancers as diverse as
breast cancer, chronic myelogenous leukemia (CML),
gastrointestinal stromal tumors (GIST), non-small cell lung
cancer (NSCLC), renal cell carcinoma (RCC) and others. And
among the 750 drugs that are currently being investigated
in the drug pipeline, a large percentage – 25-30% by
many accounts – are oral oncology agents. “Many of
these are targeted therapies that are designed to attack
a specific mutation or driver pathway in the malignancy
– a great improvement over the traditional broad-based
approach that is typical of so many conventional infused
chemotherapy options,” says Michael Kolodziej, MD, FACP,
National Medical Director for Oncology Solution for Aetna.
Many of the early oral oncolytics have already become
widely accepted and used in the oncology community,
including:
• Gleevec (imatinib mesylate) from Novartis
• Xeloda (capacitabine) from Genentech
• Revlimid (lenalidomide) from Celgene Corp.
• Tykerb (lapatinib) from GlaxoSmithKline
• Tarceva (erlotinib) from Genentech and Astellas
Oncology
• Nexavar (sorafenib) from Bayer HealthCare and
Onyx Pharmaceuticals
Newer oral oncology agents to come to market in
recent years include:
• Zelboraf (vemurafenib) from Genentech
• Tafinlar (Zabrafenib) from GlaxoSmitKline
• Imbruvica (ibrutinib) from
Pharmacyclics and Janssen Biotech
• Gilotrif (afatinib) from Boehringer
Ingelheim Pharmaceuticals
• Zydelig (idelalisib) from Gilead
Sciences
• Zytiga (abiraterone acetate) from
Janssen Biotech
“Clinical efficacy remains the ultimate driver of drug
development. In the chronic lymphocytic leukemia (CLL)
market, we see a rapid shift from cytotoxic IV-administered
chemotherapy to recently-approved orals such as ibrutinib
(Imbruvica) and idelalisib (Zydelig),” says Manuel Duenas,
Director, Global Oncology Pricing and Market Access,
for Gilead Sciences. “But this wouldn’t have happened
without strong efficacy data in tough-to-treat populations.
Ultimately, if efficacy can be achieved without the IV, the
patient benefits will ensure continued transition toward all-
oral regimens.”
And because the oral agents tend to be targeted therapies
(proven and approved for use among a specific, biomarker-
indicated sub-set of cancer patients), “the belief is that
over the long run these agents will prove to have greater
efficacy for patients who have those specific biomarkers,
compared to the conventional chemotherapy approach,”
says Kolodziej of Aetna.
Oral oncolytics are small-molecule drugs, and when produced
in tablet or capsule form, they are stable formulations so they
also enjoy long shelf life and do not tend to require special
handling or storage considerations such as refrigerated
transportation and storage that is typically required for many
traditional infused chemotherapy drugs, or today’s newer
biologic oncology options.

7
The Rise of Oral Oncology Agents
It should come as no surprise that patients generally prefer
oral medications over IV therapy for a variety of reasons –
they are easier to take and involve a treatment regimen
that is generally more convenient and less disruptive to
the patient’s life. However, “The convenience factor can
sometimes be offset by some significant challenges,”
explains Scott Dulitz, Director, Market Access Programs
Professional Relations, for Taiho Oncology. Taiho recently
received FDA fast-track designation for its oral oncology
pipeline candidate, TAS-102 (tipiracil hydrochloride),
which treats patients suffering from refractory metastatic
colorectal cancer (mCRC).
“While there are many positive aspects
to oral oncolytics, challenges remain,
ranging from reimbursement and out
of-pocket expenses to the appropriate
management of side effects and
adherence.”
Loreen Brown, MSW, Senior Vice President, Lash Group,
an AmerisourceBergen Company
Traditional IV chemotherapy agents tend to produce a very
familiar suite of side effects, ranging from fluid retention/
edema, rash, nausea, vomiting and diarrhea, to bone-
marrow suppression, platelet or white blood cell count
problems, anemia, fatigue, muscle cramps, hair loss and
more. By comparison, oral oncolytics tend to have fewer –
but different – side effects.
Most of today’s oral oncoloytics are in a class called
kinase inhibitors which operate by interrupting a certain
intracellular enzyme called kinase. These bring a different
set of side effects, such as extreme sub-cutaneous rashes
and diarrhea that can be “quite debilitating and may even
require hospitalization, and in some cases, liver toxicity,”
explains Dana Evans, MD, Director, Quality of Care and
Patient Access US Medical Affairs for Genentech.
According to recent data from ExpressScripts,5
almost 41%
of patients taking oral oncology medications are not fully
adherent to their prescribed therapies. Anywhere from
23% to 74% of patients using one of nine oral cancer drugs
studied were potentially at risk for a drug interaction that
could lead to treatment toxicity.
“Sending the patient home to take these
complex drug regimens on their own is
really a huge leap of faith.”
Burt Zweigenhaft, Vice Chairman, Onco360 Oncology
Pharmacy, Vice President of the National Association of
Specialty Pharmacy and Co-Chair of the Association of
Value-Based Cancer Care
Self-administration and Its Risks

8
Self-administration and Its Risks
Our analysis of latest research findings presents a
troubling picture: 6, 7, 8, 9
• Only 37% of adult cancer patients adhere to oral
anticancer drug regimens; two out of three fail
to take their self-administered antineoplastic
prescriptions as directed
• 7.8% of cancer survivors avoided medical care due
to cost issue, 9.9% for prescription medications
• 3 out of 4 readmissions are related to non-
adherence to prescribed drug regimens
• For payers, costs often increase as a result of
non-adherence, due to the progression of the
disease and additional side effects
• For manufacturers, roughly 10% of revenue is
lost through non-adherence, and drug efficacy is
often put into question due to poor adherence-
related issues.
Studies demonstrate that sub-optimal adherence leads
to reduced event survival in some cancer patients,10
and
wasted expenditures for payers. And when it comes to
molecularly targeted drugs, even small deviations from full
adherence may result in the emergence of drug resistance
and treatment failure, as recently evidenced by studies of
adherence in individuals with CML.11
“If patients are sitting in the infusion
room for many hours, you know they
are compliant with the prescribed
therapy, but when they’re responsible
for managing the complex pill regimen
unsupervised and unmonitored at home,
you may not actually know.”
Michael Kolodziej, MD, FACP, National Medical Director for
Oncology Solution, Aetna
For instance, in infusion room settings, specially trained
nurses have regular contact with patients and are able
to diligently focus on side effects, adverse reactions and
potential drug-drug interactions. At home, patients are
not always aware – “they may not necessarily appreciate
the significance or severity of things that are actually quite
important,” Kolodziej notes. The privacy of the home setting
can add ample cover for those patients who may be highly
motivated to downplay potential issues that could cause
their doctors to discontinue use of the potentially life-saving
drug. “This is still widely underappreciated and under-
managed,” he adds.
Because these patients are self-administering their oral
medications at home, it can also be more challenging for
oncologists to monitor potential side effects, adverse events
and drug-drug interactions. Ultimately, this will typically
increase the need for targeted nurse follow-up calls with
patients, and may require more frequent office visits for
patients for ongoing monitoring.

9
The Challenge of Adherence
Managing Reimbursement
Medical versus Pharmacy Benefit Implications
Our exploration of stakeholder perceptions shows that
barriers to sustained drug adherence with oral oncology
medications tend to be centered around these key issues:
• out-of-pocket cost considerations
• unpleasant side effects
• complex dosing regimens
• adverse events
• drug-drug interactions.
Further complicating the compliance/adherence issue is the
fact that – due to their particular mechanism of action – many
of today’s targeted oral oncology medications must be taken
without food. This calls for complex dosing schedules (for
instance, some pills must be taken several hours before or
after a meal), which compounds the adherence challenges,
especially for patients taking multiple medications.
Nonetheless, perhaps more so than with any other oncology
therapy, proper adherence is essential for effective oral
oncology drugs. Individual cancers are very specific, in terms
of the size of tumor, basal surface area and calculation of
most appropriate dose of therapy – if patients don’t follow
the prescribed regimen strictly to maintain bioavailability
of the oncology agent in the high-95th-percentile of range,
they are not going to be able to shut down the targeted
mechanism of action in the cancer. More than any other
disease, patients must be 100% compliant or they won’t
get the outcomes they want, and worse, if they are not fully
compliant and only achieve 50-80% bioavailability, they will
develop tumor resistance and thus the treatment will fail.
Making matters worse is the fact that, on average, cancer
drugs that were proven and approved under tightly
controlled clinical trial conditions can fail up to 70% of the
time in real-world patient populations.
Traditional IV chemotherapy regimens are typically covered
under the patient’s medical benefit, and through this
reimbursement mechanism, patients typically face no
co-insurance requirements on the cost of the injectible
chemotherapies.
By contrast, oral oncolotyics in pill form are typically
covered under the patient’s pharmacy benefit (or Medicare
Part D). When it comes to reimbursement, most of today’s
costly oral oncolytics are placed on tiered specialty
formulary designations that require higher out-of-pocket
copays, and in some cases co-insurance from patients.
“These drugs are typically quite
expensive. Until a patient reaches his or
her maximum out-of-pocket (OOP) limit,
they may face a significant bill”
Oral oncology patients who are Medicare Part D
beneficiaries can find themselves at risk for substantial out-
of-pocket cost share. “Especially if they are in or reach the
“doughnut hole” during their course of therapy,” explains
Dulitz of Taiho Oncology.

10
Managing Reimbursement – Medical versus Pharmacy Benefit Implications
Most fee-for-service Medicare patients receiving traditional
IV therapies will have a supplemental plan that will support
them with their 20% co-insurance, but those plans do not
provide copay support for Part D claims.
“These coverage dynamics require
many Part D beneficiaries to apply to
non-profit, charitable organizations
for support with their out-of-pocket
responsibility.”
Scott Dulitz, Director, Market Access Programs
Professional Relations, Taiho Oncology
In a study of 10,508 patients with Medicare and commercial
insurance for whom oral oncolytic therapy was initiated
between 2007 and 2009, investigators found that there was
a higher rate of drug abandonment for patients enrolled in
plans with pharmacy benefit designs that required higher
cost sharing.6
For oral oncology medications, claims with
cost-sharing greater than $500 for the patient were four
times more likely to be abandoned than claims with cost-
sharing of $100 or less. In this way, cost implications have a
direct impact on drug adherence.
“This distinction often makes out-of-pocket-costs quite high
for patients taking orals,” says Brown of Lash Group. As
shown in Figure 4, payers and providers recognize (in terms
of “agreeing” or “strongly agreeing”) that patients who are
prescribed oral oncolytics tend to have higher copays and
more reimbursement issues compared to those receiving
infused products.
0 1 2 3 4 5 6 7
I prefer to prescribe or encourage the use of oral
oncolytics vs infused products
Patients prefer oral oncolytics to infused products
I dispense or have contracts that allow physicians to
dispense oral oncolytics within their practice
Patients prescribed oral oncolytics have higher copays
than those receiving infused products
Oral oncolytics have more reimbursement issues
than infused products
My practice or plan utilizes manufacturer-supported
oral oncolytic adherence programs
My practice or plan encourages patients to participate in
oral oncolytic adherence programs provided by SPPs
Payers Providers
n Responses are based on a 7-point scale where 1 is “strongly disagree” and 7 is “strongly agree. PayerPulse™
, N=54.
Source: Xcenda, 2011.
FIGURE 4: Payer and Provider Perspectives on Oral Oncolytics vs Infused Products

11
Managing Reimbursement – Medical versus Pharmacy Benefit Implications
Furthermore, demonstrable pricing and reimbursement
disparities between orals and infused chemotherapy
options may also be influencing prescribing practices —
allowing pricing and reimbursement issues to outweigh
clinical considerations in some situations. Stakeholders
agree that this is an unwelcome development. Further
exacerbating the pricing and reimbursement disparity is the
fact that many of the earlier IV-based chemotherapy options
are now available in generic form, greatly reducing their cost
to payers and patients. While this can help take financial
issues off the table, pressure to prescribe them over newer,
more costly options may not lead to the best clinical option
for any given patient.
“For payers to want to move to this
model, physicians need to bring value to
oral dispensing by improving the patient
experience, improving patient outcomes
and ideally reducing costs.”
In the US, physicians typically receive a fee for
administering intravenous drugs, so the decision to switch
to an oral oncology option may also risk losing a revenue
stream. The move to oral oncolytics could overtly or covertly
influence their prescribing decisions.
“Historically – oncology practices have received no income
for prescribing oral oncolytics but today there is a movement
afoot to change this,” says Kolodziej of Aetna. “Obviously we
all want doctors to prescribe the most clinically appropriate
course of treatment, so through buy-and-bill and office-based
prescription dispensing, some oncology practices are able to
level this playing field a bit (by allowing for some revenue to
be generated from prescribing orals).”
Today’s payer environment – in which specialty pharmacies
and pharmacy benefits managers (PBMs) typically only
handle the distribution of oral oncology drugs that are
covered by the pharmacy benefit (not infused or injected
therapies covered under the medical benefit) – has created
another troubling situation. “By this model, different
pharmacists are managing different drugs from different
vendors within different silos, so there is no single
pharmacy program managing the entire treatment protocol
for any given patient. According to Zweigenhaft of Onco360,
the silo approach “results in clinical fragmentation, lack
of benefits coordination, and failure to harmonize support
around side effects, adverse events and potential drug-drug
interactions literally sets up the patient for clinical failure,
which can lead to poor outcomes.”
The current approach of managing and contracting in
silos seems counter-intuitive to efforts to drive outcomes
and quality. There’s a big call in the industry for better
harmonization of benefits in pharmacy, and the need for this
becomes most acute for patients with co-morbidities who
are on the most complex, combination therapies.

12
Eliminating Financial Barriers
The higher financial burden associated with today’s oral
oncolytics impacts both access and utilization and leads to
higher rates of drug abandonment. All of these factors have
a detrimental effect on drug adherence – which is critical to
deriving the desired benefit from any aggressive oncology
treatment. Behind closed doors, industry experts refer to the
“financial toxicity” of the new treatments.
To address issues related to out-of-pocket expenses (and
thereby access) for patients, drug makers are widely
offering co-pay assistance cards and discount coupons,12
which help offset some of the out-of-pocket expenses for
patients. “Traditionally, these mechanisms for financial
support were not offered for oncology drugs — but today,
many companies are offering these things in exchange
for preferred designation on formulary,” notes Evans of
Genentech. Similarly, to address some of concerns about
the high price of new oral medications, and to hence achieve
more favorable formulary status – drug makers are also
increasingly offering a variety of discounts and rebates that
benefit payers.
Another strategy is for drug companies to provide the first
month of therapy for free as part of bridging programs.
According to Duenas of Gilead Sciences, “the free month
of therapy is designed to not only offset out-of-pocket
expenses for patients, but to eliminate potential delays
in treatment initiation of up to two weeks experienced by
patients while drugs are being approved by insurers for
reimbursement.”
This has emerged as a best practice, as it addresses a number
of factors, from potential treatment delays to potential drug
wastage due to premature drug discontinuations.
100%
75%
50%
25%
0%
Price of Reference
Standard of Care
Effective New Product
Launch Price (with free
month of therapy)
Negotiated New Product
Launch Price (with free
month of therapy)
10% WAC
premium to
Reference
Standard of
Care
34%
Savings
24%
Savings
Payor
Win
FIGURE 5: A Free Month of Therapy – and its Benefits
n A free month of oral oncology therapy can provide significant gains for payers and new market entrants, especially if there is
substantial early discontinuation (drug wastage) in a particular oncology indication. Source: Manuel Duenas, Gilead Sciences.

13
Investing in Hub Support Services
In order to provide the support and education that both
patients and physicians require comprehensive and robust
patient support offerings from manufacturers are
becoming a top priority for the makers of oral agents.
Today many are partnering with specialty pharmacies and
other support program providers to address access and
adherence obstacles.
FIGURE 6: Services Typically Provided Using a
Hub Support Model
n Because the risk of drug abandonment and poor
adherence is so high with oral oncology therapy options,
leading drug manufacturers work with specialty pharmacies
and other partners to offer a range of support patients to
patients and their caregivers. Source: Taiho Oncology.
In a 2014 study that surveyed 58 payers representing
160 million lives, 95% ranked high-priced new oncology
products as “high” or an “extremely high” priority for
their plans. 50% of payors also ranked compliance
and persistency with oral oncology drugs as “high” or
“extremely high” priority.13
“Providing high-touch patient support is to focus on
developing patient confidence and skills, as well as efficient
use of resources,” says Brown of Lash Group. To achieve this,
their support services segments patients by customizing
pathways, then moving forward with evidence-bases
approaches and interventions at critical points through
outreach and education. Onco360 relies on Board-Certified
Oncology Pharmacists (BCOP) who are experienced when it
comes to medications within cancer protocols, compatibility
issues, side-effects management and more. The aim is to
quickly identify patients who have higher risk factors for
non-compliance, such as confusion, skepticism or side
effects. It’s important “to determine how much hand-holding
is needed in terms of regular phone calls, email or text
reminders and so on, and then to work with them to eliminate
the risk of failure by managing them with a higher level of
service and intervention,” says Zweigenhaft of Onco360.
Stakeholders agree that with patients taking oral
oncolytics at home, there’s a critical window for
success as the risk of failure is high. Some of the other
support techniques manufacturer can use include:
• educational support for both patients and caregivers
about self-administered treatment protocols
• educational support for likely side effects of therapy
• calendar of follow-up physician visits and reminders
• automated voice (aka “robo-call”)
• text reminders
• direct nursing staff outreach and support
• guidance on keeping a detailed medication diary
(to assist with periodic auditing by medical staff)
Provider
Coordination
Specialty
Pharmacy
Coordination
Copay
Assistance
Patient
Assistance
Refill
Reminders
Nurse
Hotline
Side Effect
Monitoring
Reimbursement
Support
Alternate
Funding
Adherence
Calls

14
Investing in Hub Support Services
“When it comes to oral oncology
treatments, the situation can go from
being a success to a catastrophic event
in a matter of just 3 to 6 cycles of therapy.
We don’t have years to figure it out with
any given patient – we have to figure it
out and get it right in a matter of weeks.”
Burt Zweigenhaft, Vice Chairman, Onco360 Oncology
Pharmacy, Vice President of the National Association of
Specialty Pharmacy and Co-Chair of the Association of
Value-Based Cancer Care
Best-in-class programs that address these issues can have
significant impact on therapy adherence. Hub-support services
can drive a 40% increase in the amount of time patients stay
on therapy, as shown by a recent program initiated by Lash
Group for a manufacturer of an oral oncology agent.
Such efforts not only benefit patients by driving better
clinical outcomes, but can help practices and find payor
support. Kolodziej of Aetna agrees that “if doctors can make
the case for better care and case management, this can
resonate with payers, as well.”
Duenas of Gilead Sciences adds that “to a modest extent, the
compliance question is also being addressed by some payers’
implementation of split-fill programs for oral oncology agents
that have significant potential tolerability issues.”
ANTIBODY-DRUG CONJUGATES AND
CANCER IMMUNOTHERAPY
THE NEXT FRONTIER IN IV-BASED
ONCOLYTICS?
While targeted oral oncology medications have
been garneting a larger slice of the overall oncology
market and drug pipelines in recent years, the sun
has not yet set on intravenously infused cancer
therapies. In fact, roughly 70-80% of the US
drug spend in cancers is today still related to
infused products. In recent years, a deeper
understanding and promising breakthroughs in
intracellular pathways has opened the door to
two other categories of oncology drugs – namely
antibody drug conjugates and immune-stimulating
therapies – and both of these generally require
intravenous administration.
“Both of these new platforms promise really
big breakthroughs in cancer treatment and
will continue to be pursued by many industry
stakeholders,” says Evans of Genentech. “As we
continue to follow the science, we are seeing
that despite great strides in the development of
proven oral oncolytics, these two new categories
of oncology agents are generally administered by
intravenous infusion – not in pill or capsule form.”
Dana Evans, MD, Director, Quality of Care and
Patient Access, US Medical Affairs, Genentech, Inc.
Antibody-drug conjugates allow a targeted antibody
to be linked to a potent chemotherapy molecule.
The antibody targets a particular protein on a
cancer cell, and then the antibody-drug conjugate
molecule enters the cancer call by a process called
endocytosis. Once the antibody-drug conjugate
is inside the cell, the linker part of the molecule
is broken down and the chemotherapy drug is
released inside the cell.
“In recent years, we’ve developed linkers that are
stable until they get inside the target cells. This
antibody targeting results in fewer side effects
because the toxic chemotherapy agent is not
released until it is inside the cancer cell – so there
is less collateral damage,” says Evans.
IN FOCUS
f READ MORE…
NOVEL THERAPIES
BEYOND ORALS

15
For oral therapeutics, the out-of-pocket burden on most
patients can create a major obstacle to optimal compliance.
Leading oral oncology manufacturers are thus deeply
invested in hub programs that provide patients and
healthcare providers not just with reimbursement support
for their products, but also tactical support services.
Those are designed to “carry out benefit investigations, to
manage prior authorization and appeals, as well as
specialty pharmacy triage and coordination,” explains
Dulitz of Taiho Oncology.
The objective of tactical support is to help patients
explore all possible avenues for financial help, including
drug maker’s co-pay assistance and coupon programs, or
patient-assistance programs provided by disease-related
foundations.
An industry leading example for oral therapeutics is
Celgene’s Fast Track for First Prescription, a “hub wrap-
around” program to expedite drug dispense time and
therapy access through relationship-driven coordinated
engagement at various touch points. So-called patient
support specialists are assigned to “each office and patient,
ensuring personal access and reimbursement support”.
As a result, Celgene reports that “patient co-pay
responsibility is reduced to $25 or less for eligible patients
taking Celgene medications”.13a
IN FOCUS NOVEL THERAPIES
BEYOND ORALSUsing Tactical
Support Services
j BACK f READ MORE…
f Meanwhile, the industry continues to make
great strides in the development of immune-
stimulating therapies that allow the immune
process that is blocked by cancer systems to be
re-activated. For example, Yervoy (ipilimumab) from
Bristol-Myers Squibb for metastatic melanoma
stimulates cytotoxic T-cells to attack cancer cells,
while a PD1 inhibitor from Merck also triggers a
better, targeted immune reaction against certain
target cancer cells.
Immunotherapy-based approaches are designed
to stimulate or enhance the body’s own immune
system to keep cancer from developing or
spreading, or remove, “re-educate” and
re-introduce specialized T-cells into the patient’s
body to produce a more vigorous immune response
against tumors using antibodies that block
conventional immune barriers. Because these
therapies stimulate the patient’s immune system
to target cancerous cells (thereby reducing damage
to normal cells) and render them more vulnerable,
they allow the immune system to recognize and
destroy them.17
Today there are several types of immunotherapy,
including monoclonal antibodies, non-specific
immunotherapies, and even cancer vaccines that
essentially teach the body’s immune system to
attack and destroy cancer cells.
“Monoclonal antibodies are able to target
intracellular pathways, and these very large
molecules usually do this by targeting a receptor
on the outside of the cell (because the molecule
itself is too large to get into the cell),” explains
Evans. “When you do this, you create an antibody-
cell immune complex that is recognized by body
as foreign body and attacked – so you have two
processes working to kill the cancer cell; you
don’t see this same mechanism of action with the
small-molecule oral therapies.”
Oncology therapies based on monoclonal
antibodies are available to treat lymphoma,
malignant melanoma and a growing range of other
cancer types.

16
f READ MORE…
BEYOND ORALSOff-label Use and
Oral Oncolytics
Off-label prescribing allows individual physicians to decide
whether or not a particular approved drug might potentially
benefit an individual patient.
According to the ACS, given the high stakes and short time
horizons associated with treating cancer, oncologists and
their patients are often more willing to try off-label drugs
compared to other medical specialties – especially for
situations for which very few approved treatment options are
available, or for patients who have run out of other options.
Stakeholders agree that not all off-label prescribing is
dangerous or ill-fated (and in some cases can prove to be
quite successful). Nonetheless, industry observers note that
the use of off-label drugs in oncology essentially amounts
to a form of clinical experimentation – an approach that
tends to fly in the face of the universal desire and existing
institutional restrictions that aim to maximize healthcare
outcomes while minimizing healthcare expenditures.
Today, about one third of intravenous chemotherapy
is prescribed off-label to cancer patients in the US,
according to a study published by the Journal of Clinical
Oncology.14
The study focused on 10 patented intravenous
chemotherapies – but did not investigate the extent of off-
label prescribing among oral agents. The US sales for the 10
therapies studied totaled nearly $12 billion in 2010. Overall,
on-label use accounted for $7.3 billion, while off-label use
totaled $4.5 billion.
Not surprisingly, off-label use of any regulated drug is also
controversial because the quality of clinical evidence to
support off-label use may not be sufficient, the practice
may expose the patient to potentially toxic therapies, and
incur preventable costs for payers that may truly produce no
clinical benefit for the patient.
Increasingly, as part of managed plan design, insurance
companies are refusing to cover costly treatment therapies
that are used for situations beyond the approved FDA label
indications because the potential clinical benefits are often
not proven, and any potential benefits may not outweigh
the cost of treatment or the potential for safety and toxicity
issues or other specific adverse health outcomes.
f To date, approved monoclonal antibodies for the
treatment of cancer include:
• Campath (alemtuzumab) from Genzyme
• Avastin (bevacizumab) from Genentech
• Erbitux (cetuximab) from Bristol-Myers Squibb
and Merck KgAA
• Yervoy (ipilimumab) from Bristol-Myers Squibb
• Arzerra (ofatumumab) from GlaxoSmithKline
• Vectibix (panitumumab) from Amgen
• Rituxin (rituximab) from Genentech
• Herceptin (trastuzumab) from Genentech
When monoclonal antibodies attach themselves to
a cancer cell, they can interrupt cancer’s progression
in a variety of ways.18
Specifically, they can:
• Encourage the patient’s immune system to
destroy the cancer cells. When a monoclonal
antibodies attach to a cancer cell, it makes them
more easily recognizable to the immune system.
• Slow the growth of cancer cells. Some cancer
cells make extra copies of the growth factor
proteins, which makes the cancer cells grow
abnormally fast. Some monoclonal antibodies
can block these receptors and prevent the growth
signal from getting through.
• Deliver radiation directly to cancer cells. When
radioactive molecules are attached to monoclonal
antibodies in a laboratory, they can be used
to deliver low doses of radiation specifically
to the tumor while leaving healthy cells alone.
Zevalin (ibritumomab tiuxetan) from Spectrum
Pharmaceuticals and Bexxar (tositumomab
combined with iodine 131) from GlaxoSmithKline
are examples of these radioactive molecules.
• Diagnose cancer. Monoclonal antibodies carrying
radioactive particles may also help diagnose
certain cancers, such as colorectal, ovarian, and
prostate cancers. Special cameras identify the
cancer by showing where the radioactive particles
accumulate in the body, and such monoclonal
antibodies can be used to determine the type of
cancer a patient may have after tissue has been
removed during a biopsy.
j BACK f READ MORE…

17
BEYOND ORALSOff-label Use and Oral Oncolytics
• Carry powerful drugs directly to cancer cells.
Some monoclonal antibodies are able to deliver
other cancer drugs directly to cancer cells. Once
the monoclonal antibody attaches to the cancer
cell, the cancer treatment it is carrying enters
the cell, causing the cancer cell to die without
damaging neighboring healthy cells. Brentuximab
vedotin (Adcetris), a treatment for certain types
of Hodgkin and non-Hodgkin lymphoma, is
one example of of an antibody-drug conjugate
(discussed above).
Given these promising advances with monoclonal
antibodies and antibody-drug conjugates, it’s clear
why IV oncolytics will maintain a strong market
position alongside oral alternatives.
Y END j BACK
Moreover, off-label use of oncology drugs can also produce
unwanted consequences for manufacturers, since the
outcomes data resulting from this practice tends to dilute
outcomes data coming from proper, on-label use.
As off-label use becomes more widespread and accepted,
it risks ‘lowering the bar’ for everyone in a sense – by
removing the incentive for drug makers to actually conduct
ongoing research to formally investigate efficacy and safety-
related issues associated with off-label use of their toxic
oncology agents.
The Tipping Point
Affordabilty and Managed-Care Success
According to the National Cancer Institute, the overall cost
of cancer treatment is projected to reach $207 billion by
202015
– a severe increase compared to 2010 expenditures
of $124.6 billion.16
The average oral oncology drug costs
between $10,000 and $12,000 per month, and not every
patient can be expected to have the desired levels of
response or tolerance.
To curtail futile use of costly therapies, private and
government payers have become much more aggressive in
their plan designs and coverage policies. The need to curb
rapidly escalating costs becomes especially important as,
fortunately, today’s growing legion of cancer survivors ends
up taking oncology medications for longer durations to
manage their disease.
Since cancer patients tend to be the most costly in the
healthcare spectrum today, and the newer oral oncology
drugs tend to be the most costly options in cancer care,
stakeholders agree that health plans have a fiduciary
responsibility to make sure they are only paying for the
most appropriate, on-label use. There is little doubt that in
today’s reimbursement environment, “pushing any drug at
any cost is not sustainable,” says Zweigenhaft of Onco360.
More oversight is established through the use of common
managed-care tactics, such as prior authorizations and step
protocols, and greater scrutiny is given to off-label use of
costly oncology therapies.

18
The Tipping Point – Affordabilty and Managed-Care Success
Zweigenhaft sums up the reimbursement reality in today’s
care market: If evidence for the use of certain drugs for
certain patients is lacking and there is equally no evidence
to prove that the use of specific drugs will have any impact
on survival, then “payers cannot be expected to keep
covering the bills – especially as the number of people living
with cancer for longer durations continues to climb.” He
notes that many of the key opinion leaders (KOL), such as
oncologist medical directors and other thought leaders,
have lately openly stated that “physicians have to stop
using drugs that will not benefit their patients.”
“Oncology drugs used to be ‘off limits’
when it comes to managed-care
strategies, but now, they are increasingly
being managed by payers, in terms of
tier formulary designations by class”
Dana Evans, MD, Director, Quality of Care and Patient
Access, US Medical Affairs, Genentech, Inc.
To achieve the most favorable formulary designation for
their drugs (and in order to maximize patient access to
them), today’s pharma companies have no choice but to
increasingly develop and present pharmacoeconomic data
that aims to illustrate the full value of the therapy.
The ability to quantify potential cost savings associated with
using oral therapy in terms of reduced hospitalizations and
emergency room admissions will help to shift the focus –
lowering costs for the overall treatment option.
In the industry, ongoing support for developing oral cancer
medications remains strong. Given the direct impact of
intracellular processes in cancer, “we still need small
molecules that can penetrate the cells and interrupt these
intracellular processes,” concludes Evans of Genentech.
“Although the trend toward more small-molecule oral oncology
treatments is well-established over the past 10 years or so,
we also see it slowing down a bit as the knowledge base
related to dysfunctional pathways, invasion of tissues and the
spread of cancer continues to grow,” he cautions.
It is thanks to a widening range of treatment options that
include not only surgery, radiation and conventional infused
chemotherapies, but newer targeted oral oncolytics and
infused immunotherapies (see our IN FOCUS section), that
long-term survival rates continue to climb. Cancer patients,
the medical community and drug developers have to work
together to identify best practices related to the treatment
of cancer. The challenges around the commercialization
of oral oncolytics illustrate that it will indeed require a
collaborative effort to overcome clinical, financial, physical
and psycho-social barriers, so that any given patient’s cancer
can be affordably treated as an ongoing, chronic condition,
rather than the de facto death sentence it once was.
To speak directly to the leading oncology stakeholders in managed markets, join us for
eyeforpharma’s 6th Annual Oncology Market Access Pricing 2015, the executive
summit of decision makers from pharma, payors, specialty pharmacies, provider
networks, GPOs and community oncology groups. The event on June 15-16 in Boston
serves as the most targeted and high-level gathering on commercialization and market access
strategies for oncology products in the US. We’ll be discussing how to leverage best-in-class
insights to secure access, adherence and product uptake in the shifting site-of-care environment.
You can secure your place here: www.eyeforpharma.com/oncologyusa

19
1 Cancer Statistics 2014, American Cancer Society, Atlanta, Ga.,
January 2014. Accessed online at: http://www.cancer.org/
research/cancerfactsstatistics/cancerfactsfigures2014/index
2 Cancer Treatment Survivorship Facts Figures, 2014-
2015, American Cancer Society, Atlanta, Ga., June 2014;
Accessed online at: http://www.cancer.org/acs/groups/
content/@research/documents/document/acspc-042801.pdf
3 DeSantis, CE; Lin, CC; Mariotto, AB, et al. (2014), Cancer
treatment and survivorship statistics, 2014. CA: A Cancer
Journal for Clinicians; doi: 10.3322/caac.21235.
4 The Global Use of Medicines: Outlook Through 2018; IMS
Health (Parsippany, N.J.); November 2014; Accessed online
at: www.theimsinstitute.org
5 Immunotherapy, University of Pennsylvania Division of
Hematology/Oncology, Philadelphia; Accessed online at:
http://www.pennmedicine.org/hematology-oncology/
patient-care/treatments/immunotherapy.html
6 Streeter SB, Schwartzberg L, Husain N, Johnsrud M. Patient
and plan characteristics affecting abandonment of oral
oncolytic prescriptions. Journal of Oncology Practice. J Oncol
Pract. May 2011; 7(3 Suppl): 46s-51s; doi: 10.1200/
JOP.2011.000316.
7 Deirdre Fuller. Will higher cancer drug costs keep patients
from taking them? Advisory Board. January 21, 2014.
8 Insight 2012, CVS Caremark.
9 Weaver KE, Rowland JH, Keith M. Bellizzi KM, Aziz NM.
Forgoing medical care because of cost: assessing disparities
in health care access among cancer survivors living in the
United States. Cancer. Published Online: June 14, 2010.
10 Geynisman, DM, Adherence to targeted oral anticancer
medications, Discovery Medicine; ISSN: 1539-6509; Discov
Med 15(38):231–241; April 2013.
11 Gater A, Heron L, Abetz-Webb L, Coombs J., Simmons J,
Guilhot F, Rea D. Adherence to oral tyrosine kinase inhibitor
therapies in chronic myeloid leukemia, Leuk Res 36(7):
817-825, 2012.
12 Shelley, Suzanne, Copay programs increased value to
manufacturers is matched by rising criticism,
Pharmaceutical Commerce, January/February 2014;
Accessed online at: http://www.pharmaceuticalcommerce.
com/latest_news?articleid=27073keyword=copay%20
programs-insurance-coupons-pharmacy
13 7 Oncology Trends on Payers’Minds: Insights to stay ahead in
the oncology marketplace, Xcenda, 2014. Accessed online
at: http://www.xcenda.com/Insights-Library/Payer-
Perspectives/7-Oncology-Trends-on-Payers-Minds/
13a Celgene Patient Support (2014): Accessed online at:
http://www.alcancercongress.org/wp-content/
uploads/2014/10/Celgene-Website-Diamond-Spotlight.pdf
14 Conti, RM., Bernstein, AC., Villaflor, VM., Schilsky, RL.,
Rosenthal, MB., and Bach, PB., Prevalence of off-label use
and spending in 2010 among patent-protected
chemotherapies in a population-based cohort of medical
oncologists, Journal of Clinical Oncology, February 2013;
doi: 10.1200/JCO.2012.42.7252.
15 Cancer care costs in the United States: Projections
2010-2020, JNCI J Natl Cancer Inst (2011) 103 (2).
16 Cancer Trends Progress Report – 2011/2012 Update,
National Cancer Institute, NIH, DHHS, Bethesda, MD,
August 2012, http://progressreport.cancer.gov
17 Immunotherapy, University of Pennsylvania Division of
Hematology/Oncology, Philadelphia; Accessed online at:
http://www.pennmedicine.org/hematology-oncology/
patient-care/treatments/immunotherapy.html
18 What is Immunotherapy? American Society of Clinical
Oncology (ASCO), Accessed online at: http://www.cancer.
net/navigating-cancer-care/how-cancer-treated/
immunotherapy-and-vaccines/what-immunotherapy
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