View this presentation to learn strategies for generating evidence that will help your product clear market access hurdles.

1. © 2017 PAREXEL INTERNATIONAL CORP.
GENERATING
EVIDENCE TO
DRIVE PATIENT
ACCESS
11 October 2017

2. © 2017 PAREXEL INTERNATIONAL CORP. / 2
THE NEW REALITY
In the current healthcare environment, regulatory approval gets a
sponsor to a new “starting line.”
The marketplace is demanding demonstration of real-world value
before fully adopting or supporting a new treatment alternative.

3. © 2017 PAREXEL INTERNATIONAL CORP. / 3
A PRODUCT MUST CLEAR FOUR HURDLES TO
ACHIEVE PATIENT ACCESS
Quality1 Safety2 Efficacy3 Value4
Regulators Payers
Key considerations of… Focus of…
Hurdles to Patient Access
Regulatory Approval is Traditionally Seen as the Key Barrier

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THE MOLECULAR BASIS OF UNCERTAINTY:
A SUBCELLULAR HYPOTHESIS - SEAN TUNIS
Decision
Makers
Low affinity receptors
for evidence. >
Knowledge
Translation #2
Health
Technology
Assessment
Knowledge
Translation #3
Identify Gaps in Evidence
Decision-making
Defective
Transport
Knowledge
Translation #1
Slow
Diffusion
Clinical
Research
Enterprise
Published
Evidence
Intellectual
Curiosity
Scientific Evidence•

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5
Clinical Benefit - Magnitude
More accepting of
shorter-term
surrogate endpoints
(eg, PFS, ORR, HbA1C,
LDL)
More demanding of
benefits in patient
relevant “final”
endpoints (eg, morbidity,
mortality, QoL)
Endpoints Study Design
More accepting of
benefits from a highly
controlled clinical
study setting
Want to know that
study benefits will be
reflected in the real-
world population to
be treated
Regulators
Payers
£ $
Payers Want to Ensure that Endpoints from RCTS
Translate Into Real Patient Benefits in Clinical Practice
HEALTH,
WELL-BEING
HEALTH
ECONOMICS

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UNCERTAINTY AROUND DRUG EFFECTIVENESS IS DRIVING
THE USE OF INNOVATIVE CONTRACTING AGREEMENTS
• How can uncertainty at the time of launch about a new drug's real
value be overcome?
• What can be done to ensure that a medicine is used by the right
patients in the real world and improved patients’ QoL?
• How can spending on the drug be contained for individuals and the
patient population as a whole?
Payers are likely to delay or refuse reimbursement if one
or more of these questions remain unanswered, especially
if a drug is expected to have a substantial budget impact.
THE
TAKEAWAY

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REAL-WORLD
CHALLENGES
7

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8
REAL-WORLD EXAMPLES: MARKET-ACCESS ISSUES
Drug Disease Issue
Consequences & mitigation
strategies
Lipoprotein Lipase
Deficiency (ultra
orphan indication)
nmDMD
(ultra-orphan
indication)
2L+ NSCLC
Hypercholesterolemia
Chronic Psoriasis
and PA
Pancreatic cancer
1st EC approved gene therapy
Small patient population, no
comparator, surrogate
endpoint
Conditional EMA approval on
Phase IIb data – only
subgroup data positive (6 min
walk test)
Trial terminated early
Lack LT follow-up
Uncertainty over DOT
Regulatory approval on
clinical trials using surrogate
endpoint (LDL-c)
Seen as innovative by NICE
but not as value for money.
Not seen as cost-effective by
IQWiG
Significant increase in OS but
only 1.8 months and no QOL
data collected
Delayed launch (EMA approved in 2012) to collect 6-yr follow up
data
>€1 million per patient price tag. DE launched in Q4 2014, UK
launch in July 2016. In May ‘16 only 1 reported sale in Europe
Rejected by SMC but has been approved by NICE under a
Managed Access Agreement, whereby the drug is made
temporarily available at a discount until more mature data is
available
Despite transformational LT survival benefit claims, have
struggled to gain positive appraisals in some obligate
cost/QALY markets (incl NICE & PBAC) in NSCLC. Economic
stopping rule used in NICE ACD.
Data sufficient for regulatory approval but not for reimbursement
(not recommended by SMC and TLV, no added benefit-IQWiG,
ASMR IV -HAS). Ongoing trials to measure CV outcomes
Strong efficacy and safety data but limited cost-effectiveness
data. Approved in August 2016 by NICE based on a confidential
discount and use in only severe patients.
HAS – deemed ASMR IV versus generic comparator, led to
exclusion from the liste en sus and being only reimbursed under
a DRG – i.e. low prices and limited access

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NEW CURATIVE AND
HIGHLY EFFICACIOUS
END-OF- LIFE THERAPIES
CREATE UNIQUE
CHALLENGES
e.g. @Hepatitis C
• “The sky-high cost of Glybera
($1.4 million)..shows single
curative therapies to fix faulty
genes may upend the
conventional pharmaceutical
model”
• What was the benefit to the
patient and the health system as
a whole?

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HARD ENDPOINTS ARE MORE SIGNIFICANT IN THE REAL WORLD
THAN SURROGATE ENDPOINTS
• Landmark Outcomes Study Shows That Repatha®
(Evolocumab) Decreases LDL-C To Unprecedented Low
Levels And Reduces Risk Of Cardiovascular Events With
No New Safety Issues
• Repatha Significantly Reduces Risk of Hard Major Adverse
Cardiovascular Events by 20 Percent
• Risks of Heart Attack, Stroke and Coronary Revascularization were
nominally reduced by 27 Percent, 21 Percent and 22 Percent,
respectively
• Patients in Study had History of Heart Attack, Stroke or Symptomatic
Peripheral Arterial Disease and Were Treated With Optimized Statin
Therapy
• Amgen agreed to Offer Innovative Refund Contracts, including a
refund of the cost of Repatha for all of their eligible patients who
have a heart attack or stroke
• Detailed Results Simultaneously Published in the New England Journal
of Medicine and Presented at the American College of Cardiology 66th
Annual Scientific Session

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CO-CREATION IS A WAY OF ENSURING EARLY BUY-IN
FROM THE MARKET
Novartis's deal with French healthcare system
Xolair (omalizumab)
Government agreed to make Xolair available at requested price, if evidence of the drug’s
real-world effectiveness was collected, according to a protocol designed in conjunction with
the payer
The study aimed to determine whether Xolair decreased the risk of hospitalization due to
exacerbations among severe asthma patients. The parties agreed that Xolair’s price would be
maintained if the evidence was positive, and would fall if not.
The results from the trial, which involved over 750 patients and was funded entirely by Novartis,
showed that the drug did decrease hospitalization risk. The relative rate of severe asthmatic
episodes fell by 40–65% among those taking Xolair (Grimaldi-Bensouda et al. 2013)
PROS
Risk-shares can allow pharma to maintain a premium price while generating the kind of peer-
reviewed real-world evidence (RWE) that will increasingly be required for uptake in all major
markets.

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PUTTING YOUR MONEY
WHERE YOUR MOUTH IS
The industry
must convince
payers that we are
willing to back our
product, with
innovative contracts
supported by strong
RWE

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WHY IS THE PATIENT EXPERIENCE SO IMPORTANT IN
SUCCESSFUL PRODUCT REIMBURSEMENT
Rare Diseases / complex LT conditions e.g. haemophilia / conditions with high unmet
needs e.g. chronic migraine, atopic dermatitis
Highly active patient associations & growing online forums discussing current and future
treatment options, clinical trials and patient experiences
Capturing and communicating the patient experience is key to reimbursement because
Payers budgets are influenced by the political environment
Conditions such as Cancer, Diabetes and CVD are likely to always be prioritised over
other conditions
Other therapy areas have to fight for their share of a limited funding pot

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PATIENT ADVOCACY SUCCESS STORIES
A regional politician in Wales stated that chronic migraine for their constituents was not
being properly managed due to a lack of funding – Payers from LHBs were put under
pressure to find the appropriate funding for the condition or receive bad press; as a
result the condition soon took priority over other conditions, all fighting for a share of
the budget (at least whilst it was in the newspapers)
Similarly, patient share-of-voice can be instrumental in lobbying Government for additional
funding for rare or chronic conditions. In the UK, Astellas successfully lobbied Parliament for a
greater allocation of funding for patients with Incontinence and the company was invited to
speak at Parliament, alongside patient group representatives. This also moved the therapy
area further up the priority list in a number of CCGs across England
In Ophthalmology, in Germany and the UK, patients with RVO in rural areas were going
untreated or left with long waiting times before they could be seen by a Consultant. In
some cases, patients were losing their sight, due to these long delays. In Germany,
Consultants were incentivised to increase the throughput of patients by being paid a
supplement for treating patients with the condition within a certain timeframe. In the UK,
a separate pot of money was agreed with the NHS purely for the treatment of these
patients
In Haemophilia A and B, patient groups are highly active and often change their treatment
options, depending on the latest available therapies. Patients with inhibitors are especially
prone to treatment failure and are always looking for new and better options for managing
their condition. Capturing the patient experience is key to convincing Patients, Clinicians and
Payers to endorse new therapeutic options in these complex disease area

15. © 2017 PAREXEL INTERNATIONAL CORP. / 15
BERLIN, GERMANY
CAPTURING THE
PATIENT
EXPERIENCE
REAL-WORLD
EVIDENCE
STRATEGY:

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WHY DO WE NEED REAL-WORLD STUDIES?
Of 20,388 US Medicare patients ≥ 65
years of age, only 1 in 5 discharged
from an acute care hospital with a
diagnosis of congestive heart failure
(CHF) met the criteria for enrollment in
3 landmark trials that guide treatment
of all CHF patients.
Masoudi FA, Havranek EP, Wolfe P, et al. Am Heart J. Aug 2003;146(2):250-257.
Most RCTs use narrow inclusion and
exclusion criteria to select the
participants most likely to benefit from
an intervention and least likely to
experience harm.
?

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Randomized Clinical Trials (RCTs) don’t reflect actual medical practice.
• Tight inclusion/exclusion criteria
• Mandated procedures and treatment
• Randomization, blinding, placebo, etc.
• Short in duration
• Homogeneous sites and patients
We need to know how a product is used and how it “performs”
under real-world conditions.
• Safety
• Clinical outcomes and effectiveness
• Economic value
• Humanistic value
BECAUSE…
Homogeneity
Heterogeneity

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EXACTLY WHAT ARE REAL-WORLD STUDIES?
Clinical research that observes clinical practice, rather than
defines it.
Patients are “real,” with varying co-morbidities, compliance, and
preferences.
The Physician prescribes an approved drug or treatment for their
patient, with no protocol mandate
The Physician treats a patient per usual care – the study doesn’t
alter their care in any way.
They generate details about patient outcomes, patient-selection
criteria, product usage, product safety, effectiveness and overall
value in the “real world.”
They are scientifically driven and clinically relevant.

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REAL-WORLD RESEARCH MODELS
PRAGMATIC ‘SPECTRUM’
Primary Interventional
Studies
Retrospective Chart
Reviews
Secondary Database
Analyses
EMR Data Analysis
Primary NIS /
Observational Studies
/ Registries
Hybrid Studies
Interventional Observational
Minimally
Interventional Studies

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UNIQUE VALUE OF REAL-WORLD DATA
• Outcomes
• Incidence and prevalence
• Standard of care and
treatment patterns
• Diagnosis distribution
• Distribution of care
• Quality of life
• Demographics (age,
gender, geography)
• Risk-sharing and value
agreements
• Cost-effectiveness
• Budget impact
• Health care costs
• Burden of illness
• Socioeconomics
(income, education,
sick-leave)
• Productivity loss
• Patient-selection criteria
• Prescription patterns
• Safety & effectiveness
• Persistance
• Compliance
• Dosage
• Referrals
• Time to treatment
• Supplement trial data
UNDERSTAND
DISEASE
CLARIFY
ECONOMICS
CHARACTERIZE
TREATMENTS

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In actual use…
• Will the product be safe and effective?
• Will the product be cost-effective?
• Will quality-of-life be enhanced?
• Are there important hypotheses worthy of further evaluation?
• Are there subsets of patients in which the product seems to work best?
• Where are the patients, and who are the treating physicians?
• For whom – and how - will physicians prescribe the product?
• How will the market be affected by the entry of the product?
• How will competitors be affected?
WHAT QUESTIONS CAN YOU ANSWER?

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= Good outcome = Intermed outcome = Bad outcome
MEAN TREATMENT DIFFERENCE MEAN TREATMENT DIFFERENCE
RISK
STRATIFICATION
WHY ARE SUBGROUPS SO IMPORTANT?

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LINKING DATA ASSETS OFFERS THE MOST
COMPREHENSIVE VIEW OF THE PATIENT EXPERIENCE
The Patient
Experience
EHR
Clinical
Data
Healthcare
Utilization &
Cost Data
from Claims
Other
Secondary
Data
Physician-
Reported
and Patient-
Reported
Measures

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DIRECT-TO-PATIENT OPPORTUNITIES ARE EMERGING
PHARMA MUST DECIDE HOW BEST TO LEVERAGE THEM
DTP Innovations Impacting RWE Generation
The delivery of direct-to-patient studies includes ‘siteless constructs’ which leverage e-consent & screening
technologies, social media, central labs & home-health professionals, wearables/devices for collecting patient
reported outcomes in real-life, as well as EMR and secondary data analysis

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SIMPLIFYING THE JOURNEY - KEY BENEFITS FOR
MOBILE HEALTH/SENSORS
The Sponsor
• Increased frequency of
data assessment
• Novel data sources and
outcomes assessment
• Improved protocol
compliance
• Lowered costs through
fewer visits
• Expansion in participation
The Site
• Better insights into
patient’s profile and health
beyond routine visits
• Reduced burden and cost
• Earlier indications of
warning signs
• Better compliance
• Eliminates recall bias
• Improved communications
The Patient
• Increased engagement,
motivation, and
compliance
• Fewer in-clinic
assessments, less travel
• Increased frequency of
endpoint assessment
• Safety: real time user
feedback
• Ease of use
The magnitude (or even existence) of benefits is critically linked to
appropriate protocol design, sensor choice and operational model

26. © 2017 PAREXEL INTERNATIONAL CORP. / 26© 2017 PAREXEL INTERNATIONAL CORP. / 26
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