Learn how to use Real World Evidence (RWE) to bridge the evidence gap between regulators and payers.

1. © 2018 PAREXEL INTERNATIONAL CORP.
UNDERSTANDING
DIFFERENT
STAKEHOLDER
REQUIREMENTS
THROUGHOUT
COMMERCIALIZATION
Richard Macaulay

2. © 2018 PAREXEL INTERNATIONAL CORP. / 2
USING RWE TO
BRIDGE THE
EVIDENCE GAP
BETWEEN
REGULATORS
AND PAYERS
• The emerging evidentiary gap
between payers and regulators
• Overview: payers vs. regulators
• Recent trends
– Payers and regulators
– New transformative therapy classes
• The evidence divergence
• How RWE can bridge this gap
• Conclusion/summary
AGENDA

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DUBLIN, IRELAND
COMPARING PAYERS
AND REGULATORS

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Quality1 Safety2 Efficacy3 Value4
Regulators Payers
Key considerations of… Focus of…
Hurdles to Patient AccessHurdles to patient access
THERE ARE 4 HURDLES THAT A PRODUCT MUST
CLEAR TO ACHIEVE PATIENT ACCESS

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…HOWEVER, THE EVIDENTIARY DEMANDS OF PAYERS
AND REGULATORS ARE DISTINCT…
Regulators Payers
KEYFOCUS
Quality Comparative benefits
Efficacy Real-world effectiveness
Safety Economic value
Product is safe and efficacious as demonstrated
through trial data
Product will offer real-world clinical value over standard of
care and represents an optimal investment of limited funds
Regulators
Payers
Evidence requirements

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… AN ADDITIONAL ITEM OF COMPLEXITY IS THE NUMBER
AND VARIETY OF PAYERS VERSUS REGULATORS
Regulators
Typically single trans-national bodies (eg, FDA/EMA)
with similar foci
Payers
A range of national, regional and local payers by market
with varying and distinct foci
The wide range of payers can be split into archetypes with similar foci
Payer archetype Market example
Cost-effectiveness
Comparative clinical effectiveness
Budget optimisation
Payer archetyping

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LONDON, U.K.
RECENT TRENDS
REGULATORS

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5
TRADITIONALLY, THE REGULATORY HURDLE WAS SEEN
AS THE KEY ONE TO OVERCOME FOR PATIENT ACCESS
New Expedited
Access Pathways
Regulatory Hurdle is Decreasing
Breakthrough
Status
Adaptive
Pathways
EfficacySafetyQuality
Regulators
DRIVENBY
FDA
EMA
Regulatory hurdle is decreasing

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ZYKADIA®
ceritinib
KEYTRUDA®
pembrolizumab
… RESULTING IN THERAPIES BEING APPROVED AT
VERY EARLY CLINICAL DEVELOPMENT STAGES
FDA approval
date
Key efficacy
data source
Expedited FDA
regulatory
pathways
29 April 2014
Phase 1 trial
Single-arm, n=163
Orphan designation
Breakthrough Status
Accelerated Approval
4 September 2014
Phase 1 trial
Single-arm, n=173
Orphan designation
Breakthrough Status
Accelerated Approval
Examples of drugs FDA approved on Phase 1 data

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BERLIN, GERMANY
RECENT TRENDS
NEW THERAPY CLASSES

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THERE ARE TRANSFORMATIONAL NEW CLASSES OF
THERAPIES SUCH AS GENE THERAPIES…
Eg. STRIMVELIS ®
Gene therapies
Gene
inserted into
a virus
Curative potential for
genetic diseases and long-
term cost savings
Indication: ADA-SCID
SoC: ERT ~$500,000/yr or HSCT
AD1115611 (Phase 1/2 trial, n=12)
100% survival (median f/u 7yrs)
Replace faulty
or missing
genes in
patients’ cells

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… PLUS CAR-T CELL AGENTS THAT SHOW
REMARKABLE EFFICACY IN ADVANCED CANCER…
Eg. KYMRIAH®
CAR-T cell therapies
Genetically
engineered
T cells
Express a
synthetic receptor
designed for a
specific target
Expand and persist in
vivo with high potency
Indication: r/r B cell ALL
ELIANA (Phase 2 trial)
83% CR/CRi at 3 months
79% 12-month OS

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.. AND IMMUNO-ONCOLOGY DRUGS WHICH OFFER LT
SURVIVAL BENEFITS ACROSS MULTIPLE CANCERS
Immuno-oncology (I-O)
Harnessing the
body’s immune
system to fight
cancer
Five FDA-approved anti-PD-1/L1
Potential for LT survival
benefits
KEYTRUDA® (pembrolizumab)
OPDIVO® (nivolumab)
TECENTRIQ® (pembrolizumab)
IMFINZI® (durvalumab)
BAVENCIO® (avelumab)
T cell
Cancer
cell
I-O agents
block immune
inhibitory
receptors
PD-1
PD-L1
Combinations

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NEW THERAPY CLASSES WITH TRANSFORMATIVE
BENEFITS WILL BE EXPEDITED APPROVAL CANDIDATES
New therapy classes
Gene
therapies
CAR-T cell
therapies
Immuno-
oncology
Offer
transformational
patient benefits
Candidates for
expedited
regulatory
approval
Approved on
earlier
clinical data
packages
Transformative
therapy classes
Key features Consequences
For diseases with
severe unmet
needs
Often in rare
patient
populations

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BOSTON, MASSACHUSETTS
RECENT TRENDS
PAYERS

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CONCURRENTLY, PAYERS ARE DEMANDING MORE
EVIDENCE TO JUSTIFY PRICE PREMIUMS…
Escalating costs Budgetary pressures
Reimbursement authorities are becoming more demanding of the
patient value of new healthcare technologies
Reimbursement hurdle

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… THIS IS A TREND THAT IS ESPECIALLY CLEAR
OUTSIDE THE US…
Ex-US pricing trends
Structural P&R reforms
Payer evidence
acceptance trends
e.g.
AMNOG
CDF
Budget impact
Clinically-meaningful benefits
In patient-relevant endpoints
From trials directly compared to
the relevant comparator
A trend for payers to
increasing demand

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… BUT THE PRICE OF MEDICINES IS INCREASINGLY A
FOCUS OF DEBATE IN THE US…
US pricing trends
Value scorecards
driven by provider
organisations
Cost-utility
evaluations by ICER
becoming prominent

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… SUCH THAT IN MANY COUNTRIES THE PAYER HURDLE
IS MORE DIFFICULT TO CLEAR THAN THE REGULATORY
Payer hurdle increasingly key in many markets
EfficacySafetyQuality
Regulators
Value4
Regulators Payers
Marketing authorisation
increasingly less seen as the
major barrier to patient
access…
… compared with the
challenges of translating this
into approval by payer bodies
(e.g. NICE, G-BA, PBAC)

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TOKYO, JAPAN
THE EMERGING
EVIDENCE GAP

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THERE IS AN EVIDENTIARY DIVERGENCE BETWEEN
THE DEMANDS OF PAYERS AND REGULATORS…
Evidentiary misalignment
Comparative Clinical Benefits
Robust Health Economic Analyses
Patient-Relevant Endpoints
Single-arm
Phase I/II data
Increasing Evidence Demands
of Payers
Evidence Provisions
of Expedited Pathways
Increasing demand for Increasing approvals on

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Mock NICE technology appraisal of a CAR-T cell therapy
Hettle et al. Health Technol Assess. 2017 Feb;21(7):1-20
… THESE NEW TRANSFORMATIVE THERAPIES WILL
DEMAND HIGH PRICES IN LINE WITH THEIR VALUE…
Prices of transformative therapies
10.07 Incremental QALY gain per patient
Price per patient (on top of SoC)>£500k
Assume NICE WTP of
£50,000/QALY

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… PLUS GENE & CAR-T THERAPIES ONLY NEED SINGLE
TREATMENTS => SUBSTANTIAL UPFRONT INVESTMENT
P&R issue of single treatment duration
Many CAR-T and
gene therapies
Require a single
treatment
Expenditure is not spread across the
duration of treatment
Entire costs must be incurred upfront

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… BUT HOW DO YOU APPROPRIATELY REIMBURSE
THERAPIES WHERE UNCERTAINTY IS SO HIGH?
Appropriate reimbursement?
High
costs
High
benefits
High
uncertainty
High
risk

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SOME THERAPIES WITH SUBSTANTIAL CLINICAL GAINS
HAVE NOT TRANSLATED INTO COMMERCIAL SUCCESS
GLYBERA® – first EC-approved gene therapy1
Regulatory
approval
• EC-approved in Oct 2012
• For hereditary LPLD (incidence ~1 per million)
Commercial
launch
• Launch price (in Germany) €1.1 million per
patient
Market
withdrawal
• May 2016 - only been used commercially once
• Nov 2017 - UniQure did not renew their
marketing authorisation
1ScienceBusiness.net (2017) World’s first gene therapy to be withdrawn in from market in Europe

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SHANGHAI, CHINA
USING RWE
TO BRIDGE THIS GAP

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GENERATING PAYER-RELEVANT CLINICAL TRIAL DATA
MAY NECESSITATE TRADE-OFFS IN TIME, COST AND RISK
Trade-offs in generating payer relevant clinical trial data
Payer-relevant
comparator
Payer-relevant
endpoints
larger
trial
Time
Cost
Risk
longer
to read
out
Time
Risk

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…BUT COMPANIES CAN ALSO USE RWE TO BRIDGE THIS
EVIDENCE GAP FOR OPTIMAL MARKET SUCCESS…
Real world
evidence
Bridging the gap
Payer evidence
demands
Evidence required
for regulatory
approval

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RWE can be used to quantify and validate:
… AND RWE CAN PROVIDE SUPPORT TO OPTIMISE
THE VALUE OF A PRODUCT IN MANY WAYS…
Real World Evidence
Disease
burden
Clinical
benefit
Economic
benefits
Epidemiology
Treatment patterns
Unmet need
Effectiveness
Safety
Performance-based
pricing schemes
Support cost-
effectiveness and
budget impact
modelling

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… WITH RWE ALREADY HAVING BEEN USED TO
SUPPORT REIMBURSEMENT ACROSS MANY MARKETS
Examples of directly using RWE in reimbursement
Market Example(s)Scheme
AIFA-Onco Registry established
in 2005 – performance-based
pricing well-established
2016 Cancer Drugs Fund reforms
as a temporary reimbursement
fund to collect RWE
Since 2011, Managed Entry
Schemes allow dynamic pricing
based on RWE
In the last 3-4 years, a trend
towards performance-based
pricing schemes
TASIGNA® (nilotinib)
TAGRISSO® (osimertinib)
XALKORI® (crizotinib)
REPATHA® (evolocumab)
ENTRESTO (SAC/VAL)
KYMRIAH (tisagenlecleucel)

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TAIPEI, TAIWAN
SUMMARY AND
CONCLUSIONS

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REIMBURSEMENT IS INCREASING BECOMING A KEY
HURDLE FOR COMPANIES, RWE OFFERS A SOLUTION
Regulators are reducing evidentiary demands for marketing
authorization through a range of new expedited approval pathways
There are a range of innovative therapies coming to market that
will likely be approved through such pathways on very early
clinical data packages, with the potential for transformational
patient benefits but where substantial uncertainty remains
Payers, whom are increasingly demanding more robust evidence
to justify price premiums, will find it very challenging to
appropriately price and reimburse such therapies
How companies navigate this emerging evidentiary gap between
regulators and payers to obtain faster reimbursement will be
increasingly key to ensuring market success
RWE offers an opportunity to fill these evidentiary gaps by
examining how medicines are used and perform in the real world

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ANY QUESTIONS

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THANK YOU
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