1. Analysis of regenerative medicine
technologies worldwide: How have
they been assessed by HTAs on a
global basis?
Plenary Session
Eric Faulkner, MPH
Director, Global Market Access, Quintiles
Adjunct Assistant Professor, Eshelman School of
Pharmacy, University of North Carolina at Chapel Hill
Executive Director, Genomics Biotech and Emerging
Medical Technology Institute, NAMCP
January 2012

2. The Value of Innovation is a Matter of
DEGREE in Healthcare Reimbursement
INNOVATION: a new idea or method: a new invention or way of doing something*
What evidence of comparative effectiveness?
What value vs. alternatives?
Is it cost-effective?
Short vs. long term effect?
Is it safe?
Marginal vs. transformative?
Does it work?
New mechanism of action?
*Source: Encarta World English Dictionary. Image source: www.bing.com
2

3. Value: The Devil is in the Detail
Building Value: The Devil is in the Detail
How much is Easy to
According to enough? say…harder
whom? to measure
VALUE = outcomes
What are the costs
best models &
approaches?
coststhe
What is
right balance?
What
benefits vs.
alternatives?
How do we get
there?
*Image source: www.bing.com

4. Value: A Gem is the Sum of its Facets
Value: A Gem is the Sum of its Facets
Because value is multi-
dimensional…it is often difficult
capture all facets
Sustainability of
Time to recovery
health or recovery Budget impact &
Survival and return to
Unmet Need
and nature of cost-effectiveness
normal activities
recurrences
Disutility of care or
treatment process Long-term Comparative
Degree of health
(e.g., diagnostic consequences of impact vs.
or recovery
errors, ineffective therapy alternatives
care)
PARTICULARLY true for regenerative medicine…
Adapted from: Michael Porter. What is value in healthcare? NEJM 2010. Image source: www.bing.com

5. Health Decision Makers View Regenerative
Medicine as a “True Innovation”
Regenerative medicine ranked comparably with molecular diagnostics and
personalized medicine as a true innovation, but decision makers were less certain
regarding cost offset potential
Technology Type Greatest Potential to Greatest Potential to
Improve Care Quality Provide Cost Offsets
(% respondents; n=121) (% respondents; n = 120)
Small molecule drugs 14.0 14.2
The
Personalized medicine 27.3 17.5
Regenerative
Medicine
Cellular therapies and 20.7 Dilemma… 9.2
regenerative medicine
Promise vs.
Molecular diagnostics 24.0 Cost 15.0
Concerns
Diagnostic imaging 9.1 5.0
Nanotechnology 16.5 10.0
Source: Survey of payers, hospital administrators and manufacturers from the National Association of Managed Care Physicians membership survey evaluation 2009-10.

6. Cell Therapies & Regenerative Medicine:
What is Different?
Issue Cell Conventional Implications
Therapies & Biologics
Regenerative
Medicines
Well understood & accepted Not well, at No • Payers and physicians may
by payers and physicians present place higher scrutiny on value
perceived as demonstration
truly novel • Commercialization may
involve additional educational
efforts and/or complexities
Involves multiple procedural Often Rarely • More like reimbursement for a
steps that may be separately device/procedure
reimbursable • Failure to achieve
(including in cell extraction,
reimbursement of any
purification and processing, and component part may
administration that may include jeopardize reimbursement of
imaging) the entire procedure
HTA will focus on the cost- Yes Not often • Requires HEOR data
effectiveness of the entire applicable collection regarding the entire
procedure procedure

7. Cell Therapies & Regenerative Medicine:
What is Different?
Issue Cell Conventional Implications
Therapies & Biologics
Regenerative
Medicines
May involve multiple billing Yes No • Lack of appropriate
codes /tariffs and/or payment codes/tariffs or payment may
centers for reimbursement of limit or preclude access and
the full procedure uptake
May involve requirements for Yes Sometimes • This is a top HTA criticism of
longer-term data collection to most cell therapies in global
demonstrate value (including markets to date
post-market follow-up data)
Strong potential to be more Often Sometimes • Higher cost means that
costly than standard of care therapies must demonstrate
(SOC) alternatives significant outcome
improvements vs. SOC
comparators
May enable a disease cure or Yes Rarely • Can alter the balance of
prolonged therapeutic effect benefit-cost tradeoffs in value
assessment

8. Can we Learn from HTAs Re: Value
Demonstration for Regenerative Medicine?
The Good
*Image source: www.photobucket.com

9. Global Evaluation of Regenerative Medicine
Health Technology Assessments (HTAs)
• Purpose of the study: Evaluate all available HTAs on cell
and gene therapies in key global HTA markets to:
– See how early regenerative medicine technologies have been
handled
– Identify key HTA criticisms that impacted reimbursement &
commercial potential
– Derive lessons for upcoming technologies in the space
• Included review of 48 HTAs and reimbursement policies
from Australia, Canada, France, Spain, Sweden, the UK
and US
– No HTAs available from Germany and Italy on the topic
– Did not include evaluation of Brazil, Russia, S. Korea, China, Japan
– Many are nonredundant…so harder to see trends on same technology
across markets
– Excluded traditional cell replacement therapies for cancer indications
(e.g., bone marrow, peripheral blood)
*Image source: www.bing.com

10. Evidentiary Criticisms in HTA
Differences Among Markets
Evidence Consideration AU CA FR DE IT ES SE UK US
Insufficient evidence of value S S NA NA NA S Y S S
Insufficient number/quality of studies S S NA NA NA Y Y S S
Lack of comparative data S S NA NA NA Y Y S S
Lack of long term data (>1 year) Y Y N NA NA Y Y Y S
Inconclusive or inconsistent outcomes S N NA NA NA NA N S S
Focus on surrogate outcomes S S NA NA NA S Y N S
Inappropriate endpoints S S N NA NA Y Y S S
Concerns regarding safety N N Y NA NA N N N S
Insufficient efficacy S S NA NA NA Y Y S S
Insufficient cost-effectiveness S NA N NA NA N Y N N
Y = yes, in all assessments (yellow); S = some (green); N = no (red); NA = not available. Abbreviations: AU = Australia, CA = Canada, FR =
France, DE = Germany, IT = Italy, ES = Spain, SE = Sweden, UK = United Kingdom, and US = United States. *Note: due to the limited number of
assessments in some markets and variability of information reported in HTAs and reimbursement policies, results should be interpreted with
caution.
N = 48 HTAs and reimbursement policies from Australia, Canada, France, Spain, Sweden, the UK and US

11. Evidentiary Criticisms in HTA
Differences Among Markets
Evidence Consideration AU CA FR DE IT ES SE UK US
Insufficient evidence of value S S NA NA NA S Y S S
Insufficient number/quality of studies S S NA NA NA Y Y S S
Aside from the US,
Lack of comparative data S Australia had the most
S NA NA NA Y Y S S
Spain and
HTAs (n=15). Many
Sweden had few
Lack of long term data (>1 year) Y were horizon scanning
Y N NA NA Y Y Y S
HTA reviews on
reports and virtually
regenerative
Inconclusive or inconsistent outcomes S N all rejected the
NA NA NA NA N medicineS
S and
technology based on
premature to
Focus on surrogate outcomes S S level of NA
NA NA S Y N S
draw conclusions
evidence/maturity and
on payer
Inappropriate endpoints S S some due to
N NA NA Y Y S S
position +
insufficient marginal
perspectives
improvement to
Concerns regarding safety N N Y NA NA N N N S
address unmet need
Insufficient efficacy S S NA NA NA Y Y S S
Insufficient cost-effectiveness S NA N NA NA N Y N N
Y = yes, in all assessments (yellow); S = some (green); N = no (red); NA = not available. Abbreviations: AU = Australia, CA = Canada, FR =
France, DE = Germany, IT = Italy, ES = Spain, SE = Sweden, UK = United Kingdom, and US = United States. *Note: due to the limited number of
assessments in some markets and variability of information reported in HTAs and reimbursement policies, results should be interpreted with
caution.
N = 48 HTAs and reimbursement policies from Australia, Canada, France, Spain, Sweden, the UK and US

12. Evidentiary Criticisms in HTA
Differences Among Markets
Evidence Consideration AU CA FR DE IT ES SE UK US
Insufficient evidence of value S S NA NA NA S Y S S
Many US HTAs were
Insufficient number/quality of studies S S NA NA NA noncoverageY
Y policies
S S
for technologies not
yet on the market.
Lack of comparative data S S NA NA NA Y Y S S
Main reason is likely
UK HTAs did not to prevent broader
Lack of long term data (>1 year) Y Y N NA NA Y Y Y S
generally include hospital use through
traditional cost- existing
Inconclusive or inconsistent outcomes S N NA NA NA NA N S S
effectiveness analysis reimbursement
seen in NICE review mechanisms for
Focus on surrogate outcomes S S NA NA NA S Y N S
(at this point). Many “unproven
technologies were technologies”
Inappropriate endpoints S S N NA NA Y Y S S
early stage, “home
Concerns regarding safety N Nbrew”,Y and/orNA NA N N N S
required physician
Insufficient efficacy S Sapproval to use
NA NA NA Y Y S S
Insufficient cost-effectiveness S NA N NA NA N Y N N
Y = yes, in all assessments (yellow); S = some (green); N = no (red); NA = not available. Abbreviations: AU = Australia, CA = Canada, FR =
France, DE = Germany, IT = Italy, ES = Spain, SE = Sweden, UK = United Kingdom, and US = United States. *Note: due to the limited number of
assessments in some markets and variability of information reported in HTAs and reimbursement policies, results should be interpreted with
caution.
N = 48 HTAs and reimbursement policies from Australia, Canada, France, Spain, Sweden, the UK and US

13. Case: Autologous Chondrocyte Implantation
for Knee Cartilage Defects
Key Takeaways:
RECOMMENDATION:
Clinical Rationale: • Technologies reviewed as
NOT recommended, except in
a bundle
context of ongoing clinical
• Few RCTs; small sample • Limited discrimination
studies
sizes; poor trial design & between major
controls technologies
Economic Rationale: • Inconsistent study • Poor study design =
designs and outcomes increased potential for
• Insufficient evidence to reported rejection
produce robust cost/QALY • Inconsistent evidence of
• Methods for mapping QoL to clinical effectiveness
Implications for
economics not sound • Proportion of post- Regenerative Medicine:
• Long-term NICE model took procedural complications
into account cost of knee • Limited long-term • Value demonstration for
replacement + QoL for 50 yrs outcomes data; when QoL-driven indications is
• ICER for mosaicplasty available, similar to difficult; align with payer
dominated ACI in modeled standard of care expectations
sceanarios • No comparison with • Focus on quality design
• Inconsistent model results conservative management
• Prepare for long-term
based on “poor” evidence follow-up

14. Case: Pancreatic Islet Cell Transplant After
Pancreatectomy
RECOMMENDATION: Key Takeaways:
Clinical Rationale:
Recommended, but with
• Poor study designs and
stipulations for educating
• Only case series were even safety can be
patients on procedure risk and
available, with study overlooked if:
stipulations on treatment
selection designs that NICE would – Population is small with
generally not consider high unmet need
under “normal”
– Outcomes are
circumstances
transformative or
• 24% to 85% of patients exceptional
Economic Rationale: were insulin-free at 6-18
months
• Extremely small, niche • In one study 75%
population with Implications for
remained insulin-free up
Regenerative Medicine:
– High unmet need to 5 years
– Limited budget impact • Accepted despite serious
• Payers recognize clear,
potential AEs, including
• No economic review included vein thrombosis, liver
transformative outcomes
in the assessment failure, pancreatic • Expect greater scrutiny for
infarct, and sepsis marginal, poorly
differentiated outcomes

15. Case: Limbal Stem Cell Transplantation for
Limbal Cell Deficiency
Key Takeaways:
RECOMMENDATION:
Clinical Rationale:
Recommended, for patients • Accepted despite high
with nonpterygium limbal cell • Out of 873 citations, only procedural costs because:
deficiency (ocular disorder) but 9 studies met inclusion – Population is limited with
weak evidence for treatment of criteria, suggesting that high unmet need
pterygium recurrence rigorous study design is – Therapy provided clear
required (only RCTs) clinical benefits
• Long-term defined as • Safety concerns
Economic Rationale: follow-up at least 6 overlooked b/c of benefits
months post-procedure
(not as rigorous as most
• Considered budget impact, regen. med assessments
but not cost-effectiveness
• Improvement in visual Implications for
• Costs estimated at >$8,000 acuity and visual function Regenerative Medicine:
to >$33,000 Cdn per eye, deemed clinically
depending on requirements significant
for follow-up and • Value scrutiny more like
retransplantation, with overall • Concerns regarding risks drugs than medical devices
costs of ~$58,000 of long-term • RCT-level data and
immunosuppression with appropriate outcomes are
allogeneic transplants key to acceptance

16. Case: Autologous Cell Transplant for
Myocardial Infarction
Key Takeaways:
RECOMMENDATION: Clinical Rationale:
Further research required to • Focus on surrogate
• Review based on 10 RCTs outcomes = perception not
determine long-term efficacy and
and 4 noncomparative ready for “prime time”
safety (horizon scan report
trials
2007) • For high risk + high volume
• All studies at the time + high cost = highest level
evaluated surrogate of payer scrutiny
outcomes (e.g., LVEF) vs.
Economic Rationale:
changes in morbidity and
mortality
• Limited cost impact analysis
• Lack of long-term data on
evaluated incremental Implications for
“hard” and/or clinically
costs of relevant procedure Regenerative Medicine:
discernable health
steps via codes/payment
outcomes
rates in the Australian
• Understand what payers
system • Insufficient evidence on
view as most important
short- and long-term
• Did NOT account for cost value outcomes
safety given risks
of cells as a commercial
associated with the • Evidence threshold for
product, but as part of a
procedure high risk/high cost
hospital procedure
indications will be HIGH

17. Case: Vaccines for Prostate Cancer
Key Takeaways:
RECOMMENDATION:
• The pricing of Provenge
No recommendation rendered; drew significant attention to
most patients on Provenge who Clinical Rationale: cellular therapies
progressed received • Some payers may have
chemotherapy, so overall value • All prostate cancer vaccines heighted concerns or
proposition is not yet clear other than Provenge were sensitivities re: cost of
Economic Rationale: viewed as investigational future therapies
• Although Provenge did not
• Not considered, although the prevent cancer progression,
$93K cost of Provenge was Implications for
it was noted to improve Regenerative Medicine:
extremely overall survival (OS)
controversial, involving a
potential Medicare National • Outside of TEC assessment • The higher the cost of a
Coverage Determination the level of OS improvement new therapy, the greater
(NCD) and involvement of US was questioned, which is the level of payer
Congress members common for many oncology scrutiny
agents today as payers
• In the US, despite costs, it is focus on the balance of • Similar acceptance
difficult/impossible not to benefits vs. costs potential for non-oncology
cover an oncology indications in the US is
agents, but harsh less certain
reimbursement limits can
apply

18. Several US Payers Maintain Preemptive
Noncoverage Policies for Regen. Therapies
Sample target indications currently not covered by leading
US payers:
– Myocardial infarction – Polymyositis
– Congestive heart failure – Autoimmune cytopenia
– Multiple sclerosis – Diabetes mellitus (type I)
– Systemic lupus erythematosus – Systemic vasculitis
– Systemic sclerosis – Celiac disease
– Rheumatoid arthritis – Crohn's disease
– Juvenile rheumatoid arthritis – Oncology (select
indications/applications)
– Idiopathic thrombocytopenic purpura
– Dematomyositis
Implications for Regenerative Medicine:
• US payers are concerned about unproven, hospital-based cell therapies
• Policies will change as evidence for tested products matures in the marketplace
Source: Indications identified through evaluation of multiple US MCO coverage policies.

19. Percentage of HTAs that Noted Key
Evidentiary Criticisms
Consider Long-term Clearly
comparator data will be characterize Rigorous
required. safety outcomes are
Plan for post- key
market data
collection
Insufficient Lack of Lack of Inconclusive Inappropriate Concerns Insufficient Insufficient
#/quality of comparative long-term or endpoints regarding efficacy cost-
studies data data inconsistent safety effectiveness
Study design (>1yr) studies
quality is key.
Device-like
studies =
N = 48 HTAs and reimbursement policies from Australia, Canada, France, Spain, Sweden, the UK and US
high
rejection
N = 48 HTAs and reimbursement policies from Australia, Canada, France, Spain, Sweden, the UK and US
potential

20. Percentage of HTAs that Noted Key
Evidentiary Criticisms
Ex-US HTAs
did not focus
Almost 50%
as much on
of HTAs
safety
noted that
studies did
not include
the right
Some endpoints
outcomes
were either CE not
unclear, mentioned
surrogate or b/c some
various were early
outcomes HTAs and/or
were technologies
reported were subject
to a less
rigorous
review
Insufficient Lack of Lack of Inconclusive Inappropriate Concerns Insufficient Insufficient
#/quality of comparative long-term or endpoints regarding efficacy cost-
studies data data inconsistent safety effectiveness
(>1yr) studies
N = 48 HTAs and reimbursement policies from Australia, Canada, France, Spain, Sweden, the UK and US
N = 48 HTAs and reimbursement policies from Australia, Canada, France, Spain, Sweden, the UK and US

21. Access Recommendations from HTA Review
Bodies/Payers
Recommendations Recommendations
from All HTAs Approximately from US HTAs &
Reviewed 60% of all HTAs Coverage Policies
recommended Reviewed
either rejection of
the technology
due to one or
40% more of the
evidentiary
criticisms 40%
presented
The majority of
60% the noncoverage 60%
policies in the US
were for
technologies that
have not yet
entered the
Rejected Accepted market Rejected Accepted

22. What does the Climate Look Like for Value
Demonstration in Regenerative Medicine?
• Regenerative medicine is “on the payer radar”
– The “storm” has been sighted & decision makers are watching carefully
• Despite the promise, there is a “perfect storm” of factors converging that
make global value demonstration more complex…particularly for ground
breaking technologies
– Driven by novelty, resource allocation pressures, and market health reform
• Early indicators may suggest storms ahead, but the key to success is
planning and preparation. Focus on:
– Solid study designs; appropriate patient targeting and sample size
– Understanding the outcomes that matter on an indication-by-indication
basis
– Plans for longer-term data collection beyond the pivotal study
– Characterizing benefits/cost balance vs. alternatives; economics matter
• Remember…for payers, saying “no” is easier than saying “yes”
– Have your emergency kit well prepared to weather climate changes in HTA
. Image source: www.bing.com 22

23. Many Other Issues Required To Understand
Value Drivers for Regenerative Medicine
•Are available codes//tariffs sufficient for key procedure
•Payers will look at the balance of outcomes steps?
relative to cost of entire procedure
•Do we need a new code/tariff? If so, what timing and info
•How will evidence development differ from required?
conventional therapies?
Coding/
Evidence
Tariff
&
Outcomes • What outcomes are important in
avoiding reimbursement rejection?
• What are the key reimbursement
Coverage
•Autologous or allogeneic? limitations that we can expect for the
therapy?
•Type or cell and persistence? Cell
Therapy
• How are process for cell
collection, preparation, and
Approach Reimbursement
administration reimbursed? and Market •Is payment level appropriate to
Access support access for each step?
Payment •What are our options for address
• What are HTA agency and payers
inappropriate payment?
Payer &
perspectives on cell therapies?
HTA
•How have payers and HTA agencies Trends
handled initial cell therapy entrants?
Site of •How does site of care influence
•What key criticisms of the value Patient Care reimbursement potential for the therapy?
proposition have been cited for cell Access
therapies? •Is special expertise required to provide the
therapy?
• Are Centers of Excellence required?
• How flexible will payers be regarding patient access?
• Are there subpopulations that are best to target?
•What information will physicians require for adoption vs.
conventional therapies?
23

24. Need for Reimbursement Planning is More
Pronounced for Regenerative Medicine
If uncertainties exist/to
Landscape, seconda confirm
ry, & primary HEOR/reimbursement
research approach
Clinical & Economic Market Implement Pivotal
Early Payer
Access Study
Value Demonstration Environment
Maker
Engagement
Plan (HEOR strategy) Research
Ancillary clinical and
Market Forecast & economic studies
Business Plan Manage the
Moving Target
Not new…just more
Market acute focus
Access, Pricing & • Due to novelty, even more reason to characterize decision
Reimbursement requirements
Reimbursement
Strategy • Understand endpoints,/outcomes trial requirements, patient Submissions &
considerations Launch
• Identify appropriate comparator and perspectives on available
Launch/Commercial alternatives
Strategy
• Understand how the procedure will fit into market
reimbursement system
• Decision maker reactions to TPP and costs

25. Reimbursement and Market Access:
Putting it All Together
• Multiple regenerative medicine technologies are moving into
clinical development, but:
o They are truly novel and not yet understood/accepted by HTA, payer and physician
decision makers: EDUCATE
o Reimbursement and commercial strategy is more complex due to combination
procedure/surgery and cellular component; technologies can touch more than one
payment system; EVALUATE – “measure twice & cut once”
o Manufacturing, distribution and market access channels are more complex than
conventional biopharmaceuticals; NAVIGATE
o Early analysis of HTAs suggests that regenerative medicines will have to
demonstrate strong clinical, economic and long-term follow-up data;
DEMONSTRATE
o “Front-loaded” cost model and “episode of care” view can complicate economic
and cost-effectiveness analysis; VENERATE – clearly understand economic
drivers
o Need for strong educational efforts and clear communication of value
proposition; COMMUNICATE – “multifaceted value…let me count the ways…”
• Reverse engineer product plans targeting reimbursement
requirements to optimize commercial potential so the pieces fit
. Image source: www.bing.com 25

26. Eric Faulkner
Director, Global Market Access
Quintiles
Thank You!
4820 Emperor Blvd.
Durham, NC 13979
919-998-7266 (office)
919-381-8306 (mobile)
Eric.Faulkner@quintiles.com
Executive Director, Genomics, Biotech and
Emerging Medical Technology Institute
National Association of Managed Care Physicians
Assistant Professor, Eshelman School of
Pharmacy, Institute for Pharmacogenomics and
Individualized Therapy
University of North Carolina at Chapel Hill