phacilitate cell gene therapy 2012 faulkner worldwide hta analysis

Analysis of regenerative medicine

technologies worldwide: How have

they been assessed by HTAs on a

global basis?

Plenary Session

January 2012

Eric Faulkner, MPHDirector, 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

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*

*Source: Encarta World English Dictionary. Image source: www.bing.com

Short vs. long term effect?

Is it cost-effective?

Does it work?

What value vs. alternatives?

Is it safe?

Marginal vs. transformative?

What evidence of comparative effectiveness?

New mechanism of action?

Value: The Devil is in the Detail

VALUE = outcomes

costs

Easy to

say…harder

to measure

According to

whom?

What is the

right balance?

How do we get

there?

How much is

enough?

What are the

best models &

approaches? What

benefits vs.

alternatives?

Building Value: The Devil is in the Detail

*Image source: www.bing.com

costs

Value: A Gem is the Sum of its Facets

Because value is multi-dimensional…it is often difficult

capture all facets

Adapted from: Michael Porter. What is value in healthcare? NEJM 2010. Image source: www.bing.com

Survival

Degree of health

or recovery

Time to recovery

and return to

normal activities

Disutility of care or

treatment process

(e.g., diagnostic

errors, ineffective

care)

Sustainability of

health or recovery

and nature of

recurrences

Long-term

consequences of

therapy

Comparative

impact vs.

alternatives

Budget impact &

cost-effectiveness

Unm

et N

eed

Value: A Gem is the Sum of its Facets

PARTICULARLY true for regenerative medicine…

Source: Survey of payers, hospital administrators and manufacturers from the National Association of Managed Care Physicians membership survey evaluation 2009-10.

Health Decision Makers View Regenerative

Medicine as a “True Innovation”

Technology Type Greatest Potential to

Improve Care Quality

(% respondents; n=121)

Greatest Potential to

Provide Cost Offsets

(% respondents; n = 120)

Small molecule drugs 14.0 14.2

Personalized medicine 27.3 17.5

Cellular therapies and regenerative medicine

20.7 9.2

Molecular diagnostics 24.0 15.0

Diagnostic imaging 9.1 5.0

Nanotechnology 16.5 10.0

Regenerative medicine ranked comparably with molecular diagnostics and

personalized medicine as a true innovation, but decision makers were less certain

regarding cost offset potential

The

Regenerative

Medicine

Dilemma…

Promise vs.

Cost

Concerns

Cell Therapies & Regenerative Medicine:

What is Different?

Issue Cell

Therapies &

Regenerative

Medicines

Conventional

Biologics

Implications

Well understood & accepted

by payers and physicians

Not well, at

present

perceived as

truly novel

No • Payers and physicians may

place higher scrutiny on value

demonstration

• Commercialization may

involve additional educational

efforts and/or complexities

Involves multiple procedural

steps that may be separately

reimbursable

(including in cell extraction,

purification and processing, and

administration that may include

imaging)

Often Rarely • More like reimbursement for a

device/procedure

• Failure to achieve

reimbursement of any

component part may

jeopardize reimbursement of

the entire procedure

HTA will focus on the cost-

effectiveness of the entire

procedure

Yes Not often

applicable

• Requires HEOR data

collection regarding the entire

procedure

Cell Therapies & Regenerative Medicine:

What is Different?

Issue Cell

Therapies &

Regenerative

Medicines

Conventional

Biologics

Implications

May involve multiple billing

codes /tariffs and/or payment

centers for reimbursement of

the full procedure

Yes No • Lack of appropriate

codes/tariffs or payment may

limit or preclude access and

uptake

May involve requirements for

longer-term data collection to

demonstrate value (including

post-market follow-up data)

Yes Sometimes • This is a top HTA criticism of

most cell therapies in global

markets to date

Strong potential to be more

costly than standard of care

(SOC) alternatives

Often Sometimes • Higher cost means that

therapies must demonstrate

significant outcome

improvements vs. SOC

comparators

May enable a disease cure or

prolonged therapeutic effect

Yes Rarely • Can alter the balance of

benefit-cost tradeoffs in value

assessment

Can we Learn from HTAs Re: Value

Demonstration for Regenerative Medicine?

*Image source: www.photobucket.com

The Good

http://media.photobucket.com/image/clint eastwood/soccermn2121/clint_eastwood.jpg?o=16

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

Evidentiary Criticisms in HTA

Differences Among Markets

N = 48 HTAs and reimbursement policies from Australia, Canada, France, Spain, Sweden, the UK and US

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.
















caution.

Aside from the US,

Australia had the most

HTAs (n=15). Many

were horizon scanning

reports and virtually

all rejected the

technology based on

level of

evidence/maturity and

some due to

insufficient marginal

improvement to

address unmet need

Spain and

Sweden had few

HTA reviews on

regenerative

medicine and

premature to

draw conclusions

on payer

position +

perspectives


















caution.

UK HTAs did not

generally include

traditional cost-

effectiveness analysis

seen in NICE review

(at this point). Many

technologies were

early stage, “home

brew”, and/or

required physician

approval to use

Many US HTAs were

noncoverage policies

for technologies not

yet on the market.

Main reason is likely

to prevent broader

hospital use through

existing

reimbursement

mechanisms for

“unproven

technologies”



Case: Autologous Chondrocyte Implantation

for Knee Cartilage Defects

Key Takeaways:

• Technologies reviewed as

a bundle

• Limited discrimination

between major

technologies

• Poor study design =

increased potential for

rejection

Implications for

Regenerative Medicine:

• Value demonstration for

QoL-driven indications is

difficult; align with payer

expectations

• Focus on quality design

• Prepare for long-term

follow-up

RECOMMENDATION:

NOT recommended, except in

context of ongoing clinical

studies

Clinical Rationale:

• Few RCTs; small sample

sizes; poor trial design &

controls

• Inconsistent study

designs and outcomes

reported

• Inconsistent evidence of

clinical effectiveness

• Proportion of post-

procedural complications

• Limited long-term

outcomes data; when

available, similar to

standard of care

• No comparison with

conservative management

Economic Rationale:

• Insufficient evidence to

produce robust cost/QALY

• Methods for mapping QoL to

economics not sound

• Long-term NICE model took

into account cost of knee

replacement + QoL for 50 yrs

• ICER for mosaicplasty

dominated ACI in modeled

sceanarios

• Inconsistent model results

based on “poor” evidence

http://www.nice.org.uk/

Case: Pancreatic Islet Cell Transplant After

Pancreatectomy

Key Takeaways:

• Poor study designs and

even safety can be

overlooked if:

–Population is small with

high unmet need

–Outcomes are

transformative or

exceptional

Implications for


• Payers recognize clear,

transformative outcomes

• Expect greater scrutiny for

marginal, poorly

differentiated outcomes

RECOMMENDATION:

Recommended, but with

stipulations for educating

patients on procedure risk and

stipulations on treatment

selection

Clinical Rationale:

• Only case series were

available, with study

designs that NICE would

generally not consider

under “normal”

circumstances

• 24% to 85% of patients

were insulin-free at 6-18

months

• In one study 75%

remained insulin-free up

to 5 years

• Accepted despite serious

potential AEs, including

vein thrombosis, liver

failure, pancreatic

infarct, and sepsis

Economic Rationale:

• Extremely small, niche

population with

–High unmet need

–Limited budget impact

• No economic review included

in the assessment

http://www.nice.org.uk/

Case: Limbal Stem Cell Transplantation for

Limbal Cell Deficiency

Key Takeaways:

• Accepted despite high

procedural costs because:

–Population is limited with

high unmet need

–Therapy provided clear

clinical benefits

• Safety concerns

overlooked b/c of benefits

Implications for


• Value scrutiny more like

drugs than medical devices

• RCT-level data and

appropriate outcomes are

key to acceptance

RECOMMENDATION:

Recommended, for patients

with nonpterygium limbal cell

deficiency (ocular disorder) but

weak evidence for treatment of

pterygium recurrence

Clinical Rationale:

• Out of 873 citations, only

9 studies met inclusion

criteria, suggesting that

rigorous study design is

required (only RCTs)

• Long-term defined as

follow-up at least 6

months post-procedure

(not as rigorous as most

regen. med assessments

• Improvement in visual

acuity and visual function

deemed clinically

significant

• Concerns regarding risks

of long-term

immunosuppression with

allogeneic transplants

Economic Rationale:

• Considered budget impact,

but not cost-effectiveness

• Costs estimated at >$8,000

to >$33,000 Cdn per eye,

depending on requirements

for follow-up and

retransplantation, with overall

costs of ~$58,000

http://www.hqontario.ca/en/index-2.html

Case: Autologous Cell Transplant for

Myocardial Infarction

Key Takeaways:

• Focus on surrogate

outcomes = perception not

ready for “prime time”

• For high risk + high volume

+ high cost = highest level

of payer scrutiny

Implications for


• Understand what payers

view as most important

value outcomes

• Evidence threshold for

high risk/high cost

indications will be HIGH

RECOMMENDATION:

Further research required to

determine long-term efficacy and

safety (horizon scan report

2007)

Clinical Rationale:

• Review based on 10 RCTs

and 4 noncomparative

trials

• All studies at the time

evaluated surrogate

outcomes (e.g., LVEF) vs.

changes in morbidity and

mortality

• Lack of long-term data on

“hard” and/or clinically

discernable health

outcomes

• Insufficient evidence on

short- and long-term

safety given risks

associated with the

procedure

Economic Rationale:

• Limited cost impact analysis

evaluated incremental

costs of relevant procedure

steps via codes/payment

rates in the Australian

system

• Did NOT account for cost

of cells as a commercial

product, but as part of a

hospital procedure

Case: Vaccines for Prostate Cancer

Key Takeaways:

• The pricing of Provenge

drew significant attention to

cellular therapies

• Some payers may have

heighted concerns or

sensitivities re: cost of

future therapies

Implications for


• The higher the cost of a

new therapy, the greater

the level of payer

scrutiny

• Similar acceptance

potential for non-oncology

indications in the US is

less certain

RECOMMENDATION:

No recommendation rendered;

most patients on Provenge who

progressed received

chemotherapy, so overall value

proposition is not yet clear

Clinical Rationale:

• All prostate cancer vaccines

other than Provenge were

viewed as investigational

• Although Provenge did not

prevent cancer progression,

it was noted to improve

overall survival (OS)

• Outside of TEC assessment

the level of OS improvement

was questioned, which is

common for many oncology

agents today as payers

focus on the balance of

benefits vs. costs

Economic Rationale:

• Not considered, although the

$93K cost of Provenge was

extremely

controversial, involving a

potential Medicare National

Coverage Determination

(NCD) and involvement of US

Congress members

• In the US, despite costs, it is

difficult/impossible not to

cover an oncology

agents, but harsh

reimbursement limits can

apply

Source: Indications identified through evaluation of multiple US MCO coverage policies.

Several US Payers Maintain Preemptive

Noncoverage Policies for Regen. Therapies

– Myocardial infarction

– Congestive heart failure

– Multiple sclerosis

– Systemic lupus erythematosus

– Systemic sclerosis

– Rheumatoid arthritis

– Juvenile rheumatoid arthritis

– Idiopathic thrombocytopenic purpura

– Dematomyositis

– Polymyositis

– Autoimmune cytopenia

– Diabetes mellitus (type I)

– Systemic vasculitis

– Celiac disease

– Crohn's disease

– Oncology (select

indications/applications)

Sample target indications currently not covered by leading US payers:

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

Percentage of HTAs that Noted Key

Evidentiary Criticisms


Insufficient

#/quality of

studies

Lack of

comparative

data

Inconclusive

or

inconsistent

studies

Inappropriate

endpoints

Concerns

regarding

safety

Insufficient

efficacy

Insufficient

cost-

effectiveness

Lack of

long-term

data

(>1yr)


Rigorous

outcomes are

key

Long-term

data will be

required.

Plan for post-

market data

collection

Study design

quality is key.

Device-like

studies =

high

rejection

potential

Consider

comparator

Clearly

characterize

safety

Percentage of HTAs that Noted Key

Evidentiary Criticisms


Insufficient

#/quality of

studies

Lack of

comparative

data

Inconclusive

or

inconsistent

studies

Inappropriate

endpoints

Concerns

regarding

safety

Insufficient

efficacy

Insufficient

cost-

effectiveness

Lack of

long-term

data

(>1yr)


Almost 50%

of HTAs

noted that

studies did

not include

the right

endpoints

CE not

mentioned

b/c some

were early

HTAs and/or

technologies

were subject

to a less

rigorous

review

Some

outcomes

were either

unclear,

surrogate or

various

outcomes

were

reported

Ex-US HTAs

did not focus

as much on

safety

Access Recommendations from HTA Review

Bodies/Payers

60%

40%

Rejected Accepted

40%

60%

Rejected Accepted

Recommendations

from All HTAs

Reviewed

Recommendations

from US HTAs &

Coverage Policies

Reviewed

Approximately

60% of all HTAs

recommended

either rejection of

the technology

due to one or

more of the

evidentiary

criticisms

presented

The majority of

the noncoverage

policies in the US

were for

technologies that

have not yet

entered the

market

22

What does the Climate Look Like for Value

Demonstration in Regenerative Medicine?

. Image source: www.bing.com

• 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

Many Other Issues Required To Understand

Value Drivers for Regenerative Medicine

Reimbursement

and Market

Access

Coding/

Tariff

Site of

Care

Payment

Cell

Therapy

Approach

Coverage

Patient

Access

Evidence

&

Outcomes

Payer &

HTA

Trends

•Are available codes//tariffs sufficient for key procedure

steps?

•Do we need a new code/tariff? If so, what timing and info

required?

•Is payment level appropriate to

support access for each step?

•What are our options for address

inappropriate payment?

• What outcomes are important in

avoiding reimbursement rejection?

• What are the key reimbursement

limitations that we can expect for the

therapy?

•How does site of care influence

reimbursement potential for the therapy?

•Is special expertise required to provide the

therapy?

• Are Centers of Excellence required?

•Payers will look at the balance of outcomes

relative to cost of entire procedure

•How will evidence development differ from

conventional therapies?

• 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?

• What are HTA agency and payers

perspectives on cell therapies?

•How have payers and HTA agencies

handled initial cell therapy entrants?

•What key criticisms of the value

proposition have been cited for cell

therapies?

•Autologous or allogeneic?

•Type or cell and persistence?

• How are process for cell

collection, preparation, and

administration reimbursed?

23

Need for Reimbursement Planning is More

Pronounced for Regenerative Medicine

Market

Access

Environment

Research

Clinical & Economic

Value Demonstration

Plan (HEOR strategy)

Market Forecast &

Business Plan

Market

Access, Pricing &

Reimbursement

Strategy

Launch/Commercial

Strategy

Implement Pivotal

Study

Ancillary clinical and

economic studies

Early Payer

Maker

Engagement

If uncertainties exist/to

confirm

HEOR/reimbursement

approach

Landscape, seconda

ry, & primary

research

Reimbursement

Submissions &

Launch

• Due to novelty, even more reason to characterize decision

requirements

• Understand endpoints,/outcomes trial requirements, patient

considerations

• Identify appropriate comparator and perspectives on available

alternatives

• Understand how the procedure will fit into market

reimbursement system

• Decision maker reactions to TPP and costs

Manage the

Moving TargetNot new…just more

acute focus

25

Reimbursement and Market Access:

Putting it All Together

. Image source: www.bing.com

• 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

Thank You!

Eric Faulkner

Director, Global Market Access

Quintiles

4820 Emperor Blvd.

Durham, NC 13979

919-998-7266 (office)

919-381-8306 (mobile)

[email protected]

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

mailto:[email protected]

phacilitate cell gene therapy 2012 faulkner worldwide hta analysis

Documents

value of innovation

facetsbecause value

facets value

building value

image source

regenerative medicineadapted

thepersonalized medicine

survey of payers