Adrian TowseDirector of the Office of Health EconomicsVisiting Professor London School of Economics

HTAi Tokyo May 2016

How can HTA’s in Asia respond to Increased Clinical Uncertainty: the potential for PBRSAs

HTAi Tokyo May 2016

Abstract for the panel (extract)

This panel will discuss the clinical implications of expedited review and consequent clinical uncertainty and will explore whether outcomes-based risk sharing might be an appropriate solution. In this regards the panel will focus on how to implement risk sharing in the region, will examine case studies and international best practice and will identify and address barriers and opportunities.

HTAi Tokyo May 2016

Agenda

• What is happening in the US and Europe?• The demand for CER / RE as well as

expedited access• Changes in drug development paradigm?

• The EU adaptive pathway• When does the evidence appear?

• The potential and reality of performance based risk sharing

• Implications for Asia

•

The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no [115303], resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution.www.imi.europa.eu

Background RWE on disease, treatments, care pathways, unmet need etc

Post Launch RWE on: use of new medicine, relative effectiveness, longer term outcomes

Potential Value Confirm Value

Comparative Trials. Pragmatic Trials, giving information on effectiveness

More Focussed Context for current care and outcomes to inform initial assessments

Evidence Synthesis to combine all sources of information: RCT + PCT + OBS

Predict Value of new Medicine

How much can be done Pre-Launch?

Or should we get to Post-Launch sooner?

Before Phase3 During Phase3 After Launch

Futurescapes: expectations in Europe for relative effectiveness evidence for drugs in 2020: http://www.futuremedicine.com/doi/pdf/10.2217/cer.15.7Futurescapes: evidence expectations in the USA for comparative effectiveness research for drugs in 2020: http://www.futuremedicine.com/doi/pdf/10.2217/cer.15.6The future of comparative effectiveness and relative efficacy of drugs: an international perspective:http://www.futuremedicine.com/doi/pdf/10.2217/cer.15.8

NEW DRUG DEVELOPMENT PARADIGM FOR 2020: MOST LIKELY SCENARIO FOR CER/RE

New Seamless Framework

Exploratory Research

Confirmatory Trials

Patient/Payer Engagement

Approval

Key Features• Patient/payer engagement early to ensure outcomes reflect those of importance to

them• Smaller targeted trial brings drug to market earlier• Bayesian/adaptive designs to improve efficiency of trial development throughout the

life cycle with clear decision points after each round of evidence development• Second trial in broader population is large simple trial with focused question• EMA requirements for post-authorization efficacy studies can be built into the second

trial• Sequential cohort studies initially used to track off-label use; data used to design

second trial

Modeling, simulation, Proof of concept trials

Enrichment, Adaptive Designs

Sponsor Activities

Partnerships

RCT Biomarker+

Reimbursement

LST Population 2

Pivotal Trials

Archetype 1: Breakthrough drug studied only in small population with biomarker

Sequential Cohort Studies

OpenLabel

HTAi Tokyo May 2016

Agenda

• What is happening in the US and Europe?• The demand for CER / RE as well as

expedited access• Changes in drug development paradigm?

• The EU adaptive pathway• When does the evidence appear?

• The potential and reality of performance based risk sharing

• Implications for Asia

•

AL Shifts Evidence Timing, Amount and Use

May 2015 Trusheim: Adaptive Pathways: What’s in it for Payers? 8

Num

ber o

f pati

ents

trea

ted

Current scenario Adaptive licensing scenario (illustrative)

Patients treated with no active surveillance

Patients in observational studies / registries

Patients in RCTs

LicenseInitial

LicenseFull

License

Time (yrs) Time (yrs)

Adapted by EU HTA from Eichler et al (2012) Adaptive Licensing: Taking the Next Step in the Evolution of Drug Approval, CP&T 91: 426-437

Phase III

= =

Source: Mark Trusheim

9

Adaptive Pathways Misconceptions

• MYTH: Evidence standards are lower» Actually increases evidence over time» Multiple decision points change timing of patient access» Quid pro quo for developers: Earlier market access in exchange for

continued monitoring and label changes based on that monitoring• MYTH: Development is fast and at lower cost

» ONLY to FIRST decision. May increase if ongoing monitoring does not leverage payer & clinical systems

» Entire clinical development program through indication roll-out & surveillance AGREED early

• MYTH: Patients gain unfettered early access» Early patients must likely participate in tracking, registries and

observational studies with associated informed consent» REMS with ‘teeth’

May 2015 Trusheim: Adaptive Pathways: What’s in it for Payers?

Source: Mark Trusheim

MOVEMENT TOWARD GREATER EVIDENCE “HARMONIZATION” IN EUROPE

Post-authorisation efficacy studies (PAES) implemented

Greater HTA and EMA coordination pre-launch

Disease registries in some countries , and progress in EHRs

Coordination across HTA bodies in demand for P-L studies, often linked to CED, P4P schemes

Collaborations across large registriesFull use of EHRs Good progress in methodsPublic-private partnerships have a major role

AP applied to a variety of drugsJoint HTA and EMA coordination for pre-and post- launch

HTAi Tokyo May 2016

Agenda

• What is happening in the US and Europe?• The demand for CER / RE as well as

expedited access• Changes in drug development paradigm?

• The EU adaptive pathway• When does the evidence appear?

• The potential and reality of performance based risk sharing

• Implications for Asia

•

12

Source: UW PBRSA Database

Total Schemes: 369

HTAi Tokyo May 2016

• MEAs are used to give access to new technologies where traditional reimbursement is deemed inappropriate.

• Three different forms of MEAs have been identified: • management of uncertainty relating to clinical and/or cost-

effectiveness;• management of utilization to optimize performance. • management of budget impact;

• The rationale for using these approaches and their advantages and disadvantages differ.

• All forms of MEA should take the form of a formal written agreement among stakeholders, clearly identifying the rationale for the agreement, aspects to be assessed, methods of data collection and review, and the criteria for ending the agreement.

Role for Managed Entry Agreements?*

*Klemp, Frønsdal and Facey on behalf of the HTAi Policy Forum (2011) IJTAHC 27: 77-83

HTAi Tokyo May 2016

HTAi Tokyo May 2016

Performance based risk sharing arrangements

To manage utilization in the real world

To provide evidence regarding decision uncertainty

- Outcomes guarantees- Money back guarantees- Conditional treatment continuation

- Budget capping- Utilization capping- Discounts- Price/volume

Coverage with evidence development

Performance linked reimbursement

Intermediate endpoint

Clinical endpoint

- Only with research

- Only in research

- Process of care

Pre-specified agreement

No pre-specified agreement

Examples of PBRSA Schemes

UK: MS RSSAus: BosentanUK: VotrientFrance: DPP4; risperidone

US Medicare: LVRS, PET, PTAS

Italy: oncology schemesUK: Velcade, Lucentis etc.

HTAi Tokyo May 2016

Key Dimensions of Taxonomies

HTAi Tokyo May 2016

An overview of practice

• Overview of the US• Case studies from the UK• Could have used:

• Sweden• Italy • Netherlands • Australia

HTAi Tokyo May 2016

HTAi Tokyo May 2016

HTAi Tokyo May 2016

Recent Public Sector Interest in the U.S.

CMS (2016) proposes to test new Medicare Part B prescription drug models to improve quality of care and deliver better value for Medicare beneficiaries:

• Risk-sharing agreements based on outcomes. This proposed test would allow CMS to enter into voluntary agreements with drug manufacturers to link patient outcomes with price adjustments.

• https://www.federalregister.gov/articles/2016/03/11/2016-05459/medicare-program-part-b-drug-payment-model

HTAi Tokyo May 2016

Velcade for Multiple Myeloma in UK

Performance-based scheme development: • Resubmission to NICE with performance-

based scheme• Conditional treatment continuation (stopping

rule after 4 cycles) and outcomes guarantee (rebate for non-responders)

• ICER with rebate, stopping rule: £20,700/QALY NICE approval

• Handling uncertainty: Mitigate negative consequences of uncertainty about value

21

HTAi Tokyo May 2016

VELCADE® Response Scheme (VRS) for patients with Multiple Myeloma at 1st relapse within the NHS in England, Wales and N.Ireland- Process Flow

Janssen-Cilag/Ortho BiotechCustomer

JC Drug SafetyVRS Administrator

Orders VELCADE

Evaluate responseafter a maximum of 4 cycles (16 vials)Response Y/N

Yes1

No2

Claim validated3

Y/NOrder further vials of VELCADE

Replacement product delivered or credit note/cash refund issued to customer

Yes

No JC advises and discusses with customer

Instruction to despatch replacement stock, issue credit note or full cash refund

VRS claim logged (Audit and Healthcare Compliance)

Signs VRS agreement with JC

VRS claim forms are sent to Customer upon receipt of signed VRS agreement

Hospital completes VRS claim form for replacement stock, credit or full cash refund for 16 vials. Fax/Post to JC

VRS Claim Form copied to JC Drug Safety Dept.

Drug Safety allocates a specific UK/DS Number and writes to clinician requesting more details on the non-response event

Notes:1 Response defined as a patient, at first relapse, with a

50% or greater reduction in serum M-protein, within 4 cycles of treatment, compared to baseline level immediately prior to VELCADE treatment

2 Non-response or minor response defined as a patient, at first relapse, having less than a 50% reduction in serum M-protein, within 4 cycles of treatment, compared to baseline level immediately prior to VELCADE treatment

NB: 15% - 20% of patients do not have measurable serum M-protein levels, and for this group Bence-Jones urine protein (urine free light chains) could be used. Response defined according to the standard EBMT (European Group for Blood and Marrow Transplantation) criteria, i.e. at least a 90% reduction, compared to baseline. This would be compared to baseline immediately prior to VELCADE treatment (and within 4 cycles).

3 Claim Validation to check:• VRS claim form completed in full and signed

HTAi Tokyo May 2016

Votrient (pazopanib) for Renal Cell Carcinoma in UK

• 12.5% discount on Votrient 's list price• Price parity with Sutent (a monthly cost of just under

GBP2,000 (US$3,085) per patient). • Future financial rebate if Votrient proves inferior to Sutent

with regards to its efficacy, in ongoing head-to-head trials. • Exact scale of the potential rebate not disclosed• The results of the COMPARZ study reported in October

2012 and showed non-inferiority in PFS

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HTAi Tokyo May 2016

UK Multiple Sclerosis Risk Sharing Scheme:The Context

NICE reviewed MS drugs for relapsing-remitting multiple sclerosis in 2001• Models: 5 year : £380K-£780K/QALY; 10: £190K-£425K; 20: £40K-£90K• “beta interferons and glatiramer acetate are not cost-effective”

•Dependent on long-term outcomes: Only 2-years of follow up data• Used assumptions + historical control to estimate long-term outcomes• Sensitive to (i) impact of a relapse on quality of life (ii) time horizon

• Performance-based scheme development• Detailed monitoring over 10 years of a cohort of patients to confirm the cost-

effectiveness of the MS treatments: Avonex, Betaferon, Copaxone and Rebif – Treatments initiated by specialist MS centres based on ABN guidelines, no bar

to clinicians prescribing for patients outside these guidelines– Outcome measure is Expanded Disability Status Score. (EDSS) – Actual outcomes reviewed every 2 years against standard MS disease (non-

treated) progression model through the EDSS scale.– Price adjustment to maintain CE threshold at £36,000/QALY

HTAi Tokyo May 2016

UK Multiple Sclerosis Risk Sharing Scheme:Two Year Results

HTAi Tokyo May 2016

UK Multiple Sclerosis Risk Sharing Scheme:Six Year Results1

Outcome of the year-6 analysis of the UK Risk-Sharing Scheme for interferon-beta and glatiramer acetate in multiple sclerosis. “The primary analysis of the scheme shows that, on aggregate, the drugs perform beyond target at 6 years, with both models showing a 42% reduction in the predicted progression of utility”1. Duddy M, Palace J. Pract Neurol 2016;16:1 4-6

HTAi Tokyo May 2016

HTAi Tokyo May 2016

Evidence from the literaturePueg-Peiro et al. (2011) conducted a systematic literature review to identify existing knowledge about the costs and benefits, assessed either quantitatively or qualitatively, of PBRSAs. Found little quantitative evidence. Neumann et al. (2011) reviewed five PBRSAs in the US and UK and conclude that they are hard to implement in practice. The results from Italy and other EU countries are also unclear and the schemes are in evolution. Overall, the literature suggests there is an important gap in structured ex post evaluation of PBRSAs. Utilisation schemes appear to have been more successful to date than CED schemes. However, the evidence is limited, mixed, qualitative, and partial.

HTAi Tokyo May 2016

Is risk-sharing feasible?

First Bottom-line: Cost and practicality of evidence collection are critical factors in deciding whether to set up a performance-based risk-sharing agreement

1. Transaction costs are key.2. Evidence collection costs are the main part of transaction

costs. 3. It only makes sense to incur these costs if the

uncertainties that can be “resolved” by the evidence are important (e.g. surrogates may take a long time)

4. If evidence collection is to occur, then (arguably) it makes sense to do this in a pre-agreed risk-sharing framework.

HTAi Tokyo May 2016

Is risk sharing feasible? (2)

Second Bottom-line: Prices need to vary with Outcomes. Can prices ever go up?

1. Withdrawal of discount may be easier than change in list price

2. Other ways to change effective revenue, e.g. expansion of approved sub-groups for use

HTAi Tokyo May 2016

Agenda

• What is happening in the US and Europe?• The demand for CER / RE as well as

expedited access• Changes in drug development paradigm?

• The EU adaptive pathway• When does the evidence appear?

• The potential and reality of performance based risk sharing

• Implications for Asia

•

HTAi Tokyo May 2016

Alternatives to outcomes-based risk sharing: Options for payers at launch

• Adopt now with no further evidence collection • Get it right at launch. But increasingly hard to resolve

all uncertainties• Coverage with evidence development with no agreement

• Renegotiation with additional information (e.g. France) but – No commitment to information collection– No commitment how new evidence will be used

• Delay adoption and collect further information – Lose benefits of access

-

HTAi Tokyo May 2016

In the short run the rate of MEA /PBRSAs may fall:• Realisation of complexity (and lack of preparedness of most

health care systems to collect data and monitor patients) • Pressure of austerity for immediate savings not sophisticated

schemesHowever, in the medium and long run it will become a routine tool for use in some cases:

• Adaptive pathways in the EU and early access - it takes time to resolve uncertainty

• Option of non-adoption of promising therapies is not credible• Key issues of information, management and exit will be

tackled

What will happen in the US and Europe

HTAi Tokyo May 2016

Implications for Asia

• Need institutional flexibility • Need to build post launch data collection

capability both registries and pragmatic trials

• Focus on transferability of “coverage with evidence development” studies

• Watch the EU Adaptive Pathways evolution and do it better and faster

Adrian TowseThe Office of Health Economics

Registered address Southside, 7th Floor, 105 Victoria Street, London SW1E 6QT

Website: www.ohe.org  Blog: http://news.ohe.orgEmail: atowse@ohe.org

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