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Managed entry agreements for pharmaceuticals: the european experience

HTA and beyond: Risk sharing
Mexico City, 7 November 2014 Advance-HTA Capacity building workshop

 Increasing cost of new medicines  Presence of a significant degree of uncertainty at the time of making coverage decisions  Need for innovative solutions to make new drugs available while ensuring the long-term financial sustainability of healthcare systems Constructing RSAs – Likely sources of uncertainty • Uncertainty around clinical evidence More robust clinical evidence is needed about who is likely to benefit • Uncertainty around cost-effectiveness Average cost-effectiveness is higher than country's WTP • Uncertainty around budget impact Budget impact is too high if all potentially eligible patients are • Uncertainty around price Not clear how pricing strategy results in a price that is significantly • Uncertainty around eligible patient population Not clear who is likely to benefit most Not clear how many patients exist in this indication

Risk Sharing and Managed Entry Agreements • Uncertainty around clinical evidence More robust clinical evidence is needed about who is likely to benefit • Uncertainty around cost-effectiveness Average cost-effectiveness is higher than country's WTP • Uncertainty around budget impact Budget impact is too high if all potentially eligible patients are • Uncertainty around price Not clear how pricing strategy results in a price that is significantly higher Uncertainty around eligible patient population Not clear who is likely to benefit most Not clear how many patients exist in this indication Combination

Options flow diagram Insurer adopts: no new Insurer adopts with Insurer refuses to evidence required additional evidence Manufacturer has option to reapply negotiation. No pre- with more evidence specified agreement Use only in research Source: Adapted from Towse, 2011

Coverage with Evidence Development • Product is covered or reimbursed when used under controlled circumstances: – RCTs – Utilisation Management Schemes (UMS) – Evidence-providing Registries – Coverage of CRC agent by Medicare via RCT and – Coverage of prostate cancer "vaccine" by Medicare via building evidence-providing registry

Conditional Coverage • Price and reimbursement are (temporary) granted but failure to achieve set targets can result in price and reimbursement changes and/or rebates – Pfizer on statins in the UK – France: Acomplia

Outcome Guarantee • Rebates or free product are given by the manufacturer when outcomes are not achieved for individual patients • Presupposes ability to monitor eligible • Example: Bortezomib case in UK through NICE

Price and Volume (Budget) Agreements • Agree a price for a specific volume • A penalty is foreseen when a new drug is overshooting a pre- set budget (PxQ) • Penalty can take the form of – Rebate or payback – Lower price for volume above agreed limit – Lower future price • Variety of payback clauses – Supplier is fully accountable – Prescriber and supplier are jointly accountable – Rebate/Payback to be shared among suppliers • Examples: Australia, France, Italy, Austria, Portugal Risks addressed by individual scheme types Main objectives of MEAs BI: Budget impact CE: Cost-effectiveness Source: Ferrario & Kanavos, 2013 Common elements of MEAs PVAs: Price-volume agreements pp: per person Source: Ferrario & Kanavos, 2013 Therapeutic classes ATC groups (according to ATC-index 2011)
A: Alimentary tract and metabolism
B: Blood and blood forming organs
C: Cardiovascular system
D: Dermatologicals
G: Genito urinary system and sex hormones
H: Systemic hormonal preparations,
excl. sex hormones and insulins
J: Anti-infectives for systemic use
L: Antineoplastic and immuno-modulating
M: Musculo-skeletal system
N: Nervous system
R: Respiratory system
S: Sensory organs;
V: Various
ATC_Mix: There was one case in Italy where a
particular AIFA-note contained medicines from
different ATC-groups.
Source: Ferrario & Kanavos, 2013  The average duration of MEAs varies between EU Member States, ranging from one year in Belgium (renewable) to up to four years in the Netherlands or for an indefinite period of time subject to review (France, Malta, UK). Main instruments linked to MEAs Examples of instruments used
Sales and expenditure

Total: 198
Patient registries
Total: 119
Czech Republic: 21 Total: 64

Online systems for
Total: 11
Actors involved in implementing MEAs  Main stakeholders involved • Insurers, drug assessment agencies, and physicians  Responsibility for negotiating the agreement with the • Insurers (e.g. NIHDI in Belgium), drug assessment agencies (e.g. AIFA in Italy, TLV in Sweden) or DoH (UK)  Responsibility for filling in the patient registries • Physicians usually in collaboration with other stakeholders (e.g. monitoring registries in Italy are managed by AIFA; an advisor physician from the National Health Insurer controls the implementation of MEAs in Belgium)  Responsibility for data provision • Manufacturers Taxonomy: A framework for analysing and evaluating MEAs Managed entry schemes
Financial schemes
Performance-based agreements
Total cost
Total cost per
Utilisation in the
Evidence regarding
real life
decision uncertainty
Performance based
Coverage with evidence
elegibility with


Initial discount Treatment interruption if drug Discount or free doses Reimbursement if drug is not effective according to after the agreed free initial doses is not effective pre-established targets threshold is reached Reassessment which may Discount if drug is Cap on number of doses/total lead to price change, not effective or cost reimbursed per patient conclusion of new less effective than after which the manufacturer agreements, or new assumes the cost reimbursement decision Negotiating a MEA from an insurer's perspective: Value Proposition  A strong Value Proposition will be insurer-centric in nature, and will contain compelling evidence that – Showcases all dimensions of value (medical/therapeutic-, patient reported outcome- and economic benefits) – Reflects the full impact of the innovation to insurers and HTAs and – Translates the clinical profile into a compelling cost/effectiveness • Using comprehensive and good quality evidence  Leveraging critical value dimensions with a view to constructing tailor-made RSA plans
Insurer-centric Value Proposition (1) • Critical elements that insurers may require include: – Differentiation relative to standard of care
Although superiority might be shown against BSC
on all primary- and secondary endpoints, it may deter payers from considering the improvement as being major
Relevant comparator (head-to-head)
A placebo-controlled trial is often seen as a
weakness. Payers prefer to see H2H trials. In the absence of H2H data payers would need to see data for detailed indirect comparison across the primary and secondary endpoints that incorporate any difference in trials. Insurer-centric Value Proposition (2) – Quality of evidence
Example overall survival: The non-significant claim on
overall survival will negatively impact the value perception. Without a clear statistical superiority claim for overall survival, insurers will consider new therapies at most comparable to existing ones despite new therapies showing considerable additional benefits on other attributes
Data collection
If time horizon is not long enough to capture full clinical-
and economic impact of disease insurers may demand long-term (real life) data
Comparative efficacy/effectiveness
Measures of effect in "real-life" conditions: Clinical- and
cost effectiveness data in real-world vs. a clinical setting
Cost effectiveness data

Additional evidence requirements • Insurers may require additional data besides the pivotal trial results through follow up studies or registries in order to reduce uncertainties including H2H comparative data that demonstrate better any treatment Data that reflect (more) statistically significant outcomes (e.g. Address uncertainties in clinical-and cost effectiveness in real world (e.g. PRO metrics) Collect real world (effectiveness) data Value is multi-dimensional… Comparative presentation of value drivers: A checklist
Drug 1 vs. Drug 2
Value drivers
Overall Survival (OS) Overall Survival (OS) Skeletal Related Effects (SRE) Skeletal Related Effects (SRE) Objective Response Rate (ORR) Radiographic Progression Free Survival (rPFS) Modified Progression Free Survival (mPFS) Biomarker Response Time to treatment discontinuation (TTTD) Patients proportion Radiographic Progression Free Survival (rPFS) Patient proportion free of Biomarker Progression Patient proportion free of Skeletal Related Effects (SRE) Biomarker Progression Innovation
Mechanism of Action (MoA) Patient convenience Special instructions Direct medical costs Outpatient visits Cost effectiveness Cost minimisation Health Insurer's Point of View  Health Insurers may be willing to confirm the content of the Value Proposition or willing to build their own version reflecting or adjusting for their own perspective. • Most of the data should be available through the peer review literature • -If not published their credibility might be questioned • -Insurers might conduct their own systematic literature review(s) to • ensure all critical evidence is incorporated • Other sources might be required for the collection of real world effectiveness data and resource use (cost of illness) • Registries and observational studies • Shape volume expectations Volume expectations  Expectations on volume are needed to inform • Follow-on products: epidemiological data on disease prevalence should be available • -WHO, CDC, national databases, peer review literature • First-in-class: data on disease prevalence might not be available • -Conduct primary data collection activities such as • observational and descriptive studies, e.g. national registries Performance based RSAs
 Choose clinically meaningful endpoints that are • Objective • Patient/disease relevant • Operational (i.e. practical and measurable) • "Cheap" to monitor • Can be monitored within a specified amount of time  Potential endpoints include biomarker response to treatment (i.e. response rate), biomarker progression following treatment (i.e. disease progression), radiographic exams, etc. Financial based RSAs
 Simpler than performance based agreements  Make use of confidential discounts between the manufacturer and the payer  Sales cap based on price-volume agreement  Based on the grounds of budget impact  Potential options include the application of single discounts, multiple discounts (e.g. 100% discount for the first 3 mo, 50% discount for the next 3 mo, ending up paying full price), and revenue or sales caps


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