1

3

Overall survival: 1st line therapy

2-year OS phase III studies mM

Bloomberg Business weekly 26 Feb 2015

Prices per month of oncology medicines

Presented By Veena Shankaran at 2016 ASCO Annual Meeting

Presented By Veena Shankaran at 2016 ASCO Annual Meeting

–

30 countries filled the survey35 oncology center included

Spain400

Belgium350

Poland1000

Belarus250

Russian Federation4000

Sweden500

Albania30

Slovenia150

30 countries, leading national melanoma centers

Switzerland: T-Vec registration and reimbursement

VEMURAFENIB DABRAFENIB VEMURAFENIB COBIMETINIB

DABRAFENIB TRAMETINIB

IPILIMUMAB PEMBROLIZUMAB NIVOLUMAB

Western Europe

Austria

Belgium ** **

Denmark

France

Germany

Greece ** **

Italy

Netherlands

Portugal ** ** ** ** ** ** **

Spain *** ***

Sweden

Switzerland **

UK

Eastern Europe

and South

Eastern Europe

Albania

Belarus

Bosnia and Herzegovina

Bulgaria

Croatia

Czech republic * * ** **

Estonia

Hungary ** ** ** ** **

Lithuania

Macedonia

Montenegro **

Poland * * ** **

Romania

Russia *** **** **** **

Serbia

Slovenia

Ukraine

Registered

Reimbursed

Not registered

Not reimbursed

*Reimbursed, but only for first-line treatment

**Reimbursed, but with large and time-consuming administrative work needed to obtain the medicine for the patient

***Reimbursed, but not fully available due to the hospital-restricted budget

****Reimbursed, but not available due to the drug shortage

Country Estimatedtotalnumber

ofmetastatic

melanomapatients

Estimated%ofpatients

treatedwithinnovative

medicines

Estimated%ofpatients

withoutaccessto

innovativemedicines

Estimatednumberof

patientswithoutaccess

toinnovativemedicines

WesternEurope

Austria 200 >90% 10%* /

Belgium 350 70-90% 10%* /

Denmark 350 >90% 10%* /

France 2000 >90% 10%* /

Germany 3000 >90% 10%* /

Greece NA 70-90% 10%* /

Italy 2000 70-90% 10%* /

Netherlands 800 70-90% 10%* /

Portugal 200 30-50% 50% 100

Spain 400 70-90% 10%* /

Sweden 100 50-70% 30%* /

Switzerland 350 70-90% 10%* /

UK 2000 10-30% 10%* /

TotalWE 11750 100

EasternandSouth-EasternEurope

Albania 30 10-30% 70% 21

Belarus 250 <10% 90% 225

BosniaandHerzegovina

60 <10% 90% 54

Bulgaria 150 30-50% 50% 75

Croatia 100 10-30% 70% 70

Czechrepublic 400 30-50% 50% 200

Estonia 50 50-70% 30% 15

Hungary 400 50-70% 30% 120

Lithuania 50 30-50% 50% 25

Macedonia 80 <10% 90% 72

Montenegro 30 10-30% 70% 21

Poland 1000 70-90% 10%* /

Romania NA 10-30% 70% NA

Russia 4000 <10% 90% 3600

Serbia 200 <10% 90% 180

Slovenia 150 >90% 10%* /

Ukraine 500 <10% 90% 450

TotalSEE 7450 5128

TotalWE+EE+SEE 19250 5228

• 19250 patients with metastatic melanoma in Europe• 7450 (39.7%) treated in Eastern and South-Eastern

Europe• 5128/7450 (69%) do not have the access to first-line

therapy recommended by the European guidelines(ESMO, EDF/EORTC/EADO).

• 5228/19250 (27%), i.e. almost third of all metastaticmelanoma patients do not have access to innovativemedicines.

*never in the first-line treatment

Serbia: vemurafenib reimbursed (without MEK inhibitor)pembrolizumab reimbursed for BRAF negative patients

Croatia: dabrafenib trametinib reimbursed pembrolizumab reimbursed

Romania: vemurafenib, dabrafenib trametinibnivolumab reimbursed

Estonia: nivolumab, pembrolizumab reimbursed BRAF+MEK inhibitor reimbursed

DELAY IN ACCESS THROUGH REIMBURSEMENT: 4-5 YEARS

Country nivo+ipi

Austria X

Belgium X

Bulgaria

Croatia

Cyprus

Czech Republic

Denmark X

Estonia

Finland X

France X

Germany X

Greece XHungary

Iceland

Ireland

Italy

Latvia

Lithuania

Luxembourg

Malta

Netherlands X

Norway

Poland

Portugal

Romania

Slovakia

SloveniaSpain X

Sweden X

Switzerland X

United Kingdom X

EMA registration: May 2016

Reimbursed in 32.4% countries

• Difficulties in implementing CU and EAP programmes:

– unharmonised legislative in some countries

– programmes are active only until the EMA registration, while reimbursementis in significant delay

• Insufficient number of clinical studies

– At least one clinical study for stage IV melanoma was available in 12/13 (92%) Western centers, and 6/17 (35%) from Eastern Europe centers in the surveyperiod.

• Clinically meaningful benefit of the treatment

• Acceptable toxicity profile

• Improvement of quality of life

17

18

19

MCBS v1.1

20

• Grading derived from the ESMO-MCBS provides a backbone for value evaluations for cancer medicines.

• ESMO-MCBS A+B for curative therapies and 4+5 for non-curative therapies should be highlighted for accelerated assessment of value and cost-effectiveness.

• While a high ESMO-MCBS score does not automatically imply high value (that depends on the price), the scale can be used to frame such considerations and can help public policymakers advance ‘ accountability for reasonableness’ in resource allocation deliberations

21

22

Presented By Elisabeth De Vries at 2017 ASCO Annual Meeting

1. ESMO in current and future guidelines

2. Doctors in everyday practice (patient care and teaching)

3. Academic groups

4. Industry

5. Organisations and countries using the scale as policy tool

23

Presented By Elisabeth De Vries at 2017 ASCO Annual Meeting

24

1. ESMO in current and future guidelines

2. Doctors in everyday practice (patient care and teaching)

3. Academic groups

4. Industry

5. Organisations and countries using the scale as policy tool

25

Presented By Elisabeth De Vries at 2017 ASCO Annual Meeting

VEMURAFENIB DABRAFENIB VEMURAFENIB COBIMETINIB

DABRAFENIB TRAMETINIB

IPILIMUMAB PEMBROLIZUMAB NIVOLUMAB

Western Europe

Austria

Belgium ** **

Denmark

France

Germany

Greece ** **

Italy

Netherlands

Portugal ** ** ** ** ** ** **

Spain *** ***

Sweden

Switzerland **

UK

Eastern Europe

and South

Eastern Europe

Albania

Belarus

Bosnia and Herzegovina

Bulgaria

Croatia

Czech republic * * ** **

Estonia

Hungary ** ** ** ** **

Lithuania

Macedonia

Montenegro **

Poland * * ** **

Romania

Russia *** **** **** **

Serbia

Slovenia

Ukraine

Registered

Reimbursed

Not registered

Not reimbursed

Switzerland: T-Vec registration and reimbursement

ESMO-MCBS could be used as a policy tool in HTA and reimbursement decisions at the national level?

29

30

Presented By Elisabeth De Vries at 2017 ASCO Annual Meeting

31

WHO Essential anti-

neoplastic medicines 2015

• Added: nilotinib and dasatinib for imatinib resistant CML

• Establishment of EML cancer medicines working group to coordinate comprehensive evaluation of cancer medicines for the EML

• Cooperation between ESMO and WHO: possible implementation of ESMO-MCBS in evaluation of medicines for the WHO essential list?

32

Non-curative setting: 1st line

33

Medication Trial nameFirst author

Early crossover

Primary outcome

PFScontrol(months)

PFS gain (months)

PFS HROS control(months)

OS gain(months)

OS HR

Increase in 2-year OS ≥10%

QoL ToxicityESMO MCBS v1.1 non-curative

DABRAFENIB TRAMETINIB COMBI-D

Long G 2015, 2017 no PFS 8.8 2.2 0.67 18.7 6.4 0.63 YES + 4

VEMURAFENIB COBIMETINIB

COBRIM Ascierto P 2016 no PFS 7.2 1 0.58 17.4 4.9 0.65 YES + 4

IPILIMUMAB Maio 2015 Maio 2015 yes OS 2.6 0.2 0.76 6.4 2.1 0.72 YES 4

NIVOLUMABCHECKMATE 066

Robert 2015 Atkinson SMR 2015 no OS 2.2 2.9 0.43 11.2 NR 0.43 YES + 4

PEMBROLIZUMABKEYNOTE-006

Robert 2015 Schachter ASCO 2016 yes OS 3.3 5 0.58 15.9 16.4 0.7 YES 4

NIVOLUMAB + IPILIMUMAB

CHECKMATE 067

Larkin 2015 Larkin AACR 2017 Scadendorf2017 no OS 4 4.6 0.42 NR NR ND ND same + 3

NIVOLUMAB + IPILIMUMAB PDL1

CHECKMATE 067Larkin 2015 Larkin AACR 2017

no OS 3.9 6.2 0.57 NR NR ND ND 4

Curative setting

34

Medication Trial name First authorEarly crossover

Primary outcome

PFScontrol(months)

PFS gain (months)

PFS HROS control(months)

OS gain(months)

OS HR

Increase in 2-year OS ≥10%

>5% imp. of survival at ≥3 year FU

QoL Toxicity

ESMO MCBS v1.1 curative

ESMO MCBS v1.1 non-curative

DABRAFENIB TRAMETINIB COMBI-D Long G 2015, 2017 no PFS 8.8 2.2 0.67 18.7 6.4 0.63 YES YES + A 4

VEMURAFENIB COBIMETINIB

COBRIM Ascierto P 2016

no PFS 7.2 1 0.58 17.4 4.9 0.65 YES NA + ND 4

IPILIMUMAB Maio 2015 Maio 2015yes OS 2.6 0.2 0.76 6.4 2.1 0.72 YES YES A 4

NIVOLUMAB CHECKMATE 066Robert 2015 Atkinson SMR 2015 no OS 2.2 2.9 0.43 11.2 NR 0.43 YES YES + A 4

PEMBROLIZUMABKEYNOTE-006

Robert 2015 Schachter ASCO 2016

yes OS 3.3 5 0.58 15.9 16.4 0.7 YES YES A 4

NIVOLUMAB + IPILIMUMAB

CHECKMATE 067Larkin 2015 Larkin AACR 2017

no OS 4 4.6 0.42 NR NR ND ND NA same + ND 3

NIVOLUMAB + IPILIMUMAB PDL1+

CHECKMATE 067Larkin 2015 Larkin AACR 2017

no OS 3.9 6.2 0.57 NR NR ND ND NA ND 4

Adjuvant interferon-alpha meta analysis Ives NJ et al. Eur J Cancer 2017; 82: 171-83.OS improvement 3% at 5 years (HR 0.9, CI 0.85-0.97), grade BSubgroup analysis: Ulcerated tumors OS improvement 10.5% at 10 years (HR 0.77, CI 0.64-0.92), grade A

Adjuvant ipilimumab, EORTC 18081OS improvement 11% at 5 years (HR 0.72), grade ASubstantial toxicity, QoL not deteriorated, downgrade to B?

ESMO 2017: Dabrafenib+trametinib ?Vemurafenib ?Pembrolizumab ? 35

36

0

10

20

30

40

50

60

70

80

90

100

Vemurafenib Dabrafenib Vemurafenibcobimetinib

Dabrafenibtrametinib

Ipilimumab Pembrolizumab Nivolumab Nivolumabipilimumab

(%)

registration reimbursement

ESMO MCBS 4 4 4 (5) 4 (5) 4 4 (5) 4 (5) 3 (4)

Perc

enta

ge o

f co

un

trie

s

o EU Directive – recommendation that registered medicine should be available on the market in 120 days, but delays are common

o EU Network for Health Technology Assessment: o Harmonization of cost-effectiveness analysis until 2020o Parallel submissions to EMA and EU HTA proposedo Common EU price?o ESMO-MCBS as a tool for centralized prioritization?

o Harmonization of reimbursement process?o Added value reimbursement prioritization based on the central

assessment of added value for each medicine OR assessment of added value at the national level

Pricing?

National reimbursement listing determinants of new cancer drugs: a retrospective analysis of 58 cancer treatment appraisals in 2007–2016 in South Korea. Kim ES, et al. Expert Rev Pharmacoecon Outcomes Res. 2017 Jan 3:1-9.

• Three variables increased the likelihood of reimbursement listing:• clinical improvement, • below alternative’s price, • risk-sharing arrangement.

• Cancer drug’s listing increased from 17% to 47% after risk-sharing agreement implementation.

• Take an active role through involvement in professional oncological organizations to start and maintain a dialogue with:

– European and national policy makers

– Patients’ organizations

– Pharmaceutical industry

• to improve the access to innovative medicines for their patients.

• Education of practicing oncologists is necessary to ensure basic understanding of the process of drug approval and reimbursement in order to be able to actively participate in the process.

43

• A dynamic tool with planned revisions and updates based on careful and transparent revision process

• Commitment to “accountability for reasonableness”

• Could serve as useful tool for establishing a fair process for priority setting in public policy

• Further adjustments: patient reported outcomes

44

Thank you for your attention!

EU Policy Committee, Global Policy Committee

Working Group for the access to medicines

Task Force for innovation in skin cancer care