Access to care: towards better use of resources by

taking into consideration clinical benefit

Alexandru ENIU, MD, PhDCancer Institute Ion Chiricuţă

Cluj-Napoca, Romania

Coordinator, ESO Eastern Europe and Balkan Region programme (EEBR)

Chair, ESMO Global Policy CommitteeESMO Executive Board Member

We are currently experiencing a cancer epidemic

Global Cancer Trends (IARC)Human Development Index (2008-2030)

Some punching statements:(which are VERY REAL!)

“Globally, more people die of cancer than of tuberculosis, malaria, and HIV/AIDS combined”

“The majority of the estimated 13 million cancer deaths in 2030 will occur in limited-resource countries, with higher case fatality”

“21.6 million new cases per year: how can we find resources for that?”

Atun et al, Lancet Oncol 2015; 16: 1153–86

Pillar one: pathology

WITHOUT PATHOLOGY:

How to treat cancer ?

How to report cancer incidence?

How to plan cancer control?

Adesina et al, Lancet Oncol, 14(4), 2013

Figure 9. Coverage of radiotherapy services according to country as determined by global equipment databases, an activity-basedoperations model, cancer incidence, and evidence-based estimates of radiotherapy needEstimates depend on the nature of equipment use...

Pillar two: Radiotherapy

90% of the population in LMICs lacks access to radiotherapy

Radiotherapy access in Europe

Rosenblatt E, et al. Lancet Oncol 2013;14:e79–86

“only 5% of patients in LIC and 20% in MICs have access to safe,

affordable, and timely cancer surgery”

Some evident challenges with limited resources?

Significantly limited health care resources pose unique challenges

Unavailable parameters prohibit the use of guidelines

Because of lack of resources, we are forced sometimes to make decisions against our best medical knowledge

Clinician= manager of scarce resourcesWith the current trend of meaningful advances that

come at a high cost, even traditionally “wealthy” systems struggle

Resource-stratified guidelines: BHGIIncremental allocation & implementation

Eniu A et al, Cancer: 113 (8 suppl), 2008

*** If the costs associated with trastuzumabwere substantially lower, trastuzumab would be used as a limited-level therapy.

Basic level: Core resources or fundamental services necessary for any breast health care system to function.

Limited level: Second-tier resources or services that produce major improvements in outcome such as survival.

Enhanced level: Third-tier resources or services that are optional but important, because they increase the number and quality of therapeutic options and patient choice.

Maximal level: Highest-level resources or services used in some high resource countries with lower priority on the basis of extreme cost

Anderson et al, The Breast J: 12 (1), 2006

NCCN Framework for Resource Stratification

Disparities in cancer outcomes (survival ) across Europe

De Angelis, et al: Cancer survival in Europe 1999–2007 by country and age: EUROCARE-5Lancet Oncol, 2013

Factors accounting for cancer outcomes disparities

Disparities in cancer care

General population health and

lifestyle

Cancer “workforce”

Patient Access & Availability of

Cancer Medication

(Late) Stage at diagnosisHealth

systeminfrastructure

Cancer care infrastructure

(priority devices?)

Lancet Oncol 2014

Access to cancer medication:What are the obvious problems?

Health professionals

PharmaNational bodies

Not enough quality/benefit obtained with new strategies/drugs

Dramatically increasedpricing

Incoherentreimbursement strategy

PatientAccess to

Cancer Medication

ESMO Anti-Neoplastic Medicines Surveys

Perception survey to map access to cancer medicines, including WHO Essential Medicines, reporting on:

Approval status ( yes/no) across Europe and the world Informative for new drugs

Reimbursement ( yes/no) Highlight differences in cancer policies Residual (out of pocket) cost to patients Delays in access due to special authorization

Actual availability Drug shortage for old drugs Unavailability in the pharmacy (parallel export) for expensive drugs

Cherny, Sullivan, Torode, Saar, Eniu Ann Oncol. 2017 Nov;28(11):2633–2647Cherny, Sullivan, Torode, Saar, Eniu Ann Oncol. 2016 Aug;27(8):1423-43

Adjuvant breast cancer: : formulary inclusion and availability : TAMOXIFEN

AvailabilityFormulary and cost to patients

Availability

Drug shortages affect several essential, old and inexpensive drugs (tamoxifen, doxorubicin, cisplatin, 5-FU, bleomycin…)

Not an issue of resources!Cherny, Sullivan, Torode, Saar, Eniu Ann Oncol. 2016 Aug;27(8):1423-43

WHO ESSENTIAL MEDICINES LIST 2015Solid Tumors

Cytotoxics Cytotoxics Cytotoxics Hormones

bleomycin docetaxel irinotecan anastrozole

calcium folinate doxorubicin methotrexate bicalutamide

capecitabine etoposide oxaliplatin dexamethasone

carboplatin fluorouracil paclitaxel leuprorelin

cisplatin filgrastim rituximab tamoxifen

cyclophosphamide gemcitabine trastuzumab

dacarbazine Ifosfamide+mesna vinblastine

dactinomycin imatinib vincristine

vinorelbine

• UICC Task Force on EML: UICC, Dana Farber Cancer Institute, ESMO, ASCO, SIOP, US NCI, NCCN International & others• New drugs, tumor-specific indications

http://www.who.int/medicines/publications/essentialmedicines/EML2015_8-May-15.pdf

Adjuvant breast cancer:Cost & availability - Tamoxifen

Free

<25% cost

25-50% cost

Discount >50% and <100%

Full cost

Not available

Missing data

High

Upper Middle

Low Middle

Low

Multi-use EML

Country Bleo CarboP CisPCyclo (IV) Cyclo (tab) DTIC Dox. Epir. Etop (IV) 5FU Ifos.

MTX (IV)

MTX (tab) VBL VCR

ArgentinaAustraliaCanadaChileCyprusIsraelJapanKorea, SouthOmanQatarSaudi ArabiaSingaporeUnited Arab EmiratesUSAAlgeriaBrazilChinaColombiaIranKazakhstanLebanonMalaysiaMexicoPeruSouth AfricaThailand TunisiaTurkeyBangladeshEgyptGhanaIndiaKenyaMoroccoPakistanPalestineSudanVietnamZambiaAfghanistanBurkina FasoTanzaniaUgandaZimbabwe

COST AND AVAILABILITY

Metastatic breast cancer (formulary inclusion and cost to patients): Anti-Her2 therapy

Trastuzumab

Trastuzumab TDM-1

TDM-1

Lung cancer :formulary inclusion and cost to patients: Targeted therapy

Erlotinib Crizotinib

Erlotinib Crizotinib

The pharmaceutical company requests marketing authorization Evaluation by EMA (high degree of transparency!)

Approval by the European Commission

Time 0: the new drug is effective and safe – valid for whole EU

Europe explodes into 28 (27...) different countries…

The present scenario

5 yrs 10 yrs2 yrs

The development of an ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS)

ESMO• Recognizes the need for clear and unbiased statements regarding the

magnitude of clinical benefit from new therapeutic approaches supported by credible research

• Wants to highlight treatments which bring substantial improvements

to the duration of survival and/or the QoL of cancer patients

use the scale for accelerated: registration reimbursement evaluation incorporating ESMO-MCBS,

value and cost effectiveness considerationsCherny, N et al, Ann Oncol epub 30 May 2015

How will the ESMO-MCBS be used?

• When a new anticancer drug is EMA approved, its benefit will be «scaled» by a dedicated ESMO committee

• Drugs which obtain the highest scores (A&B or 5&4):

1. will be highlighted in the ESMO guidelines2. represent the highest priority for rapid

endorsement by national bodies across Europe

54321

A

B

C

Curative Non-curative

Cherny, N et al, Ann Oncol epub 30 May 2015

Factors taken into account for ESMO-MCBS

Magnitude of Clinically Benefit

Overall survival,

Progression free survival

Toxicity

Costs

Prognosis of the

condition

Quality of Life

HR,Long term survival,

RR

Cherny, N et al, Ann Oncol epub 30 May 2015

Field testing Breast CancerMedication Trial Setting Primary

outcomePFS

controlPFS gain

PFS HR OS control

OS gain

OS HR QoL ESM0MCBS

Chemo +/-trastuzumab

HERA (Neo)AdjuvantHER-2 positive tumors

DFS 2 y DFS 77.4%

8.4% 0.54 (0.43-0.67)

A

T-DM1 vs capecitabine + lapatinib

EMILIA 2nd line metastatic after trastuzumab failure

PFS & OS 6.4 m 3.2 m

0.65 (0.55-0.77)

25 m 6.8m

0.68 (0.55-0.85)

Laterdeterioration

5

Trastuzumab + chemo +/-pertuzumab

CLEOPATRA1st line metastatic PFS 12.4 m 6 m 0.62(0.52-0.84)

40.8 m 15.7 m

0.68(0.56-0.84)

~ 4

Lapatinib +/-trastuzumab

EGF104900

3rd line metastatic PFS 2 m 1 m 0.73(0.57-0.93)

9.5 m 4.5 m

0.74 (0.57-0.97)

4

Capecitabine+/- lapatinib

Geyer, 2006

2nd line metastatic after trastuzumab failure

PFS 4.4 m 4 m 0.49 (0.34-0.71)

NS 3

Eribulin vs other chemo

EMBRACE 3rd line metastaticafter anthracycline& taxane

OS 10.6 m 2.5 m

0.81 (0.66-0.99)

2

Paclitaxel +/-bevacizumab

Miller, 2007

1st line metastatic PFS 5.9 m 5.8 m

0.6 (0.51-0.70)

NS ~ 2

Exemestane+/- everolimus

BOLERO-2 Metastatic after failure aromatase inhibitor+PFS >6 m

PFS 4.1 m 6.5 m

0.43 (0.36-0.54)

NS ~ 2

Example of using MCBS data: Breast cancer, Romania

Medication SettingPrimary outcome

ESMO-MCBS

Availability and cost

Preapproval (Barrier to

access) Chemotherapy +/-trastuzumab

(Neo)adjuvant HER-2 positive tumours

DFS A Yes YesT-DM1 vs lapatinib + capecitabine

2nd line metastatic after trastuzumab failure

PFS and OS 5 NoTrastuzumab + chemotherapy +/-pertuzumab

1st line metastatic PFS 4 No

Lapatinib +/-trastuzumab

3rd line metastatic PFS 4 NoCapecitabine +/-lapatinib

2nd line metastatic after trastuzumab failure

PFS 3 NoEribulin vs other chemotherapy

3rd line metastatic after anthracycline and taxane

OS 2 NoPaclitaxel +/-bevacizumab

1st line metastatic PFS 2 Yes Yes

Exemestane +/-everolimus

Metastatic after failure of aromatase inhibitor (with PFS > 6 mth)

PFS 2 No

COST AND AVAILABILITY

Level Economic Development Country Lapat. (MBC) Pertuz. (MBC) TDM-1 (MBC) Erlot (Lung) Gefit (Lung) Afatnin (Lung) Crizot (Lung) Cetux (CRC) Panitum (CRC) Sunit (RCC) Pazop (RCC) Axitin (RCC) Soraf (RCC) Everol (RCC) Temsir(RCC) Ipilim (Melan)Vemuraf. (Melan.) Abirat. (Prost) Enzalut. (Prost)

ESMO-MCBS 4 4 3 4 4 4 4 4 4 4 4 4 3 3 4 A/3 4 4 4

High Income

Argentina

Australia

Canada

Chile

Cyprus

Israel

Japan

Korea, South

Oman

Qatar

Saudi Arabia

Singapore

United Arab Emirates

USA

Upper mIddle Income

Algeria

Brazil

China

Colombia

Iran

Kazakhstan

Lebanon

Malaysia

Mexico

Peru

South Africa

Thailand

Tunisia

Turkey

Lower middle income

Bangladesh

Egypt

Ghana

India

Kenya

Morocco

Pakistan

Palestine

Sudan

Vietnam

Zambia

Low income

Afghanistan

Burkina Faso

Tanzania

Uganda

Zimbabwe

AlwaysUsuallyHalf the timeOccasionallyNeverNot availableMissing data

New Medications with ESMO-Magnitude of Clinical Benefit Scale score >3

Value based payment

• Payment for cancer medicines is a budget decision for the health care system

• Decisions must be made on objective and verifiable criteria where expenditures are compared to relevant alternative uses within and outside cancer care

• Value based payment requires development of sophisticated systems where payment is based on outcome in clinical practice

APHINITY: Intent-to-Treat Primary Endpoint Analysis Invasive Disease-free Survival

4yr iDFS absolute benefit = 1.7%

Number needed to treat: 112

Presented by Gunter von Minckwitz at 2017 ASCO Annual Meeting

112 * 48182=5.396.384 EURO!!

Recent statement by the American Statistical Association about p-values

• P-values do not measure the probability that a hypothesis is true.

• Scientific conclusions and policy decisions should not be based only on p <0.05.

• A p-value does not measure the size of an effect or the importance of a result.

• By itself, a p-value does not provide evidence regarding a model or hypothesis.

July-6-18

Clinical Benefit, Price and Approval Characteristics of FDA-approved New Drugs for Treating Advanced Solid Cancer, 2000-2015 A. Vivot, Ann OncolDOI:https://doi.org/10.1093/annonc/mdx053Published: 08 February 2017

There is a very poor link between spending and outcomes…

this does not mean that countries such as Romania do not need more funding

Quality of Care !!!

What are the solutions to improve cancer medicine access?

Health professionals

PharmaNational bodies

Care about benefit: MagnitudeOf Clinical Benefit Scale

Justum PretiumReimburse the reasonable medicines(public policy)

PatientAccess to

Cancer Medication

Conclusions Disparities exist in access to cancer medicines Drug shortages affect several “essential”, old and inexpensive

drugs THIS SHOULD BE UNACCEPTABLE !

Inequalities exist in availability and patient costs, especially for newer, more expensive drugs, across Europe

Stratified guidelines (BHGI, NCCN) and benefit scales (ASCO framework, ESMO MCBS) can inform the process of prioritization access to medicines, when resources are limited

Open discussions among stakeholders regarding cost, value and reimbursement priorities are a must ( and have started) to identify sustainable solutions

Way forward

The current situation, where new therapies providing marginal benefit in highly selected patients are approved at high price, is neither desirable nor sustainable

Consideration of “clinical benefit” and “value” that includes quality and consistency of evidence for effectiveness, toxicity, and cost is welcome

Pressure should be put on registration agencies (FDA, EMA) to use a criterion of value for approval, rather than statistical significance of an outcome measure

WE, as oncologists, should stop saying it is not our problem, and act using these evidence

July-6-18