The WHO Essential Medicines List

and Access to Cancer Medications

in Low and Middle Income Countries

Gilberto de Lima Lopes, Jr., M.D., M.B.A, F.A.M.S.

Centro Paulista de Oncologia and Hcor Onco, Oncoclinicas do Brasil Group

Johns Hopkins University School of Medicine

In Adults in the US

In Men cancer death

rates have dropped

21%

In Women 12%

Overall 2/3 of patients live

for 5 years or longer

compared to less than

50% several decades ago

American Cancer Society 2009-2012

Photo Credit: G Lopes, Chicago 2013

For those of us who treat patients in low and middle income countries most of these advances are an inspiration and represent hope for the future...

...but not our current reality

Cancer mortality to incidence ratios

USA Europe LMICs

0.36 0.48 0.68

Lopes [Senior Author]: Global Health Equity: Cancer Care Outcomes Disparities in High,

Middle and Low Income Countries. J Clin Oncol special issue on Global Oncology, in press.

Based on Data from GLOBOCANPhoto Credit: G Lopes, Copacabana Beach, Rio de Janeiro 2013

Example:

Latin

America

Lopes [co-author] in Goss et al, Planning Cancer Control in Latin America and the Caribbean Lancet Oncology 2013

Copyright: Elsevier, used with permission

Low and Middle Income Countries Spend

Less in Cancer Control

Lopes. Access to Cancer Medications in Low and Middle Income Countries.

Nature Rev Clin Oncol 2013. Copyright: Nature Publishing, used with permission

Numbers represent economic

burden per cancer patient in

US$ (and as a percentage of

GDP/Capita)

Low and Middle Income countries represent more than half of cancer cases, 6.2% of global cancer costs and 89% of the cancer global expenditure gap

UN Resolution 61/225 on Diabetes (2006)

Political Recognition

UN Political Declaration on NCDs

• Historic political commitment for cancer

and the other NCDs

• 22 action orientated commitments

covering prevention, treatment and care

• A springboard to set a new Global NCD

Framework

“What gets measured, gets done”

WHO DG, Margaret Chan

UN Resolution 61/225 on Diabetes (2006)Political Recognition

Outline

Background

The WHO model EML

The 2015 Committee Decision and How we got here

How can LMICs afford the medications in the list?

What is the WHO model EML?

Definition

“Essential medicines are those that satisfy the priority health care needs of the

population. They are selected with due regard to public health relevance,

evidence on efficacy and safety, and comparative cost-effectiveness.”

Former WHO Model List had 30 cancer medicines

• Full reviews of the cancer medicines on the WHO EML list had been carried in

1984, 1994 and 1999

References:

www.who.int/medicines/publications/essentialmedicines

Shulman, Wagner, Barr, Lopes, Torode, Magrini et al. Proposing Essential Medicines to Treat Cancer:

Methodologies, Processes, and Outcomes. J Clin Oncol 2015, special issue on Global Oncology. In Press.

What opportunity does the model EML provide for national advocacy?

At least 156 out of 194 Member States have national EMLs

Model list is a response to MS requests – since 1977

Guide the definition of national EMLs: identify priority

medicines for procurement and prioritization at the

institutional level

A central component of Universal Health Coverage

2012-2013 WHO EML cycle

Applications for the addition of trastuzumab and imatinib submitted jointly by

DFCI and UICC in November 2012

Campaign to secure support: 20 letters of support received and posted on WHO

website from ASCO, ESMO, BHGI, PIH, SLACOM, Ministry of Health of

Rwanda, Max Foundation and others

Presentation at the Expert Committee meeting in April 2013 to defend the two

applications and section review proposal

Thanks to the financial support of LIVESTRONG

The request for a section review

Report of the 19th Expert Committee (oct. 2013)

Acknowledgement of the growing public health importance of

cancer and the need for countries to consider the addition of

highly effective but high cost cancer drugs in the context of

evidence-based treatment regimens;

Urgent need for a review of sub-section 8.2 in terms of

structure and medicines included – decision on

trastuzumab and imatinib reported until the review is

completed;

UICC Task Team

The UICC-convened task force was charged with creating a new framework for evaluation of drugs for inclusion in the WHO Essentials Medicines List

Members of the Task team include:

DFCI, UICC, ASCO, NCCN International, NCI, ESMO -working in collaboration with the WHO EML Secretariat

2014-2015 – Timeline

May 14 JuneJuly –

Nov

Dec-

March 15April

May-

June1

5

Concept

note

accepted

by WHO

• Agreed on

core set of

cancer types

and set of

regimens

• Gap analysis

vs EML

Expert

Committee

Review

Expert

Committee

Meeting

Decision

made and

results

disseminated

•Feedback WHO

• Prepare & submit

proposals for

change by Nov

2014

Proposed EML Framework

Four Main Dimensions with Three Levels Each:

Efficacy and Safety of Therapy

Cure, Near Cure, Prolongation of Survival/Palliation of Symptoms

Adequate Safety

Burden of DiseaseLow, Mid and High Incidence

Cost Effectiveness of Drug/Regimen

Highly Cost Effective, Cost Effective and Not Cost Effective

Resource Requirements for Drug Use

Low, Middle and High requirement levels

Low Medium High

Incidence of Disease

Treatment Goal

Cure or “near cure”

Significant

prolongation of

survival

Palliation of

symptoms with

small benefit in

survival

Leukemia and

Lymphomas in Children

HIGHEST PRIORITY

Adjuvant Breast CancerCML

Adjuvant Colon CancerLymphomas

in Adults

Stage III Ovarian Cancer

Metastatic Breast Cancer

HIGH

PRIORITY

Metastatic

Pancreatic Cancer

Metastatic

Lung Cancer

LOWEST PRIORITY

GISTMetastatic Prostate Cancer

Metastatic

Bladder Cancer

LOW PRIORITY

Low priority could become High Priority if Highly Cost Effective

Highly Cost Effective

[Cost/QALY equal or less than GDP/capita]

Cost Effective

[Cost/QALY up to 3x GDP/Capita]

Not Cost Effective

[Cost/QALY > 3x GDP/Capita]

P

R

I

O

R

I

T

Y

1. Different levels for low income, low middle income and high middle income countries.

2. Health systems should see the CE evaluation as a tool to discuss/negotiate prices of priority medications

not as a rigid recommendation.

FOR EACH CATEGORY

BHGI-Like Approach: Metastatic Colon Cancer

Level Drugs

Basic BSC Alone

Limited 5FU Alone

Enhanced + Oxaliplatin, Irinotecan

Maximal + Cetuximab/Panitumumab,

Bevacizumab

De

cre

asin

g C

E

ICER

US$

450

44,500

80,000

Source: Management of colon cancer: resource-stratified guidelines from the Asian

Oncology Summit 2012. Lopes [Senior Author] in Ku et al, Lancet Oncology Vol 13

November 2012

Disease-based Briefings Prepared for 29 Types of Cancer

• AML and APL (Adult and Pediatric)

• Chronic Lymphocytic Leukemia

• Chronic Myelogenous Leukemia (Adult and Pediatric)

• Diffuse Large B-Cell Lymphoma

• Early Stage Breast Cancer

• Early Stage Cervical Cancer

• Early Stage Colon Cancer

• Early Stage Rectal Cancer

• Epithelial Ovarian Cancer

• Follicular Lymphoma

• Gastrointestinal Stromal Tumor

• Gestational Trophoblastic Neoplasia

• Locally Advanced Sq Carcinoma of the Head and Neck

• Hodgkin Lymphoma

• Kaposi Sarcoma

• Metastatic Breast Cancer

• Metastatic Colorectal Cancer

• Metastatic Prostate Cancer

• Nasopharyngeal Carcinoma

• Non-small Cell Lung Cancer

• Ovarian Germ Cell Tumors (Adult and

Pediatric)

• Testicular Germ Cell Tumors (Adult and

Pediatric)

Pediatric-Specific

• Acute Lymphoblastic Leukemia

• Burkitt Lymphoma

• Ewing Sarcoma

• Hodgkin Lymphoma

• Osteosarcoma

• Retinoblastoma

• Rhabdomyosarcoma

• Wilms Tumor

Global participation

Authors and reviewers were experts from all 6 inhabited continents

The Task Force Suggested the

Inclusion of 22 Medications

16 Have Been Approved

“Following a review requested by the previous Expert Committee in

2013, the Committee recommended the addition of 16 new

medicines and endorsed the use of 30 medicines listed currently

as part of proven clinically effective treatment regimens. These

medicines will be included on the complementary list of the EML

for the treatment of specific cancers. The Committee

recommended that the Model Lists should specify the cancers for

which use of each medicine is recommended.”

WHO, May 2015

A New Total of 46 drugs

*Denotes newly added

Allopurinol, Anastrozole*, Asparaginase, ATRA*, Bendamustine*,

Bicalutamide*, Bleomycin, Calcium folinate, Capecitabine*, Carboplatin,

Chlorambucil, Cisplatin*, Cyclophosphamide, Cytarabine, Dacarbazine,

Dactinomycin, Daunorubicin, Dexamethasone, Docetaxel, Doxorubicin,

Etoposide, Fludarabine*, Fluorouracil, G-CSF*, Gemcitabine*,

Hydrocortisone, Hydroxycarbamide, Ifosfamide, Imatinib*, Irinotecan*,

Leuprolide* (Class), Mercaptopurine, Mesna, Methotrexate,

Methylprednisolone, Oxaliplatin*, Paclitaxel, Prednisolone, Procarbazine,

Rituximab*, Tamoxifen, Thioguanine, Trastuzumab*, Vinblastine, Vincristine,

Vinorebine

High Cost Medications

Including:

Imatinib for CML and GIST

Trastuzumab for early and advanced HER2 Breast

Cancer

Rituximab for lymphomas

The 6 That Were Not

Nilotinib and Dasatinib for CML

Arsenic Trioxide for APL

Gefitinib and Erlotinib for EGFR mutated NSCLC

Diethylstilbestrol for prostate cancer

Photo Credit: G Lopes, Garden @ WHO, 2015

Our Biggest Challenge Starts Now!

Cost Implications of Adding Trastuzumab

UICC WHO EML Task Force. http://www.who.int/selection_medicines/committees/expert/20/applications/cancer/en/

Cost Implications of Adding Rituximab

UICC WHO EML Task Force. http://www.who.int/selection_medicines/committees/expert/20/applications/cancer/en/

Birth of a Drug

1

Approved

Drug

10,000

Compounds in

Drug

Discovery250 drug

candidates in

pre-clinical

testing5 drugs in

Phase I-III trials

IND

Submission

10-15 years

Munos. Lessons from 60 years of pharmaceutical innovation. Nat Rev Drug Disc 2009

Pammolli. The productivity crisis in phrmaceutical R&D. Nat Rev Drug Disc 2011

The Cost of Developing New Drugs Has Escalated

US$ 138 Million

1975

DiMasi et al. The Price of Innovation: New Estimates of Drug Development Costs. J Heath Econ 2003 and press release from the

Tufts group in 2015

US$ 318 Million

1987

US$ 802 Million

2000

US$ 2.6 billion

2015

Current Access to Innovative

Cancer Drugs in SE Asia

Summary of the First South East Asia Cancer Care

Access Network Meeting and SurveyLopes et al. 2011. Available at

http://www.ispor.org/regional_chapters/Singapore/documents/presentation%20of-the-SE-

Asia-Cancer-Care-Access-Network.pdf

Access to Innovative Cancer Drugs

in SE Asia: Overall Index

00.10.20.30.40.50.6

How to Improve Cost Effectiveness?

Decreasing Cost and Increasing Value of Cancer

Medications

Making Drug Development Cheaper and More Effective

Using Biomarkers

Using Generics, Biosimilars, Price Discrimination and

Access programs

Biomarkers Improve Cost-Effectiveness

Sorafenib in HCC (No biomarker): 1.6 LY at a Cost of US$ 80k/LY

Trastuzumab (Her2Neu): 1.44 QALY at US$ 19 k/QALY

and generates societal income

in the adjuvant setting

Oncotype Dx in Adjuvant Breast: Generates Cost Savings

EGFR Mutation Testing and EGFR TKI: Generates Cost Savings

Lopes, JCO 2007, ASCO GI 2009, BMC Cancer 2010, ASCO and WCLC 2011, Cancer 2012

Biomarkers Decrease Clinical Trial Risk and

Cost of Drug Development

In Breast Cancer, the use of Her2 increases the rate

of success by 50% and decreases cost by 30%

In Lung Cancer, the use of biomarkers increases trial

success rates from 11 to 60% and decreases

development cost by 27%

Parker, Lopes et al, Breast Cancer Res Treat 2012

Falconi, Lopes et al, ASCO 2013, WCLC 2013, JTO 2014

Copyright Nature Publishing, used with permission

Options to Increase Access

Copyright Nature Publishing, used with permission

How to Increase Access

Most Important and Effective Options:

Quality generics (and Compulsory Licensing?)

Price Discrimination, aka, Affordable Pricing

Adequate Healthcare Funding:

Universal Coverage

Value-Based Insurance Design

PPP - Global Fund to fight cancer in LMIC

Lopes. Access to Cancer Medications in Low and Middle Income Countries. Nature Rev Clin Oncol 2013

Generics

Generic medicines account for 69% of all prescriptions

dispensed in the United States, yet only 16% of all

dollars spent on prescriptions. (source: IMS Health)

Cost of Medication my drop by 80% after introduction

of a generic

In the US the use of generics has saved greater than

US$ 734 billion over a decade

Potential Savings with Generics in

Low and Middle Income Countries Are Significant

Generic substitution for four commonly used drugs can

amount to savings in excess of US$800 million in India

every year

In one small retrospective study and one small prospective

registry, efficacy and safety of commonly used drugs was

equivalent with generic or originator drug in India

Lopes G. Ann Oncol 2013 and BMC Cancer 2015 (submitted)

Generics and Biosimilars: Challenges

Patient and Health Care Workers Perception

Quality Issues

Except for growth factors such as G-CSF and EPO only

India has had significant experience with Biosimilars

in Oncology

Lopes. Access to Cancer Medications in Low and Middle Income Countries. Nature Rev Clin Oncol 2013

Compulsory Licensing

WTO – TRIPS Agreement went into effect in January 1995

Allows countries to produce/import generics while medications

are still protected by patent on grounds of public interest

Widely used for AIDS medications

Occasionally used for cancer medications

The US threatened its use to create stockpiles of ciprofloxacin

during Anthrax scare

Lopes. ASCO Connection 2014.

Compulsory Licensing: A Double Edged Sword in the fight for access to cancer medications in low- and middle-income countries.

Compulsory Licensing in Oncology

Thailand in 2008

Docetaxel, Letrozole, Erlotinib, [Imatinib]

Savings in excess of US$ 140 million

India in 2012

Sorafenib

Lopes. ASCO Connection 2014.

Compulsory Licensing: A Double Edged Sword in the fight for access to cancer medications in low- and middle-income countries.

Compulsory Licensing: Challenges

Decrease in investment

In Egypt, Pfizer pulled out of a new planned factory when

the country issued a compulsory license for Sildenafil

Office of the US Trade Representative withdrew duty-free

status of three Thai products

Lopes. ASCO Connection 2014.

Compulsory Licensing: A Double Edged Sword in the fight for access to cancer medications in low- and middle-income countries.

Price Discrimination [including Access Programs]

Important concept in Economics and Business

Companies charge different prices in different markets or

segments, increasing number of consumers able to

afford a product or service

Widely used outside of health care [Think of discounts and

rebates in electronics, for instance]

Price DiscriminationIMS data: Little Variation in Average Unit Price (USD)

per Country for all drugs combined [Lopes, 2011]

0

50

100

150

200

Index

Singapore

Malaysia

Thailand

Indonesia

Philippines

Vietnam

Price Discrimination

[including Access Programs]

Many pilot projects have led to an increase in access and,

in some cases, revenue

Some companies now have specific policies to provide

medications at a different cost in low and middle income

countries [GSK in all emerging markets, ROCHE in India]

Price Discrimination: Challenges

Parallel Imports

Political Backlash in higher income countries,

especially in times of economic difficulties

Lower prices might still not be low enough in the

absence of Universal Coverage and Economic

Development

Public Private Partnerships:

The GAVI Alliance and The International

Finance Facility for Immunization

The global alliance for vaccines and immunization receives

funding from donors such as the Bill and Melinda Gates

foundation and the World Bank combined with technical

assistance from the WHO and UNICEF

GAVI and IFFI

Additional 325 million children immunized

5.5 million premature deaths averted

In cancer prevention, GAVI has created a market for low

cost interventions and has helped decrease the cost of

each dose of hepatitis B vaccine to US$0.50 and of HPV

vaccine to US$5

Proposal:

A Global Fund and Alliance

to Fight Cancer in LMIC

A Global Fund to Fight Cancer would—through

engagement, goal setting and multiple-stakeholder

involvement—provide recipient countries with incentives

to create and develop their health and human capital

infrastructures with adequate technical support.

Global Fund to Fight Cancer in LMIC

The alliance of funding and technical partners would unify

efforts, support the creation and implementation of cancer

control plans and make available cancer interventions in

a stepwise fashion, led in the most cost-effective way

Global Fund to Fight Cancer in LMIC

The alliance could also help create a functioning market for

the provision of low-cost interventions where none exists

today, fostering innovation and lowering costs.

Furthermore, we envisage that the alliance would support

negotiations with industry to facilitate the implementation

of tiered pricing schemes in low-income countries.

Photo Credit: G Lopes, Kolkata, India, 2013

What we saw today

Cancer is a major global health care issue

Access is or will be a major issue in ALL countries

The WHO Essential Medicines List helps set a starting point, not the final destination and is a major victory in our global public health fight against cancer

Low Income Countries in particular will need help accessing all of the drugs on the list

A Series of Policy Options exist that could help them do so

How to do it!

It will take the whole world to control cancer

in low and middle income countries

We need the creation of a global fund to fight

cancer, a cancer alliance and international

finance facility bringing together donors, the

world bank, WHO, IAEA, UICC, NGOs,

Industry and other stakeholders to effectively

tackle cancer control in low income countries

How you can help:

Thank You!

Strive not to be a success,

but rather to be of value.

Albert Einstein