carlos henrique barrios

Clinical Research as an Alternative

Porto Alegre, November 2016

The Cancer Epidemic

Carlos H. Barrios, M.D.

Hospital do Câncer Mãe de Deus

PUCRS School of Medicine

Latin American Cooperative Group, LACOG

Porto Alegre, Brazil

POTENTIAL CONFLICTS OF INTEREST

• Clinical Research: Pfizer, Novartis, Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Roche/Genentech, Lilly, Sanofi, Taiho Pharmaceutical, Mylan, Merrimack, Merck, Abbvie, Astellas Pharma, Biomarin, Bristol-Myers Squibb, Daiichi Sankyo, Abraxis BioScience, AB Science, Asana Biosciences, Medivation, Daiichi Sankyo, Exelixis, ImClone Systems, LEO Pharma, Millennium

• Academic Research Projects: CPO, PUCRS, LACOG, GBECAM, INCA-Brazil.

• Advisory Boards and Consulting: Boehringer-Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai, Bioepis.

• No financial conflicts to declare.

Realidade Epidemiológica

Aumento da incidência de câncer internacionalmente

EnvelhecimentoAumento da PopulaçãoIncorporação de Fatores de Risco

Mais da metade dos casos de câncer são esperados em países em desenvolvimento

Incidência de câncer deve duplicar em 2020

Em 2030 a incidência por câncer deve aumentar em 78% (África do Sul, China, Índia) e em 98% em regiões menos desenvolvidas

Mortalidade por Câncer deve superar CV em 2030 (OMS) (já está acontecendo nos US)

World Health Organization, The global burden of disease: 2004 update.The Lancet Oncology, Early Online Publication, 1 June 2012, doi:10.1016/S1470-2045

Câncer: Um Desafio Global

Novos Casos2000 - 10,000,0002010 - 15,000,0002030 - 27,000,000

Mortes2000 - 6,200,0002010 - 10,000,0002030 - 17,000,000

• Cancer poses a major threat to public health worldwide, and incidence rates have increased in most countries since 1990.

• In 2013, there were 14.9 million new cancer cases and 8.2 million cancer deaths.

• The trend is a particular threat to developing nations with health systems that are ill-equipped to deal with complex and expensive cancer treatments.

JAMA Oncol. doi:10.1001/jamaoncol.2015.0735Published online May 28, 2015.

Goss P, et al. Lancet Oncology, 2103

Educação da PopulaçãoAcesso ao Sistema de SaúdeAcesso à novas Tecnologias:

Métodos diagnósticos modernosDrogas mais eficazes

Discrepâncias Internacionais

INCIDÊNCIA DE CASOS DE CÂNCER POR 100.000 HABITANTES, BRASIL 2012-2014

POR ESTADO

FONTE: INCA, ESTIMATIVAS 2012 E 2014.

POR REGIÃO

O RIO GRANDE DO SUL É O ESTADO COM MAIOR INCIDÊNCIA

DE NOVOS CASOS DE CÂNCER NOS ÚLTIMOS ANOS.

FONTE: OMS – OPAS, 2012

INCA, 2014

COMISSIÓN HONORÁRIA DE LUCHA CONTRA EL CÁNCER (URUGUAY), 2011.

SEGUNDO A OMS, A ESTIMATIVA DE INCIDÊNCIA DE CÂNCER NO MUNDO É MAIOR EM REGIÕES DESENVOLVIDAS (NORTE

AMÉRICA E EUROPA). NO CONTINENTE SUL AMERICANO O URUGUAI É O PAÍS COM MAIOR INCIDÊNCIA.

TX - INC.

243,22

TX - INC.

306,37

TX - INC.

456,20

TX - INC.

187,13

TX - INC.

330,17

TX - INC.

374,41

TX - INC.

471,66

TX - INC.

208,77

COMPARANDO O RS E POA NO ÂMBITO GLOBAL, O CENÁRIO É EQUIVALENTE AO DE

PAÍSES COM AS MAIORES TAXAS DE INCIDÊNCIA (APRESENTANDO TAXAS MAIORES QUE

AS DO URUGUAI.

ESTIMATIVA DA INCIDÊNCIA DE CASOS DE CÂNCER PARA CADA 100.000 HABITANTES NO MUNDO (OMS, 2012)

PRINCIPAIS CAUSAS DE MORTE EM PORTO ALEGRE (FONTE: SECRETARIA MUNICIPAL DE SAÚDE DE PORTO ALEGRE, 2014.)

Nº MORTES POR CAUSA DE NEOPLASIAS – ULTIMOS 7 ANOS

PRINCIPAIS CAUSAS DE MORTENº MORTES POR DOENÇAS CARDIOVASCULARES – ULTIMOS 7 ANOS

NOS ULTIMOS 7 ANOS EM PORTO ALEGRE, AS MORTES POR DOENÇAS CARDIOVASCULARES APRESENTARAM

QUEDA DE 4,11%, ENQUANTO AS MORTES POR NEOPLASIAS CRESCERAM EM 12,64%.

26.4%

22.9%

Cancer “Globalization”

Cancer is a global challenge that

will (only) be met by global

participation

'The Scream' by Edvard Munch 1893, National Gallery Oslo, Norway

• Consider strategies to address discrepancies

• 15-25% of tumors are related to smoking

• Screening for Breast Cancer, CRC, Prostate?,

Lung?...

• Screening and vaccination for Cervical Cancer

• Addressing the Obesity epidemic

• Vaccination against Hepatitis B

• Vaccination against HPV

• Clinical Research

• Other…

Danaei G et al. Lancet 366: 1784–1793, 2005

Katz IT, et al. N Engl J Med 354: 1110–1112, 2006

Cavalli F. Nature Clin Practice Oncol, 3:582, 2006

Addressing Cancer Globalization…

Descobrir novos tratamentos capazes de superar aqueles já existentes, além de imprimir inovação a medicamentos já consolidados só é possível através de uma investigação minuciosa: a pesquisa clínica.

Pesquisa Clínica

• Desenvolvimento de novas formas para prevenir, diagnosticar e tratar o câncer.

• Através de estudos clínicos podemos comprovar se novos tratamentos são seguros e/ou mais eficazes que os tratamentos atuais.

Pesquisa Clínica

Tratar

Diagnosticar

Manejo de Sintomas Doença

Prevenir

Manejo Eventos

Adversos

CANCER TRIALS (CLINICALTRIALS.GOV)

• ClinicalTrials.gov currently lists 223.743 studies with locations in 190 countries.

• 56.232 studies in Cancer.

Source: www.ClinicalTrials.gov Accessed August 28nd, 2016


• ClinicalTrials.gov currently lists 56.232 studies in Cancer.


4,5%

53,7%

Clinical Cancer Research in South America - 2016

World 56.232

South America 1.378 (2.4%)

Argentina 572Brazil 977 (1.7%)Chile 285Colombia 207Ecuador 24Peru 278Uruguay 25Venezuela 44


Regulatory Requirements

Local Legislation

Approval Timelines

Trial design/Placebo

Intellectual Property

FDA acceptability of data

Drug approval issues

Bio-banking legislation

Academic trials

Health Care System and access issues

Standards of Care

Local Infrastructure; Quality Assurance and Control

Bio-Banking infrastructure

Faster recruitment

Diverse populations (treatment naïve)

Trial design should recognize Cultural and Ethnic diversities that may have safety and efficacy consequences

Informed Consent and Ethical considerations

SOPs

Lower costs

Cooperative Groups

CRO’s

New Markets

Human resources and expertise

GLOBALIZATION OF CLINICAL

TRIALS

Infrastructure and Health Care Environment

Cost and Expertise

Implications

Operational Implications

Regulatory Implications

Barrios CH, Werutsky G, Martinez-Mesa J.J Am Soc Clin Oncol Educ Book. 2015;35:e132-9.

doi: 10.14694/EdBook_AM.2015.35.e132.

Clinical Cancer Research• Essential to improve therapeutic

results• “Virtuous Circle” of clinical

research: all involved do benefit• Offers “state of the art” therapy• Qualified investigators and large

number of patients (LA)• Should be a strategic priority• Need to recognize and address

bureaucratic and all other barriers that stall development

Brasil e a Pesquisa Clínica em Oncologia

• Oferece o melhor tratamento disponível “state of the art” (mesmo para o grupo controle).

• Particularmente significativo para o Brasil onde o melhor tratamento disponível NÃO esta disponível para a maior parte da população (SUS) e participação em pesquisa oferece NO MÍNIMO o tratamento convencional ideal/ótimo.

Breast Cancer: Number of Cases/year 57.120

Cases in the public system-SUS (73.7%) 42.097

Stages I/II/III (94%) 39.571

HER2 positive patients (20%) 7.914

Number of deaths avoided by Trastuzumab/y (8.8%) 696

Deaths in HER2 positive women (2005-2012)* 4872

Estimated number of deaths in early HER2 positive patients due to lack of access to adjuvant Trastuzumab in the public system in

Brazil 2005-2012.

INCA. Câncer de mama. http://www2.inca.gov.br/wps/wcm/connect/tiposdecancer/site/home/mama, Jan 2014.

IBGE. Pesquisa Nacional por Amostra de Domicílios, 2008 [acesso March 2,

2014].http://www.ibge.gov.br/home/estatistica/populacao/panorama_saude_brasil_2003_2008/PNAD_2008_saude.pdfN)

Simon, SD, et al. Projeto Amazona I, GBECAM

Perez E, ate al. J Clin Oncol 32:374, 2014.

* Presumes constant incidence and mortality 2005-2012

Barrios C, et al. JCO, Brazilian Edition, 2015.

http://www2.inca.gov.br/wps/wcm/connect/tiposdecancer/site/home/mama

http://www.ibge.gov.br/home/estatistica/populacao/panorama_saude_brasil_2003_2008/PNAD_2008_saude.pdfN)

Why do Clinical Trials in Latin America?

• The ability to conduct research is essential to the development of a high quality, sustainable, health system

• Motivations of each stakeholder may differ• Government, Institutions, Pharma, Patients,

Physicians, others

• Everyone has something to gain

In their paper “Clinical Trials Infrastructure as a Quality Improvement Intervention in Low and Middle Income Countries”, Denburg and colleagues address an important and very pragmatic issue with potential transforming impact in health care systems in low and middle-income countries (LMICs). They hypothesize of a clinical trials infrastructure effect that could impact patient care unrelated and outside the constraints of direct clinical research participation.

This infrastructure is broadly defined by the authors as being the organizational culture, systems and expertise that develop as a product of participation in cooperative clinical trials. This would lead to quality improvements within a specific institution that could also be extended to the overall health care system resulting in better outcomes potentially benefiting other patients independent of their individual participation in trials. They further hypothesize, escalating the impact of the notion, that creating this infrastructure may represent a pillar of health care system development.


• The questions (hypotheses) that need to be addressed to improve care in low resource settings frequently differ from those that are given highest priority in high resource settings

• More than half of all cancer is in developing countries – this represents a valuable, but largely untapped source of potentially unique knowledge of value to all

Saturation of Clinical Trial Sites

RegionNumber of Trial Sites

(per 1M Population)

US 82

Western Europe 11

Central / Eastern Europe 8

Latin America 2

Asia Pacific < 1

Source: Raps Focus, 2009, Latin American CTAs

Studies Conducted (1996-2016)

Last Update: Jun, 2016

.

71

57

14 1412

8 9

59N=244

Patients Screened/Enrolled

0

500

1000

1500

2000

2500

Screened Enrolled

2420

1553

Last Update: Jul, 2016.

projetocura.org

lacog.org.br

Faça parte do CURA.Entre em contato.

Fernanda [email protected]

Clinical Research as an Alternative


The Cancer Epidemic







• With Clinical Trials we offer State of the Art medical management to patients that may not have any access or the basic resources to receive even the most basic care.

In their paper “Clinical Trials Infrastructure as a Quality Improvement Intervention in Low and Middle Income Countries”, Denburg and colleagues address an important and very pragmatic issue with potential transforming impact in health care systems in low and middle-income countries (LMICs). They hypothesize of a clinical trials infrastructure effect that could impact patient care unrelated and outside the constraints of direct clinical research participation.

This infrastructure is broadly defined by the authors as being the organizational culture, systems and expertise that develop as a product of participation in cooperative clinical trials. This would lead to quality improvements within a specific institution that could also be extended to the overall health care system resulting in better outcomes potentially benefiting other patients independent of their individual participation in trials. They further hypothesize, escalating the impact of the notion, that creating this infrastructure may represent a pillar of health care system development.

Clinical Cancer Research• Essential to improve therapeutic

results• “Virtuous Circle” of clinical

research: all involved do benefit• Offers “state of the art” therapy• Qualified investigators and large

number of patients (LA)• Should be a strategic priority• Need to recognize and address

bureaucratic and all other barriers that stall development

• Consider strategies to address discrepancies

• 15-25% of tumors are related to smoking

• Screening for Breast Cancer, CRC, Prostate?,

Lung?...

• Screening and vaccination for Cervical Cancer

• Addressing the Obesity epidemic

• Vaccination against Hepatitis B

• Vaccination against HPV

• Clinical Research

• Other… Danaei G et al. Lancet 366: 1784–1793, 2005

Katz IT, et al. N Engl J Med 354: 1110–1112, 2006

Cavalli F. Nature Clin Practice Oncol, 3:582, 2006

Addressing Cancer Globalization…


• ClinicalTrials.gov currently lists 223.743 studies with locations in 190 countries.

• 56.232 studies in Cancer.



• ClinicalTrials.gov currently lists 56.232 studies in Cancer.


4,5%

53,7%

Clinical Cancer Research in South America - 2016

World 56.232

South America 1.378 (2.4%)

Argentina 572Brazil 977 (1.7%)Chile 285Colombia 207Ecuador 24Peru 278Uruguay 25Venezuela 44


2698

1575

1069

966903

670

664

619

544

530

424

364

328306

261244

219 194141140133127

Breast

Prostate

Skin

Colorrectal

Lung

Stomach

Uterus

Thyroid

Cervix

Head and Neck

LNH

Sarcoma

Melanoma

Larynx

Esophagus

Kidney

Brain

Pancreas

Mieloma

Luekemia

LH

Hepatic

New Cases of Cancer

LACOG Members Institutions

Number of new cases per month = 13.119

Challenges and Perspectives


Breast Cancer in Latin America






• LA-Caribbean region

• A complex region of 600 million people, 33 countries and 14 territories

• 320mi (54%) have no health-care coverage

• Factors behind exclusion from health care:

• Language barriers, unemployment, underemployment, geographic isolation, low education levels and health illiteracy

• For the poorest populations:

• Even in the context of free health care, limited access by the inability to pay medication costs, lack of affordable transportation, inconvenient clinic operation and long waiting times

Goss P, et al. Lancet Oncol, 2013, 14:391

Latin American Facts

Lee B, Liedke P, Barrios CH, et al. Lancet Oncol, 2012; 13:e95.

Latin American Facts

• Region will be overwhelmed by cancer over the next 2 decades resulting in:

• Significant human suffering

• A sharp rise in costs

• Cancers are diseases of ageing people

• By 2020 in LA >100 million people > 60 years

• By 2030: 1∙7 million new diagnoses and 1 million deaths/y


Statement of the Problem: Cancer Control in LA and the Caribbean


Projection of Cancer Incidence Burden 2012-2030

Bray F, Piñeros M. Cancer patterns, trends and projections in Latin America and the Caribbean: a global context. Salud Publica Mex 2016;58:104-117.International Agency for Research on Cancer. WHO Cancer Mortality Database [accessed on November 17, 2015].

Available at: http://wwwdepiarc fr/WHOdb/WHOdb htm 2014.

Public 75%

Public 40%

6.2% LMIC


Estimated Increase in the

Number of Cancer Cases

in LA 2009-2020

• Cancer in LA

•Less frequent than US (163 vs. 300/100.000)

•But overall mortality/incidence ratio is 60% higher (0.59 in LA vs. 0.35 in US)

•Largely (but not only) because of more advanced disease at diagnosis



PRINCIPAIS CAUSAS DE MORTE EM PORTO ALEGRE (FONTE: SECRETARIA MUNICIPAL DE SAÚDE DE PORTO ALEGRE, 2014.)

Nº MORTES POR CAUSA DE NEOPLASIAS – ULTIMOS 7 ANOS

PRINCIPAIS CAUSAS DE MORTENº MORTES POR DOENÇAS CARDIOVASCULARES – ULTIMOS 7 ANOS

NOS ULTIMOS 7 ANOS EM PORTO ALEGRE, AS MORTES POR DOENÇAS CARDIOVASCULARES APRESENTARAM

QUEDA DE 4,11%, ENQUANTO AS MORTES POR NEOPLASIAS CRESCERAM EM 12,64%.

26.4%

22.9%


• Breast cancer is the most common cancer and kills more women than any other tumor type.

• In 2012 more than 114,900 women were diagnosed and 37,000 women died from Breast Cancer.

• If current trends continue, by 2030, the number new diagnosis will increase 46% and the mortality will reach 78.000 cases a year.

• Breast Cancer cases are projected to increase to over 595,900 and breast cancer deaths to over 142,100 by 2030 in the Americas.

PAHO, Fact Sheet Breast Cancer, 2014.GLOBOCAN 2012. Available from: http://globocan.iarc.fr.

Justo N, et al. The Oncologist, 2013, 18:248-256

Breast Cancer Burden and Age of Diagnosis and Death in LA

Delays in Diagnosis of Breast Cancer in Latin America

• Studies from Brazil and Mexico, showed that the average delay between presentation to a doctor and diagnosis of BC was around 6-7 months.

• In Peru the delay has been estimated in 4-5 months.

• Delays in diagnosis of longer than 12 weeks are considered to affect stage and consequently outcomes and survival

Amadou A, et al. Salud Publica Mex 2014;56:547-554

Mammography Screening in Latin America

A Review of Breast Cancer and Outcomes in Latin America, PAHO

Justo N, et al. The Oncologist, 2013, 18:248-256

Breast Cancer Stage at Diagnosis in LAThe reduced survival is partly due to the fact that around 30%-40% of patients are diagnosed in stages III and IV

Outcomes of Breast Cancer in Latin America

A Review of Breast Cancer and Outcomes in Latin America, PAHO, 2010.

• BC prognosis has improved significantly over the last 50 years.• 5 year survival rates are now over 85% in countries with best outcomes. • In LA, data on survival is scarce and fragmented

• Available information shows a wide disparity across and within countries. • Only in a few countries 5-year survival surpasses 70%

Bray F, Piñeros M. Cancer patterns, trends and projections in Latin America and the Caribbean: a global context. Salud Publica Mex 2016;58:104-117.International Agency for Research on Cancer. WHO Cancer Mortality Database [accessed on November 17, 2015].

Available at: http://wwwdepiarc fr/WHOdb/WHOdb htm 2014.

INCIDENCE MORTALITY

Despite the scarcity of cancer registries, we estimate that in most countries, breast cancer incidence and mortality are increasing.

Trends in BC Incidence and Mortality

ASR per 100.000

Breast Cancer in Latin America: Mortality


• If current trends continue, by 2030, the number new diagnosis will increase 46%. • Breast Cancer cases are projected to increase to over 595,900 and breast cancer

deaths to over 142,100 by 2030 in the Americas.

The Lancet. Published Online November 26, 2014http://dx.doi.org/10.1016/S0140-6736(14)62038-9

Central analysis of population-based registry data

Individual tumour records from 279 population-based cancer registries67 countries for 25.7 million adults (age 15–99 years) and 75 000 children (age 0–14 years) diagnosed with cancer during 1995–2009

Stomach, Colon, Rectum, Liver, Lung, Breast, Cervix, Ovary, and Prostate in adults, and Adult and childhood Leukemia.

Caveat:Only 6% of the Latin American population is covered by PBCRs compared with 96% of the US population and 32% the EU population. The Lancet. Published Online November 26, 2014

http://dx.doi.org/10.1016/S0140-6736(14)62038-9

1995-1999

2000-2004

2005-2009

78.2% (73.5-82.8)

86.9% (84.3-89.5)

87.4% (84.8-90.0)

Breast Cancer in LA – 5 year survival

Breast cancer deaths registered in the MortalityData System (SIM/WHO) and census data on the resident population collected by the Brazilian Institute ofGeography and Statistics (IBGE/WHO)

Breast Cancer Mortality to Incidence Ratios

Goss P, et al. Lancet Oncol, 2013, 14:391Lee B, Liedke P, Barrios CH, et al. Lancet Oncol, 2012; 13:e95

All Cancer Mortality to Incidence Ratios

Curado MP, et al. Annals of Global Health 2014;80:370-377.

The ratio between mortality and incidence in LatinAmerica is 0.59, higher than the European Union (0.43)and the United States (0.35), which reflects better support ofcancer treatment in developed countries.

New Technologies/Drugs Uptake in Latin America

• In Latin America, uptake of new treatments is slow, almost marginal in some countries.

• This is related with the health care systems’ coverage limitations.


BREAKDOWN OF SALES OFNEW MEDICINES (2009-2013)

3%9%

10%

55%

23%

Source: IMS Health MIDAS, April 2014.EFPIA, European Federation of Pharmaceutical Industries and Associations, 2014.

88%


• The economic burden of Breast Cancer is significant, and it can be clearly observed that countries allocate insufficient resources to tackle the disease.

• Women go undiagnosed, uncared for or treated with suboptimal therapies; which results in high morbidity and the associated societal costs.

• Vast inequities exist in access to BC health care in the region and within countries which translates in unequal results in BC outcome.


Women Children Men Total

First Class

Women (servants)

Died: 4 (0)

Survived: 113 (24)

% Survived: 97% (100%)

First Class

Children

Died: 1

Survived: 6

% Survived: 86%

First Class

Men (servants)

Died: 104 (10)

Survived: 55 (2)

% Survived 34% (17%)

First Class

Total

Died: 119

Survived: 200

% Survived: 63%

Second Class

Women (servants)

Died: 13 (0)

Survived: 78 (1)

% Survived: 86%

Second Class

Children

Died: 0

Survived: 25

% Survived: 100%

Second Class

Men (servants)

Died: 135 (4)

Survived: 13

% Survived: 8% (0%)

Second Class

Total

Died: 152

Survived: 117

% Survived: 43%

Third Class - Steerage

Women

Died: 91

Survived: 88

% Survived: 49%


Children

Died: 55

Survived: 25

% Survived: 31%


Men

Died: 381

Survived: 59

% Survived: 13%


Total

Died: 527

Survived: 172

% Survived: 25%

www.encyclopedia-titanica.orgwww.ithaca.edu/staff/jhenderson/titanic.html

Public 75%

Public 40%

Health Expenditure by Country: (% of GDP by

Private and Public Sectors)

6.2% LMIC


Low and Middle Income Countries Spend

Less in Cancer ControlMedical Cancer Control spending per new cancer diagnosis

Numbers represent economic burden per cancer patient in US$ (and as a

percentage of GDP/Capita)

Adapted from: 1. Economist Inteligence Unit. Breakaway: The global burden of cancer— challenges and opportunities [Internet]. 2009. Available de: http://www.livestrong.org/pdfs/GlobalEconomicImpact2. United Nations. Per capita GNI at current prices [Internet]. 2012. Available de: http://data.un.org/Data.aspx?d=SNAAMA&f=grID%3A101%3BcurrID%3AUSD%3BpcFlag%3A13. United Nations. World Population Prospects, the 2010 Revision [Internet]. 2011. Available de: http://esa.un.org/wpp/index.htm4. Lopes G, et al. Nature Rev Clin Oncol 2013.

Central America

and Mexico

$7.39

http://esa.un.org/wpp/index.htm

Public 75%

Public 40%

6.2% LMIC


Cost per-patient:

New Cancer Case

in LA 2009

• Cancer represents a significant challenge for

all LA and Caribbean countries.

• The evolving epidemiological transition will

inevitably result in overwhelming human and

financial consequences over the next few

years.

Conclusions

Conclusions

• Breast Cancer represents (and will definitely

remain) a significant burden for the region.

• Significant heterogeneity among and within

countries as well as important gaps in

prevention, screening and treatment are

identified in the LA-Caribbean region.

• Outcomes remain insufficient and require the

active engagement of society and medical

professionals.

Challenges and Perspectives








Source: IMS Health MIDAS, December 2014.Global Oncology Trends Report, 2015.

IMS Institute for Healthcare Informatics.

45 NEW MOLECULAR ENTITIES LAUNCHED 2010-2014 BY INDICATION

Pesquisa Clínica

Pesquisa Clínica

Tratar

Diagnosticar

Manejo de Sintomas Doença

Prevenir

Manejo Eventos

Adversos

• Estudo Clínico

• Experimento Científico: Controlado