1. Impact of Clinical Trials on Cancer Care in Low- and Middle – Income Countries Prof. Dra. Lucía Delgado Pebé Directora del Servicio de Oncología Clínica Hospital de Clínicas - Montevideo, Uruguay Presidente del Grupo Oncológico Cooperativo Uruguayo International Clinical Trials Workshop FLASCA, ASCO, NCI, ONS. September, 11-13 2014. Córdoba, Argentina

2. Cancer Incidence (IARC, 2014) CANCER year 2012 14.1 million new cases (57% in developing countries) 1.3 million in Caribbean and Latin America CANCER by the year 2030 21.4 million new cases (70% in developing countries) 1.7 million in Caribbean and Latin America

3. All Cancer Mortality/Incidence Ratio (IARC, 2010) European Union: 0.43 Latin America: 0.59 USA: 0.35

4. Why to do Clinical Cancer Research in Developing Countries? (1) With regards to other regions there are differences in incidence and mortality The most frequent cancers may be different to those in developed countries regarding the primary location and biological characteristics.

5. Cancer Incidence and Mortality Worldwide Less vs More Developed Countries

6. MEN Cancer Incidence and mortality.UICC, 2005. INCIDENCEMORTALITY

7. INCIDENCEMORTALITY WOMEN Cancer Incidence and mortality.UICC, 2005.

8. There can be ethnic differences in drug metabolization and tolerance to treatment and differences in response to therapy. Why to do Clinical Cancer Research in Developing Countries? (2) Acces to and coverage of Health Services may not be similar.

9. Local research can contribute to identify treatments that can be useful and also be affordable in less developed countries The Relevance of Cancer Research in Developing Countries As a consequence, studies conducted in developed countries may not respond to the needs and characteristics of the population and Health Systems in countries with fewer resources

10. As clinical trials have become more expensive, the proportion financed by the pharmaceutical industry (PI) has increased. As a logical consequence, the Pl has a major influence on topics selected for clinical trials Academic vs Pharma Industry driven Clinical Research

11. Treatment guidelines are based on clinical trials Why to do Academic Clinical Research? As a result of the growing sponsorhip of the PI, there exists an increasing influence of the commercial sponsors on therapeutic guidelines

12. Pharmaceutical Industry sponsored investigation is important and should be continued BUT Academic, independent investigation should have a much more important role than the present one Clinical Trials in Latin America Academic vs Sponsored by Pharma Industry Clinical Trials in Latin America Academic vs Pharma Industry Driven

13. Academic vs Pharma Industry driven Clinical Research Main objectives of industry driven and academic driven clinical trials 1. Development of new drugs/interventions 2. Development of new therapeutic strategies (multidisciplinary, new 3 combinations or indications of know drugs) 3. Rapid incorporation of new discoveries in clinical practice 4. identification of ineffective/ redundant therapeutic strategies PharmaceuticalIndustry Academy

14. Therapeutic clinical research is expensive which makes it difficult to be state funded HOWEVER What is the health care cost, if the standard of care is based on clinical studies that develop non affordable or non relevant treatments for our patients? Academic Clinical Trials in LA Main Concern: FUNDING

15. Example: treatment of advanced Hepatocellular Carcinoma

16. Sistemic Therapy of Advanced Hepatocellular Carcinoma Estudios Respuestas objetivas Sobrevida sin progresion Sobrevida global SORAFENIB N= 137 (Fase II) JCO, 2006 2.2%4.2 meses9.2 meses Poliquimioterapia con GEMOX N= 34 (Fase II) Cancer, 2007 18%6.3 meses11.5 meses SORAFENIB Vs PLACEBO N= (Fase III) N Engl J Med, 2008 2.0% vs 1%5.5 vs 2.8 meses 10.7 vs 7.9 meses

17. Fase III (vs Placebo)

18. Open studies: “SORAFENIB WITH O WITHOUT CHEMOTHERAPY IN TREATING PATIENTS WITH ADVANCED HEPATOCARCINOMA” Source: clinicaltrials.gov Sistemic Therapy of Advanced Hepatocellular Carcinoma Is GEMOX as efective as Sorafenib?

19. Why to do Clinical Cancer Research in Developing Countries? A)ENSAYOS CLINICOS Academica PARA REALIZAR ESTUDIOS EN LOS QUE NO SE INTERESA LA INDUSTRIA FARMACEUTICA 1)IDENTIFICAR FACTORES PREDICTIVOS DE BENEFICIO CON TERAPIAS QUE HOY SE INDICAN A TODOS PARA BENEFICIAR UNOS POCOS (EJ BEVACIZUMAB) 2)PARA IDENTIFICAR TRATAMIENTOS EFECTIVOS DE BAJO COSTO (ENSAYAR DROGAS DE BAJO COSTO EN NUEVAS COMBINACIONES O INDICACIONES (LOS RESULTADOS PUEDEN SER MUY BUENOS. EJ: DOCETAXEL CON HT EN PRIMERA LINEA DE CA DE PROSTATA) O COMPARAR DROGAS DE ALTO COSTO CON DROGAS DE BAJO COSTO QUE HAN MOSTRADO RESULTADOS EN FASE II 3)PARA ENSAYAR DOSIS MENORES y DURACIONES MENORES (EJ DEL TRASTUZUMAB ADYUVANTE) (MENOS COSTOSAS Y MENOS TOXICAS) O MENORES DURACIONES EN ADYUVANCIA (MENOS COSTO Y TOXICIDAD) 4)PARA CONFIRMAR EFICACIA Y TOXICIDAD DE NUESVOS TRATAMIENTOS EN LAS POBLACIONES LATINOAMERICANAS YA QUE LAS DIFERENTES CARACTERISTICAS BIOLOGICAS DEL TUMOR Y LAS DIFERENCIAS ETNICAS PUEDEN DETERMINAR DIFERENCIAS

20. Survival rates of patients treated in centers participating in clinical trials tend to be better. Du Bois A et al, Int J Gynecol Cancer 2005 Peppercorn J et al, Lancet 2004 Hebert Croteau N et al, Breast Cancer Res Treat 2005 Clinical Research versus use of Clinical Guidelines in improving outcomes: Why to do Clinical Cancer Research in Developing Countries? (3)

21. Fuente: The benefit of participating to clinical reserarch. N. Hébert-Crosteau, J. Brisson, J. Lamaire and J. Latreille. Breast Cancer Researcha and Treatment (2005) 91:279-281

22. Better outcomes for patients treated at hospitals that participate in clinical trials: (a) adherence; (b) mortality. Selby P, and Autier P Ann Oncol 2011;22:vii5-vii9 © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com

23. Development of research is essential to the development of a high quality, sustainable, health system Scientifically trained oncologists are more able to analyze the information and to identify the relevant one Why to do Clinical Cancer Research in Developing Countries? (5)

24. To obtain data that allows to assess the efficacy and cost-benefit ratio of any intervention in the natural history of a disease (what applies in one population or environment does not necessarily apply in another) The questions that need to be addressed to improve cancer care in developing countries frequently differ from those that are prioritized in developed ones Why to do Clinical Cancer Research in Developing Countries? (6)

25. In frequent and devastating neoplasms ( a little improvement in survival may be relevant) In rare tumors it substitutes small trials (carried out at the same time in several countries) that are inconclusive The Importance of Multinational Clinical Trials

26. Clinical Research in Latin America NEEDS AND CHALLENGES FLASCA’s Perspectives To increase the participation in relevant multinational clinical studies, that comply with international ethic norms and with the current local regulation and conducted by a adequately trained team It should be offered to a greater percentage of patients, the possibility to participate in these kind of studies

27. To support: - research programs oriented to the local/regional problems - academic clinical studies that take into account the cancer characteristics at the local/regional level and treatments that can be financed in our countries Clinical Research in Latin America NEEDS AND CHALLENGES FLASCA’s Perspectives

28. Thank you!!