1. Current situation of Clinical Research in Latin America International Clinical Trials Workshop FLASCA, ASCO, NCI, ONS. September, 11-13 2014. Córdoba, Argentina Prof. Dra. Lucía Delgado Pebé Directora del Servicio de Oncología Clínica Hospital de Clínicas - Montevideo, Uruguay Presidente del Grupo Oncológico Cooperativo Uruguayo

2. Research and Health Development in Latin America PRESENT SITUATION Biomedical research: - there are countries with highly qualified investigators, well equiped laboratories and acceptable funding Clinical, Epidemiological and Health System Research: - conditions are lacking in many areas: especially funding - represents only ~ 10% of the entire research

3. Especially phase III trials Less participation in phase I and early phase II studies (requiere high levels of specialization and excellent infraestructure) From the 90’s: international clinical trials (era of the “mega trials”) Little participation in the conception, design, analisis of the results and authorship (most Clinical trials generated out of LA) Evolution of Clinical Trials in Latin America

4. PubMed + LILACS N° public/millón habit USA B,F,G, I,S,UK A,B,C,P,Uy LA group: 8 and 6 times less than USA and EU group Publications on Cancer 2009-2013

5. PubMed + LILACS Nº/million inhab USA B,F,G, I,S, UK A,B,C,P,Uy LA group: 40 and 30 times less than USA and EU group

6. N°trials/million inhab LA group: 17 and 14 times less than USA and UE group USA B,F,G, I,S, UK A,B,C,P,Uy

7. No of studies in the world: 174.443 http:// www.clinicaltrials.gov Accessed: setiembre 2014

9. Growing interest of developed countries to integrate LA in international studies: - Increasing number of cancer cases - Qualified human resources - Investigational quality similar to developed countries - Less number of competitive studies Clinical Trials in LA CURRENT SITUATION

10. So, participation in clinical trials generated outside LA, has increased Hartmann M, Hartmann-Vareilles F. www.plosclinicaltrials.org. 2006 Nature Reviews Drug Discovery 2008; 7, 13-14 However: The proportion of publications from LA has not significantly changed, nor intellectual participation in multinational clinical trials conception, design and result analysis Limited or no development of clinical trials generated in LA persists Clinical Trials in LA CURRENT SITUATION

11. PubMed + LILACS Nº/million inhab USA European Group LA Group 2000-2004 2009-2013

12. Survey on Challenges to Clinical Trials ASCO International Affairs Committee Seruga B, Sadikov A, Cazap L, Delgado L, Digumarti R, Leighl N, Meshref M, Minami H, Robinson E, Yamaguchi N, Pyle D, Cufer T. Web-based survey 300 oncologists from 24 countries. 80 responders: 41 from HIC and 39 from LMIC 90% from academic hospitals With regards to academic clinical trials, lack of finances reported as the most important obstacle and lack of patients as the less important in both, HIC and LMIC.

13. Academic Clinical Research In Latin America Main Barriers Insuficient funding Regulatory Framework (costs, administrative obligations) Research team structure, training and dedication

14. Some countries do not have specific funding for investigation in health and in those that do, the amount is insuficient Academic Clinical Research in LA Main Barriers: FUNDING WHO: advises to invest in health research and development at least 2% of the cost in Health Most LA countries dedicate less than that. i.e. Uruguay has dedicated ≈ 0.1% Fernández J.E. Estructura del funcionamiento y gasto de la investigación biomédica. Facultad de Medicina. Uruguay, 2005.

15. 20002010 Argentina0.49%0.61% Uruguay0.26%0.40% Brazil1.01%1.16% Colombia0.12%0.19% LA and Caribbean0.50%0.75% Spain0.90%1.38% USA2.70%2.89% Research and Development State Funding - % GDP (RICYT, 2010)

16. 20002010 Argentina3457 Uruguay14 48 Brazil38 128 LA and Caribbean 2366 Spain 132 412 USA938 1306 Research and Development State Financial– US dollars/inhabitant (RICYT, 2010 )

17. Table 8. Priorization and relative investment ($PPA), 2006

18. Lack of adequate funding has been one of the main obstacles for the development of academic clinical trials Main costs that reduce the possibility of independent research (mostly associated to current legislation): - Drug supply (experimental, standard) - Insurance policy coverage - Administrative and structural costs Academic Clinical Trials in Latin America INSUFICIENT FUNDING

19. The cost increase of the clinical trials is paralell with the raise in the proportion sponsored by the Pharmaceutical Industry (PhI). Clinical Trials FUNDING In Latin America, the proportion of clinical studies financed by the PhI is far superior to the one observed in the developed countries.

20. Cancer Clinical Trials (open interventional studies) Financial Sources Register: clinicaltrials.gov (September 2014) USA:38% EU Group:59% LA76% Pharmaceutical Industry

21. Argentina(75/83) 90% Brazil(116/179) 64% Chile(23/25) 90% Uruguay (5/6) Register: clinicaltrials.gov (9/2014)

22. Several LA countries have regulatory policies that garanties the safety of its patients These policies are established through their health agencies/ministeries Clinical Trials in LA CURRENT REGULATORY FRAMEWORK

23. Clinical Trials in LA Regulatory Framework: Main Agencies - Argentina: ANMAT (Administración Nacional de Medicamentos, Alimentos y Tecnología Médica) - Brazil: ANVISA (Agencia Nacional de Vigilancia Sanitaria) - Colombia: INVIMA (Instituto Nacional de Vigilancia de Medicamentos y Alimentos) - Peru: INS (Instituto Nacional de Salud) - Uruguay: MSP/Dpto. de Evaluación de Tecnologías - Chile: ISP (Instituto de Salud Pública)

24. Clinical Trials in LA Regulatory Framework Revision Process: Limiting Steps In some LA countries the revision process is secuecial: 1° Ethics Committee (EC), 2° Competent authority (CA) (step that takes the most time). In USA and the EU the revision process is parallel, that means that the communications to the EC and the CA can be done at the same time (Limiting step: revision by the EC) D. Hurley, RAPS 2008 Cámara Argentina de Organizaciones de Investigación Clínica, 2011

25. Average time of approval (*) (months) Country 5 -6Peru 3 – 4Mexico 4.5– 5.5 Chile 8 – 10.5Brazil 5.5 – 6.5Argentina Clinical Trials in LA Regulatory Framework Revision Process: Average Time (*) EC + Competent Authority Cámara Argentina de Organizaciones de Investigación Clínica, 2011

26. Clinical Trials PRESENT REGULATORY FRAMEWORK … Clinical trial costs Complexity and workload for clinical trials activation Delays in clinical trials activation (4 to 11 months) Workload for SUSARS’ management Quality improvement of clinical trials Increase in patients’ protection Contributes to harmonizing its conduction Exponential increase in… ? Cortesy of T Cufer

27. Clinical Trials in Latin America EDUCATION AND TRAINING

28. Current Situation of Clinical Research in LA Conclusions Clinical trials represents an even smaller proportion and almost a 100% are conceived, proposed and financed outside the region It represents a small proportion of cancer research (<10%) In 80% of them, the Pharmceutical Industry is the main sponsor

29. A greater participation of LA researchers is necessary in the conception, design and results analisis of international clinical trials Investigación Clínica en Uruguay y América Latina Conclusions Academic independent clinical trials support is needed: - Education and training of research teams - Adequate funding (state, hybrid) - Regional harmonization of an adequate regulatory framework - Institutional support

30. Thank you!! International Clinical Trials Workshop FLASCA, ASCO, NCI, ONS. 11-13/9/2014. Córdoba, Argentina Prof. Dra. Lucía Delgado Pebé Directora del Servicio de Oncología Clínica Hospital de Clínicas - Montevideo, Uruguay Presidente del Grupo Oncológico Cooperativo Uruguayo