MULTICENTRIC TRIALS Nise Yamaguchi MD, PhD Health Minister Representative – São Paulo State MULTICENTRIC TRIALS

O congresso nos EUA é uma iniciativa concorrente. Ocorreram anteriormente três congressos mundiais reunindo compradores institucionais – grandes seguradoras, etc. – e provedores de serviços de saúde: Alemanha, Chipre e Marbella. O congresso nos EUA é uma iniciativa concorrente. Source: World Bank

Brazil General Data Population, total (millions): 192 Urban 80%; Rural 20% Surface area (sq. mi, million): 3.3 GNI (current US$, billions): 1,309.2 GNI per capita, (current US$): 7,350 Brazilian Economy Services 52%; Industry 35%, Agriculture 13% Ocorreram anteriormente três congressos mundiais reunindo compradores institucionais – grandes seguradoras, etc. – e provedores de serviços de saúde: Alemanha, Chipre e Marbella. O congresso nos EUA é uma iniciativa concorrente.

NHS is an important component for national development, not an extra expenditure: The heath sector has become a core component of industrial dynamics and a driver of innovation. Brazilian Trade Balance in the health sector has been US$ 7 billions negative annually (medicines, immunobiologicals). R&D can dramatically reduce external dependence, growing the economy while distributing income. Brazil is among the largest world producers of vaccines, pharmaceuticals and immunobiologicals; Brazil ranks 3rd among developing countries in the number of indexed scientific articles published: Publication grew from 3,665 (1990) to 30,021 (2008)

Mortalidade Proporcional no Brasil, 1930 - 2005 CHALLENGES – THE BRAZILIAN HEALTH Mortalidade Proporcional no Brasil, 1930 - 2005 Transição Epidemiológica * Até 1970, os dados referem-se apenas às capitais Fonte Barbosa da Silva e cols. In: Rouquairol & Almeida Filho: Epidemiologia & Saúde, 2003 pp. 293.

Infant Mortality Rate. Brazil and regions, 1990 - 2007 CHALLENGES – THE BRAZILIAN HEALTH Infant Mortality Rate. Brazil and regions, 1990 - 2007 Infant Mortality Brazilian Goal for 2015: 15,7 deaths per 1000 alive Newborns Source: CGIAE/DASIS/SVS/MS MIX: cálculo da mortalidade infantil utilizando metodologia RIPSA, que combina dados diretos do SIM/SINASC dos estados com boa qualidade (ES, SP, RJ, PR, SC, RS, MS e DF), com estimativas dos estados com baixa qualidade.

SERVICE IN THE SUS+Unified Health System 64 mil establishments registered with SUS More than 70% of the population uses only the SUS 130 million vaccines applied/year 188 thousand patients per year with access to antiretroviral therapy 2,3 billion outpatient procedures / year 11,3 million hospitalizations per year 254 million medical visits per year

INDUSTRIAL COMPLEX of HEALTH A new look at health: development, generating wealth and jobs. Using the purchasing power of the State Support for the expansion of productive capacity R&D in the strategic agenda of health Network technology to support industries 300 million USD in buying capacity per year 8 new projects with drug and devices companies total 250 million USD per year

INDUSTRIAL COMPLEX of HEALTH The size of the national dimension Existence in Brazil of a tradition of production (the most developed in Latin America) Universal health care: a large public demand Scientific infrastructure and human resources A well-structured regulatory system health organized on a national basis Macroeconomic stability (investment grade) GDP growth (annual): 25% Reduction of income disparities (major impact on the market) Industrial Complex Priority in national politics.

INDUSTRIAL COMPLEX OF HEALTH PPPs (April 2009): nine partnerships among seven pulbic labs and ten private companies for the production of 24 drugs A self sufficiency path in Vaccines production: in five years the federal government investment raised more than 1200 %, up to R$ 21,06 millions in 2008. Mission to the Great Britain in September 2009 and agreement for the production by GSK of Pneumococcal vaccines

Investigating Clinical Trial Costs: Comparative analysis of trial cost components in key geographies Market Research News , March 2011

Process flow and calendar days among stakeholders for one phase III cooperative group trial. Dilts D M et al. Clin Cancer Res 2010;16:5381-5389 ©2010 by American Association for Cancer Research

Phase III Clinical Trial Development: A Process of Chutes and Ladders Dilts DM et al, Clin Cancer Res Nov 15, 2010 Process steps, potential loops, and number of stakeholders involved in activating and opening a phase III cooperative group trial Cooperative groups* CTEP and CIRB Cancer centers* Total Process steps† ≥458 ≥216 ≥95 ≥769     Working steps† ≥399 ≥179 ≥73 ≥651     Decision points 59 37 22 118 Potential loops 26 15 8 49 No. of stakeholders involved 11 14 36

Investigator’s costs ~200 hours per subject Thirty-two percent of the hours were devoted to nonclinical activities, such as institutional review board submission and completion of clinical reporting forms. ~6000 US$ per patient ~2000 US$ for non clinical purposes

Phase III multicentric trials-NCI 2.5 years from formal concept review to study opening. Time to activation at one group ranged from 435 to 1,604 days, and time to open at one cancer center ranged from 21 to 836 days. At centers, group trials are significantly more likely to have zero accruals (38.8%) than nongroup trials (20.6%; P < 0.0001).

Emerging Markets rapid recruitment of treatment naive patients from large patient pool cost benefits associated with lower labour and service fees improved transparency and compliance with international regulations expansion of CROs improved hospital and facilities infrastructure huge future commercial value in emerging trial markets.

CLINICAL RESEARCH IN BRAZIL CHALLENGES AND PERSPECTIVES

Brazil as a big player VERY WELL TRAINED TEAMS PHYSICIANS, RESEARCH NURSES, STUDY COORDINATORS MANY PATIENTS OF DIFFERENT DISEASES AN ACTIVE REGULATORY BODY MARKET SHARE OF IMPORTANT PRODUCTS

Comitês de Ética em Pesquisa registrados pelo Sistema CEP-CONEP 2-RR 106 – Nordeste 37 – Norte 3-AP 11-AM 21-CE 4-MA 13-PA 5-RN 12-PB 5-PI 21-PE 2-AC 4-TO 4-AL 6-RO 2-SE 32-BA 4-MT 12-DF CONEP 15-GO 39 – Centro Oeste 69-MG 305 – Sudeste 4-MS 15-ES 59-RJ 162-SP 34-PR 24-SC 109 – Sul 51-RS Total: 596CEP´s Fonte: CONEP/CNS/MS Agosto de 2010 21

Evolução dos CEP/ANO Fonte: CONEP/CNS/MS Agosto de 2010 ANO QUATIDADE DE CEPs CREDENCIADOS NO ANO QUATIDADE DE CEPs CANCELADOS NO ANO Nº TOTAL DE CEPs ATIVOS NA CONEP/ANO Nº TOTAL DE CEPs ATIVOS NO SISNEP/ANO 1996 ------------------- ----------------- ------------------ -------------- 1997 83 1998 45 128 1999 35 1 162 2000 34 195 2001 44 4 235 9 2002 38 269 7 2003 78 29 318 13 2004 89 25 382 141 2005 101 454 92 2006 10 527 64 2007 47 573 41 2008 598 2009 23 20 599 18 2010 24 596 15 TOTAIS 754 (**) 157(*) 596(*) 429 (*) (**) Número total de CEPs registrados pela CONEP desde 1996 até agosto de 2010. (*) Dados estatísticos de 1996 até agosto de 2010 Fonte: CONEP/CNS/MS Agosto de 2010 22

THE UNIVERSE OF CLINICAL RESEARCH AT THE CRB-BRAZIL In the majority of cases: international research with international cooperation, with samples’ shipping to be studied abroad; phase III Equipments, devices and reagents, either new or still non registered in the country 46% Clinical Research (more than 400 submissions in total, every year)

DIFFICULTIES IN CLINICAL RESEARCH DELAY OF THE REQUIRED PROCESS: PROTECTION OF THE SUBJECT OF RESEARCH INTERPRETATION BIAS SHIPMENT OF SAMPLES ABROAD EDUCATION AND IMPROVEMENT OF THE SYSTEM COLLABORATION AMONG INSTITUTIONS

Traditional Site Feasibility Process Incomplete study & budget info Not getting specific enrollment projections Not allowing time for proper assessment Requesting Free feasibility assessments Not leveraging investigator database Not explaining site selection criteria

In-Depth Feasibility Questionnaires Synopsis / Protocol Recruitment number &timelines Budget Legal requirements

FEASIBILITY AS INVESTIGATOR, DO YOU BELIEVE AT THIS DESIGN OF CLINICAL TRIAL? YOUR COMMITMENT TO THE STUDY THE AMOUNT OF TIME AND WORKLOAD YOU WILL DEDICATE TO THE STUDY YOUR CENTER RESOURCES AND MANAGEMENT

FEASIBILITY DISEASE PREVALENCE NUMBER OF PATIENTS AND TIMELINES POTENTIAL STAKEHOLDERS ACCRUAL METHODOLOGY

CLINICAL RESEARCH AT THE PUBLIC SYSTEM NEW REGULATIONS BUDGET ALLOCATION PROFILE OF THE REGIONAL CENTERS POSSIBILITIES FOR INFRASTRUCTURE AND ALL STEPS OF CLINICAL RESEARCH DISEASES AND SITUATIONS OF INTEREST FOR THE PUBLIC SYSTEM

Brazilian Network of Clinical Research Health Ministery Department of Science and Technology (DECIT) and the Science and Technology Ministery- Agencies for Research and Innovation Calls for diseases prevalent in the public system Opportunities and challenges

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Resources for Research Different states have agencies for research, mostly in basic research Innovation departments Public and Private Partnerships Academic development Donnations Sponsors International Collaboration

Plannification of costs not covered Organization of the site Different sources of money University or Hospital based Infrastructure covered by the institution? Needs and Assessments Planning is essential

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