MULTICENTRIC TRIALS Nise Yamaguchi MD, PhD

Health Minister Representative – São Paulo State

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%

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)

CHALLENGES – THE BRAZILIAN HEALTH

* Até 1970, os dados referem-se apenas às capitais

Fonte Barbosa da Silva e cols. In: Rouquairol & Almeida Filho: Epidemiologia & Saúde, 2003 pp. 293.

Mortalidade Proporcional no Brasil, 1930 - 2005 Transição Epidemiológica

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1930 1935 1940 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005

Infecciosas e parasitárias Neoplasias Causas externas Aparelho circulatório Outras doenças

CHALLENGES – THE BRAZILIAN HEALTH

Source: CGIAE/DASIS/SVS/MS

Infant Mortality

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.

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

0

10

20

30

40

50

60

70

80

90

100

Brasil Norte NordesteSudeste Sul Centro-Oeste

Taxa

por

1000 N

V

Brazilian Goal for 2015:15,7 deaths per 1000 alive Newborns

Infant Mortality Rate.Brazil and regions, 1990 - 2007

• 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

SERVICE IN THE SUS+Unified Health System

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

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 11 36

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

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

11-AM13-PA

4-MT

4-MS

15-GO

12-DF

24-SC

34-PR

162-SP

69-MG

59-RJ

15-ES

32-BA

4-MA

5-PI

21-CE5-RN12-PB

51-RS

4-AL2-AC 4-TO

21-PE

2-SE

37 – Norte

39 – Centro Oeste

106 – Nordeste

305 – Sudeste

109 – Sul

Total: 596CEP´s

CONEP

6-RO

2-RR

3-AP

Fonte: CONEP/CNS/MSAgosto de 2010

Fonte: CONEP/CNS/MS Agosto de 2010

Evolução dos CEP/ANO

ANOQUATIDADE 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 ----------------- 83 --------------

1998 45 ----------------- 128 --------------

1999 35 1 162 --------------

2000 34 1 195 --------------

2001 44 4 235 9

2002 38 4 269 7

2003 78 29 318 13

2004 89 25 382 141

2005 101 29 454 92

2006 83 10 527 64

2007 47 1 573 41

2008 34 9 598 29

2009 23 20 599 18

2010 20 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

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

19 Centers

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

THANK YOU!