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;
CHALLENGES – THE BRAZILIAN HEALTH
Mortalidade Proporcional no Brasil, 1930 - 2005
Transição Epidemiológica
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
1930 1935 1940 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005
Infecciosas e parasitárias
Neoplasias
Causas externas
Aparelho circulatório
* Até 1970, os dados referem-se apenas às capitais
Fonte Barbosa da Silva e cols. In: Rouquairol & Almeida Filho: Epidemiologia & Saúde, 2003 pp. 293.
Outras doenças
CHALLENGES – THE BRAZILIAN HEALTH
Infant Mortality Rate.
Brazil and regions, 1990 - 2007
Brazilian Goal for 2015:
15,7 deaths per 1000 alive
Newborns
100
90
Taxa por 1000 NV
Infant Mortality
80
70
60
50
40
30
20
10
0
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
Brasil
Norte
Nordeste
Sudeste
Sul
Centro-Oeste
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
11
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
106 – Nordeste
2-RR
37 – Norte
3-AP
11-AM
21-CE
4-MA
13-PA
5-RN
12-PB
5-PI
2-AC
4-TO
6-RO
32-BA
4-MT
21-PE
4-AL
2-SE
12-DF
CONEP
15-GO
39 – Centro Oeste
4-MS
69-MG
15-ES
162-SP
305 – Sudeste
59-RJ
34-PR
24-SC
51-RS
Total: 596CEP´s
109 – Sul
Fonte: CONEP/CNS/MS
Agosto de 201
Evolução dos CEP/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
-----------------
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 (*)
ANO
(**) 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
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!