Life Science Forum Basel 2010 Comparison of Clinical Trials in the industrialized world and Africa Christian Burri; Swiss Tropical and Public Health Institute
Department of Medicines Research
Basel, 23rd June 2010 Comparison of Clinical Trials in the industrialized world and Africa Life Science Forum Basel
PD Dr. Christian Burri Head of Department
Swiss Tropical & Public Health Institute
The Swiss TPH … … is an associated institute of the University of Basel … has the mandate to contribute to the improvement of the health of populations internationally and nationally through excellence in research, services, and teaching & training at the levels of innovation, validation & application … has over 500 staff from 40 nations thereof ~100 PhD students
1 Life Science Forum Basel 2010 Comparison of Clinical Trials in the industrialized world and Africa Christian Burri; Swiss Tropical and Public Health Institute
Swiss Tropical & Public Health Institute
The Swiss TPH … … the Swiss Tropical Institute (STI) was founded in 1943 as a public organisation based on a local government act … became the “Swiss Tropical and Public Health Institute” (Swiss TPH) at the beginning of the year 2010 after the integration of the Institute of Social & Preventive Medicine (ISPM) of the University of Basel … is supported at ~20 % by the Swiss Federal Government & Canton of Basel- Stadt … earns the greater part of funding through competitively acquired project funds and the earnings of the Service Departments
Agenda
• Contribution by the Swiss Tropical & Public Health Institute • Background • Overview on trials conducted in Africa • Trials in resource limited settings in Africa • Access to medicines
2 Life Science Forum Basel 2010 Comparison of Clinical Trials in the industrialized world and Africa Christian Burri; Swiss Tropical and Public Health Institute
Swiss TPH contributions
Research Development Implementation
Clinical Testing
Phase I Phase II Phase III Drug Preclinical Phase IV Systems Discovery Application
Parasite Chemotherapy - Screening
HAT - Orally available diamidines
Malaria drug discovery Molecular Immunology P.f. malaria: Development of a subunit vaccine candidate Intervention optimization
Cost and cost-effectiveness of large-scale insecticide treated nets and indoor residual spraying programmes
Systems optimization Effects of scaling up antiretroviral therapy for HIV/AIDS on health systems in BF, Tz & Ug (ARVMAC)
Intermittent preventive treatment for malaria in infants
Innovation >> Validation >> Application
Swiss TPH contributions
Research Development Implementation
Clinical Testing
Phase I Phase II Phase III Drug Preclinical Phase IV Systems Discovery Application
Clinical Trials – µCRO: Pharmaceutical Medicine Unit
Pharmaceutical Sciences & Services Pharmaceutical Health Services
Design Implementation Management Monitoring Auditing Teaching & Training Capacity Building
Innovation >> Validation >> Application
3 Life Science Forum Basel 2010 Comparison of Clinical Trials in the industrialized world and Africa Christian Burri; Swiss Tropical and Public Health Institute
STI Clinical Research Background Trials 1990 –2010 Clinical Trials with STI / ISPM / Swiss TPH participation • 10 Phase I Trials • Malaria, Shigella • 22 Phase II Trials • Malaria, HAT, Hookworms, Schistosomiasis, Buruli Ulcer • 19 Phase III Trials • Malaria, HAT, Hookworms, Schistosomiasis • 1 Phase IIIb / Effectiveness Trials • Malaria • 21 Phase IV Trials • Malaria, HAT, Hep A, Hep B, Schistosomiasis, Tb • 8 Intervention Studies • Malaria, vitamin A, zinc, rational drug use, environment, water purification, HIV, Cholera • 3 Research / descriptive / observational studies • HAT, cholera, surgical site infection
Background Geographic overview on poverty
Percent of national populations living on less than $1.25 per day UN Estimates 2000-2007
Source: http://en.wikipedia.org/wiki/File:Percentage_population_living_on_less_than_$1.25_per_day_2009.svg
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Background Worldwide life expectancy at birth 2008
Source: http://en.wikipedia.org/wiki/File:Life_Expectancy_2008_Estimates_CIA_World_Factbook.png
Background Burden of disease
Source: Equitable access: research challenges for health in developing countries - A report on Forum 11, People’s Rep. of China, 2007
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Background Burden of disease (2002 – 2030)
Source: PLoS Medicine, 2006, Mathres & Loncarn
Background Partition of World Pharmaceutical Market
2008 Africa Japan • US$ >900 billion Europe 1% 16% 29% Latin America 8%
Middle East Australasia 2% 1% US Southeast Asia & 34% China 7%
Canada 2007 2% • Per capita health expenditure • USA ~ US$ 6’100 • CH ~ US$ 4’000 • Tanzania ~ US$ 29 • Rep. Dem. Congo ~ US$ 15
Sources: PhRMA 2002, 2005; http://www.aegis.com/NEWS/BW/2007/BW070638.html & Human Development Report, 2007
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Background Costs of drug development
$800 Million to develop a single drug
Synthesis & Extraction 10% Biological Screening 14% Toxicological and Safety Testing 5% Formulation and Stability 7% Clinical Evaluation: Phase I, II, III 29% Clinical Evaluation: Phase IV 12% Process Development Mfg & QC 8% Regulatory: IND & NDA 4% Bioavailability 2% Other 9%
0 20 40 60 80 100 Percentage
Source: Tufts Center for the Study of Drug Development, 2001; PhRMA Annual Survey, 2001
Trials in resource-limited settings Motivation • Lower costs of research • Mainly due to salary levels • Cost per case report at first-rate academic medical center in India approximately $1,500 to $2,000 • Ca. 10x higher in the United States • Large pool of potential research participants • (ICH)-GCP rules wide spread adopted • Increasing bureaucracy and regulatory environment in industrialized countries • Expected lower regulatory barriers
• New interventions for local use
Source: S. Glickman 2009, New England Journal of Medicine
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Tropical and poverty related diseases “The new landscape”
PPP direct R&D spend (including projections to 160 2006)
140
120
100
In kind (estimated) US$ US$ 80 Total direct R&D spend Millionen
60
40
20
0 2000 2001 2002 2003 2004 2005 2006
MMV iOWH TB DNDi Alliance • Neglected disease and product funding in 2008: US$ 2.956 Bio • 31 diseases listed • Total R&D expenditure by pharmaceutical industry 2006: US$ 89 Mio
Sources: Moran 2005, New Landscape of Neglected Disease Drug Development; Medicines Australia 2008
Clinical trials in Africa Clinical trial sites November 2007
Source: S. Glickman 2009, New England Journal of Medicine
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Clinical trials in Africa Clinical trials conducted November 2007
Source: S. Glickman 2009, New England Journal of Medicine
Clinical trials in Africa Excellence centers in clinical research
Source: Adapted and updated from AMANET
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Clinical trial in Africa Number of trials per country Country #
South Africa 252
Uganda 43
Tanzania 34
Kenya 30
Mali 21
Zambia 17
Ghana 12
Malawi 12
Burkina Faso 10
Nigeria 9
Zimbabwe 8
Mozambique 7
Gambia 6
Senegal 6
Cameroon 5 Total 591
Source: International Clinical Trials Registry Platform, Status 20.04.2009
Clinical trial in Africa Ongoing trials in South Africa by indication
Source: South African Clinical Trial Register, Status 22.06.2010
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Trials in resource-limited settings in Africa Variation in quality of trial sites
Manhiça Health Research Centre, Mozambique ARCEAU at Kin SOPH, DRC
Ifakara Health Institute, Tanzania CDTC Maluku, DRC
Trials in resource-limited settings in Africa Benefits • Capacity building in less developed countries and areas • Fostering of relationship between physicians globally • Comprehensive insight into efficacy and safety of interventions
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Trials in resource-limited settings in Africa Factors to be considered • Trial objectives • Type of design • Control group • Choosing trial’s blind • Bias and confounding factors • Sample size • Randomization procedure • Patient recruitment • Compliance • Staff qualification and training needs • Logistics
Trials in resource-limited settings in Africa Specific problems encountered
Specific and typical problems encountered • Lack of experience in the conduct of clinical trials • Insufficiently trained / inexperienced staff • Overworked physicians • Low level infrastructure • Cultural differences • Illiterate patients • No nursing care
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Trials in resource-limited settings in Africa Caveat - Ethical Issues
• Ethical consideration • Interest of host country (population) • Cultural differences • Lack of patients protection • Future supply of investigational product • Lack of regulations and structures • Research professionals • Medical professionals • Independent Ethics committees
Trials in resource-limited settings in Africa Caveats – Access to treatment
• Availability of intervention after trial • Research in communities that are not intended to be major markets for the products under testing can be ethically problematic • Helsinki Declaration 2008 – Paragraph 18 Every medical research study involving human subjects must be preceded by careful assessment of predictable risks and burdens to the individuals and communities involved in the research in comparison with foreseeable benefits to them and to other individuals or communities affected by the condition under investigation
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Trials in resource-limited settings in Africa Caveat - Fair Treatment of Subjects
• Informed consent • Indicate research character of project • Ensure comprehension • Consideration of education • Illiteracy • Deviations from individual consent • Prior permission of community representative • Supplemented consent of husband • Consultation of family members • But: Individual consent is always required
• Compensation schemes for participants • Tendency to be higher than wages of hospital staff
Trials in resource-limited settings in Africa Minimum ethical standards Site level National level Sponsor level Staff understanding of the importance Timely ethical review by designated Study design respecting the local of a correct patient information and a national or thematic Ethics committee situation, correct informed consent process capacities and cultural constraints
Respect of right for anonymity of trial Timely approbation of cleared trial by Ethical review in sponsor (or CRO) participants drug authorities or Ministry of home country unless host country IEC Health and controlled importation of is certified the investigational product
Community information and Trial registration involvement Fair information of all potential Publication of results participants (complete, simple wording) Consent at relevant levels
Individual consent of all participant
Written consent as a standard option; alternatives with sufficient justification where necessary
Fair compensation for trial participation
Source: Kupefer & Burri, Intl. J. Parasitology 2009
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Trials in resource-limited settings in Africa Minimum standards according to GCP Site level National level Sponsor level The presence of educated medical Monitoring and surveillance of ongoing Responsibility for quality assurance staff and nursing care projects and quality control Capacities for documentation and Qualified personnel for the trial archiving design, trial management and medical expertise Assurance of confidentiality Trial registration
Accurate reporting and verification of Insurance for participants the data Adherence to the protocol Financing
Version control for protocol and Notification and submission to informed consent regulatory authorities Correct, timely reporting and handling Information on investigational product of adverse and serious adverse drug (investigators brochure) reactions Infrastructures for correct storage and Manufacturing, packaging, labelling, use of the investigational medicinal (coding) and supply of investigational product product Notification of end of study
Reporting
Source: Kupefer & Burri, Intl. J. Parasitology 2009
From efficacy to effectiveness Access…. to medicines
SANRU Program
SANRU Program
CB
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From efficacy to effectiveness Factors influencing effectiveness
• Depending on • Adequate R & D • Quality of product • Diagnosis • Reliable information • Availability • Affordability • Accessibility • Pharmacovigilance
Manhiça Health Research Centre Bagamoyo Research & Training Units - IHI
… sometimes work is easy…
Lambarene – Albert Schweitzer Hospital Queen Elisabeth Hospital Blantyre
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CS … and sometimes we go a long way…. CB
CB Dr. Jannin, WHO
http://www.swisstph.ch/
GP
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