Databases presentation Vaccine Clinical Trials Mark Hatherill South African Tuberculosis Vaccine Initiative (SATVI) University of Cape Town November 2014 1
Databases presentation Regulatory Environment Sponsors & Funding Study Community Recruitment & Consenting Inclusion & Exclusion Criteria Vaccines & Vaccination Adverse Events & Morbidity Diagnostic Endpoints Subject Retention Data Management Sample Biobanks Publication 2
Databases presentation How long does it take for ethical & regulatory approval? SATVI TB vaccine trials 2004 – 2012 Geldenhuys et al, SAMJ Challenges in Africa Developing regulatory structures/regulations… Developing regulatory capacity… Mismatch = delay (Sponsors/Funders) 3
Sponsor Rights & Responsibilities Sponsors, Funders, Clinical Trial Sites Pharma Regulatory Responsibility Regulatory Responsibility Trial Implementation Project Management Meet Agreed Targets Adequate Financial Support Participant Safety Supply Investigational Product Data Integrity 4
Databases presentation Funding Infrastructure & equipment Adapt/refurbish buildings New structures in the field 5
Databases presentation Funding Transport specimens to the Lab Vehicles Transport participants & staff Access to the research clinic Urban vs Rural Infant vaccine trials Safety Families 6
Databases presentation Funding Personnel Staff are the main cost driver in most large-scale vaccine trials Rural Sites (distance) Infant Vaccine Trials (complexity) Need for diverse skills Administration Quality 7
Sponsors Funders Pharma Clinical Trial Sites The relationship between the Major Partners and Clinical trial Sites is inherently unequal Unavoidable imbalance arising from financial dependence 8
Worst-case Scenario: “Trial Farming” Clinical Trial Site role = Work-for-Hire implementation of research Trial Sites may be complicit in their own scientific marginalisation , if their focus is on the financial benefits of partnership Marginalisation of Clinical Trial Sites = Opportunity lost… …to add scientific value from the Site’s unique viewpoint 9
What Do Clinical Trial Sites Need? Maslow’s Hierarchy The Science!!!! Communication Transparency Respect Alignment Capacity Building Project Funding 10
Databases presentation Selecting the Right Study Population Phase I First in human Safety and Immunogenicity Phase II Dose-finding Age De-escalation Proof-of-principle in the population of interest Phase III Efficacy in the population of interest Phase IV Post Licensure 11
Clinical Trials of TB Vaccines 12
FIH & Phase 1 Birth Infancy Childhood Adolescence Adulthood Low TB Exposure Settings (Europe & North America) ------------------------------------------------------------------------------------------ High TB Exposure Settings (Africa & Asia) MTB MTB MTB Birth Infancy Childhood Adolescence Adulthood Phase 1b-4 BCG Pre-exposure Post-exposure Therapeutic 13
Databases presentation The Study Community Each study community is different! Attitudes to health & disease Attitudes to vaccination Attitudes to research Community Advisory Boards, & research workers from the community, are key to success Recruitment Retention Adverse events 14
Databases presentation Recruitment & Consenting How are potential participants contacted? Clinics Workplace Churches/NGOs Door-to-Door Word-of-Mouth Databases Shopping malls Information sessions Consenting (family input) Assent of minors 15
Databases presentation Compensation vs Undue Coercion What is the role of participant compensation & incentive schemes? Money – how much? Groceries, vouchers Primary health care Access to referral / best practice 16
Databases presentation Screening & Exclusion Criteria Particularly affects FIH and Phase I vaccine trials It may be difficult to find “healthy adults” Issues: HIV, TB infection, smoking, ethanol, pregnancy, BMI 17
Databases presentation Screening: What are the “normal ranges” for developing countries? 18
Databases presentation Retention How do we minimize loss to follow-up? Communication is key Home visits (distance/staff) Mobile phone/text message Deal with out-migration Relationship with participants 19
Databases presentation Vaccines & Vaccination We need more than the usual pharmacy! Pharmacist: Control of investigational product Dispensing Cold chain Documentation 20
Databases presentation Cold Chain Not enough to maintain the cold chain Documentation & Proof 21
Databases presentation Adverse Events vs Community Morbidity How do we distinguish AEs related to study vaccine from community morbidity? Relatedness Timing Rates Mortality & post-mortem diagnosis Surveillance (AEs and Endpoints) 22
Impact of surveillance methodology… Question: What is the impact of active vs. passive surveillance on PTB case detection in children less than 2 years of age? High High low Case Detection rate PTB Disease Severity Low Passive Active Surveillance Intensity
Surveillance in TB vaccine trials The incidence rate of something we never look for is zero If we look too hard, we may not find what we seek – TB: Disease of poverty, age-related, chronic , preventable / treatable – Trial intervention has potential to decrease case burden in study population (Hawthorne effect) • Health service awareness, Rx adult contacts, Rx suspects • INH prophyaxis of children – Active surveillance • Increase TB case detection rate and AE detection rate • Suspect TB cases detected more early and treated effectively • Decreased case severity • Decreased certainty of diagnosis
Variability not related to components of systems (6/9 micro+radiol+clinical), but to how they were combined: “and” / “or” 25
The importance of objectivity • Paediatric radiologists • Blind review • 2/3 majority • Specific features • Specific anatomical sites 26
Databases presentation Data Management Sophisticated, secure data systems in the field Electronic vs hard copy data capture Where are the data? Security / hazards On-shore / off-shore Access to data 27
Data ownership Access to data for future studies Academic outputs Sample ownership and biobanking Investigators as custodians Use of samples for future studies Representation on biobank governance 28
Databases presentation Publication Who writes the paper? Investigator vs Sponsor priorities Permission vs Right to Review 29
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