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Methodological approaches to study safety and efficacy/effectiveness data under
emergency use conditions in consenting health workers in affected countries
Matthias Egger
Institute of Social- and Preventive Medicine (ISPM)University of Bern, Switzerland
Centre for Infectious Disease Epidemiology and ResearchUniversity of Cape Town, South Africa
Objectives
• To make vaccines that were shown to have acceptable safety andimmunogenicity available to front-line health workers in the affectedareas
• To collect data on safety and efficacy/effectiveness
• Critical data versus ‘nice to have data’
Ethical considerations - from report of Advisory Panel to WHO• There should be shared understanding of the criteria for such use by
everyone involved (patients, clinicians, families, communities …).• The uncertainty about safety/efficacy of the intervention in humans
should be acknowledged and transparently communicated to all stakeholders. Fostering unfounded expectations should be avoided.
• Emergency/compassionate provision of vaccine should not divert resources from supportive care and public health measures.
• Appropriate scientific data on outcomes resulting from compassionate use, should be collected and shared and rapidly. The panel emphasized that this is a moral obligation.
• It should not preclude or delay the initiation of ore conclusive investigations of the intervention in properly designed clinical studies.
Rationale• In Monrovia, in mid-August, about half our patients were health-care
workers. There was a lot of a health-care transmission going on. • Armand Sprecher, MSF
• As of 23 September 2014, 375 HCWs are known to have developed EVD (67 in Guinea, 184 in Liberia, 11 in Nigeria, and 113 in Sierra Leone). 211 HCWs have died as a result of EVD infection (35 in Guinea, 89 in Liberia, five in Nigeria, and 82 in Sierra Leone).
• WHO Ebola Response Roadmap Update, 26 September 2014
An overview of clinical research: the lay of the land
Grimes & Schulz Lancet 2002
Possible study designs• Randomized controlled trial
• Different doses of one vaccine• Different vaccines (ChAd-EBO versus VSV-EBO)
• Randomized stepped wedge design• Non-randomized comparative study
• Before after comparison• Historical controls
• Registry / clinical database• Case-control study
Stepped wedge design
Smith and Morrow, 1996Brown & Lilford BMC Res Meth 2006Mdege J Clin Epi 2011Debate in J Clin Epi 2012
• Phased introduction on a facility byfacility basis until all facilities havereceived intervention
• Order in which facilities are offeredvaccination is randomized
• Time points informed by• Urgency, immunology, incubation
period
• Reduced power
Stepped wedge design
Smith and Morrow, 1996Brown & Lilford BMC Res Meth 2006Discussion papers in J Clin Epi 2012
• Standardized data collection needs tobe in place from the start in all facilities
• Blinding of health care workersimpossible• Sense of false security?
• Blinding of outcome assessmentpossible but difficult
• (Reduced statistical power)
• “It’s not just health-care workers who are at high risk of infection.
There are laboratory technicians, janitors in health facilities, and health staff helping with burial procedures, who are all exposed to infection”
• Michael Kurilla, NIH
Eligibility
Settings, eligibility, study duration• Settings
• Ebola Treatment Centers• Health centers• Hospitals …
• Staff at increased risk• Nurses, doctors, lab workers, janitors, drivers, reception staff …
• Informed consent• Exclusion criteria
• Pregnancy, HIV?
• Study period• 6 months
Efficacy endpoints
• Active ascertainment of EVD and deaths• Death primary endpoint• Lab confirmed case• Suspected case• Probable case
www.who.int/csr/resources/publications/ebola/ebola-case-definition-contact-en.pdf?ua=1
www.brightoncollaboration.org
Safety data collection• Will be informed by results from phase 1
• Active ascertainment
• SAEs, AEs• Blood samples: days 0, 28, (180) for lab
safety parameters and immunogenicity
DSMB (data and safety monitoring board)
• Crucial role• Stopping rules• Adaptations
Recommendation
• Randomized stepped wedge design• Non-randomized comparative study
• Before after comparison• Historical controls
• Registry / clinical database
What should be done now
• Address legal and regulatory issues• Identify potential sites• Liaise with local stake holders and communities
• Qualitative research?
• Liase with local Ethics Committees / IRBs / MoH• Write study protocols• Do retrospective analysis (where possible) and prospective
monitoring of EVD among health care workers
Thank you