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