Srinivas Murthy, MD, MHSc, FAAP, FRCPC University of British Columbia Critically ill children and adaptive trials for comparative effectiveness research Srinivas Murthy, MD, MHSc, FAAP, FRCPC University of British Columbia Global Forum on Bioethics in Research Bangkok, Thailand November 2017
Disclosures I have no actual or potential conflict of interest in relation to this presentation I sit on local and regional ethics committees I am a clinician and clinical researcher, not a statistician
Background Critically ill children Weak evidence base Expert-based recommendations
Background Acute respiratory failure + Infection Huge disease burden Stated area of need by global community For both pandemic and inter-pandemic periods
Background Research on acutely ill children Parental stress Achieving informed consent Timeliness of interventions
Background Research on acutely ill children in LMICs Resource availabilities
Proposed trial design Population: Critically ill children with acute respiratory failure due to presumed infection Interventions: antibiotics, fluids, oxygen strategies; - comparative effectiveness of frequently used management strategies
Proposed trial design Design: ‘Adaptive’ randomization, ‘platform’ trial Setting: Intensive care units in both low- and high-income settings. Primary Outcome: Either mortality or HRQL-28d
Antibiotic (A) Adaptive Randomization Fluids (F) Oxygen (O)
Comparative effectiveness research “compares the results of one approach for managing a disease to the results of other approaches”* “investigates methods, already in use…to treat a heterogeneity of patients”** *AHRQ, 2009 **BMJ, 2010
Consent models Prospective consent AF O
Consent models Delayed consent Delayed consent +/- Re-consent AF O
Consent models Waived consent Delayed consent +/- Re-consent AF O
Consent models Waived consent Prospective consent +/- Re-consent AF O
Consent models Informed consent for complex trials “…informed of all aspects of the trial that are relevant to the subject’s decision to participate’* -the trial treatment and the probability for random assignment to each treatment *ICH GCP
Consent models Requirements for altering consent -minimal risk -alteration has no adverse effect on participant welfare -impracticable
CE research and waivers/delay of consent Minimal Risk Participant welfare Impracticable ? ✓
Provider autonomy Antibiotic (A) Fluids (F) Oxygen (O)
Questions Is an alteration of consent appropriate for ‘minimal-risk’ interventional studies of this sort? Adaptive randomization is complex, but (likely) benefits study participants. How to build that into informed consent? What further ethical work is required before implementing a trial such as this?
Srinivas.murthy@cw.bc.ca