1. 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

2. 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

3. Background Critically ill children Weak evidence base
Expert-based recommendations

4. Background Acute respiratory failure + Infection Huge disease burden
Stated area of need by global community
For both pandemic and inter-pandemic periods

5. Background Research on acutely ill children Parental stress
Achieving informed consent
Timeliness of interventions

6. Background Research on acutely ill children in LMICs
Resource availabilities

7. 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

8. 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

9. Antibiotic (A)
Adaptive Randomization
Fluids (F)
Oxygen (O)

10. 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

11. Consent models
Prospective
consent AF O

12. Consent models
Delayed consent
Delayed consent
+/- Re-consent AF O

13. Consent models
Waived
consent
Delayed consent
+/- Re-consent AF O

14. Consent models
Waived consent
Prospective consent
+/- Re-consent AF O

15. 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

16. Consent models Requirements for altering consent -minimal risk
-alteration has no adverse effect on participant welfare
-impracticable

17. CE research and waivers/delay of consent
Minimal Risk
Participant welfare
Impracticable ? ✓

18. Provider autonomy
Antibiotic (A)
Fluids (F)
Oxygen (O)

19. 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?