1. Ebola, study design, and Ethics Nancy E. Kass, ScD Berman Institute of Bioethics and Bloomberg School of Public Health

2. Outline for today Ethical tension in “standard” randomized, placebo-controlled trials How this is heightened in Ebola context What is an adaptive trial? Why is this any different, ethically? And what else should we thinking about?

3. Ethical tensions in RCTs, generally Tensions between a doctor’s duties to the individual patient vs. need to improve care for future patients Between deontological duties vs. utilitarian commitments

4. Ethics “solution”: Equipoise If we don’t “know” if the experimental treatment is actually better– if there are no data to support that one arm is better than the other-- then we have equipoise Yet Problems can Remain: – False dichotomy --Knowledge is not yes/no- it’s on a spectrum – Amount of certainty required for widespread treatment recommendations may be different from uncertainties that doctor or patient might accept

5. Debates for Ebola treatment trials Point of View #1: Ethically, how can we deny potentially lifesaving treatment to people who are dying– even acknowledging some uncertainty? Point of View #2: – Especially when people are dying in vast numbers, there is an ethical duty to learn what works; – And there is no ethical violation to use placebos if we don’t know whether the intervention works

6. Impact of Children’s Oncology Group: decline in mortality from pediatric cancer 1975-2000 (thanks to Steve Joffe for slide)

7. Additional context for treatment trials

8. ETHICS IS NOT SIMPLY FIGURING OUT WHICH “SIDE” POSES BETTER ARGUMENTS Is there another option altogether?

9. Other options? Adaptive trials? In an adaptive trial, the study design is altered… – while study is being conducted – Based on what is learned In an adaptive trial, the trial’s design is changed along the way as we learn new things about the intervention

10. Many types of adaptive trials Example #1 Adaptive approach #1: – Multi-arm randomized trial – Patients randomized to one of several different experimental treatments or to placebo – Much higher percentage of patients get something – Study arms are dropped if interim analysis shows another arm is better

11. Examples of adaptive trials? Example #2 Start giving experimental drug to a smaller number of patients (e.g., 40 sick patients) Record what happens with survival If dramatic (“magic bullet”) e.g., 80-100% survival, – then we know the drug works! – No need for randomized trial

12. Ethics and adaptive trials If early results suggest intervention is not dramatically better than historical experience, unclear whether it is working… – Then change design: randomize against placebo – Less troubling ethically to randomize if unclear whether or how much drug works If interim analysis suggests maybe is better, change design: randomize unequally e.g., 70:30, etc.

13. Ethics and adaptive trials In all cases, fewer patients assigned to arm believed “currently” to be the inferior arm – Meurer argues (JAMA 2012) this will also reduce therapeutic misconception Commitment to learning with rigor sustained Does not eliminate ethical tension but significantly reduces it

14. Other design considerations? Ethically: Must provide supportive care-- may be most important piece of “compassion” = only thing we know makes a difference in survival How to manage in informed consent? Change consent language with each design change? Technically: Only works when endpoints are clear (e.g., death) and occur relatively quickly Requires quality/ongoing DSMB Requires nimble and sophisticated study team