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Ebola, study design, and Ethics. Nancy E. Kass, ScD Berman Institute of Bioethics and Bloomberg School of Public Health. Outline for today. Ethical tension in “standard” randomized, placebo-controlled trials How this is heightened in Ebola context What is an adaptive trial?
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Ebola, study design, and Ethics Nancy E. Kass, ScD Berman Institute of Bioethics and Bloomberg School of Public Health
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?
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
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
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
Impact of Children’s Oncology Group: decline in mortality from pediatric cancer 1975-2000(thanks to Steve Joffe for slide)
Is there another option altogether? Ethics is not simply figuring out which “side” poses better arguments
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
Many types of adaptive trialsExample #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
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
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.
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
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