1. Outcome-adaptive randomization: some ethical issues
Julius Sim
Keele Clinical Trials Unit
Research Institute for Primary Care and Health Sciences
Keele University, UK

2. Outline of talk Conventional versus outcome-adaptive randomization
The moral case for outcome-adaptive randomization
Some problematic ethical issues
equipoise
consent
methodology

3. Adaptive clinical trials
Adjustments are made to the trial while it is in progress, regarding:
The number of arms
Number and timing of interim analyses
Case definition
Allocation ratio

4. Conventional vs outcome-adaptive randomization
Conventional approach to randomization
Outcome-adaptive randomization
Fixed (usually 1:1) allocation ratio at outset
Allocation remains fixed
Initial allocation adjusted in the light of accruing data, to favour the superior treatment
Judgment on relative benefit is suspended until end of trial (or planned interim analysis)
Judgment on relative benefit is continually re-appraised

5. The moral case for adaptive randomization
A distinction can be made here between collective and individual ethics:
Collective – doing what is best for the population of future patients
Individual – doing what is best for individual patients in the trial
Adaptive randomization is often considered to affirm individual ethics (Pullman & Wang, 2001; Legocki et l, 2015)

6. Equipoise

7. The principle of equipoise
A trial is ethical in as much as the researcher (or the clinical community) is genuinely uncertain of the relative aggregate effectiveness of the treatments being tested (Fried, 1974; Freedman, 1987)
Hence, at the outset of the trial, no patient is knowingly disadvantaged by being randomized

8. Equipoise
In conventional randomization, equipoise is not re-evaluated during the trial (except at any interim analyses) – judgment is suspended
In adaptive randomization, equipoise is continually re-evaluated – and the allocation ratio adjusted accordingly

9. Equipoise and adaptive randomization – 1
Patients are still allocated to the inferior treatment, although at a lower rate
This compensates for a loss of equipoise, but does not restore it
Some patients are therefore knowingly disadvantaged

10. Equipoise and adaptive randomization – 2
The principle of ‘individual ethics’ is undermined
Need to be confident that not only the proportion but also the number of patients allocated to the inferior treatment is smaller than in conventional randomization

11. Informed consent

12. Informed consent and adaptive randomization – 1
Moral force of consent depends upon:
An understanding of what the study involves
An ability to give – or withhold – consent freely and autonomously

13. Informed consent and adaptive randomization – 2
Problems in terms of understanding:
Complexity of adaptive randomization may be hard to convey (Saxman, 2015)
The therapeutic misconception may be reinforced – participants may believe that allocation is personalized rather than random (Appelbaum et al, 1987)

14. Informed consent and adaptive randomization – 3
Problems in terms of information:
If equipoise is continuously revised, the information on which consent is based must be updated accordingly:
for new participants, and
for those already in the trial
If this cannot be achieved, consent is not adequately informed and loses moral force

15. Methodological issues

16. Methodological implications of adaptive randomization – 1
To be morally sound, a study must be methodologically sound (Emanuel et al, 2000)
Adaptive randomization may face challenges of:
confounding (population drift, alongside changing allocation ratio)
loss of blinding (repeated monitoring of outcome)
outcomes (hard to use long-term outcomes)
sample size (may require larger numbers)

17. Methodological implications of adaptive randomization – 2
If, overall, designs using adaptive randomization are methodologically less robust than those using conventional randomization…
…they lose some of their ethical authority on that basis.

18. Conclusion
Outcome-adaptive randomization has the merit of seeking to maximize benefit for patients in the trial, but it also raises other ethical issues that are potentially problematic

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20. References
Appelbaum PS et al (1987) False hopes and best data: consent to research and the therapeutic misconception. Hastings Center Report 17: 20–24
Emanuel EJ et al (2000) What makes clinical research ethical? JAMA 283: 2701–2711.
Freedman B (1987) Equipoise and the ethics of clinical research. New England Journal of Medicine 317: 141–145.
Fried C (1974) Medical Experimentation: Personal Integrity and Social Policy. Amsterdam: North-Holland.
Legocki LJ et al (2015) Clinical trialist perspectives on the ethics of adaptive clinical trials. BMC Medical Ethics 16: 27
Pullman D, Wang X (2001) Adaptive designs, informed consent, and the ethics of research. Controlled Clinical Trials 22: 203–210.
Saxman SB (2015) Ethical considerations for outcome-adaptive trial designs. Bioethics 29: 59–65.