Chasing Unicorns

1. Chasing Unicorns Jerry Menikoff Office for Human Research Protections

2. Disclaimer The views expressed in this presentation do not necessarily represent the views of the Department of Health and Human Services or any subdivision thereof.

3. Types of LHS Studies ●Observational or secondary use of data ● Interventional – altering the type of care provided to someone from what they otherwise would have received ● Often arms in interventional LHS are “within standard of care”

4. Risks in LHS Interventional Research ●Some interventional research can be minimal risk ● E.g., comparing marketed meds for mild headaches; adding an intervention to one arm that has little “down” side (providing additional services)

5. Risks in LHS Interventional Research ●But some have claimed that “standard of care” LHS interventional research is always minimal risk ● Claim is that since doctor could have given you either arm’s treatment as clinical care, no “additional risk”

6. Risks in LHS Interventional Research ●For Common Rule, that claim is wrong ● Different versions of standard of care can have significantly different risks ● Changing a person’s care from one standard to another can therefore sometimes be greater than minimal risk

7. Risks in LHS Interventional Research ● Note: the rules could be changed ● A utilitarian approach could be taken: doing research without consent could generate knowledge more quickly, albeit some subjects end up being worse off

8. Example: SUPPORT NIH-funded trial on premature infants: ● 2005 to 2009, 1300 babies, 23 centers ● Randomized to low or high O2, within standard of care ● Concerns about increased retinopathy (ROP) at higher end, and increased death or neurological impairment at lower end

9. Oxygen distrib. goal pre-SUPPORT at many centers (per Duke c.f.)

10. Oxygen distribution goal in SUPPORT

11. Change in oxygen distribution resulting from SUPPORT

12. Draft Guidance ●In 2014, OHRP releases draft guidance about “standard of care” research ● http://tinyurl.com/SUPPORTguidance

13. After the Draft Guidance ●After draft guidance release, prominent advocates of “this is always minimal risk” stance changed the conversation ● They now avoided discussing SUPPORT-like scenarios ● Shifted discussion to very different scenario

17. The Editors, NEJM 2014;371:2125-26

18. Kraft, et al., Clinical Trials 2016

21. Change in cases being discussed ●Suddenly, a focus on research where no pre-existing concern about specific risk differences – thus nothing specific to warn subjects about. ● Q1. Is this the research we should do? ● Q2. Is this the research people are doing (do many such studies actually exist)?

22. Q1. What research to prioritize? ●In a world of limited resources, should we prioritize research comparing: (i) treatments where no differences suspected (ii) treatments where we already suspect differences, but are not sure

24. Q2. What research are we doing? ●As an empirical matter, are we doing a great deal of “no suspected differences” research? ● Note that the people pushing this approach keep using theoretical examples

25. Q2. What research are we doing? ●SUPPORT ● Tapering steroids in patients with granulomatosis ● High or low dose aspirin for preventing cardiovascular disease

26. Q2. What research are we doing? ●Frequency of CT scans for following lung nodules ● Chlorthalidone versus hydrochlorothiazide for treating hypertension

27. Change in oxygen distribution resulting from SUPPORT

29. THE END