1. The Minimal Risk Standard Revealed Leah Belsky Ezekiel J. Emanuel Kimberly Thompson David Wendler

2. The Imperative for Pediatric Research Less than 1/3 of drugs prescribed to children have been tested in children. Pediatricians are regularly prescribing drugs that have not been proven safe and effective in children. To improve pediatric medicine, more pediatric research is needed.

3. Protecting Pediatric Subjects The importance of conducting pediatric research must be balanced with protection of individual research subjects. Ensuring protection is especially important in non-beneficial research.

4. Smallpox Vaccine Development of a vaccine for smallpox offered important possible benefits to children. Toxicity studies were needed before efficacy studies could be conducted. Toxicity studies posed risks to subjects without any potential medical benefit.

5. How Much Risk is Acceptable? It is widely agreed that non-beneficial research is acceptable when risks are sufficiently low. What constitutes “sufficiently low”? How much risk is acceptable in this context?

6. The US Federal Regulations IRBs may approve studies that do not offer pediatric subjects a prospect of direct benefit when the risks are ‘minimal’ or a ‘minor increase’ over minimal.

7. What is Minimal Risk? The federal regulations define minimal risk as the: “Probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests” 45CFR 46.102(i)

8. Are These Procedures Minimal Risk? An MRI without sedation in healthy 11 year- olds. Allergy skin testing in healthy 11 year-olds. 3 blood draws in healthy 7 year-olds. One dose of Ritalin.

9. What do U.S. IRB Chairs say? MRI w/out sedation in healthy 11 year-olds

10. What do US IRB Chairs Say? Allergy skin testing in healthy 11 year olds

11. Unjustified Variability? The variability in IRB assessment of the risks of procedures may result in inappropriate review: Approving some risky studies, or Disapproving some safe studies.

12. Judgment in the Absence of Data IRB members may assume they are familiar with the risks of daily life or rely on intuition. Psychological studies show that individuals’ risk perception is severely and systematically flawed. –People focus on how familiar an activity is or how much control they have when participating. To ensure accurate application of the minimal risk standard, we must quantify the risks of daily life.

13. Fundamental Questions How should we interpret the minimal risk standard? What do the data on risks of daily life imply about minimally risky research procedures?

14. DISCLAIMER The views expressed in this presentation do not represent the views of the NIH, DHHS, or any other government agency or official. These are not their views.

15. 3 Conceptions of Minimal Risk 1.The Procedure Based Standard 2.The Relative Standard 3.The Objective Standard

16. Procedure-based Standard Categorizes as minimal risk only those procedures that children regularly encounter during ordinary life. Blood draws and eye exams are minimal risk, but MRIs and glucose tolerance tests are not. This standard seems consistent with Federal Regulations’ references to “ordinarily encountered in daily life.”

17. Problems Federal regulations do not limit minimal risk procedures to procedures children actually encounter in daily life. Rather, the risk level of research procedures must be no greater than the risk level of every day activities, including medical procedures. –Hypnosis

18. The Relative Risk Standard Which children’s daily lives should serve as the baseline for determining when research risks are minimal? The relative risk standard categorizes as minimal risk those risks that the children enrolled regularly experience in daily life. Minimal risk is “relativized” to the population under study.

19. Problems This relative standard has the potential to take advantage of the worst off for the benefit of others. Reminder: We are talking about research that does not offer a prospect of direct benefit!

20. The Objective Risk Standard The objective risk standard categorizes as minimal risk those risks that average, healthy, normal children experience during the course of daily life. Institute of Medicine: IRBs “should interpret minimal risk in relation to the normal experiences of average, healthy, normal children.”

21. The Risk Threshold Activities of daily life pose different levels of risk to children. Bike riding is more dangerous than napping or reading a book. The minimal risk standard insists that research risks ‘cannot be greater than’ the risks that average, healthy, normal children face in daily life.

22. The Risk Threshold Research risks cannot exceed the range of risks presented by daily life activities. Research risks must lie below the top of the range of daily life risks. Therefore, the risks of research procedures must not be riskier than the riskier activities of daily life.

23. Summary A given research procedure is minimal risk if the –(i) risks posed by the research procedure –(ii) do not exceed the risks of the riskier activities –(iii) in the daily life of average, healthy, normal children.

24. What are the Risks of Daily Life for Average, Healthy, Normal, Children…

26. Mortality Risks Risks of Riding in a Car Risk of Death per trip Deaths per Day Ages 1-14 1 per 50 million 1 Ages 15-19 1 per 5 million 3.8

27. Morbidity Risks Total injuries Visit ERNeed Surgery Break Bones Baseball 1,40030012030 Basketball 2,400300160180 Martial Arts 1,5001006120 Sports Injuries per million episodes of participation

29. Risks of Procedures Compared Per million events Sweating/ Nausea SyncopeSurgeryDeaths Drawing Blood 3750 Allergy Skin Testing 16250 Research Apheresis 10,000< 500 Basketball160 Car Ride0.4

30. Psychological Risks These risks do not include psychological risks. However, life poses psychological risks, even for average, healthy, normal children. –Taunts –Social exclusion

32. Applying the Minimal Risk Standard Section CFR §46.407 allows submission of protocols deemed unapprovable by the IRB for DHHS review.

33. Evaluating a 407 submission Precursors to Diabetes in Japanese American Youth –Purpose: to examine the influence of ethnicity and puberty on glucose metabolism and Type 2 diabetes risk –Demographic: 450 healthy, normal children 8-11 years old –Procedures: Blood draw MRI scan 2 administrations of 25% glucose intravenously Measurement of body composition by means of DEXA

34. Evaluating the Procedures Blood draw: minimal risk by definition MRI: risks of anxiety and discomfort seem no greater than that experienced daily DEXA Measurement: low doses of radiation, less psychological risk than MRI Glucose infusions: ?

35. Evaluating the Procedures Glucose infusions: –Experts suggest that in two different experiences with 800 children and 225 children, there were no deaths, injuries requiring an ER visit, or injuries of any kind. –Sweating, Nausea, and Fainting were the worst side effects

36. Applying the Minimal Risk Standard Appraisal of trials forwarded by IRBs for 407 review by the Secretary of DHHS suggests that many do actually meet the criteria for minimal risk.

37. Conclusions Minimal Risk must be defined by data. We must be wary of considering intuitions about risks. Data on Risks of daily life: –Cars:.02 deaths per million car rides –Sports: 2,400 injuries per 1 million events Many procedures ruled unacceptable actually meet the minimal risk criteria.