1. Determining Minimal Risk
Angela Bain, IRB Specialist

2. Risk Assessment
So we all know that risk is a function of probability and magnitude. The IRB has to consider the likelihood that something will happen (that harm will result) and how bad that harm would be.

3. 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 (i)
Note the underlined elements. These will be examined in further detail later in the presentation.

4. Expedited vs. Committee Review
Under the proposed revised regulations, the “default” assumption will be that a study otherwise eligible for expedited review will be considered minimal risk unless a reviewer documents the rationale for classifying the study as involving more than minimal risk.
Higher-risk studies should be subject to the highest level of scrutiny. Research involving more-than-minimal risk requires review by a convened IRB
Since research that is eligible for expedited review can involve only research activities that are included in the approved list, very few such studies will involve more than minimal risk. The upcoming change in federal regulations will better assure that the level of review is well targeted to the level of risk. Pay attention to the underlined statement. The IRB still has a responsibility or “ability” (depending on how you view it) to determine that a project represents more than minimal risk even if the procedures involved are on the Expedited list.

5. 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
OHRP justified the upcoming changes in regulations by citing the variability found in IRB determinations of risk. So how are we doing with our risk assessments? In HSO’s assessment of the UGA IRB, we don’t see the second result very often. BUT- Given that our clinical research portfolio is likely to grow in the near future, we expect an increase in partnerships and collaborations that may affect on other biomedical and social behavioral research. So any study we would normally expect to see in this committee may include procedures that we need to learn how to assess appropriately and consistently.

6. Data Based Determinations
Recommendations in the NPRM specifically state “Determinations about the risks imposed by various research activities should be based upon appropriate data.”
Because the IRB has the ultimate authority to determine risk and should have some guidance that they are following best practices, the revised regulations will require OHRP to review/update the list of Expedited categories to be every 8 years. That will help. But in the meantime, we should make our determinations via some systematic process.

7. Judgement 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.
Here’s what happens if we don’t have a systematic process for determining level of risk.

8. How should we interpret the minimal risk standard?
The Procedure Based Standard
The Relative Standard
The Objective Standard
So how should we interpret the minimal risk standard? Here are three common method: Procedure Based, Relative, Objective.

9. Procedure-based Standard
Categorizes as minimal risk only those procedures that people 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.
For example, the board could provide guidance for HSO staff regarding other procedures to help us route submissions for review to Expedited or Committee like we are doing for common exercise protocols.

10. Problems
Federal regulations do not limit minimal risk procedures to procedures people 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.
As you may already be thinking---there are problems with this approach. You can probably think of a lot of procedures that this board has reviewed that don’t really happen to people ordinarily (there’s that word again) but that we have assessed as minimal risk. Why? Because we may have been thinking of harm involved with the procedure for research as compared to harm involved with the procedure outside of research. More on that later.

11. The Relative Risk Standard
Which people’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 people enrolled regularly experience in daily life.
Minimal risk is “relativized” to the population under study.
So maybe the appropriate assessment of risk can only be made in context of population. We do have that discussion in meetings all the time, right? A treadmill protocol involving walking for 20 minutes at a moderate rate (e.g., 4 miles an hour) can be minimal risk for a 45 year old healthy male but may be more than minimal risk for a 78 year old man with a chronic condition and balance issues. This method is called the Relative Risk Standard.

12. Problems
This relative standard has the potential to result in an unjust distribution of risks.
A population-specific definition unjustly permits individuals to be exposed to higher levels of risk under the minimal risk category, simply because their daily lives are filled with greater risk than healthy individuals or those living in safe conditions.
But OHRP has typically had big problems with using this standard, particularly when reviewing studies in international settings. Some discussions and guidance have gone so far as to say that only US living conditions should be considered when assessing specific population risks. Any problem with that? How about the differences in ordinary life for urban youth in a crime-ridden area versus country living in Oconee county?

13. The Objective Risk Standard
The objective risk standard categorizes as minimal risk those risks that average, healthy, normal people experience during the course of daily life.
The IRB must ensure that the application of the general population standard does not result in the inadvertent application of an adult minimal risk standard to child participants.
So that leaves us to the Objective Risk Standard. One where we insert the concepts of “average” “normal” and “experience”. These seem like very subjective terms to include in a method based on objectivity. Even using “people” as a term can be a problem since age can be very important when determining risk level.

14. The Risk Threshold
Activities of daily life pose different levels of risk to people
Bike riding is more dangerous than napping or reading a book.
Data on Risks of daily life:
Cars: .02 deaths per 1 million car rides
Sports: 2,400 injuries per 1 million events
People with diabetes, regardless of age, spend more time sticking their fingers than people who do not have diabetes.
Let’s make some very basic statements: Can we agree on these?

15. The Risk Threshold
The minimal risk standard insists that research risks ‘cannot be greater than’ the risks that average, healthy, normal people face in daily life.
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.
How about these? Do we agree that: (read each item---discuss)

16. Summary A given research procedure is minimal risk if the
risks posed by the research procedure do not exceed the risks of the riskier activities
in the daily life of average, healthy, normal people.
If we agree with all of those statements on the previous slide, here is a summary.
If we do not agree, we should come up with a UGA IRB summary of how we approach assessment of risk level.

17. Overestimation and Underestimation of Risk
The vagueness of the definition of minimal risk leads to both overestimation and underestimation of risk, due in large part to:
The lack of specificity in examples provided for minimal risk under the expedited risk category
Difficulty distinguishing research risk from participant vulnerabilities
The tendency to apply subjective estimations of the level of harms
UGA rarely assesses projects as “more than minimal risk? Why?

18. What did we learn?
We must be wary of considering intuitions about risks and should instead define what we do consider
Minimal Risk must be defined by data: is this only the list of expedited categories or can our new guidances help (e.g., exercise, radiographic procedures)?
People first: population-specific harms are important
Whatever we decide about how we (UGA IRB) want to assess level of risk, we should make sure that our method is documented and that our processes include our consistent application of our method. Our method should at the very least consider: (read underlined items on slide)