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Risk and Benefit

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In order to fulfill its mission of protecting research subjects, the IRB must ensure that all risks have been minimized and that they are reasonable in relation to the anticipated benefits.

Risk - Benefit Assessment

45 CFR 111(a)
Criteria for IRB Approval

(2) Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result...

For the complete citation see 45 CFR 46.111.

The term risk - benefit assessment is preferred rather than the metaphor risk-benefit ratio. The reason is risks and benefits are not measured using comparable scales. Risk is measured in terms of probability of harm while benefit is an aspirational hope whose probability generally can't be measured.

The investigator and the IRB should proceed by doing the following:

  • Assessment of all of the risks associated with the research by identifying all potential harms that could befall a subject and the magnitude and the probability of those harms;

  • Ensuring that the appropriate steps have been taken to minimize the risks that are identified; and

  • Assessment of the possibility and importance of potential benefits to subjects (if any) and to science and society.

The research may be approved by the IRB provided that the benefits outweigh the risks to participants.

Risks

Risk is assessed by the probability and magnitude of potential harms that may befall a participant from an intervention or monitoring procedure.

Risk associated with a procedure is a summation of the probabilities of all possible harms multiplied by the magnitude of those harms. Factors that impact risk include:

  • the procedure (possible harms);
  • the person performing the procedure (training, experience, skill);
  • the setting (privacy protections, availability of resuscitation equipment, etc.); and
  • the characteristics of the research subject (age, health status).

It is the investigators obligation to explain what will be done, by whom and to whom and where it will be done. Protocols and applications that incompletely describe the study procedures frequently result in requests for more information.

References

  1. Weijer C. The ethical analysis of risk. J Law Med Ethics. 2000;28(4):344-61
  2. Rid A, et al. Evaluating the risks of clinical research. JAMA 2010;304(13):1472-9
  3. Wendler D et al. Quantifying the federal minimal risk standard. JAMA. 2005 17;294(7):826-32

Minimal Risk

Definition: 45 CFR 102(i.)

Minimal risk means that the probability 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.

The meaning of minimal risk is hotly debated partly because the definition creates 2 separate standards (risks of daily life and the risks of routine procedures) but also because it isn't clear how to index those risks - the lives of healthy children or the lives of the proposed study population.

Indexing Risk:
The debate regarding how to index risk appears to be settled. The overwhelming majority believe that risk should be indexed to the lives of healthy children living in safe environments. To do otherwise would justify exposing more vulnerable children (sick children or those in risky living situations) to greater risk in the research context.

Risks of Daily Life versus Routine Examinations:
The risks of routine examination (stethoscopic exam, palpation, ear examination, etc.) are generally fairly trivial. To limit participation of healthy children to such minimal risks would be to halt research progress.

The risks of daily life include risks that may seem too great for healthy child volunteers. For example, the risks of driving in a car include severe injury, post-traumatic stress, disability and death. Death occurs at a rate of 0.06 per million car trips. The daily risk of death for children is approximately 1.5 deaths per million children per day.

IRB Assessment of Risk:
The IRB reviews the information provided by the investigator about the possible harms and the likelihood of those harms when assessing the level of risk of a procedure. In the eIRB application, the investigator is requested to make their assessment of the level of risk. The IRB takes all of the information and then tries to determine if the risks are consistent with one of the two standards for minimal risk.

Parents use their judgment to determine which activities they'll allow for their children. Most parents will permit their children to play basketball or soccer, even though these sports carry risk of harm. On the other hand, many parents don't permit their children to play football, or their teens to drive late at night by themselves. The risks of these activities could be said to carry at least a minor increase above minimal risk.

Unfortunately, the exact risk of study procedures, even common ones, is frequently unknown. When this is the case, the IRB is forced to rely on its best judgment and precedent.

Benefits

The IRB may weigh the risks to adult participants against the benefits to society and science and decide (or not) to allow the research to proceed. When vulnerable subjects take part, the regulations place limits on the extent of risk permitted. Children may only participate in greater than minimal risk research (more than a minor increase above minimal) when there is a prospect for direct benefit.

Direct benefits to subjects can never be guaranteed. The history of medical research is littered with physiologically plausible interventions that have failed to work. Approximately 9 out of 10 new therapeutics that undergo testing in humans fail in clinical trials. Research that offers the participants a prospect for direct benefit is the most one can hope for.

Types of Benefit

Nancy King has defined three types of benefit that may occur in the context of clinical research (J Law Med Ethics. 2000 Winter;28(4):332-43)

Direct Benefit

  • Defined as benefit arising from receiving the intervention being studied;

Indirect Benefit

  • Collateral Benefit:
    A benefit arising from being a subject, even if one does not receive the experimental intervention (for example, a free physical exam and testing, free medical care and other extras, or the personal gratification of altruism);

  • Aspirational Benefit:
    Or benefit to society and to future patients, which arises from the results of the study.

What is the basis for assessing prospect for direct benefit?

When the investigator proposes that the research offers a prospect for direct benefit, they must then support that contention with sufficient evidence for the IRB to reach the same conclusion. Failure to provide sufficient information to support the claim of benefit inevitably results in delay in approval.

Evidence supporting a claim of direct benefit should be supported by:

  • Pre-clinical studies including trials in relevant animal models (age appropriate);
  • Clinical trials in adults (if appropriate);
  • Summary of the investigator's review of the literature including related interventions;
  • Investigator's Brochure or product label (drug trials)

The investigator has an ongoing obligation to update the information supporting the prospect for benefits to subjects. Reports from the literature, warning letters, SAE reports or results from other ongoing clinical trials that alter could alter the IRB's assessment of prospect for benefit (positively or negatively) must be reported promptly to the IRB.

There is agreement about the nature of risk from some procedures. While the CHOP IRB endeavors to maintain consistency across its committees and expedited reviewers, the proposed subject population, the setting and the persons conducting the research vary and therefore, the IRB may come to different conclusions about the risk of the same procedure for different studies.

A complete listing of the minimal risk procedures listed by OHRP and FDA along with explanations for each category is provided on the Expedited Review page of the IRB's website.

Medical Procedures (without Ionizing Radiation)

Blood Draw / Venipuncture

Expedited Review:
Minimal risk research is be eligible for expedited review but the criteria depend on the funding source.

Federally Funded Research and Research Subject to FDA Regulations

Expedited Review:
The volume for healthy, non-pregnant adults is limited to 550 mL, over 8 weeks and no more frequently than 2x per week. For other adults and child participants to be eligible, the volume of blood must be limited to either 3 mL/kg or 50ml, whichever is less, over 8 weeks and no more frequently than 2x per week.

Full Board Review:
The full board must review all federally funded protocols that involve volumes of blood greater than or more frequent than what is list above.

Non-Federally Funded Research

The IRB follows the NIH Clinical Center Guidelines for the maximum volumes that it will approve for research only purposes. The IRB may choose the reduce the amount and frequency depending on the age of the subject, their underlying disease or condition and the anticipated blood losses from other causes (e.g. surgery, routine care, etc.)

Adults:
"The amount of blood that may be drawn from adult patients and volunteers (i.e., those persons 18 years of age or older) for research purposes shall not exceed 10.5 mL/kg or 550 mL, whichever is smaller, over any eight week period."

Children:
"For pediatric patients, no more than 5 mL/kg may be drawn for research purposes in a single day, and no more than 9.5 mL/kg may be drawn over any eight-week period."

IV catheter insertion Generally the IRB considers IV insertion to be minimal risk whether for infusion or for use for multiple blood draws (eg, a PK study). However, the discussion should address the number of insertion attempts that will be permitted, the skill of the individuals placing the catheter and efforts to mitigate subject discomfort (e.g., use of topical anesthesia).
Skin Biopsy

For federally funded research and research subject to FDA regulations, skin biopsy is not on the list of procedures which may be reviewed using expedited procedures. Therefore, all federally funded or FDA-regulated protocols involving skin biopsy must go to the full board. Protocols involving skin biopsy that are not federally funded or subject to FDA regulations may be reviewed using expedited procedures.

Minimal Risk (requires full board review if federally funded or subject to FDA regulations):
Skin biopsies that are limited to a few millimeters and do not require sutures are considered by the CHOP IRB to be equivalent in risk to i.v. catheter insertion.

Greater than Minimal Risk:
Any skin biopsy that requires suturing will be considered a minor increase above minimal risk. In addition, the subject's underlying condition might make the procedure greater than minimal risk (e.g. coagulopathy, hemophilia).

Additional Biopsies

Endoscopic biopsy of the GI tract, liver biopsy and kidney biopsy may be performed as part of clinical care or as part of a monitoring procedure needed to assess treatment outcome. In these situations, the risks of the procedures are clinical or are considered necessary as part of the benefit of the research treatment. However, when additional biopsies are obtained for research-only purposes and the research is federally funded or subject to FDA regulations, the full board of the IRB must review the risks.

Minimal Risk (requires full board review if federally funded or subject to FDA regulations):
The IRB has reviewed the risks associated with additional lower and upper GI biopsies and generally finds them to be no greater than minimal risk when they are part of a clinically indicated procedure. When the study is federally funded or FDA-regulated, full board review is required; otherwise, the research may be reviewed using expedited procedures.

Greater than Minimal Risk:
Liver and kidney biopsy have risks of bleeding that exceed what is considered minimal risk. These may be either a minor increase above minimal risk or, depending on the the subjects underlying medical condition, greater than a minor increase.

General Anesthesia and Sedation

The IRB considers sedation and general anesthesia to be a minor increase above minimal risk for healthy children and when the procedures are performed by a qualified practitioner. For children that are sicker (American Society of Anesthesiologists Physical Status 3, 4 or 5), the IRB will review the investigational plan to determine whether or not the procedures qualify as a minor increase.

Prolongation of the duration of sedation and general anesthesia may be considered either minimal risk or a minor increase above minimal risk, depending on the duration and clinical circumstances.

Repeated requirements for sedation and general anesthesia may be either a minor increase above minimal risk or greater than a minor increase depending on the number of procedures and the child's underlying condition.

Gadolinium or Other Contrast Agents The IRB has generally determined that iv contrast agents are a minor increase above minimal risk. For research approved under 45 CFR 45.405 (direct benefit), the IRB may permit one parent's signature is all that is needed provided the radiologic procedure requiring contrast is essential for monitoring the study outcome (i.e., contrast is required as part of the assessment of the intervention providing direct benefit). However, for all other research, the IRB will approve the research under 45 CFR 46.406 and require two parents signatures.

Radiology Procedures Involving Ionizing Radiation

The CHOP IRB in collaboration with the UPenn Radiation Safety Committee and with input from CHOP Radiology as established the following general guidelines for level of risk from radiation exposure for research procedures.

Minimal Risk Exposures to ionizing radiation of up to 100 mrem/year (1 mSv) is generally considered minimal risk. The UPenn RDRC may determine that there additional factors that increase the risk for a particular subject population.
Minor Increase Above Minimal Risk Exposures to ionizing radiation of 101 - somewhere between 500-5000 mrem/year are consistent with a minor increase above minimal risk. The determination on the upper limit of permissible exposure will be determined by the UPenn RDRC and will depend on subject factors and the indication.
Greater than a Minor Increase Above Minimal Risk Exposures to ionizing radiation >5000 mrem/year will be considered greater than a minor increase above minimal risk. This level of radiation exposure will only be approved for research where the radiation exposure is related to an intervention providing a direct benefit to the research subjects.