What does the researcher have to consider when evaluating the risks and benefits of a study?

Potential risks fall into five broadly-defined categories. Research Compliance Services and the CPHS/IRB will weigh the potential risks of research against the potential benefits as part of the review process. Researchers are expected to take steps to minimize potential risks.

• Physical risks

  • Physical risks include physical discomfort, pain, injury, illness or disease brought about by the methods and procedures of the research. A physical risk may result from the involvement of physical stimuli such as noise, electric shock, heat, cold, electric magnetic or gravitational fields, etc. Engaging a subject in a social situation which could involve violence may also create a physical risk.

• Psychological risks

  • Psychological risks include the production of negative affective states such as anxiety, depression, guilt, shock and loss of self-esteem and altered behavior. Sensory deprivation, sleep deprivation, use of hypnosis, deception or mental stresses are examples of psychological risks.

• Social/Economic risks

  • Social/Economic risks include alterations in relationships with others that are to the disadvantage of the subject, including embarrassment, loss of respect of others, labeling a subject in a way that will have negative consequences, or in some way diminishing those opportunities and powers a person has by virtue of relationships with others. Economic risks include payment by subjects for procedures not otherwise required, loss of wages or other income and any other financial costs, such as damage to a subject's employability, as a consequence of participation in the research.

• Loss of Confidentiality

  • In all research involving human subjects, confidentiality of identifiable information is presumed and must be maintained unless the investigator obtains the express permission of the subject to do otherwise. Subjects have the rights to be protected against injury or illegal invasions of their privacy and to preservation of their personal dignity. The more sensitive the research material, the greater the care that must be exercised in obtaining, handling, and storing data. In order to minimize the risk for loss of confidentiality, investigators should only collect personal information that is absolutely essential to the research activity. If personal data must be collected, it should be coded as early in the activity as possible and securely stored so that only the investigator and authorized staff may access it. Identities of individual subjects must never be released without the express consent of the subject. In addition, if an investigator wishes to use data for a purpose other than the one for which it was originally collected and the data are still identifiable (e.g. a code list for the data still exists), the investigator may need to obtain consent from the subjects for the new use of the data.

• Legal risks

  • Legal risks exist when the research methods are such that the subject or others will be liable for a violation of the law, either by revealing that the subject or others have or will engage in conduct for which the subject or others may be criminally or civilly liable, or by requiring activities for which the subject or others may be criminally or civilly liable.

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 (table). 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.