Are Risks to Subjects Reasonable in Relation to Anticipated Benefits?

Why make separate determinations of whether risks are minimized and whether risks are reasonable?

IRB committee members are asked to identify, assess, and determine that risks are minimized. They are also asked to determine that risks are reasonable in relation to anticipated benefits, if any, from the research. The reason IRB committee members are asked to make two separate determinations about risks (that they are minimized, and that they are reasonable) is that in some proposed studies risks might be minimized, but the risks may not, upon review, turn out to be reasonable. Consider the following examples that illustrate cases where risks may be minimized, but were still not reasonable.

The United States government released low levels of radiation into the environment during the 1950s-1970s to study the impacts of population exposures to radiation. These secrete experiments were the subject of intense scrutiny when they were disclosed during the 1990s.(1) Even if a low amount of radiation was released in some experiments (risks may have been minimized), nevertheless concerns were expressed that releasing any amount of radiation into the environment would not be reasonable in relation to anticipated benefits. The subsequent public review of these experiments, including a Presidential apology indicate that upon consideration, even if the risks were minimized, the risks were not reasonable. (Moreover, the fact that the experiments were conducted in secret raises additional concerns about voluntary participation and equitable subject selection).

An experiment funded by NIH was designed to study how lung function differs in asthmatic and healthy people.(2) The goal was to try to understand why airways remain open when irritating chemicals are inhaled. Healthy people, and people with asthma, were divided into groups and asked to inhale either saline (placebo) or an irritant, hexamethonium, which can temporarily paralyze some nerves in the airways. All participants then took an asthma test. A woman died during this study, even though medical interventions were available; The Johns Hopkins University, where the study was conducted, subsequently admitted fault in its oversight. The study raised questions about whether exposing healthy people to such a risk would be reasonable (even if the risks were minimized by having medical care readily available).

These examples illustrate how risks might be minimized, but still not be reasonable. For example, the risks in the examples above might be minimized by using the lowest possible exposure or dose, or by having ready access to medical care. Nevertheless, the risks were not reasonable. As a IRB committee member, you need to identify the risks, evaluate whether they are minimized, and evaluate whether they are reasonable.

Use your own words

It is important that you write out your reasons for coming to your own determination about whether risks are reasonable. Explain your own reasons for making the determination for each study. Base your analysis on your experience, on your reading of the protocol and associated study materials, and by asking questions of the Ethics and Human Research Protection Program staff if you need additional information.

Points to consider

Some factors to consider when determining that risks are reasonable in relation to anticipated benefits include the following

• What are the potential harms? Are they reversible (treatable)?
• What is the risk of harm? Is the risk of harm reasonable in relation to anticipated benefits?
• Who might be at risk of harm? Is it the research participant alone, or to the participant and others (like the mother and her unborn fetus, or to a participant and the family), or is the risk mainly to third parties?
• Is the harm reasonable? Is the risk of harm something a reasonable person would take on? When you are thinking of a "reasonable person" who do you have in mind--it can be helpful for you to try to articulate your assumptions as you prepare to discuss a study with your colleagues on the IRB.
• What are the benefits, if any, to the participants?
• What is the potential for the study to contribute to scientific knowledge (consider the specific ways the study could result in changes in medical practice, for example, or changes in FDA’s approval of a drug or device)
• In thinking about whether risks are reasonable, when possible consider empirical evidence in your analysis. In general, people tend to be poor judges of risk--overestimating those risks that are new, and risks that are outside people’s personal experience, while at the same time underestimating those risks with which they are familiar. (Consider the novel risks posed by a study to familiar, everyday risks like driving a car, or riding on a motorcycle). It may not be possible to identify empirical or epidemiological risks for all treatments or procedures in research, but you may find it helpful to identify a range, and doing so may help you discuss the issue with your colleagues.

Additional examples

In a study of a new drug for treatment of HIV, suppose the new drug has risks that are similar to other drugs in its class, but that the drug holds out the prospect of benefit because patients whose HIV is resistant to other drugs might do better on the new drug. In such a case IRB members would need to identify and assess the risks of the new drug, and then determine whether the risks of the new drug are reasonable, perhaps when compared with other drugs (most relevantly, the other drugs patients would most likely be taking). As an IRB member you would need to consider whether risks are minimized (for example, by using sound research design, and other considerations) and consider whether the risk is reasonable. Would the potential for the new drug to perform better in patients whose HIV is resistant to existing drugs constitute a reasonable benefit? Would it make a difference, when determining whether the risks are reasonable, if participants included those whose HIV is well-controlled with existing medication, but who were being offered an opportunity to shift to a study medication that promised fewer side-effects?

In an epidemiological study of patterns of a drug-resistant sexually-transmitted infection in male patients at a county health department sexually-transmitted disease clinic, a researcher proposes to collect specimens via a urethral swab. The urethral swab will be conducted as part of standard of care, but suppose that in order to collect enough specimens for research, the study would need to involve more swabs than would be done as part of standard of care. The IRB would need to identify and evaluate the risks and benefits (is a swab harmful, or only painful?), and then would need to determine whether the risks of the treatments or procedures in the research are reasonable in relation to anticipated benefits or contributions to scientific or scholarly knowledge. Is it reasonable to ask participants who are already undergoing one swab to consider volunteering for additional swabs? What are the potential risks and benefits to the participants, and what is the potential that the study would result in benefits to the population (for example, would the results of the study inform prevention efforts, or better help clinicians treat patients?)

In a survey, participants are asked questions that might be sensitive (about sexual behavior, or illegal drug use). IRB committee members would need to identify the risks (which include risks due to violation of confidentiality), and determine whether the risks are reasonable in relation to anticipated benefits, if any, of the survey for individual participants, the population, or for general scientific or scholarly value.

Summary

IRB members need to identify and assess risks, and then determine whether they are reasonable. As an IRB committee member, you can improve the quality of committee discussions by explaining your reasons in your own words. You should base your determination on your reading of the protocol, and ask questions of staff if you need additional information. Explaining your thought process will help your colleagues understand your reasoning, and will help facilitate discussion among committee members.

Notes

1. Moreno JD, Haddour A, Brewe S, McWilliams T. Undue Risk: Secret State Experiments on Humans. Taylor & Francis Group, 2000.
2. Savulescu J, Spriggs M. The hexamethonium asthma study and the death of a normal volunteer in research. Journal of Clinical Ethics 2002; 28, 3-4.