Balancing Benefit and Risk in Clinical Research
Madeleine M. Jester, RN, JD

Abstract

When an institutional review board (IRB) evaluates a research proposal, it must also consider if the risks to the research subjects are justified by the benefits to be gained. This risk analysis focus on the short-term effects of the research on the individual subject, and not the long-range benefits of the research to mankind.

The IRB must first determine if the premise of the research is valid, and look at the nature and magnitude of the risk to the participants. The IRB then decides if the estimates of the probability of harm or benefit to study subjects are reasonable. There will be a greater tolerance for higher risks in research on some types of products more than others, depending on such factors as the severity of the disease and the availability of other treatments.

It is very important to this process that sponsors provide as much data as possible to the IRBs making these risk-benefit determinations, and not minimize important information about side effects that could impact the assessment of the risk-benefit ratio.

The Regulations and Risk Analysis

Federal regulations require IRBs, in reviewing research studies, to determine that any risks to which research subjects are exposed are reasonable in relation to any expected benefits they might get from participating. IRBs must evaluate this in light of the significance of any knowledge to be gained from the research. The IRB must consider only the risks and benefits of the research itself, rather than the risks the subjects would experience from other therapies they would receive if not in the study. This risk analysis is concerned with short-term effects of the research on the individual subject, and not with possible long-range benefits to mankind of the knowledge gained during the conduct of the research.¹

Guidelines for Risk Assessment

The Declaration of Helsinki, adopted by the World Medical Assembly, states that biomedical research cannot be done legitimately unless the importance of the objective is in proportion to the risk to the subject. The Declaration further clarifies this by stating that each research project must be carefully assessed to look at predictable risks in comparison to foreseeable benefits to the research subject or others. According to the Declaration, concern for the interest of the individual must always prevail over any scientific or societal interest.²

In the United States IRB members can consult the Belmont Report, a guidance document developed by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, that discusses the basic ethical principles underlying the conduct of research. This report outlines a method IRB members can use to determine if the risks to which research subjects would be subjected are justified by the benefits to be gained.

According to this method, those doing the review gather and assess information about all aspects of the research, and consider alternatives systematically and in a nonarbitrary way. The aim is to make the assessment process more rigorous, and the communication between the IRB and the investigator less ambiguous and more factual and precise. First, the IRB determines if the premise of the research is valid, and looks at the nature, probability and magnitude of the risk. Based on known facts or available studies, the IRB then makes a determination about whether the estimates of the probability of harm or benefit are reasonable.³

Factors Impacting Acceptable Risk

There will be a greater tolerance for higher risks in research on some types of products more than others, when protocols are being reviewed by IRBs. This also holds true when regulators are reviewing a drug application or research study for approval. How favorably an application or clinical protocol is reviewed hinges upon four variables. The first is the nature of the disease and toxicity of the drug under development. Generally, the more severe the disease and the greater the need for new therapies, the more toxicity is acceptable. The second is the existence of other therapies; if there are alternative treatments, any new proposed therapy should be as safe or safer than that which is already available. Third, the IRB or the regulator must consider if studies are being done and risks assessed in the populations that will most likely be exposed to the product after it is approved. The fourth variable is whether the endpoints or outcomes being tested in the studies for the product are true measures of clinical benefit.⁴

Conclusion

It is very important to this process that sponsors of research keep the above variables in mind in developing products. They should provide the IRB with all the data available on the previous use of the test article in animals and humans, so the IRB can make an accurate determination of the risks involved.

A sponsor or investigator must not leave out or minimize important information about toxicity’s or side effects that could change the risk-benefit ratio considerably. This could create greater exposure to liability for the sponsor, and put study subjects at greater risk of harm than is necessary.

See also IRBs-The Basics, IRBs-Are They Still Working?

References

1. Code of Federal Regulations, section 21 CFR 56.111

2. Shuster, E., Fifty Years Later: The Significance of the Neuremberg Code, The New England Journal of Medicine, 337(20), p 1440

3. The Belmont Report, Ethical Principles and Guidelines for the Protection of Human Subjects of Research, The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, Department of Health, Education and Welfare, April 18, 1979

4. Miller, L., Ph.D., Risk-Benefit Assessment: The "Greased Pig" of Drug Development, from a paper presented at a 7/92 DIA workshop, "Methods and Examples for Assessing Benefit/Risk and Safety for New Drug Applications"