Intentional Human Dosing Studies for EPA Regulatory Purposes Scientific and Ethical Issues (2004) / Chapter Skim
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4 A Risk-Benefit Framework for Assessing Intentional Human Dosing Studies
4 A Risk-Benefit Framework for Assessing Intentional Human Dosing Studies
Pages 84-109
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From page 84... ...
The committee decided that it could a provide a framework for clarifying some specific issues regarding the use of intentional human dosing studies for EPA regulatory decision-mak 84
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From page 85... ...
POTENTIAL BENEFITS FROM INTENTIONAL HUMAN DOSING STUDIES The Common Rule under which EPA conducts and sponsors studies requires that "risks to subjects" must be "reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result" (40 CFR §26.111(a)
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From page 86... ...
With regard to compensation, NBAC's report on Ethical and Policy Issues in Research Involving Human Participants illustrates one significant viewpoint. NBAC expresses the concern that treating compensation as a benefit for purposes of the Common Rule's balancing of risks and benefits "would inappropriately skew judgments concerning risks and potential benefits, because nearly any level of research risk could be offset by such
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From page 87... ...
Committee members did agree, however, that if compensation were the only benefit of an intentional human dosing study, this would be inadequate to justify any risk. Because generally in human studies conducted for EPA regulatory purposes there are no other personal benefits to participants beyond compensation (however that is judged as a benefit)
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From page 88... ...
. This conclusion hinges on the committee's determination regarding what constitutes a societal benefit for purposes of evaluating the ethical validity of human dosing studies conducted for EPA regulatory purposes.
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From page 89... ...
Recognizing the possible differences in such downstream consequences is a necessary step when comparing the risks and benefits that may result from intentional human dosing studies. It is important to note that it is not clear whether or how such issues should be considered within the current regulatory framework for hu
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From page 90... ...
. as among those research risks that fall within the purview of its responsibility." It is not apparent from the text of the Common Rule what this language is intended to mean in the context of studies conducted for EPA regulatory purposes.
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From page 91... ...
Health-based approaches -- such as the ambient air quality setting process of the Clean Air Act or the process for setting tolerances for pesticide use on food on the basis of a "reasonable certainty of no harm," and the risk-benefit balancing approaches, such as the licensing process for nonfood use pesticides -- require information that relates exposure to the substance to types and levels of harm. In other words, they require some assessment of the risks associated with the substance.
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From page 92... ...
. These default assumptions allow risk-management decisions that are based on human risk assessments to be made under conditions of uncertainty, an unavoidable necessity.
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From page 93... ...
Numerous specific pronouncements by the agency regarding default assumptions bear out the desirability of replacing default assumptions with scientific results. For example, the Draft Water Quality Criteria Methodology Revisions state that "When adequate data are available they are used to make accurate exposure predictions for the population(s)
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From page 94... ...
. There is strong evidence that Congress has consistently shared with the executive branch the view that when science is to be relied on to supply information pertinent to a regulatory decision, the best available science should be employed.
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From page 95... ...
Regardless of the statute and the science involved, improvements in the accuracy and reliability of the science improve the quality of information that is relied on for making ultimate regulatory decisions. It is hard to imagine that Congress would not consider the improvement of the quality of scientific information to be a benefit to the regulatory processes that it has asked EPA to implement.
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From page 96... ...
In addition to its stated general preference for replacing default assumptions with scientific findings, EPA has expressed a specific preference for supplementing animal data with human data when conducting human risk assessments. EPA has said that it looks to human data whenever possible in completing human risk assessments: "If adequate human studies (confirmed for validity and applicability)
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From page 97... ...
In terms of the risk-benefit calculus that would be applied to judging the ethical acceptability of a human study, the way to take this difference into account is first by making a careful determination of what the risks are and then weighing those risks against any benefits that might result from the study. The committee concludes that it is a matter of established and sound public policy that the use of the best available science -- including the replacement of default assumptions with reliable scientific information-constitutes a societal benefit.
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From page 98... ...
Building on these principles, the following section provides the committee's perspective on how the balancing of risks and benefits should be approached with respect to human studies conducted for EPA regulatory purposes. BALANCING RISKS AND BENEFITS Of the three basic ethical principles governing the protection of research participants -- respect for persons, beneficence, and justice -- beneficence is the one that, in the context of this report, requires the greatest exercise of subjective judgment with the least amount of guidance from established policy or precedent.
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From page 99... ...
that there should be a role for a centralized review body operating under EPA's auspices to review human studies conducted for EPA regulatory purposes. In the next section, the committee provides an overview of the kinds of risks and benefits that such studies may present.
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From page 100... ...
Even though some of the intentional dosing studies conducted for these purposes pose no identifiable risk to participants, the committee is reluctant to consider any toxicant dosing study a minimal risk study within the meaning of the Common Rule. Importantly, the committee concludes that any human dosing study conducted for EPA regulatory purposes, regardless of how safe it may appear to be, and even if it could be judged by some to pose minimal risk under the Common Rule, should be reviewed both by an IRB and by the Human Studies Review Board recommended in Chapter 6.
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From page 101... ...
For these reasons, in describing the range of risks posed by the human dosing studies addressed in this report and how those anticipated risks might be balanced against potential benefits, the committee does not use the terminology of "minimal risk" or "minor increase over minimal risk." Rather, the committee uses other terms that describe the anticipated risk or lack thereof, as discussed below, but will do so free of the implications the term "minimal risk" carries as applied in other settings under the Common Rule. This approach also is intended to better reflect the nature of the human dosing studies that are generally conducted for EPA purposes and the range of possible human responses to chemical exposures.
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From page 102... ...
The third category of risk includes studies at doses that elicit a biological response in either the structure or function of the organism that is potentially detrimental to health, or adverse, and thus poses an identifiable risk to study participants. This category theoretically encompasses a wide range of risks.
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From page 103... ...
As discussed earlier, the committee concludes that under the riskbenefit balancing required by the principle of beneficence and the Common Rule, personal benefits to participants are insufficient by themselves to justify human dosing studies conducted for EPA regulatory purposes. This means that risks to participants imposed by human dosing studies must be justified by the societal benefits that are anticipated to come from a successful study, if they are to be justified at all.
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From page 104... ...
The OP-related human dosing studies submitted to EPA's pesticide program have measured cholinesterase inhibition as a biomarker of exposure and potential toxicity, rather than as a toxic endpoint per se. As explained in Chapter 3, an independent review could conclude that there is a reasonable certainty in such studies of no harm occurring to study participants.
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From page 105... ...
There are a number of ways in which a human dosing study could provide benefits to society beyond the minimum benefit of improving the accuracy of regulatory decision making, including the following: · The study results in a more stringent regulatory standard. Human dosing studies that are reasonably expected to result in more stringent permissible limits for chemicals in the environment or food supply not only improve the scientific quality of the regulatory decision by substituting the more relevant human data for animal data, they also confer a potential public health benefit.
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From page 106... ...
In the case of air pollutants, for example, intentional human dosing studies under controlled conditions may be the only or best way to reliably estimate the dose-response relationship in humans. Evidence from such studies could be needed to enable EPA to set standards it might not otherwise have been able to set or to set standards that are more fully protective of public health.
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From page 107... ...
At the other extreme, a study in a medically vulnerable population (e.g., children) that has the potential to cause adverse responses and whose potential to cause lasting harm is uncertain poses risks that would be difficult for potential benefits to outweigh, unless perhaps the substance being tested provided significant health benefits to the study participants or to the class of individuals to which they belong.
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From page 108... ...
The committee assumes that human studies conducted for EPA regulatory purposes do not confer personal benefits on study participants. This means that the risk-benefit balancing required under the principle of beneficence depends on the evaluation of a societal benefit.
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From page 109... ...
These ultimately must be resolved through EPA's publicly transparent policy deliberations and through the case-by-case decisions of duly constituted review bodies charged with protecting the interests of participants in particular studies. REFERENCES Environmental Protection Agency (EPA)
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