Intentional Human Dosing Studies for EPA Regulatory Purposes Scientific and Ethical Issues (2004) / Chapter Skim
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5 Ethical Considerations in the Review of Intentional Human Dosing Studies
5 Ethical Considerations in the Review of Intentional Human Dosing Studies
Pages 110-131
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From page 110... ...
. In addition to meeting standards of scientific validity, as discussed in Chapter 3, intentional human dosing studies also must pass a rigorous risk-benefit analysis, which itself involves both science and ethics, as discussed in Chapter 4.
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From page 111... ...
. In addition, although the Common Rule provides a framework for the ethical review of research involving humans, it does not fully and completely specify what should be done in key areas, such as risk-benefit analysis and assessment, the selection of research participants, informed consent, remuneration for research participation, compensation for research-related injuries, and the use of ethically tainted data, all of which are discussed in this chapter.3 The committee's ethical analysis therefore draws on many different sources in addition to the Common Rule, including the Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research (National Commission, 1979)
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From page 112... ...
This analysis noted some important similarities, along with several differences, between intentional human dosing studies and Phase 1 pharmaceutical testing, especially because neither offers a reasonable prospect of direct benefit to the research participant. In fact, the Phase 1 study is more likely to provoke adverse effects.
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From page 113... ...
prior animal studies and, if available, human observational studies; b. a demonstrated need for the knowledge to be obtained from intentional human dosing studies; c.
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From page 114... ...
Both principles are involved in judgments about remuneration for participation in research involving toxicants. SELECTION OF RESEARCH PARTICIPANTS According to the Common Rule, IRBs should not approve a research protocol involving humans unless "selection of subjects is equitable" (40 CFR 26.111(3)
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From page 115... ...
As discussed in previous chapters, investigators and IRBs have a responsibility to minimize risks to research participants. Among the several ways available to minimize risk, investigators in intentional human dosing studies usually can select participants without known health conditions that put them at increased risk for adverse effects from the experiment.
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The provisions of Subpart D leave open the possibility of research involving deliberate exposure of children to toxicants as long as the research undergoes rigorous scrutiny, at times by a nationally consti
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Recommendation 5-2: Participant Selection Criteria IRBs reviewing intentional human dosing studies should ensure that the following conditions are met in selecting research partici pants: a. Selection should be equitable.
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Although the consensus is that remuneration for participation in research should be just or fair, there is little agreement in theory or in practice about what constitutes just or fair payment. Disagreement can certainly be expected about payment for participation in intentional human dosing studies.
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. In line with these patterns, many argue that research participants should be paid for their time and inconvenience, as well as their expenses, but are concerned about providing payment for incurring risk, which some would rule out altogether.
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Moreover, EPA, in conjunction with other federal agencies, should consider developing further guidance on remuneration for partici pation in intentional human dosing studies, including guidance regarding whether remuneration should reflect the level of risk as well as the time and inconvenience involved. INFORMED CONSENT Voluntary, informed consent by research participants (or permission by their surrogate decision makers)
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. Thus, focusing solely on disclosure is not enough; it is appropriate to be concerned about what participants in intentional human dosing studies comprehend.
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Recommendation 5-4: Best Practices in Informed Consent EPA should develop and disseminate to relevant IRBs, investiga tors, and sponsors a list of best practices regarding informed con sent in intentional human dosing studies. EPA should encourage all sponsors and investigators to adopt these practices, and it should require their adoption in studies it sponsors or conducts.
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To allay these concerns, it is important to ensure that participants in intentional dosing studies understand crucial information that has been disclosed, and this generally will require direct assessment of comprehension. Researchers can learn from other studies how best to carry out these assessments.
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The committee concludes that justice and fairness require sponsors of intentional human dosing studies to go beyond existing legal requirements and create a mechanism that, at a minimum, ensures that research participants receive free medical care for injuries incurred in the research. As NBAC writes: Because the costs of research injuries should not be borne by the injured participants and because support for a compensation system should be provided by those most likely to profit or derive other benefits from it, sponsors and institutions should be assigned responsibility for funding such a system (2001)
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From page 125... ...
The committee concludes that, as a general rule, EPA should not use data from ethically problematic studies to inform its regulatory efforts. Studies Submitted for Regulatory Decisions After EPA Establishes New Standards After EPA establishes new rules and procedures, those who submit data from intentional human dosing studies should produce evidence that 9The report of the EPA SAB and the FIFRA SAP held that participants in research "should have rights to compensation if they are injured as a result of the experiment" (EPA, 2000, 21)
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From page 126... ...
It also will be necessary for the EPA Human Studies Review Board to review submitted studies in order to determine whether they were ethically conducted. If the research is determined to be unethical, two important goals may come into conflict: first, using the best scientific data to protect the public and, second, avoiding incentives for the conduct of unethical research involving humans and undermining important ethical principles.
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From page 127... ...
Recommendation 5-6: Studies Completed After Implementation of the New Standards EPA should operate on the strong presumption that data obtained in studies conducted after implementation of the new rules1 that do not meet the ethical standards described in this report will not be considered in its regulatory decisions. Under exceptional circum stances, studies that fail to meet these ethical standards may pro vide valid information to support a regulatory standard that would provide greater protection for public health.
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From page 128... ...
To be sure, some ethical standards proposed in this report for future intentional human dosing studies have only been articulated or at least stressed in recent years (e.g., just selection of and fair payment to research participants) , and some remain unsettled (e.g., compensation for research-related injuries)
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Exceptional cases in which the Human Studies Review Board determines that unethically conducted studies may provide valid information to support a regulatory standard that would provide greater protec tion for public health should be presented to a special, outside panel, described in Recommendation 5-6, for consideration. This special, outside panel should consider recommending the use of such data only with the requirement that the ethical concerns raised by the study are documented and made publicly available, along with relevant materials and commentary, on the EPA web site.
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From page 130... ...
SUMMARY This chapter addressed the ethical considerations that remain after the determination is made that a research protocol is scientifically valid and that its probable benefits outweigh its risks. These ethical considerations involve voluntary informed consent and the fair selection and recruitment of potential research participants, including fair payment for participation and compensation for research-related injuries (which in
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From page 131... ...
2002. Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects (adopted 18th WMA General Assembly.
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