Controlled Human Inhalation-Exposure Studies at EPA (2017) / Chapter Skim
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2 Foundational Aspects of Human-Subjects Research
2 Foundational Aspects of Human-Subjects Research
Pages 17-32
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From page 17... ...
, "What are the risks of clinical adverse events posed to CHIE study participants in past studies? " (Chapter 4)
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From page 18... ...
In contrast, the methods for characterizing risk of adverse events to study subjects draws upon language and conventions of epidemiology, toxicology, risk assessment, and communication sciences. AIR POLLUTION HEALTH EFFECTS SCIENCE FOR MANAGING AIR QUALITY EPA states that one of its purposes is to ensure that "all parts of society -- communities, individuals, businesses, and state, local and tribal governments have access to accurate information sufficient to effectively participate in managing human health and environmental risks" (EPA 2017b)
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From page 19... ...
Primary 1 hour 75 ppbf 99th percentile of 1-hour daily maximum concentrations, averaged over 3 years Secondary 3 hours 0.5 ppm Not to be exceeded more than once per year a The Clean Air Act requires EPA to set two types of NAAQS: primary NAAQS to protect public health, and secondary NAAQS to protect the public welfare from known and anticipated adverse effects (such as crop damage from pollutant exposure)
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The conversation is informed by social norms and sensibilities, by acknowledgment of past mistakes and transgressions, by divergent views about the risks and benefits of this type of research, and by discussions about what constitutes informed consent of human study subjects. In this chapter, we provide a framework for our deliberations, and reference documents that are benchmarks in this continuing conversation.
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From page 21... ...
The agency has used results of CHIE studies of O3 exposure and respiratory symptoms, conducted within and outside of EPA, to inform the O3 NAAQS decisions in 1979, 1997, 2008, and 2015. In the 2000s, there was greater use of PM CHIE studies to investigate possible mechanisms of health effects observed in epidemiologic studies.2 As stated in Chapter 1, EPA asked the National Academies of Sciences, Engineering, and Medicine to assess whether it is warranted to continue to conduct CHIE studies as part of EPA's larger research agenda for community air pollutants and, if so, to recommend guidance to improve methods of characterizing risks to study subjects and improving informed consent.
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The seven requirements are social or scientific value, scientific validity, fair subject selection, favorable risk–benefit ratio, independent review, informed consent, and respect for potential and enrolled subjects. None of the requirements can stand alone as a sufficient justification for a human-subjects research project.
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The human subjects should be free to bring their participation to an end when they judge their physical or mental health would make continuation impossible. The scientist in charge must be prepared to terminate the experiment when there is probably cause to believe that continuation is likely to result in injury, disability or death to the experimental subject.
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Protection of Human Subjects ("Common Rule")
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Respect for potential and Respect for subjects by Respect for subject autonomy Scientific knowledge; ethical and enrolled subjects (1) permitting withdrawal from and welfare legal knowledge; knowledge of the research, particular subject population (2)
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Step 1 requires that the proposed study achieve a minimum level of social value. Rather than do ing that analysis after determining risks, Rid and Wendler believe that analyzing the expected value is an essential first step that focuses the research more appropriately.
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From page 27... ...
, and that risks are appropriately communicated to the subjects. The statement of task for this committee specifically asks it to provide "a template to characterize reasonably foreseeable risks, in terms of the nature, frequency, and magnitude of possible risks, which could be used in obtaining informed consent from potential study participants." Of course, before the committee can consider how such risks should be communicated, it is important to consider how the potential clinical adverse effects of concern can be identified and characterized.
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From page 28... ...
That presents a more stringent criterion than for a hypothetical risk.3 Because CHIE studies involve volunteers who will derive no therapeutic benefit from participation in the research, it is tempting to compare this criterion to "first in human studies" such as Phase 1 drug studies or even studies such as the hexamethonium study described above. But that is generally not an apt comparison because, unlike Phase 1 drug studies, or a study using a relatively novel agent as the challenge, EPA has a great deal of data about the various pollutants' biologic effects gleaned from epidemiologic studies, animal studies, and previous CHIE studies.
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From page 29... ...
The committee focused on factors that could alter participant susceptibility to study-related risks, such as preexisting medical conditions. The IRB process provides an opportunity to demonstrate that the research methods focus on the question posed by the study, align with the social values identified in Step 1, and are nonduplicative.
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EPA has the responsibility for reporting serious adverse events, or any serious protocol noncompliance, to the reviewing IRB and to federal officials, should such occur. Additionally, prior to proposing the study, and while the study is ongoing, the PI is required to consider prior human, animal, and other biologic effects data that are available, to ensure that studyrelated risks to the study subjects are outweighed by the utility of the study results for informing airquality management decisions.
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From page 31... ...
The definition of a serious adverse event calls for a judgment as to whether an effect results in "a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions." For example, a cough lasting only 1 or 2 days after participation in a CHIE study would likely be considered an adverse event, while a cough that began soon after participation in a CHIE study and lasted many months would likely be a serious adverse event.
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From page 32... ...
The use of standard terminology for reporting adverse events to the IRB is intended to provide a common language to facilitate the IRB's work in balancing risks and benefits.
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