7

Communication about Informed Consent in Controlled Human Inhalation Exposure Studies

INTRODUCTION TO INFORMED CONSENT AND THE COMMON RULE

Chapter 6 introduced the concept of exposure comparators and recommended that, for communication with Institutional Review Boards (IRBs) and study participants, risk should be characterized using exposure comparators. These comparators should be useful in explaining and putting into perspective the exposures planned for the study. Chapter 6 also explains how the comparators were developed. This chapter expands upon Chapter 6, and focuses specifically on the communication of risk to study participants through the informed-consent process. It also provides recommendations regarding the content of consent documents and the assessment of participants’ understanding of informed consent.

As discussed in Chapter 2, the ethical principles governing informed consent have been forged over many decades in response to abuses to human subjects who participated in experiments when consent was either entirely absent or deeply compromised (Faden et al., 1986). The Belmont Report, describing the basic principles widely accepted as the undergirding ethical norms for The Common Rule, lists “respect for persons” as its first principle. This principle “incorporates at least two ethical convictions: 1) that individuals should be treated as autonomous agents; and 2) that persons with diminished autonomy are entitled to protection” (NCPHSBBR 1979). Thus, informed consent has, as its basic aim, the protection and enhancement of the autonomy of research participants. It is composed of three essential elements: (1) a disclosure process provided by investigators to an individual capable of making a decision that is free of duress or coercion, (2) a deliberation process between researchers and potential participants to ensure understanding, and (3) a decision to participate or not, grounded in the prospective participants’ values.

In fulfilling the disclosure requirement, the Common Rule enumerates important items to be disclosed. Some of the most important areas of disclosure are (1) the nature and purpose of the research, (2) the procedures to be followed in the protocol, (3) “reasonably foreseeable risks or discomforts,” and (4) any potential benefit to participants [45 CFR 46] (NRC, 2004a). “Reasonably foreseeable risks” are not further defined in the regulations and can therefore be a source of ambiguity and misunderstanding. This report has provided further guidance on this point in Chapter 2, as well as later in this chapter.

The deliberation process requires study personnel to not only inform, but to actively enable potential participants to “deliberate effectively” about risks and benefits, and to understand the social aims of the research (King, 2005). Facilitating such effective deliberation is often not simple and is fraught with pitfalls. Participant deficits in scientific literacy, and risk and benefit miscalculation, often confounded by poor understanding of probability and other numeric information, can be major barriers to a valid consent. The committee’s view is that expressing risk using exposure comparators (see Chapter 6) will mitigate the difficulties in understanding risks due to poor numeric comprehension, and also the concerns that numerical estimates of risk might be uncertain (Pleasant et al., 2016). To help with this task, this chapter contains recommendations about effective communication with study participants.

While there are a very few trials with human subjects in which consent is not mandatory (Emanuel et al., 2000), for the vast majority of studies informed consent is understood as a sine qua non for ethically and legally permissible research. While not sufficient by itself, consent is absolutely necessary. This is

especially true for controlled human inhalation exposure (CHIE) studies involving volunteers, and for which societal benefits are the overriding aim, with no personal medical benefits for participants other than previously unrecognized conditions being discovered in the medical screening process. The following sections describing risks and benefits are critical to this chapter’s focus on communication, given the importance of clear communication of potential risks and benefits during the disclosure process element of informed consent for the CHIE studies.

Risks

Risk characterizations are an especially important part of disclosure to potential participants. Every effort is needed to ensure that these characterizations are accurate, scientifically grounded, intelligible to people, and inclusive of a discussion of “reasonably foreseeable risks,” as required by the Common Rule (see Chapter 2):

• Reasonably foreseeable risk disclosure is a requirement of the Common Rule, but it does not include all possible risks. An overly detailed list of all possibilities can result in a less valid consent process, since it groups the anticipated or likely risks with those that are only distant possibilities. The result is not clarity or decisional enablement, but confusion (Resnik, 2013; Rid et al., 2010). So while not all possible risks belong in a consent disclosure process, inclusion of risks that are potentially remote but of great magnitude should be considered part of a complete disclosure (King, 2000). According to Resnik (2013), a risk is reasonably foreseeable if there is credible evidence to expect that a harm might occur. Evidence for risks might be obtained from empirical research, past experience, or scientific or mathematical principles.
• Addressing risks of concern to participants is also part of a valid consent. Allowing people to judge risks for themselves and determine if they are willing to assume those risks is essential in respecting the autonomy of participants. In addition, answering all questions of participants, even those concerning the most improbable risks and hypothetical possibilities, is necessary for a valid informed consent.
• The use of “real-life” exposure comparisons in risk descriptions might be conducive to participant understanding but needs an evidentiary or expert opinion foundation to be credible. For example, phrases such as “You could potentially inhale a similar amount if you visited a large city, such as Los Angeles, New York, or Mexico City on a smoggy day” need to have such backing to avoid misunderstanding. In addition, communication of numeric risk estimates (such as extra risk of 1 in 100,000 exposed) can be particularly challenging and necessitates quantitative literacy skills of both researcher and the study participant. Participants’ perceptions might influence their beliefs and understanding of these comparisons and these perceptions need to be acknowledged and discussed.

Benefits

The Common Rule states that risks to subjects must be “reasonable in relation to anticipated benefits” to research subjects, and in relation to the importance of the potential knowledge to be gained from the research [40 CFR 26.111(a)(2)]. The Belmont Report added another obligation: “to give forethought to the maximization of benefits and the reduction of risk that might occur from the research investigation” (NCPHSBBR 1979). Beyond these statements, little guidance about benefit disclosure was provided. Most codes of research ethics were designed with research on new medical therapies and the protection of patient-subjects in mind. The Nuremberg Code is focused on nonpatient subjects, but it was silent about subject benefits.

The CHIE studies conducted by the U.S. Environmental Protection Agency (EPA) involve human-subjects research of a nonmedical nature that exposes volunteers, with the ultimate goal of producing knowledge to shape sound environmental standards. Because of these differences, a clear delineation of

the types of benefits relevant to EPA research is called for. This taxonomy builds upon and expands the categorization of benefits in NRC (2004a) as “societal” and “personal.”

Societal Benefits

Societal benefits are the overriding purpose of all research, but they play an especially prominent role in EPA CHIE studies. In this context, societal benefit can mean better health for specific populations or for society generally if the results lead to improved health policy. However, societal benefit is always an aspiration, a hoped-for outcome, rather than a certainty. The CHIE studies conducted by EPA offer no medical benefits to exposed participants and, therefore, are justified solely by the value of the knowledge to be gained from the research.

Even though societal benefits provide the overriding ethical justification for EPA studies, potential volunteers typically see benefits accruing to them personally as relevant to their decision to participate.

Personal Benefits

• Medical benefits to research participants: Multiple studies have shown that research participants, especially those who are ill, typically overestimate the potential for direct medical benefits for themselves from participation. Some individuals also fail to differentiate research participation from routine clinical care, and thereby labor under a “therapeutic misconception” (Henderson et al., 2007). This is not a major hazard for studies involving healthy volunteers. Yet, even with healthy volunteers, there is potential for misunderstanding if physical exams required for enrollment eligibility are construed by investigators or participants as a medical benefit. Such inclusion/exclusion exams are not a medical benefit because they are not part of a doctor–patient relationship in which the patient’s well-being, rather than scientific knowledge, is the primary aim. Such eligibility exams may, however, result in information of value for individual participants.
• Health information of value to participants: Either in the exams involved for enrollment eligibility or in the required activities of research protocols, participants may learn something of value with regard to their health status. For example, they may become aware of hypertension or a cardiac problem that needs medical attention. Such health benefits may or may not accrue, and are in any case fortuitous and not an objective of inclusion/exclusion procedures. Descriptions of such procedures need to be carefully distinguished from medical examinations or therapeutic interventions. For example, model benefit language for distinguishing medical benefits from health information of value to the participant in EPA CHIE studies might include the following:

  There will be no personal medical benefits to you from participating in this study. You will receive a health exam [include details] at no charge to you, but this exam is to determine your suitability for participation in the research, and is not equivalent to a medical exam given by your doctor.

• Benefits of altruism: Research participants can reap psychologic benefit from knowing that they contribute to scientific progress. In some understandings of research ethics, the altruistic participant is viewed as the most desirable. Altruistic individuals may see participation as a moral obligation of citizenship, as a gift to science or humankind, as a religious responsibility, or in a variety of other ways. Altruistic actions are considered virtuous because they are undertaken without expectation of reciprocity or recognition, and because the resulting benefits accrue to others. Purely altruistic acts are likely rare, and motivation for most human activities is not accurately described as either entirely altruistic or egoistic, but having elements of each. Accurately assessing motives of research participants can be very challenging, so benefits accruing from altruistic motives cannot be assumed and best practices would not make them a consideration in EPA CHIE trials.

• Financial benefits: Payment of healthy volunteers for research is usually considered apart from the risk–benefit calculus by IRBs. It is discussed here because payment is often necessary to secure recruitment of healthy volunteers, and because many subjects clearly see money as an associated benefit, perhaps as the most important benefit, for participating. Payments are typically offered to compensate for the time required by participation, lost wages, travel costs, and inconvenience and other obligations imposed by the study (NBAC 2001, NRC, 2004a). The ideal amount of compensation is a combination of fair payment for the time and other burdens required, and a middle ground between enough money to attract potential subjects, but not so much as to create an undue influence. Payments or other inducements are “undue” when they tempt volunteers to assume risks they would not otherwise take, or “prompt subjects to lie or conceal information that would otherwise disqualify them as participants” (Fisher, 2009; Macklin, 1981; Miller, 2003). Some have suggested that a minimum hourly wage for research participation with no upper limits on the compensation is an appropriate standard (Shamoo and Resnik, 2006). In CHIE studies the appropriate level of compensation, including consideration of upper limits, is best determined for each trial by common agreement of investigators and the IRB.

Often both benefit and risk are portrayed as the same for all research participants, but both are better understood as mediated by social position and financial need (Fisher, 2015). Care needs to be taken when recruiting low-income volunteers, students, others in vulnerable social or financial positions, and potentially study repeaters (three of the EPA studies reviewed included repeat participants) for whom monetary rewards could alter their judgments about risks.

RESEARCHER COMMUNICATION AND PARTICIPANT UNDERSTANDING OF INFORMED CONSENT

Risk Perception and Risk Communication

Risk perception is a subjective assessment by a person based on his or her beliefs regarding the probability of a potential hazardous event or activity and how it will affect him or her. Individual philosophies, principles, and past experiences can shape one’s beliefs about perceived risk. The severity of the risk and the overall public opinion of the risk can also affect individual risk perceptions (Beecher et al., 2005; Slovic, 1987). All of those factors need to be considered in the development of informed-consent documentation and in the communication by investigators about human-subjects research (Raich et al., 2001). A person’s recall or ability to relate to an experience with a particular risk can help improve risk comprehension (Anderson and Iltis, 2008; Keller, 2011).

Risk communication is “any purposeful exchange of information about health or environmental risks between interested parties” (Covello et al., 1987). This information incorporates understanding, ideas, and actions as they relate to risks (Anderson and Iltis, 2008; NRC, 1989, 2005). In the communication of risk associated with exposure to putative hazards, comparisons may be made to help research participants understand the risks they might encounter from exposures in the study compared to risks they might encounter from exposures in their daily lives (see Chapter 6).

There are several ways to communicate the risk of an exposure, and assessing the most effective strategies for comparing risk of one exposure to other similar exposures is an important field of study (Johnson, 2004a, 2004b; Keller, 2011). The effectiveness of comparisons might depend on the target audience’s risk perceptions and their cognitive processes used to assess the risk and on the specific exposure to the risk (Williams, 2004). Exposure comparison can be used to help individuals understand a risk and its potential effects by drawing from their past experiences with exposures to other hazards in order to make the comparison more meaningful. When utilizing exposure comparison as a communication strategy, it is essential to compare exposures related to similar kinds of risk (CDC, 2014). Utilizing more familiar and comparable risks can be beneficial, especially for those with less experience with risk interpretation. For example, the risk of lung cancer or respiratory disease associated with cigarette smoking is

considered common knowledge; therefore, utilizing this exposure as a comparison for gauging other hazards thought to be linked to lung cancer, cardiovascular diseases, or respiratory diseases can result in more accurate interpretations of risk levels even among individuals with poorer numeracy skills (Keller, 2011; Keller et al., 2009). Comparing exposures related to risks that are less similar in nature (e.g., likelihood of dying from smoking versus from an industrial accident) can be confusing and misleading (Sandman, 1987). As per Chapter 6, it is recommended that, for communication with study participants, short-term risks be characterized in a descriptive, comparative manner using exposure equivalents that are relevant and understandable for participants. Also, comparative exposure scenarios should be fully documented so that the reasonableness of the comparison can be evaluated.

Participant Comprehension of Informed Consent

People’s perceptions and comprehension of risk on informed-consent forms and throughout the informed consent process are often influenced by the presentation and framing of the information and literacy levels (Anderson and Iltis, 2008; Fortun et al., 2008; Keller and Siegrist, 2009; Peters et al., 2011; Raich et al., 2001; Reynolds and Nelson, 2007; Sand et al., 2012; Stunkel et al., 2010). Language, length of forms, and the presentation of the material, such as use of graphics and categorization of information, influence understanding of risk (Raich et al., 2001). In addition, information framed positively produces a different level of risk perception compared with negatively framed information. An example of this is using a phrase such as “chance of survival” as opposed to “chance of death,” which could influence participants’ perceptions about an exposure and, therefore, whether or not they choose to participate (Anderson and Iltis, 2008; Peters et al., 2011).

One’s understanding of basic mathematical concepts can influence risk interpretation. Health professionals tend to overestimate patients’ health literacy skills and the clarity of their own communication (Dickens et al., 2013; Howard et al., 2013). Results from the 2012 Program for the International Assessment of Adult Competencies, for example, demonstrated that the U.S. average literacy score was 270 or at Level 2 (Level 5 or scores between 376 and 500 demonstrate highest proficiency) (U.S. Department of Education, 2012). Health care professionals and researchers need to be aware of a patient’s literacy level, especially concerning complex medical issues. A patient might struggle with unfamiliar terminology, which can impair his or her ability to receive needed care, which exacerbates the disparity among individuals with lower education levels (Davis et al., 2002). This is relevant not only in discussions between patient and provider, but also in the development of written materials, such as research and medical consent forms. Studies examining the reading level of consent forms find that consent resources are written at an upper high school (grades 10-12) to college (grade 13) level, which exceeds the average literacy level of general populations (Ittenbach et al., 2015; Paasche-Orlow et al., 2003, 2013; Sand et al., 2012; Taylor and Bramley, 2012). Sample consent language from one of the CHIE studies documents provided to the committee by EPA (OMEGACON) includes the following, which is written at a college reading level: “This gene, glutathione-S-transferase (GSTM₁) is one of several genes responsible for protecting your body against oxidants such as some air pollutants, and some recent studies have shown that people carrying a mutation in this specific gene, which renders this gene inactive, may be more susceptible to the effects of air pollutants.”

Assessing Participant Comprehension

There is an important need to ensure individuals’ comprehension of informed-consent documentation and messages communicated verbally by study researchers. Much of the work conducted in this area has been focused on consent for participation in clinical trials (IOM, 2015).

A review of 44 intervention studies using strategies for improving comprehension of informed consent demonstrated that interventions providing additional written information (such as information specific to a procedure or brief information booklet in addition to the written consent form), audio/visual (AV) methods (such as mainly use of AV materials in addition to standard informed consent), extended discus-

sions (such as discussions about procedural risks or more broadly about the procedure itself), and using test-feedback methods (such as asking patients to repeat back information from consent discussions) were considered effective in improving comprehension about risks and general knowledge about a medical procedure (Schenker et al., 2010). Most studies, however, only assessed understanding of procedural risk, and not about benefits, alternatives, and general knowledge of the research. Only 6 of the 44 studies reviewed assessed all four of these components of comprehension, although 32 studies found that methods applied were effective in improving comprehension of risk and/or general knowledge. An earlier systematic review of interventions aimed to increase understanding of the consent process in clinical research suggested that multimedia and enhanced discussions about consent forms have limited effects on improving participants’ comprehension of research protocols and that one-on-one discussions with research staff might have a stronger influence on understanding (Flory and Emanuel, 2004).

Other research, however, has demonstrated that presenting risk information in a multimedia/video (nonprinted) format alone, or to supplement printed forms, also has resulted in improved comprehension of health and risk information (Wang et al., 2015; Wanzer et al., 2010), including improved understanding of research consent-related information by individuals with lower literacy (Afolabi et al., 2015). Utilizing multimedia formats to supplement presentation of the informed-consent form resulted in greater comprehension among parents and guardians regarding a child’s endoscopy procedure (Wanzer et al., 2010). An EPA training course on the consent process recommends oral presentations, educational materials (such as printed brochures), and videos to provide participants with additional information about study procedures (EPA 2014c).

Assessing Participant Comprehension in EPA CHIE Studies

For the CHIE studies considered by the committee, EPA used a consent checklist with 13 statements to gauge participant comprehension. Participants are asked to respond “yes” or “no” to statements, including the following:

• “I understand that I will undergo controlled exposure to the air pollutant ozone (at a concentration of 300 ppb) during the course of this study”;
• “I understand that there are risks associated with my participation in the study”; and
• “A study team member discussed potential risks associated with participation in this study, and the measures that will be taken by the study team to reduce risk, with me.”

After participants respond to the checklist items, they are given the opportunity to ask questions about the study and their involvement in it.

Additional tools and approaches for ensuring participants’ understanding of research protocols that could improve EPA’s checklist method are described here.

Ensuring participants have answers to key questions: The Institute of Medicine workshop and report on informed consent and health literacy included presentation of a curriculum for community members making decisions regarding research participation (IOM, 2015). A list of 10 key questions that individuals should ask of a researcher prior to participating in a study was presented (see IOM workgroup report, Chapter 3). These questions are applicable to EPA’s CHIE studies. Questions were as follows: (1) What is the main purpose of the study?; (2) What will I be asked to do during the study?; (3) How will I benefit from participating in this study?; (4) What are the possible risks?; (5) How will the results be shared?; (6) How will my personal information be kept confidential?; (7) How long is the study going to last?; (8) Are there any reimbursements or incentives offered?; (9) Who is funding the study?; and (10) What are the credentials of the researcher and the researcher’s institution?

Brief screening tool: The Single Item Literacy Screener (SILS) is a published tool designed to quickly assess comprehension. The SILS uses a single question to determine a participant’s ability to read and comprehend health-related information. An individual would be posed with the question, “How often do you need to have someone help you when you read instructions, pamphlets, or other written material from your

doctor or pharmacy?” Responses are measured with a Likert-type scale ranging from never needing help to always needing help. Individuals scoring at or below a determined level should be provided with additional resources to facilitate comprehension of the materials (Morris et al., 2006). While this is a quick and easy literacy assessment, it will not be relevant for individuals who may not ever read such materials and an analogous screening question may need to be developed for this group of individuals.

Study-specific survey instrument: Studies have gauged participants’ comprehension of clinical research study protocols (Chappuy et al., 2010; Ittenbach et al., 2015; Stunkel et al., 2010). Few published tools exist that ask specific questions about the consent form language itself in order to gauge comprehension of the specific aspects the study and the type of participation involved. Shafiq and Malhotra (2011) developed a 24-item survey to evaluate clinical research participants’ understanding of an informed-consent form. The questionnaire was developed specifically for the study being conducted. Multiple-choice response options were provided to participants regarding topics such as study background (nine questions), study design (six questions), and participants’ rights (nine questions). By having potential participants complete their survey, they were able not only to evaluate people’s comprehension of the information, but also to help build trust between researchers and individuals participating in the study.

Teach-back methods: More limited research has been conducted on verbal health literacy or people’s understanding of prose or numeric information received through oral exchanges (Nouri and Rudd, 2015). One important strategy being considered is referred to as “teach-to-goal” or the “teach-back” method. The method involves one-on-one discussions between the study team member and a participant. This method not only helps the participant comprehend the information, it also allows the study team to assess the participant’s level of understanding (Tamariz et al., 2013). Teach-back involves a three-part process: (1) assessing comprehension, (2) offering feedback, and (3) reevaluating comprehension. The goal of this process is to provide a comprehensive explanation of the interventions to which participants will be subjected, tailored to their level of understanding. This method also provides an opportunity for the study team to determine whether the information provided was understood by the participants (Flowers, 2006; Kripalani et al., 2008; Tamura-Lis, 2013). Using teach-to-goal methodology in the review of the research consent process has demonstrated significant improvements in comprehension by individuals from diverse backgrounds and with lower literacy levels (Kripalani et al., 2008; Sudore et al., 2006). Examples of teach-back educational materials include the following:

• Agency for Healthcare Research and Quality (AHRQ) Reference Guide on teach-back methods, http://www.ahrq.gov/sites/default/files/wysiwyg/professionals/education/curriculum-tools/shareddecisionmaking/tools/tool-6/share-tool6.pdf;
• AHRQ’s Teach-Back Self-Evaluation and Tracking Log, http://www.ahrq.gov/sites/default/files/wysiwyg/professionals/quality-patient-safety/quality-resources/tools/literacy-toolkit/healthliteracytoolkit.pdf; and
• University of North Carolina at Chapel Hill Sample teach-back method videos, http://www.nchealthliteracy.org/teachingaids.html.

RECOMMENDATIONS

Informed-Consent Document Development

Overall, there are some limitations with current consent documents for the CHIE studies. Some of the existing informed-consent documents reviewed by the committee contain complicated and technical language that requires high literacy and numeracy skills. In addition, exposure comparators, presented in those documents, might not be familiar or relevant to participants (see Chapter 6). EPA should use a more plain-language presentation of risk information in consent documents for all IRB protocols. In general, development of consent documents should include these steps:

• Use a credible evidence standard (such as empirical research, experience, or scientific or mathematical principles) to determine what risks can reasonably be considered foreseeable in the study.
• Explore exposure-related health effects that have been reported in studies that used similar CHIE study interventions and in epidemiologic and animal studies.
• Consider how content should be framed within the document (such as positive frame versus negative frame) and the influence this might have on potential participants. EPA should conduct a pilot test of consent information that uses different frames and assess which has more of an impact on participants consenting to participate in CHIE studies.
• Provide accumulated information on the occurrence of serious adverse events associated with previous CHIE studies, and the resolution of these events (as discussed in Chapter 5) to illustrate that a study involves risks of serious adverse events that can be anticipated and those that cannot be anticipated.
• Characterize reasonably foreseeable risks by using an easily understood perspective and incorporating relevant exposure comparator scenarios into language about the study (see Chapter 6). The comparators should be evidence based and their development explained.
• Include and delineate all reasonably foreseeable risks and any risks likely to be perceived as important by the participants. CHIE studies typically impart a very small increase in the cumulative exposure to ambient air pollution over an individual’s lifetime, and there is no credible evidence to suggest that chronic effects be considered among the reasonably foreseeable risks of those studies. However, potential participants might be concerned about long-term risks because of associations between long-term exposure to air pollution and chronic effects. Therefore the likelihood of chronic effects needs to be included in informed-consent communications.
• Describe uniformly the risks from experimental procedures that are used often (such as bronchoscopy) and indicate how the risk profile of the study subjects (such as mild asthmatic) has been taken into account.
• Communicate clearly that CHIE studies offer no medical benefit to exposed individuals.
• Conduct readability assessments using validated instruments such as SMOG or Flesch-Kincaid Reading Grade Level on all content intended for study participants to ensure grade 6-8 level. See McLaughlin (1969) and Kincaid et al. (1975).
• Supplement consent documents with audiovisual materials to present consent information to ensure that study information is more accessible for individuals with lower literacy and numeracy, and that the language is culturally appropriate.

Assessing Participant Comprehension and Consent Communication

EPA should strive in all CHIE studies to ensure that obtaining informed consent is a two-way discussion with potential participants. EPA is currently employing a 13-statement checklist to assess participants’ understanding of informed-consent documents. To improve the way it ensures participants’ understanding of research protocols, EPA should modify the current informed-consent checklist to involve a more in-depth assessment of participant comprehension of risks of participation and societal benefits accrued by these studies. The agency should use tools and approaches described in this chapter, including the following:

• Asking participants specific questions about the study to ensure understanding of consent form,
• Using teach-back methods with participants during the consent process, and
• Continuing to provide participants with the opportunity to ask questions.