5
Ethical Considerations in the Review of Intentional Human Dosing Studies

INTRODUCTION

A principal theme of this report is that science and ethics are closely related. As explained in previous chapters, intentional human dosing studies must be both scientifically and ethically justifiable. A human research protocol could be scientifically valid but ethically unacceptable (e.g., because the investigator failed to get informed consent); however, it cannot be ethically acceptable if it does not conform to standards of good research design and conduct.1 In this sense, sound research design is the first step in developing an ethically acceptable protocol. For these reasons, scientific and ethical considerations need to be integrated in the review and evaluation of research involving humans (IOM, 2003). 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.

This chapter addresses the ethical considerations that remain after determining that a research protocol is scientifically valid and that its

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A report from the Environmental Protection Agency (EPA) Joint Science Advisory Board and the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAB/SAP) noted the following: “Bad science is always unethical; research protocols that are fundamentally flawed, such as those with sample sizes inadequate to support reasonable inferences about the matter in question, are unjustifiable” (EPA, 2000, 2).



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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues 5 Ethical Considerations in the Review of Intentional Human Dosing Studies INTRODUCTION A principal theme of this report is that science and ethics are closely related. As explained in previous chapters, intentional human dosing studies must be both scientifically and ethically justifiable. A human research protocol could be scientifically valid but ethically unacceptable (e.g., because the investigator failed to get informed consent); however, it cannot be ethically acceptable if it does not conform to standards of good research design and conduct.1 In this sense, sound research design is the first step in developing an ethically acceptable protocol. For these reasons, scientific and ethical considerations need to be integrated in the review and evaluation of research involving humans (IOM, 2003). 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. This chapter addresses the ethical considerations that remain after determining that a research protocol is scientifically valid and that its 1   A report from the Environmental Protection Agency (EPA) Joint Science Advisory Board and the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAB/SAP) noted the following: “Bad science is always unethical; research protocols that are fundamentally flawed, such as those with sample sizes inadequate to support reasonable inferences about the matter in question, are unjustifiable” (EPA, 2000, 2).

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues probable benefits outweigh its risks. These include voluntary informed consent; fair selection and recruitment of potential research participants, including fair payment for their participation; and compensation, including the provision of medical care, for research-related injuries.2 The chapter concludes with recommendations regarding whether and, if so, how the Environmental Protection Agency (EPA) should use ethically tainted data. The aim of this chapter is to formulate standards of ethical acceptability of intentional human dosing studies. Because some standards identify a minimum that must be met in any such study, while others point to ideals that should guide such research, it is important to distinguish what is ethically unacceptable from what falls short of ethical ideals. Federal regulations would not be applicable to many third-party intentional dosing studies, because although EPA has accepted the Common Rule, which governs the research that it conducts or funds, this rule does not apply to privately funded toxicant research. Also, EPA has not adopted Subpart B (fetuses, pregnant women, and human in vitro fertilization), Subpart C (prisoners), or Subpart D (children). 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), Good Clinical Practice (GCP) guidelines (FDA, 2003), the Declaration of Helsinki (WMA, 2002), bioethics literature, recent studies by the National Academy of Sciences/Institute of Medicine, a report by the National Bioethics Advisory Commission (NBAC, 2001), a report by the National Human Research Protections Advisory Committee on research with children,4 and policies and practices 2   Informed consent and review by an Institutional Review Board (IRB) are considered the major pillars in the system for protecting the rights and welfare of participants in research (NBAC, 2001). 3   This report does not address all the ethical considerations that are relevant to the evaluation of intentional dosing studies. Instead, it concentrates on the ethical considerations that are especially unclear or controversial in intentional dosing studies, while presupposing the other ethical conditions, such as confidentiality. 4   See ohrp.osophs.dhhs.gov/nhrpac/documents/nhrpac16.pdf.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues that have evolved in the conduct of research (see Chapter 2). Even though these sources agree on the importance of Institutional Review Board (IRB) review and informed consent, they are frequently unclear, indeterminate, inconsistent, and even contradictory regarding other issues related to toxicant research. Hence, in this report the committee often presents its own judgments, based on the best available arguments, or recommends a process that over time can more fully address such issues. Studies in which people are intentionally exposed to toxicants, which are conducted generally to make the case for setting a less stringent exposure standard, are intuitively troubling and even repugnant to many people. Such studies seem to be ethically wrong—“It’s wrong to poison people”—and further discussion does not even seem necessary. The committee took note of these responses but sought to examine closely how toxicant studies are similar to, and different from, other human studies, so that the wide experience could contribute to its deliberation about which kinds of studies are ethically defensible in light of the available evidence and society’s basic moral values. Understanding that virtually all chemicals can be poisonous to humans at some dose, the committee compared studies that involve the intentional exposure of humans to toxicants with studies that involve deliberate exposure to other kinds of chemicals. 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. Both types of study should be evaluated according to prevailing ethical standards, in the Common Rule and elsewhere, for assessing human research protocols. Neither kind of study can be ethically justified unless it passes rigorous scrutiny on both scientific and ethical grounds.5 Recommendation 5-1: Criteria for Scientific and Ethical Acceptability Studies that do not meet the highest scientific and ethical standards should not be carried out or accepted by EPA as input to the regula- 5   The motives of the different sponsors also may be similar: both a pharmaceutical company and a pesticide company, to take these two examples, may be motivated primarily by a desire for increased revenues. One seeks to get a drug approved for sale, and the other seeks a higher tolerance level to increase the sale of pesticides. These motives may be primary or secondary and may be accompanied by various additional motives. In any case, neither motive necessarily disqualifies the research on ethical grounds. However, the presence and perhaps primacy of these motives underscores the need for stringent standards and procedures to protect the rights and welfare of research participants.  

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues tory decision-making process. Necessary conditions for scientifically and ethically acceptable intentional human dosing studies include: prior animal studies and, if available, human observational studies; a demonstrated need for the knowledge to be obtained from intentional human dosing studies; justification and documentation of a research design and statistical analysis that are adequate to address an important scientific or policy question, including adequate power to detect appropriate effects; an acceptable balance of risks and benefits and minimization of risks to participants; equitable selection of participants; free and informed consent of participants; and review by an appropriately constituted IRB or its foreign equivalent. Examples of unethical studies include the following: studies that are unnecessary because the desired information can be obtained by other means, such as animal studies or human observational studies, without resorting to the intentional exposure of research participants to toxicants; studies that lack prior and appropriate animal studies; studies that are not designed to yield scientifically valid information that addresses important scientific or policy questions; studies that have an unacceptable risk-benefit balance or that fail to minimize risks to participants; studies whose selection of research participants is inequitable; studies for which the consent of the participants is not informed and voluntary; and studies that have not been reviewed by an appropriately constituted IRB. Other recommendations in this chapter specify these ethical criteria in more detail. Several of them reflect the ethical principles presented in the Belmont Report: beneficence, justice, and respect for persons (National Commission, 1979). While the discussion of risk-benefit analysis and scientific validity in the two preceding chapters largely reflected ethical considerations based on the principle of beneficence, this chapter focuses mainly on ethical considerations based on the principles of justice and

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues respect for persons. The principle of justice guided the committee’s judgments about the selection and recruitment of participants in research and compensation for research-related injuries, while the principle of respect for persons shaped the committee’s recommendations about voluntary informed consent by potential research participants. 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)). This requirement derives from the principle of justice identified in the Belmont Report. If a research protocol has a satisfactory overall ratio of risks and potential benefits, it satisfies the demands of beneficence, but not necessarily the demands of justice. The principle of justice directs attention to the distribution of risks and benefits—who will gain the benefits and who will bear the risks and other burdens of research—not just the overall risk-benefit ratio (Beauchamp and Childress, 2001; EPA, 2000; National Commission, 1979). It is easier to identify and avoid some unjust distributional patterns—for example, the deliberate selection of certain relatively powerless groups to bear the burdens of research—than it is to design and implement a fully just distribution. Furthermore, as the Belmont Report noted, researchers and institutions may lack the power to counteract some social factors, such as socioeconomic status, that result in higher rates of enrollment by members of certain groups (National Commission, 1979). Several aspects of the ethical requirement of equitable, fair, or just selection of research participants merit attention. First, on scientific grounds, as discussed in Chapter 3, the study population needs to be representative of the target population of interest in order for the research results to be applicable. Although variations in gender and race/ethnicity may not signify the true scope of biologic variation affecting response to toxicants, they may be helpful proxies and thus should be considered in participant selection. The selection of research participants also should be inclusive in order to avoid the exploitation and the appearance of exploitation of any particular social group. As the Belmont Report observed in discussing the principle of justice: [T]he selection of research subjects needs to be scrutinized in order to determine whether some classes (e.g., welfare patients, particular racial and ethnic minorities, or persons confined to institutions) are systematically selected simply because of their easy availability, their compro-

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues mised position, or their manipulability, rather than for reasons directly related to the problem being studied (National Commission, 1979, 7). The Belmont Report and the Common Rule both note that various conditions can render some persons more “vulnerable to coercion or undue influence” and hence create the need for “additional safeguards” to protect their rights and welfare as potential research participants. Potentially vulnerable populations include children, prisoners, persons with mental disabilities, and economically or educationally disadvantaged persons. Vulnerability may reflect limited abilities to make informed choices (e.g., limited mental capacity) or constraints on free choices (e.g., imprisonment or economic disadvantage). From the standpoint of just or fair selection and recruitment of research participants, it is not justifiable to enroll persons who lack the capacity to consent to their involvement, even if surrogate decision makers grant permission, when the research offers them no prospect of direct personal benefit and carries more than minimal risk or when the needed information could be obtained through studies with individuals who have the capacity to consent. Concerns about voluntariness led the Department of Health and Human Services (DHHS) Office for Human Research Protections (OHRP) to raise questions about “undue influence” when employees and students of institutions sponsoring or conducting the research serve as participants in research that offers no prospect of direct benefit. Concerns about undue influence also may arise in other cases, such as including in studies the employees of companies that make the products being tested. Under some circumstances, a person may feel compelled to participate in a dosing study, perhaps especially when the person or entity conducting the study has substantial power over the potential participant. The Common Rule permits consent to be sought only “under circumstances … that minimize the possibility of coercion or undue influence.” A separate issue arises from proposals to enroll individuals who are more susceptible to harm in research protocols, as can occur, for example, in studies of the effect of aerosolized pollutants on individuals with lung diseases such as asthma. 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. In general, individuals who would face higher risks in the experiment should not be selected. An exception might be warranted if their participation is needed to answer a question of major importance in the regulatory process. However, even then, this exception should be made only when additional measures are taken to ensure an

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues acceptable balance of risks and potential benefits. These measures could include making sure that a review is conducted of a volunteer’s possible participation by his or her physician or another physician not involved in the study, monitoring during the study, and reinforcing the usual medical advice given to patients. Such measures can help to provide an acceptable balance of risks and potential benefits for the individual participant. Children represent a special case. They are vulnerable because they lack decision-making capacity and are greatly influenced by adults. There also is reason to believe that children may be more susceptible to certain adverse effects of toxicants because of changes that occur during development and because of age-dependent differences in metabolism, disposition, and target organ sensitivity. Infants and toddlers are often particularly susceptible. For example, lead is more toxic to the developing child than it is to adults in both the short and long term. The fear of greater adverse effects is reflected in the requirement of the Food Quality Protection Act that EPA add a 10-fold safety factor to account for children’s possible increased susceptibility that can be rebutted only by “reliable data.” A major question, then, is whether and, if so, under what conditions, it is permissible to conduct research to learn more about the susceptibility of children. DHHS has addressed the tension between the need for greater knowledge about children and the need to protect children from harm and exploitation in research. Subpart D of the Common Rule (Additional DHHS Protections for Children Involved as Subjects in Research) greatly restricts the enrollment of children in research that involves greater than minimal risk without the prospect of direct medical or health benefit. Such research may be approved by an IRB if it is likely to yield generalizable knowledge about the children’s “disorder or condition” and ways to ameliorate that “disorder or condition,” but only if the risk represents “a minor increase over minimal risk,” the intervention or procedure “presents experiences to subjects that are reasonably commensurate with … their actual or expected medical … situations,” and the parents grant permission and the children assent. Research that would not otherwise be approvable under these criteria, however, could be approved if the DHHS Secretary, in consultation with a panel of experts, determines that it “presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children,” the study will be conducted in accord with “sound ethical principles,” and the parents grant permission and the children assent (45 CFR 46.407(a)). EPA should adopt Subpart D, and, in any event, should adhere to its requirements. 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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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues tuted panel, and the investigation will increase the understanding of a serious problem affecting the health of children. Simply improving the accuracy of risk assessments for regulatory decision making would not justify research under this subpart. The ethical problems of conducting dosing studies in children emphasize the importance of conducting rigorous epidemiological studies in children. Nonetheless, if EPA followed the model provided by Subpart D and meets the requirements of that subpart outlined above, then research involving children that otherwise would not be approved could be considered and perhaps approved by a special panel. Recommendation 5-2: Participant Selection Criteria IRBs reviewing intentional human dosing studies should ensure that the following conditions are met in selecting research participants: Selection should be equitable. Selection of persons from vulnerable populations must be convincingly justified in the protocol, which also must justify the measures to be taken to protect those participants. Selection of individuals with conditions that put them at increased risk for adverse effects in such studies must be convincingly justified in the protocol, which also must justify the measures that investigators will use to decrease the risks to those participants to an acceptable level. EPA should adopt Subpart D of the Regulations for the Protection of Human Research Subjects. At a minimum, EPA should adhere to Subpart D’s requirements for research involving children. PAYMENT FOR PARTICIPATION IN RESEARCH Another issue of justice, as well as of respect for persons, involves remuneration for participation in research.6 Paying research participants is “a common and long-standing practice in the United States” (Dickert et al., 2002, 368), perhaps because of the need to provide incentives as part of recruitment and because the moral principles of fairness and gratitude 6   The IRB Guidebook (available at ohrp.osophs.dhhs.gov/irb/irb_guidebook.htm) proposes that the term “remuneration” be used for payment for participation in research and that “compensation” be reserved for payment or provision of medical care for research-related injuries.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues support providing payment to those who bear the burdens of research on behalf of society. In any event, difficult questions remain: How much money should research participants receive? And for what should they receive payment—their time, inconvenience, discomfort, or level of risk? Can remuneration—or some level of remuneration—create a problem for research subjects’ voluntary, informed consent? 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. Furthermore, federal regulations and guidance are relatively quiet on this subject, warning about “undue influence” without, however, specifying what counts as undue. One difficulty is that undue influence depends on context. Wherever the remuneration is set, it will influence the decisions of some more than others. In particular, it will be more important to those for whom it will make a significant financial difference, i.e., poor people. Although the committee does not purport to be able to resolve the ethical difficulties surrounding remuneration of research participants, it believes that some general guidance may be useful. A major ethical concern is that payments should not be so high that they create an “undue influence” or offer undue inducement that could compromise a prospective participant’s examination and evaluation of the risks or the voluntariness of his or her choices. This concern is greatest, of course, when the studies involve significant risks. Other concerns are that payments should not be so low as to recruit disproportionately high numbers of economically disadvantaged persons and that they should fairly pay participants for their contribution to research.7 7   One committee member (Lave) believed that this discussion about payment misses the point. Undue influence is important, but the amount of money that constitutes undue influence differs among individuals. An impoverished person might be willing to take considerable risks and bear considerable pain in exchange for a few hundred dollars. Thus, the investigator and the IRB should assume that any reasonable level of payment will unduly influence some potential participants. The experimental protocol must strive to detect cases where a potential participant has concealed information or lied in order to participate, despite the fact that this person has characteristics that greatly increase his risk of being harmed in the experiment, or if he believes that the existence of symptoms would exclude him from the experiment or force his early exit, reducing the amount of his payment. Assuming that all potential participants will tell the truth and conceal no information because the payment does not constitute undue influence is a mistake. Furthermore, participants will deliberately conceal adverse symptoms that would remove them from the experiment, if they believe that doing so would erode the amount of their payment. The protocol must make every effort to get participants to be truthful in revealing their symptoms without fear that remu-

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues In its guidance on “Payment to Research Subjects,” the Food and Drug Administration (FDA) notes that: Financial incentives are often used when health benefits to subjects are remote or non-existent. The amount and schedule of all payments should be presented to the IRB at the time of initial review. The IRB should review both the amount of payment and the proposed method and timing of disbursement to assure that neither is coercive or present undue influence (21 CFR 50.20). In particular, the FDA guidance indicates that payment should be prorated for the time of participation in the study rather than extended to study completion, because the latter could compromise the participant’s right to withdraw at any time. Despite such guidance, there appears to be wide variation among IRBs, sponsors, and investigators in policies and practices involving remuneration for research participation. Indeed, a recent study of institutional policies reports that “few data are available on guidelines used by research organizations to make decisions about paying subjects” (Dickert et al., 2002, 368). This study notes that few of the 32 research organizations surveyed had formal policies to guide the amount or circumstances of payment, a situation that generates uncertainty about whether safeguards against unfair or coercive payment are adequate (Dickert et al., 2002). According to this study, participants in some research receive payment for time (87 percent of organizations), inconvenience (84 percent), travel (68 percent), incentive (58 percent), or incurring risk (32 percent) (Dickert et al., 2002). 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. However, attitudes may differ considerably when the risk is a minor and transient symptom or discomfort (e.g., sleepiness or dizziness) rather than a substantial harm. Sometimes the arguments for limiting payment to time and inconvenience reflect the belief that participation in research is an altruistic act. It is al-     neration will be eroded. A final point is that a much higher level of remuneration will be required to get potential participants with higher income to volunteer for the experiment. If we take seriously the notion that participants should be representative of the population to be served, remuneration will need to be raised. Higher remuneration means that still more participants are likely to attempt to hide risk factors or lie so that they can participate in the experiment and earn the remuneration. Thus, the attention paid to remuneration is largely wasted, because the protocol needs to focus on detecting factors that would put the participant at higher risk, despite his or her attempts to conceal them or to lie.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues most certainly true that the prospect of financial remuneration motivates many people to participate in research and that it is often a necessary and sometimes a sufficient condition for their participation. Indeed, it is difficult to believe that people who agree to participate in dosing studies of toxicants are motivated only by altruism and not by the desire to make money. It thus seems highly likely that remuneration will affect participation. Because at present there is no practical or theoretical consensus regarding remuneration, the committee recommends that sponsors, investigators, and IRBs closely attend to the ethical and scientific implications of different strategies, particularly regarding payment for incurring risk. Protocols submitted to IRBs should indicate and justify proposed levels and purposes of remuneration, which also should be clearly stated in the accompanying consent forms. Recommendation 5-3: Payment for Participation IRBs, all relevant review boards, investigators, and research sponsors should ensure that payments to participants in intentional human dosing studies are neither so high as to constitute undue inducement nor so low as to be attractive only to individuals who are socioeconomically disadvantaged. Proposed levels of and purposes for remuneration (e.g., time, inconvenience, and risk) should be scrutinized in light of the principles of justice and respect for persons. Moreover, EPA, in conjunction with other federal agencies, should consider developing further guidance on remuneration for participation 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), is a major element in the system of protection of research participants. The consent requirement expresses the principle of respect for persons, including respect for and promotion of autonomous choices. The Common Rule stresses this requirement, as do other codes of research ethics, including the Nuremberg Code (1949), the Declaration of Helsinki, and GCP guidelines. This section focuses on the disclosure and comprehension of information as part of the consent process. Despite the strong consensus about the importance of informed con-

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues sent, various studies indicate that those who have agreed to participate in research often do not comprehend its basic features (Joffe et al., 2001; Miller et al., 1996). Although these studies are frequently limited because they focus on what participants later recall, they raise legitimate ethical concerns about the validity of consent in many experiments. Problems may arise, in part, because much ethical discourse focuses on the obligation to disclose information, rather than on the obligation to ensure participant comprehension. For example, the Common Rule specifies much of what should be disclosed to participants, including the nature and purposes of the research, the procedures used, “any reasonably foreseeable risks or discomforts to the subject,” and any potential benefit, but it provides less guidance about how to ensure participant comprehension. The focus on disclosure also results in part from IRBs’ attention to the consent form rather than to the process of consent. Whatever the forms say, and however clearly they say it, incomplete understanding or misunderstanding is common. Even if the consent forms are clear about the experimental nature of the study, a “therapeutic misconception,” that is, a mistaken belief that the research offers a real hope of medical or health benefit to participants, may emerge. For example, recruiting advertisements can affect participants’ understanding (and copies of these advertisements could be requested by IRBs along with the consent form). Thus, focusing solely on disclosure is not enough; it is appropriate to be concerned about what participants in intentional human dosing studies comprehend. One simple approach would be to administer, at the time of the consent, a short multiple-choice test, which could indicate how well the participants understand the disclosed information (EPA, 2000, 20). Among the protocols reviewed by the committee, some proposed informed consent procedures that used best practices, while others presented deficient informed consent procedures. Several studies provided information about the research in ways that were ethically problematic: A study of toluene inhalation failed to disclose that its purpose was to determine the toxicity of toluene in order to determine exposure levels. The consent form did not say that toluene is an environmental pollutant. A study administering particulate air pollutant to normal volunteers involved bronchoscopy as one of the research procedures. The consent form did not list death as a serious but remote risk of this study. In contrast, the low risk of death is routinely disclosed to patients during the consent process for bronchoscopy as a clinical procedure. Furthermore, in one highly publicized study, a healthy research volunteer died after bronchoscopy (Steinbrook, 2002). Other studies administered concentrated ambient air particles to

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues persons with asthma or chronic obstructive lung disease who had been instructed to forgo their usual maintenance therapy. The risks of these studies were understated in the protocol and the consent form. Although the consent forms characterized the research risks as minimal, these studies do not meet the criteria for minimal risk as defined in the Common Rule. While everyday experience can include exposure to comparable levels of such particles, it is not usual for persons with asthma or chronic obstructive lung disease to withhold their customary bronchodilator or to exercise strenuously under such circumstances. Furthermore, the consent forms did not clearly state that there was risk the study could induce an asthma attack or exacerbate chronic obstructive lung disease, which could be avoided if the participant continued to take his or her regular asthma medications or did not participate in the study at all. Finally, it is misleading to compare the risk of the research to the risk of visiting a large (polluted) city, because those with asthma would be advised to take their regular medications when visiting a polluted city—or even to increase them—and to stay indoors to avoid exposure to pollutants.8 In light of the documented problems with informed consent and its importance in helping to assure the ethical integrity of intentional dosing studies, the committee recommends that steps be taken to strengthen the informed consent process. One way to do this is to identify best practices regarding informed consent in such studies and to encourage other investigators to adopt them. Recommendation 5-4: Best Practices in Informed Consent EPA should develop and disseminate to relevant IRBs, investigators, and sponsors a list of best practices regarding informed consent 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. The initial version of this best practices document should include but not be limited to the following: Practices to describe the purpose of the study clearly in laypersons’ terms. Some studies convey in clear, simple lay language how toxicant studies differ from clinical trials: 8   These three studies and the associated consent forms were approved by IRBs. Two were approved by research university IRBs and one by an industry-sponsored IRB.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues “The purpose of this research study is to determine what dose of a pesticide can be safely administered to human beings.” “This study is not designed to provide you a direct medical benefit.” “This study is not designed to improve your health.” Practices to describe the risks clearly in laypersons’ terms, including remote but serious risks. Toxicant studies need to make clear to potential participants the risks of the study, particularly those that are unlikely to be obvious: Risks should include any requirements to stop usual medications or deviate from usual medical advice. The remote risk of death to a healthy volunteer from an invasive procedure such as bronchoscopy needs to be described. This is standard practice in clinical medicine, where such procedures are performed with the prospect of direct clinical benefit to the person undergoing the procedure. In a research setting that is not designed to provide benefits to participants, the level of disclosure of risks should be even greater than in clinical practice. Potential participants should be informed of any reproductive risks or risks to offspring. Practices to assess whether participants comprehend the information disclosed to them. Disclosure of information to prospective participants in research is only one step in the consent process. It also is essential that the participants comprehend the disclosed information and how it applies to their decision to enter the study. Concerns have been raised that participants may not understand how toxicant research differs from clinical trials that hold the prospect of direct clinical benefit from the administered substance. 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. Such a list of best practices should be used to stimulate investigators and IRBs to consider what consent procedures would be most appropriate for a particular study, not as inflexible requirements that must be applied in every case. A practice that works well in one study may not be appropriate in another. In addition, a list of best practices is not meant to be exclusive. A research team may devise an approach that constitutes an innovative advance over previous consent procedures. The goal of the list is to focus attention on the consent process and to encourage investigators and IRB members to consider how to strengthen it.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues COMPENSATION FOR RESEARCH-RELATED INJURIES Debate continues in the United States about whether compensation should be provided for research-related injuries. The Common Rule requires only that when research involves more than minimal risk, information should be disclosed regarding whether medical treatment and other compensation will be provided for research-related injuries. Many critics of the U.S. policy believe there should be more than disclosure of information about compensation and call for the provision of medical care for research-related injuries without cost to the participants and, in addition, for compensation for lost wages, disabilities, and death. These claims are based on the belief that research participants, whatever their motivations, accept risk on behalf of society. When participants are injured, justice, fairness, and gratitude mandate, at a minimum, the provision of needed medical treatment without cost to the participant. Further study is needed regarding the provision of other types of compensation. In the United Kingdom, several studies involving deliberate exposure to toxicants indicated that participants who were injured in the research would receive compensation. For example, a Dichlorvos study conducted by Medeval, a malathion study conducted by Cheminova, and a Phosmet study conducted by Inveresk provided for no-fault compensation for physical injuries caused by the research. One study stated that in the event of “any bodily injury caused by my participation in the study,” compensation would be paid “without having to prove that the injury arose through negligence or that the study compound was defective.” The amount of compensation “shall be calculated by reference to the amount of damages commonly awarded for similar injury by an English court if liability is admitted.” In addition, some of the studies in the United Kingdom provided for monetary compensation if long-term disability resulted from injuries incurred during the studies. In countries with universal access to medical care, research participants would be expected to receive medical care for injuries suffered in research regardless of the cause. That cannot be assumed in the United States. 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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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues The operation and scope of such a compensation system require further attention, because of difficulties in determining causation when medical problems appear some time after participation in research.9 Recommendation 5-5: Compensation for Research-Related Injuries At a minimum, sponsors of or institutions conducting intentional human dosing studies should ensure that participants receive needed medical care for injuries incurred in the study, without cost to the participants. In addition, EPA should study whether broader compensation for research-related injuries should be required. THE USE OF RESULTS FROM ETHICALLY PROBLEMATIC STUDIES A final question concerns what role, if any, ethically problematic or unethical studies should play in EPA’s regulatory decisions. The committee concludes that this question will rarely arise, especially after EPA formulates its standards and procedures, and worries that it may be magnified out of proportion to its overall frequency. Nonetheless, when this question does arise in real cases, it can be an ethically vexing one. In addressing it, the committee considered the relevance of several distinctions: those between data submitted by industry as part of EPA’s process of regulatory decision making and data retrieved by EPA; between data drawn from studies conducted before EPA’s anticipated rulemaking in light of this committee’s recommendations and studies conducted afterwards; and between the failure to obtain voluntary informed consent and the failure to realize other ethical standards. 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 9   The 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). The report notes that, because injuries may not become evident until long after the study has ended, investigators need to indicate to IRBs (and in consent forms) their “plans for ascertaining the subjects’ health status for some period after the end of the experiment, and ensure that each subject is given clear information about how to deal with problems that might emerge later”(21).

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues those studies were conducted ethically and in accordance with the new rules and procedures. After the proposed new procedures have been fully implemented, those who submit studies will presumably have had the benefit of advance protocol review by the EPA Human Studies Review Board proposed in Chapter 6, as well as EPA’s clarification of the relevant ethical standards. 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. If the EPA Human Studies Review Board determines that the submitted research breached fundamental ethical standards, but also determines that the data would be important in protecting the public, what should it do? In such cases, the committee recommends that EPA convene a special, outside panel (distinct from the Human Studies Review Board) to examine the case for and against using the data. Such an exceptional procedure signifies the seriousness of any possible reliance on data from research that violates important ethical standards. The outside panel should include members of the public as well as experts, because the judgments that are required are not only scientific and technical but also involve societal values and because the judgments will need to be explained and justified to the public. Even though the panel will need to specify the relevant substantive standards as it wrestles with real cases, the following points are relevant. The panel should first determine whether the data are “crucially important” for protecting public health and whether they are necessary in the sense that they could not otherwise be obtained, with reasonable certainty within a reasonable period, without exposing additional research participants to harm. In part because this standard’s key terms and concepts are imprecise, the panel’s judgment will be required in determining whether the answers to both questions are affirmative. It is critically important for EPA to deter future unethical conduct even as, in extraordinary circumstances, it considers and relies on data from unethical research to protect public health. In such circumstances, the committee concludes that it would be possible, through the creation of the special panel described above, and through adherence to stringent substantive standards, to use unethically obtained data to protect the public without creating an incentive for future breaches of the relevant ethical rules. Nonetheless, some argue that it is not sufficient to establish safeguards

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues to prevent future ethical abuses; instead, they contend, EPA should totally reject ethically tainted research data. This argument charges that deriving societal benefits from unethical research retrospectively legitimizes such research and undermines the ethical principles discussed earlier in this chapter. Indeed, this argument holds that accepting the benefits of such research involves society in a kind of symbolic approval of and complicity in the unethical research, even after the fact. This line of reasoning tends to support an absolute renunciation of the benefits of knowledge gained through unethical research. Although this stance has strong appeal, especially as a way to express society’s commitment to fundamental values in research involving humans, it would sacrifice another important societal value, namely, the protection of public health. It is difficult enough to resolve this debate in concrete cases—as was evident in the dispute several years ago about whether EPA should use data from Nazi experiments on the effects of phosgene. However, it is virtually impossible to resolve this debate in the abstract, especially when the kinds of cases envisioned are not as egregiously or as blatantly unethical as the Nazi experiments, which included the intention to harm research subjects. Thus, instead of attempting to resolve this dispute in the abstract, the committee recommends the conduct of a rigorous review by the special, outside panel of actual cases using stringent substantive standards that should, at a minimum, prevent the creation of incentives for any future abuses. 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 circumstances, studies that fail to meet these ethical standards may provide valid information to support a regulatory standard that would provide greater protection for public health. Under these circumstances, EPA should convene a special, outside panel, consisting of relevant experts and members of the public, to examine the cases for and against considering data from such studies. Enacting regulatory standards based on data from such studies without requiring toxicants to be administered to additional people to repli- 1   The committee uses the term “rules” informally to mean guidance, guidelines, policy, protocols, rules, or regulations.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues cate them might better protect the public health, but in order to strongly deter sponsors and researchers from conducting unethical studies, these data should not be used to favor the sponsor’s interests in loosening regulatory standards. The special outside panel (convened by EPA or as an ad hoc panel of the Human Studies Review Board) should make its judgment by considering: whether the data are crucially important for protecting the public, and whether the data cannot otherwise be obtained, with reasonable certainty within a reasonable period, without exposing additional research participants to the risk of harm. Unless the panel can answer both questions affirmatively, it should recommend that EPA not consider the data in question. Studies Completed Before Publication of EPA’s New Rules Consideration of the use of data that were collected before the new standards are in effect raises particularly vexing issues. One question is whether it is fair to judge past studies with humans by current ethical standards. 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). However, informed consent has earlier roots, for instance, in the Nuremberg Code’s emphasis on voluntary consent in the late 1940s and in the Declaration of Helsinki’s attention to informed consent from the 1950s on. And IRB review has been considered an important procedure for ethical review since it was required in 1966 for human research funded by the Public Health Service. The options range between the following two basic policies: Reject all studies that do not provide clear evidence that they meet standards for ethical research involving humans. Accept all studies unless they violated fundamental ethical standards. The evidentiary requirements for these two options differ. In the first, the researchers must provide the evidence of compliance with ethical standards; in the second, EPA would accept the studies unless there is evidence of the violation of fundamental ethical standards. The committee

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues favors the second option because of ethical concerns about not considering scientifically valid data from completed studies. If such data are not considered, it may be necessary to conduct additional research to obtain similar data to protect the public, thus subjecting additional research participants to risk. Moreover, it would be difficult and often impossible to obtain evidence about whether past studies, especially those in the distant past, met ethical standards. Adequate documentation often is not available. Publications before 1975 do not usually indicate whether investigators obtained IRB approval and informed consent. This lack of documentation is true even for federally funded studies, which, after 1966, were required to obtain IRB approval and informed consent. In some medical specialties, even more recent publications do not consistently state whether informed consent and IRB approval were obtained, and even when publications do mention informed consent and IRB review, they almost never provide the kind of detailed information that would be required by the Human Studies Review Board in its review. Furthermore, for older studies, it may be difficult to obtain copies of the protocol or consent forms and procedures if the investigator has retired or died. Recommendation 5-7: Studies Completed Before Implementation of EPA’s New Standards EPA should accept scientifically valid studies conducted before its new rules2 are implemented unless there is clear and convincing evidence that the conduct of those studies was fundamentally unethical (e.g., the studies were intended to seriously harm participants or failed to obtain informed consent) or that the conduct was deficient relative to then-prevailing ethical standards. 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 protection 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. Recommendation 5-7 applies both to studies submitted to EPA as part of the regulatory process and to studies that EPA has retrieved from the 2   See footnote 1.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues literature. More specific questions have arisen about a number of third-party studies that were completed and submitted to EPA after the mid-1990s. There is debate about whether EPA should consider and rely on these studies of deliberate exposure to pesticides. According to the committee’s recommendation, EPA may consider and rely on them if they provide scientifically valid and relevant data, unless there is evidence that they violated fundamental ethical standards or the then-prevailing ethical standards. Because these studies were conducted with a view to submission of the data to EPA as part of its regulatory decision making, more evidence should be available about their compliance with certain ethical standards governing research involving humans. Specifically, for such recent studies, it would be expected that the full protocol, consent forms and procedures, and documentation of IRB approval would be available. After all, EPA’s long-time standards already exclude certain unethical conduct of the sort envisioned by this recommendation. One such standard appears in the October 21, 1972, amendments to the Federal Insecticide, Fungicide, and Rodenticide Act (P.L. 92-516). According to this statute, it is unlawful to test pesticides on humans unless they are fully informed about the tests’ nature and purposes as well as any reasonably foreseen health effects and they freely volunteer to participate (EPA, 2000, 30; Latham and Watkins, 2003, 2). In the public comments on the EPA notice of proposed rulemaking, pro-industry advocates argued that it would be unfair and illegal to hold studies to standards that were not legally required at the time the study was conducted. However, ethical guidelines may be morally binding even if they are not legally binding. Some ethical lapses—such as the intention to seriously harm participants—violate universal and timeless ethical principles even if they are technically not legally prohibited. Similarly, carrying out an experiment without the permission of participants or of their surrogates would be considered a grave ethical failure. Even if there were no legally binding requirement for informed consent from participants, the Nuremberg Code of 1949 and the Declaration of Helsinki of 1964 clearly establish that failure to obtain informed consent from participants is unethical, and a requirement for consent was included in the Kefauver-Harris Amendments to the Food, Drug, and Cosmetic Act in 1962. 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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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues cludes the provision of medical care without cost to participants injured in research). After analyzing how these ethical considerations apply to toxicant studies, the chapter examined the arguments about whether EPA may use data from ethically problematic and unethical studies for regulatory purposes. The committee concludes that, as a general rule, EPA should not use data from unethical studies. However, the committee also recommends standards and procedures for exceptional cases in which information from such studies would support a regulatory standard that provides greater protection for public health. REFERENCES Beauchamp, T. L., and J. F. Childress. 2001. The Principles of Biomedical Ethics. New York: Oxford University Press. Dickert, N., E. Emanuel, and C. Grady. 2002. Paying research subjects: an analysis of current policies. Annals of Internal Medicine 136(5):368-373. Environmental Protection Agency (EPA). 2000. Comments on the Use of Data from the Testing of Human Subjects: A Report by the Science Advisory Board and the FIFRA Scientific Advisory Panel. EPA-SAB-EC-00-017. Washington, D.C.: EPA. Available at www.epa.gov/science1/pdf/ec0017.pdf. Food and Drug Administration (FDA). 2003. Good Clinical Practices. Available at www.fda.gov/oc/gcp. Institute of Medicine (IOM). 2003. Responsible Research: A Systems Approach to Protecting Research Participants. Washington, D.C.: National Academy Press. Joffe, S., E. F. Cook, P. D. Cleary, and J. C. Weeks. 2001. Quality of informed consent in cancer clinical trials: a cross-sectional survey. The Lancet 358:1772-1776. Latham and Watkins, LLP. 2003. Re: Protection of Human Participants in Third Party Research STLP-Q-02-02-A. Letter to Anne-Marie Mazza, NAS, on behalf of CropLife America, June 20, 2003. Miller, C. K., D. C. O’Donnell, H. R. Searight, and R. A. Barbarash. 1996. The Deaconess Informed Consent Comprehension Test: an assessment tool for clinical research subjects. Pharmacotherapy 16(5):872-878. National Bioethics Advisory Commission (NBAC). 2001. Ethical and Policy Issues in Research Involving Human Participants: Vol. 1. Bethesda, MD: U.S. Government Printing Office. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (National Commission). 1979. Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Washington, D.C.: U.S. Government Printing Office. Nuremberg Code. 1949. Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10, Vol. 2, 181-182. Washington, D.C.: U.S. Government Printing Office. Steinbrook, R. 2002. Improving protection for research subjects. The New England Journal of Medicine 346(18):1425-1430. World Medical Association (WMA). 2002. Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects (adopted 18th WMA General Assembly. Helsinki, Finland, June 1964; amended: 29th WMA General Assembly, Tokyo, Japan, October 1975; 35th WMA General Assembly, Venice, Italy, October 1983; 41st WMA General Assembly, Hong Kong, September 1989; 48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996; and 52nd WMA General Assembly, Edinburgh, Scotland, October 2000. Note of Clarification on Paragraph 29 added by the WMA General Assembly, Washington 2002). Ferney-Voltaire, France: WMA.