6
Payments Related to Children’s Participation in Clinical Research

Interviewer: What if I offer you money [to participate in a study]?

10Y[ear-old]: Well, I don’t know. It wouldn’t really make a difference to me.

Interviewer: It wouldn’t? What about a lot of money?

10Y (laughs): Probably, a little difference.

Interviewer: So, so what is a lot of money?

10Y: Ah well, the drug study that we did was a hundred and thirty dollars, I think.

Interviewer: Was that a lot of money?

10Y: For me it is!

Interviewer: So did you decide (to participate) based on how much money that was?

10Y: No, not really.

Interviewer: No? Would you have done it if I didn’t offer you any money?

10Y: Sure.

Robert M. Nelson, unpublished interview, 1999

Because enrolling sufficient numbers of children in clinical research is often a significant challenge, investigators and research sponsors have tried various strategies to recruit more children. These strategies include expanding studies to more sites, using new methods such as Internet listings to publicize trials, and offering payments or gifts to children and parents to make participation less burdensome or more attractive. Although they are often appropriate and desirable, payments related to research participation may raise ethical questions. The researcher asking the questions above was probing for how much influence payment might have on a child’s decisions about research participation. Despite the child’s last response, the answers overall provide somewhat conflicting signals about how strongly money might affect the child’s decision making.

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Ethical Conduct of Clinical Research Involving Children 6 Payments Related to Children’s Participation in Clinical Research Interviewer: What if I offer you money [to participate in a study]? 10Y[ear-old]: Well, I don’t know. It wouldn’t really make a difference to me. Interviewer: It wouldn’t? What about a lot of money? 10Y (laughs): Probably, a little difference. Interviewer: So, so what is a lot of money? 10Y: Ah well, the drug study that we did was a hundred and thirty dollars, I think. Interviewer: Was that a lot of money? 10Y: For me it is! Interviewer: So did you decide (to participate) based on how much money that was? 10Y: No, not really. Interviewer: No? Would you have done it if I didn’t offer you any money? 10Y: Sure. Robert M. Nelson, unpublished interview, 1999 Because enrolling sufficient numbers of children in clinical research is often a significant challenge, investigators and research sponsors have tried various strategies to recruit more children. These strategies include expanding studies to more sites, using new methods such as Internet listings to publicize trials, and offering payments or gifts to children and parents to make participation less burdensome or more attractive. Although they are often appropriate and desirable, payments related to research participation may raise ethical questions. The researcher asking the questions above was probing for how much influence payment might have on a child’s decisions about research participation. Despite the child’s last response, the answers overall provide somewhat conflicting signals about how strongly money might affect the child’s decision making. In preparing this report, the Institute of Medicine (IOM) was charged

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Ethical Conduct of Clinical Research Involving Children with considering “whether payment (financial or otherwise) may be made to a child, parent, guardian, or legally authorized representative for the participation of the child in research.” This chapter describes the different kinds of payments offered to parents and children, reviews the ethical concerns about such payments, and describes the regulations or guidance provided by federal agencies and others to investigators, institutional review boards (IRBs), and sponsors of research. It also reviews the very limited literature on the use and effects of payments and other incentives. Although they are not payments for research participation as such, the chapter also considers policies and practices on compensation to participants for research-related injuries and payments to physicians for recruiting children to clinical studies. TYPES OF PAYMENTS RELATED TO RESEARCH PARTICIPATION Wendler and colleagues (2002) have distinguished four types of payment related to participation in research: reimbursements for expenses (e.g., parking or bus fare); compensation for the time and inconvenience involved in research participation (e.g., payment at minimum wage for some or all of the hours required of a research participant); appreciation payments at token levels (e.g., $25, toys, gift certificates, or movie coupons); and incentive payments that offer amounts for participation in research that are not limited to reimbursement, compensation, or token levels. The committee found the above categories helpful in distinguishing differences among types of payments and discussing payment practices that may unduly influence decisions about research participation. Often, however, research protocols lump payments into one sum, which can make it difficult to determine whether a payment (and how much of payment) is intended to reimburse expenses, compensate for time, express appreciation, or provide an additional incentive for research participation. An explicit identification of the purpose of a payment may help investigators and IRBs evaluate that purpose and also consider reasonable variations in payment practices or amounts, including those that arise from differences in research sites. For example, parking expenses for a 2-hour research visit at a city hospital could run more than $20, whereas parking at a suburban hospital might be free. For purposes of this report, “nonfinancial payments” include gifts such as toys, computer games, and books. Gifts are usually—but not always—nominal in value and are typically given as tokens of appreciation. Other

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Ethical Conduct of Clinical Research Involving Children forms of nonfinancial payment might include services that investigators offer to parents or children to make research participation more attractive or less burdensome (e.g., additional health information or medical monitoring or tours of a research laboratory). One rationale for using movie coupons, gift certificates, or other noncash tokens of appreciation in certain studies, for example, studies involving adolescents at risk for illegal drug use, is to prevent them from using the cash for purposes that might be harmful to their health (e.g., to buy drugs). In general, the committee believed that it is appropriate and fair to permit investigators to provide payments to parents and children for expenses related to a child’s participation in research that they would not otherwise incur. Parents and children, especially if they are economically disadvantaged, should not be asked to bear costs that result solely from research participation. As discussed below, payments may be determined in different ways, but no payment should be so large or be timed in such a way as to unduly influence parents’ or children’s decisions about research participation. For example, providing a small payment at the end of the study may encourage completion, but making the entire payment contingent on completing a study could distort a parent’s or a child’s decision about continued participation in a study. Payments should not influence parents’ or children’s decisions to participate in research when such participation is not in a child’s best interest. ETHICAL PRINCIPLES AND REGULATORY POLICIES Ethical Concerns About Payments to Children and Parents As discussed in Chapter 5, ethical standards for participation in research require that the agreement to participate be freely given, that is, be neither coerced nor unduly influenced by psychological, financial, or other pressure. The major concern about financial incentives—as defined above—is that they may distort decisions about research participation, especially for economically disadvantaged individuals or families. Because parents have the authority to permit a child’s participation in research, safeguards against coercion or undue influence on parents are important to ensure that the child’s best interests are protected. This chapter focuses on payments, but undue influence on decisions about research participation can come in other forms, including psychological pressure from personal physicians who are also investigators with a stake in the research. In the words of the Belmont Report, undue influence occurs “through an offer of an excessive, unwarranted, inappropriate or improper reward or other overture in order to obtain compliance” (National Commission,

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Ethical Conduct of Clinical Research Involving Children 1978a, p. 14). Guidance from the U.S. Department of Health and Human Services (DHHS) stated that “[a]n offer one could not refuse is essentially coercive (or ‘undue’)” (OPRR, 1993, online, unpaged). Faden and Beauchamp (1986) argue, however, that if coercion is defined as the use of a threat of punishment or harm to influence choice, then payment is not coercion as such. The committee agrees with this distinction. Unfortunately, no bright line distinguishes proper and reasonable payments to parents and children from payments that are inappropriate. A mix of group or individual circumstances may determine when a particular type or level of payment crosses the line. What is excessive in one situation may not be in another, and reasonable people may sometimes differ in their judgments. Although payments to research participants may have different purposes, for example, fairness, payments may also be intended to influence enrollment decisions. Thus, expense reimbursement for transportation and parking costs may both be fair and also encourage some people to participate in research (especially research with no prospect of benefiting them) when they might otherwise be reluctant to do so. Reimbursement for expenses is not thought to pose the risk of unduly influencing parents’ or children’s decision making. (To minimize paperwork and discretionary judgments about appropriate expense levels, flat payments, e.g., $20 per research visit, may be made to cover reasonable local transportation costs and other minor outlays.) With respect to compensation payments, Wendler and colleagues (2002) note that determining the appropriate compensation for time and inconvenience poses several problems. To cite just one problem, an amount that neutralizes the burden of research participation for one family may exceed it for another and, thereby, act as an inducement. To avoid the unintentional creation of incentives for low-income individuals, some have argued for setting compensation at the level for essential unskilled jobs or at minimum wage (see, e.g., Dickert and Grady, 1999; and Dickert et al., 2002). If, however, parents are not employed or are employed less than full-time (as is more likely in low-income areas), then paying them at minimum wage to bring their child in for a study might be judged to be little different from paying the parent for the child’s participation. If such payments are proposed for studies that focus on low-income populations, IRBs should assess the potential for undue influence. An alternative strategy might be to provide night and weekend hours to accommodate research participation by working families who cannot afford to take time off from work. Is it ethical to pay parents purely for the use of their child in research (i.e., to offer an incentive payment as defined above)? Most sources that the committee consulted either explicitly opposed such payments to parents or omitted such payments from the categories of payments that they endorsed

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Ethical Conduct of Clinical Research Involving Children (see, e.g., Grodin and Glantz, 1994 and the discussion of organizational statements later in this chapter). The committee agrees that such incentive payments are not appropriate in pediatric studies. Some have argued that any token payment to children for participating in research should not be discussed with them until after research is completed for fear of unduly influencing their decisions (AAP, 1995). Wendler and colleagues (2002) disagree, arguing that this practice requires investigators to conceal “pertinent” information as part of the process of seeking permission and assent and, thereby, risk deceiving parents or children who inquire about payment (Wendler et al., 2002, p. 168). On balance, the committee agrees that it is best to mention token or other payments during the permission and assent processes. Federal Regulations and Other Policies on Payment Related to Research Participation Federal regulations on the protection of human participants in research do not explicitly mention payments related to participation. They do state that informed consent must be sought “only under circumstances … that minimize the possibility of coercion or undue influence” (45 CFR 46.116; 21 CFR 50.20). This provision is generally interpreted by federal officials and IRBs to require an assessment of whether any payments related to research participation are substantial enough that they might distort decision making. Participants must also be provided “a statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits” (45 CFR 46.116(a)(8); 21 CFR 50.25(a)(8)). However, federal regulations also require investigators to describe “the consequences of a subject’s decision to withdraw from the research and procedures for orderly termination of participation by the subject” (45 CFR 46.116(b)(4); 21 CFR 50.25(b)(4)). This implies that researchers must explain to parents (and, sometimes, children or adolescents) how withdrawing from the study would affect any payments that they were to have received; for example, a bonus payment for completing the study. Office for Human Research Protections The Office for Human Research Protections (OHRP) supplements federal regulations with guidance on a variety of topics. Its primary guidance on payment to research participants appears to be provided by Protecting Human Research Subjects: Institutional Review Board Guidebook, which

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Ethical Conduct of Clinical Research Involving Children was last revised more than a decade ago (OPRR, 1993). The guidebook outlines the major issues that IRBs should consider in reviewing payment provisions in a research protocol. It also refers readers to a Food and Drug Administration (FDA) information sheet on payment to research subjects (discussed below). In the section on analysis of study risks and benefits, the document emphasizes that payments to research participants should not be considered in assessing whether a protocol’s risks are reasonable in relation to its potential benefits (OPRR, 1993, Ch. 3, online, unpaged). The guidebook does not offer specific guidance about payments related to children’s participation in research. Much of the guidance is relevant to pediatric research, but some does not apply. For example, the additional protections provided to child research participants would likely preclude approval of the kinds of higher-risk studies that might, for healthy adult volunteers, provide larger-than-usual incentive payments for the acceptance of greater research risk. (Some IRBs do not permit such risk-related incentive payments for adults participants in research.) The IRB guidebook stresses that IRBs are responsible for ensuring that consent is not coerced or unduly influenced but is truly voluntary. “Offers that are too attractive may blind prospective subjects to the risks or impair their ability to exercise proper judgment” and “may prompt subjects to lie or conceal information that, if known, would disqualify them from enrolling—or continuing—as participants in a research project” (OPRR, 1993, Ch. 3, online, unpaged). In the discussion of IRB evaluation of incentives for enrollment in studies that involve risk or discomfort, the guidebook notes that there are disagreements among the IRB members about what practices are appropriate. As IRBs assess proposed payments to research participants, the guidebook advises them to consider not only a participant’s health status, employment status, and education level but also his or her financial, emotional, and community resources. This advice also applies to the consideration of payments to parents of prospective child research participants. On its website, OHRP summarizes “common findings” about noncompliance with federal regulations based on the compliance determination letters that it has sent to institutions (http://ohrp.osophs.dhhs.gov/references/findings.pdf). The list of common findings under the heading “informed consent” includes “enrollment procedures that did not minimize the possibility of undue influence or coercion” (OHRP, 2002c, online, unpaged). One letter of determination included, among many issues, a concern that the IRB had not recognized that free care could result in undue influence on subjects or families (McNeilly, 2001).

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Ethical Conduct of Clinical Research Involving Children Food and Drug Administration The FDA’s primary guidance document for investigators provides some specific advice about the timing of payments and the information to be provided by investigators to IRBs and research participants (FDA, 1998d). The advice does not mention payments to parents or children. In general, payment should accrue during the course of a study (e.g., per visit) and should not be contingent upon completion of the study (although a small bonus for completion is acceptable). Protocols should provide IRBs with details about the type, level, and timing of payments to participants at the time of initial review and the details should also be included in the informed consent form. The guidance does not include specific details or examples to illustrate unacceptable practices. The FDA has also issued as guidance the report E11 Clinical Investigation of Medicinal Products in the Pediatric Population, which was developed by the International Conference on Harmonisation (FDA, 2000b; ICH, 2000b). The guidelines recommend that “[r]ecruitment of study participants should occur in a manner free from inappropriate inducements either to the parent(s) or legal guardian or the study participant” (FDA, 2000b, p. 12). The guidelines state that expense reimbursement and subsistence costs may be included in protocol design, but these payments should be reviewed by the ethics review board. The guidelines of the Council for International Organizations of Medical Sciences state that a “guardian asked to give permission on behalf of an incompetent person should be offered no recompense other than a refund of travel and related expenses” (CIOMS, 2002, Guideline 7). USE OF PAYMENTS IN RESEARCH INVOLVING CHILDREN Little systematic information is available about the use of various kinds of payments or other incentives for participation in either adult or pediatric studies. A commentary on the ethics of paying for children’s participation in research cited a review of data from a clinical trials listing service that suggested that a quarter of pediatric trials provided for payments (Wendler et al., 2002). The largest amount mentioned was $1,500 to cover time and travel costs for families participating in a study of a psoriasis drug, but details about how this amount was determined were not provided. Trial listings and recruitment notices often describe payments very generally without making clear whether they are restricted to reimbursement for expenses or compensation for time. This lack of specificity may be intended—and, indeed, required by IRBs or research institutions—to discourage initial expressions of participant interest in research participation based primarily on the promise of payments beyond expenses. Some IRBs

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Ethical Conduct of Clinical Research Involving Children or research institutions prohibit mention of the actual amount of a payment in a recruitment notice, allowing only a general statement about the type of payment that will be provided (e.g., “reimbursement for expenses”). In a study comparing research involving children with cancer and research involving children with diabetes, Broome and colleagues (2001) found that participants in cancer studies were never offered financial incentives (in the words of the investigators). In contrast, participants in diabetes research listed financial incentives as a key reason for participating. For research protocols that offer a potential of direct benefit, particularly in an acute-care situation, the view seems to be that investigators do not need to include any incentives because parents’ desire to have access to the investigational drug or procedure is the driving force in decision making. In addition many of the costs normally associated with research participation (e.g., parking and transportation) would be incurred anyway in connection with clinical care for an acute problem. The policies of one research consortium provide an example of reasonable payment for the time spent by participants in research. The Therapeutic Development Network (TDN) of the Cystic Fibrosis Foundation approves payment for time and expenses. It cautions that such payment “should not be excessive and should not be perceived as an inducement to participate” (TDN, 2003, p. F-2.). For time spent in research, TDN suggests that study participants be reimbursed as follows: Inpatient study: $150 per full day Outpatient study: <2 hours . . . . . . . . . . $ 25.00 2 to <4 hours . . . . . . . $ 50.00 4 to <8 hours . . . . . . . $ 75.00 8 to 12 hours . . . . . . . $100.00 These TDN payment guidelines are monitored regularly and are changed on the basis of cost-of-living increases, IRB feedback, and parent and patient input. The guidelines do not sanction varying payment based on the risk presented by a study. TDN has received favorable comments from several IRBs regarding the helpfulness of its standardized approach that is consistent across studies and sensitive to ethical issues regarding payment. Flexibility in applying the guidelines is provided as a safeguard. The guidelines clearly state that the local IRB has the final decision regarding the actual payments at each site. A recent review of 127 studies (not limited to health research) involving adolescents reported that 55 percent of all studies and 40 percent of health studies provided for payments (Borzekowski et al., 2003). Fifty percent

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Ethical Conduct of Clinical Research Involving Children were paid in cash and 38 percent with vouchers. The mean payment value per research session was $26 (range, $1 to $100), and the average total amount for research involving multiple sessions was $82 (range, $1 to $600). One recent study looked specifically but somewhat indirectly at practices in pediatric research through a survey of IRB chairs who reported that their institutions conducted some pediatric research (Weise et al., 2002). Of the 128 IRB chairs included in the analysis (response rate, 36 percent), two-thirds reported that their institutions had approved at least one protocol that offered payment to the parents of children who were research participants. Ten percent reported that they had not approved any studies that offered payment, and just over 20 percent reported that no protocols involving payment had been submitted. The IRB chairs reported that payments for studies at their institutions ranged between $1 and $1,000 for cash payments and between $10 and $500 for bonds. (The median minimum amount of cash payment was $10, and the median maximum amount of cash payment was $100.) The great majority reported that payment was discussed before the child’s enrollment in the research protocol. IRBs that reviewed a larger percentage of pediatric protocols were more likely than other IRBs to require investigators to make changes in their plans for paying research participants or their parents. The article did not clearly distinguish among reimbursement, compensation, appreciation, and incentive payments and did not provide study details; for example, how payment amounts were determined. In another study, researchers in the Clinical Bioethics unit at the National Institutes of Health surveyed individuals at 32 organizations who were involved in developing, conducting, or reviewing clinical research (Dickert et al., 2002). The organizations included academic research centers, drug companies, contract research organizations, and independent IRBs. Although the study did not focus specifically on pediatric research, the results raise concerns about the adequacy of institutional information and policies on payment. According to the investigators, only one respondent reported that no studies involved payments to research participants, and another respondent had no information. As discussed further below, only 38 percent of the organizations reported having policies on payments related to research participation. Less than one in five of the organizations had any systematic way of tracking studies involving payments, and thus, most could not provide a “confident estimate” of the proportion of studies in which subjects were paid. The results did not distinguish among types of payment. However, in a discussion of institutional guidance about payment practices, the authors report that “most organizations said that subjects were paid for the time (87 percent), inconvenience (84 percent), or travel (68 percent) associated with research participation” and “[t]hirty-two per-

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Ethical Conduct of Clinical Research Involving Children cent reported that subjects were paid for incurring risk” (Dickert et al., 2002, p. 370). IRB POLICIES AND PRACTICES In the study by Weise and colleagues (2002) cited earlier, only 6 of 128 of the IRB chairs whose responses were included in the analysis reported that their IRBs had written policies about payments to research participants. Of the five written policies reviewed by the authors, all permitted payment related to expenses or burdens associated with participation. Two of the written policies reviewed prohibited payments as “inducements” but provided neither further explanations nor examples of the types of payments that would constitute inducements. Of the organizations in the study by Dickert and colleagues (2002) cited earlier, 38 percent of the organizations that were included in the analysis reported that they had written policies on payment to research participants. Of the 17 IRBs included in the study, 9 had written policies on payment. Some organizations (31 percent) approved payments only for the parents; a smaller group (19 percent) approved payments only for the child; 42 percent approved payments for both. Almost half the organizations had some restrictions on how payments could be described (e.g., prohibiting mention of specific payment amounts). None reported that they forbade any mention of payment in recruiting advertisements. One, however, prohibited reference to payment in pediatric studies. Consistent with the survey findings, the institutional payment policies varied among the unrepresentative examples reviewed by the committee. Most policies were consistent with the guidance provided by DHHS (e.g., full payment should not be contingent on completion of a study), but they were sometimes less detailed. Some mentioned the ethical concerns underlying the policies. At the University of California at Los Angeles, for example, the policy notes that children “are in a dependent relationship to adults and easily manipulated in an academic or clinical setting” and that “incentives or rewards for participation may be used but should not be so valuable, within the value system of the child, as to sway their legitimate reluctance to participate” (UCLA, 1997, sec. 6-6). At the Children’s Hospital Boston, the policy on payment explicitly states that “[i]t is sometimes desirable to provide subjects and their parents compensation for their participation in research projects” (e.g., taxi fare, babysitting fees, lunch, cash remuneration in lieu of expense payments, parenting books, and infant formula but not lotteries or prize drawings). Children themselves should be given a small toy or gift certificate when possible. The policy emphasizes that “[i]n all instances, compensation should not be so large as to act as an inducement for subjects to participate

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Ethical Conduct of Clinical Research Involving Children regardless of how minimal the risk may be” (Children’s Hospital Boston, 2003, unpaged). STATEMENTS OF PROFESSIONAL ORGANIZATIONS In its 1995 statement on the ethical conduct of drug studies with pediatric populations, the Committee on Drugs of the American Academy of Pediatrics (AAP) stated that remuneration, compensation, and indemnification are ethical payment practices based on current societal standards. It also observed that “serious ethical questions arise when payment is offered to adults acting on behalf of minors in return for allowing minors to participate as research subjects” (AAP, 1995, p. 293). As noted and questioned earlier in this chapter, the statement recommended that investigators refrain from discussing gifts or appreciation payments with children until after the research is completed. In its 2003 statement to the Institute of Medicine (IOM) committee, AAP emphasized that “parents should not profit from placing their child in research,” even when the research does not present “significant risk” (AAP, 2003, p. 12). In contrast, for research that involves no burden to the child beyond inconvenience (i.e., no discomfort, unpleasantness, or tangible risk), “remuneration may be a major incentive for participation and completion of the study and it is appropriate in this context to compensate children for their efforts in a manner comparable to compensating adult research subjects,” as long as the payment is not used to coerce (unduly influence) children or their parents into agreeing to participation (p. 12). Research projects may also waive treatment costs if the IRB and investigators judge that such payment-in-kind will not “be coercive of participation.” Other organizations presented statements to the IOM committee in which they indicated that it is appropriate to reimburse expenses or compensate for time or inconvenience. These organizations include the Association of Medical School Pediatric Department Chairs, the Cystic Fibrosis Foundation, the Society for Pediatric Research (which mentioned only “expenses”), the Allergy & Asthma Network/Mothers of Asthmatics, Public Citizen’s Health Research Group, and the Genetic Alliance. None of these groups explicitly endorsed incentive payments to parents or children. OTHER CONCERNS ABOUT PAYMENT RELATED TO CHILDREN’S RESEARCH PARTICIPATION Compensation for Research-Related Injuries If an adult or child suffers a research-related injury that is not the result of malfeasance or negligence, that person has no legal avenue to recover

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Ethical Conduct of Clinical Research Involving Children treatment costs or lost earnings. However, provisions to compensate research participants for research-related injuries may be a factor for parents who are deciding whether to enroll their child in research. For research involving more than minimal risk, federal regulations require that informed-consent forms include information about whether compensation or medical treatment may be available in the event of a researchrelated injury, how to get further information, and whom to contact in the event of such an injury (45 CFR 46.116 (a)(6 and 7);21 CFR 50.25(a)(6 and 7)). No federal regulations require compensation for research-related injuries. The Council for International Organizations of Medical Sciences has endorsed the provision of compensation for physical injuries related to research. Specifically, their guidelines state that “[i]nvestigators should ensure that research subjects who suffer injury as a result of their participation are entitled to free medical treatment for such injury and to such financial or other assistance as would compensate them equitably for any resultant impairment, disability or handicap. In the case of death as a result of their participation, their dependants are entitled to compensation” (CIOMS, 2002, Guideline 19, online, unpaged). In addition, investigators are not to ask research participants to waive these rights. Several foreign countries have policies providing for some compensation for research-related injuries (IOM, 2003a). The IOM report Responsible Research identified some government agencies (e.g., the Veterans Administration and the National Institutes of Health (NIH) Clinical Center) that provide or cover short-term medical expenses for research-related injuries (IOM, 2003a). It located only one private organization, the University of Washington that paid long-term medical costs related to such injuries. The report recommended that organizations conducting research cover at least medical and rehabilitation costs for research participants who are injured as a direct result of participating in research, without regard to fault. It also recommended that DHHS collect data on the incidence of research-related injuries and analyze their costs. In addition, organizations that accredit IRBs include such compensation as a requirement of accreditation. Payments to Physicians for Recruiting Child Research Participants Although the committee was not asked to examine the issue of payment to clinicians for enrolling child patients in research, this is an increasingly important issue in pediatric research. In the research context, a finder’s fee is a payment (or sometimes a nonfinancial reward) that is made to a clinician in exchange for referring or recruiting a research participant and that is

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Ethical Conduct of Clinical Research Involving Children not directly linked to the reasonable costs of identifying potential research subjects (e.g., searching medical records). The finder’s fee may be contingent on the actual participation of the referred individual in the research, and the provision of such a fee may or may not be disclosed to the referred patient. The ethical concern is that physicians who accept finder’s fees have a conflict of interest that may lead them to make recommendations that are not in their patients’ best interests and may undermine the trust between patient and physician, whether or not the payment is disclosed to the patient (see, e.g., Flegel, 1997 and Goldner, 2000). The American Medical Association has explicitly condemned the practice of paying finders’ fees and similar incentives to physicians who recruit their patients for clinical trials (AMA, 1994, 1999). A 2000 report from the Office of the Inspector General of DHHS questioned the practice and noted that many IRBs do not review these kinds of recruitment practices (OIG, 2000b). It recommended that federal agencies clarify that IRBs have the authority to review such practices. It also recommended that FDA and OHRP cooperate to provide guidance to IRBs about these and other recruiting practices. Current IRB policies are not catalogued anywhere, but an informal review of institutional web sites indicates that policies vary. Some IRBs or research institutions ban the offering or accepting of finder’s fees, whereas, others discourage but do not forbid them. Finder’s fees are illegal in some states. The recruitment by physician-investigators of their own patients as research participants also raises concerns. It is an attractive and convenient research strategy, especially given the challenges of recruiting sufficient numbers of children for pediatric studies. Nonetheless, it raises ethical questions. As described by the National Bioethics Advisory Commission, this is one of the situations that IRBs should “recognize and avoid,” as it creates susceptibility to harm or coercion (NBAC, 2001b, p. iv). The committee agrees. In addition, the practice may blur the distinction for a patient between research and treatment and contribute to the therapeutic misconception as discussed in Chapter 5. IMPROVING PRACTICES AND POLICIES ON PAYMENT RELATED TO CHILDREN’S PARTICIPATION IN RESEARCH Payments to parents and children can be ethical elements of research involving children if these payments are established, reviewed, and implemented in a thoughtful and consistent manner and adhere to the principles of ethical research. Investigators, sponsors, and IRBs should be vigilant in scrutinizing financial payments for the possibility of undue influence on parents’ or children’s decision making. They should also be alert to nonfi-

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Ethical Conduct of Clinical Research Involving Children nancial practices that may distort decision making, for example, inappropriate advertising or solicitations for research participation by primary care physicians that take advantage of the trust that families place in them. At the same time, IRBs should be receptive to investigators’ creative but ethically responsible efforts to reduce financial barriers that may discourage parents, especially economically disadvantaged parents, from agreeing to their child’s participation in research. These efforts should be considered in the broader context of strategies to respect and accommodate the legitimate needs of families, especially families already stressed by a child’s serious illness. Because little information exists on how parents and children perceive and respond to different payment practices, investigators and IRBs lack useful information to guide them in making decisions about what practices threaten parent or child judgment. Given current efforts to increase the number of children involved in research, federal policymakers should solicit ideas for studies that could illuminate the ethical and practical implications of different kinds of payments related to children’s participation in research. A variety of methods may be appropriate for such studies, including focus groups; surveys; and interviews of investigators, parents, and older children or adolescents. Evaluations of the use of study or consent monitors might also provide insights into investigator behaviors (e.g., whether and how payment is discussed) and parent and child responses. Written Institutional Policies on Payment Even in the absence of data about the impact of payment practices on parent and child judgments, IRBs and research institutions should develop written policies on payments related to research participation. By developing such policies, IRBs can consider how different practices may serve or compromise ethical principles for the conduct of human research outside of the context of an individual protocol. Such a deliberation will not eliminate uncertainty or subjectivity in decision making about payment practices, but it should help achieve a fairer and more consistent approach to decision making about individual protocols. Although written policies can not cover every contingency presented by actual research protocols, they should be detailed enough to provide investigators with useful guidance as to what is and what is not acceptable for pediatric studies. In addition, examples of wording about payments that the IRB has approved for consent and permission forms can be helpful to investigators. In addition to requiring that protocols include descriptive details about proposed payments (e.g., use of a bonus for completion of a study), IRBs should require that researchers present, as part of a protocol, the rationale

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Ethical Conduct of Clinical Research Involving Children for why any payments that they propose to make to parents or children are appropriate. Researchers should also explain how payment amounts are determined (e.g., taking the age of the child participants into account in selecting gifts of appreciation). Recommendation 6.1: Institutional review boards, research institutions, and sponsors of research that includes children and adolescents should adopt explicit written policies on acceptable and unacceptable types and amounts of payments related to research participation. These policies should specify that investigators disclose the amount, the recipient, the timing, and the purpose (e.g., an expense reimbursement or a token of appreciation to a child) of any payments as part of the process of seeking parents’ permission and, as appropriate, children’s assent to research participation; avoid emphasis on payments or descriptions of payments as benefits of participating in research during the permission or assent process; and obtain institutional review board approval for the disclosure of information about payments in advertisements and in permission and assent forms and procedures. In general, any type of payment related to a child’s participation in research should be discussed during the process of seeking parental permission. Information about payment should also be included in the consent and permission form. When appropriate, payments to children or adolescents should likewise be discussed during the process of seeking their agreement to research participation. That discussion should be appropriate to the child’s maturity, psychological condition, and other characteristics. Although descriptions of payment arrangements in permission and assent forms should be scrutinized by IRBs, failure to provide information on approved arrangements could discourage low-income parents from permitting their child’s participation in research and could also deter adolescents from agreeing to participate in research. In addition, parents may expect certain kinds of payments on the basis of their knowledge or perceptions of other studies and may feel misled if they discover at the end of the study that they are being paid differently. Categories of Acceptable Payments Certain types of payments to parents or adolescents are usually if not always acceptable, for example, reimbursement for reasonable expenses that are necessary for research participation. The specifics may vary, but examples of reasonable expenses are costs of transportation to the research

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Ethical Conduct of Clinical Research Involving Children site, parking, lodging, meals, and babysitting. Other payments are never appropriate in pediatric research, for example, paying parents for the use of their child in research. Compensation to parents for lost wages or time may be appropriate under carefully scrutinized circumstances. One objective of IRB and institutional policies on payments related to children’s participation in research should be to encourage equal access to study participation regardless of a family’s economic status. At the same time, policies should prevent practices that risk exerting an undue influence over the parents’ decisions. If a low-income parent cannot afford to lose time from work to take a child to a research site, then some form of compensation (e.g., at the minimum wage) may be reasonable and fair. For some parents, the barrier may not be lost wages for hours missed but fear of losing their job if they take time off. To respond to the diverse barriers to children’s research participation, nonfinancial strategies to equalize participation opportunities should also be considered, for example, adjusting the times or places for research visits. In certain instances, for example, when IRBs allow flexibility in devising arrangements with individual families, it may be appropriate for them to specify that a family or child advocate independently assess the appropriateness of the arrangements and the decision of a family to enroll a child. Recommendation 6.2: In addition to offering small gifts or payments to parents and children as gestures of appreciation, investigators may also—if they minimize the potential for undue influence—act ethically to reduce certain barriers to research participation when they reimburse reasonable expenses directly related to a child’s participation in research; provide reasonable, age-appropriate compensation for children based on the time involved in research that does not offer the prospect of direct benefit; and offer evening or weekend hours, on-site child care, and other reasonable accommodations for parental work and family commitments. Although controversial, it may be appropriate under certain circumstances to pay adult volunteers larger amounts for agreeing to participate in higher-risk research that will not directly benefit them. Likewise, it may be appropriate to pay adults more for engaging in higher-risk work, subject to socially sanctioned health and safety regulations. What is acceptable for competent adults is, however, often not acceptable for children. Child labor laws present a case in point. In general, the issue of risk-related payment should not arise in research involving children because federal regulations

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Ethical Conduct of Clinical Research Involving Children (if they are interpreted as recommended in Chapter 4) substantially limit the amount of risk to which children can be exposed in research without the prospect of direct benefit. The potential for harm must be minimal or only slightly more than minimal. Given this appropriate conservatism, the committee believed that it would be inappropriate—even within these narrow boundaries—to allow financial encouragement for children’s participation in research based on the level of risk involved. The recommendation above allows, however, for reasonable, age-appropriate compensation for those whose research participation is associated with more time or inconvenience (e.g., for adolescents who must take time away from a job). Payment for Research-Related Injuries Consistent with the recommendations of an earlier IOM committee and other groups, this committee also recommends compensation for child participants who are injured in the course of research. Depending on their medical condition, children who are permanently injured as a result of research participation may live with the consequences of an injury for a far longer period than an adult so injured. The committee also agrees that DHHS should collect data on the incidence of research-related injuries and should analyze their costs. Recommendation 6.3: Research organizations and sponsors should pay the medical and rehabilitation costs for children injured as a direct result of research participation, without regard to fault. Consent and permission documents should disclose to parents (and adolescents, if appropriate) the child’s right to compensation and the mechanisms for seeking such compensation. Payments to Investigators or Others As described in Chapter 2, FDA and NIH have adopted policies to encourage investigators and research sponsors to include children in research. Chapter 2 also described the challenges that pediatric investigators face, including recruiting sufficient numbers of children for many kinds of studies. Given the combination of government policies and existing recruitment problems in some areas of research, policymakers, research institutions, and IRBs should be attentive to the recruitment practices proposed in pediatric protocols and should strongly discourage or forbid bonuses or similar financial incentives to physicians for enrolling their pediatric patients in research. Recommendation 6.4: Investigators and their staffs may appropriately be reimbursed for the costs associated with conducting research. Pay-

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Ethical Conduct of Clinical Research Involving Children ments in the form of finder’s fees or bonuses for enrolling a specific number of children or adolescents are unethical and should not be permitted. CONCLUSION Payments related to research participation have a role to play in reducing barriers and equalizing access to research participation. The primary concern is that certain types or levels of payment may unduly influence a parent’s or child’s judgment about research participation and encourage decisions that are not in the child’s best interest. Payments to physicians for enrolling children in research also raise questions about undue influence and conflict of interest. Such payments should be limited to reimbursement for costs related to the conduct of research. Although the specifics of an individual protocol may affect judgments about what payment practices are appropriate, IRBs should develop written policies to provide basic guidance for investigators and IRB members in developing or reviewing protocols and reduce inconsistent, ad hoc judgments. The process of developing written policies should encourage more systematic reflection on the fit between different payment practices and the ethical standards for clinical research involving children.