- Email: [email protected]
Appropriate compensation of pediatric research participants: Thoughts from an Institute of Medicine committee report
APPROPRIATE COMPENSATION OF PEDIATRIC RESEARCH PARTICIPANTS: THOUGHTS FROM AN INSTITUTE OF MEDICINE COMMITTEE REPORT BONNIE W. RAMSEY, MD
ver the past century, the health of children in the United States has dramatically benefited from advances in biomedical research, including vaccines that have nearly eradicated polio1 and chemotherapy to treat pediatric cancer.2 All of these medical advances resulted from clinical research involving children as participants. The critical role of well-designed research involving children continues today as we translate the scientific knowledge gained from genomics, proteomics, and other frontiers of molecular biology into new life-saving therapies for a variety of pediatric disorders. Yet in recent years, the majority of studies testing safety and efficacy of new medications have included only adults. Even in the past decade, only 20% of new drugs have been approved for pediatric labeling.3 As a result, clinicians caring for children are frequently forced to empirically treat children with therapies untested in this population. Legislation in the late 1990s, including the US Food and Drug Administration (FDA) Modernization Act of 19974 and the subsequent FDA “Pediatric Rule” in 1998,5 has provided both incentives and requirements to pharmaceutical companies to test the safety and efficacy of drugs in children. Congress subsequently passed the Best Pharmaceuticals for Children Act of 2002,6 extending the Pediatric Exclusivity Act of 1997 to 2007 and thereby providing 6 months additional market exclusivity to companies that test the safety and efficacy of their drugs in children. In addition, this Act established a federal funding program to study drugs off-patent for pediatric usage. Although it is very encouraging that these measures should provide children more rapid access to new therapies, we, as a society, must always balance this acquisition of new knowledge against the protection of these vulnerable research participants who lack the legal right and, frequently, intellectual capacity to decide whether they wish to accept risk for uncertain benefit. Because of concerns about the adequacy of the system for protecting child participants in research, the Best Pharmaceuticals for Children Act of 20026 requested that the Institute of Medicine (IOM) prepare a report reviewing federal regulations and recommending optimal practices for the ethical conduct of research involving children. The IOM established a 14-member committee, chaired by Dr Richard Behrman, in January 2003 to focus on seven charges outlined in the Act, including: (1) the appropriateness of the regulations for children of various ages; (2) the interpretation of regulatory criteria for approaching research; (3) the processes for securing parents’ and children’s agreement to a child’s participation in research; (4) the expectation and comprehension of children and parents about participating in research; (5) the appropriateness of payments related to the child’s participation in research; (6) compliance with and enforcement of federal regulations; and (7) the unique roles and responsibilities of Institutional Review Boards (IRBs).6,7 The committee reviewed federal regulations, as well as existing data in the literature and federal reports. Public forums were held to receive input from patients, families, advocacy groups, and professional societies. The committee formed a consensus and developed both overarching themes and recommendations that were published in a book entitled, Ethical Conduct of Clinical Research Involving Children.7 I had the opportunity to participate as a member of this committee and to share in the provocative and enlightening discussions as we all weighed the critical balance between furthering knowledge and protection against harm. It is beyond the scope of this article to review all aspects of the IOM report. I will focus on one of the important charges we addressed: whether payment (financial or otherwise) may be made to a child, parent, guardian, or legally authorized representative for participation of the child in research.6
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PAYMENTS TO CHILDREN FOR RESEARCH PARTICIPATION As the committee reviewed the limited existing data from the literature regarding payment of pediatric research participants, we weighed the difficult balance between the use of monetary or other forms of compensation to incentivize research participation versus protection of children and families against undue influence of the perceived reward. To make our recommendations, we carefully reviewed federal regulations and subsequent guidance documents from federal agencies, including the Office of Human
CF CFR FDA
Cystic fibrosis Code of Federal Regulations US Food and Drug Administration
IOM IRB
Institute of Medicine Institutional Review Board
From the University of Washington School of Medicine, Seattle, Washington. Reprint requests: Dr Bonnie W. Ramsey, Children’s Hospital and Regional Medical Center, 1100 Olive Way, Suite 500, Mailstop: MPW 5-4, Seattle, Washington 98101. E-mail: [email protected]. J Pediatr 2006;149:S15-S9 0022-3476/$ - see front matter Copyright © 2006 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2006.04.045
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Research Protection and the FDA. We also looked to professional societies or international councils that have previously considered the ethics of payment of children for research. We considered the types of payments to children, parents, and guardians that were or were not appropriate, and who should make these decisions, and we discussed the circumstances that bring the child and family to seek medical care and how that may impact compensation. The reader is encouraged to read Chapter 6 of the committee report,7 which summarizes the committee’s recommendations. The federal regulations provided in 45 Code of Federal Regulations (CFR) 468 and 21 CFR 509 are not prescriptive with regard to the type or amount of monetary or other compensation to research subjects of any age. Rather, they provide principles upon which institutional boards and investigators should make their judgment. It is stated in 45 CFR 46.116 and 21 CFR 50.20 that informed consent must be sought “under circumstances that minimize the possibility of coercion or undue influence” and that participants must 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” (45 CFR 46.116 (a) and 21 CFR 50.25 (a)). The key ethical concept of these regulations is minimizing undue influence, which is essential to the concept of a voluntary consent process. Undue influence could result from the size of the inducement, the method of payment (eg, requiring subjects to complete a study before payments), or the penalty of withdrawal from research (eg, loss of free medical care). All these ramifications of payment must be considered. More recently, two guidance documents have more directly addressed payments for patient recruitment, including pediatric research. In 2000, the FDA issued a guidance developed by the International Conference on Harmonisation entitled, Guidance on E11 Clinical Investigation of Medicinal Products in Pediatric Population.10 Excerpts from this report state that “the pediatric population represents a vulnerable subgroup. Therefore, special measures are needed to protect the rights of pediatric study participants and to shield them from undue risk.” The report goes on to state that recruitment (Section 2.6.2) of study participants “should occur in a manner free from inappropriate inducements either to the parent(s) or legal guardian or study participant. Reimbursement and subsistence costs may be covered in the context of a pediatric clinical study. Any compensation should be reviewed by the IRB/IEC.” The Council for International Organizations of Medical Sciences was even more detailed and prescriptive in its Ethical Guidelines for Biomedical Research Involving Human Subjects, Guideline 7.11 It states that “subjects may be reimbursed for lost earnings, travel costs and other expenses incurred in taking part in a study; they may also receive free medical services. Subjects, particularly those who receive no direct benefit from research, may also be paid or otherwise compensated for inconvenience and time spent. The payments should not be so large, however, or the medical services so extensive as to induce prospective subjects to S16
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consent to participate in the research against their better judgment (undue inducement). All payments, reimbursements and medical services provided to research subjects must have been approved by an ethical review committee.” With regard to vulnerable subjects, the guidelines 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.” Federal regulations and guidance place the review process for patient recruitment, including monetary or other inducements, as a responsibility of IRBs (45 CFR 46.116 and 21 CFR 50.20). FDA guidance recommends that IRBs “review the amount of payment and the proposed method and timing of disbursement to assure that neither are coercive or present undue influence.”12 Based upon limited published data13 from a survey of IRBs reviewing pediatric protocols, it appears that only a minority of boards have any written policy or formula for determining a monetary value for appropriate payment. Of the 128 institutions responding (36%), 84 (66%) had approved payment to children for participation, of which 42% approved payment to both parent/guardian and child, 31% to parent only, and 19% to child only. A second study surveying nonpediatric IRBs14 also found that only a minority has written guidelines. Not surprisingly, the IRB policies tend to follow federal guidance and require disclosure of payment to parent/guardian and child during the informed consent process before enrollment. This approach contrasts with the 1995 guidelines published by the American Academy of Pediatrics Committee on Drugs.15 This guideline accepted the use of payment to children for research participation, but it recommended that “it [remuneration] is not discussed before the study’s completion” and should not go beyond a token gesture to minimize undue influence. The IOM committee also sought data on the frequency and types of payment that are currently being provided to pediatric research participants. There is, unfortunately, very limited data available on payment of pediatric participants. A review of one public listing of clinical trials, Centerwatch,16 in 2000, suggested that approximately 25% of pediatric trials offered payment.17 This lack of published data is not surprising because there has been no systemic collection of data on the number and type of clinical trials in the United States or number and demographic information on research participants. Thus, it is impossible to ascertain the true scope of payment practices. Recommendations from two IOM committees, Responsible Research: A Systems Approach to Protecting Research Participants18 and Ethical Conduct of Clinical Research Involving Children,7 stressed the importance of obtaining such data on clinical research. The recent statement by the International Committee of Medical Journal Editors19 has recommended registration of all clinical trials that may impact clinical practice. Although payment practices are currently not part of the information collected in this registration process, at a minimum these recent changes will allow investigators and consumers to better understand the research process and its ethical conduct. The Journal of Pediatrics • July 2006
Table I. Types of payment for research participation 1. Reimbursement payments compensate parents and children for their direct research-related expenses and should be based on the actual costs (eg, transportation, meals, lodging) that families incur. 2. Compensation payments compensate parents and children for the time and inconvenience of research participation. Levels of compensation payments should be a function of the demands (clinic visits, hospital stays, research procedures) that research places on families. 3. Appreciation payments are bonuses given after children’s participation to thank them for their efforts. 4. Incentive payments encourage children’s research enrollment. Payments may be designed to act as incentives, for instance, when an investigator intentionally reimburses families above their actual costs to encourage enrollment. Payments may also inadvertently act as incentives if they unintentionally exceed families’ costs and, thereby, act as incentives without being intended as such.
Table II. CF Therapeutics Development Network reimbursement policy Type of expense Outpatient study (not requiring an overnight stay in the hospital)
Inpatient study (requiring at least one overnight stay in the hospital) Partial days should be compensated based on the outpatient schedule above. Mileage Other expenses
Source: Wendler et al.17
A survey of adolescents involved in research20 found that 40% of health-related studies provided payments, of which 50% was cash and 38% were vouchers. Broome et al21 compared payment practice by type of illness and found that studies involving children with cancer did not offer financial incentives, whereas patients with diabetes mellitus, in general, expected payment. It is also difficult to determine the purpose of the payment (ie, travel reimbursement vs inducement) as most payments are lumped together. Having reviewed federal regulations, guidance documents, and limited existing data, the committee focused on several key issues, including the need to better define types and appropriateness of payments in research involving children, the characteristics of the participant/family dyad that influence the decision process, and the need for institutions responsible for research oversight to establish consistent written policies. When considering the types of payments for research participation, Wendler et al17 defined four categories (reimbursement, compensation, appreciation, and incentive), shown in Table I, that are helpful in considering the concepts of “undue influence” and “coercion.” The committee agreed with reimbursement of expenses as justified in almost all research studies. One specialty that has not traditionally covered expenses is pediatric oncology,21 where it is commonly assumed that access to a life-saving therapy is the primary incentive and that patients are coming to the medical facility for clinical rather than research purposes. Whether these policies change as cancer becomes a more chronic illness remains to be seen. In cystic fibrosis (CF), another chronic life-threatening illness, a research consortium, the CF Therapeutics Development Network has established a policy approved by a committee composed of investigators, parents, and patients to standardize payments
Amount ⬍2 hours $30.00 2–4 hours $60.00 4–8 hours $85.00 8–12 hours $115.00 $170.00/day
Current federal mileage rate Additional reimbursement for parking fees and meals should be made at the rates applicable for the participating study site.
across all 18 participating sites based upon time and expenses (Table II). These guidelines are reviewed annually and updated based upon cost of living. The policy states, however, that the local IRB must review and approve any final payment schedule. Surveys of IRBs at the network sites have found them to be receptive to the policies and have, for the most part, accepted the recommendations. Appreciation payments, which may be cash or noncash gifts, were considered acceptable as long as they were ageappropriate and of nominal monetary value, thus not providing undue influence. Undue influence was defined in the Belmont Report22 as “an offer of an excessive, unwarranted, inappropriate or improper reward or other overture in order to obtain compliance.” In my personal experience, adolescents pose the greatest challenge because money is an important measure of importance and independence and can cloud judgment. Our CF center has multiple protocols open at any one time. It is not uncommon for an adolescent to arrive in clinic and say, “Tell me all the studies going on and exactly how much each pays!” even though it is our policy not to discuss payment in the consent process. Our committee agreed that nonmonetary gifts (ie, tickets to a football game) may be more appropriate. Incentive payments to improve recruitment and retention were considered unacceptable as these payments are likely to impact the decision-making process. Of particular concern are large payments based upon study completion rather than visit-based payments. Payment for increased risk should never be considered acceptable as this approach may place payment in the “benefit” category of the risk:benefit ratio assessment, which is not appropriate. In establishing the CF Therapeutics Development Network payment policy (Table II), the Principal Investigators had a discussion regarding increased payment for a visit including a bronchoscopy procedure requiring
Appropriate Compensation Of Pediatric Research Participants: Thoughts From An Institute Of Medicine Committee Report
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anesthesia versus a blood draw. It was universally agreed that this approach would give the wrong message to patients and families and was not approved. Thus, all payments are based upon time and expenses. Compensation for time and inconvenience of patients and families was a more challenging concept for the committee to review and reach agreement. The basic principle of compensation is well-defined by Wendler17 as the amount required to “zero out” the families’ burden from research participation without providing an “incentive.” These burdens may include travel expenses and time, lost work time, emotional stress, etc. Clearly, each family is unique, and here is where the status of the child/parent dyad becomes important. Parents with highly paid professions likely need no compensation, whereas a self-employed, manual laborer might lose both wages and a job, posing a significant burden. Because it is not possible to individualize payments based upon parental wage, it has been recommended that if research subjects and/or parental time is compensated, it should be at the minimum wage of unskilled, essential jobs.23 Whether this payment should be directed to the parent, child, or both depends upon IRB interpretation.13 The discussions within the committee focused upon two opposing concerns. On one side we wanted to ensure equal access for research participation regardless of the family’s cultural or socioeconomic background, and parental compensation may decrease the barrier to participate. On the other side, several members raised concerns about the fine line between compensation and undue influence, particularly in a family of limited means. Ultimately, it is the responsibility of the IRB to weigh these conflicting forces. In the past month, I had a personal experience that helped place this issue into context. I approached an adolescent patient with CF and her parents about participation in a clinical trial for a new therapeutic agent. The family had faced a recent job loss by the father and change in employment by the mother. They lived a significant distance from the medical center. I began discussions regarding the study rationale, risks versus benefits, and study procedures but had not addressed the issue of compensation for participation. Compensation was clearly defined in the consent form, which the parents had not yet read. The adolescent expressed significant interest, but the parents were reluctant and claimed “lack of time” and a “long trip over the mountains.” Going against my usual policy to not emphasize compensation, I noted that we would cover the costs of gas for the trip and compensate them for their time. The parents’ faces lit up and both stated that they had always wanted to have both of their children with CF participate in research trials but were too proud and embarrassed to admit that they could not afford the money for gas. This conversation made me realize that I had unintentionally created a barrier to their participation and had made them feel “unworthy.” There are other cultural barriers to research participation beyond travel expenses and time from work among underserved populations. Compensation for these expenses, however, may reduce one important barrier. Investigators S18
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should also consider night and weekend hours or other mechanisms to minimize personal loss of work. An issue not addressed by Wendler was compensation for research-related injury that is not a result of negligence. Federal regulations require that participants and families be informed whether compensation (termed indemnification) is provided and whom to contact in the event of injury (45 CFR 46.116 (a) and 21 CFR 50.25). Pharmaceutical sponsors do provide compensation for research-related injuries involving their investigational drug or device, for studies they initiate. By contrast, the majority of investigator-initiated studies (frequently based at academic centers) do not provide compensation. An exception noted by the IOM in its Responsible Research: A Systems Approach to Protecting Research Participants18 report was the University of Washington and its affiliated medical centers. There have been several recent reports18,7 that all strongly endorsed the provision that research organizations and sponsors supporting clinical studies must pay for medical costs of children injured as a direct result of research participation. Successful recruitment of patients for participatation in pediatric trials may be challenging. With many orphan diseases,24 accrual of adequate patients requires enrollment from multiple sites, and families frequently travel long distances to reach medical facilities. Therefore, payment is a necessary compensation for time and expenses. To minimize the potential for undue influence, individual investigators, institutions, IRBs, and research consortia should establish written policies defining appropriate and inappropriate payments, including amount, timing, and purposes of reimbursement. These policies should be transparent to participants, families, and the community. Payments should not be portrayed as a benefit of research participation or considered in the assessment of the risk:benefit ratio. Regular review of policies should encourage investigators and IRBs to reflect on the ethical principles upon which the policies are based (ie, the protection of our children).
REFERENCES 1. Roberts L. Polio: health workers scramble to contain African epidemic. Science 2004;305:24-5. 2. Simone JV. Childhood leukemia: successes and challenges for survivors. N Engl J Med 2005;141:166-71. 3. Steinbrook R. Testing medications in children. N Engl J Med 2002;347:1462-70. 4. US Food and Drug Administration. Modernization Act of 1997 (FDAMA-1997), section 505A. Available online at: http://www.fda.gov/oc/ fdama/default.htm. 5. US Food and Drug Administration. Regulations requiring manufacturers to assess the safety and effectiveness of new drugs and biological products in pediatric patients. Final rule. (21 CFR Parts 201, 312, 314, and 601). December 2, 1998. Available online at: http://www.fda.gov/ohrms/ dockets/98fr/120298c.pdf. 6. Best Pharmaceuticals for Children Act, Pub. L. 107-109, 107th Cong. (January 4, 2002). 7. Institute of Medicine. Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press; 2004.
The Journal of Pediatrics • July 2006
8. Department of Health and Human Services. Protection of human subjects(45 CFR 46). October 1, 2001. Available online at: http://www.access.gpo.gov/nara/cfr/waisidx_01/45cfr46_01.html. 9. US Food and Drug Administration. Protection of human subjects. (21 CFR 50). April 1, 2002. Available online at: http://www.access.gpo.gov/ nara/cfr/waisidx_02/21cfr50_02.html. 10. Food and Drug Administration, HHS. International Conference on Harmonisation: guidance on E11 clinical investigation of medicinal products in pediatric populations. Fed Regist 2000 Dec 15;65(242):78493-4. 11. Council for International Organizations of Medical Sciences. International Ethical Guidelines for Biomedical Research Involving Human Subjects. November 2002. Available online at: http://www.cioms.ch/ frame_guidelines_nov_2002.htm. 12. US Food and Drug Administration. Guidance for institutional review boards and clinical investigators. 1998 Update: cooperative research. Rockville, MD: US Food and Drug Administration; 1998. Available online at: http://www.fda.gov/ohrt/irbs/research.html. 13. Weise KL, Smith ML, Maschke KJ, Copeland HL. National practices regarding payment to research subjects for participating in pediatric research. Pediatrics. 2002;110:577-82. 14. Dickert N, Emanuel E, Grady C. Paying research subjects: an analysis of current policies. Ann Intern Med 2002;136:368-73. 15. American Academy of Pediatrics. Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics 1995;95:286-94.
16. CenterWatch clinical trials listing services. Boston: CenterWatch; 2000. Available online at: http://www.centerwatch.com. 17. Wendler D, Rackoff JE, Emanuel EJ, Grady C. The ethics of paying for children’s participation in research. J Pediatr 2002;141:166-71. 18. Institute of Medicine. Responsible Research: A Systems Approach to Protecting Research Participants. Washington, DC: The National Academies Press; 2003. 19. De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al; International Committee of Medical Journal Editors. Clinical trial registration: a statement from the International Committee of Medical Journal Editors. N Engl J Med 2004;351(12):1250-1. 20. Borzekowski DL, Rickert VI, Ipp L, Fortenberry JD. At what price? The current state of subject payment in adolescent. J Adolesc Health 2003;33:378-84. 21. Broome ME, Richards DJ, Hall JM. Children in research: the experience of ill children and adolescents. J Fam Nurs 2001;7:32-49. 22. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Washington, DC: US Government Printing Office; 1979. 23. Dickert N, Grady C. Paying research subjects: an analysis of current policies. N Engl J Med 1999;341:198-203. 24. US Food and Drug Administration. Orphan drug regulations. (Part 316 Subpart C Section 316.3). Available online at: http://www.fda.gov/ Orphan/21cfr316.html.
Appropriate Compensation Of Pediatric Research Participants: Thoughts From An Institute Of Medicine Committee Report
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ver the past century, the health of children in the United States has dramatically benefited from advances in biomedical research, including vaccines that have nearly eradicated polio1 and chemotherapy to treat pediatric cancer.2 All of these medical advances resulted from clinical research involving children as participants. The critical role of well-designed research involving children continues today as we translate the scientific knowledge gained from genomics, proteomics, and other frontiers of molecular biology into new life-saving therapies for a variety of pediatric disorders. Yet in recent years, the majority of studies testing safety and efficacy of new medications have included only adults. Even in the past decade, only 20% of new drugs have been approved for pediatric labeling.3 As a result, clinicians caring for children are frequently forced to empirically treat children with therapies untested in this population. Legislation in the late 1990s, including the US Food and Drug Administration (FDA) Modernization Act of 19974 and the subsequent FDA “Pediatric Rule” in 1998,5 has provided both incentives and requirements to pharmaceutical companies to test the safety and efficacy of drugs in children. Congress subsequently passed the Best Pharmaceuticals for Children Act of 2002,6 extending the Pediatric Exclusivity Act of 1997 to 2007 and thereby providing 6 months additional market exclusivity to companies that test the safety and efficacy of their drugs in children. In addition, this Act established a federal funding program to study drugs off-patent for pediatric usage. Although it is very encouraging that these measures should provide children more rapid access to new therapies, we, as a society, must always balance this acquisition of new knowledge against the protection of these vulnerable research participants who lack the legal right and, frequently, intellectual capacity to decide whether they wish to accept risk for uncertain benefit. Because of concerns about the adequacy of the system for protecting child participants in research, the Best Pharmaceuticals for Children Act of 20026 requested that the Institute of Medicine (IOM) prepare a report reviewing federal regulations and recommending optimal practices for the ethical conduct of research involving children. The IOM established a 14-member committee, chaired by Dr Richard Behrman, in January 2003 to focus on seven charges outlined in the Act, including: (1) the appropriateness of the regulations for children of various ages; (2) the interpretation of regulatory criteria for approaching research; (3) the processes for securing parents’ and children’s agreement to a child’s participation in research; (4) the expectation and comprehension of children and parents about participating in research; (5) the appropriateness of payments related to the child’s participation in research; (6) compliance with and enforcement of federal regulations; and (7) the unique roles and responsibilities of Institutional Review Boards (IRBs).6,7 The committee reviewed federal regulations, as well as existing data in the literature and federal reports. Public forums were held to receive input from patients, families, advocacy groups, and professional societies. The committee formed a consensus and developed both overarching themes and recommendations that were published in a book entitled, Ethical Conduct of Clinical Research Involving Children.7 I had the opportunity to participate as a member of this committee and to share in the provocative and enlightening discussions as we all weighed the critical balance between furthering knowledge and protection against harm. It is beyond the scope of this article to review all aspects of the IOM report. I will focus on one of the important charges we addressed: whether payment (financial or otherwise) may be made to a child, parent, guardian, or legally authorized representative for participation of the child in research.6
O
PAYMENTS TO CHILDREN FOR RESEARCH PARTICIPATION As the committee reviewed the limited existing data from the literature regarding payment of pediatric research participants, we weighed the difficult balance between the use of monetary or other forms of compensation to incentivize research participation versus protection of children and families against undue influence of the perceived reward. To make our recommendations, we carefully reviewed federal regulations and subsequent guidance documents from federal agencies, including the Office of Human
CF CFR FDA
Cystic fibrosis Code of Federal Regulations US Food and Drug Administration
IOM IRB
Institute of Medicine Institutional Review Board
From the University of Washington School of Medicine, Seattle, Washington. Reprint requests: Dr Bonnie W. Ramsey, Children’s Hospital and Regional Medical Center, 1100 Olive Way, Suite 500, Mailstop: MPW 5-4, Seattle, Washington 98101. E-mail: [email protected]. J Pediatr 2006;149:S15-S9 0022-3476/$ - see front matter Copyright © 2006 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2006.04.045
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Research Protection and the FDA. We also looked to professional societies or international councils that have previously considered the ethics of payment of children for research. We considered the types of payments to children, parents, and guardians that were or were not appropriate, and who should make these decisions, and we discussed the circumstances that bring the child and family to seek medical care and how that may impact compensation. The reader is encouraged to read Chapter 6 of the committee report,7 which summarizes the committee’s recommendations. The federal regulations provided in 45 Code of Federal Regulations (CFR) 468 and 21 CFR 509 are not prescriptive with regard to the type or amount of monetary or other compensation to research subjects of any age. Rather, they provide principles upon which institutional boards and investigators should make their judgment. It is stated in 45 CFR 46.116 and 21 CFR 50.20 that informed consent must be sought “under circumstances that minimize the possibility of coercion or undue influence” and that participants must 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” (45 CFR 46.116 (a) and 21 CFR 50.25 (a)). The key ethical concept of these regulations is minimizing undue influence, which is essential to the concept of a voluntary consent process. Undue influence could result from the size of the inducement, the method of payment (eg, requiring subjects to complete a study before payments), or the penalty of withdrawal from research (eg, loss of free medical care). All these ramifications of payment must be considered. More recently, two guidance documents have more directly addressed payments for patient recruitment, including pediatric research. In 2000, the FDA issued a guidance developed by the International Conference on Harmonisation entitled, Guidance on E11 Clinical Investigation of Medicinal Products in Pediatric Population.10 Excerpts from this report state that “the pediatric population represents a vulnerable subgroup. Therefore, special measures are needed to protect the rights of pediatric study participants and to shield them from undue risk.” The report goes on to state that recruitment (Section 2.6.2) of study participants “should occur in a manner free from inappropriate inducements either to the parent(s) or legal guardian or study participant. Reimbursement and subsistence costs may be covered in the context of a pediatric clinical study. Any compensation should be reviewed by the IRB/IEC.” The Council for International Organizations of Medical Sciences was even more detailed and prescriptive in its Ethical Guidelines for Biomedical Research Involving Human Subjects, Guideline 7.11 It states that “subjects may be reimbursed for lost earnings, travel costs and other expenses incurred in taking part in a study; they may also receive free medical services. Subjects, particularly those who receive no direct benefit from research, may also be paid or otherwise compensated for inconvenience and time spent. The payments should not be so large, however, or the medical services so extensive as to induce prospective subjects to S16
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consent to participate in the research against their better judgment (undue inducement). All payments, reimbursements and medical services provided to research subjects must have been approved by an ethical review committee.” With regard to vulnerable subjects, the guidelines 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.” Federal regulations and guidance place the review process for patient recruitment, including monetary or other inducements, as a responsibility of IRBs (45 CFR 46.116 and 21 CFR 50.20). FDA guidance recommends that IRBs “review the amount of payment and the proposed method and timing of disbursement to assure that neither are coercive or present undue influence.”12 Based upon limited published data13 from a survey of IRBs reviewing pediatric protocols, it appears that only a minority of boards have any written policy or formula for determining a monetary value for appropriate payment. Of the 128 institutions responding (36%), 84 (66%) had approved payment to children for participation, of which 42% approved payment to both parent/guardian and child, 31% to parent only, and 19% to child only. A second study surveying nonpediatric IRBs14 also found that only a minority has written guidelines. Not surprisingly, the IRB policies tend to follow federal guidance and require disclosure of payment to parent/guardian and child during the informed consent process before enrollment. This approach contrasts with the 1995 guidelines published by the American Academy of Pediatrics Committee on Drugs.15 This guideline accepted the use of payment to children for research participation, but it recommended that “it [remuneration] is not discussed before the study’s completion” and should not go beyond a token gesture to minimize undue influence. The IOM committee also sought data on the frequency and types of payment that are currently being provided to pediatric research participants. There is, unfortunately, very limited data available on payment of pediatric participants. A review of one public listing of clinical trials, Centerwatch,16 in 2000, suggested that approximately 25% of pediatric trials offered payment.17 This lack of published data is not surprising because there has been no systemic collection of data on the number and type of clinical trials in the United States or number and demographic information on research participants. Thus, it is impossible to ascertain the true scope of payment practices. Recommendations from two IOM committees, Responsible Research: A Systems Approach to Protecting Research Participants18 and Ethical Conduct of Clinical Research Involving Children,7 stressed the importance of obtaining such data on clinical research. The recent statement by the International Committee of Medical Journal Editors19 has recommended registration of all clinical trials that may impact clinical practice. Although payment practices are currently not part of the information collected in this registration process, at a minimum these recent changes will allow investigators and consumers to better understand the research process and its ethical conduct. The Journal of Pediatrics • July 2006
Table I. Types of payment for research participation 1. Reimbursement payments compensate parents and children for their direct research-related expenses and should be based on the actual costs (eg, transportation, meals, lodging) that families incur. 2. Compensation payments compensate parents and children for the time and inconvenience of research participation. Levels of compensation payments should be a function of the demands (clinic visits, hospital stays, research procedures) that research places on families. 3. Appreciation payments are bonuses given after children’s participation to thank them for their efforts. 4. Incentive payments encourage children’s research enrollment. Payments may be designed to act as incentives, for instance, when an investigator intentionally reimburses families above their actual costs to encourage enrollment. Payments may also inadvertently act as incentives if they unintentionally exceed families’ costs and, thereby, act as incentives without being intended as such.
Table II. CF Therapeutics Development Network reimbursement policy Type of expense Outpatient study (not requiring an overnight stay in the hospital)
Inpatient study (requiring at least one overnight stay in the hospital) Partial days should be compensated based on the outpatient schedule above. Mileage Other expenses
Source: Wendler et al.17
A survey of adolescents involved in research20 found that 40% of health-related studies provided payments, of which 50% was cash and 38% were vouchers. Broome et al21 compared payment practice by type of illness and found that studies involving children with cancer did not offer financial incentives, whereas patients with diabetes mellitus, in general, expected payment. It is also difficult to determine the purpose of the payment (ie, travel reimbursement vs inducement) as most payments are lumped together. Having reviewed federal regulations, guidance documents, and limited existing data, the committee focused on several key issues, including the need to better define types and appropriateness of payments in research involving children, the characteristics of the participant/family dyad that influence the decision process, and the need for institutions responsible for research oversight to establish consistent written policies. When considering the types of payments for research participation, Wendler et al17 defined four categories (reimbursement, compensation, appreciation, and incentive), shown in Table I, that are helpful in considering the concepts of “undue influence” and “coercion.” The committee agreed with reimbursement of expenses as justified in almost all research studies. One specialty that has not traditionally covered expenses is pediatric oncology,21 where it is commonly assumed that access to a life-saving therapy is the primary incentive and that patients are coming to the medical facility for clinical rather than research purposes. Whether these policies change as cancer becomes a more chronic illness remains to be seen. In cystic fibrosis (CF), another chronic life-threatening illness, a research consortium, the CF Therapeutics Development Network has established a policy approved by a committee composed of investigators, parents, and patients to standardize payments
Amount ⬍2 hours $30.00 2–4 hours $60.00 4–8 hours $85.00 8–12 hours $115.00 $170.00/day
Current federal mileage rate Additional reimbursement for parking fees and meals should be made at the rates applicable for the participating study site.
across all 18 participating sites based upon time and expenses (Table II). These guidelines are reviewed annually and updated based upon cost of living. The policy states, however, that the local IRB must review and approve any final payment schedule. Surveys of IRBs at the network sites have found them to be receptive to the policies and have, for the most part, accepted the recommendations. Appreciation payments, which may be cash or noncash gifts, were considered acceptable as long as they were ageappropriate and of nominal monetary value, thus not providing undue influence. Undue influence was defined in the Belmont Report22 as “an offer of an excessive, unwarranted, inappropriate or improper reward or other overture in order to obtain compliance.” In my personal experience, adolescents pose the greatest challenge because money is an important measure of importance and independence and can cloud judgment. Our CF center has multiple protocols open at any one time. It is not uncommon for an adolescent to arrive in clinic and say, “Tell me all the studies going on and exactly how much each pays!” even though it is our policy not to discuss payment in the consent process. Our committee agreed that nonmonetary gifts (ie, tickets to a football game) may be more appropriate. Incentive payments to improve recruitment and retention were considered unacceptable as these payments are likely to impact the decision-making process. Of particular concern are large payments based upon study completion rather than visit-based payments. Payment for increased risk should never be considered acceptable as this approach may place payment in the “benefit” category of the risk:benefit ratio assessment, which is not appropriate. In establishing the CF Therapeutics Development Network payment policy (Table II), the Principal Investigators had a discussion regarding increased payment for a visit including a bronchoscopy procedure requiring
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anesthesia versus a blood draw. It was universally agreed that this approach would give the wrong message to patients and families and was not approved. Thus, all payments are based upon time and expenses. Compensation for time and inconvenience of patients and families was a more challenging concept for the committee to review and reach agreement. The basic principle of compensation is well-defined by Wendler17 as the amount required to “zero out” the families’ burden from research participation without providing an “incentive.” These burdens may include travel expenses and time, lost work time, emotional stress, etc. Clearly, each family is unique, and here is where the status of the child/parent dyad becomes important. Parents with highly paid professions likely need no compensation, whereas a self-employed, manual laborer might lose both wages and a job, posing a significant burden. Because it is not possible to individualize payments based upon parental wage, it has been recommended that if research subjects and/or parental time is compensated, it should be at the minimum wage of unskilled, essential jobs.23 Whether this payment should be directed to the parent, child, or both depends upon IRB interpretation.13 The discussions within the committee focused upon two opposing concerns. On one side we wanted to ensure equal access for research participation regardless of the family’s cultural or socioeconomic background, and parental compensation may decrease the barrier to participate. On the other side, several members raised concerns about the fine line between compensation and undue influence, particularly in a family of limited means. Ultimately, it is the responsibility of the IRB to weigh these conflicting forces. In the past month, I had a personal experience that helped place this issue into context. I approached an adolescent patient with CF and her parents about participation in a clinical trial for a new therapeutic agent. The family had faced a recent job loss by the father and change in employment by the mother. They lived a significant distance from the medical center. I began discussions regarding the study rationale, risks versus benefits, and study procedures but had not addressed the issue of compensation for participation. Compensation was clearly defined in the consent form, which the parents had not yet read. The adolescent expressed significant interest, but the parents were reluctant and claimed “lack of time” and a “long trip over the mountains.” Going against my usual policy to not emphasize compensation, I noted that we would cover the costs of gas for the trip and compensate them for their time. The parents’ faces lit up and both stated that they had always wanted to have both of their children with CF participate in research trials but were too proud and embarrassed to admit that they could not afford the money for gas. This conversation made me realize that I had unintentionally created a barrier to their participation and had made them feel “unworthy.” There are other cultural barriers to research participation beyond travel expenses and time from work among underserved populations. Compensation for these expenses, however, may reduce one important barrier. Investigators S18
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should also consider night and weekend hours or other mechanisms to minimize personal loss of work. An issue not addressed by Wendler was compensation for research-related injury that is not a result of negligence. Federal regulations require that participants and families be informed whether compensation (termed indemnification) is provided and whom to contact in the event of injury (45 CFR 46.116 (a) and 21 CFR 50.25). Pharmaceutical sponsors do provide compensation for research-related injuries involving their investigational drug or device, for studies they initiate. By contrast, the majority of investigator-initiated studies (frequently based at academic centers) do not provide compensation. An exception noted by the IOM in its Responsible Research: A Systems Approach to Protecting Research Participants18 report was the University of Washington and its affiliated medical centers. There have been several recent reports18,7 that all strongly endorsed the provision that research organizations and sponsors supporting clinical studies must pay for medical costs of children injured as a direct result of research participation. Successful recruitment of patients for participatation in pediatric trials may be challenging. With many orphan diseases,24 accrual of adequate patients requires enrollment from multiple sites, and families frequently travel long distances to reach medical facilities. Therefore, payment is a necessary compensation for time and expenses. To minimize the potential for undue influence, individual investigators, institutions, IRBs, and research consortia should establish written policies defining appropriate and inappropriate payments, including amount, timing, and purposes of reimbursement. These policies should be transparent to participants, families, and the community. Payments should not be portrayed as a benefit of research participation or considered in the assessment of the risk:benefit ratio. Regular review of policies should encourage investigators and IRBs to reflect on the ethical principles upon which the policies are based (ie, the protection of our children).
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8. Department of Health and Human Services. Protection of human subjects(45 CFR 46). October 1, 2001. Available online at: http://www.access.gpo.gov/nara/cfr/waisidx_01/45cfr46_01.html. 9. US Food and Drug Administration. Protection of human subjects. (21 CFR 50). April 1, 2002. Available online at: http://www.access.gpo.gov/ nara/cfr/waisidx_02/21cfr50_02.html. 10. Food and Drug Administration, HHS. International Conference on Harmonisation: guidance on E11 clinical investigation of medicinal products in pediatric populations. Fed Regist 2000 Dec 15;65(242):78493-4. 11. Council for International Organizations of Medical Sciences. International Ethical Guidelines for Biomedical Research Involving Human Subjects. November 2002. Available online at: http://www.cioms.ch/ frame_guidelines_nov_2002.htm. 12. US Food and Drug Administration. Guidance for institutional review boards and clinical investigators. 1998 Update: cooperative research. Rockville, MD: US Food and Drug Administration; 1998. Available online at: http://www.fda.gov/ohrt/irbs/research.html. 13. Weise KL, Smith ML, Maschke KJ, Copeland HL. National practices regarding payment to research subjects for participating in pediatric research. Pediatrics. 2002;110:577-82. 14. Dickert N, Emanuel E, Grady C. Paying research subjects: an analysis of current policies. Ann Intern Med 2002;136:368-73. 15. American Academy of Pediatrics. Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics 1995;95:286-94.
16. CenterWatch clinical trials listing services. Boston: CenterWatch; 2000. Available online at: http://www.centerwatch.com. 17. Wendler D, Rackoff JE, Emanuel EJ, Grady C. The ethics of paying for children’s participation in research. J Pediatr 2002;141:166-71. 18. Institute of Medicine. Responsible Research: A Systems Approach to Protecting Research Participants. Washington, DC: The National Academies Press; 2003. 19. De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al; International Committee of Medical Journal Editors. Clinical trial registration: a statement from the International Committee of Medical Journal Editors. N Engl J Med 2004;351(12):1250-1. 20. Borzekowski DL, Rickert VI, Ipp L, Fortenberry JD. At what price? The current state of subject payment in adolescent. J Adolesc Health 2003;33:378-84. 21. Broome ME, Richards DJ, Hall JM. Children in research: the experience of ill children and adolescents. J Fam Nurs 2001;7:32-49. 22. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Washington, DC: US Government Printing Office; 1979. 23. Dickert N, Grady C. Paying research subjects: an analysis of current policies. N Engl J Med 1999;341:198-203. 24. US Food and Drug Administration. Orphan drug regulations. (Part 316 Subpart C Section 316.3). Available online at: http://www.fda.gov/ Orphan/21cfr316.html.
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