Bone Marrow Transplantation (2015) 50, 15–19 © 2015 Macmillan Publishers Limited All rights reserved 0268-3369/15 www.nature.com/bmt
SPECIAL REPORT
Children as hematopoietic cell donors in research: when is it approvable? NN Shah1, AS Wayne1,2, C Grady3, T Fry1 and D Wendler3 With increasing frequency, allogeneic hematopoietic cell transplantation involving children is being performed in the research setting. Allogeneic hematopoietic cell transplantation, however, cannot be performed without a hematopoietic stem cell (HSC) donor. This donor is often a sibling of the recipient and may also be a child. In such circumstances, it is unclear whether or how the federal regulations for pediatric research apply to the minor donors. This introductory paper reviews the issues to be considered while evaluating studies that use HSCs obtained from minor donors and identifies areas where further research is needed. In the era of increasing applicability for donor-derived cellular therapies, we provide a suggested framework for determining when minor donors qualify as human research subjects and when their participation can be approved under the federal regulations. Bone Marrow Transplantation (2015) 50, 15–19; doi:10.1038/bmt.2014.224; published online 20 October 2014 INTRODUCTION Two thousand allogeneic hematopoietic stem cell (HSC) transplants are performed annually in children in the USA, many on research protocols. For approximately one-third, the HSC donor is also a child,1 typically a healthy sibling who undergoes BM harvest or large volume apheresis for collection of peripheral blood stem cells. Recognizing that HSC donors face risks2–5 (Table 1) without the potential for direct medical benefit, the American Academy of Pediatrics recently published guidelines specifying when minors may ethically serve as HSC donors for a standard (nonresearch) transplant.6 This raises the need for guidance on when minors may donate HSCs in the research setting. Federal regulations allow institutional review boards (IRBs) to approve research in pediatric subjects only when it offers the prospect of direct benefit to the child participants or when the risks are sufficiently low. Because these regulations were designed for patients and healthy volunteers, it is unclear when and how they apply to minors who serve as donors for patients who receive a hematopoietic cell transplant (HCT) on a research protocol. Accordingly, there may be significant confusion among researchers, IRBs, those who fund the research and institutions conducting research involving minors. This is highlighted by a recent case in which a large, multi-institutional, cooperative group pediatric transplant trial was closed by an IRB at a single participating site.7 Current lack of guidance is problematic and will become even more significant with increasing application of allogeneic cellular therapies. To ensure ethical conduct of clinical research involving minor donors as well as success in completing trials involving potentially life-saving HCT therapies, further clarity is needed. To protect minor donors, while allowing important clinical research to be conducted, two questions needed to be addressed: (1) Are minors who donate cells in the context of a research transplant themselves research subjects, and (2) if so, when is the minor donor’s involvement approvable under federal regulations governing pediatric research? In this introductory paper, we 1
discuss issues involved in the evaluation of research involving minor donors and suggest an approach (Figure 1) that can be used to address these questions. USE OF MINOR DONORS ON RESEARCH PROTOCOLS Are donors human subjects? The first question is whether minors who donate cells as part of a research protocol qualify as human research subjects who are covered by the federal regulations governing pediatric research (Figure 2) (Table 2). The Department of Health and Human Services (DHHS) regulations define a ‘human subject’ as a ‘living individual about whom an investigator conducting research obtains (1) data through intervention or interaction with the individual or (2) identifiable private information’ (45CFR §46.102). If investigators perform a research intervention on the minor donor or collect research data through interaction with the donor, the donor would qualify as a human subject. Obtaining identifiable private information about donors through general interaction needed for the transplant evaluation, however, would not qualify the recipient as a human subject, unless investigators use the private identifiable information for research purposes. Food and Drug Administration (FDA) regulations (which apply to all clinical investigations regulated by the FDA or supporting products regulated by the FDA) define a ‘human subject’ as an ‘individual who is or becomes a participant in research, either as a recipient of the test article or as a control’ (21 CFR §50.3g). In the majority of cases, where the test article is administered to the HSC recipient, the donor will not qualify as a research subject under FDA regulations. In addition, in our view, the donor should be considered a research subject when the donor is exposed to risks that would not be present but for the research itself. Consider as an example a situation in which the transplant would not be performed except as a part of research, such as when it is being performed for a nonstandard indication. In this case, the donor is exposed to risks
Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; 2Children’s Center for Cancer and Blood Diseases, Children’s Hospital of Los Angeles, University of Southern California, Los Angeles, CA, USA and 3Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, MD, USA. Correspondence: Dr NN Shah, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 1W-3750, 9000 Rockville Pike, Bethesda, MD 20892-1104, USA. E-mail: [email protected] Received 29 May 2014; revised 22 August 2014; accepted 27 August 2014; published online 20 October 2014
Regulations for minor hematopoietic stem cell donors NN Shah et al
16 Table 1.
Medical risks to transplant donor
BM harvest
PBSC apheresis
Risks of general anesthesia
Central line placement with associated risks of pain, infection, bleeding and damage to the blood vessel Anemia Exposure to red blood blood transfusion (if needed to ‘prime’ the extracorporeal apheresis circuit for smaller donors) Exposure to red blood cell transfusion (if needed based on the Filgrastim with associated risks of pain, elevated white blood cell count and volume of marrow collected) splenomegaly with (rare) rupture Pain — Infection —
Abbreviation: PBSC=peripheral blood stem cell.
Step 1
Are the minor donors research subjects?
No
Federal regulations do not apply to the minor donor
Yes Step 2
Are there research risks?
No
Research can be approved by an IRB in all children (404/50.51)
Yes Step 3
Are the research risks greater than minimal?
No
Research can be approved by an IRB in all children (404/50.51)
Yes Step 4
Does the research offer donors a prospect of direct benefit?
Yes
No Step 5
Are the research risks greater than a minor increase over minimal?
No
Research can be approved by an IRB in all children provided the risk-benefit ratio is as favorable as available alternatives (405/50.52) Research can be approved by an IRB if it is likely to yield generalizable knowledge about the donor’s condition’ (406/50.53)
Yes Step 6
Research cannot be approved by an IRB(407/50.54)
Figure 1. Step assessment of risk to minor HSC donors in research settings. Step 1: Donors are research subjects when they meet the FDA or DHHS definition, or when the research introduces added risks. Step 2: Research risks are any risks that the donors would not face absent the research. Step 3: Research risks qualify as minimal when they do not exceed the risks ordinarily encountered in daily life or the risks acceptable for minor donors in the clinical setting. Step 4: Most transplant research does not offer the donor a therapeutic ‘direct benefit.’ Step 5: Most transplant research is designed to yield generalizable knowledge about the recipient’s condition, and not the donor’s condition. Step 6: Research that is greater than a minor increase over minimal risk that does not offer the potential of direct benefit cannot be approved by an IRB. The research must be reviewed and approved by an expert panel in order to be considered further.
(medical and/or psychological) that would not be present absent the research. In summary, this analysis suggests that minor donors should be considered research subjects under the following conditions (Table 2): 1. The investigators collect data or private identifiable information from the donor for research purposes. ((45CFR §46.102); DHHS) 2. The donor is the recipient of the test article or investigational device or serves as a control. ((21 CFR §50.3g); FDA) 3. The donor faces risks they would not face absent the research. Are there research risks? When minor donors qualify as research subjects, IRBs must evaluate whether they face research risks. Risks of a standard donation may include risk of anesthesia, vascular access line placement, filgrastim administration and apheresis,2,3 as well as psychological risks, such as donor guilt, if recipient outcomes are poor.8,9 However, FDA and DHHS regulations direct IRBs to consider as research risks only those risks that ‘result from the research, as distinguished from risks Bone Marrow Transplantation (2015) 15 – 19
of therapies subjects would receive even if not participating in the research.’10 Accordingly, when standard HSC collection procedures are performed, and the donor would have donated in the clinical setting (for a standard indication), the risks of a standard donation should not count as research risks. This suggests that HSC donors face research risks in four settings: 1. The research includes additional procedures or interventions that the donor would not face while donating in the nonresearch setting. 2. The research replaces one or more of the standard collection procedures with alternative or experimental approaches. 3. It is expected that the individual would not serve as a donor except in research (for example, the recipient indication for the HSCT procedure is not standard). 4. The investigational transplant poses greater risks to the recipient in comparison with a standard transplant, in which case the research might lead to increased risk of donor guilt should the recipient sustain transplant-related morbidity or mortality. © 2015 Macmillan Publishers Limited
Regulations for minor hematopoietic stem cell donors NN Shah et al
17 Minor increase over minimal risk
Minimal riska
More than a minor increase over minimal risk
Prospect of direct benefit
Section 46.405/50.52 Approvable by IRB 1. Risks justified by anticipated benefit 2. Risk/benefit profile as favorable as alternatives 3. Parental permissionb 4. Child’s assentc
Section 46.404/50.51 Approvable by IRB
No prospect of direct benefit
1. Parental permissionb 2. Child’s assentc
Section 46.406/50.53 Approvable by IRB 1. Commensurate with subjects’ experience 2. About subjects’ disorder or condition 3. Parental permissionb c 4. Child’s assent
Section 46.407/50.54d Approvable by secretary/commissioner 1. Expert consultation 2. Public review and comment 3. Addresses a serious problem affecting children 4. Consistent with sound ethical principles b 5. Parental permission 6. Child’s assentc
Figure 2. Federal Regulation for Pediatric Research and Associated Requirements. a‘Minimal’ risk is defined as risks that are not greater than the risks ‘ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests’ (§46.102 i/50.3 k). bPermission of one parent is sufficient for categories 404/50.51 and 405/50.52; permission of both parents, if reasonably available, is required for 406/50.53 and 407/50.54; the requirement for parental permission may be waived in cases that satisfy the conditions for waiver of informed consent. cAssent, defined as affirmative agreement, is required only if the IRB judges that the subjects are capable of providing assent; assent may be waived if the ‘intervention or procedure involved in the research holds out a prospect of direct benefit that is important to the health or well-being of the children and is available only in the context of the research’ (46.408 a/50.55) and also in cases that satisfy the conditions for waiver of informed consent. dThe 407/50.54 categories cover research that is not approvable in sections 404/50.51, 405/50.52, or 406/50.53. Hence, a study might fall into the 407/50.54 categories even though it does not pose more than a minor increase over minimal risk. For example, a study that poses a minor increase over minimal risk, but does not concern the subjects’ disorder or condition, could be referred for review in the 407/50.54 categories.
Table 2.
Examples for determining when a minor donor is a research subject
Category
Response Human Subject
Example/Clarification
Are data or private identifiable information collected for research purposes?
No
No
Yes
Yes
No
No
Yes
Yes
Is the donor donating hematopoietic stem cells No (HSC) for a nonstandard transplant? Yes
No
Research question implicates the recipient only. No private identifiable information or data from the donor are used for research purposes Additional blood, beyond what is clinically indicated, is obtained from the donor to perform additional research analysis. Standard procurement procedures alone would not qualify donor as a research subject If the donor is the target of the research intervention, then the donor is a human subject Donation for a standard transplant indication, albeit in research, may not qualify the donor as a human subject If the donor were providing HSCs for a recipient for whom transplant is not a standard indication and is only performed in the research setting
Is the donor the direct recipient of a drug or investigational device?
Yes
EVALUATING RESEARCH RISKS The federal regulations include four categories of pediatric research that are defined by the risk-benefit profile of the study in question (Figure 2). Minimal risk research IRBs can approve the enrollment of all children in ‘minimal’ risk research (45 CFR §46.404/50.51), defined as research that poses risks no greater than the risks ordinarily encountered in daily life or during routine examinations or tests (45 CFR §46.102i/50.3k). Most commentators interpret the risks ‘ordinarily encountered in daily life’ as those faced by average healthy children.11 Although this ‘objective’ interpretation protects children who face excessive © 2015 Macmillan Publishers Limited
risks in their daily lives (such as children who live in war-torn regions), it is challenging to apply to HSC donors. Consider a protocol testing new procedure that is designed to reduce the rate of complications associated with HSC collection. In this case, the risks to the donor in the research setting may be lower than the risks in the standard clinical setting. However, the risks of the HSC collection are still greater than the risks encountered in daily life by average children. Hence, the objective interpretation implies that this donor faces greater than minimal risk without a prospect of benefit, even though the risks associated with the research may well be lower than the risks the donor would face in the nonresearch setting. To avoid this counterintuitive outcome, whereby a donor could donate for a nonresearch transplant but not for a research transplant that Bone Marrow Transplantation (2015) 15 – 19
Regulations for minor hematopoietic stem cell donors NN Shah et al
18 would pose similar or decreased risks, we suggest that the research risks to a donor be considered minimal risk when they are no greater than the risks that this donor would otherwise face in the context of a standard procurement procedure. Does the research offer the prospect of ‘direct’ benefit to the donor? Research that is greater than minimal risk can be approved by an IRB when it offers subjects a compensating potential for ‘direct’ benefit (CFR §46.405/50.52). Although altruism and helping an ill sibling may offer some benefit to donors, most commentators and the American Academy of Pediatrics maintain that these do not represent direct therapeutic benefits. We support this approach as important for protecting pediatric subjects from the possibility that all pediatric research could be categorized as having potential for direct benefit on the grounds that it offers subjects the chance to help others. Greater than minimal risk research IRBs can also approve greater than minimal risk pediatric research when the risks do not exceed a ‘minor’ increase over minimal and the research is likely to ‘yield generalizable knowledge about the subject’s disorder or condition.’ (CFR §46.406/50.53). However, transplant research is typically designed to yield generalizable knowledge about the recipients’ condition, not the donors’. This suggests that the research involvement of minor donors typically cannot be approved in this category. CATEGORY §46.407/§50.54 Pediatric research that is not approvable by an IRB in the first three categories may be evaluated for possible approval in category §46.407/§50.54. Approval in this category requires review and recommendation by a panel of experts, an opportunity for public comment and final approval by the Commissioner of the FDA or the Secretary of DHHS. However, because this process is quite complex, labor intensive and time-consuming, it has been used rarely.12 Indeed, following the closure of the cooperative group HSC trial by a single participating center IRB,7 407 review was conducted and, while successful in reopening the trial, the long delay resulted in poor accrual and eventual closure prior to enrolling sufficient patients to address the primary question. TRANSPLANT FOR NONSTANDARD INDICATIONS Transplants performed in the research setting for nonstandard or novel indications pose special challenges and controversy. As previously stated, in such circumstances, we believe that the donor would qualify as a research subject, on the basis that participation in the research presents a research risk that would not be present except for the research (transplant for nonstandard indication). Taking into consideration the risks of a standard donation (for example, anesthesia or central line placement), which may be greater than minimal risk, and without the prospect of direct benefit, an IRB may not be able to approve such protocols for enrollment of minor donors. It seems counterintuitive, however, to prevent a minor from donating when the donation process itself poses the same risks to the donors, and the transplant offers a potential for benefit (for example, potential cure) comparable to that when transplantation is offered for standard nonresearch indications. For instance, consider the situation in which a transplant is being performed in the research setting for a novel life-threatening condition (for example, immunodeficiency) for which no other curative therapies exist, but where there is evidence to suggest that transplant may provide potential benefit. Despite the fact that transplant has not been established as the standard of care, a transplant in the Bone Marrow Transplantation (2015) 15 – 19
research setting may be the only available therapy to provide potential cure for a recipient with such a rare disorder. To address this issue, we take the view of an ‘analogous donor,’ and consider those donations in which the risks are no greater than the risks of commonly allowed procurements to be minimal research risk as for any other ‘analogous’ minor donor who would donate in a nonresearch setting. On the basis of the scenario above, and in circumstances in which there is evidence for potential of benefit to the recipient, we believe that such a protocol (for example, transplant for nonstandard indications) could be approved as posing minimal research risks for the donor (§46.404/50.51) using the ‘analogous donor’ approach, if the following pertain: ●
●
Although the donation is not performed regularly in the clinical setting for this disease, there is good evidence that the protocol offers the potential for important (and possibly curative) medical benefit to the recipient and an IRB has approved the protocol for the recipient. The risks of the donation are no greater than the risks of donation faced by an ‘analogous’ minor donor in the clinical setting for established indications.
In contrast, when the evidence of benefit from transplantation for a specific disease is controversial, or evidence of benefit is lacking, exposing minor donors to risk of HSC collection would require review by a 407 expert panel. AREAS OF ONGOING RESEARCH Much of this discussion has been based on the assumption that there is a clear established standard of care procurement procedure for minors with an established method for risk assessment. Efforts to define standards for collection procedures to minimize risk and optimize safety to minor donors are ongoing.2,3,5 As these standards become available, they can serve as a benchmark for determining whether the particular collection procedures that minors undergo pose additional risks beyond those associated with established clinical practice. It is similarly unclear how emerging technology, such as experimental manipulation of collected HSCs, may affect donors. The National Marrow Donor Program, which applies to adult unrelated donors, considers the use of any investigational device on a donor specimen to qualify the donor as a research subject. On the basis of our framework, experimental manipulation of donated cells would implicate the individual as a research subject only if it posed new risk to the donor (with risk assessment compared with standard methods), or it required the collection of private information from the donor for research purposes. Future efforts in the area of donor ethics should address the development of formal guidelines as to whether manipulation of the cells per se should imply that the donor is a research subject. Another important area of active research in transplantation includes assessment of the psychosocial risks that donors face.8,9,13 Incorporation of psychosocial risks in the risk assessment of minor donors is an area that is often not fully integrated, but needs to be incorporated—and specifically focusing on the risks in the research setting. However, in some cases it is possible that the psychosocial risk to the donor will be identical to those in the clinical setting; in other cases it is possible that donors could experience greater psychosocial risk, especially if benefit to the recipient is less certain. In addition, our proposed framework is based on the interpretation that a healthy minor donor generally cannot be considered as having a condition (that is, 46.406 cannot be applied to minor donors) and that they are not recipients of direct benefit (that is, 46.405 cannot apply). However, not all agree with © 2015 Macmillan Publishers Limited
Regulations for minor hematopoietic stem cell donors NN Shah et al
this view, and achieving a consensus on interpretation of the 405 and 406 statutes will be important to standardizing assessment of a minor donor on a research protocol. Along these lines, further streamlining of the 407 processes to help facilitate, rather than impede, research involving minor donors, and establishment of federal guidelines that involve healthy donor research, would be valuable in improving the evaluation of minor donors. CONCLUSION With the goal of protecting pediatric donors while allowing development of potentially life-saving therapies involving transplantation of cellular products from these allogeneic donors, we have proposed a systematic method to assess when minor donors qualify as research subjects, and when their participation can be approved under federal research regulations. We hope that this summary and algorithm, in addition to ongoing efforts to improve the safety of and minimize risks to minor donors, will provide a more comprehensive and systematic way for local IRBs and protocol development teams to evaluate the role of minor donors in transplant protocols. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research and the Warren Grant Magnuson Clinical Center.
DISCLAIMER The views expressed are the authors’ own. They do not represent any position or policy of the NIH, DHHS or US government.
© 2015 Macmillan Publishers Limited
19
REFERENCES 1 Pasquini M, Wang Z. Current Use and Outcome of Hematopoietic Stem Cell Transplantation. CIBMTR Summary Slides: Milwaukee, WI, USA, 2013. 2 Pulsipher MA, Chitphakdithai P, Logan BR, Shaw BE, Wingard JR, Lazarus HM et al. Acute toxicities of unrelated bone marrow versus peripheral blood stem cell donation: results of a prospective trial from the National Marrow Donor Program. Blood 2013; 121: 197–206. 3 Styczynski J, Balduzzi A, Gil L, Labopin M, Hamladji RM, Marktel S et al. Risk of complications during hematopoietic stem cell collection in pediatric sibling donors: a prospective European Group for Blood and Marrow Transplantation Pediatric Diseases Working Party study. Blood 2012; 119: 2935–2942. 4 Grupp SA, Frangoul H, Wall D, Pulsipher MA, Levine JE, Schultz KR. Use of G-CSF in matched sibling donor pediatric allogeneic transplantation: a consensus statement from the Children's Oncology Group (COG) Transplant Discipline Committee and Pediatric Blood and Marrow Transplant Consortium (PBMTC) Executive Committee. Pediatr Blood Cancer 2006; 46: 414–421. 5 Pulsipher MA, Chitphakdithai P, Logan BR, Navarro WH, Levine JE, Miller JP et al. Lower risk of serious adverse events and no increased risk of cancer after PBSC versus bone marrow donation. Blood 2014; 123: 3655–3663. 6 American Academy of Pediatrics CoB. Children as hematopoietic stem cell donors. Pediatrics 2010; 125: 392–404. 7 Memo Stem Cell Committee. ASCT0631, A Phase III Randomized Trial of G-CSF Stimulated Bone Marrow vs Conventional Bone Marrow as a Stem Cell Source in Matched Sibling Donor Transplantation, 2011. 8 Packman W, Weber S, Wallace J, Bugescu N. Psychological effects of hematopoietic SCT on pediatric patients, siblings and parents: a review. Bone Marrow Transplant 2010; 45: 1134–1146. 9 Wiener LS, Steffen-Smith E, Fry T, Wayne AS. Hematopoietic stem cell donation in children: a review of the sibling donor experience. J Psychosoc Oncol 2007; 25: 45–66. 10 Pulsipher MA, Nagler A, Iannone R, Nelson RM. Weighing the risks of G-CSF administration, leukopheresis, and standard marrow harvest: ethical and safety considerations for normal pediatric hematopoietic cell donors. Pediatr Blood Cancer 2006; 46: 422–433. 11 Field MJ, Behrman RE. The Ethical Conduct of Clinical Research Involving Children. The National Academies Press: Washington, DC, 2004. 12 Ross LF. Convening a 407 panel for research not otherwise approvable: "Precursors to diabetes in Japanese American youth" as a case study. Kennedy Inst Ethics J 2004; 14165–186. 13 Wiener LS, Steffen-Smith E, Battles HB, Wayne A, Love CP, Fry T. Sibling stem cell donor experiences at a single institution. Psychooncology 2008; 17304–307.
Bone Marrow Transplantation (2015) 15 – 19
Copyright of Bone Marrow Transplantation is the property of Nature Publishing Group and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
SPECIAL REPORT
Children as hematopoietic cell donors in research: when is it approvable? NN Shah1, AS Wayne1,2, C Grady3, T Fry1 and D Wendler3 With increasing frequency, allogeneic hematopoietic cell transplantation involving children is being performed in the research setting. Allogeneic hematopoietic cell transplantation, however, cannot be performed without a hematopoietic stem cell (HSC) donor. This donor is often a sibling of the recipient and may also be a child. In such circumstances, it is unclear whether or how the federal regulations for pediatric research apply to the minor donors. This introductory paper reviews the issues to be considered while evaluating studies that use HSCs obtained from minor donors and identifies areas where further research is needed. In the era of increasing applicability for donor-derived cellular therapies, we provide a suggested framework for determining when minor donors qualify as human research subjects and when their participation can be approved under the federal regulations. Bone Marrow Transplantation (2015) 50, 15–19; doi:10.1038/bmt.2014.224; published online 20 October 2014 INTRODUCTION Two thousand allogeneic hematopoietic stem cell (HSC) transplants are performed annually in children in the USA, many on research protocols. For approximately one-third, the HSC donor is also a child,1 typically a healthy sibling who undergoes BM harvest or large volume apheresis for collection of peripheral blood stem cells. Recognizing that HSC donors face risks2–5 (Table 1) without the potential for direct medical benefit, the American Academy of Pediatrics recently published guidelines specifying when minors may ethically serve as HSC donors for a standard (nonresearch) transplant.6 This raises the need for guidance on when minors may donate HSCs in the research setting. Federal regulations allow institutional review boards (IRBs) to approve research in pediatric subjects only when it offers the prospect of direct benefit to the child participants or when the risks are sufficiently low. Because these regulations were designed for patients and healthy volunteers, it is unclear when and how they apply to minors who serve as donors for patients who receive a hematopoietic cell transplant (HCT) on a research protocol. Accordingly, there may be significant confusion among researchers, IRBs, those who fund the research and institutions conducting research involving minors. This is highlighted by a recent case in which a large, multi-institutional, cooperative group pediatric transplant trial was closed by an IRB at a single participating site.7 Current lack of guidance is problematic and will become even more significant with increasing application of allogeneic cellular therapies. To ensure ethical conduct of clinical research involving minor donors as well as success in completing trials involving potentially life-saving HCT therapies, further clarity is needed. To protect minor donors, while allowing important clinical research to be conducted, two questions needed to be addressed: (1) Are minors who donate cells in the context of a research transplant themselves research subjects, and (2) if so, when is the minor donor’s involvement approvable under federal regulations governing pediatric research? In this introductory paper, we 1
discuss issues involved in the evaluation of research involving minor donors and suggest an approach (Figure 1) that can be used to address these questions. USE OF MINOR DONORS ON RESEARCH PROTOCOLS Are donors human subjects? The first question is whether minors who donate cells as part of a research protocol qualify as human research subjects who are covered by the federal regulations governing pediatric research (Figure 2) (Table 2). The Department of Health and Human Services (DHHS) regulations define a ‘human subject’ as a ‘living individual about whom an investigator conducting research obtains (1) data through intervention or interaction with the individual or (2) identifiable private information’ (45CFR §46.102). If investigators perform a research intervention on the minor donor or collect research data through interaction with the donor, the donor would qualify as a human subject. Obtaining identifiable private information about donors through general interaction needed for the transplant evaluation, however, would not qualify the recipient as a human subject, unless investigators use the private identifiable information for research purposes. Food and Drug Administration (FDA) regulations (which apply to all clinical investigations regulated by the FDA or supporting products regulated by the FDA) define a ‘human subject’ as an ‘individual who is or becomes a participant in research, either as a recipient of the test article or as a control’ (21 CFR §50.3g). In the majority of cases, where the test article is administered to the HSC recipient, the donor will not qualify as a research subject under FDA regulations. In addition, in our view, the donor should be considered a research subject when the donor is exposed to risks that would not be present but for the research itself. Consider as an example a situation in which the transplant would not be performed except as a part of research, such as when it is being performed for a nonstandard indication. In this case, the donor is exposed to risks
Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; 2Children’s Center for Cancer and Blood Diseases, Children’s Hospital of Los Angeles, University of Southern California, Los Angeles, CA, USA and 3Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, MD, USA. Correspondence: Dr NN Shah, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 1W-3750, 9000 Rockville Pike, Bethesda, MD 20892-1104, USA. E-mail: [email protected] Received 29 May 2014; revised 22 August 2014; accepted 27 August 2014; published online 20 October 2014
Regulations for minor hematopoietic stem cell donors NN Shah et al
16 Table 1.
Medical risks to transplant donor
BM harvest
PBSC apheresis
Risks of general anesthesia
Central line placement with associated risks of pain, infection, bleeding and damage to the blood vessel Anemia Exposure to red blood blood transfusion (if needed to ‘prime’ the extracorporeal apheresis circuit for smaller donors) Exposure to red blood cell transfusion (if needed based on the Filgrastim with associated risks of pain, elevated white blood cell count and volume of marrow collected) splenomegaly with (rare) rupture Pain — Infection —
Abbreviation: PBSC=peripheral blood stem cell.
Step 1
Are the minor donors research subjects?
No
Federal regulations do not apply to the minor donor
Yes Step 2
Are there research risks?
No
Research can be approved by an IRB in all children (404/50.51)
Yes Step 3
Are the research risks greater than minimal?
No
Research can be approved by an IRB in all children (404/50.51)
Yes Step 4
Does the research offer donors a prospect of direct benefit?
Yes
No Step 5
Are the research risks greater than a minor increase over minimal?
No
Research can be approved by an IRB in all children provided the risk-benefit ratio is as favorable as available alternatives (405/50.52) Research can be approved by an IRB if it is likely to yield generalizable knowledge about the donor’s condition’ (406/50.53)
Yes Step 6
Research cannot be approved by an IRB(407/50.54)
Figure 1. Step assessment of risk to minor HSC donors in research settings. Step 1: Donors are research subjects when they meet the FDA or DHHS definition, or when the research introduces added risks. Step 2: Research risks are any risks that the donors would not face absent the research. Step 3: Research risks qualify as minimal when they do not exceed the risks ordinarily encountered in daily life or the risks acceptable for minor donors in the clinical setting. Step 4: Most transplant research does not offer the donor a therapeutic ‘direct benefit.’ Step 5: Most transplant research is designed to yield generalizable knowledge about the recipient’s condition, and not the donor’s condition. Step 6: Research that is greater than a minor increase over minimal risk that does not offer the potential of direct benefit cannot be approved by an IRB. The research must be reviewed and approved by an expert panel in order to be considered further.
(medical and/or psychological) that would not be present absent the research. In summary, this analysis suggests that minor donors should be considered research subjects under the following conditions (Table 2): 1. The investigators collect data or private identifiable information from the donor for research purposes. ((45CFR §46.102); DHHS) 2. The donor is the recipient of the test article or investigational device or serves as a control. ((21 CFR §50.3g); FDA) 3. The donor faces risks they would not face absent the research. Are there research risks? When minor donors qualify as research subjects, IRBs must evaluate whether they face research risks. Risks of a standard donation may include risk of anesthesia, vascular access line placement, filgrastim administration and apheresis,2,3 as well as psychological risks, such as donor guilt, if recipient outcomes are poor.8,9 However, FDA and DHHS regulations direct IRBs to consider as research risks only those risks that ‘result from the research, as distinguished from risks Bone Marrow Transplantation (2015) 15 – 19
of therapies subjects would receive even if not participating in the research.’10 Accordingly, when standard HSC collection procedures are performed, and the donor would have donated in the clinical setting (for a standard indication), the risks of a standard donation should not count as research risks. This suggests that HSC donors face research risks in four settings: 1. The research includes additional procedures or interventions that the donor would not face while donating in the nonresearch setting. 2. The research replaces one or more of the standard collection procedures with alternative or experimental approaches. 3. It is expected that the individual would not serve as a donor except in research (for example, the recipient indication for the HSCT procedure is not standard). 4. The investigational transplant poses greater risks to the recipient in comparison with a standard transplant, in which case the research might lead to increased risk of donor guilt should the recipient sustain transplant-related morbidity or mortality. © 2015 Macmillan Publishers Limited
Regulations for minor hematopoietic stem cell donors NN Shah et al
17 Minor increase over minimal risk
Minimal riska
More than a minor increase over minimal risk
Prospect of direct benefit
Section 46.405/50.52 Approvable by IRB 1. Risks justified by anticipated benefit 2. Risk/benefit profile as favorable as alternatives 3. Parental permissionb 4. Child’s assentc
Section 46.404/50.51 Approvable by IRB
No prospect of direct benefit
1. Parental permissionb 2. Child’s assentc
Section 46.406/50.53 Approvable by IRB 1. Commensurate with subjects’ experience 2. About subjects’ disorder or condition 3. Parental permissionb c 4. Child’s assent
Section 46.407/50.54d Approvable by secretary/commissioner 1. Expert consultation 2. Public review and comment 3. Addresses a serious problem affecting children 4. Consistent with sound ethical principles b 5. Parental permission 6. Child’s assentc
Figure 2. Federal Regulation for Pediatric Research and Associated Requirements. a‘Minimal’ risk is defined as risks that are not greater than the risks ‘ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests’ (§46.102 i/50.3 k). bPermission of one parent is sufficient for categories 404/50.51 and 405/50.52; permission of both parents, if reasonably available, is required for 406/50.53 and 407/50.54; the requirement for parental permission may be waived in cases that satisfy the conditions for waiver of informed consent. cAssent, defined as affirmative agreement, is required only if the IRB judges that the subjects are capable of providing assent; assent may be waived if the ‘intervention or procedure involved in the research holds out a prospect of direct benefit that is important to the health or well-being of the children and is available only in the context of the research’ (46.408 a/50.55) and also in cases that satisfy the conditions for waiver of informed consent. dThe 407/50.54 categories cover research that is not approvable in sections 404/50.51, 405/50.52, or 406/50.53. Hence, a study might fall into the 407/50.54 categories even though it does not pose more than a minor increase over minimal risk. For example, a study that poses a minor increase over minimal risk, but does not concern the subjects’ disorder or condition, could be referred for review in the 407/50.54 categories.
Table 2.
Examples for determining when a minor donor is a research subject
Category
Response Human Subject
Example/Clarification
Are data or private identifiable information collected for research purposes?
No
No
Yes
Yes
No
No
Yes
Yes
Is the donor donating hematopoietic stem cells No (HSC) for a nonstandard transplant? Yes
No
Research question implicates the recipient only. No private identifiable information or data from the donor are used for research purposes Additional blood, beyond what is clinically indicated, is obtained from the donor to perform additional research analysis. Standard procurement procedures alone would not qualify donor as a research subject If the donor is the target of the research intervention, then the donor is a human subject Donation for a standard transplant indication, albeit in research, may not qualify the donor as a human subject If the donor were providing HSCs for a recipient for whom transplant is not a standard indication and is only performed in the research setting
Is the donor the direct recipient of a drug or investigational device?
Yes
EVALUATING RESEARCH RISKS The federal regulations include four categories of pediatric research that are defined by the risk-benefit profile of the study in question (Figure 2). Minimal risk research IRBs can approve the enrollment of all children in ‘minimal’ risk research (45 CFR §46.404/50.51), defined as research that poses risks no greater than the risks ordinarily encountered in daily life or during routine examinations or tests (45 CFR §46.102i/50.3k). Most commentators interpret the risks ‘ordinarily encountered in daily life’ as those faced by average healthy children.11 Although this ‘objective’ interpretation protects children who face excessive © 2015 Macmillan Publishers Limited
risks in their daily lives (such as children who live in war-torn regions), it is challenging to apply to HSC donors. Consider a protocol testing new procedure that is designed to reduce the rate of complications associated with HSC collection. In this case, the risks to the donor in the research setting may be lower than the risks in the standard clinical setting. However, the risks of the HSC collection are still greater than the risks encountered in daily life by average children. Hence, the objective interpretation implies that this donor faces greater than minimal risk without a prospect of benefit, even though the risks associated with the research may well be lower than the risks the donor would face in the nonresearch setting. To avoid this counterintuitive outcome, whereby a donor could donate for a nonresearch transplant but not for a research transplant that Bone Marrow Transplantation (2015) 15 – 19
Regulations for minor hematopoietic stem cell donors NN Shah et al
18 would pose similar or decreased risks, we suggest that the research risks to a donor be considered minimal risk when they are no greater than the risks that this donor would otherwise face in the context of a standard procurement procedure. Does the research offer the prospect of ‘direct’ benefit to the donor? Research that is greater than minimal risk can be approved by an IRB when it offers subjects a compensating potential for ‘direct’ benefit (CFR §46.405/50.52). Although altruism and helping an ill sibling may offer some benefit to donors, most commentators and the American Academy of Pediatrics maintain that these do not represent direct therapeutic benefits. We support this approach as important for protecting pediatric subjects from the possibility that all pediatric research could be categorized as having potential for direct benefit on the grounds that it offers subjects the chance to help others. Greater than minimal risk research IRBs can also approve greater than minimal risk pediatric research when the risks do not exceed a ‘minor’ increase over minimal and the research is likely to ‘yield generalizable knowledge about the subject’s disorder or condition.’ (CFR §46.406/50.53). However, transplant research is typically designed to yield generalizable knowledge about the recipients’ condition, not the donors’. This suggests that the research involvement of minor donors typically cannot be approved in this category. CATEGORY §46.407/§50.54 Pediatric research that is not approvable by an IRB in the first three categories may be evaluated for possible approval in category §46.407/§50.54. Approval in this category requires review and recommendation by a panel of experts, an opportunity for public comment and final approval by the Commissioner of the FDA or the Secretary of DHHS. However, because this process is quite complex, labor intensive and time-consuming, it has been used rarely.12 Indeed, following the closure of the cooperative group HSC trial by a single participating center IRB,7 407 review was conducted and, while successful in reopening the trial, the long delay resulted in poor accrual and eventual closure prior to enrolling sufficient patients to address the primary question. TRANSPLANT FOR NONSTANDARD INDICATIONS Transplants performed in the research setting for nonstandard or novel indications pose special challenges and controversy. As previously stated, in such circumstances, we believe that the donor would qualify as a research subject, on the basis that participation in the research presents a research risk that would not be present except for the research (transplant for nonstandard indication). Taking into consideration the risks of a standard donation (for example, anesthesia or central line placement), which may be greater than minimal risk, and without the prospect of direct benefit, an IRB may not be able to approve such protocols for enrollment of minor donors. It seems counterintuitive, however, to prevent a minor from donating when the donation process itself poses the same risks to the donors, and the transplant offers a potential for benefit (for example, potential cure) comparable to that when transplantation is offered for standard nonresearch indications. For instance, consider the situation in which a transplant is being performed in the research setting for a novel life-threatening condition (for example, immunodeficiency) for which no other curative therapies exist, but where there is evidence to suggest that transplant may provide potential benefit. Despite the fact that transplant has not been established as the standard of care, a transplant in the Bone Marrow Transplantation (2015) 15 – 19
research setting may be the only available therapy to provide potential cure for a recipient with such a rare disorder. To address this issue, we take the view of an ‘analogous donor,’ and consider those donations in which the risks are no greater than the risks of commonly allowed procurements to be minimal research risk as for any other ‘analogous’ minor donor who would donate in a nonresearch setting. On the basis of the scenario above, and in circumstances in which there is evidence for potential of benefit to the recipient, we believe that such a protocol (for example, transplant for nonstandard indications) could be approved as posing minimal research risks for the donor (§46.404/50.51) using the ‘analogous donor’ approach, if the following pertain: ●
●
Although the donation is not performed regularly in the clinical setting for this disease, there is good evidence that the protocol offers the potential for important (and possibly curative) medical benefit to the recipient and an IRB has approved the protocol for the recipient. The risks of the donation are no greater than the risks of donation faced by an ‘analogous’ minor donor in the clinical setting for established indications.
In contrast, when the evidence of benefit from transplantation for a specific disease is controversial, or evidence of benefit is lacking, exposing minor donors to risk of HSC collection would require review by a 407 expert panel. AREAS OF ONGOING RESEARCH Much of this discussion has been based on the assumption that there is a clear established standard of care procurement procedure for minors with an established method for risk assessment. Efforts to define standards for collection procedures to minimize risk and optimize safety to minor donors are ongoing.2,3,5 As these standards become available, they can serve as a benchmark for determining whether the particular collection procedures that minors undergo pose additional risks beyond those associated with established clinical practice. It is similarly unclear how emerging technology, such as experimental manipulation of collected HSCs, may affect donors. The National Marrow Donor Program, which applies to adult unrelated donors, considers the use of any investigational device on a donor specimen to qualify the donor as a research subject. On the basis of our framework, experimental manipulation of donated cells would implicate the individual as a research subject only if it posed new risk to the donor (with risk assessment compared with standard methods), or it required the collection of private information from the donor for research purposes. Future efforts in the area of donor ethics should address the development of formal guidelines as to whether manipulation of the cells per se should imply that the donor is a research subject. Another important area of active research in transplantation includes assessment of the psychosocial risks that donors face.8,9,13 Incorporation of psychosocial risks in the risk assessment of minor donors is an area that is often not fully integrated, but needs to be incorporated—and specifically focusing on the risks in the research setting. However, in some cases it is possible that the psychosocial risk to the donor will be identical to those in the clinical setting; in other cases it is possible that donors could experience greater psychosocial risk, especially if benefit to the recipient is less certain. In addition, our proposed framework is based on the interpretation that a healthy minor donor generally cannot be considered as having a condition (that is, 46.406 cannot be applied to minor donors) and that they are not recipients of direct benefit (that is, 46.405 cannot apply). However, not all agree with © 2015 Macmillan Publishers Limited
Regulations for minor hematopoietic stem cell donors NN Shah et al
this view, and achieving a consensus on interpretation of the 405 and 406 statutes will be important to standardizing assessment of a minor donor on a research protocol. Along these lines, further streamlining of the 407 processes to help facilitate, rather than impede, research involving minor donors, and establishment of federal guidelines that involve healthy donor research, would be valuable in improving the evaluation of minor donors. CONCLUSION With the goal of protecting pediatric donors while allowing development of potentially life-saving therapies involving transplantation of cellular products from these allogeneic donors, we have proposed a systematic method to assess when minor donors qualify as research subjects, and when their participation can be approved under federal research regulations. We hope that this summary and algorithm, in addition to ongoing efforts to improve the safety of and minimize risks to minor donors, will provide a more comprehensive and systematic way for local IRBs and protocol development teams to evaluate the role of minor donors in transplant protocols. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research and the Warren Grant Magnuson Clinical Center.
DISCLAIMER The views expressed are the authors’ own. They do not represent any position or policy of the NIH, DHHS or US government.
© 2015 Macmillan Publishers Limited
19
REFERENCES 1 Pasquini M, Wang Z. Current Use and Outcome of Hematopoietic Stem Cell Transplantation. CIBMTR Summary Slides: Milwaukee, WI, USA, 2013. 2 Pulsipher MA, Chitphakdithai P, Logan BR, Shaw BE, Wingard JR, Lazarus HM et al. Acute toxicities of unrelated bone marrow versus peripheral blood stem cell donation: results of a prospective trial from the National Marrow Donor Program. Blood 2013; 121: 197–206. 3 Styczynski J, Balduzzi A, Gil L, Labopin M, Hamladji RM, Marktel S et al. Risk of complications during hematopoietic stem cell collection in pediatric sibling donors: a prospective European Group for Blood and Marrow Transplantation Pediatric Diseases Working Party study. Blood 2012; 119: 2935–2942. 4 Grupp SA, Frangoul H, Wall D, Pulsipher MA, Levine JE, Schultz KR. Use of G-CSF in matched sibling donor pediatric allogeneic transplantation: a consensus statement from the Children's Oncology Group (COG) Transplant Discipline Committee and Pediatric Blood and Marrow Transplant Consortium (PBMTC) Executive Committee. Pediatr Blood Cancer 2006; 46: 414–421. 5 Pulsipher MA, Chitphakdithai P, Logan BR, Navarro WH, Levine JE, Miller JP et al. Lower risk of serious adverse events and no increased risk of cancer after PBSC versus bone marrow donation. Blood 2014; 123: 3655–3663. 6 American Academy of Pediatrics CoB. Children as hematopoietic stem cell donors. Pediatrics 2010; 125: 392–404. 7 Memo Stem Cell Committee. ASCT0631, A Phase III Randomized Trial of G-CSF Stimulated Bone Marrow vs Conventional Bone Marrow as a Stem Cell Source in Matched Sibling Donor Transplantation, 2011. 8 Packman W, Weber S, Wallace J, Bugescu N. Psychological effects of hematopoietic SCT on pediatric patients, siblings and parents: a review. Bone Marrow Transplant 2010; 45: 1134–1146. 9 Wiener LS, Steffen-Smith E, Fry T, Wayne AS. Hematopoietic stem cell donation in children: a review of the sibling donor experience. J Psychosoc Oncol 2007; 25: 45–66. 10 Pulsipher MA, Nagler A, Iannone R, Nelson RM. Weighing the risks of G-CSF administration, leukopheresis, and standard marrow harvest: ethical and safety considerations for normal pediatric hematopoietic cell donors. Pediatr Blood Cancer 2006; 46: 422–433. 11 Field MJ, Behrman RE. The Ethical Conduct of Clinical Research Involving Children. The National Academies Press: Washington, DC, 2004. 12 Ross LF. Convening a 407 panel for research not otherwise approvable: "Precursors to diabetes in Japanese American youth" as a case study. Kennedy Inst Ethics J 2004; 14165–186. 13 Wiener LS, Steffen-Smith E, Battles HB, Wayne A, Love CP, Fry T. Sibling stem cell donor experiences at a single institution. Psychooncology 2008; 17304–307.
Bone Marrow Transplantation (2015) 15 – 19
Copyright of Bone Marrow Transplantation is the property of Nature Publishing Group and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
