Despite the increase in the rate of organ donations from deceased donors in recent years, the demand for deceased donor organs continues to exceed the supply of transplantable organs (see Chapter 1), making it important to maximize transplant opportunities and the likelihood that available organs will adequately function in recipients. Organ donor intervention research has the potential to improve outcomes for transplant recipients and to increase the number of transplants. Nevertheless, realizing this potential depends on the willingness of donors and their surrogates to allow the research to be done and on the willingness of transplant teams and transplant candidates to accept organs on which research has been performed. Trust in the U.S. organ donation and transplantation system and its processes involves confidence in and reliance on facts and nuances being fully and fairly communicated. Questions remain as to what the donation and transplantation community and society as a whole should do to maintain that trust, as opposed to what merely must be done to be in legal and regulatory compliance.
Obtaining authorization for donation from organ donors (or their surrogates) and consent for transplantation from transplant candidates has been required for decades. However, the conduct of organ donor intervention research raises important questions regarding the authorization and consent processes for both donors and transplant candidates:
- From an ethical and policy perspective, is authorization from the donor or the donor surrogate required to conduct research on
- donated organs prior to transplantation? If yes, to what level of detail?
- Does a donor’s authorization for transplantation automatically include authorization for research followed by transplantation? If so, under what circumstances?
- From an ethical and policy perspective, is consent from the potential organ recipient needed prior to that individual accepting a donated organ that has been involved in research? If yes, to what level of detail? How should these research processes be structured and organized to ensure a trustworthy system (see Chapter 4)?
In setting the context for its examination of this research, the committee reviewed 15 clinical studies that involved organ donor intervention research in order to determine (1) how researchers in the United States interpret the laws and regulations that apply to their studies, and (2) how studies conducted in countries other than the United States, which are subject to different laws and regulations, address these questions (see Table 3-1). This is only a snapshot of organ donor intervention studies (reviews include Feng, 2010; Dikdan et al., 2012) and points to issues to be discussed throughout the chapter regarding research authorization from donors and donor families and consent from transplant recipients.
Examples of Organ Donor Intervention Research Studies: Authorization for Research on Deceased Organ Donors
The investigators in several of the studies listed in Table 3-1 obtained authorization prior to including deceased donors in their research protocols. In studies by Ware and colleagues (2014) and Niemann and colleagues (2015), for example, if a deceased donor had not previously authorized donation, then the investigators asked the potential donor’s surrogate to authorize donation for the purposes of transplantation and of research. Niemann and colleagues (2015) noted that in the cases where a surrogate declined donation for the purpose of research out of concern that the organ would be used solely for research, the surrogate was asked whether donation would be authorized specifically for the study in question since the study included research followed by transplantation; in cases where a surrogate then agreed to research, “an addendum was made to the authorization form specifically stating authorization for enrollment in this donor management trial” (Niemann et al., 2015, supplementary appendix, p. 7).
In their review of authorization procedures used in a range of studies conducting deceased donor intervention research, Rey and colleagues (2011) noted:
If the decedent’s preferences are known, corresponding consent standards for organ donation should be followed; family assent would be encouraged but not required for decedents who had indicated preferences for research participation, and surrogates would not be authorized to consent if the decedent had clearly refused. (p. 281)
The committee’s analysis of the laws, regulations, and procedures for obtaining authorization for deceased organ donors will be provided later in this chapter.
Examples of Organ Donor Intervention Research Studies: Research Consent from Recipients of the Target Organ
Whether the research protections for human subjects that are detailed in the U.S. Federal Policy for the Protection of Human Subjects, the Common Rule, apply to recipients of organs that have been part of a research study has been the subject of debate and concern (Rey et al., 2011; Glazier et al., 2015; Carome and Wolfe, 2016). The majority of the studies summarized in Table 3-1 did not obtain research consent from the recipients of the organ that was the target of a deceased donor intervention. In those studies that did not obtain consent, the rationale was not fully detailed in the published description of the study. Ware and colleagues (2011) explained that
informed consent from lung recipients is not required in the BOLD study because the study poses minimal risk, it has traditionally been the role of the transplant surgeon to determine the relative risk of an organ, and, finally, there is no precedent in the transplant community for requiring recipient consent for donor management studies that pose minimal risk. (p. 54)
By contrast, Rey and colleagues (2011) offered the opinion that “recipients may obtain organs subjected to the donor interventions or organs from a control donor” and they are thus “no less ‘human research subjects’ than are recipients of blood products, bioprosthetic devices, or pharmaceuticals that have been randomly assigned to one or another preparative intervention” (p. 281).
One of the studies involved research interventions and data collection on the donors only, with no data collected from the recipients (i.e., Pérez-Blanco et al., 2005). (Note this study was not conducted in the United States and would have been subject to different laws and regulations.) Rey
Case Studies Involving Organ Donor Intervention Research
|Study Authors||Study Publication Year||Location||Donor Intervention||Target Organ||Non-Target Organ(s) Followed|
|Studies Conducted in the United States|
|Niemann et al.||2015||CA and NV, U.S.||Hypothermia||Kidney||All|
|Ware et al.||2014||CA and NV, U.S.||Nebulized Albuterol||Lung||All|
|Guarrera et al.||2010||NY, U.S.||HMP||Liver||n/aa|
|Koneru et al.||2005||NJ, U.S.||IPC||Liver||None|
|Studies Conducted Outside of the United States|
|Bral et al.||2017||Canada||NMP||Liver||n/aa|
|Ravikumar et al.||2016||U.K.||NMP||Liver||n/aa|
|Oniscu et al.||2014||U.K.||NRP||Kidney, Liver, Pancreas, Lung||None|
|D’Amico et al.||2013||Italy||NAC||Liver||None|
|Watson et al.||2010||U.K.||HMP v CS||Kidney||n/aa|
|Jochmans et al.||2010||Europe||HMP v CS||Kidney||n/aa|
|Schnuelle et al.||2009||Europe||Dopamine||Kidney||All|
|Moers et al.||2009||Europe||HMP v CS||Kidney||n/aa|
|Venkateswaran et al.||2008||U.K.||MP +/– T3||Lung||Heart, Liver, Kidney|
|Kotsch et al.||2008||Germany||MP||Liver||Kidneys|
|Pérez-Blanco et al.||2005||Spain||T3||Liver, Pancreas, Heart, Lung||None|
NOTE: CS = cold storage; HMP = hypothermic machine perfusion; IPC = ischemic preconditioning; IRB = institutional review board; MP = methylprednisolone; n/a = not available; NAC = N-Acetylcysteine; NMP = normothermic machine perfusion; NRP = normothermic regional perfusion; OPO = organ procurement organization; RCT = randomized controlled trial; T3 = triiodothyronine; U.K. = United Kingdom.
aEx vivo research, no non-target organ(s).
bConsent for participation in research was not explicitly stated in article.
|RCT||# of OPOs/Centers||# of Donors||# of Recipients||Reviewed by IRB||Consent from Donor or Surrogate for Research||Consent from Recipient of Target Organ||Consent from Recipient of Non-Target Organ|
|Studies Conducted in the United States|
|Studies Conducted Outside of the United States|
SOURCES: Koneru et al., 2005; Pérez-Blanco et al., 2005; Kotsch et al., 2008; Venkateswaran et al., 2008; Moers et al., 2009; Schnuelle et al., 2009; Guarrera et al., 2010; Jochmans et al., 2010; Watson et al., 2010; D’Amico et al., 2013; Oniscu et al., 2014; Ware et al., 2014; Niemann et al., 2015; Ravikumar et al., 2016; Bral et al., 2017.
and colleagues (2011) argued that, strictly speaking, in the types of studies where no data are collected from recipients, the recipients might not be considered human research subjects under current regulations.
For example, if outcomes of such studies were limited to metrics such as the number of organs recovered or results of recovered organ biopsies [performed before transplantation], then recipients would not be research participants because there are no recipient data collected. Recipient consent would be unnecessary. (Rey et al., 2011, p. 282)
But these same authors go on to argue that there is little difference, from the perspective of the recipient, between donor intervention studies that collect data on the recipients and those that do not; “in both cases, recipients are exposed to similar risks and could receive similar organs. Thus, requirements for research consent should apply equally to all recipients of organs regardless of investigators’ decisions to collect recipient data” (Rey et al., 2011, p. 282).
Disclosing clinical risks is a routine part of the process for obtaining consent from a candidate for organ transplantation. In the above interpretations of regulations, disclosing clinical risks is viewed as including the disclosure of clinical risks that arise from research involved organs. This issue will be explored below, along with the debate about whether in the absence of collecting specific, additional data for research purposes—that is, beyond the clinical data routinely reported about transplant recipients—recipients of research organs are research subjects whose research-related consent is also required.
Examples of Organ Donor Intervention Research Studies: Research Consent from Recipients of Non-Target Organs
When a research intervention is administered to a deceased donor prior to organ recovery and the intent is to have an effect on a specific organ such as a kidney (i.e., the target organ), the intervention could potentially affect other organs that will also be transplanted (i.e., non-target organs). None of the studies included in Table 3-1 indicated that they had sought consent from the recipients of non-target organs. However, the reasons that argue in favor of considering the recipients of target organs as human research subjects may apply equally to recipients of non-target organs because the research intervention may have an impact on the non-target organ and thus on its recipient. The potential for effects on non-target organs was explicitly recognized by Niemann and colleagues (2015 [noted in supplementary materials to the journal article]), and they excluded deceased donors who had the potential to donate a heart or a lung from the trial until preliminary
data provided assurance that hypothermia did not have deleterious effects on these organs. Notably, the preliminary data did not rule out the possibility of deleterious effects but instead provided evidence that any such effects were not dramatic enough to become apparent in the preliminary data. Similarly, donors with the potential for split liver donation were permanently excluded from the trial because of the potential for hypothermia to have deleterious effects on coagulation during dissection. These concerns about non-target organs highlight the possibility that some interventions, such as adjusting the body temperature of a donor, could influence any organs subsequently transplanted from that donor. This report will examine the controversies surrounding whether and under what conditions recipients of non-target organs become research subjects and need to be so informed so that they can choose whether to provide research-related consent or refusal.
OVERVIEW OF THE LAWS AND REGULATIONS GOVERNING ORGAN DONATION, TRANSPLANTATION, AND RESEARCH PARTICIPATION
Uniform Anatomical Gift Acts
The United States operates its organ donation system under an “opt-in” model in which the individual while alive or the next of kin or surrogate after the individual’s death must explicitly choose to donate organs. In contrast, several European (e.g., Austria, Belgium, France, and Spain) and South American (e.g., Argentina, Colombia) nations utilize an “opt-out” system that presumes donor authorization and participation in the absence of an explicit objection (Shepherd et al., 2014; Samuel, 2017). U.S. states began enacting organ donation and procurement legislation in the 1960s when organ transplantation became a viable medical procedure. In 1968 the National Conference of Commissioners on Uniform State Laws promulgated the Uniform Anatomical Gift Act (UAGA) with the intent of promoting uniformity among states and simplifying the process of obtaining organs from deceased persons (Goodwin, 2006). The UAGA is not a federal law, but rather is a template that states can use in developing their own laws governing anatomical gifts. Each state and the District of Columbia adopted the 1968 UAGA (AOPO, 2017). Due to its universal adoption, the 1968 UAGA is sometimes mistaken as federal law.
The act permitted adults of sound mind to donate all or any body parts at death and required that donor intent be expressed in writing and signed by the declarant and two witnesses. In the absence of the decedent’s authorization of donation prior to his or her death and in the absence of the decedent’s known objection, the UAGA permitted the decedent’s next of kin to donate the decedent’s organs. To minimize confusion regarding
who among next of kin is legally authorized to donate, the UAGA ranks relatives’ legal authority to donate their deceased kin’s organs by status. For example, the law ranks spouses above siblings, adult children, and parents. Even though the 1968 UAGA assigned priority to the decedent’s prior decision to donate, it did not clearly state that the decedent’s decision to donate (in contrast to the decedent’s objection to donation) should override the next of kin’s choice (NCCUSL, 1968). However, this priority was explicitly stated in the Comments to the 1968 UAGA: “Subsection (e) [of Section 2] recognizes and gives legal effect to the right of the individual to dispose of his own body without subsequent veto by others” (NCCUSL, 2003, p. 117). The lack of clarity in the UAGA itself (in contrast to the Comments), made it easier for organ procurement teams to allow objecting next of kin to override the decedent’s prior expressed decision to donate organs (Goodwin, 2006).
The commissioners revised the UAGA in 1987 and again in 2006. The revisions in the 1987 UAGA were intended to accomplish several goals. First, they were intended to increase the supply of organs to meet rapidly growing demand. That is, while the 1968 UAGA clarified the status of who was legally authorized to donate, it did not explicitly attempt to increase the organ supply (NCCUSL, 1987), even though that was an implicit goal. Second, the 1987 UAGA was drafted to come into compliance with the newly adopted federal law, the National Organ Transplant Act (NOTA).1 NOTA, enacted in 1984, banned the exchange of organs for “valuable consideration,” for example, paying donors for organs (NCCUSL, 1987). The 1968 UAGA had not indicated whether organs could be sold, leaving the issue open to interpretation (NCCUSL, 1968). The 1987 version adopted the ban on selling organs, but the “valuable consideration” language of NOTA was (and continues to be) subject to interpretation by the U.S. Department of Justice. (A more detailed discussion of NOTA appears in the following section.)
The 1987 UAGA also removed the requirement that two witnesses sign the donation document. Furthermore, it stressed that an individual’s choice to donate organs cannot be revoked by others, thereby removing any uncertainty in this matter. It also granted medical examiners and coroners the authority to authorize the removal of a “body part” for transplantation under certain conditions when no prior objection by the decedent was known (sometimes misleadingly termed “presumed consent”) and when efforts had been made to contact the next of kin (NCCUSL, 1987). Only 26 states adopted the 1987 UAGA—other states adopted non-uniform amendments to their anatomical gift acts—resulting in a lack of uniformity among the states (NCCUSL, 2006).
1 National Organ Transplant Act, Public Law 98-507, 98th Cong. (October 19, 1984).
Drafters of the 2006 UAGA removed the provision that allowed medical examiners and coroners to authorize removal of a “body part” for transplantation (NCCUSL, 2006), particularly in response to controversies that had arisen regarding body part removal without authorization and to disparities in race and class that had been observed in these decisions. For example, a California study revealed that more than 80 percent of “presumed consent” cornea donors were black and Latino and that none of the families had been notified that the Los Angeles Coroner’s office had procured their decedents’ corneas (Goodwin, 2006). In some instances, where corneas were recovered, the relatives were not asked about their authorization for donation (Frammolino, 1997a,b) and others explicitly stated that they did not authorize donation (Goodwin, 2006). Some municipalities were sued in the wake of the 1987 UAGA, specifically in relation to this provision (O’Neill, 1998). Relatives of persons whose tissues were removed without authorization claimed that the states had violated their constitutional rights and desecrated their deceased relatives’ bodies.2
Like the prior iterations of the UAGA, the 2006 law—the most recent version (last amended in 2009)—provides that individuals aged 18 years or older may choose or refuse to make an anatomical gift. The law also permits anyone applying for a driver’s license to offer authorization, allows for symbolic or oral communication of donative intent, disallows the possibility of authorization for the removal of body parts for transplantation by a medical examiner’s office without the decedent’s or the surrogate’s authorization, and lets individuals other than the decedent make an anatomical gift unless the decedent expressly refused donation during his or her lifetime. The gift may be of the entire body or parts of the body, and the donor determines whether the gift will be used for education, teaching, research, or transplantation. The UAGA establishes the donation as property that can be transmitted to others by authorization of the decedent before death, by will, by next of kin or surrogate after death, or, in their absence, by the state (NCCUSL, 2006). This statutory scheme is similar to that provided for other forms of property. With the goal of improving uniformity in the organ donation legislation across states, the 2006 UAGA, like the 1987 version, includes a first-person authorization provision preventing any family member or other responsible party from overriding a decedent’s documented wish in favor of donation, just as they cannot override the decedent’s refusal to make a gift. The act allows for express authorization to make an anatomical gift in several forms, including through a statement or symbol on a driver’s license or a donor card or via a donor registry (NCCUSL, 2006).
2Newman v. Sathyavaglswaran, 287 F.3d 786, 800 (9th Cir. 2002); Brotherton v. Cleveland, 923 F. 2d 477, 481 (6th Cir. 1991).
As of June 2017, 46 states, the District of Columbia, and the U.S. Virgin Islands had adopted the 2006 UAGA (Uniform Law Commission, 2017b). However, many of the states that enacted the 2006 UAGA have added or modified amendments, while others have yet to adopt the updated act (Verheijde et al., 2007, HRSA, 2011). As a result, the application of the 2006 UAGA remains inconsistent (Uniform Law Commission, 2017a). Furthermore, each state maintains its own donor registry with many of these registries linked to drivers’ licenses. States also may differ on what qualifies as authorization (HRSA, 2011). Despite these differences, all states must comply with the federally mandated ban in NOTA on the exchange of organs for “valuable consideration” because federal law supersedes any state provisions on this issue.
National Organ Transplant Act of 1984
No national system existed before 1984 to oversee the recovery and allocation of organs from deceased donors for transplant. Because organs were in short supply, there was competition for and unequal access to donor organs. In response, Congress passed NOTA (McDonald, 1988). The intent of NOTA is to ensure an equitable allocation of donor organs and to increase the number of organs available for transplantation. NOTA defines organs as the heart, lungs, liver, kidney, pancreas, and other organs, such as the small intestine, designated by the Secretary of the U.S. Department of Health and Human Services (HHS). NOTA also bans the sale of human organs for transplantation, with violations of the law punishable by up to 5 years in prison and a fine of $50,000. However, NOTA allows transplant surgeons, hospitals, transporters, and organ procurement organizations (OPOs) to receive compensation for their services. Following NOTA’s enactment, the Uniform Law Commission amended the UAGA, as noted above, to prohibit the purchase and sale of organs for transplantation (NCCUSL, 1987), but generally it remains legal to purchase and sell blood products, sperm, and ova (Cohen, 2012).
NOTA authorized the Secretary of HHS to form the nationwide Organ Procurement and Transplantation Network (OPTN) to coordinate the donation and transplantation system and process. The Omnibus Budget Reconciliation Act of 19863 requires that all medical centers performing organ transplantation participate in the OPTN or forfeit their eligibility for federal Medicare and Medicaid payments. While membership in the OPTN is voluntary, in practice this legislation made membership in the OPTN and
3 Omnibus Budget Reconciliation Act of 1986, Public Law 99-509, 99th Cong. (October 21, 1986).
compliance with OPTN policy mandatory for all U.S. transplant centers because all of them accept federal payments.
In 1998 HHS promulgated regulations known as the “Final Rule”4 to guide both the structure and the operation of the OPTN and to direct the OPTN to standardize transplant waitlist criteria and to group transplant candidates by medical urgency in order to allocate organs to the sickest patients first. Per NOTA requirements, the OPTN maintains a national waitlist of organ transplant candidates, allocates deceased donor organs to candidates on the waitlist, establishes policies concerning organ allocation, sets quality standards for the acquisition and transplantation of organs, coordinates the transportation of organs from OPOs to transplant hospitals, analyzes and publishes data concerning transplantation, and reports comparative costs and outcomes from the nation’s transplant centers.
The United Network for Organ Sharing (UNOS) is a private nonprofit entity under contract with the Health Resources & Services Administration (HRSA) to operate the OPTN. NOTA also established regional OPOs, which are nonprofit entities responsible for coordinating the acquisition, preservation, and transportation of organs from donor hospitals to transplant centers. OPTN divides the United States into 11 geographic regions, which are further divided into donation service areas (DSAs); a DSA is a defined geographical area that is served exclusively by a single OPO (OPTN, 2017a). The DSAs vary widely in terms of population size, the number of transplant centers and candidates, and the death rate of potential organ donors (SRTR, 2017b). UNOS promulgates the policies and standards for OPOs, and all OPOs are members of the OPTN (OPTN, 2017d). Members of the OPTN also include transplant centers, histocompatibility laboratories, medical scientific organizations, and public organizations.
The OPTN’s policies primarily focus on how individual organs are allocated among waitlisted candidates. There are separate policies for each organ (heart, lungs, liver, kidneys, intestine, and pancreas). Allocation policies take into consideration the location of the transplant candidates and the first criterion for the matching process, with the exception of livers, is the identification of a candidate within the OPO or donor hospital’s DSA. If a suitable candidate is not found locally, OPTN/UNOS can offer the organ to regional candidates, followed by national candidates (OPTN, 2017a). OPTN/UNOS uses allocation algorithms that consider compatibility and other factors to identify suitable transplant candidates for specific organs. In general, the algorithms take into consideration a candidate’s current medical condition, the length of time spent waiting for an organ, and in some cases a candidate’s prognosis as determined by objective clinical tests (OPTN, 2017a). The allocation systems frequently undergo revision.
4 42 C.F.R. Part 121.
The transplant coordinator from a transplant center enters each transplant candidate’s medical information into the OPTN/UNOS database, UNetSM, and designates the candidate as “active”—meaning that the candidate can receive an organ at any given time—or “inactive”—meaning either that the candidate is not medically suitable for transplantation at that time or that the candidate needs to complete eligibility requirements before being listed as active. The database matches information about a donor organ with the medical characteristics of active candidates on the waitlist. This generates a list that ranks active candidates according to the allocation rules. The OPTN offers the organ to the transplant center of the top-ranking matched candidate. If the organ is refused by either the transplant candidate or the candidate’s transplant hospital, the OPTN contacts the next highest ranking matched candidate’s transplant center. The process continues until the OPTN finds a candidate (and transplant hospital) willing to accept the organ (OPTN, 2017a). OPOs receive fees for coordinating this process; under NOTA these fees are defined as “reasonable payments associated with the removal, transportation, processing, preservation, quality control, and storage of a human organ.”5
In 1987 NOTA established the Scientific Registry of Transplant Recipients (SRTR) to track information about transplant candidates and recipients and transplant procedures that are deemed necessary for the ongoing evaluation of organ transplantation. The SRTR databases contain both historical and up-to-date information about the transplantation process, including detailed information on waitlist candidates, transplant recipients, and survival statistics. These data help inform the development of “evidence-based policy to support analysis of transplant programs and OPOs, and to encourage research on issues of importance” related to transplantation (SRTR, 2017a).
The Common Rule
The Federal Policy for the Protection of Human Subjects, or the Common Rule, was published in 1991 and is the basic set of U.S. federal regulations that protect all human subjects in any federally funded research. Specifically, it states “the basic provisions for institutional review boards, informed consent, and Assurances of Compliance,” and it “applies to all research involving human subjects conducted, supported or otherwise subject to regulation by any federal department or agency which takes appropriate administrative action to make the policy applicable to such research.”6 In addition, “Research that is neither conducted nor supported by a federal
5 National Organ Transplant Act, Public Law 98-507, 98th Cong. (October 19, 1984).
6 45 C.F.R. § 46.101.
department or agency but is subject to regulation as defined in § 46.102(e) must be reviewed and approved, in compliance with § 46.101, § 46.102, and § 46.107 through § 46.117 of [the Common Rule], by an institutional review board (IRB) that operates in accordance with the pertinent requirements of this policy.”7 It is relevant to note that research covered under the Common Rule also “may be subject to further appropriate review and approval or disapproval by officials of the institution.”8
The Common Rule states that “Human subject means a living individual about whom an investigator (whether professional or student) conducting research obtains (1) Data through intervention or interaction with the individual, or (2) Identifiable private information.”9 By virtue of not being “living individual[s],” donors who are declared deceased by neurologic or circulatory criteria (see Chapter 1) fall outside of the protections of the Common Rule, and therefore obtaining permission from deceased individuals (or their surrogates) is not required for their participation in research. To be clear, even though the requirement of informed consent under the Common Rule does not apply to deceased donors, authorization for organ donation, even if the organs are used only for research purposes, is still required under the UAGA. The ethical principles inherent in the UAGA focus on respect for persons by honoring the decedent’s determination of what should be done with his or her body after death (see Chapter 2).
A final rule10 amending provisions of the Common Rule was promulgated on January 19, 2017, with an effective date of January 19, 2018 (Federal Register, 2017). The final rule “is intended to better protect human subjects involved in research, while facilitating valuable research and reducing burden, delay, and ambiguity for investigators” (Federal Register, 2017, p. 7149). The purpose of the new regulatory action is to promote research by asking human subjects to “assume risk to advance the research enterprise, which benefits society at large” (Federal Register, 2017, p. 7149). The revised definition of human subjects reads,
Human subject means a living individual about whom an investigator (whether professional or student) conducting research: (i) Obtains information or biospecimens through intervention or interaction with the individual, and uses, studies, or analyzes the information or biospecimens; or (ii) Obtains, uses, studies, analyzes, or generates identifiable private information or identifiable biospecimens. (Federal Register, 2017, p. 7260)
7 45 C.F.R. § 46.101 (a)(2).
8 45 C.F.R. § 46.112.
9 45 C.F.R. § 46.102(f).
10 This final rule of the Common Rule is not to be confused with the Final Rule that guides the structure and operation of the OPTN.
Even with this revised language, deceased donors are still not considered human subjects within the meaning of the Common Rule, although authorization for donation is still required for compliance with the UAGA. The Common Rule’s regulations that are pertinent to transplant recipients are discussed in detail later in the chapter.
U.S. Food and Drug Administration Regulations
The U.S. Food and Drug Administration (FDA) has regulations pertaining to research on deceased organ donors that are similar to but not identical with those in the Common Rule. The corresponding definition in FDA regulations reads, “Human subject means an individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy human or a patient.”11 FDA regulations do not specify whether one must be alive to be a human subject. Nevertheless, this language has been understood by ethics, regulatory, and legal communities to imply that deceased donors are not human subjects because they are neither “healthy humans” nor “patients,” and it is strained to think they become a participant in research after death (Glazier et al., 2015; Rodrigue et al., 2016). However, significant confusion remains in the transplant community as to how to interpret the above language (Rodrigue et al., 2016). The committee interpreted the regulations to mean that neither the Common Rule nor FDA’s human subjects research regulation applies to deceased organ donors even though the UAGA still applies to deceased donors. (Later in this chapter, consideration is given to whether and to what extent these regulations may apply to the transplant recipients of donor organs that have been a part of research.)
UAGA and Donation
The 2006 UAGA identifies four distinct purposes of an anatomical gift: transplantation, therapy, research, or education (see Box 3-1). The problem the committee grappled with is the conjunction of “transplantation” and “research” or, more specifically, organs that are the subject of research, conducted either in a deceased donor or after organ recovery from a deceased donor, and then made available for transplantation. Making a gift for one of the four identified purposes (e.g., transplantation) does not in and of
11 21 C.F.R. § 50.3(g) and § 56.102(e).
itself preclude using the gift for another purpose (e.g., research) unless the donor or surrogate has specified otherwise, such as opting out of the other purpose at the time of authorization.
This is made clear by Section 8(f) of the 2006 version of the UAGA12:
(f) In the absence of an express, contrary indication by the donor or other person authorized to make an anatomical gift under Section 4, an anatomical gift of a part for one or more of the purposes set forth in Section 4 is not a limitation on the making of an anatomical gift of the part for any of the other purposes by the donor or any other person under Section 5 or 10. (p. 29)
Therefore, it is plausible to read this section of the UAGA as treating the authorization for either transplantation or research to constitute authorization for the type of research that is the focus of this report, i.e., organ donor
12 See also comment to Section 8: “Under subsection (f) the donor’s gift of a part for one purpose does not preclude another person from expanding the gift to include another purpose under either Section 5 or 10. For example, suppose the donor signs a document of gift stating: ‘I give my kidney for transplantation.’ Following the donor’s death, an individual listed in Section 9 could expand that gift to include research in the event the kidney was not medically suitable for transplantation. The right to expand the purposes of the gift can be restricted by the donor” (NCCUSL, 2006, p. 31).
both purposes (transplantation and research) should be authorized to comply with the UAGA and ensure that the gift is used consistent with the donor’s intent. This is also consistent with the ethical directive to maintain the public’s trust in the donation system and provide appropriate transparency as to how donated organs are used. As a matter of practice this can be achieved by confirming that a donor’s authorization in a registry or an authorization form signed by an appropriate surrogate includes research use of gifted organs and tissues.
It is important to recognize the donor’s right under the UAGA to direct how the anatomical gift can be used. An organ specifically gifted only for transplantation purposes cannot be used for research without violating the UAGA (which includes criminal penalties for certain intentional violations). The OPO [organ procurement organization] and the transplant team, as custodians of the gift are responsible for ensuring that the organs are used only for the purposes authorized. (Glazier et al., 2015, p. 2254)
The committee believes that this ambiguity deserves clarification. As it stands, such ambiguity may be an obstacle in advancing innovative organ procurement and transplantation strategies. Thus, resolving these concerns will be key to improving the overall donation and transplantation system in the United States.
The UAGA discussion thus far has focused on authorization by the decedent. However, as mentioned in Section 4 of the Act, other individuals, such as next of kin, may also authorize a gift.14 Most often in the cases
13 Part of the difficulty lies in the lack of definitions of the four purposes. As the comment to Section 4 of the UAGA states, “The terms ‘transplantation, ‘therapy,’ ‘research,’ and ‘education’ are not defined in this [act]. Rather, they are defined by their common usage in the communities to which they apply. In general terms, transplantation refers to the removal and grafting of one individual’s body part into the body of another individual. Research is a process of testing and observing, the goal of which is to obtain generalizable knowledge, while therapy involves the processing and use of a donated part to develop and provide amelioration or treatment for a disease or condition. Education posits the use of the whole body or parts to teach medical professionals and others about human anatomy and its characteristics” (NCCUSL, 2006, p. 19). This seems to suggest a view that transplantation is one thing, research another, and never the two shall meet. But of course, the category that is the focus of this report is exactly where the two intersect. The separateness of the categories in the minds of the drafters is further reinforced by the sample gift authorizations that the UAGA authors review in their comments on Section 5 one of which has a check box for three configurations “Transplantation or therapy” versus “Research or Education” versus “Both” and the other with check boxes for “only transplantation and therapy,” “only research and education,” and “transplantation, therapy, research, or education” (NCCUSL, 2006, pp. 22–23).
14 Details about which individual qualifies as a surrogate to make a gift are clarified in Section 9 of the UAGA.
where a surrogate authorizes the gift, the laws still apply in the same manner as when the donor him- or herself authorizes the gift, and thus the interpretation of the relevant laws remains the same.
One other section of the UAGA that has relevance to how authorization for donor intervention research should be approached is Section 11, which gives priority to transplantation or therapy over research or education (see Box 3-2). However, two ambiguities in the language complicate the interpretation of how to handle organ donor intervention research followed by transplantation under this Section. The first ambiguity is the language of Subsection (d):
if there is more than one purpose of an anatomical gift set forth in the document of gift but the purposes are not set forth in any priority, the gift must be used for transplantation or therapy, if suitable. If the gift cannot be used for transplantation or therapy, the gift may be used for research or education. (NCCUSL, 2006, p. 39)
In the context of this report, the UAGA indicates that a gift specified for transplantation cannot be used for research (when also specified) unless it is impossible to use that organ for transplantation. This limitation raises the question whether conducting research on the donor or the donor organ when it will be followed by transplantation comports with or violates this rule. That is, would it be correct to say that the organ “was used for transplantation” under the first sentence of Subsection (d) or to say the organ “was used for research” under the second sentence of Subsection (d)? The second sentence only takes effect when the organ “cannot be used for transplantation,” but the intended endpoint of organ donor intervention research is the act of transplanting the organ. Although the research and the transplantation are sequential in time due to necessity, they are a conjoined process. However, the organ might ultimately not be transplanted because (1) the research made the organ unusable; (2) the organ was unusable and was not repaired by the research; or (3) the organ is not transplanted because of other circumstances unrelated to the research. But in the case of donor intervention research, the intent of the research is to improve the transplant outcome for current and future transplant recipients.
The second ambiguity pertains to Section 11(f), which states that
if a document of gift specifies only a general intent to make an anatomical gift by words such as “donor,” “organ donor,” or “body donor,” or by a symbol or statement of similar import, the gift may be used only for transplantation or therapy, and the gift passes in accordance with Subsection (g). (NCCUSL, 2006, p. 39)
This raises the question of whether “transplantation or therapy” as used in this section includes research followed by transplantation. Importantly, several states have already adopted laws that allow organs to also be used for research (in addition to transplantation) when only a general intent to make a gift has been authorized (Glazier et al., 2015).
In summary, the language of the UAGA is ambiguous concerning when it is permissible to conduct research on deceased organ donors or recovered donor organs that will be followed by transplantation.15 The committee
15 To be fair, there is an arguable work-around in the act itself. As a comment in Section 11 explains, “If a gift made under Section 4 is limited to transplantation or therapy by Section 11(e) or (f), procurement organizations could approach persons with a priority to make gifts under Section 9 to expand the purpose of the gift to include research or education and obtain their consent to use the gift for those purposes in the event the gift is unsuitable for transplantation or therapy.” This seems to suggest that the OPO could approach a donor family and ask them to expand their gift to allow not just “transplantation” but “research followed by
considered several potential approaches to rectify this ambiguity. One option would explicitly add research followed by transplantation as an additional purpose for donation in the UAGA and explicitly recognize that the donor or surrogate can authorize donation for the purposes of transplantation, research followed by transplantation, therapy, research, or education. If such a change were made, then when the donor or surrogate specified transplantation but not research followed by transplantation, the organ would not be available for organ donor intervention research. Such an approach would maximally empower the individual authorizing donation to express his or her preferences, but it could potentially overload the individual with too many choices and engender choice paralysis (Iyengar and Lepper, 2000). The committee was concerned that many potential donors
transplantation.” It is a unclear whether the drafters intended for this provision to be used in this way because they included the proviso “in the event the gift is unsuitable for transplantation or therapy,” which is not true in the type of research that is the subject of this report.
would inaccurately interpret the term “research followed by transplantation” to involve objectionable manipulations of the body and thus refuse to participate in research that they would otherwise want to participate in if they fully understood what the actual research entailed and its potential benefit to the organs, to the recipients of these organs, and to the field of transplantation. Because much of the authorization occurs at departments of motor vehicles (DMVs),16 it would also impose burdens on those who work at those institutions to be prepared to counsel those considering donation about the differences between authorization for transplantation and authorization for research followed by transplantation. The committee also recognized, based on past experience, that amending the UAGA to explicitly discuss the category of research followed by transplantation and securing the wide adoption of the revised version would be no easy task.
Another option that the committee considered is to amend the UAGA to explicitly recognize that when the potential donor or the surrogate does not specify otherwise, the authorization for transplantation should be treated as also encompassing authorization for research followed by transplantation. If such an approach were taken, the next revision of the UAGA could explicitly recognize that authorization for transplantation also authorizes research followed by transplantation. This option would be desirable if one believed that when potential donors or surrogates authorize transplantation, they are seeking to make a gift of life, and research followed by transplantation is aimed at making such a gift of life more effective, without foreseeably compromising the quality of the gift of the specific organ. While there may be some potential donors who would be comfortable with donation for transplantation but not with donation for research followed by transplantation, such donors could explicitly state that their donation is for transplantation only. To ensure transparency and respect for each individual’s right to decide, donors would need to understand that they have this option and would need to be provided with opportunities to learn more about organ donor intervention research and to be informed that the aim of this research is also to transplant the organs. Explicit information would need to be widely disseminated (including through DMVs, registries, and other sources of organ donation information) so that donors would be aware that by authorizing transplantation they would also be authorizing research followed by transplantation. In this way, those individuals who may be concerned about the research use of their organs (followed by transplantation) can clarify what they do and do not want to authorize.
In exploring these options the committee did not identify empirical evidence that quantified the public’s sentiment on these options. More work
16 These agencies have varying names across states and the acronym DMV is used here to simplify the discussion.
needs to be done to learn about the strengths and limitations of each of these options and to determine how best to provide potential donors and surrogates with clear choices that move the field of organ transplantation forward in saving and improving lives. Specifying the rules would bring much needed clarity to the UAGA, protect OPOs and transplant teams from the risks of operating in a legal “grey zone,” and provide a set of clear default rules for donors so that they can understand what will happen based on what kind of gift they authorize.
There are other issues regarding the UAGA and research followed by transplantation that need clarification. For those individuals or surrogates who indicate a general intent to donate but do not indicate a specific purpose for that donation, the committee concludes that authorization for donation should be treated as also encompassing authorization for research followed by transplantation. Several states already have laws in place that go in this direction in that a general intent to donate authorizes transplantation and also that it authorizes research if the organ cannot be used for transplantation (Glazier et al., 2015). The UAGA could make this explicit and note that the general intent to donate would authorize research followed by transplantation.
First Person Donation: Individuals Providing Authorization
The most common occasion on which an individual specifies preference for being an organ donor is at the time of obtaining or renewing a driver’s license at a state DMV. There are 53 donor registries through these agencies (i.e., in each of the 50 U.S. states, the District of Columbia, Puerto Rico, and the U.S. Virgin Islands) (HRSA, 2017). In addition, Donate Life America operates a donor registry at the national level (Donate Life America, 2017).
Although the practice of providing authorization for organ donation at a DMV may be perceived as standardized, it is hardly systematic or nationally uniform. The committee obtained and reviewed the organ donation authorization forms of 26 different DMVs (25 states and the District of Columbia). These forms were ones that were accessible through the DMV websites. Wide variation was seen in how organ donation was addressed in these forms (see Box 3-3 for select examples of the variation). Furthermore, there can be a lack of communication between DMVs and hospital databases and a lack of sharing the information across state lines (e.g., if an individual registered in one state but died in another state, it may be difficult to ascertain whether the individual chose to be an organ donor). As a result, an individual’s intention to donate could be missed because the established systems do not always allow for effective coordination and communication among institutions.
These challenges are compounded by the fact that there is no standard practice for recording an individual’s preferences for donating organs for the purpose of research, whether through a declaration at DMV or through another nongovernmental declaration. In fact, many DMV forms are silent regarding donation for the purpose of research: Only 2 out of the 26 forms that the committee reviewed had any mention of research related to organ donation. One such example—New York—is shown in Box 3-3. In instances where research is not specified, the OPO would need to get authorization for research from the surrogate because, as stated earlier in this chapter, the UAGA default legal provisions hold that if a person has agreed to be a donor with no further clarification about research, this authorizes transplantation or therapy only, and authorization must be obtained for using the gift for other purposes (i.e., the “grey area” referred to earlier in this chapter in the discussion of the UAGA).
OPOs and the Donate Life America registry provide information to the general public regarding organ donation through different media, including websites, brochures, handouts, and contact information for relevant organizations (e.g., OPOs, OPTN/UNOS, Association of Organ Procurement Organizations). However, there are no requirements for what information about organ donation options, including research, should be provided to individuals who are contemplating registering to be an organ donor. The lack of guidance and the need to be transparent with the public raise the question whether there should be federally mandated requirements for donor registries concerning what information must be provided at the time of registration, how questions of donation should be worded, and what information should be made available on websites, brochures, handouts, etc.
Processes for obtaining authorization for organ donation, including for what purposes the donated organ may be used, should be made more consistent across the United States. Such consistency would make the process simpler and more informative to the individual considering donation as well as making the process more useful to transplant professionals acting on that information. Importantly, if organ donor authorization processes were more uniform in offering all potential options, donor intent would be more transparent. Simplifying the process would mean that organizations acting as donor registries would use one simple set of language for providing information and obtaining authorization. Anyone considering donation would receive the same options and information for donation no matter where they registered. Establishing the same format, level of detail, options, and clear explanations would demonstrate transparency in the process presented to those determining whether or not to donate and whether to qualify their decision by permitting or refusing organ donor intervention research prior to transplantation. Full disclosure and transpar-
ency are essential for establishing and ensuring long-term public trust in organ donation and transplantation.
Parallel to this, and as a reinforcement, lay language informational content should be developed and provided to individuals considering the options for donation. Messaging and communication strategies regarding organ donation and donor intervention research need to be developed and thoroughly tested to meet the health literacy needs across the general public. It will be important to identify the potential benefits of transplantation with organs that have been the object of organ donor intervention research in awareness and educational programs about organ donation. This is particularly important for populations who may be suspicious of research because of a long history of biomedical research abuses (see Chapter 2). The committee concluded that the testing, development, and implementation of lay-friendly materials that explain donor intervention research and put it in the wider frame of increasing opportunities for organ transplantation will work toward improving transparency and public trust in the organ donation system.
The goal will be to have well-developed and standardized information templates that can be provided at the time that individuals register their decisions for donation, with an option to be referred to a website for more detailed information, etc. In addition, the information that each OPO receives on each potential donor should be uniform, which would make the entire donation and transplantation process more seamless. The committee recognizes that revising DMV forms, website links, and OPO informational content will be challenging but believes that particularly in this joining of organ donation and research—both areas that deserve careful consideration, participation, and endorsement by the general public—taking the time and placing an emphasis on communications and public information is critically important.
Additionally, attention needs to be placed on implementing a single national organ donor registry. To accomplish this will require extensive coordination and standardization. Model state legislation could be helpful in facilitating a merger of registries as could federal regulatory changes to centralize the management of this effort.
Surrogates Providing Authorization for Organ Donation and Research
Family involvement in the donation process is important for transparency and public trust, regardless of whether it is the donor or a surrogate who provides the authorization. The surrogate and family, who may bear the experience on a personal level for their lifetimes, can influence others regarding donation. When the donation process is managed well, it propagates trust and respect, which are critical to the donation and transplantation process (see Chapter 2).
Every donation scenario differs. Current practice varies from state to state and from OPO to OPO regarding informing the donor’s family or other surrogate of a decedent’s declaration of intent to be an organ donor and seeking the family or surrogate’s permission for donation (Chon et al., 2014). When a potential donor has not provided authorization for donation or when there is no evidence of authorization for donation, a designated requestor approaches the surrogate, who has the choice of whether to provide authorization for donation, including any specific exclusions, such as certain organs that cannot be donated or certain purposes for which the organs cannot be used. Generally, designated requestors work for the local OPO, but in remote hospitals, the requestors may be trained by the OPO but not work for it. Requestors are often accompanied by hospital personnel who have been caring for the potential donor and family (LifeSource, 2011). These requestors assume primary responsibility for the organ donation process. A requestor may use different styles and formats in discussing donation and research with surrogates, depending on the specific circumstances surrounding an individual donor (LifeSource, 2011), so the information provided to different surrogates can vary.
The discussion of organ donation with a surrogate often occurs at a time when the surrogate’s cognitive capabilities are stressed because of the sudden crisis of a friend’s or family member’s death, which is often unexpected. This sensitive situation is made even more complex if the designated requestor must explain both donation and research options under time constraints and determine on a case-by-case basis how much information is enough, too much, or too little. This can put the organ recovery team at risk of applying undue and inappropriate influence on the family. Planning ahead by having materials for the requestor to share about the inclusion of donor research as part of transplantation can help to reduce stress about decisions for donation.
Authorization for Pediatric Donors
Minors made up approximately 9.4 percent of all deceased organ donors in the United States in 2016 (OPTN, 2017b). The committee considered organ donor intervention research as it pertains to pediatric donors and concluded that pediatric donors should be included as potential participants in donor intervention research unless excluded because of certain weight or size criteria. For minors—generally those who are less than 18 years old—the authorization process for organ donation allows the minor’s parents or guardian to make decisions about post-mortem organ donation.
For older children who die, parents or guardians may be able to incorporate what they know about the minor’s values and preferences into their
decision about organ donation. It is possible, for example, that a minor may have had a discussion with his or her parents regarding donation, perhaps as a result of a program on organ donation that the minor experienced in school (Cárdenas et al., 2010; Li et al., 2013). Thus, the parents or guardian may know whether their minor child would or would not have wanted to be a donor. This can influence their decision whether to provide authorization for their child’s donation, a fact that reinforces the need for educating the public regarding organ donation and related research.
Providing Organ Donor Intervention Research Findings to Families, Surrogates, and the Public
Providing basic information about transplant recipients to the families and surrogates of deceased organ donors is common when the provision of such information has been agreed upon by both parties. In 2011, a task force of stakeholders convened to make recommendations to help standardize the information that is provided (OPTN, 2017c). Similarly, findings from organ donor intervention research should also be shared with organ donor surrogates and families in addition to being shared with the public. Providing the research findings in aggregate form will increase transparency about the research while also demonstrating the societal benefit of organ donor intervention research.
In accord with the policies of OPTN and with other standards of medical care, transplant recipients go through a clinical consent process before undergoing transplant surgery. Beginning at the time of initial intake, through the process of being added to the transplant waitlist, and at the time of a specific organ offer, discussions between the potential transplant recipient and the clinical transplant coordinator, the transplant surgeon, and other clinicians focus on the risks, the processes, and the opportunities for transplantation, including the options regarding increased risk organs. In being added to the transplant wait list, potential transplant recipients are notified about OPTN policies and processes regarding the collection of a standard set of data that are used in de-identified form for transplantation reporting and statistics. In the context of this report, the committee focuses on the added complexities involved in being the recipient of an organ that has been the target of a research intervention prior to transplantation (with the intervention occurring while the organ was in the deceased donor or after being removed from the donor but prior to transplantation) or the recipient of a non-target organ that was potentially exposed to the research
intervention that occurred prior to removal of the organs from the donor. This section examines the effective and ethical implementation of the laws that ensure human research subject protections with particular attention to the following questions:
- Are recipients of research organs human research subjects?
- What are the issues regarding informed consent?
- How can the informed consent processes use risk stratification?
- How can consent be most effectively obtained given the time-sensitive nature of these decisions?
- What are the issues for post-transplant follow-up?
Recipients of Research Organs: Are They Human Research Subjects?
As noted earlier in the chapter, the new revision to the Common Rule states two criteria for being designated a human subject of research and thus being afforded a set of highly regulated research protections:
Human subject means a living individual about whom an investigator (whether professional or student) conducting research: (i) Obtains information or biospecimens through intervention or interaction with the individual, and uses, studies, or analyzes the information or biospecimens; or (ii) Obtains, uses, studies, analyzes, or generates identifiable private information or identifiable biospecimens. (Federal Register, 2017, p. 7260)
Even though deceased organ donors are not considered human subjects in research as defined by the Common Rule and FDA regulations (see discussion earlier in this chapter), there is still debate about whether recipients of organs targeted in donor intervention research and recipients of non-target organs exposed to donor intervention research are human subjects under the regulations. The committee acknowledged the range of types of organ donor intervention research interventions and considered several research scenarios in looking at these issues.
For three types of studies, the decision about human research subjects is not controversial:
- Studies using de-identified data—As long as the use of de-identification data meets the Common Rule’s requirements, the research participants would not be defined as human research subjects.
- Studies that explore outcomes only prior to transplantation—These types of studies collect data on and analyze the effects of interventions on the organs themselves prior to transplantation, without
- evaluating how the transplanted organs—target or non-target—function in recipients and without collecting or examining any data from the transplant recipient(s) about patient or graft function after transplantation. Because the recipients of target and non-target organs involved in these types of studies would not meet the Common Rule’s definition of a human subject, obtaining research informed consent from the recipients would not be required. However, because research is part of the organ’s clinical history, maintaining transparency and trust in the organ donation and transplantation process will require that the potential transplant recipient be informed about the research intervention as part of the clinical informed consent process for transplant surgery. Additionally, the committee is concerned that these types of studies may be missing opportunities to increase the knowledge about how to improve organ quality and function (for target and non-target organs) and would urge the data be collected and studied where feasible, which would require appropriate human research protections.
- Studies that collect additional patient data or biospecimens—These studies would collect data from transplant recipients beyond the standard-of-care follow-up. For example, blood draws, biopsies, or other measures of organ function could be required as part of the research protocol in order to assess the effectiveness of the research intervention. In these cases, as per the Common Rule regarding data collection, the transplant recipients would be deemed to be human research subjects and the single IRB (see Chapter 4) would oversee the implementation of human research subjects protections. As discussed below, the extent of the protections may vary based on the risk level of the intervention as determined by the IRB. If the research intervention were conducted in the deceased donor prior to removal of the organs then there would be the possibility of all organs being affected and therefore, all recipients of target or non-target organs would be human research subjects. If the research intervention were conducted on a specific organ after its removal from the body and prior to transplantation, then only the recipient of the intervention organ could be affected and only he or she would be a human research subject.
There is less clarity and more controversy about a fourth type of study in which some intervention on the donor or donor organ has been done for research purposes but the only data from organ recipients that would be collected are part of standard-of-care follow-up (Carome and Wolfe, 2016; Heffernan and Glazier, 2017). In other words, the standard-of-care followup data are being used both for clinical and for research purposes. In these
cases, much of the determination of whether the transplant recipients are research subjects hinges on the wording of the Common Rule regarding research data and noting that data of concern are those obtained by investigators “through intervention or interaction with the individual.”17 The Common Rule defines “intervention” to include “both physical procedures by which data are gathered (for example, venipuncture) and manipulations of the subject or the subject’s environment that are performed for research purposes.”18 Because organ donor intervention research modifies organs and assesses the function, efficacy, and safety of those modified organs in transplant recipients, the committee believes that the subject or the subject’s environment is being manipulated for research purposes. As noted in the Common Rule, when data generated from a research intervention are linked to the transplant recipient, or identifiable private information is being used or analyzed, the transplant recipient qualifies as a human research subject. The recipient’s clinical consent, which applies, for example, to his or her acceptance of an increased risk organ, would not be sufficient for acceptance of a research organ when data from the recipient will also be linked to the intervention performed on the organ prior to transplantation, even if those data were collected as part of standard of care. In these cases, the committee believes that the single IRB should require informed consent for research participation, unless it determines in appropriate cases that the criteria for alteration or waiver of informed consent are met.
Figure 3-1 summarizes the above discussion and includes issues regarding levels of risk and informed consent that are discussed in the following sections of this chapter.
Recipients of Research Organs: What Are the Issues Regarding Informed Consent?
Concerns have been expressed that treating recipients of transplanted research organs as human subjects would create nearly insurmountable logistical problems because allocation of the organs occurs after the research intervention has been administered (Heffernan and Glazier, 2017).
These concerns focus on the difficulty of obtaining prior IRB approval in the absence of knowing which institutions will receive the research organs and on the difficulty of obtaining advance research-related informed consent from potential recipients. While such possible consequences and barriers are certainly a reason for caution, pragmatic considerations alone should not dictate the outcome of legal, regulatory, and ethical analysis. In fact, treating recipients of transplanted research organs as human subjects
17 45 C.F.R. § 46.102(f).
18 45 C.F.R. § 46.102(f).
need not create insurmountable obstacles to organ donor intervention research. Thus, the committee, in line with several developments in human subjects research, recommends a single IRB review for these studies (see Chapter 4). The committee also proposes—and develops in a subsequent section of this chapter—a two-step consent process and other practices that can expedite the process of obtaining research-related informed consent. Moreover, as discussed below, in some instances waiver or alteration of informed consent may be a possibility for some kinds of protocols.
The Common Rule lays out several criteria for IRB approval of research involving human subjects:
- “Risks to subjects are minimized”
- “Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result”
- “Selection of subjects is equitable”
- “Informed consent will be sought from each prospective subject or the subject’s legally authorized representative”
- “Informed consent will be appropriately documented”
- “When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects”
- “When appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data”19
Moreover, if any of the prospective subjects “are likely to be vulnerable to coercion or undue influence,” other regulations require additional safeguards.20 Vulnerable populations include children, prisoners, etc.
The Common Rule also delineates several general requirements for an individual’s or a surrogate’s consent to research participation. It mandates that the IRB require researchers to disclose that the study involves research; to describe “any reasonable foreseeable risks or discomforts”; to describe any reasonably expected benefits to the subject or to others; to disclose “appropriate alternative procedures or courses of treatment, if any”; to indicate the extent of the protection of confidentiality; to specify that participation in research is voluntary; etc.21 When appropriate, other elements of information for consent shall be provided, such as the additional costs to the subject and any effects of the subject’s decision to withdraw from the research.22 The alteration of some elements of informed consent or even a
19 45 C.F.R. § 46.111(a).
20 45 C.F.R. § 46.111(b).
21 45 C.F.R. § 46.116(a).
22 45 C.F.R. § 46.116(b).
waiver of the requirement of informed consent can be approved by the IRB under some stringent circumstances to be discussed below.
There are reasons to include children in donor intervention research, the most salient being that organs are scarce and children should not be excluded from receiving such organs if a transplant is deemed to be in their best interest. There are cases where research is done simultaneously with adults and children, and regulations from the 1990s and 2000s encourage an earlier enrollment of children.23
For recipients who are minors, parents or legal guardians are legally empowered to provide consent for transplant and research. While obtaining child assent is often encouraged, the federal regulations allow an IRB to make a determination on whether the minor’s assent can be waived.24 Again, the committee thought that these determinations should be made by the single IRB, proposed in Chapter 4, in light of the time constraints and life-saving therapies that are being offered. One could imagine a decision to waive assent requirements up front but to inform the minor at some future time in order to show respect for the minor’s increased autonomy.
Considerations Regarding Non-Target Organs
The committee believes that the IRB will need to carefully consider the issues regarding non-target organs in order to ensure respect for the recipient, maintain confidence in the transplantation system, and gain knowledge about the impact of donor research interventions. In research that aims to improve donor outcomes, the effects that interventions aimed at a target organ may have on other organs must be included in the risk–benefit calculation when deciding whether the research may go forward (see the discussion of beneficence and fairness in Chapter 2). As with all recipients of organs involved in organ donor intervention studies, recipients of non-target organs (whether deemed to be human research subjects or not) need to be informed that they are receiving an organ that has been part of a research study.
Second, because this research aims to increase the quality and quantity of organs that will be viable for transplantation, it is critical to gain knowledge about whether or not there is an impact of the intervention on
23 Best Pharmaceuticals for Children Act, Public Law 107-109, 107th Cong. (January 4, 2002). Food and Drug Administration Modernization Act of 1997, Public Law 105-107, 105th Cong. (November 21, 1997).
24 45 C.F.R. § 46.408(a).
the non-target organs and the extent of that impact. Researchers should be encouraged to analyze data on non-target organs in order to assess whether interventions targeted on a specific organ have effects on other organs. In some cases, data that are routinely collected as part of normal transplantation follow-up protocols might be sufficient, but, for other studies, additional data collection may be important.
Third, the committee acknowledges that the level of risk to the recipient may differ among the target and the non-target organs in the same study. As will be discussed in the following section, the informed consent process may be altered by the IRB depending on the risk level.
How Can the Informed Consent Processes Use Risk Stratification?
Concerns have been raised that requiring informed consent for organ donor intervention research that poses no more than minimal risk is too burdensome under the time constraints imposed by the transplantation process. Under the Common Rule, “an IRB may approve a consent procedure which does not include, or which alters, some or all of the elements of informed consent.”25 Given the time constraints that are present when allocating deceased donor organs to transplant candidates (see Chapter 1), altering the elements of informed consent for transplant recipients might be useful and appropriate when donor intervention research poses no more than minimal risk to the recipient. This section examines the potential for alteration or waiver of informed consent depending on risk level and discusses the need for a common vernacular regarding levels of risk.
Research That Poses No More Than Minimal Risk
The Common Rule states that the requirement for informed consent can be altered or even waived as follows:
An IRB may approve a consent procedure which does not include, or which alters, some or all of the elements of informed consent set forth in this section, or waive the requirements to obtain informed consent provided the IRB finds and documents that:
- The research involves no more than minimal risk to the subjects;
- The waiver or alteration will not adversely affect the rights and welfare of the subjects;
- The research could not practicably be carried out without the waiver or alteration; and
25 45 C.F.R. § 46.116(d).
- Whenever appropriate, the subjects will be provided with additional pertinent information after participation.26
The committee concluded that organ donor intervention research that entails no more than minimal risk may meet these four criteria under some circumstances. Although there is significant risk in becoming a transplant recipient in general, here “minimal risk” refers only to the additional risks that could be incurred by the research participation itself. The Common Rule defines minimal risk as existing when “the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.”27 The committee did not render judgment as to whether trials that randomize transplant recipients to different standards of care—as in comparative effectiveness research—should generally be classified as minimal risk; instead, it left this for the IRB to determine on a study-by-study basis.
It is important to note that while the determination of minimal risk is necessary for a waiver or alteration of informed consent for research, it is not sufficient. Criteria 2, 3, and 4 identified above must also be met. Regarding criterion 2, the clinical consent information provided to the potential recipient could provide the needed information on the minimal risk research protocol to the recipient. Given the deleterious effects of delay in allocating deceased donor organs, researchers may be able to make the case that criterion 3 regarding practicability applies in some studies where the intervention poses no more than minimal risk. Criterion 4 requires that recipients be given additional information at a later time. Given that transplant recipients are followed closely after transplantation, it may be possible to provide some types of information after participation (including sharing aggregate results) but as the Common Rule recognizes it will be for the IRB to determine what is appropriate.
The committee concluded that the single IRB (see Chapter 4) is the body that should review and assess the systematic risk appraisal conducted by the research investigators and should determine whether an alteration or waiver of consent is appropriate for a given study. This determination should be made on a study-by-study basis. The Common Rule allows IRBs to determine that consent can be totally waived for certain studies deemed to be of minimal risk. If the single IRB makes the decision for a waiver in an organ donor intervention research study, the committee emphasizes the need to reveal the organ’s research history (for target and non-target organs) during the clinical informed consent process because
26 45 C.F.R. § 46.116(d).
27 45 C.F.R. § 46.102(i).
that is part of its clinical history and ensuring that the potential transplant recipient knows the full history is required by the ethical principle of respect for persons (see Chapter 2).
For minimal-risk research, the Secretary’s Advisory Committee on Human Research Protections has endorsed less burdensome approaches to obtaining consent (such as oral consent) that might be appropriate (OHRP, 2015). While the candidate would sign a standard clinical consent form for organ transplantation, either a brief consent form or a verbal consent could be adequate for this type of research participation under some circumstances. Again, the committee concluded that the single IRB (see Chapter 4) is the body that should determine how consent will be documented for studies of minimal risk (e.g., brief consent with certain elements waived or verbal consent with certain elements waived).
Questions arise as to whether research informed consent could be justifiably waived for research participants who are randomized to a purely observational arm or an arm that delivers the standard of care for the center where the transplant is being performed. After all, the organs that these individuals receive would not differ from what they would have received had they not been enrolled in research (i.e., they are the control arm), and the data collected would not differ from the standard data collected from all transplant recipients. The committee leaves it to the judgment of the single IRB, on a study-by-study basis, to determine whether it is appropriate to approve an alteration of the elements of informed consent or even waive the requirement for research informed consent for such research participants. The IRB should also determine whether respect for the rights and welfare of these transplant recipients requires that they be informed of their participation at some future time (Criterion 4 above).
Research That Poses More Than Minimal Risk
In the cases of research that poses more than minimal risk, federal regulations do not permit the alteration or waiver of research informed consent, and researchers must use the standard consent processes for clinical trials as defined in the Common Rule.28 Among other things, candidates should be given a full description of the research intervention being investigated, the possible risks and benefits of the research, the extent to which additional follow-up will be needed, and the degree of invasiveness that follow-up would entail. This information should be provided so that the candidate can use the information in his or her decision about whether to accept the organ and participate in the research.
28 45 C.F.R. § 46.116 and § 46.117.
Facilitating the Risk Discussion: Developing a Common Vernacular
As noted in Chapter 1, time is a critical factor for preserving a donor organ prior to transplantation. During the short time window for carrying out a transplantation before the organ loses its viability, it is unrealistic to expect members of the transplant team and transplant candidate to fully digest the data and clinically relevant information necessary to understand the scientific rationale and exact potential risk for clinical harm to a recipient of a research organ. Therefore, a common vernacular should be developed to (1) inform transplant teams about the degree of risk for harm that their patients can anticipate if they accept a specific research organ (target or non-target); and (2) inform potential recipients, in terms they can quickly and easily understand, about the risk for harm that they assume if they accept a research organ.
In considering what that common vernacular might be, the committee took guidance from discussions on binning genomic information before providing it to patients (Berg et al., 2011; NCHS Board of Scientific Counselors, 2012). The goal of those discussions was to create a categorical, patient-driven, and streamlined approach to the clinical evaluation of novel genomic variants and to facilitate patient engagement, with consideration given to “how to determine and operationalize criteria for clinically relevant genetic findings with a dire duty to warn threshold” (NCHS Board of Scientific Counselors, 2012). One solution was to bin genomic information into three separate categories (NCHS Board of Scientific Counselors, 2012). In followup on that same model, Berg and colleagues (2011) suggested that binning would allow clinicians to create categories delineated by scope of clinical utility into which genetic variants can be assigned on an a priori basis.
For purposes of informing transplant teams and candidates about research organs (target and non-target), the committee suggests that the Donor-Research Oversight Committee and the single IRB, described in Chapter 4, explore categorizing each study’s potential to cause harm to recipients. Studies could, for instance, be categorized into three bins: (1) no more than minimal risk, (2) at most, a minor increase over minimal risk, or (3) more than a minor increase over minimal risk. Bins may be referred to using a common risk scale of 1+, 2+, 3+. Organs categorized as minimal risk would be 1+, while organs categorized as significant risk for their recipients would be 3+.
A significant advantage of a routinized scale would be that it would allow transplant centers to learn their transplant candidates’ risk tolerance for research organs and note this at the time of listing using a standardized tool. Transplant candidates would only be offered organs that fit their risk tolerance preferences, thus further facilitating efficiency in the allocation of donor organs without compromising transplant candidates’ preferences.
Importantly, transplant candidates should have the opportunity to alter their risk preferences at routine intervals, just as they can change their preference about accepting organs from increased risk donors. This is a process that will need to evolve as OPTN and transplant centers, in conjunction with the research oversight structure recommended in Chapter 4, explore how best to inform transplant candidates about research organs, and identify ways to convey risk.
How Can Consent Be Most Effectively Obtained Given the Time-Sensitive Nature of These Decisions?
The limited window of time during which an organ is viable for transplantation and during which many steps in the transplantation process must take place (see Chapter 1) necessitates careful consideration about how to most effectively inform transplant candidates about organ donor intervention research. Additionally, transplant candidates receive a wealth of information from the time of intake through the time of discussing a transplant organ offer and need to have the time to fully learn about organ donor intervention research and make a determination about whether they may wish to receive a transplant organ that has been part of this research.
In order to find a balance between the laws and regulations relevant to organ donor intervention research and the need to ensure that organs do not become unusable due to an excessive elapse of time, the committee proposes the following two-stage process for obtaining consent from transplant candidates who could receive a target or non-target research organ. In this process, the first stage would involve providing information on donor intervention research and would ask the transplant candidate to make a decision on whether they would want to consider receiving a research organ, which could involve the collection of research data (see details below). This first stage is part of the clinical consent process that begins at the time of intake and continues through wait listing. The second stage would occur when an organ is being offered to the transplant candidate and would follow research informed consent processes as determined by the single IRB. The committee considered other options that would require revisions to the Common Rule but concluded that the proposed two-stage process should stay within current human research subjects protection regulations and that this process offers the best opportunities to
- fully inform transplant candidates about organ donor intervention research at a time when they can consider the risks, benefits, and alternatives in depth,
- provide a thorough informed consent process for participation in research, and
- allow the process to be conducted as expeditiously as possible by only doing the more in-depth informed consent processes with those candidates who have expressed an interest in receiving a research organ.
First Stage: Informing Transplant Candidates About Donor Research at the Time of Intake or Listing
It is common for clinicians to discuss increased-risk organs with transplant candidates to identify whether each candidate wants to be approached when such organs are available for transplantation (Seem et al., 2013). These conversations typically occur at intake—that is, when patients are evaluated as potential transplant candidates—or at listing—that is, when patients are placed on transplant waiting lists. At these same times, clinicians could provide information on donor intervention research and ask whether the transplant candidate wants to be considered for a research organ (target or non-target organ). The information provided would include an overview of organ donor intervention research and an explanation of the range of research studies that might occur during the time the transplant candidate is waiting for an organ. The information provided to the patient would not include details on specific research protocols as this information would likely not be available. These initial discussions would enable transplant candidates to become familiar with the possibility of receiving research organs at a time when they are not pressed to make an urgent decision about a specific organ. It will also give each transplant candidate the opportunity to think about whether he or she may be interested in considering a research organ at a later time if one became available (while being able to opt out later), similar to deciding whether to consider increased-risk donor organs. The discussion would need to lay out the ramifications of the transplant candidate’s decision regarding research organs and note that at any point while on the transplant waiting list, the transplant candidate can change his or her decision regarding whether to be notified about a research organ.
At this stage, each transplant candidate should be informed that
- Opting out of being notified about research organs signifies that the transplant candidate will not be told about research organs when those organs become available.
- Opting in to being notified about research organs:
- Signifies that the transplant candidate will be told when a research organ becomes available and will go through an IRB-approved consent process.
- If the research is determined to pose more than minimal risk, the transplant candidate will go through a full in
- Signifies that the transplant candidate will be told when a research organ becomes available and will go through an IRB-approved consent process.
- formed consent process used for human subjects in research as approved by the IRB.
- If the IRB determines that the research is no more than minimal risk, it may approve the alteration of elements of informed consent (see discussion of alteration of consent above).
- If the research does not involve the collection and analysis of data on follow-up outcomes, then the transplant candidate will be asked for clinical consent, similar to what is done for increased-risk donor organs.
- Involves decisions about whether to accept or decline a specific research organ at the time it becomes available.
- If the candidate declines a specific research organ at any time, he or she can still consider other research organs at later times.
- Each candidate’s decision in this phase of the process of whether to opt in to considering a research organ would be recorded in UNetSM, the OPTN database housing organ transplant waiting list data. This database is used by OPTN/UNOS to make determinations regarding organ allocations, and the notation on willingness to accept a research organ would be one of many factors used in determining the allocation for a given research organ.
- At any time, the transplant candidate can change her or his mind with regard to opting in or opting out of receiving a research organ.
- Going forward, the transplant candidate’s willingness to be approached about receiving a research organ will be reassessed at the same time(s) that their transplant team re-assesses their willingness to receive increased risk donor organs that are not part of research protocols.
- If the transplant candidate does accept a research organ, she or he can opt out of participating in any post-transplant follow-up specific to the research study, but the organ would not be removed unless determined to be causing harm, and the routine data collected from all transplant recipients would continue to be collected and used as permitted by OPTN policies.
During these discussions of donor intervention research, each transplant candidate should be given the opportunity to opt out of being offered research organs that become available in the same way that they can opt out of being approached when increased risk organs become available. The transplant candidate should also be given the opportunity to be offered research organs that, in the opinion of their transplant team, may be compatible with the degree of risk that the transplant candidate is willing to
tolerate. (This process on stratifying risks is further described above and would require that the transplant team thoroughly evaluate each transplant candidate’s risk tolerance for personal harm as the result of accepting a research organ.) Allowing transplant candidates to opt out of being offered research organs or to agree to consider only organs that fit their risk tolerance will reduce the time that organ placement and transplant teams spend allocating organs to candidates and thus reduce the likelihood of delays to allocation which may result in the organ being injured and rendered unusable for transplantation.
While transplant candidates have the right to opt out of being approached about research organs, it is incumbent upon clinicians and transplant programs to fully inform transplant candidates and make sure that they understand the consequences of opting out. For example, clinicians should make sure that candidates understand that opting out of considering research organs may lengthen the time it takes for them to get a transplant because of the limited supply of organs and the challenges of finding an appropriate organ. Clinicians should inform transplant candidates that some research organs may have been procured in ways that are consistent with current standards of care, with the research designed simply to determine which standard procedures might best promote transplant success. Although this discussion about considering a research organ would first occur at intake or at listing, it should not be a one-time-only discussion. The discussion should be revisited at regular intervals with the candidate’s transplant team so that the candidate has opportunities to change his or her decision.
Second Stage: At the Time of Organ Offer for Transplantation
If a potential candidate is willing to consider receiving a research organ, then when the time arrives for the candidate to be offered a specific research organ, details on the research protocol would be provided and the appropriate level of informed consent, as determined by the single IRB, would be obtained. The clinician and clinical transplant coordinator would be trained in human subjects research protections, would have information on the specific research protocol, and would work to succinctly describe the research intervention, answer the potential recipient’s questions regarding research participation, and ensure that the research informed consent process is conducted as required.
The level of information provided in this second stage would not be unusual and can be done expeditiously. As is standard practice, transplant teams inform potential recipients about the nature of the candidate organ (e.g., the approximate age of the donor, the health of the donor, the mode of the donor’s death) and whether the organ donor has been designated as
being of increased risk (OPTN, 2017a). Transplant teams give potential recipients this information so that they can decide whether accepting the available organ is in their best interest. In much the same manner, clinicians should inform transplant candidates who have expressed an interest in potentially considering research organs when an organ is part of a research study so that the candidates can factor this information into their decision about whether to go forward with the transplantation of a particular organ. In many cases it will be appropriate for the transplant clinicians to also make a recommendation to the candidate about whether, in their judgment, accepting a particular organ would be in the candidate’s best interest. Clinicians will have access to the details of the study protocol through UNetSM and through the registry of donor intervention studies (see Chapter 4), and if there are questions about the research study protocol, clinicians working directly with the potential recipient can be in touch with the research study staff.
As discussed above, the second stage for considering a research organ has two pathways defined according to the risk level of the research: (1) research that poses no more than minimal risk, and (2) research that poses more than minimal risk. Use of a common framework for discussing risks with transplant candidates will be important in moving the decisions forward as expeditiously as possible.
What Are the Issues for Post-Transplant Follow-Up?
Regardless of whether a transplant recipient receives an organ in the context of no-more-than-minimal-risk research or greater-than-minimal-risk research, at the time of any research-specific follow-up or procedures, recipients should be informed that they can withdraw from research-specific follow-up at any time. They can withdraw from extra data collection and extra interventions that go beyond whatever interventions may be considered necessary and recommended for their clinical care. Withdrawal from research would not, of course, involve the removal of the organ unless the organ’s presence was thought to be causing harm in some way. In addition, they cannot withdraw from standard observational data that are collected routinely after any organ transplant and placed in the UNOS database.
GOAL 1: Improve transparency and public trust in the organ donation process for research followed by transplantation.
RECOMMENDATION 1: The Organ Procurement and Transplantation Network, organ procurement organizations (OPOs), the Health
Resources & Services Administration, advocacy organizations, and professional associations involved in educating the general public and obtaining individual and surrogate authorization should explore, develop, and test communication strategies and materials that explain organ donor intervention research and should implement and disseminate those resources for which effective messaging has been identified. Information resources to be developed include
- Template language to be used by all U.S. organ donor registries (e.g., departments of motor vehicles [DMVs], national registry) to ensure consistency across registries in the language used to obtain authorization for organ donation. This language should explain organ donation options in language that takes into account the wide range of degrees of health literacy among the public.
- Templates for DMVs, OPOs, and other entities that advocate for organ/tissue donation to use for communicating a consistent set of facts about organ donor intervention research across websites and other dissemination methods.
- Standardized talking points for communicating with donor surrogates and families about organ donor intervention research. These should include, at a minimum, information about donation, transplantation, and research in language that takes into account the wide range of degrees of health literacy among the public.
GOAL 2: Improve the coordination and sharing of information about donor preferences.
RECOMMENDATION 2: All active donor registries in the United States should coordinate in order to ensure a single, unified secure national donor registry that is easily accessible to organ procurement organizations. All donor registry information collected by departments of motor vehicles should automatically feed into this single national registry. Model state legislation should be developed to facilitate this merger.
GOAL 3: Clarify legal guidance on organ donation for the purpose of research followed by transplantation (organ donor intervention research).
RECOMMENDATION 3: The National Conference of Commissioners on Uniform State Laws should explore revisions to the Uniform Anatomical Gift Act (UAGA) that would clarify the authorization of organ donation for the purpose of research followed by transplantation. The following possible clarifications to the UAGA should be considered:
- When a decedent has stated a general intent to make an anatomical gift, without further specification, research followed by transplantation is permitted.
- Organ procurement organizations should be explicitly empowered to seek from a donor’s surrogate the expansion of the authorization for an existing gift for any purpose to be used for research followed by transplantation.
The committee also considered two options for resolving the ambiguities in the UAGA and state laws, but sensitive to trust and transparency felt this issue requires more public consultation. Therefore, the committee recommends that the Organ Procurement and Transplantation Network and transplant community should engage in public consultation and determine whether to amend the UAGA and state laws to
- Specify that when the decedent has authorized transplantation this denotes that the gift is authorized for research followed by transplantation, or
- Specify research followed by transplantation as an additional purpose of donation that would be added to the list of choices for the donor.
GOAL 4: Promote informed consent for transplant recipients’ participation in organ donor intervention research in a manner that is compatible with the logistical complexities of organ transplantation.
RECOMMENDATION 4: Transplant centers and organ procurement organizations, in collaboration with the Organ Procurement and Transplantation Network/United Network for Organ Sharing, professional associations, and patient advocacy organizations should develop and implement a protocol for notifying and educating potential organ transplant recipients about the possibility of being offered an organ that has been exposed to a research intervention and seeking informed consent if they agree to be part of the research study. Specifically,
- At intake and at regular intervals thereafter, all potential recipients should be provided with information about organ donor intervention research and asked whether, at the time of organ offer, they would potentially consider accepting an organ (target organ or non-target organ) that was part of a research study. As a result of time constraints at the time of the organ offer for transplantation, only potential recipients who have previously agreed to consider
- research organs should be approached with the option to accept an available research organ.
- At the time of being offered an organ for transplantation, each transplant candidate who will potentially receive an organ that is part of a research study—be it a target organ or a non-target organ—should be provided with information about the specific research protocol and should follow the single institutional review board’s approved informed consent process for participating in that specific research study (including possible alteration or waiver of informed consent) and accepting the particular research organ offered. Given the importance of minimizing delays, information about the research protocol should be imparted through a process that ensures equitable, effective, and efficient placement and transplantation.
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