Opportunities for Organ Donor Intervention Research Saving Lives by Improving the Quality and Quantity of Organs for Transplantation (2017) / Chapter Skim
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3 Legal, Regulatory, and Policy Frameworks for Organ Donation and Research Participation
3 Legal, Regulatory, and Policy Frameworks for Organ Donation and Research Participation
Pages 67-114
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From page 67... ...
Organ donor intervention research has the potential to improve outcomes for transplant recipients and to increase the number of transplants. Never theless, 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.
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From page 68... ...
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.
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From page 69... ...
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)
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From page 70... ...
2008 Germany MP Liver Kidneys Pérez-Blanco et al. 2005 Spain T3 Liver, None Pancreas, Heart, Lung NOTE: CS = cold storage; HMP = hypothermic machine perfusion; IPC = ischemic preconditioning; IRB = i nstitutional 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.
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From page 71... ...
LEGAL, REGULATORY, AND POLICY FRAMEWORKS 71 Consent Consent from Consent from Donor or from Recipient # of Surrogate Recipient of Non OPOs/ # of # of Reviewed for of Target Target RCT Centers Donors Recipients by IRB Research Organ Organ Yes 2 370 572 Yes Yes No No Yes 1 506 152 Yes Yes No No No 1 40 40 Yes Unknown Yes n/aa Yes 1 62 62 Yes No Yes No No 1 10 9 Yes Unknown Yes n/aa No 2 20 20 Yes Yes Yes n/aa No 3 21 49 No No No No Yes 1 214 140 Yes No Yes No Yes 5 46 90 Yes No Yes n/aa Yes 206 164 Yes No No n/aa Yes 60 264 487 Yes Yes No No Yes 60 336 672 Yes Yesb No n/aa Yes 60 48 Yes Yes No No Yes 1 100 100 Yes Yesb No No Yes 1 52 None Yes Yes No No followed 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.
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From page 72... ...
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)
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From page 73... ...
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.
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From page 74... ...
. 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)
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From page 75... ...
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)
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From page 76... ...
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.
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From page 77... ...
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.
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From page 78... ...
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.
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From page 79... ...
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)
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From page 80... ...
. 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.
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From page 81... ...
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)
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From page 82... ...
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.
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From page 83... ...
. However, two ambiguities in the language complicate the interpretation of how to handle organ donor intervention research followed by transplantation under this Section.
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From page 84... ...
. 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.
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From page 85... ...
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.
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From page 86... ...
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)
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From page 87... ...
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.
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From page 88... ...
You are cer tifying that you are: 18 years or older; consenting to donate all of your organs and tissues for transplantation, research, or both; authorizing DMV to transfer your name and identifying information to DOH for enrollment in the Registry; and authorizing DOH to allow access to this information to federally regulated organ donation organizations and NYS-licensed tissue and eye banks and hospitals, upon your death. "ORGAN DONOR" will be printed on the front of your DMV photo document.
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From page 89... ...
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
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From page 90... ...
Messaging and communication strategies regarding organ donaion and donor intervention research need to be developed and t 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.
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From page 91... ...
. 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.
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From page 92... ...
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.
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From page 93... ...
, 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.
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From page 94... ...
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 re search 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.
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From page 95... ...
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 l ogistical problems because allocation of the organs occurs after the research intervention has been administered (Heffernan and Glazier, 2017)
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From page 96... ...
96 OPPORTUNITIES FOR ORGAN DONOR INTERVENTION RESEARCH FIGURE 3-1 Research authorization and consent decision points. NOTE: IRB = institutional review board.
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From page 97... ...
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: 1.
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From page 98... ...
. As with all recipients of organs involved in organ donor intervention studies, recipients of nontarget organs (whether deemed to be human research subjects or not)
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From page 99... ...
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)
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From page 100... ...
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)
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From page 101... ...
. 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.
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From page 102... ...
Organs categorized as minimal risk would be 1+, while organs categorized as significant risk for their r ecipients 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.
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From page 103... ...
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
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From page 104... ...
. 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.
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From page 105... ...
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
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From page 106... ...
Second Stage: At the Time of Organ Offer for Transplantation If a potential candidate is willing to consider receiving a research o rgan, 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.
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From page 107... ...
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.
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From page 108... ...
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)
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From page 109... ...
GOAL 4: Promote informed consent for transplant recipients' par ticipation 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 Trans plantation Network/United Network for Organ Sharing, professional associations, and patient advocacy organizations should develop and implement a protocol for notifying and educating potential organ trans plant 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.
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From page 110... ...
2010. Effects of classroom education on knowledge and attitudes regarding organ donation in ethnically diverse urban high schools.
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2017. Are transplant recipients human subjects when research is conducted on organ donors?
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From page 112... ...
2011. Informed consent in research to improve the number and quality of deceased donor organs.
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From page 113... ...
2016. Deceased d onor intervention research: A survey of transplant surgeons, organ procurement profes sionals, and institutional review board members.
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