4

Research Approval, Implementation, and Oversight: Ensuring Quality and Trust

This report has examined several gaps, barriers, and opportunities in current laws, regulations, policies, and practices concerning deceased organ donor intervention research carried out as part of efforts to increase the number and improve the quality of transplantable organs. Without a central organization that can coordinate and facilitate cooperative research among a large number of institutions, this promising research is not likely to proceed at the volume, quality, and pace needed. Moreover, oversight and monitoring are needed to ensure adherence to the relevant ethical, legal, and regulatory policies and thus to promote public trust. This chapter outlines a framework for centrally administered oversight of deceased organ donor intervention research, concentrating on its essential functions.

The policy objectives that an organ donor research oversight framework should seek to achieve are to

• Ensure that scientific objectives in no way compromise the interests of deceased donors, donor families, transplant candidates or recipients, or the public. For example, interventions should always be consistent with, or seek improvements in, the care and management for donors and for transplant recipients.
• Engender the highest level of confidence from organ donors, their families, the general public, transplant candidates and recipients, donor hospitals and transplant centers. All must trust that their interests will not be compromised by research programs.
• Ensure that research activities are medically important, scientifically valid, and well conducted and that they do not compromise

• the mission of donor hospitals or transplant programs. For example, studies aimed at improving transplantation for one organ should not compromise the quality of other organs that might be recovered from the same donor.
• Foster the provision of clinically useful data. Studies should be designed so that they provide information that supports critical evaluation and improvements in patient outcomes.

This chapter provides the committee’s recommendations for extensive, independent, transparent, and ethics-based oversight and management of organ donor intervention research. The entire edifice of organ donation and transplantation is held together by bonds of trust among the public, prospective donors, family members of deceased donors, transplant candidates, transplant recipients, transplant centers, donor hospitals, and organ procurement organizations (OPOs), and these bonds must be retained when organ donor intervention research is implemented as a vital part of organ donation and transplantation.

CENTRALIZED MANAGEMENT OF DECEASED ORGAN DONOR INTERVENTION RESEARCH: BACKGROUND AND RATIONALE

Research has led to significant improvements in organ graft survival and transplant recipient health outcomes (Watson and Dark, 2012; Barker and Markmann, 2013). However, far less research has been conducted on improving the viability and quality of organs from deceased organ donors (organ donor intervention research). To ensure that this relatively new frontier in organ donation and transplantation research progresses in an ethical, expedited, and logistically feasible manner, centralized management and oversight are needed. Several of the unique challenges to conducting organ donor intervention research illustrate the rationale for a more centralized research system:

• Brevity of the timeframe: Time is extremely limited due to concerns about the viability of the organs. Finding the appropriate recipient(s) and making the most of the gift of an organ or organs involves making rapid decisions, which in turn requires clearly defined, well-vetted, and centralized processes and policies.
• Target and non-target organs: Because much of this research is conducted prior to the recovery of the organs from the deceased donor, the intervention may have the potential to affect not only the target organ but also the non-target organs. Recipients of non-target organs must be informed in a way that is similar to how recipients

• of target organs are informed, thus adding to the complexity of the overall process (see Chapter 1).
• Numerous and geographically dispersed stakeholders: An organ donor managed by 1 of the 58 OPOs in the United States can provide up to eight solid organs, each of which could be transplanted by different transplant programs across the country and allocated using varied distribution schemes. Donor intervention research involving donors, donor families, OPO staff, transplant staff, and recipients (target and non-target organ) adds another layer of complexity to this already multifaceted and time-driven system.
• Fairness: Donated organs are a scarce and valued national resource. The critical donor organ shortage and the life-and-death nature of organ donation and transplantation require a fair and equitable system for organ allocation. Organ allocation is, for the most part, moving away from a local and regional model toward a national model. The local and regional allocation models had produced significant differences in the chances for an organ transplant candidate to receive a donor organ offer depending on where in the country the candidate lived or, in some cases, where the candidate resided in relation to his or her transplant center. Under the national model, organs can be sent across the country. A donor intervention research oversight system must ensure that any research activities that are pursued do not substantially alter the way in which organs are distributed, including the types of individuals who are eligible. Information on the research efforts must be accurately communicated with clinical stakeholders and potential recipients so as not to negatively affect potential recipients’ access to organ offers.
• Consistency: Successful research requires consistency of performance across the multiple institutions and disparate geographic locations. Consistency will be best achieved through centralization of clinical oversight and through institutional review board (IRB) functions.
• Efficiency: For donor intervention research to flourish, mechanisms need to be established to coordinate and facilitate initiation and implementation of multi-center research investigations across a wide geographic area. By reducing the number of parallel and dispersed processes, a centralized oversight approach diminishes major administrative barriers to implementation, completion, and dissemination of research studies.

In 2014–2015 organ donation and transplantation professionals serving on the Donor Intervention Research Expert Panel (DIREP, see Chapter 1 for more information) concluded that an area of research as complex as

organ donor intervention research should be overseen by an independent central authority (Abt et al., 2015). As conceived by the DIREP, central oversight should serve three functions: (1) evaluating and approving proposals based on scientific merit; (2) providing ethical oversight, including the duties of an IRB, if indicated; and (3) monitoring efficacy and safety. Under this model, a central authority would act as the clearinghouse for all donor proposals and as the safety monitor for active studies. Subsequent discussions on how best to address the needs of this field led to the initiation of the National Academies of Sciences, Engineering, and Medicine study and this report. The committee preparing this report independently examined the needs and challenges in the field and came to the conclusion that central management of organ donor intervention research is necessary. The framework for that management and oversight is provided in this chapter.

FRAMEWORK FOR CENTRALIZED MANAGEMENT

Clinical research is ethically sensitive in part because patients—to whom physicians owe a duty of care—are exposed to risks and burdens to advance goals that may be external to them (namely, advancing medical knowledge for the potential benefit of future patients). As such, physician-researchers and the institutions that oversee them maintain divided loyalties. Policies established to protect human subjects have sought to resolve this moral tension by requiring that human research studies undergo prospective and independent ethical review by committees (in the United States, these committees are IRBs). The stipulations governing IRB membership require a board to include, in addition to subject matter experts, lay individuals who represent a broad spectrum of interested constituents. U.S. federal regulations specify criteria that IRBs should apply to the ethical review of research protocols (see Chapter 3). The National Academies committee sought to develop an approach for centralized management of donor intervention research that would incorporate these key features of an ethics-based review of research protocols.

Organ donor intervention research involves three different parties as participants in the research—donors, target organ recipients, and non-target organ recipients—with each deserving specific considerations, all of which are needed to ensure that a respectful, fair, and trustworthy donation and transplantation system is in place in the United States. For deceased organ donors, their families, and their surrogate decision makers, the focus is on fulfilling these people’s decisions regarding organ donation and honoring their gift of life for other individuals. For both target organ recipients and non-target organ recipients, the protections necessitate exploring and implementing appropriate informed consent processes for research participants as determined by the IRB.

The committee considered the structure for oversight of organ donor intervention research and recommends that the framework should consist of three affiliated entities:

• a centrally administered and standing Donor-Research Oversight Committee (D-ROC),
• a single IRB for donor intervention research, and
• data safety monitoring boards (DSMBs).

The goals and responsibilities of each of these are described in detail below. The committee recognizes that other models could be developed for oversight; however, it believes that the functions it describes should be considered key elements of whichever model is used. Organizational relationships between D-ROC, the single IRB, and the DSMBs should be constructed such that these entities work independently but cooperatively.

DONOR RESEARCH OVERSIGHT COMMITTEE

The committee envisions D-ROC as a centrally administered standing committee. As part of its charter, D-ROC should be empowered to work with stakeholders to prioritize, review, implement, and track research protocols as well as to develop and disseminate information about organ donor intervention research. D-ROC should be a newly formed entity chartered to coordinate and oversee donor intervention research. Having such an oversight body will require adequate staff and appropriate expertise in governance, information technology, transplant medicine and surgery, organ donation and procurement, ethics, and law as well as public representation. Discussions below highlight organizational and funding issues.

Context

A centrally administered committee or board responsible for coordinating complex research protocols across institutional and geographic boundaries is not without precedent. As noted in Box 4-1, the Clinical Trials Working Group (CTWG) helped restructure the National Cancer Institute (NCI)-supported national clinical trials enterprise devoted to using molecular medicine to advance oncologic clinical practice (NCI, 2005). The NRG Oncology Foundation administers a national program that conducts “practice-changing” multi-institutional clinical and translational research on gynecologic, breast, and prostate cancers. Another example comes from the United Kingdom, where the Research, Innovation and Novel Technologies Advisory Group (RINTAG) supports innovation and research expected to lead to improved rates of organ donation or improved organ function

and better outcomes for organ transplant recipients (NHS Blood and Transplant, 2017).

With regard to the steps necessary to create a cohesive national research system to carry out well-conducted clinical trials, CTWG identified four initial critical goals (NCI, 2005). The committee adapted these goals for a system for D-ROC’s support of donor intervention research as follows:

• Ensure coordination and cooperation among the functionally diverse components: All members of the organ donation and transplantation community should be represented, including community members, donor families, transplant recipients, OPOs, transplant centers, donor hospitals, federal regulatory agencies, and industry.

• Establish mechanisms to prioritize and monitor clinical studies: Create a standard and transparent process to prioritize proposals based on scientific quality, clinical need, and donor availability and to monitor active protocols for efficacy and safety, with reassessments of priorities as needed as the studies unfold.
• Standardize tools and procedures: Standard processes should be developed to ensure fairness and minimize conflict among stakeholders, to promote effective trial design that will lead to valid new knowledge, to maintain consistency across diverse geography and across the range of organ donation and transplant professionals and organizations involved in this research, to maximize data capture and opportunities for data sharing, to minimize duplication

• of effort, and to facilitate the progressive development of a donor intervention research clinical trials network.
• Reduce operational barriers: Strive for operational efficiencies that reduce time to implementation, maximize study participant accrual, catalog ongoing research efforts, and minimize costs without sacrificing safety.

D-ROC Core Competencies and Responsibilities

The committee envisions D-ROC as a centralized organization that would provide oversight to organ donor intervention research and would link with a single IRB devoted to these studies and with the DSMB working with each study to facilitate research and research dissemination. D-ROC would have responsibilities for overseeing the integration of deceased organ donor intervention research nationally to achieve the goals outlined in this report. D-ROC’s core responsibilities are highlighted in Box 4-2. The core competencies necessary to meet these responsibilities would include transplantation clinical care and research, transplant epidemiology, governance, law, ethics, relevant scientific and medical disciplines, project management and conflict resolution, communications, information technology, and data analysis. An essential part of this responsibility would be to ensure that relevant stakeholders from the donor and recipient communities are involved and that research results are widely and appropriately disseminated. An envisioned “life-cycle” for a donor intervention research proposal and the roles for the D-ROC in the process are described later in this chapter.

Review and Prioritize Donor Intervention Proposals

One of the major responsibilities of D-ROC would be to perform the initial review of all proposals for organ donor intervention research for

their scientific merit and clinical impact. D-ROC should establish a core set of policies that set conditions for the submission of protocols to the research oversight system. Conditions should include commitments to

• disclosing potential conflicts of interest;
• systematic review of evidence supporting each trial;
• prospective trial registration;
• active dissemination of results, including publication in the peer-reviewed literature;
• reporting of results according to contemporary standards; and
• dissemination of data, according to data-sharing and privacy standards.

One of the key assessments that will need to be made by clinical and research teams, in conjunction with the IRB, is whether their activity qualifies as a research study or as a quality improvement (QI) effort, with the latter being a local activity that is not within the purview of D-ROC oversight. As discussed in Chapter 1, there is an ongoing discussion about the boundaries between quality improvement and research in this field, as is the case in many areas of medicine (Casarett et al., 2000; Baily et al., 2006). Given this situation, the committee urges that D-ROC and the single IRB establish clear criteria—including paradigmatic cases of QI and research—that transplantation teams might use in deciding whether their activities would fall under D-ROC’s purview and also make clear the implications of any decisions based on those criteria, particularly implications regarding patient consent and oversight mechanisms. Many surgical procedures, including those in transplantation, have emerged through an iterative and incremental series of cases, a process that in some cases leans toward QI. However, the boundaries between QI and research depend on many factors, including the nature and extent of the process changes, the way that interventions are conducted, and the nature of patient outcomes follow-up. The criteria developed by D-ROC to differentiate QI and research in organ donor intervention studies and the mechanisms that D-ROC uses to implement and enforce those criteria will need to place utmost emphasis on ensuring the safety of transplant recipients (target organ recipients and non-target organ recipients) and upholding the public’s trust and confidence throughout the organ donation and transplantation process.

An early goal of D-ROC should be the development of a standard tool that D-ROC and the research, clinical, and transplant communities can use to differentiate QI and research and determine the need for IRB approval. For example, the Research Institute of the Children’s Hospital of Philadelphia developed a set of questions and a worksheet on this issue based in part on work by the Hastings Center (Baily et al., 2006; CHOP

Research Institute, 2015; see Table 4-1). The criteria offered by Casarett and colleagues (2000) are also helpful. A concern of the committee is that investigators may use QI as a mechanism for avoiding the more time- and resource-intensive efforts required to adhere to human research protections. Therefore, the committee urges that careful attention be paid to the development of criteria delineating these two distinct pathways for donor inter-

TABLE 4-1
Quality Improvement or Research Worksheet

Issue and Guidance		Rating
1	Are patients randomized into different intervention groups in order to enhance confidence in differences that might be obscured by nonrandom selection? Randomization done to achieve equitable allocation of a scarce resource need not be considered and would not result in a yes here.	yes	no
2	Does the project seek to test issues that are beyond current science and experience such as new treatments (i.e., is there much controversy about whether the intervention will be beneficial to actual patients, or is it designed simply to move existing evidence into practice?). If the project is performed to implement existing knowledge to improve care—rather than to develop new knowledge—answer “no.”	yes	no
3	Are researchers who have no ongoing commitment to improvement of the local care situation (and who may well have conflicts of interest with the patients involved) involved in key project roles? Generally answer “yes” even if others on the team do have professional commitments. However, where the project leaders with no clinical commitment are unaffiliated with the project site, it may be that the project site is not engaged—and does not require IRB approval/oversight—even if the project leaders’ roles do require IRB oversight at their institutions.	yes	no
4	Is the protocol fixed with a fixed goal, methodology, population, and time period? If frequent adjustments are made in the intervention, the measurement, and even the goal over time as experience accumulates, the answer is more likely “no.”	yes	no
5	Will there be delayed or ineffective feedback of data from monitoring the implementation of changes? Answer “yes” especially if feedback is delayed or altered in order to avoid biasing the interpretation of data.	yes	no
6	Is the project funded by an outside organization with a commercial interest in the use of the results? Is the sponsor a manufacturer with an interest in the outcome of the project relevant to its products? Is it a nonprofit foundation that typically funds research, or internal research accounts? If the project is funded by third-party payers through clinical reimbursement incentives, or through internal clinical/operations funds vs. research funds, the answer to this question is more likely to be “no.”	yes	no

NOTES: If the weight of the answers tends toward “yes” overall, the project should be considered “research” and approved by an IRB prior to implementation. If the weight of the answers tends toward “no,” the project is not “research” and is not subject to IRB oversight unless local institutional policies differ. Answering “yes” to sequence #1 or #2—even if all other answers are “no”—typically will result in a finding that the project constitutes research. It is important to consult with your local IRB if you are unsure how they would handle a particular case, as the analysis of the above issues cannot always be entirely objective and IRB policies and approaches vary significantly.

SOURCE: CHOP Research Institute, 2015. Reprinted with permission from Rachel Nosowsky, Esq.

vention studies so that the option to conduct QI studies is not abused. For example, D-ROC could randomly audit QI activities to examine whether donation and transplantation centers are using QI appropriately. Both QI and research efforts will play a critical role in advancing the field.

Because of the scarcity of organs available for transplantation and the potential for many donor intervention research studies occurring at the same time, D-ROC will need to determine priority among the research studies. As discussed by Gelinas and colleagues (2017), when a pool of patients is limited, clinical trials for the relevant patient population will end up competing for participants, with the competition likely resulting in low patient accrual and recruitment shortfalls for the individual studies. An early priority of D-ROC could be to develop the criteria by which it will assess and prioritize new protocols for donor intervention research. Criteria will be needed in order to limit the negative effects of competition on the ability of researchers to recruit and successfully enroll donor organs and transplant candidates in studies. The review by D-ROC would assign an impact/priority score to each proposed protocol based on variables that would include but not be limited to

• scientific strength;
• the balance between risks and probable benefits (with input from the single IRB; see description of the responsibilities of the IRB);
• the potential to increase the number and quality of donated organs for transplantation and the potential to improve graft and patient outcomes;
• fairness and justice, including fairness in subject selection and the potential to improve outcomes for underserved populations;
• inclusion and exclusion criteria of the proposed research;
• any impact on ongoing or planned studies; and
• the innovative quality of the proposed study.

Based on these priority factors, D-ROC would make its decisions regarding the approval and implementation of the study and would work with the IRB to ensure that the risk level and other information on the research would be communicated in an expedited manner to allow for informed decisions by the transplant team and the potential recipients. D-ROC would have responsibilities to ensure that its processes and policies adhere to the strictest ethical standards and also to facilitate the optimal allocation of organs that are involved in research.

Assess and Monitor the Impact of Organ Donor Intervention Research on Organ Allocation

Some organ donor intervention research could have the potential to have negative impacts on waitlist transplant candidates by distorting the organ allocation system. Beyond evaluating the balance of risks and benefits to participants in a specific study (a task for both the D-ROC and the single IRB), it will also be important to consider a study’s potential impact on the allocation of organs within the national system and on the morbidity and mortality of waitlist transplant candidates as well as its possible effects on transplant outcomes for all organs, including non-target organs, that are exposed to the research intervention.

Donor intervention research protocols could threaten fairness and equity in organ distribution in a variety of ways, as suggested by the following examples. First, a study could restrict the allocation of research organs to a subset of transplant candidates because of protocol inclusion and exclusion criteria. Such an attempt to advance knowledge of how to treat this subset of transplant candidates and future patients might mean that organs are directed preferentially to candidates based on their protocol eligibility rather than priority on the wait list. It is important to avoid this kind of restriction in a study design. Second, transplant candidates who decline a research organ may wait longer for a transplant and, in the process, may become sicker and even die before receiving another organ offer. As a result, some transplant candidates or transplant teams may feel pressure to accept research organs. Third, donor intervention research targeted at a particular organ may have an impact on non-target organs. Even if it is unlikely, for example, that a specific intervention targeting kidneys will have a negative impact on the efficacy or safety of heart transplantations, this cannot be ruled out in advance and thus raises a concern about fairness and equity in the organ allocation processes.

D-ROC should assess research protocols to determine whether they have possible negative impacts on donor organs or recipients. To this end, D-ROC could require researchers to provide an impact statement that indicates the likelihood, severity, and distribution of possible adverse impacts and how they can be avoided or mitigated. Where possible, D-ROC should require changes in studies that are designed so as to minimize adverse impacts and reduce inequitable distribution, and it should assign priority to studies with little likelihood of serious adverse effects.

Because it is difficult to predict such adverse effects with precision, systematic monitoring should be the responsibility of D-ROC. Accordingly, D-ROC should develop a comprehensive monitoring plan. This plan goes beyond the monitoring undertaken by the single DSMB, which focuses on participants in the research trial. This broader monitoring, by contrast,

would focus on a complex set of possible impacts on parties outside of those directly participating in the research trial. For example, if monitoring reveals that some donor intervention research has a negative impact on transplant candidates on the waiting list for a particular target organ or on recipients of non-target organs, the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) will need to determine the appropriate course of action to ensure the fair distribution of organs donated for transplantation. Robust and dynamic tools such as dashboard technology should be employed to manage this complex process.

Coordinate and Facilitate Clinical and Research Informatics and Promote Communications

A primary role for D-ROC will be ensuring that the necessary informatics and communications infrastructure is in place and actively implemented to facilitate and promote organ donor intervention research. The goals of data sharing include facilitating discovery science while avoiding duplication and ensuring reproducibility; increasing the understanding of human disease; improving the design, efficiency, and quality of clinical trials; and managing the cost and administrative burden of clinical research (IOM, 2015). All of these goals are consistent with the aims of a national program in organ donor intervention research. The Institute of Medicine report on responsible data sharing (2015) made four recommendations that could be applied to thinking about data sharing for the organ donation and transplantation communities:

• Principals in clinical trials should create and foster a culture of sharing the trial data as standard operating procedure and should “commit to responsible strategies aimed at maximizing the benefits, minimizing the risks, and overcoming the challenges of sharing clinical trial data for all parties” (p. 4).
• Both the investigators and sponsors of clinical trials should share the various types of trial information and data as appropriate.
• Researchers should use data agreements and create independent review panels for trial data stewardship.
• Issues related to database infrastructure, technology, workforce, and sustainability need to be addressed.

Online registry of organ donor intervention studies A single online registry of organ donor intervention studies is needed to catalog these research studies with the goal of providing access to non-proprietary study information. The registry should be a dynamic tool that can be used by the D-ROC, donation service areas, investigators, and clinicians to anticipate resource

use, set budgets, and track research activity across the organ transplantation field. Additionally, the registry could provide information to the general public on the studies. The registry database could be implemented using an existing platform such as www.ClinicalTrials.gov. The registry should be readily accessible to transplant candidates, health care providers, and the interested public (including prospective donors).

Examples of registry data to be included are study status (e.g., active studies, completed studies, studies in queue, studies under review, studies requested to address specific areas of interest), basic study design elements (e.g., projected start and close date, sample size, arms, eligibility), and links to contact information. Ideally, the registry would be a useful tool for the prioritization of new proposals—for example, as an aid to identify studies that might compete or place stress on overlapping resources.

Data management tools and data sharing Coordinated data management tools will also be critical to the success of organ donor intervention research in several ways. First, in order to track the outcomes of this research, investigators will need to be able to identify the research organ in UNet^SM1 and other relevant databases, including the Scientific Registry of Transplant Recipients (SRTR) database that brings together multiple data sources, so that outcomes of recipients of research organs can be followed and analyzed (SRTR, 2017). Data fields will need to be added to allow for the designation of the organ as a research organ, to note other relevant information about the research, and to link to the research protocol so that potential recipients can be informed about the research protocol and research outcomes can be identified and tracked. D-ROC should lead this effort in collaboration with OPTN/UNOS, OPOs, professional associations, and other stakeholders.

Second, information on the research studies will need to be shared with transplant center clinicians and with potential organ recipients to enable decisions regarding offers of research organs (see Chapter 3). This information could be provided through current mechanisms for sharing information about clinical transplant decisions (e.g., UNet^SM) or through other mechanisms determined to be efficient and fair.

Additionally, other data-sharing tools and approaches could be used to facilitate organ donor intervention research. One possibility is increasing the sharing of donor management data to enable the development of innovative or novel donor management strategies. Data sharing between

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¹ UNet^SM is an online database system with the OPTN/UNOS data (October 1, 1987, and forward) on every organ donation and transplant event in the United States (UNOS, 2017). UNet^SM has a variety of modules that are used to register transplant candidates for the waiting list, conduct organ matching, and store data on transplant candidates, organ donors, and transplant recipients (UNOS, 2017).

OPOs and also between OPOs and transplant programs that is coordinated or overseen by D-ROC has the potential to address this need. OPOs collect data prospectively and in real time, beginning as soon as the OPO is notified of a potential donor and continuing through the post-transplant time period for those potential donors who become actual donors. In addition to collecting mandated data such as demographics, history, and organ function, OPOs collect information on vital signs, medications administered and dose adjustments, fluid levels, test results of all kinds, and any interventions that are administered. Although OPOs collect these data, the data generally remain isolated and are used primarily to inform local practice or for documentation should questions arise about a particular transplantation. The combined data of all OPOs would be a powerful source with which to guide innovation and support the development of novel strategies for organ donor intervention research. Thus, another focus for D-ROC’s informatics could be to develop a pan-OPO donor management database that connects with existing relevant data sources.

Promote scientific and public communications D-ROC’s website, as well as other information technology and communications resources, should be developed and maintained with a focus on ensuring that research results are disseminated broadly to the transplant community, to the broader research community, and to the general public. As noted in Chapter 3, messaging and communications on donor intervention research need to meet the health literacy needs across the general public. After a trial is completed, the results should be shared with the organ donation and transplantation community, the broader scientific community, and the public through standard mechanisms (e.g., presentations, articles) as well as innovative research dissemination mechanisms. Not just “positive” results but also inconclusive and negative results need to be published and presented. In this context negative and inconclusive results are as important as positive results for preventing the repetition of disproven hypotheses. Outcomes, learnings, and safety alerts could be disseminated through multiple avenues of communication.

To assure the rapid communication of findings and to avoid conflicts between stakeholders, D-ROC should establish rules of conduct for investigators for publication, presentations, publicity, intellectual property, data access, non-disclosure agreements, relationships with industry sponsors, and personal rights and responsibilities. Additionally, D-ROC should produce an annual public report of all its professional and operational activities. This could include summaries and references for concluded, active, and pending studies.

Promote Effective Trial Design

One challenge in deceased organ donor intervention research is that the most accurate and precise method of determining outcomes and significance—the large, multicenter, randomized controlled clinical trial—is very difficult to perform in this context. There are opportunities to explore other research designs for these studies, as is being done in other areas of clinical research (Chow and Chang, 2008; Califf et al., 2012; Lauer and D’Agostino, 2013). D-ROC should facilitate the exploration of appropriate and innovative and effective research designs for the questions to which it seeks answers. Ensuring the validity of research using innovative approaches can be a responsibility of the D-ROC and could help solidify public trust (IOM, 2013a,b). These efforts can also assist in determining the quality and strength of the evidence that research generates, which is essential to developing standards of care (see the discussion of the principle of validity in Chapter 2).

Maintain Liaisons with Key External Groups

To help maintain the alignment of all stakeholders and facilitate organ donor intervention research, D-ROC should establish formal working relationships with key external agencies and organizations—for example, with the Centers for Medicare & Medicaid Services (CMS). In this case, the common goal would be to ensure that the CMS conditions of participation (defined below) are constructed to encourage and not penalize organizations that participate in organ donor intervention research.

Conditions of participation are policies and regulations designated by CMS to identify and maintain high-quality effective donation and transplantation programs (see Box 4-3). Transplant centers, OPOs, and donor hospitals must meet conditions of participation standards in order to be eligible to participate in and receive reimbursement through Medicare and Medicaid. The sustainability of these programs is thus tied to meeting these performance and outcome measures. When an institution considers participating in a donor intervention research study, the potential for the study to affect the institution’s outcomes relevant to the conditions of participation may be a major factor in its decision whether to participate. CMS has made some changes to its criteria that are intended to address these issues (see Box 4-3). D-ROC could work with CMS to create conditions of participation incentives that foster positive attitudes toward donor intervention research and align with those of the organ donation and transplant community.

SINGLE IRB FOR ORGAN DONOR INTERVENTION RESEARCH

Because organ donor intervention research will likely involve coordination across multiple OPOs, donor hospitals, and transplant centers, it will be necessary to obtain consent from recipients across many sites in a very short period of time and to have all potential sites on board with the centralized processes. This is particularly important for donor hospitals, which may only occasionally be involved in the organ donation process and may not be familiar with organ donor intervention research.

The standard model of IRB oversight for multi-site studies, in which each research institution has to review and approve the research protocol, is poorly suited to the context in which organ donor intervention studies take place. Local IRB oversight—with the challenges of inconsistent amendment requirements and the near-certain guarantee of these studies being conducted across many transplant centers—would likely severely limit the feasibility of donor intervention research. Taking these two things together, the committee concluded that a single IRB for all of organ donor intervention research is necessary to ensure adequate human subjects protections under the conditions in which this research will be performed. The single

IRB would make the decisions regarding informed consent for research for recipients of both target and non-target organs (discussed in depth in Chapter 3). The single IRB could be an independent central IRB or another alternative is to designate a current IRB to be the IRB of record with all institutions signing a letter of agreement (e.g., see smartirb.org).

A single IRB would offer the advantages of developing and maintaining core expertise in organ donor intervention research. The IRB would oversee human research protections and ensure that processes are followed in accord with the relevant regulatory and policy requirements and guidance, particularly the federal Common Rule for human research protections.²

Box 4-4 summarizes the recent determination by the National Institutes of Health (NIH) that single IRBs are preferred for multisite research because they decrease the burden of redundant reviews by creating one platform for protocol analysis and oversight. Furthermore, the final rule for federal policy on human subjects protections stipulates the use of a single IRB for multi-institutional trials; while most provisions of the Final Rule take effect in January 2018, this requirement will not take effect until January 2020 (Federal Register, 2017). The Final Rule for human subjects protections also “removes the requirement to conduct continuing review of ongoing research for studies that undergo expedited review and for studies that have completed study interventions and are merely analyzing study data or involve only observational follow-up in conjunction with standard clinical care” (Federal Register, 2017).

Examples of single IRBs include those used by NeuroNext and NCI (Marsolo, 2012; Mascette et al., 2012; Check et al., 2013; Flynn et al., 2013) (see Box 4-5). Multicenter trials using a single IRB have the potential to accelerate enrollment and subject accrual since timeframes for the approval process vary widely between local IRBs. The single IRB can be an effective, convenient, and efficient method of addressing the need for an IRB operating in a complex environment.

The single IRB has the mandate to determine that “risks to subjects are reasonable in relation to anticipated benefits.”³ One of its responsibilities would be to conduct a prospective risk–benefit assessment of each research protocol that is based on the systematic appraisal conducted by the investigators of the balance of risks (probability and magnitude of harms) to transplant recipients and the probable benefits to recipients and to future transplant candidates (see the discussion of beneficence/utility in Chapter 2). This would include determining the potential risk and impact of the research protocol on both the target organ(s) and non-target organs. As discussed in Chapter 3, the committee suggests that studies be categorized into three

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² 45 C.F.R. Part 46.

³ 45 C.F.R. § 46.111.

levels: 1+ (no more than minimal risk), 2+ (slightly greater than minimal risk), and 3+ (significant risk). The IRB’s assessment of the risk level would be conveyed to D-ROC as part of the input into D-ROC’s prioritization of the study. The designated risk level would be used to develop the informed consent plan. Part of the informed consent plan would also include the delineation of data collection efforts relevant to human subjects for the research study as determined by the investigators working with the single IRB and the DSMB.

The Common Rule sets some minimum requirements for IRB composition and delineates the IRB’s responsibility in the review of research.⁴ IRBs are required to include at least five members with “varying backgrounds to promote complete and adequate review of research activities.” IRBs shall also be

For the single IRB on organ donor intervention research, expertise would be needed in organ donation and transplantation, relevant medical and scientific disciplines, ethics, and law, and it would require members who bring both donor and recipient perspectives to the board.

DSMBs

DSMBs are independent committees that oversee the conduct of clinical trials. They serve several broad purposes. First, they are charged with reviewing incoming study data in order to assure that the risk–benefit ratio of an ongoing trial has not shifted. DSMBs can advise study sponsors to discontinue or amend the design of a study under certain conditions. For example, the DSMB could determine, on the basis of the incoming study data, that the investigation has become unsafe for participants and thus should be terminated early. Or it could determine that efficacy has been established before the study was scheduled to end. Moreover, severe protocol deviations or seriously flagging recruitment could indicate that the research will probably not produce valid results and that its probable benefits no longer outweigh its risks to participants. Second, DSMBs can advise on and evaluate protocol amendments. For example, if recruitment becomes

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⁴ 45 C.F.R. 46 § 107 and 45 C.F.R. 46 § 109.

⁵ 45 C.F.R. 46 § 107.

a concern, DSMBs can advise on broadening eligibility criteria in order to access a wider population. Third, DSMBs can evaluate whether patients need to be informed of new developments in a trial. In contrast with IRBs, there are fewer regulatory or legal standards for DSMB oversight. DSMBs typically have a charter that stipulates roles and responsibilities.

The DSMB for a research study establishes study-stopping criteria based on outcomes for target and non-target organ recipients. The DSMB would need to interface with the investigators before study initiation to ensure that outcomes necessary for monitoring target organs and non-target organs (and the recipients those organs have been transplanted into) are built into the protocol as needed. Safety concerns should be brought directly to the DSMB while other issues, such as opportunities to improve efficiency or to make operational changes based on observations in the field, may be acted on by mechanisms established by D-ROC.

The DSMBs for organ donor intervention research could be organized around a single research study or a set of studies. The key as described below will be for D-ROC to have the administrative capacity to establish DSMBs as they are needed.

STRUCTURE AND OPERATIONS FOR CENTRALIZED MANAGEMENT OF ORGAN DONOR INTERVENTION RESEARCH

The centralized management of organ donor intervention research will require the involvement and commitment of the organ donation and transplantation community. The committee explored several options for the management structure that could best get this endeavor off the ground and running.

One option would be for D-ROC to be a collaborative effort managed by multiple agencies and organizations. Although the full range of expertise of the donation and transplantation community is needed for any endeavor of this nature to succeed, the committee believes that there is value in having a more centralized approach to the management of this research effort. A second option would be to form a non-profit research organization. NRG Oncology provides an example of a successful approach (NRG Oncology, 2017). The committee sees value in this option but at this point in the evolution of organ donor intervention research there may not yet be the base of funding support to make this option viable. It is one option that could be strongly considered at some point in the future.

A third option would be to organize D-ROC under the auspices of OPTN. OPTN provides the long-term ongoing organizational structure that through the Health Resources & Services Administration’s (HRSA’s) support sets policies and implements allocation, data collection, and many other efforts that enable organ donation and transplantation to be carried

out effectively. The development of OPTN policies includes public participation and comment and this would be valuable in the initiation of D-ROC and in the working out of the details of D-ROC’s structure and operations. Organizationally, OPTN/UNOS could add the staffing needed to implement D-ROC and could draw on and supplement its robust voluntary network of experts to find the appropriate technical, clinical, governance, regulatory, legal, and public awareness expertise needed. Additionally, donor families and transplant recipients are integral to the work of OPTN/UNOS and would be vital to D-ROC’s efforts. D-ROC could also draw on OPTN/UNOS staffing and volunteer expertise to develop and sustain the DSMB capabilities needed.

The committee emphasizes the urgent need to implement the centralized management of organ donor intervention research in order to facilitate this research that is critically needed to improve the quantity and quality of organs for transplantation. Implementation of D-ROC could be done in phases with OPTN and the donation and transplant community establishing a charter, initial funding, rules for governance, administrative policies and a framework that should include a single IRB, the integration of DSMBs for the specific studies, and a plan for project and data management and communications. After the initial framework is established, D-ROC could evolve into a more complex organization.

The committee believes that it is critical to the success of organ donor intervention research that all donor intervention research studies should be reviewed by a single IRB that has the appropriate scientific, ethical and regulatory expertise. As previously discussed, the committee recognizes that the IRB function could be done by (1) creating an independent central IRB or (2) contracting with an existing IRB that has appropriate scientific, ethical and regulatory expertise. The single IRB for organ donor intervention research may be a free-standing (central) IRB or part of an academic medical center willing to serve as the IRB of record for the multiple sites. The committee believes that D-ROC should have flexibility in determining how to best constitute or contract out the single IRB’s functions.

Organizational working relationships among D-ROC, the single IRB, and the DSMBs will need to be constructed so that independence is achieved but with close communication, in part through the data sharing mechanisms outlined above.

Setting up the organizational framework in the manner described above will provide the opportunities for funding from multiple sources. Research investigators will be funded by the usual mechanisms for biomedical research (primarily government, industry, foundation, and institutional support). In addition to the potential for HRSA and other government agency funding sources, further funds for D-ROC could include fees and income from research opportunities (e.g., industry partnerships, process improvement consultation, donations). Funding for the single IRB and for the work

of the DSMBs could come from member fees, fees for application review, and consultation services.

TIMELINE AND INTEGRATED PROCESS

The research process envisioned by the committee would consist of three stages: (1) submission and approval of research protocols; (2) planning, implementation, and monitoring; and (3) the analysis and dissemination of results and archiving in a retrievable catalog. D-ROC, the single IRB, and the DSMB for the specific study would work together to oversee the implementation and dissemination of donor intervention research, which is critically needed to improve the lives of individuals through improving the quality and quantity of donated organs.

Stage 1: Submission and Approval

Research proposals would be submitted to D-ROC. An initial review by the D-ROC would assign an impact/priority score to the proposed protocol based on the variables described earlier in the chapter. The IRB would provide input to D-ROC on the risk level. Any issues identified by the IRB would be negotiated with the study sponsor and researchers. Proposals would not move forward until approved by the single IRB and D-ROC.

If approved for implementation, a protocol would be submitted to the study’s DSMB. The DSMB and the study sponsor would directly negotiate stopping rules, monitoring practices, and other criteria deemed appropriate for the conduct of the proposed study. Upon approval and before initiation, the research protocol would be registered in the public database as discussed above. Sponsors would determine whether and when to interact with the U.S. Food and Drug Administration.

Stage 2: Planning, Implementation, and Monitoring

After approval by the IRB and the study’s DSMB, D-ROC would work with researchers to develop a management plan, and the study protocol would be implemented. The study data would be managed using the data management tools developed for this purpose. Monitoring goals should include identifying safety signals and assessing sentinel events to ensure that study safety and protocol continuity are maintained. Patient accrual progress would be updated in the registry periodically (at least semi-annually, and potentially quarterly). The informed consent process would move forward according to the determinations of the single IRB.

Stage 3: Analysis and Dissemination

At the close of a study, the study outcomes and non-proprietary results (high level) would be promptly disseminated to the transplantation community through peer-reviewed publications and presentations at scientific meetings, regardless of whether the outcomes on the primary endpoints are positive, inconclusive, or negative. D-ROC would receive notice and a copy of all peer-reviewed abstracts and published manuscripts. All reporting would meet the standards of trial reporting (e.g., Consolidated Standards of Reporting Trials; see CONSORT, 2017). Additional dissemination through external newsletters, websites, and public and professional meetings would be encouraged. After a period of time, research teams would, upon request, make anonymous or de-identified individual participant data available to other researchers in order to support meta-analyses and the pooling of results from individual studies. D-ROC could serve as a “learned intermediary” to ensure that patient privacy is adequately protected and that requests for individual participant data have merit (Mello et al., 2013). Each study would be cataloged and archived for future reference. All Health Insurance Portability and Accountability Act (HIPAA) compliance guidelines would be followed when using individual patient data (HHS, 2013; HIPAA Journal, 2016).

The goal is for the research results to be used by the donation and transplantation community to improve the quantity and quality of donated organs and thus honor the gift of life provided through deceased donors to improve the lives of transplant recipients.

SUMMARY AND RECOMMENDATIONS

In order to effectively enhance the quality and increase the quantity of donated organs for transplantation, research oversight will be needed to approve well-designed organ donor intervention protocols. To promote feasibility while maintaining the same protections that would hold in other research realms, the committee recommends an organizational structure to oversee deceased organ donor intervention research planning, approval, implementation, and reporting.

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