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Advisory Committee on Organ Transplantation
U.S. Department of Health and Human Services
August 23 - 24, 2011
Dr. Mark Barr welcomed the group and noted there would be a change in the agenda due to a scheduling conflict. As a result, Ms. Cornell’s presentation was moved up as the first agenda item before the introductions and opening remarks.
Alignment of CMS Regulatory Requirements with the OPTN - Work Group Report - Danielle Cornell, R.N., B.S.N., CPTC
Ms. Cornell presented by telephone. She provided background on the establishment of the working group. She showed a slide illustrating decreased donor transplants and noted there had been long-term growth in these transplants from 1996 – 2006. In 2007, CMS released the Final Rule for transplant centers, which included performance measures; there has essentially been no growth since then. Organ Procurement Organization (OPO) agreements expired in 2006, which is the time that deceased donation levels became flat. The data indicate there have been an increasing number of discards in all categories, i.e., Expanded Criteria Donor (ECD), Standard Criteria Donor (SCD). In the last few years, many donations have not been placed because transplant centers have not accepted them.
The workgroup sought to understand if the Centers for Medicare and Medicaid Services (CMS) regulations for OPOs and transplant centers conflict. Specifically, it explored whether the fact that transplant and donor volumes have recently flattened or decreased after 20 years of sustained growth was due to transplant centers’ concerns about outcomes and performance measures. The theory was that the drop in transplant volumes could stem from fear of outcomes data that could lead to fewer referrals, loss of contracts, additional CMS site visits, loss of revenue and/or increased expenses, lower incentives for experimental procedures, and closure of program(s).
The workgroup originally only had ACOT members, but later expanded to include many other experts from the donation and transplantation communities, including representatives from Association of Organ Procurement Organizations, OPOs, American Society of Transplant Surgeons (ASTS), American Society of Transplantation (AST), the Alliance, Scientific Registry of Transplant Recipients (SRTR), United Network for Organ Sharing (UNOS), and CMS. The group divided up into two subgroups (these can also be thought of as two steps in the process).
Subgroup 1 (Step 1) looked at UNOS’ classification of donors and UNOS/Organ Procurement and Transplantation Network (OPTN) data requirements, and explored the possibility that donors should not be classified at all. This group reviewed and compared the OPTN and CMS data definitions and the respective performance metrics for OPOs and transplant centers, and assessed how the relative entities within HHS utilize this information to assess OPO and transplant center performance.
Subgroup 2 (Step 2) worked on developing possible SRTR Risk Adjustment and data models/algorithms for organs to provide the opportunity for improved utilization of all organs. The group also further discussed the possibility of partially blinded data.
Ms. Cornell reported that it appeared that the workgroup’s hypothesis was accurate. She said that the workgroup could probably create a full recommendation for the ACOT by mid-November.
Dr. Barr thanked Ms. Cornell for pushing this issue forward and noted that many people have been thinking about this for some time. Dr. Barr encouraged new ACOT members to join the workgroup and reminded them that they can serve on multiple workgroups/ committees.
Co-incidental to these efforts, ASTS and AST were invited to participate on the most recent ACOT workgroup call. The organizations followed up by sending a joint document entitled, “Transplant Center (TC) and Organ Procurement Organization (OPO) Certification Requirements Should be Modified to Reduce Organ Wastage.” This document should be entered into the ACOT records (Attachment A). Dr. Barr noted that the joint document was very good and in sync with the ACOT workgroup. It says:
The misalignment and inconsistencies between CMS outcomes requirements for TCs and OPOs inhibit optimal organ donor strategies and contribute to organ wastage, which is a significant problem in the field of transplantation. In 2009, 3,145 kidneys were procured from Expanded Criteria Donors (ECDs); 44% (1372) were discarded of which 75% were donors under the age of 65. This strongly suggests that a large number of these kidneys were potentially transplantable, with good outcomes. Such wastage is inconsistent with the national objective of increasing rates of transplantation.
This problem is exacerbated by CMS certification regulations for TCs and OPOs. CMS regulations encourage OPOs to increase the number of all types of organs from all types of donors (from ideal to marginal, brain dead or donors after cardiac death (DCD)). These regulations incentivize OPOs to maximize organ retrieval, without consideration of whether the organs retrieved are appropriate for transplantation or whether transplantation of these organs will result in positive patient outcomes. By contrast, TCs are required to meet stringent transplant recipient outcomes requirements, regardless of donor organ quality: Risk-adjustment methodologies are grossly imperfect and renal-centric and therefore TCs risk losing Medicare certification for accepting and transplanting organs associated with poor outcomes. Also, TCs are penalized for not accepting and transplanting organs procured and offered to their patients, even though the TC deems the organs clinically unsuitable for transplantation into their particular patient(s).
The OPO certification regulation not only reflects performance metrics that are inconsistent with those imposed on TCs, but also results in increased Medicare expenditures and increased overall transplantation costs. By pursuing all organs (good and bad – including marginal organs), the OPOs incur significant expenditures as a result of “dry runs” (donor team deployed, but organs not procured and therefore not transplanted), and “discards” (procured organs that are subsequently discarded, i.e., not transplanted). The costs associated with dry runs and discards are allocated to the Standard Acquisition Charge (SAC) for transplanted organs, driving increases in the SACs for transplanted organs and increasing the cost of transplantation. For Medicare beneficiaries, Medicare pays the full SAC; and therefore, it is CMS that ultimately incurs the additional cost.
For non-Medicare beneficiaries (the majority of non-renal transplant recipients), case-rates negotiated with third party payers include the SAC paid by the TC to the OPO for the organ; and therefore, the additional cost of dry runs and discards affects TC margins directly and may impact the TC’s ability to negotiate future case-rates with payers. Moreover, additional clinical costs of using marginal organs (not related to SAC; items such as increased recipient length of stay) incurred by TCs result in higher payments by both CMS and third party payers.
Potential Solutions--Short Term Options:
i) Eliminate marginal organs from calculations of both “expected” and “observed” transplant outcome rates. This would require modification of risk adjustment methodologies and CMS Interpretive Guidelines (IGs), but no regulatory change. One potential downside to this solution would be that TCs might be encouraged (incentivized) to increase marginal organ transplantation, without regard to potential outcomes.
ii) Calculate both “expected” and “observed” rates separately for standard and marginal organs. Again, this would require modification of risk adjustment methodologies and CMS IGs, but no regulatory change. One potential hurdle to this solution would be establishing the “benchmark” for marginal organs, although this could be achieved initially using retrospective data and tweaked further by prospectively analyzed data. Under this model, TC compliance with outcomes criteria would be applied to both standard criteria and marginal organs, but accreditation decisions would be heavily weighted towards standard organs.
iii) For TCs that are not compliant with CMS outcomes criteria, “expected” and “observed” rates would be separately recalculated to determine whether standard organ outcomes fall into compliance (without consideration of marginal organ outcomes). If so, a condition level determination would not be made by CMS, and the TC would not be publically “tagged” by CMS. Instead, a remediation plan would be provided by the TC to address deficiencies in outcomes for marginal organs. This would result in the application of SRTR data for its intended purpose of remediation, and not the punitive “bright-line” test that it currently serves. Again, no regulatory change and no changes in the IGs would be needed. Instead, this would constitute a slight modification to the “mitigating circumstances” process and guidelines, in line with previous suggestions by the ASTS both during and subsequent to the public comment period.
Potential Solutions--Long term Options:
i) Funding for research to develop improved risk-adjustment methodologies for both standard and (especially) marginal donor and recipient variables.
ii) Improving the informed consent process, including especially improving effective communication with potential recipients regarding the risks and benefits of accepting marginal organs, the performing center’s outcomes for both standard and marginal organ transplants, and the outcomes of other area transplant centers.
iii) A unification of the cultures of CMS, HRSA, and the Collaborative that emphasizes a reduction in organ wastage and a focus on linking organ donation initiative metrics (OPO Performance) with transplant outcomes (TC Performance).
iv) Allocation policy reform with a focus on reducing organ wastage and improving transplant outcomes.
v) Revise the OPO outcomes requirements to reflect a risk-adjusted model for yield.
Dr Barr noted that the first sentence was the key one: “The misalignment and inconsistencies between CMS outcomes requirements for TCs and OPOs inhibit optimal organ donor strategies and contribute to organ wastage, which is a significant problem in the field of transplantation.” The suggested solutions match up to the workgroup’s two subgroups (e.g., steps).
Ms. Cornell stated that she very much appreciated the joint document and felt it nicely summarized many individuals’ and groups’ thoughts. This communication will probably spark the AOPO and the Alliance to issue something about OPO issues, but Ms. Cornell said she did not expect any such documents to conflict with the communication from ASTS and AST. She said that she was unsure if AOPO would endorse this letter 100 percent without some additions, but would probably agree with it with the addition of OPO metrics.
Dr. Barr added that it sounded as if discussions along these issues were occurring within HRSA’s Division of Transplantation (DoT) and other agencies. Step 1 particularly involved work with the SRTR on data analysis. On the last workgroup call, someone mentioned that there was a consensus meeting with UNOS scheduled for early 2012, which might present some opportunities. He cautioned, however, that much work must be done to prepare for that conference.
Dr. David Gerber said that he seconded everything in the communication and thought the joint document was fantastic. He felt it was critical to identify the problems and the fact that the SRTR’s reports were being used in unintended ways. Efforts to address this problem must occur in a stepwise fashion and with CMS’ help. He added that the performance outcomes really drive these things.
Dr. John Fung said that perception has become reality. People believe using an ECD disproportionately affects the outcomes. His center looks at outcomes for ECD, SCD, and DCD for all organs and has found that risk adjustment for kidney is not disadvantageous for outcomes. In other words, it does not necessarily create a penalty in terms of expected versus observed outcomes. There is a need to dissect this better, since centers stop doing ECDs and use better organs for healthier patients.
Dr. Barr added that, on the conference call, participants talked about the fact that only the kidney has SCD and ECD definitions. Centers also backpedal on their sicker recipients. The question is: what data should be gathered? For kidneys, the differences in recipients’ cardiac disease are variable depending on how data are put into the database; the devil is in the details. Ms. Cornell stated that, at the moment, the way things are defined may work (i.e., ECD, SCD); but if one were to rewind the clock and think about what is a SCD or ECD, it gets complicated. Someone with health problems could still be a SCD; the current definitions miss some details.
Dr. Barr asked what the next step was, specifically with respect to the 2012 meeting. He queried if the ACOT and the workgroup should sit with the ex officio members and try to work on data analysis issues. He expressed the opinion that there was a need to chart out solutions and problems to a greater extent. Ms. Cornell added that other groups are working on this as well; there are many pieces and there is a need to organize who is working on what and how far they have gotten. This must start with classification of donors. Conference calls should occur more than once a quarter at this point.
Dr. James Eason noted that the term “marginal organ” is obsolete. Dr. Barr commented that UNOS had tasked a committee to come up with equivalent definitions at some point. The thoracic community said it was a spectrum and would not cubbyhole it… it is all shades of gray. The problem is that few data exist on cause and effect for outcomes. The donor data have not been exploited yet. DonorNet contains a lot of narrative that is hard to catalogue and assess.
Ms. Jan Finn noted that there is a forthcoming study with a few OPOs’ observed and expected outcomes, which should be ready in the first quarter of 2012. Charlie Alexander and Jeffrey Orlowski were the authors. From the audience, Mr. Orlowski, AOPO’s Past President, commented that this was the Donor-Adjusted Risk Model, which has just been approved by UNOS to evaluate OPO yield. It looked at donor variables entered into UNOS system as part of OPO reporting. The metric includes about 57 variables in a 4-year cohort of recovery data; and it compares the outcomes to the cohort and projects an expected yield. It is being used to evaluate the OPOs, but could be used to look at donor outcomes as well.
Dr. Barr asked about the data source and the response was that it is the standard data the OPOs submit on deceased donor registration forms. The model was created by the previous SRTR contractor; and the data have been analyzed by the current SRTR contractor. The OPOs can see their observed versus expected yield (by total and organ by organ) on their part of the SRTR website. They can look at outcomes and comparisons by donor hospital, region, and coordinator. This can drive improvement from the OPO side.
Dr. Barr asked again what the next steps would be. Mr. Alexander responded that the greatest opportunities probably were in evaluating the definitions. Working from flawed definitions would just improve a flawed product and so there is a need to look at donor risk and correlate to donors, which may change the type of donors who are pursued.
August 24, 2011
Vascularized Composite Allografts - W.P. Andrew Lee, M.D., Professor and Chairman, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine
Vascularized Composite Allografts (VCA) is a new frontier in reconstructive surgery and transplantation surgery. A new national society was formed 3 years ago and now has over 200 members. VCA can be any skin, subcutaneous tissue, muscle, bone, blood vessel, nerve. It is “customized reconstruction” in which tissue is replaced with like tissue. Internationally, a variety of procedures are performed including tongue, trachea, knees/joint, femur, and face. The difference between VCA and organ allograft is that the former is not life-saving, but it is life giving. Dr. Lee showed slides of patients who had received bilateral hand transplants and face transplants.
Dr. Lee also showed slides of the first U.S. face transplant, which occurred about 3 years ago. He noted that among military veterans, hand loss can be devastating. There has been no increase in veterans’ use of prosthetics since the time of the Vietnam War. These prosthetics are too heavy and painful, and often fit badly. Prosthetics cannot replace the hand’s multiple uses, and so VCA transplantation is a good solution. Internationally, there have been 68 hand transplants in 49 patients thus far, most of them in Europe.
What is particularly interesting is that brain MRIs (magnetic resonance imaging) show cortical regeneration: the brain learns to control the new hand, even after years of dormancy. Functional outcomes include improve quality of life in 83% percent of patients; 90% of patients returned to work and had improved manual skills; 100% had protective sensation within 6-12 months; and 88% regained subtle discriminative sensation.
VCA uses triple immunosuppressants, which do have side effects (e.g., diabetes and basal cell carcinoma). Thomas E. Starzl Transplantation Institute at University of Pittsburgh has proposed pre-treatment plus minimal immunosuppressant, and has verified outcomes in labs using swine that have been infused with stem cells. Results indicate tolerance after infusion. A clinical trial has found that topical tacrolimus can prolong graft survival. There is a protocol called the Pittsburgh Protocol for Hand Transplant on this, funded by the Department of Defense and the University of Pittsburgh Medical Center. The study has transplanted eight hands in five patients with the longest follow-up of 29 months. Dr. Lee discussed the selection criteria, including match size, gender, skin, and blood type.
The sequence of limb recovery is similar to organ transplantation, and takes a lot of rehabilitation. The cellbased immunomodulatory protocol is safe and well-tolerated. Patient compliance with medications and therapy are essential for favorable outcomes. Hand allografts have been maintained for 2.5 years with lowdose Tacrolimus monotherapy. Minimizing immunosuppression broadens the indications for reconstructive transplantation. The unique aspect of this is that it is possible to diagnose skin rejection externally and treat it externally with topical therapy: 50% of rejection can be treated just with topical therapy.
There are vulnerabilities, however. There may be a loss of public trust because this is disfiguring to the donor. There may be loss of confidentiality for the donor because faces are recognizable. There also may be negative perceptions about allocation policies and inequalities. Further, it is hard to track outcomes.
Dr. Lee closed by asking the ACOT to recommend that the Secretary define VCA as “organs” under the National Organ Transplant Act (NOTA).
Dr. Barr noted that there has been incredible progress in this area. Anyone who has heard presentations by psychiatrists knows that the benefits to patients are huge, especially for face transplant recipients. The pressing issue is how to help the field. The situation is reminiscent of what happened 20 years ago when transplantation moved beyond kidney transplantation.
Richard Durbin thanked Dr. Lee for his presentation and for the recommendation that OPTN serve as the clearinghouse. The Division of Transplantation has been in discussion with FDA for several years about this since, technically, VCA are “tissues.” DoT agrees that they are more like organs due to issues such as ischemia time, the need for immunosuppressants, and so forth. NOTA gave HHS oversight of OPTN for specific organs, as well as other organs that the Secretary may specify by regulation (such expanded specification has been done previously for intestines, for example). DoT is in discussions with the FDA about the possibility of including VCA in the organ definition. It would require a regulatory process but a decision is expected shortly.
Dr. Barr asked if the ACOT needs to strongly endorse this or if it was already happening. Dr. Durbin responded that it would be helpful for the ACOT to weigh in. Ms. Alexandra Glazier moved to make the following recommendation:
The ACOT recommends that the Secretary redefine VCA as “organs” under NOTA.
The motion was seconded by Dr. Raymond Benza and passed unanimously. Ms. Emily Levine, HHS Senior Attorney, stated this change would empower the OPTN to provide oversight for this area and that the legal team would include background about this for the recommendation.
Dr. Velma Scantlebury asked if there were any relevant OPO issues. Ms. Glazier reported that, in New England, facilities were working on face transplants and it is going well. The OPOs strongly support this area being under the OPTN. Dr. Barr added that, if the definition changes, then all of the benefits from NOTA and the OPTN will be applied. The OPOs are an integral part of that.
Dr. Barr asked Mr. Alexander to speak from the audience about whether there was a way to expedite this on the OPTN side. Mr. Alexander said the OPTN has been working hand-in-hand with HRSA. The OPTN believes it is equipped to handle this area and supports doing so. The infrastructure is in place and ready to go. The OPTN contract ends in 2012, so the timing is perfect. The change does have to go through public comment and so there will be some time before a final rule comes out, however.
Organ Donation and Transplantation Alliance - Lori Brigham, President of the Donation and Transplantation Alliance, President and Chief Executive Officer of the Washington Regional Transplant Community
Ms. Brigham noted that the Alliance was formed to continue the momentum and process improvements that HRSA started during the Breakthrough Collaborative. When that initiative wound down, people wanted to continue the work because so much progress had been made. HRSA facilitated this and formed the new organization, which represents a broad joint constituency. The Alliance is a partnership and collaboration of national organizations including the American College of Healthcare Executives, American Hospital Association, AST, ASTS, AOPO, Society of Critical Care Medicine, The Joint Commission, and UNOS.
The internal objectives are to coordinate with HRSA to fill the gaps in the national Breakthrough Collaborative and partner for future efforts and to continue to engage donor hospitals, OPOs, and transplant centers incorporating proven Collaborative methods. HRSA and the Alliance are partnering to capture best practices, duplicate them, and then spread them. The goal is to improve the “quality” of donation and transplantation by spreading the leading practices of “high performers” that have achieved outstanding outcomes.
Strategic priorities are to partner with HRSA to refine national performance measures and renew commitment to performance improvement; partner with HRSA to develop a national education and training system to support Community of Practice; and promote a Federal financial and regulatory climate that increases the number of successful transplants in the United States. Each strategy has a specific purpose.
Ms. Brigham showed a slide that depicted the overarching national goals and the many different strategies being employed to address each one of them. Successful efforts to increase the numbers of donors per year and the numbers of organs transplanted will result in a decrease among the numbers of patients who die on the national waitlist. Each strategy (which was depicted by a different colored box) has its own specific purpose, but they all create momentum to help save lives. The national organ donation and transplantation situation is multi-faceted and must be addressed on many different fronts. Each one of these segments is affected by the others, so partnering is necessary to create action across them.
The Alliance held a Performance Improvement Summit in August 2011. Over 130 participants met to discuss ways to implement processes that have been successful in other organizations and fields; to link performance improvement and quality efforts; and to leverage the power of committed leaders.
The HRSA/Alliance Donor Management Task Force has had two meetings (August 2010 and May 2011). The Task Force has focused on advancing the scientific knowledge that influences organ donor management practices; promoting adoption of critical care and quality improvement practices in each donation service area (DSA) that optimize organ viability and increase the number of organs transplanted from each donor; ensuring that all patients meeting the neurologic criteria for determination of death are pronounced in a timely manner so that organ donation intentions may be fully honored; and ensuring that each donation case occurs using the most appropriate donation pathway, either donation after neurologic determination of death (DNDD) or donation after cardiac determination of death (DCDD).
Task Force members consist of representatives from each of the 11 regions of the national OPTN. Participants come from high-performing DSAs and include intensivists, neurologists, neurosurgeons, transplant physicians and surgeons, and organ procurement professionals. At-large Task Force members represent national organizations such as the American Academy of Neurology, American Association of Critical Care Nurses, AST, AOPO, and Society of Critical Care Medicine.
The Task Force chairpersons are members of the Organ Donation and Transplantation Alliance Board of Directors and represent the ASTS and the Society of Critical Care Medicine.
A National Donor Management Summit will be held in Missouri in October 2011 and focus on integrating effective management principles and practices into the continuum of end-of-life care, and helping facilities better manage donors to improve donor yield and outcomes.
Leadership is an important component in performance improvement. Since 2008, there has been an annual CEO/Executive Leadership Summit for hospital leadership, OPO leadership and hospital association leaders. These have been very successful programs to build understanding, investment and commitment to donation among hospital leadership throughout the nation. The next Summit will be held in St Louis on October 18-19, 2011, and will bring together leadership to find ways to transform donation by building partnerships.
These efforts will culminate in the 2012 National Learning Congress, to be held in Grapevine, Texas, in the fall of 2012. The faculty will be appointed by the end of the fourth quarter in 2011.
The activities being conducted nationally include: Transplant Center Task Force, National Learning Congress, CEO/Executive Leadership Summit, Quality Improvement Task Force and Performance Improvement Summit, Donor Management Task Force, Pediatric and Adult Donor Management Summit, and the DSA and Regional Action Teams.
Ms. Cynthia Puryear commented that she recently was asked in an interview why so many organs “go to the grave” and she suggested that education was needed to increase the number of organs used. She said that she did not see enough effort going into educating communities and approaching families. Ms. Brigham responded that Donate Life America is a key partner on community education, and that all procurement associations have educational programs. It is important to get hospitals into this process as well. While a lot is being done, it is definitely not enough — because there are still individuals who are not registered organ donors.
Dr. Barr commented that AHA issues are very important in terms of unrealized potential. The members of this group all live and breathe transplantation but, for most community hospitals (where the donors are), it is a blip on the screen. This issue can be approached using either a carrot or a stick. Including providers in the discussion and the process is the carrot. Dr. Barr expressed frustration with what he felt was a lack of communication and cooperation that results in a lack of testing, scheduling time, etc. One often hears about organs that are lost because it was not possible to get a test done, or a CT scan, or so on. This is one place that perhaps the stick from CMS and/or the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) could be helpful and is currently under-enforced. He asked how regulations for AHA member organizations can be used to make organ donation more important to the hospitals.
Ms. Brigham responded that, in her view, regulation will not solve the problem. Solving it really comes down to working relationships with the hospitals in the middle of the night, which is why having leadership engaged is so critical. She said that when a person’s boss is engaged in an issue and there are performance improvement measures on it, the issue becomes a focus and incredible progress can be made. For example, Prince George’s Hospital (in Maryland) came to the 2008 Summit with a 33% conversion rate and 1.2 organs per donor. Now the hospital is a HRSA medal winner with an 80% conversion rate and 3.6 organs per donor. Making this sort of progress takes time, engagement, and leadership. AHA’s support gives credibility and incentivizes the members. Transplant centers lead the way. When center programs are strong, they can contact community hospitals to partner; if the center is not doing well, it is not possible to get the hospitals on board.
Dr. Barr reiterated that he felt that JCAHO and CMS regulation could be better and there is a lack of accountability. He felt there were clearly chronic players that do not seem to care. It has to become a sentinel event where logistical problems occur for the hospital if left unaddressed. Ms. Brigham agreed that this takes time and buy-in. Ms. Sandy Andrada concurred with Ms. Brigham. The Alliance’s work with hospitals is key, while the OPOS are doing this from the other side to build relationships with the operating room manager or critical care nurse. In the last 5 years, there has been a significant improvement across the country in terms of building a culture of donation in every hospital.
Ms. Brigham thanked HRSA for the agency’s support.
Dr. Fung said that there was a need for a unified message and a better front to push donation in a thoughtful way. Dr. Barr commented that he deferred to Ms. Brigham and others who deal with this day-in and day-out. He understands the message that trust is key. Nonetheless, he said, there are definitely bad players out there, and sentinel events that CMS and JCAHO could use to improve the situation. Specifically, he said he was referring to work-ups and logistical issues on the part of the hospitals. For example, there used to be more under-reporting of deaths until the OPO started looking at death files. Any enforcement should occur independently of the OPO, however, to protect the relationships between the OPOs and hospitals.
Dr. Eason added that incentives are important as well as enforcement. Ms. Brigham agreed and said that incentives were the Task Force’s goal. It is looking for “out of the box” ways to resolve issues.
Dr. Thomas Nakagawa commented that quality end of life care should include donation; this should not be separate. This is where education has to occur, on what happens when a patient dies. Education is needed for students, nurses, and allied health professionals. It is emotional to lose a patient, and donation may not be the first thing providers think about. However, if donation were more in the end of life sphere, the situation would improve.
Circulatory Determination of Death - James Bernat, M.D., Professor of Neurology and Medicine, Dartmouth Medical School
Dr. Bernat presented before the ACOT at the August 2011 meeting on the analysis of a HRSA-recruited panel for the controlled donation after circulatory determination of death (cDCDD). He provided an update.
Dr. Bernat began by noting that the words “irreversible” and “permanent” are often used synonymously but have an important distinction. Irreversible means something that “cannot be undone; irrevocable”: it is absolute and univocal. Permanent means “continuing without change; enduring”: it is equivocal and contingent. Something that is irreversible cannot be reversed using current technology, while something that is permanent will not be restored spontaneously or through intervention. The set of permanently lost functions encompasses those that are lost irreversibly; in other words, permanence rapidly yields irreversibility.
With a circulatory criterion of death, permanent cessation is the traditional standard of death. Dr. Bernat provided an example: a patient dying of advanced metastatic cancer is admitted for palliative care and found on rounds without a heartbeat and breathing. He is declared dead by permanent cessation of circulation and respiration without requiring proof that they ceased irreversibility.
With DCDD death determination, the medical profession has implicitly accepted the permanence standard. Permanence always produces incipient, rapid, and inevitable irreversibility. Its use is inconsequential in the outcome, and removing organs does not cause death.
“Auto-resuscitation” raises the issues of what duration of cessation of circulation shows permanence. There are several different protocols with different recommendations, including the Pittsburgh Protocol (2 minutes), the Institute of Medicine protocol (5 minutes), and the Society of Critical Care Medicine (SCCM) Ethics Committee and National Conference on DCD Standards (not less than 2 minutes or greater than 5 minutes).
Data published last year are relevant to this issue (Hornby K et al. Crit Care Med 2010; 38:1246-1253.) In controlled circumstances, auto-resuscitation occurs but there is no return of circulation. This is contrasted with uncontrolled circumstances (e.g., as in failed cardiopulmonary resuscitation [CPR]), where there have been reported instances of auto-resuscitation with restored circulation up to seven minutes after CPR stops. In planned withdrawal of life-sustaining therapy in the intensive care unit, as occurs in controlled DCDD, auto-resuscitation to pulseless electrical activity (PEA) can occur up to 65 seconds after asystole; no return of circulation. In failed CPR, as occurs in uncontrolled DCDD, auto-resuscitation to restored circulation can occur up to 7 minutes after CPR is abandoned.
Dr. Bernat’s group looked at controlled circumstances. His panel recommends using the term “DCDD” (rather than “cardiac”) and relying on the permanence standard of death. The panel notes that correctly declared death respects the deceased donor rule. It recommends the use of blood flow measurements to assess absence of circulation and selection of a conservative interval of asystole. The panel believes that only modified Extra Corporeal Membrane Oxygenation (ECMO) is acceptable, with explicit consent. Heart recovery in DCDD is acceptable (restarting the heart in another person does not impact the fact that the donor has no circulation and is dead.) The field should promote uniformity in death determination, and new protocols should have ethical safeguards to increase trustworthiness of donation. The panel suggests the benefit of additional research, especially around uncontrolled donation after circulatory determination of death (uDCDD).
With respect to uDCDD, the New York City uDCDD protocol raises interesting questions about whether ECMO reperfusion restrictions are necessary. It may be unnecessary to prove permanence because failure to re-establish circulation after failed CPR proves irreversibility. Further analysis is necessary to settle this point and to incorporate auto-resuscitation data. Questions include: Is circulatory cessation in uDCDD patient already irreversible, so the waiting period and reperfusion ban required in cDCDD to establish the equivalence of permanent and irreversible becomes unnecessary? What is the relevance of auto-resuscitation data after failed CPR?
Dr. Scott Halpern spoke from the audience to note that his team had provided an accompanying editorial on these recommendations. While it is not appropriate to rehash the debate, he said it should be noted that the positions put forth are only the product of the panel members’ work. He added that there is considerable plurality of opinion about whether the recommendations are adequate or not.
Dr. Halpern continued that “permanence” reflects decision-making on the part of clinicians and that the data results are predicated on less than 100 cases. One would need 10,000 cases to rule out even a 1 in 1,000 risk of auto-resuscitation. The recommendations are predicated on the rationale that one has to adhere to the dead donor rule, which is predicated on the assumption that that is the best way to promote public trust. Yet, that assumption has never been shown to be true. He said people place no importance on the circumstances or timing of death when they are considering donation. The field should consider what the public would think if it were known that doctors were preventing opportunities to donate. Dr. Bernat noted there was not time to have this debate at the ACOT meeting, but the ACOT members should be aware that it was published in Chest.
Derivation of the Uncontrolled Donation After Circulatory Determination of Death Protocol for New York City - American Journal of Transplantation Article - Stephen P. Wall, M.D., MS, MAEd, Department of Emergency Medicine, New York University School of Medicine
Dr. Wall began by saying he was honored to be before the ACOT to present the New York team’s work. The New York team was funded by HRSA to derive an out-of-hospital Uncontrolled Donation after Circulatory Determination of Death (UDCDD) program that would be accepted and sustained by New York City residents and to evaluate impact of the new UDCDD program on members of the public approached for organ donation and on transplant recipients. The ideas behind UDCDD in the field are based on the experiences of Spain and France, and the findings of the recent Institute of Medicine (IOM) report. The potential is huge; he noted that Spain has essentially removed its waiting list for kidneys through this process.
The study used participatory action research methods and the SEED-SCALE process for social change to guide the development of the UDCDD protocol. The study took place in New York City from July 2007 through September 2010. The team went into the community through town hall meetings to get buy-in from everyone possible. It
A signed memorandum of understanding is now in place. Dr. Wall showed a slide to illustrate the protocol and described the process used. A focused neurological examination is used to observe for evidence of brainstem function. The Organ Procurement Unit’s doctor is credentialed to perform this examination. Preservation activities include: Heparin 30,000 U; t-PA 100 mg; chest Compressions (1 minute); bag valve mask ventilation; transport to the Organ Preservation Vehicle (OPV). Automated cardiopulmonary support occurs en route to the hospital. At the hospital, a second brain stem examination is conducted to assess whether reinstitution of cardiopulmonary support impaired “the natural progression to brain death in the newly deceased.”
As noted in the recent article, “a clinically appropriate, ethically sound UDCDD protocol for out-of-hospital settings has been derived.” Further, “this program is likely to be accepted by New York City residents given that the protocol was derived through partnership with government officials, subject experts, and New York City community participants.”
Subject expert reaction included the following: “Although there is much merit to the efforts of the New York UDCDD Study Group, we remain concerned that restoring aspects of circulation will be perceived as negating permanent loss of circulation that would justify the declaration of circulatory death as we currently define it and that confusion and controversy around this issue could be a setback for organ donation and UDCDD protocols.” Critics believed the use of cardiopulmonary support for organ preservation after death would “retroactively negate” the prior death determination by circulatory-respiratory criteria.
In response to these concerns, Dr. Wall stressed that vigorous efforts are made to resuscitate the patient and restore spontaneous circulatory function. Death is determined when all “standard of care” efforts at resuscitation have failed. Only after death is declared is organ donation considered and presented to a party authorized to make this decision. It is inappropriate to extrapolate the panel logic to the New York City UDCDD Program. As Dr. Bernat noted, future research is needed to expand analysis to uncontrolled DCDD and to study attitudes of physicians and public about invasive procedures and permanence standard.
During the study, nine locations were entered: seven were private residences and two were nursing homes. The report analysis indicates that the protocol is accepted by the public. There were no cases eligible for preservation and no cases eligible for donation, however. (Pittsburgh did not get any cases, either.) There were 35 cases that were missed by the team. This is largely because patients under age 60 are taken directly to the emergency room (ER), although almost all were declared dead once they arrived there. Also, in public settings, people are taken to the hospital so the team missed those cases, too.
Dr. Wall reviewed what went well. The program was well-received by the public (officials were nervous but people actually liked it). The team communicated well; the conversations on scene were successful; and there was significant learning through experience. Areas that were problematic included difficulty with the coordination of all of the agencies involved; equipment issues; confusion about reasons for donor ineligibility; and protocol violations.
Discussion (Dr. Wall and Dr. Bernat)
Dr. Fung noted that the idea of going to the ER to intercept cases is more efficient and grants access to the hospital resources as well. He asked which other jurisdiction had been successful with uncontrolled ECDs, and Dr. Wall responded that this occurred in Washington D.C. At the Washington Hospital Center, Dr. Jimmy Light spearheaded a movement that was successful due to a law that allowed the team to do preservation without the need for prior consent. It is easier to get such a law implemented in a city compared to a state, he commented. In hindsight, Dr. Wall suggested that a law might have been a better way to go in New York. He stressed that the key point is that each area is culturally different and any projects have to be specific to the community needs. In some cultures in New York, this can be very challenging, which is why the team wanted to specifically ask about donation. The goal was for people to be angry that organs were not donated rather than being angry that they were.
Dr. Barr asked if a program such as this was possible without presumed consent. Dr. Wall responded that the team pursued presumed consent for preservation and people said, it’s OK if you ask us at the time. However, the government was so concerned about this issue that it mandated the individual had to be previously registered.
Ms. Glazier asked Dr. Bernat if his group looked at how circulation is defined. He responded that she had hit the nail on the head. The question is does the re-establishment of circulation change the status of the individual? He noted that he did not want to prejudge that issue with his response.
Ms. Brigham noted that a rewrite of UNOS’ model elements of controlled DCD is forthcoming and will be put out in the next public comment cycle, which is timely. Dr. Barr noted there is a public trust and public education facet to this issue; the more opinions expressed in the public comment, the better. He applauded this work, and noted that such trial-and-error efforts are very difficult.
Dr. Eason noted that New York City has done a lot of work and invested a lot of effort in this. While there has not been much product, he felt that the team was on to something. This is work that is worth continuing. Dr. Wall said that it was very important to re-convene Dr. Bernat’s panel and make funding available to continue this work.
Ms. Mary Pohl, from XVIVO Perfusion, spoke from the audience, saying that there is a lack of patients because they do not have approval for donation. She asked if it was possible to do compressions on the way to the hospital and then, when the individual got to the ER, get the permission there. Dr. Wall responded that Dr. Tom Egan came to talk to the New York team about this. Putting in the balloon occluder precludes lung donation because it results in pulmonary edema. It turns out that cold profusion is good for lungs but not good for other organs. This fact drove the protocol. Kidney, liver, and lung interests’ may conflict. He added that survival for out-of-hospital cardiac arrests has increased significantly. Because of how New York City is, it was not possible to have a team in every hospital; but it was possible for the team to follow ambulances to the hospital.
Donor Management Task Force Declaration of Death Workgroup - Galen V. Henderson, M.D. Director, Neurocritical Care and Neuroscience Intensive Care Unit, Brigham and Women's Hospital
The Task Force was founded in 2010 to further progress toward increasing the number of organ donors and transplantable organs in the United States. The Task Force is co-sponsored by HHS, HRSA, and the Organ Donation and Transplantation Alliance (the Alliance). The Task Force has addressed opportunities to improve outcomes of, and decrease the variation among, OPOs and hospitals in donor management practices.
The Task Force’s purposes are to: 1. Advance the scientific knowledge that influences organ donor management practices; 2. Promote the adoption of critical care and quality improvement practices that optimize organ viability and increase the number of organs transplanted from each donor; 3. Assure that all patients who meet the neurologic criteria for determination of death are pronounced in a timely manner so that organ donation intentions may be fully honored; and 4. Assure each donation case occurs using the most appropriate donation pathway: donation after neurologic determination of death (DNDD) or donation after cardiac determination of death (DCDD).
The Task Force includes representatives from each of the 11 regions of the national OPTN. Participants come from high performing DSAs and include intensivists, neurologists, neurosurgeons, transplant physicians and surgeons and organ procurement professionals. At-large task force members: American Academy of Neurology (AAN), American Association of Critical Care Nurses, AST, AOPO, and Society of Critical Care Medicine. The Chairpersons are representatives of the Organ Donation and Transplantation Alliance Board of Directors and the ASTS and the Society of Critical Care Medicine.
The Task Force reviews current organ donation performance data and consider published (and/or soon to be published) guidelines and recommendations from national organizations. Information and experience are used to make recommendations to hospitals, organ procurement organizations, donation service areas, national organizations and the Federal government about opportunities for action to improve donor management practices.
There are three subcommittees: The Scientific Knowledge Work Group identifies the research projects necessary to improve organ donor management practices and outcomes. The DSA Practices Work Group develops recommendations that can be implemented by DSAs and hospitals to improve the quality and outcomes of donor management practices.
The Declaration of Death Work Group promotes the timely declaration of death using neurologic criteria in all appropriate cases, and develops strategies that preserve the possibility of donation and/or honor donation intentions and preserve organ viability when the possibility of neurologic death is not certain or has not yet occurred.
There are four steps to making brain death determination: Clinical evaluation (prerequisites); 2. Clinical evaluation (neurologic assessment); 3. Ancillary tests; and 4. Documentation. Documentation is very important. There are three cardinal features of a clinical evaluation of neurological assessment: coma, absence of brainstem reflexes, and apnea.
Brain death is a clinical diagnosis. Ancillary testing is not required unless the clinical exam is drawn into question. Even ancillary testing is potentially confounded in certain circumstances. Clinical judgment remains paramount. The Task Force findings are that: 1. The process for declaring brain death varies nationally; 2. This variation is detrimental to the overall mission of donation; 3.The Task Force feels strongly that there needs to be a stronger national standard regarding the determination and declaration of brain death, allowing for more consistency in the declaration of brain death process across the U.S.
The Workgroup requests that the ACOT ask the Secretary of HHS to encourage OPOs and other organization that have an impact on the organ donation process to adopt a common model for brain death determination in potential donor patients.
The Workgroup is not recommending that the OPO community play a role in determining death of potential organ donors. It requests that OPOs partner with hospital critical care teams to evaluate the hospital’s declaration of brain death as a factor in the overall suitability of the patient for organ donation, ensure the hospital’s policy has been followed, and the declaration of brain death is documented in the medical record for every donation case.
Recommendations for consideration on Declaration of Death based on Neurologic Criteria:
In summary, Dr. Henderson noted that this issue is of critical importance in safeguarding the precious gift of organ donation and transplantation and maintaining public trust in the process. The Task Force believes that ACOT should encourage the adoption of a national OPO standard for brain death determination and documentation, as a factor in organ donation suitability. This is critical in creating a more consistent national practice of declaring brain death in the donor patient population.
Ms. Brigham commented that the Task Force has done great work on this issue. There is a need for better standards for more transparency. It is important to send the message back to the community that an appropriate declaration of death is critical.
Dr. Barr asked UNOS to comment. From the audience, Mr. Alexander stated that the organization has not had a specific charge to address this; it is being handled by an OPO committee and has not yet come to the Board of Directors. Ms. Brigham suggested that ACOT could recommend this be done – start with OPTN, get it added into the conditions of participation. Mr. Durbin said ACOT could refer this issue to a workgroup for review and possibly endorse it.
Ms. Glazier expressed the view that putting this in the conditions of participation was a good idea. The OPOs have the responsibility to ensure brain death policies are being followed, but they are not involved in the declaration itself. fThe hospitals and their clinicians do this. Dr. Barr added there should be standard protocols for this.
Dr. Fung stated that, about once a year, his team gets a case which is inadequately documented by brain death and the whole team has to come back. It’s infrequent, but suggests the need for a better standard. Dr. Barr concurred that this happened in his region as well (i.e., for the declaration to be inadequate), which becomes a public trust issue.
Ms. Glazier reiterated that the OPOs have no authority to ensure hospital practice. Mr. Durbin suggested that an ACOT work group review this language and any recommendations. Dr. Nakagawa also suggested that other societies be brought on board to back up the American Academy of Neurology and build community consensus.
Financial Challenges of Kidney Paired Donation, John Friedewald, M.D., OPTN Kidney Transplantation Committee
Dr. Friedewald began by describing the need for kidney paired donation (KPD). Blood type and crossmatch incompatibility exclude approximately one-third of kidney transplant candidates from receiving a living donor kidney transplant. It is estimated that a successful KPD program could increase the number of kidney transplants by 1000 – 2000. According to the Congressional Budget Office, KPD could provide a cost savings of $500 million over the next 10 years.
Commercial payors favor KPD as well because it is better for the patient and cheaper for the insurance companies. For example, Optimum Health reports that it saves $400,000 for pre-emptive transplant, which also avoids 33 months of End Stage Renal Disease (ESRD) care (this is the average length of time on the waitlist).
The OPTN KPD program began running matches in October 2010 and did two transplants in December 2010. There are three three-way matches pending (total 9 transplants), and two non-directed donor chains pending (one 12 transplant and one 7 transplant chain). It has gone slowly because the patients are challenging (two-thirds are highly sensitized, for example). Many other programs are doing KPD as well, and Dr. Friedewald expressed the view that they might be keeping pairs that are easy to match regionally or locally, and putting the harder-to-match ones into the national pool.
Factors that increase matching include: the ratio of easy-to-match and difficult-to-match pairs in the pool; the candidate’s ability to enter the system with multiple donors; the donor’s options (travel to matched recipient versus kidney is transported); and the number and blood type of pairs and non-directed donors in the pool. Non-directed donors are the key to the system working well.
KPD has added costs. It requires more frequent or involved calculated panel reactive antibody (CPRA)/Single Antigen bead luminex testing. There are the expenses of donor travel, shipping the organ, shipping blood for crossmatching, and repeated crossmatching (if the donor is matched often). Further, there is the additional coordinator’s time and cost to manage these patients and the KPD program at the center.
Financial barriers include the perception that, if multiple donors are evaluated for KPD, the center may only be reimbursed for one evaluation (the use of a Transplant Center Standard Acquisition Charge SAC [SAC] dilutes this effect). There is no reimbursement for donor travel (unless the person meets eligibility requirements for Living Donor Assistance Program), and Medicaid often will not pay physicians for nephrectomy conducted in other states.
A national SAC would be good for some cases but does not account for cost difference in various sites. A national SAC is not a charge representing the cost of a specific kidney but a charge that represents the average cost associated with acquiring that type of kidney (in this case, living donor kidney). It would be all-inclusive (direct and indirect) and include physician services up to the admission to the hospital for donation. A SAC is usually calculated once per year.
The advantage of a SAC is that it eliminates questions when individual donor costs are incurred; dilutes issues of multiple donors for a single recipient; and can be transparent between centers as soon as match is made. The disadvantages include the fact that some centers could have SACs much higher (or that are perceived to be much higher) than the amount that other centers believe a single donor evaluation should cost due (this occurs due to overhead, waste, etc.). It is unclear how “extra” costs would be treated (i.e., if the recipient center requests additional tests over the donor center’s standard evaluation), and that isolating donor-only costs may represent new administrative processes for some centers.
A national living donor SAC does not account for regional variance in cost. It simplifies reimbursement, however, making it the same for all, no matter who recovered the kidney. It would require CMS regulation changes and does not address physician fees. There also is an administrative burden in terms of who would determine the SAC and on what basis.
The alternative of using departmental charges creates an itemized bill for costs associated with a specific donor for a specific recipient that can be billed to the recipient’s transplant center. Transplant centers must bill SAC to Medicare or third-party payors for organs acquired and transplanted. The advantages are that the recipient center will be confident it is paying only for costs associated with the specific donor (the “buyer” sees exactly what is being paid for). The costs could vary in every case, however; and it will be difficult to include overhead, labor, and other costs for the donor hospital. Using departmental charges would require more negotiation at every match, which may slow down the ability to do matches.
Treating donor complications also is a challenging area and one that could lead to controversy. Questions on this area include: Who decides what to treat, how to treat, and where to treat? Does this vary if there is a donation-related complication? What if the recipient is no longer eligible? Contractual agreements between transplant centers should spell this out before the transplant occurs.
Although the KPD financial workgroup is addressing these issues, UNOS does not have any fiscal authority and no overriding authority at the moment for other coalitions. The group’s main influence, therefore, is to develop recommendations on using SAC versus departmental charges (for the KPD pilot); determine standard procedures for either method; gain the cooperation of third party payors; set guidelines for negotiations between centers; and provide peer-to-peer guidance to administrators in constructing center-specific SAC (or departmental charges). The workgroup is leaning towards supporting a standard SAC.
Dr. Friedewald closed by raising other key issues. Should the OPOs manage the financial process and bill the SAC to recipient center? What happens when things go bad (including transportation failure, primary non-function, major donor complication, and donor death)? A standard contractual agreement or memorandum of understanding needs to be established addressing business agreement/Health Insurance Portability and Accountability Act (HIPAA), failure plans, and warranty. Agreements would be needed between the transplant center and “matchmaker,” between both transplant centers, between recipient center’s and donor center’s physician group, between the physician group and the commercial payor, and possibly others.
Possible next steps include:
The fact that state Medicaid plans may not pay for a donor search outside the state is a key issue.
Dr. Barr asked what discussions have been held with transplant center administrators. Dr. Friedewald responded that he was not sure far this has gotten. For example, the Medicaid issue has not been figured out yet. Dr. Fung asked why CMS did not cover the cost of kidney searches outside the state. Dr. Barr answered that state Medicaid plans all differ in terms of what they allow. The huge number of differences between states is a problem.
Dr. Fung asked if the commercial payors have been involved in the committee’s discussion and what conversations had occurred on a generalized risk pool. Dr. Friedewald commented that the commercial payors have been involved in subcommittee discussions and support a risk pool. These conversations have not happened with CMS yet.
Dr. Barr asked what the ACOT could do to be helpful. Dr. Friedewald did not have anything specific yet and primarily wanted to provide an update. In the next 6-12 months, the goal is to have firm ideas and recommendations to present to the ACOT.
Dr. Eason commented that there are at least two private payors doing this, and asked what the advantage was for OPTN being involved with KPD. Mr. Alexander commented from the floor that the OPTN infrastructure is a way to have an effective review and look out for the patients’ best interests. This is an opportunity to provide service to transplant centers and beneficiaries. Dr. Eason felt this was not an issue of public trust. Centers are still responsible for reporting what happens, as with any other transplant. Mr. Alexander responded that reporting is one thing; having the purview to manage it and conduct peer review is another. Reporting is not enough all by itself.
Dr. Gerber noted that he appreciated the financial information presented but, from an operational standpoint, the marketplace was ahead on this issue. OPTN should look at what to facilitate in terms of the current systems. There are resources that are valuable to the system, such as the Alliance. In terms of next steps, KPD is a small subset of kidney donation. Looking at complications and problems should be done broadly in terms of costs. Costs should not be allocated differently for this smaller group of patients (i.e., KPD).
Mr. Alexander responded that the pre-UNOS days were an example of clinicians not sitting back, but driving the field forward. VCA is moving ahead without regulation, as well. KPD is the same way. If one waits for OPTN to get authority and create systems, it will hinder innovation and advances. No one is critical of where the community sits
Dr. Scantlebury asked if the donors are insured or not, and if there are different criteria for donor selection and uniformity. Dr. Friedewald responded that the insurance status does not matter in terms of the model since all of the costs are borne by the recipient center. Some matches do not go through because the recipient center might reject on other criteria after the selection has occurred.
Dr. Barr asked what the next step is – to keep on with the discussion and with OPTN and UNOS activities. Dr. Friedewald responded that the committee is making progress in terms of a national SAC charge. Medicaid patients may need more clarification and it might be hard to solve some of those issues.
Mr. Doug Morgan, Deputy Associate Administrator for Healthcare Systems, commented that, as a past Medicaid director, he would be more likely to have a memorandum of understanding with an organization within his state than one outside of the state because the former is a known entity. He might be interested in partnering with an out-of-state institution if it had higher outcomes. There would have to be pre-conditions about eligible candidates with coverage. Medicaid programs are under extreme duress financially right now. He suggested that the group talk to the Association of Medicaid Directors as well as CMS.
Dr. Barr asked what the percentage increase would be in terms of volume. Dr. Friedewald said that the hurdles are logistical. The longer chains and the more complex matches fall apart so it requires work to keep them together. It may be a while before the increases were as high as 1000 – 2000, but each match run was going better and much learning was occurring. Opening this up to all living kidney donor centers will remove a disincentive.
Dr. Fung asked about integrating current paired donations that occur outside OPTN into OPTN. Dr. Friedewald said there is no requirement that prevents this. If centers would put all of the pairs into all the systems simultaneously, there would be a big jump.
Dr. Eason asked what resources are needed. Mr. Alexander said that OPTN just hired its first full-time KPD coordinator and is working with centers to submit pairs. The IT program is on-going. Past mandates that created barriers (i.e., not being able to use open chains) have recently been removed and this is ramping up in terms of the number that OPTN can facilitate.
Douglas H. Morgan, M.P.A., Deputy Associate Administrator, Healthcare Systems Bureau, Health Resources and Services Administration
Mr. Morgan thanked Dr. Scantlebury for her leadership role with the ACOT, which has been very much appreciated. He also thanked Dr. Barr for taking up the chair’s position. Mr. Morgan said that he will be working with the ACOT to help the entity do the best possible job. ACOT recommendations are considered very seriously and progress has been made on them.
Mr. Morgan expressed his support to Ms. Patricia Stroup, who has done a great job as the ACOT staff person. Ms. Stroup is the liaison to the agency and the Secretary and keeps information flowing. The ACOT meets twice a year; the next meeting will occur by phone. This will probably be the norm for the next few years: to have one meeting in person and one on the phone each year.
Dr. Barr added that it is nice to be able to put names with faces of ACOT members and also of HRSA staff. He encouraged ACOT members and members of the public to give Ms. Stroup ideas about speakers and topics.
Grantee Report, Organ Donor Research in the Hispanic Community - Eusebio Alvaro, PhD; and Jason Siegel, PhD, Claremont Graduate University, Claremont, California
Dr. Siegel introduced the studies, which were funded through HRSA’s public education and behavioral science research areas. He said this presentation would address mass media organ donor campaigns (primarily focused on Hispanics), the importance of organ donation messages, and the use of the IIFF model – (1) Immediate and Complete Registration Mechanism, (2) Information, (3) Focused Engagement, and (4) Favorable Activation.
Project 1 occurred in Tucson and Phoenix and was funded by HRSA’s Social/Behavioral Grant Program. Hispanic media is particularly cost-effective in terms of the ability to saturate the market. The campaign included television and radio messages about donation’s benefits. The radio spots featured a church spokesperson who discussed the Catholic Church’s official position on donation. This was done because religious beliefs can be a barrier to donation. The ads showed where a donated organ goes and the good it does in terms of recipients’ full lives.
Pre- and post-campaign testing was conducted. Post-tests indicated that religious concerns about donation were successfully addressed by the campaign. There was an increase in family conversations about donation and other positive indicators, as well. There was no impact in terms of the number of registrations but Arizona did not have a registry at the time, and several other broader barriers were also at work. Evaluation in Phoenix showed the same positive results. There was a significant correlation between media exposure and organ donation beliefs in both Tucson and Phoenix. The number of Hispanics on the waiting list increased 27%, and the number of Hispanics who received transplants increased 33%.
Project 2 replicated the project in Las Vegas and was funded by HRSA’s Public Education Grant Program. Post-test evaluation showed there were significant increases in the number of Hispanics who said they intended to find out more information about organ donation; talk to their family about becoming an organ donor; and sign up to be an organ donor.
The public education campaign had positive results in niche-market campaigns targeting low-knowledge groups and was associated with reductions in organ donation barriers. It had a positive impact on organ donation discussions as well as stated behavioral intentions. There is some evidence for positive impact on organ donor behavior (i.e. consent).
Dr. Alvaro discussed the studies assessing types of organ donation messages. In Study 1, messages were displayed on kiosks to promote organ donation. The project goals were to create a donor registry, drive registration via computer kiosks located in high-traffic areas, and to test various registration messages. The messages varied on the kiosks in order to test four appeals with focus groups: 1) Counter-argument (countering the reasons people say they are not an organ donor); 2) Emotional appeal; 3) Identity (people are in favor of it so you should act on that belief); and 4) Procrastination (you are planning on this, why wait?). The best message, which generated the biggest increase in donations (from one to three per day), was the counter-argument message that refuted the myth that a person might be too old or ill to be a donor.
Study 2 focused on messages delivered at swap meet (weekend events attended by 30-40,000 Hispanics). The project was conducted at two sites in Phoenix and one in Tucson. The project had a tent at the swap meet where everything was held constant except the type of message displayed. Messages varied between counter-arguments (your age is not a barrier), empathy messages (Maria’s kids need her), and vested interest (you help yourself by registering). Empathy messages generated twice as many registrations as the other messages.
In Study 3, swap meet participants watched videos that addressed organ donation myths, such as the myth that doctors let a person die if he or she is a donor. The study wanted to explore the fear that talking about such myths solidifies them in the public’s mind. The four tested messages focused either on positive or negative empathy (i.e., positive: a relative is getting an organ, vs. negative: a relative is not getting an organ) and mentioned the death myth. If the person was in the positive empathy group, the death myth made no difference to registration. But, people with negative empathy registered at a rate of 50% (this is much higher than the typical rate of 15%). The empathy/expectation appeal resulted in more then twice as many registrations than the information appeal or the vested interest appeal.
IIFF is a behavioral science model to guide organ donation registration behavior. It is designed to address the gap between the fact that people support organ donation but do not sign up to be donors. The problem is, organ donation is not something people think about on a regular basis and they do not get much out of registering in the short-term. This is why supportive views do not change into action. The IIFF model offers behavioral support to encourage registration among those who support donation. (It is not effective with those who oppose donation.) IIFF has four aspects: 1. Immediate and Complete Registration Mechanism; 2. Information; 3. Focused Engagement; and 4. Favorable Activation. Using the IIFF model fosters registration rates of 40 percent.
Immediate and Complete Registration Mechanism: People need to be able to register right away. In focus groups, 37.1% of registrants said that “an immediate opportunity was provided” was their rationale for registering. Forty percent of participants in a Town Hall meeting registered when a card was provided at end of the meeting, compared to just 10% who registered when the card was not provided on-site. Email is more effective than radio/TV ads for this reason because the person can click through the link to register, making it immediate.
Information: People are responsive to information that addresses their barriers. For 76% of focus group participants, a lack of information was cited as a reason for prior non-registration. In the Kiosk Poster Study, the “information” condition resulted in as much as three times as many registrations than the least effective condition. In the Swap Meet Video Study, over 50% of those who were exposed to a somber video countering death myths registered as donors versus 36% registered when death myths were not countered.
Focused Engagement: People have to be focused on an issue before they will act. Kiosks at baseball games resulted in fewer than 10 registrations (e.g., less than 5%) presumably because the individuals were not focused on organ donation, but on sports.
Favorable Activation: People need to be in the right mood; donation has to be what is on their mind. This suggests that the DMV may not be the best place to seek registrations (the average yield is about 30%). In the Swap Meet Donor Booth Study, a focus on empathy and expectations led to the greatest amount of registrations. As noted, in the Swap Meet Video Study, over 50% of those exposed to a somber mood video that countered death myths registered versus 36% of those exposed to a positive mood video that countered death myths registered.
The IIFF model offers a new understanding of organ donation behavior. IIFF can have an impact on science by improving campaign evaluation designs and methods as well as improved understanding of effective message types. It can also have an impact on practice through the nationwide dissemination of effective messages and community partnerships (i.e., with the Hispanic community).
Dr. Fung asked if the work occurred before or after Arizona’s recent anti-immigration bill. The response was that it mainly occurred before. One of the challenges was, in fact, that some law enforcement officials were conducting immigration enforcement at swap meets in Phoenix, which decreased attendance at these events.
Mr. Reg Green said positive messages could be successfully reinforced in news editorial content, as well. Organ donation rates have quadrupled in Italy since his son was murdered and became a donor there; everyone knows the story. The media made all the difference and there are a lot of opportunities to tell the story to local media.
Dr. Andrew Schaefer asked if the studies occurred at various times of day. The response was that this did occur. Dr. Schaefer asked if there was any exploration of differences among donation rates for those who sign up on their own versus those who are part of a campaign. The response was that there have been a lot of discussions about what to do when there is a signed donor card but the family says no to the donation; but this does not seem to have happened, according to the OPO information.
Dr. Wall noted that HRSA limits the amount of funding which can be spent on these interventions. This restriction needs to be removed so people can be more creative. Ads like this cost $1000 – $10,000 per minute to produce. He asked what the outcome metric was and if this had been validated. The response was that the outcome was whether the person was registered on the Arizona donor registry (this is a first-person, legally binding registration). The speakers agreed about the need for basic research and for more money on the developmental side. They stated that everyone in the field would benefit from spending money on developing messages and conducting basic research.
A question was asked about the Hispanics’ immigration status. The answer was that 90-100% of the participants’ parents were not born in the U.S. and most of the participants were not born here either. Most are not well-acculturated and have low reading levels; 80% have an elementary-level education. The studies indicate there is a need for different messages for Anglos and Hispanics, as well as for dominant and non-dominant Hispanics. In other words, there is a need for different messages within the Hispanic community based on their acculturation levels.
Dr. Scantlebury commented that the study asked participants if they knew anyone who needed a kidney and if they knew anyone on dialysis. She said that people may not always know the connections between being on dialysis and needing a kidney transplant. The speakers concurred that there is a big knowledge gap. People know others who have diabetes or who are on dialysis, but they do not report that they know someone who needs a kidney. People need more information about this.
OPTN Deceased Donor Potential Study - Kevin A. Myer, MSHA, Business Director
The study was funded by HRSA. The team assembled a talented and multi-disciplinary team of researchers under the direction of Karl McCleary as the Principle Investigator (PI) and Gary Hirsch as the Co-PI. A large and experienced Stakeholder Committee also informs and assists the research team from viewpoints representing OPO, DSA, and transplant centers, as well as views from professionals who do not work in the transplantation field.
Three subgroups work in parallel to drill into specific research questions around donor potential: the OPO, data, and clinical subgroups. The study seeks evidence about changing patterns of mortality and epidemiology in using geography to characterize future organ donor potential in the United States. It applies systems dynamics approaches and expertise to characterize and understand the complex relationships among the many agents in the system of organ donation and transplantation. The evidence-based findings will be delivered to HRSA in September 2012.
The study does not include policy formation and analysis, focus on allocation or distribution, or make any recommendations on differing geographic units of measure or operational approaches. It is not focused on current understandings or classifications typically used for compliance reasons (ECD, SCD, etc.). Primarily, the study differs in that it focuses on discovering evidence about donor potential without getting into areas involving decisions about allocation and organ distribution.
Examples of emerging approaches include using the lens of geography, mortality patterns, mapping and visualization, and disease prevalence. These new approaches will help DSAs understand both the population that is donating and the population that needs preventive care and/or transplantation.
Mr. Myer provided an overview of the Research Strategy, which includes both the systems dynamics model and the mortality side. Even within differences around geography and mortality, there are more complex system-level factors impacting donor potential that need to be elucidated and understood. In the system, there is both independence and interdependence, and the concept of isolating certain aspects of the system without considering the complex relationships and influences on those isolated aspects may create misunderstandings about certain causal relationships.
The group seeks the smallest geographic region possible for its study of mortality. There are lots of ways to look at medical geography. The team is working towards linking databases by county and zip code to achieve specificity. Mapping and visualization are powerful ways to show information and there is an entire science behind generation of these maps. Nevertheless, the assumptions regarding motor vehicle crash mortality rates by geographic units may be challenged by such illustrations. There is extraordinary variation in the U.S. by 100,000/population with county units selected to look at traumatic brain injury, for instance.
Declining Rates of Donation/Geographical and Other Variations in Organ Distribution Work Group Report - John Fung, M.D.
Dr. Fung began by commenting that the ACOT members have heard about declines in the donor rates that are currently being explored by another workgroup. He reminded everyone that, in 2010, the OPTN passed a resolution stating: “Resolved, that the Liver and Intestinal Organ Transplantation Committee shall be charged with making recommendations to reduce geographic disparities in waitlist mortality.”
The urgency in addressing this is indicated by the allocation formula that gives an individual a Model End Stage Liver Disease (MELD) score ranging from 6-40, with higher number indicating greater level of illness. With a MELD score under 15, the person is not defined as having severe liver disease and has lower rates of mortality on the waitlist. A MELD score of over 35 indicates the person is among the sickest of the chronically ill, and this group has higher rates of mortality on the waitlist. Individuals who have a MELD score between those numbers have intermediate results on the waitlist.
In 2005, new regulations by the OPTN Liver Committee resulted in a requirement that a patient has to have a MELD score of over 15 to receive priority. As a result, there have been a diminishing number of individuals transplanted with a MELD under 15, which has resulted in fewer deaths among those on the waitlist.
Last year, the Committee distributed a survey on allocation and released a document with the results afterwards. One respondent asked why the survey was reprioritizing a National Share policy for scores greater than 15. Most respondents supported it, believing that broader sharing is appropriate with patients who have higher rates of mortality on the list. The idea for additional prioritization of those with higher MELD scores also was explored (there is already prioritization for Status 1 patients). The survey asked about support for a regional mandated share for those with scores of 29, 32, and 35. Changing the allocation system in this way would shift the national share up a level.
The OPTN Region 8 MELD 29 study addressed this issue about 3 years ago. In a compromise, there was regional sharing of deceased donor livers for non-Status 1 patients if their Laboratory MELD score was ≥ 29. OPTN accepted this variance as a test of the impact of wider sharing of livers. The agreement was to accept this variance in Region 8 for 2 years, then review the impact of this wider sharing.
Previous estimates of the impact of wider regional sharing have been based on modeling and depended on a number of assumptions. The Region 8 MELD 29 experience is the result of an actual “real world” test of one specific policy in one of the OPTN eleven regions. The OPTN Region 8 MELD 29 Policy was activated on May 8, 2007. Two eras were compared: Era 1 (May 7, 2005 – May 8, 2007) and Era 2 (May 9, 2007 – April 17, 2009). The study compared outcomes of all patients listed during these two eras in Region 8, using outcomes in two similar OPTN regions (Regions 6 and 7) as time controls.
Compared to similar regions, patients who were transplanted in Region 8 with a MELD > 29 did better. They had better access to organs and were transplanted earlier. The Region 8 MELD 29 policy had the intended effect of substantially shortening the time to transplant for, and reducing the waiting list death of, patients with MELD scores ≥ 29. Despite this, there was no net effect on the entire listed population in Region 8, compared with Regions 6 and 7, on the following: time to transplantation; death on the waitlist or prior to transplant; graft loss or patient death following transplant; or overall death following listing.
Dr. Fung showed a variety of slides that illustrated the benefits seen in the study. The OPTN Committee adopted Share 15/35.
However, appropriations language inserted into the House of Representatives’ Conference Report on the Consolidated Appropriations Act of 2010 mandates that, at least 6 months before any change in the liver allocation policy is implemented, OPTN must submit a report analyzing and describing the potential impact of any changes to broaden the geographic allocation of livers on the following:
This is likely to preclude the Liver Committee’s recommendations from being enacted. Despite the model being extremely robust in predicting the number of lives saved as well as other benefits, this congressional language will require a pilot demonstration before Share 15/35 can be implemented on the national level. Dr. Fung stressed that, if the congressional requirement is not addressed, the field risks not being able to move ahead to address geographic inequities in organ sharing.
Dr. Fung presented a draft resolution for ACOT’s consideration:
“In keeping with the provision of the Final Rule to distribute ‘organs over as broad a geographic area as feasible … and in order of decreasing medical urgency,’ the ACOT requests the Secretary to endorse the OPTN models that demonstrate improvements in correcting geographic inequities, improve the likelihood of transplantation for the most medically urgent and decrease wait-list deaths and that the policies that derive from these models satisfy the conditions set forth in the House Conference Report – Consolidated Appropriations Act 2010.”
He concluded by noting that, as alternatives to the current allocation system, the use of concentric circles has many positive aspects, such as eliminating arbitrary geographic boundaries, distribution based on donor location rather than the transplant center, and current use and acceptance by the thoracic organ community. This system would substantially change liver distribution and may not be “feasible” given current sentiments and restrictions, as concentric circles could not be classified as a small, incremental step, and has not been piloted in any way.
He contrasted liver with lung allocation: the development of lung allocation score (LAS) was designed to maximize benefit of lung transplantation. It is based on disease type (post-transplant survival), disease severity (waitlist survival), and expected survival after transplant. The LAS value is normalized on a range from 1 to 100; time on waitlist does not count except for pediatric (< 11 years of age). In the allocation algorithm, lungs are first allocated to local lung patients followed by allocation to five zones delineated by concentric circles of 500-, 1,000-, 1,500-, 2,500-mile radii with the donor hospital as its center.
Dr. Fung presented a second potential recommendation for ACOT’s consideration:
“Due to the varying size of DSAs throughout the United States, the conflicting role of the OPO in serving transplant centers versus increasing organ donation, and with clear DSA differences in access to transplantation by DSA, the ACOT requests the Secretary to direct the OPTN to eliminate the DSA as the unit of distribution"
Discussion (Dr. Fung and Mr. Myer)
Mr. Alexander spoke from the floor and noted that OPTN is planning to respond as well. For the OPTN to conduct a demonstration project with statistical significance would conflict with the Final Rule, since the OPTN does not have the right to change allocation policies without the process of public comment. It seems impossible to do the demonstration project as Congress requested. OPTN/UNOS President is driving this issue. Mr. Alexander noted that the current process focuses on consensus-building and that consensus could never be achieved around the congressional requirement.
Dr. Eason complained that the language in the Act does not even describe the facts correctly. He asked if a Region 8 pilot would satisfy this requirement, or if a simulation model would do so. It is important to note that this requirement conflicts with the Final Rule. The whole system has inequities in it due to the very fact that the DSA is the first unit of distribution of livers. Until that fact is addressed, everything else is a band-aid. The “N” will never be large enough to show statistical significance and people will die in the meantime.
Dr. Fung asked how willing Congress would be to accept the models. Lung allocation models are circles around the donor and have been very effective. He said that it was incredible that the field is being bogged down over this political issue. There is no reason to believe the Liver Simulated Allocation Model (LSAM) is any different from the Thoracic Simulated Allocation Model (TSAM).
Dr. Eason added that for LSAM, lives are saved at every level of sharing. They have looked at 25, 29, 32, 35, at concentric rings, at regional sharing – all show lives saved. Dr. Barr concurred; this was even endorsed by centers on the East and West coasts, which have ocean boundaries and less of an ability to go out in concentric circles. He doesn’t see how there would be any argument about whether or not to save 100 lives a year. He suggested that ACOT should inform the Secretary that what is being asked for is not feasible. The experiment and modeling have been conducted and there are conservative estimates. Mr. Alexander noted that SRTR is looking at concentric circles for liver and other organs.
Dr. Eason said that the very fact that the DSA is the first unit of allocation drives a lot of the problems; a lot of discards occur because of the DSA. Non-aggressive centers reject the organ and that increases the cold ischemic time, which perpetuates the problem.
Mr. Durbin commented that ACOT recommendation (#51) addressed this issue and read the language aloud. Dr. Barr said that, based on ACOT Recommendation #51 and the Bill, it is not clear what the next step should be.
Mr. Durbin suggested sending a clarifying letter to the Secretary about this liver issue. He added that DoT has provided some additional resources to SRTR to look at different distribution issues. Dr. Barr added that a letter to the Secretary could note that the 2005 changes could never have been made if the congressional requirement had been in place. The letter should include language describing the 50% drop and death rate declines stemming from the allocation changes. Dr. Fung commented that, if anything, in Regions 6-7, deaths increased while Region 8 had no change.
The ACOT will put together a summary and submit it to Ms. Stroup.
Disease Transmission and Informed Consent, Scott Halpern, M.D., Ph.D., Assistant Professor of Medicine and Epidemiology, Division of Pulmonary and Critical Care Medicine, University of Pennsylvania School of Medicine
Dr. Halpern began by noting that the group has been talking about geographic variations in organ donation. Similarly, there is a lack of standardization about informed consent as individuals enter the waitlists. This is true within organs, across regions, and nationally.
In the ideal world, informed consent is grounded in the best available evidence regarding probabilities and magnitudes of risks; the best available evidence regarding how potential organ recipients make decisions (including pitfalls of human decision-making); and sound ethical principles.
As a framework for the discussion, Dr. Halpern noted that transplantation always carries some risk of donor-derived disease transmission. Scarcity drives the increasing use of donors harboring non-standard risk profiles. (He added that scarcity is even greater due to the fact that some people cannot get on the list because entrance is limited.) Therefore, choices must therefore be made that pit the interests of individual recipients against the interests of all potential recipients.
The goals of organ allocation are to maximize the number of lives saved; maximize the number of (quality-adjusted) life-years gained; and avoid inequities (differences in access based on morally irrelevant patient characteristics).
People are remarkably adept at overstating the importance individuals place on autonomy. In fact, in every domain in which it’s been studied (e.g., end-of-life care), people prefer shared decision-making over the doctor deciding or the patient deciding alone.
There are three potential informed consent options: 1. Organ-specific consent at the time of offer; 2. Myriad, specific categories to opt into or out of at time of listing; or 3. A few, discrete categories to opt into or out of at time of listing.
Option 1 is not actually consent at all because it does not promote autonomy. It creates a false trust that the risks are well-defined, is inefficient, leads to information overload, and has the potential for social biases to drive organ allocation.
Option 2 is likewise problematic because it also creates the false trust that risks are well-defined. It is burdensome for both clinicians and patients and reduces the quality of consent due to decision fatigue. The categories may be arbitrarily (and variably) defined.
Option 3 has many characteristics of a preferred consent model. It offers thorough, shared decision-making about goals at the time of listing by which patients make a choice to accept or reject “non-standard” organs (this could be subdivided into two or three general risk categories). Patients declare whether their decision would change if their clinical status deteriorated and they lost decisional capacity and may revisit their decision at any time (but have no mandate to do so). The transplant physicians retain discretion to use their own judgment on offers.
Dr. Fung asked what the legal interpretation is and if this is consistent with the informed consent process. Ms. Glazier noted that informed consent is not well defined in the realm of medical treatment; occasionally it is defined by statute, but that is unusual. Usually, from a legal perspective, this develops over decades from case law using “reasonableness” standards. There are questions of implementation, in terms of regulation. It’s not clear how specific this could get.
Dr. Halpern said the devil is in the details in terms of implementation. Some documentation of compliance at the OPO level with these practices could be a condition of funding. Ms. Glazier objected that the OPO does not have any relationship with recipients and that informed consent falls on transplant centers and surgeons. She continued that OPTN has a policy (policy 4), but that it was general and more related to risk assessment. Dr. Halpern suggested enacting a new policy and gaining data at the program level about who selected what category. These data could be monitored.
Dr. Barr said that the New England Journal of Medicine paper was terrific and it was important to bring this to the real world. There have been some OPTN Ad Hoc Disease Transmission Advisory Committee (DTAC) issues. He asked what the ACOT might do to help. Dr. Halpern responded that influencing policy is not one of his primary skill sets. He encouraged the ACOT to think about the regulators who need to be targeted to implement these changes and how they can get information in a unified manner. Dr. Halpern has talked with DTAC members and is on the CDC expert panel. He said it was not clear how all of the bodies and communities intersect. He offered to talk with Dr. Barr and Ms. Glazier and help draft something.
FDA Proposed Guidelines, M. Sue Leffell, Ph.D., Johns Hopkins University School of Medicine
Dr. Leffell opened by saying that she appreciated the opportunity to speak with ACOT this afternoon on this important issue. As a former member of the ACOT, she knows very well the entity’s role in alerting the Secretary to potentially harmful issues.
Dr. Leffell provided background on the FDA oversight of clinical laboratory testing. She noted that, to date, the FDA has not exercised enforcement over laboratory-developed tests (LDTs), which include assays developed in labs using FDA-regulated components, as well as what she described as “home-brewed” reagents. The latter include kits and/or reagents labeled as “research use only” (RUO) and “investigative use only” (IUO). Dr. Leffell provided definitions for RUO and IUO, as well as “medical devices.”
The proposed regulation is in the form of a guidance document about medical devices. FDA actions to date on the subject of histocompatability include the ASR Guidance Document (Analyte Specific Reagents) released in September 2007. There was a Public Meeting on Oversight of LDTs in July 2010, which was provoked by a growing concern over “genetic testing” and personalized medicine. (There was a contention that improperly validated LDTs used in diagnosis and treatment management could put patients at risk.) The IUO/RUO Guidance document was released in June 2011 and is now out for public comment with responses requested by September 1, 2011.
FDA guidance does not usually establish legally enforceable requirements, but instead acts as recommendations for industry and FDA staff. The guidelines might lead to loss of exemption for RUO/IUO labeling under Investigational Device Exemption (IDE) regulation, and has a possible impact on clearance for in vitro diagnosis (IVD).
Dr. Leffell stated that the concern with this current regulation is that it is all-encompassing. It will prohibit the use of IUO/RUO reagents in laboratory-developed tests; and it will prohibit the use of IVD cleared tests for applications that are not covered by FDA review, despite any laboratory validation. A company selling IUO/RUO products should “halt” sales to labs using these products for diagnostic purposes, and no transition period is currently permitted. This will negatively affect all areas of laboratory medicine by prohibiting the use of IUO or RUO reagents in lab-developed tests. The guidance puts another responsibility on industry. Past guidance documents have just concerned quality indicators and performance measures
Dr. Leffell continued that the guidance will affect all clinical laboratory testing and includes specific language directed toward transplantation, which reads: “The use of tests on organ or tissue donor specimens is considered to be a clinical diagnostic use when the results of the test are applied to make recipient management or transplant decisions.”
The potential negative impact on solid organ transplantation includes:
Dr. Leffell provided two examples of advances that might be lost to sensitized transplant candidates: 1. Improved organ allocation resulting from calculated panel reactive antibody (CPRA) policy and increased allocation to sensitized patients; and 2. Increased survival benefit from transplantation after desensitization. Both rely on LDTs that are modified for assessment of relative alloantibody levels. Despite high sensitivity and inherent variability, correlations of solid phase reactions can be made with crossmatch and clinical outcomes. Comparisons of serial samples provide reliable estimates of antibody increases or decreases.
The regulations also are unnecessary as oversight of histocompatibility labs already exists. These are regulated under the 1992 amendments to the Clinical Laboratory Improvement Act (CLIA 42 USC 263a). Under the FDA 2007 ASR Guidance Document, labs certified for high complexity testing under CLIA may develop and validate tests using ASRs and general reagents. There is extensive documentation of test validation and on-going quality assurance required under CLIA and by American Society for Histocompatibility and Immunogenetics, College of American Pathologists, and UNOS accreditation. Histocompatibility is recognized as specialty requiring subjective interpretation and different external proficiency testing requirements. Extensive documentation exists for most histocompatibility LDTs. Dr. Leffell showed a slide on specific CLIA language that applies to this area.
The FDA guidance is aimed at genetic testing but will have severe impact on transplantation as it would not be possible to do virtual cross matches under this guidance. The negative unintended consequences include: reduced access to transplantation for sensitized candidates; reduced deceased donor availability for non-renal candidates without “virtual crossmatches”; no desensitization or post-transplant monitoring except on research protocols; and loss of incentive for industry and academic center medical laboratory development on new assays. This will affect all areas of laboratory medicine.
Dr. Leffell noted that an alternative and preferable approach is to provide an exemption to LDTs for which there is documentation of validation and clinical benefit and recognize and accept the review of LDT validation performed in CLIA-certified, high-complexity laboratories.
Dr. Leffell urged the ACOT to comment on this issue and pass along a recommendation to the Secretary. She also noted that it is entirely appropriate for individuals to submit their own comments (until September 1, 2011).
Dr. Barr said that Dr. Leffell was preaching to the choir; the question was how to impact suggestions. He said that he assumed ASH has made a statement to the FDA and Dr. Leffell concurred that this was correct. She added that the transplant center directors are also sending letters in. Dr. Leffell suggested that it would be good for everyone to give the same message about concerns over the broadness of this proposal and support the alternative to let labs continue to operate under CMS regulations.
Dr. Barr said the field would be dead in the water if this goes through. The solution is reasonable; the question is, logistically, what the ACOT can do, officially. He invited Dr. Hurley to talk and then have a discussion about both presentations.
HLA Typing by Sequencing - Carolyn Hurley, Ph.D., Georgetown University
Dr. Hurley thanked the ACOT for the invitation to speak on this issue. She commented that she is also a member of the NMDP Histocompatibility Advisory Group.
Studies show the importance of matching HLA at the allele level, in terms of increased survival. Currently, matching occurs at the ag level HLA-A,B and allele level DRB1; most transplant centers type at HLA-A,B at allele resolution. The expectation is that better matching will lead to better outcomes.
Unrelated donors, and likely cord blood units, are selected based on allele-level matching with the patient. DNA sequencing is the most accurate method to assess identity of alleles in the context of the racially and ethnically diverse U.S. population. The complexity of the HLA system, which is increasing over time, requires flexibility to continually fine-tune tests. The current oversight (CLIA accreditation) can address accuracy and quality of LDTs.
The FDA guidance has the potential to negatively impact access to critical reagents and testing procedures essential to meet HLA-matching needs of U.S. patients who require unrelated hematopoietic stem cell transplantation.
Ms. Levine said that the ACOT can make a recommendation to the Secretary. The Chair’s report to the Secretary can also include this and it will be shared with the FDA. The ACOT deliberations have to be public however, so this cannot occur after the meeting. ACOT members could meet by phone, and could certainly submit individual comments.
Dr. Scantlebury asked what has the biggest impact. Dr. St. Martin responded that individuals submitting comments is not mutually exclusive to the ACOT submitting a recommendation. Dr. Barr agreed that all of the individual members can submit comment.
Dr. Scantlebury submitted the following recommendation, which was seconded and unanimously passed.
The ACOT concludes that the FDA’s IUO and RUO guidance document for laboratory-developed testing has serious unintended consequences for the field of transplantation, including:
The ACOT recommends that the FDA recognize and accept LDT testing performed in CLIA-certified, high-complexity histocompatibility laboratories.
Update on Advisory Committee on Blood Safety and Availability (ACBSA) - Jerry Holmberg, Ph.D., Executive Secretary
Dr. Holmberg spoke by telephone and provided an update on Advisory Committee activities and Departmental activities. He spoke in an effort to increase coordination and collaboration of issues that cross Federal agencies.
Dr. Holmberg showed a slide to illustrate the tangle of agencies engaged in this work.
He noted that the ACOT’s Recommendation #52 stated: “The ACOT recommends that the Secretary encourage HRSA and CMS to resolve the regulatory inconsistencies between CMS and OPTN.” This summer, the ACBSA met on a regular basis and at least by phone several times a week to discuss issues related to blood, cells, tissues and organs. It also had several meetings with CMS, the CDC, the FDA, and HRSA.
Dr. Holmberg stated that the Office of the Assistant Secretary for Health (ASH) provides a unique place within the Department to coordinate activities and issues to ensure harmony of thought. Current activities include examining the World Health Assembly’s call for improvement in the safety and efficacy of donations and transplantations by promoting international best practices and thinking about how this can best be accomplished
In terms of transplantation, the OASH is interested in how the U.S. can collaborate in collecting data including adverse events and reactions on the practices, safety, quality, efficacy, epidemiology and ethics of donation and transplantation. In terms of the WHA resolution 63.12, which HHS endorsed, are there areas of safety concern that should be addressed by the ACBSA in the future? WHA 63.12 calls for establishment or strengthening of systems for the safe and rational use of blood products. This raises the question: does the U.S. have a system for the safe and rational use of blood products? If yes, what are some areas of needed improvement in light of patient blood management? If no, what does the Committee recommend to establish safe and rational use of blood products in light of patient blood management? Do data support guidelines or performance measures for the rational use of blood in patient blood management? In a review of the WHA 63.12, are there areas of safety and sustainable ability of blood and blood products that should be addressed by the Committee in the future?
In light of that, the ACBSA has recommended that the Secretary establish a task force to:
The Committee recommends that the Secretary:
The Committee recommends that the Secretary:
Dr. Holmberg noted that a comment had been made earlier about the power of Advisory Committee recommendations and wanted to emphasize that these recommendations are considered very carefully and taken very seriously.
Dr. Barr noted that some of the ACBSA recommendations overlap with those made by the ACOT on solid organ transplant. He asked if ACBSA sought the ACOT’s endorsement of anything or if the discussion was mainly informational. Dr. Holmberg responded that it was primarily informational because he felt it would be helpful to update the ACOT on the ACBSA’s activities.
Dr. Barr requested that Dr. Holmberg let the ACOT know how it can help and to send Ms. Stroup ideas for upcoming agenda items. Dr. Holmberg agreed to do so, noting that the ACSBSA and ASH are striving to be more transparent. He commented that he communicates regularly with Ms. Stroup.
Dr. Barr suggested that, since there is overlap, ACOT and ACBSA could have ex officio members on each other’s committees. Dr. Holmberg agreed that this was a possibility. The ACBSA is currently restructuring its charter to enhance representation by the tissue and organ communities.
Ms. Stroup announced that the ACOT’s next meeting will occur by telephone in February or March 2012. (Members will be polled about the best time.) She announced that all of the meeting slides will be posted on the ACOT website and emailed to the ACOT members. In addition, she had received written materials from a member of the public, Jane Zill, which will be shared with the ACOT members and attached to the summary notes (Attachment B).
Ms. Stroup thanked all of the ACOT members for their continued hard work, and thanked the new members for volunteering. She expressed deep appreciation to Dr. Scantlebury for her many years of hard work for ACOT and to Dr Barr for agreeing to be the Chair for 2 years. She asked members to please tell her what their interests are in terms of the working groups.
The meeting adjourned.