Advisory Committee on Organ Transplantation

U.S. Department of Health and Human Services
Advisory Committee on Organ Transplantation (ACOT)

Summary Notes from Meeting
Washington, D.C.
May 6–7, 2004

Welcome and Update

Nancy Ascher and Jack Kress

Nancy Ascher started by saying that she looks forward to the important contributions this committee makes to the arena of organ transplantation. The outcome of this meeting will be guidance and direction to the subcommittees to be the basis of recommendations they will generate for the November meeting. She said that she does not anticipate any recommendations being developed at this meeting.

She introduced Jim Burdick, the director of the Division of Transplantation, who was standing in for Michelle Snyder, the Associate Administrator of HRSA. Burdick commented on an important upcoming transition: Jack Kress, the executive director of ACOT, is moving on this summer to a study assignment under the aegis of HRSA at the Albany Medical College in New York State. He pointed out some of the highlights of Kress's tenure with the U.S. Department of Health and Human Services (HHS) as he worked on legal and ethical matters. Most significantly to ACOT, Kress was involved in developing the early structure of ACOT and its processes. He saw to the development of all of its recommendations, which he then shepherded through the department. He has facilitated progress after recommendations have been approved. In every way, he has been a major factor and supporter in our efforts. Burdick presented Kress with a Special Acts Award and certificate to recognize his dedicated service to ACOT.

Burdick went on to introduce the new executive director of ACOT—Thom Balbier—who has worked at HHS since 1977, primarily in the area of scientific and governmental aspects of vaccine programs. Balbier briefly addressed the group, saying that he was looking forward to working in this important field and meeting the committee members.

Kress thanked the participants and the audience. He noted that he has a long history in the Albany area and looks forward to returning to research. He plans to continue to work on organ donation reform and improvements. He plans to start by learning what happens at the ground level. He expressed his thanks to the ACOT members. He noted that there will be a long transition period during which he and Balbier will overlap to ensure that ACOT's efforts will continue seamlessly.

He then introduced the next item on the agenda—tissue and body part concerns—noting that this topic has grown out of two developments: (1) the efforts of former ACOT member Margaret Coolican, who pushed us into the realm of tissue and body parts; and (2) recent events and adverse publicity in that field, which may affect organ donation. We need to ask about what we need to do in this area.

Panel on Tissue and Body Parts Concerns

Moderator: Michael Seely
Panelists: Todd R. Olson, Hon. Margaret W. Henbest, Ronn Wade

Michael Seely thanked the committee for including this topic, which was brought to light by the media. It has had top billing in many large media outlets. The integrity of the national organ transplant system is at stake. We have not spent much time on other forms of donation, but we need to consider these issues. Currently, the federal regulatory framework does not represent a consistent approach. Certain aspects of tissue recovery and handling are subject to inspection by the Centers for Medicare & Medicaid Services (CMS), and other aspects are subject only to a voluntary accreditation process. Whole body donation and use is largely unregulated, although there may be rules and guidelines for oversight within institutions.

Margaret Coolican was motivated to bring this issue to the attention of Kress who in turn directed the issue to the attention of this subcommittee. The fact is that there are many more tissue donors than organ donors every year. Tens of thousands of lives are benefited by tissue donation. Whole body donation is also significant. Any single event in any of these arenas affects the others. The public does not distinguish among these different areas.

Todd R. Olson

Albert Einstein College of Medicine

Seely introduced Todd R. Olson, who runs the Anatomical Gift Program at the Albert Einstein College of Medicine in the Bronx, New York, and who is also a council member of the American Association of Clinical Anatomists. He has received wide press lately as he has been speaking out against the practices that led to recent scandals in willed body and tissue donation programs.

Olson opened by saying that anatomists and the transplant community have mutual concerns: "For the past 30 years, our two fields have walked parallel paths, but our interests and differences are intertwined: Our differences are far more significant in our eyes than they are in the public's." He stated that many of his anatomical colleagues have called him to say they have been waiting for 20 years to gain a place in this forum.

He noted that the public lacks even a basic understanding of the distinctions among the different types of donation. We are all educators in respect to organ, tissue, and whole body donation. Public education and education of the media are key roles. He made a special request of the media representatives present at the meeting to tell the "good parts of the story."

In the absence of education, Olson continued, donation scandals will likely diminish public confidence in all types of donation. If it affects one school, it affects all. To ferret out the wrongdoers, it is necessary to follow the money. He specifically mentioned the scandals at the University of California-Los Angeles, Tulane University, University of California-Irvine and others that have been featured in recent headlines.

He noted that really there is nothing shocking or surprising going on. If anything, these events must be called predictable. These situations arise when people of limited means decide to ignore professional responsibilities and institutional trust for personal gain. Where does the money come from to motivate this behavior? Ultimately, Olson said, it comes down to "Physician, heal thyself."

Physicians themselves and professional societies need to step up and say that they care. They are obligated to require detailed oversight and accounting for materials used in educational programs. Ethical practices in patient care do not cease with the final breath; the need to respect the human body is at the center of the doctor-patient relationship. "As anatomists," Olson said, "we are doing a great deal. We work with willed-body programs so that those who convey material from place to place are acting in concert with donor's wishes." He mentioned some specific legislative and institutional efforts in Texas, California, New York State, and at the University of Pittsburgh School of Medicine aimed at reviewing or regulating willed-body and tissue donation programs. He referred to several articles on the topic.^{1, 2, 3, 4, 5}

Olson also spoke about the return of the resurrectionists (grave robbers). He mentioned a recent article in Harper's Magazine about modern-day resurrectionists⁶ and related the story of William Burke and William Hare who went on a killing spree out of greed in Scotland in the 1800s. Their activities were perpetrated against the citizens of Edinburgh where Hare owned a boarding house. One of his pensioners died, still owing 4 pounds in rent. Hare enlisted the help of another resident—Burke—and took the remains to a disreputable anatomist who paid them 7 pounds. Thus was initiated the monetary motivation to kill pensioners for money. Needless to say, there was great public concern and riots. In New York, the militia had to be called out under similar circumstances.

Those who had teaching materials (i.e., body parts) were able to run anatomy schools. The anatomists did not ask where the materials came from, and this is the story happening again today. Modern-day resurrectionists deal with donors who are making donations that can save lives. What is needed is a clear paper trail for body parts being used in education.

Olson offered several recommendations:

1. Expand public education.
2. Encourage information sharing regarding tissues, organs, and body parts.
3. Approve changes to the Uniform Anatomical Gift Act to deal with the rapidly expanding body parts industry.
4. Establish a national central clearinghouse for parts used in anatomical research that can serve as a go-between for sites of access and sites of need.
5. Insist that organizations involved in oversight and regulation of tissue banks approve only appropriate and legal uses of bodies, body parts, and tissues.
6. Ethical considerations must extend to the remains of those who have given to promote medicine.

Olson urged those in attendance not to let this issue go away without taking constructive action, saying, "This controversy will come to your doorstep as well."

Hon. Margaret Henbest

Idaho House of Representatives

Seely then introduced Representative Margaret Henbest from Idaho. She has served in the Idaho state legislature for 8 years. She is working to help the public understand what donation is about. She is also a pediatric nurse practitioner and has a particular interest in disclosure issues.

Henbest said that she became aware of controversy surrounding body donation about 6 years ago when she was contacted by a constituent who was monitoring the activity of a county coroner. Coroners are elected officials in Idaho and are not held to any standards. Two-thirds of Idaho's coroners are funeral directors. The constituent said that the coroner was involved in a business enterprise that was harvesting heart valves. There were legal and ethical concerns, and yet there were no laws that prohibited this practice.

She spoke about the experience of another constituent who was distraught about the organ donation surrounding the death of his daughter. The daughter had indicated prior to her death that she was willing to donate her organs, and her family wished to honor that wish. They discovered, however, that her long bones had also been procured. The family had no idea that the donation would include other tissues. They were left with unresolved grief.

Subsequently, Henbest did some research on tissue donation, storage, and the profitability of organ and tissue transplantation. She learned about the fact that the regulations governing organ donation differ significantly from those addressing tissue donation. She noted some specific concerns:

• Inadequate regulation of the tissue industry that could lead to disease transmission.
• Inadequate registration of those who handle body parts: In 1998, the requirement for registration were removed by Idaho's Department of Health and Welfare. There was no punishment for not registering.
• Extreme profitability of this industry: We must follow the money.
• Inadequate requirements for informed consent: Consent is not exclusively for organs, but for tissues, as well.
• Regulatory loopholes that allow profiteering for use of body parts research and education: There is concern because current regulations are silent on the use of body parts for research and education as opposed to transplantation, which is regulated.

Idaho rewrote the state's Anatomical Gift Act. The goal was to provide higher standards for informed consent. Henbest observed that now, "when you apply for a driver's license in Idaho, you receive a detailed brochure about how your body parts might be used, and you are advised about available resources and your rights. You can designate the exact purposes for the use of your body, tissues, and parts. Parallel information is given to families. Because we have elevated the degree of consent, we are moving toward direct consent. Donation rates have increased in our state." She noted that it is important for people to know the uses of their donated bodies. Therefore, Idaho has taken the law another step: to add a preferred designation for for-profit or not-for-profit use of the individual's body.

According to Henbest, forthcoming legislative sessions will address mandatory accreditation of tissue banks, as well as for-profit tissue and body part programs. She said that we need federal regulation so that the country does not end up with a patchwork approach. We did not anticipate all the uses for tissues and body parts when 40 years ago we drafted the Uniform Anatomical Gift Act (UAGA). She also mentioned a recent poll in England that indicated that the public is reluctant to have their DNA used in research. Another issue at the fore has been military use of bodies for testing artillery.

Henbest concluded by saying that a high tide floats all ships. We must remember this adage because the public does not differentiate. We cannot be silent any longer.

Barry Kahan asked Henbest about what types of donation have increased in Idaho since the institution of better conformed consent. Henbest replied that they have a database but have not drilled down yet to see which types of donations are increasing. She noted, however, that 15% more people have indicated via the Department of Motor Vehicles (DMV) their willingness to be a donor. Seely said that this more complex approach to consent might have decreased donations, but such is not the case apparently. Kahan observed that, in general, the more information you give people, the less likely they are to read it or to sign it. Henbest replied that she does not know whether people are reading the brochure cover to cover, but it has not been a barrier to donation.

Olson was asked about what has happened with anatomical donation in New York State since recent events. He noted that donors fall into two different profiles. Some donors do so out of humanitarian and altruistic motivation in gratitude for medical care and to advance science. The second type of donors—a significant number—donate for financial reasons. They are seeking a way around funeral costs. Some people are donating because they want to give money to their children. He observed that they are receiving more interest from people who now recognize the value of their bodies.

Henbest volunteered to provide copies of Idaho's organ donation brochure and informed consent form to ACOT. She also indicated a willingness to work on getting more data on the effects of the new legislation on donation rates.

Michael Williams mentioned an article he reviewed for Critical Care Medicine that dealt with the notion of desecration. Social, personal, and religious overtones are there. We must not forget the role of religious and faith communities. Henbest agreed that those issues constitute the underpinning for this discussion. The public is outraged when these issues come to light. We must also address the enticement of profitability. To build enough groundswell and interest, we must act in partnership with religious organizations.

Olson concurred with Henbest's comments, saying that transparency is the key. We must emphasize education and disclosure.

Ronald S. Wade

Maryland State Anatomy Board

Ronald Wade has directed Maryland's body donation program for 30 years. Wade noted that as organ transplants have became more successful, people had that alternative to consider. When he came on board, one of the first things he did was try to reorganize so that body donation became more acceptable. Historically, most bodies for study were unclaimed bodies or from tuberculosis sanitariums, but now people want to leave a legacy by improving medical care for the next generation.

Surgical study labs were set up for training physicians, shock-trauma personnel, emergency medical technicians, military medics, and others. The number of bodies used in gross anatomy is less than 300. The cause of death is not important; the donation will not be refused. "We stand by our promise to accept the donation."

The study of anatomy has changed. Courses are shorter, and some courses are doing away with dissection altogether, but there is a continuing and increasing need to enhance surgical training. To meet the need for training material, a whole gamut of body brokers and for-profit tissue banks has sprung up.

Wade said that he dealt yesterday with a university in the Midwest about a push to obtain body parts from a broker. The bodies are being obtained in the south. The State of Maryland will assist with transferring remains out of state, but the transfer must be through an institution.

It is illegal to function as a broker or deal with a broker in Maryland. Without requirements for serological testing, proper facilities, and a social and medical history, dealing with bodies and body parts is a high-risk situation. In Maryland, no surgical conferences may be held in hotels or conference centers to prevent disease transmission. Some brokers are going to funeral directors who receive finder's fees. They may even pay for use of a funeral home facility. These practices raise ethical concerns. Wade deals only institution to institution to eliminate brokers. He has a duty to the public, citizens, and the medical community to ensure that everything is done to high standards in compliance with public policy and with respect for donors and their families.

Carlton Young commented that this situation appears to be an exploding problem. He expressed concern about desecration-denigrating human bodies to the level of commodities. He noted that the transplant community is always battling over the issue of valuable consideration. How can we modify the UAGA to raise the standard?

Wade said that the legal value of a body is zero dollars. For example, it is impossible to insure bodily remains for transportation. Many people in Maryland carry organ donor cards or kidney cards. He used to conduct surveys of donors. People are aware. People are commonsensical. It is a changing culture. There is a real need in medical schools for anatomical study materials.

Olson observed that this is an international issue. Brokers can work together with funeral directors. European doctors have indicated that they acquire body parts from the United States, Romania, and elsewhere. Trade appears to go the other way as well. We need tracking systems across borders.

Wade said that uniform donor laws are being framed to have parameters for minimal standards. Regulations differ from state to state presently.

Young asked how we can support these efforts to modify the UAGA. Kress said that ACOT has done so in the past and will do so again. We need only to decide which subcommittee is the most appropriate for this work.

Susan Gunderson said that she knows little about whole body donation even though she runs an organ procurement organization (OPO). She continued, "We have come to understand tissue donation. We have our heads in the sand if we think we are immune from the fallout from unethical and illegal practices in willed-body programs."

Kathy Turrisi suggested that perhaps ACOT needs to branch out and encompass these other areas that impact organ donation. Perhaps we need to rethink our very name, which presently refers only to "organ transplantation."

A New Way of Looking at the Problem: The Burden of Disease and Its Progression

Lawrence G. Hunsicker
Henry Krakauer

Kress presented Lawrence Hunsicker, a former ACOT member who is also a past president of the United Network for Organ Sharing (UNOS) and the American Society of Transplantation. He is here today primarily because he is chair of the UNOS Data Working Group. Hunsicker has been investigating the burden of disease from a statistical point of view. Also involved in this research are Henry Krakauer, an epidemiologist, and Monica Lin, a statistician. They will describe an intriguing new way of looking at the quality of life.

Hunsicker noted that the Data Working Group (DWG) was created by the Division of Transplantation to coordinate between the Scientific Registry of Transplant Recipients (SRTR) and the Organ Procurement and Transplantation Network (OPTN) to make sure that the right data are collected in appropriate and efficient ways. The DWG is advisory to UNOS and the scientific committee of SRTR.

Analysis of transplant outcomes has so far focused on time to death and time to graft loss. Although these are clearly important outcomes, with improving patient and graft survival they are no longer the only relevant outcomes to consider. Hunsicker reviewed some reasons why it is not sufficient to consider only graft and overall survival. For these reasons, ACOT has charged the DWG with looking into quality of life issues.

The term quality of life (QOL) is not a standard or well-understood concept. There is a rationale for a new approach. For example, there is a strong likelihood that alternative outcomes such as morbidity and functional status will be highly correlated with mortality risk. Cumulative morbidity and functional status can be measured on many occasions and may offer greater statistical power in analyses. Time-series analyses on nonterminal outcomes may permit early intervention on high-risk patients.

Many years of work led by Henry Krakauer has resulted in the identification of five domains or dimensions of transplant outcomes that constitute the burden of illness. They are:

1. Mortality
2. Cumulative morbidity (adverse medical events, including graft loss and other events, primarily evidenced at least initially by hospitalizations)
3. Disability/functional status (ability to perform functions required/desired in daily life)
4. Psychological distress (e.g., depression, anxiety)
5. Resource use (effort/resources needed to care for the patient, again focusing initially on hospitalization).

Hunsicker explained for each of the five proposed domains the existing data sources, and he proposed some additional sources.

Mortality

Data on mortality are now captured by the OPTN/UNOS system and are supplemented by death data from the Social Security Master File or National Death Index. These data are quite complete.

Cumulative Morbidity

At least initially, this domain would be evidenced by hospitalization data. Limited hospitalization data are now collected on transplant recipients. The new forms will ask post-transplant patients about all hospitalizations since last reports. UNOS/OPTN collects no data about waiting-list patient hospitalizations. CMS collects complete data on kidney candidates and recipients who have Medicare primary coverage. As a starter, the DWG has obtained consent from Pennsylvania and Virginia to get comprehensive hospitalization data on transplant candidates and recipients from those states. Transplant centers do not have these data.

Functional Status

UNOS/OPTN collects functional status information on transplant recipients at transplant and on follow-up forms, but for transplant candidates, the data on functional status is collected only at the time of registration. Although these data correlate with outcomes, the grading is not sufficiently granular to capture less-than-gross loss of function. Nevertheless, these data may be useful because they are highly predictive of mortality.

The DWG proposes to capture additional information on functional status in a pilot study using the SF36 physical status scale and replacing the current UNOS functional scale (The New York Heart Scale — four points) on the transplant form with the Karnofsky Index. The Karnofsky Index (Figure 1) represents 11 levels of function ranging from normal to minor impairments that do not adversely affect function to a moribund state to death. It is the standard, best validated objective scale for functional status, and it can be completed at the time of patient clinic visits in less than one minute.

This proposal was discussed at the Data Advisory Committee meeting in late April. This will not be an effortless change. Someone will have to collect the data and complete the scale during clinic visits. Vanderbilt University has been acquiring Karnofsky data for some time.

Figure 1. The Karnofsky Index

Psychological Distress

Presently, no data are collected by UNOS/OPTN on this domain. The DWG proposes to collect this information from the SF-36 mental health subscale. This instrument is widely used to assess mental and psychological status.

Resource Use

UNOS/OPTN currently collects no data on this domain, although NOTA charged OPTN and SRTR with collecting financial data on the costs of transplants. At least initially, the DWG proposes to focus on hospitalization resource use by estimating from hospitalization data the effort needed to care for the patient. The basis will be uniform coding based on DRG weights and length of stay.

For which patients do we need to track these five domains? The benefit of the transplant is the total difference between projected outcomes based on whether the transplant is performed or not performed. In addition, we should think about including those who are not transplanted but live with chronic disease. That issue, however, is outside the scope of today's discussion.

Hunsicker made it clear that there is no intent for the proposed analyses to force any particular approach to the formulation of deceased donor organ allocation or other UNOS/OPTN policy. The proposed approach to analysis will simply inform UNOS/OPTN committees more broadly about the outcomes of transplantation. The Board and the Committees are free to use the information as they deem appropriate.

To what extent will these domains correlate with morbidity and mortality? It is conceivable that many patients who receive lung transplants, for example, do not have longer lives but their QOL post-transplant may be very much greater. In any event, a person who is considering a lung transplant may wish to look at the impact of transplant on survival and functional status. The best approach for analysis, then, may be combination of multiple outcomes in a model with a multivariate outcome. That is, outcomes in all five domains can be considered as a single vector (per individual). In this approach, the mutual correlations among the outcomes are observed directly (as the covariance matrix) in the analysis. This approach is objective and leaves weighting to policy makers and patients.

Using combined analysis of multiple outcomes may be leading the way for the rest of the health community, but it is not a slam-dunk. Not all groups may wish to pursue this line of thinking. Others may wish to work out different approaches. Let many investigators look at these data using different analytic approaches.

In addition, different analysts may have different goals. Some may strive to optimize use of limited resources (organs or funds); others may seek to optimize outcomes for a particular patient.

Analyzing Multiple Outcomes for Transplant Candidates and Recipients

Robert Wolfe

The Data Advisory Committee is looking at several different mathematical approaches, according to Robert Wolfe. We are looking at the benefit of transplantation although it involves many different outcomes. Wolfe listed two rate measures (mortality, hospitalization) and four scaled measures (days in hospital, resource use, functional status, and psychological distress). Scaled measures are determined at different points in time and then the averages are weighted.

Wolfe also said that analyses will continue to be done as they always have been; the multiple outcomes model will be an addition. Traditional methods for modeling combined outcomes are based on the following tenets:

• Outcomes are often correlated. Patients high on one outcome might be high on another.
• Correlation can arise from shared measured characteristics: Covariates predict multiple outcomes. For example, diabetics have both high hospitalization and high death rates.
• Correlation can be modeled with regression: One outcome predicts another. For example, mortality can be predicted by recent hospitalization and recent low functional status.

Wolfe highlighted two innovative methods for analyzing correlated outcomes. First, frailty models introduce a patient specific covariate to account for correlation. Frailty is an unmeasured covariate that predicts the outcomes of interest (rates or means). The frailty for each patient is imputed to fit the outcomes for that patient. Second, Bailey, Krakauer, and Lin have developed an innovative method to analyze correlated outcomes.

Modeling the Components of the Burden of Disease

R. Clifton Bailey

Clifton Bailey said that an analytical plan is needed for collecting and analyzing data. We have chosen to use each component as a cumulative measure, but the problem remains of how to put the measures together. A probability summary is a consistent way of dealing with these outcomes — morbidity, mortality, and resource use. We use mathematical representations to capture the essence of these components (domains). It is necessary to deal with the correlations conjointly.

He showed several graphs, including the declining hazard pattern of post-transplant mortality. The risk of dying is very high immediately after a procedure, and then the risk declines. Post-listing mortality has a different pattern of increasing hazard. The post-transplant morbidity curve rises and then falls.

When modeling, they make use of the explanatory variables that they want to model. Morbidity and resource use could be modeled in any of several different ways. In every case they have used the cumulative distribution form. Each of those, in turn, is made to depend on these explanatory factors. Therefore, the correlations output by the model will be case-specific. For example, they may arrive at one set of correlations for diabetics and another set for nondiabetics.

Trivariate Multiple Outcomes Model

Monica Lin

Monica Lin discussed how data were developed for applying the trivariate, multiple outcomes model. The focus has been on the post-transplant period. The data set is based on a cohort of Medicare-eligible patients listed in 1996 and followed until the end of 2000. Transplants are included only if they occurred prior to 2000 (minimum of 1 year of post-transplant follow-up. Data sources are:

• OPTN: Data on patient characteristics at listing and transplant, and on disability (from the follow-up form).
• USRDS: Data on hospitalizations from consolidated OPTN and Medicare data (sole source on experience on dialysis).
• Medicare: SS Death Master File. Data on hospitalizations (morbidity and resource use).

The model may provide an evidence-based, objective answer to the question posed by many patients, "What will happen to me?" Estimates are made by simultaneously modeling survival, resource use, and morbidity.

Among the questions that the model could address include these:

• Benefit: What is the outcome for the average patient with and without transplant?
• Subgroups: What differences are there among different patient subgroups?
• Policy 1: Which patient currently on the list is likely to benefit most from receiving this organ?
• Policy 2: How would outcomes be changed by proposed policy changes?
• Individuals within subgroups: How much variation is there among individuals?
• Correlation: Are the individuals who are at high risk for one outcome also at high risk for other outcomes?

The DWG is continuing work on simultaneously modeling of four outcomes and is also looking into waitlist outcomes. A paper has been submitted to the American Journal of Transplantation.

Some discussion ensued. Hunsicker made a point about distinguishing between policy formulation and the personal decisions made by patients and their doctors. OPTN focuses on policy, but ACOT may wish to take a broader view to reflect patients' preferences. Discussions about possible outcomes occur all the time between transplant surgeons and their patients, but there have not been any data to inform these discussions. These data allow the patient to make decisions about the tradeoffs involved.

According to Hunsicker, the Data Advisory Committee (DAC) was concerned about the additional burden on transplant centers that would result if the Karnofsky Index were adopted, although the vote was 18-2 in favor of adopting the Karnofsky index. DAC proposed a pilot study for collecting SF-36 data that would involve random sampling with oversampling of certain subgroups. Centers will not need to get separate Investigative Review Board (IRB) approvals.

Nancy Ascher asked if the analysis takes into account a center effect. She suggested simplifying the language describing the model and she recommended that in order for patients to weigh risk and benefit, the center effect becomes paramount. Hunsicker replied that the model is not intended to look at center effect. He agreed that the model might be improved by incorporating center effects.

Barry Kahan said that it could be an onerous task to collect data. He asked if it would be possible to go to a pharmaceutical company and test some of the hypotheses with data that have already been collected on existing cohorts.

Hunsicker replied that the only burden will be associated with the letters and consent forms patients receive regarding the Karnofsky index. Some patients will ask about the letter they will receive. The consent letters will be very detailed. He also said that in regard to conducting a retrospective study that the existing cohorts are not very standard.

Kahan said that in virtually every clinical study, we have already collected Karnofsky and SF-36 data. We could set up two study arms and test the models.

Hans Sollinger noted that clinical practice is evolving very quickly. We have learned how to deal with extended donors. We can almost equalize outcomes using various protocols to conserve kidney function. It is a challenge to keep up with these radical changes in our clinical approaches. Looking at retrospective data would be a useful scholarly practice, but to base clinical decisions on old data could be perilous.

Flora Solarz said that with the growing waitlist, we do not know what outcomes we are promising our patients. We need to look at this seriously and weigh the ethical implications. We talk much about informing patients and that is what this discussion is really all about. Resource use seems parallel to hospitalization. It may be more useful to consider resource utilization by the patients than by the hospitals. Another danger is that predictions about hospitalizations could raise the eyebrows of insurance companies when they decide who will be transplanted.

Hunsicker (to Sollinger) said that collecting the data does not necessarily mean that a recommendation will flow from it. The present is always different from the past, but we cannot just throw away those data. We are always better off knowing something than not knowing something. Regarding Solarz's comments, he said that it would be very useful to know something about the individual's costs in terms of resource utilization, but we have to look at the costs we can get at more easily.

Kathy Turrisi noted that, in the past, staff at the center were the ones who completed the Karnofsky or SF-36 forms. It would be more useful if the patients themselves were asked for their input on the forms. Hunsicker replied that the plan is to mail out the full SF-36 forms to the patients because the centers do not necessarily know how the patients are doing. The Karnofsky Index would be done by the centers. We will have to carry out a fair bit of education to get the forms filled out correctly.

Young urged caution because if we hone things down too precisely, we may think we know what's best. If the model outcomes are memorialized as policy, might patients be denied transplant because of the potential for poor outcomes due to their race, co-morbidities, or other factors? It could get so burdensome that we will not transplant because of potential risks. We must be very careful because the data could be misused.

Michael Williams expressed reservations about using specific percentages in patient discussions. These are just probabilities. We need to present data in useful ways. Trouble arises when patients are promised specific outcomes. It is best to say that we will try our very best, but here are the risks.

Hunsicker said that having the data would help inform these discussions. For example, with livers we have found that the sickest patients are not futile transplants; this is the group that actually receives the most benefit from transplantation.

Robert Gibbons congratulated the group for looking at a broader field of outcomes. We are already using statistical models albeit inefficient ones for making transplant decisions. For example, the Model for End-stage Liver Disease (MELD) is based on a univariate model. We need to continue in this path to look at multivariate outcomes.

Amadeo Marcos said that we cannot continue using only patient and graft survival as outcome measures. The issue is to do what is best for patients. What is the weight that will be given to each factor? Policy decisions will continue to be made by the various appropriate committees of OPTN.

Three Decades of Struggles and Triumphs: Reflections on 30-Plus Years of Transplantation

Clive O. Callender

Clive Callender is the founder and head of the Minority Organ and Tissue Transplantation Program (MOTTEP). He has performed more than 300 kidney transplants. He left Minnesota in 1973 and started the program at Howard University. He shared some of his ideas and thoughts as he reflected back on his 30-year career.

Callender identified 14 critical issues facing the transplantation community:

1. Organ donor/organ recipient disparity: As of January 2004, this disparity represents 60,000 people. More than 16 people die daily because of the organ donor shortage. Callender said that the situation seemed hopeless when he started because African Americans used to donate organs at lower rates than other ethnicities because of many factors. This trend, however, has changed. Minorities, who represent 25% of the American population, made up 15% of donors in 1990 but comprised 28.5% of donors in 2000. In 1990 the organ donor/million rate for Blacks was 22.4; in 2000 it had risen to 40.8.
2. The Green Screen: The Green Screen is a symbol for the lack of dollars or medical insurance or the ability to pay for health care or the medication necessary to sustain the health provided by transplantation. African Americans constituted only 10% of those waiting for livers in 1995, yet African Americans die more frequently of liver failure than do Whites. "If you didn't have the green, you couldn't get on the waitlist and you would die." The role of the Green Screen in renal transplantation is undefined, but it must exist because people are denied transplants due to a lack of means to pay for post-transplant immunosuppressive therapy. Callender mentioned the film "John Q." The Green Screen is underappreciated as an obstacle to transplantation. We are all accountable because we won't approve the taxes necessary to pay for transplants for those of limited means.
3. Prevalence and incidence rates for kidney failure in Blacks (African Americans) and other minorities: The incidence and prevalence rates of end-stage renal disease (ESRD) for Blacks (African Americans) and other minorities are disproportionately high because of their increased susceptibility to diabetes and hypertension (twice that of Caucasians).
4. Disproportionate effect of human immunodeficiency virus (HIV) on Blacks (African Americans) when compared to Caucasians: It is not clear why the nephropathy of HIV is so largely a problem of African Americans. Blacks (African Americans) with HIV experience HIV nephropathy at 10 times the rate of other ethnic groups. In fact, 93% of all AIDS nephropathy cases reported are in African Americans.
5. Dialysis survival rates for Blacks: Blacks have patient survival rates on dialysis that are superior to Caucasians. Callender discussed some data regarding 1-year and 2-year mortality rates of African American and Caucasian ESRD patients on dialysis, showing that African Americans do much better on dialysis than do Caucasians, but is this good news or bad news? The USRDS report demonstrated that healthier blacks remain on dialysis whereas healthier whites are transplanted. This is really a negative data item. We cannot compare until transplantation rates are equalized.
6. Race and science: Callender emphasized the need for completely replacing the term "race" with the word "ethnicity" in science. The human genome mapping project demonstrated conclusively that all humankind, Homo sapiens, belongs to one race. This finding once and for all makes it clear that in science the issue of race is an illusion that must be done away with. Using "race" is divisive and renews the sociopolitical construct that denies the positive aspects of each ethnic group and reenergizes the superior/inferior designation. We are all one race with different ethnicities. This change must occur throughout the scientific community, the U.S. Census Bureau, and the Office of Management and Budget, until the term "race" is replaced by ethnicity in all scientific journals and census data.
7. Compliance rates for Blacks: Blacks and Latinos are no more noncompliant than other ethnic groups. The groups that are least compliant are adolescents and health care professionals!
8. Unique post-transplantation drug responses in African Americans (Blacks): Blacks after transplantation metabolize transplant medications differently than Caucasians and other ethnic groups, thereby altering their responsiveness to these medications. One of the reasons is that Blacks are more immunoresponsive than other ethnicities. One study showed that 90% of African Americans were hyperimmune in contrast to 66% of Caucasians when pre-transplant immune responsiveness is studied. Therefore, it is clear that Blacks require more powerful immunosuppressive therapy than other ethnicities. In addition, cyclosporine is poorly absorbed in Blacks. Prednisone's side effects (hypertension, diabetes, and obesity) tend to be especially problematic for African Americans. Blacks have to pay more to get effective doses of Cellcept because the effective dose for African Americans is higher than for Caucasians. In many instances, gastrointestinal and bone marrow intolerance are problematic for African Americans. The necessity of using lower doses may increase the likelihood of acute rejection episodes. Tacrolimus — one of the most potent immunosuppressants — is associated with the development of posttransplant diabetes at twice the rate in African Americans and Latinos than when it is used in Caucasians. In addition, development of insulin dependence tends to be permanent in African Americans in contrast to the situation with Latinos and Caucasians who generally experience reversible insulin dependence. Part of the reason may lie in genetic differences in the P450 cytochrome oxidase system or in the higher level of immune responsiveness of African Americans. Elucidation of this enigma may improve graft survival for African Americans.
9. Delayed transplantation referrals for Blacks and other minority patients: Blacks are referred later for kidney transplants, are placed on the waitlist later, and are transplanted later than Caucasians, regardless of financial status. Callender referred to the work of Alexander and Sehgal⁷ who objectified and, for the first time, put in print what had been suspected for some time: Blacks, women, and poor people encounter barriers to transplantation. Danovitch, Cohen, and Smits⁸ propose using the European (Eurotransplant) model, which defines waiting time as beginning when the patient begins hemodialysis in an uninterrupted fashion. This simple change would level the playing field in regard to delayed referral times for African American transplant candidates.
10. Waiting times for Blacks and other minorities in transplantation: Waiting times for kidneys are twice as long for Blacks and other minorities as for Whites. A study by Roberts et al.⁹ shows that we have made some improvements in transplantation rates for Blacks, but we still have a long way to go.
11. The fate of kidneys and other organs transplanted into Blacks: African Americans after transplantation of kidneys and other organs have 10% to 20% poorer graft survival rates than all other ethnic groups (at 2–5 years after transplantation). This trend is evident whether the organ was recovered from a living related donor, living unrelated donor, or a deceased donor. Why is not known. In 1977 Opelz et al.10 first reported that kidney donor and graft survival rates in African Americans were the poorest among all ethnic groups. A subsequent analysis of the OPTN/UNOS database showed that Black recipients of deceased donor or living donor kidneys were associated with statistically significantly poorer graft survival regardless of donor ethnicity. Black recipients of deceased livers and hearts had significantly lower graft survival rates when receiving organs from Whites, Blacks, or Latinos. The reasons for these ethnic differences are unknown. When looking into half lives for kidney transplants across all ethnic groups, it can be seen that Asians have the most favorable half lives and African Americans have the shortest half-lives (living or deceased donor transplants). It had been hoped that increasing the numbers of black donors would increase graft survival, but that may not be true. Many hypotheses have been offered and disproven (e.g., too few black donors, HLA mismatch, inequitable distribution). The negative correlation of hypertension, hyperimmune responsiveness, and institutional racism seem clear. Why hypertension is such a highly negative correlate remains a mystery and should be a focal point for research and study. The newest immunosuppressive regimens may provide some answers. The most hopeful and most correctable problem is institutional racism. There is a need for changing lifestyles and thereby reducing the need for organ transplantation. MOTTEP is already addressing this.
12. The fate of donated African American kidneys and other organs: When African American organs are transplanted into African Americans or Caucasians, they have significantly inferior graft survival. Black to black donation has the highest relative risk of graft loss (kidney or liver). African American kidney donors survive for shorter periods than all other ethnicities. It would be inappropriate to recommend, however, that all organs donated by African Americans should be considered high risk. The data reflect the need for more research. We do not understand the reasons for the graft survival disparity, nor do we have a strategy to overcome this.
13. Inequitable allocation schema: Inequitable, discriminatory allocations were the consequence of HLA antigen matching at the A and B loci. The work of Roberts et al. was instrumental in ending a system that was ethnically discriminatory to Blacks since 1989. UNOS abolished antigen matching at the HLA-A locus by 1994 and the B locus by 2002. Eliminating these criteria has increased public trust in the donation and allocation processes.
14. The effects of institutionalized racism: Deep-rooted conscious or subconscious classifications of ethnic groups into superior and inferior classes may be the most important obstacle to overcome to eliminate transplant health disparities. "Institutionalized racism" is a term that is unrecognized in the field of ESRD or transplantation. To say it is taboo is an understatement. Yet, as we look at the disparities discussed previously, it appears that few items are as pervasive or as understudied as the phenomenon in this field. The human genome project has made it clear that we are all the same species, yet this insidious attitude persists. The pathophysiologic consequences of institutionalized racism have been demonstrated by Jules Harrell¹¹ and others since 1982. Institutional racism is likely responsible for the longer waiting times for Blacks compared to Whites for kidney transplantation, delayed referral of Blacks for kidney transplantation, Blacks receiving kidney transplants later than Whites, and Blacks being referred later, if at all, for extrarenal transplants.

Callender recommended the following actions for eliminating ethnic disparities:

• Provide adequate funding for further research into the 14 highlighted areas.
• Allocate an additional $200 million to the National Center on Minority Health and Health Disparities to address research questions and help eliminate the disparities in transplantation and donation.
• Eliminate the word "race" and replace it with the term "ethnicity" in the science and health arena and in the federal government.
• Develop a national strategic plan with goals and implementation dates with a community-based effort to eliminate institutionalized racism by educating and empowering the minority and majority communities.
• Encourage the involvement of the minority communities in health prevention activities to help ameliorate the need for organ transplantation.
• Develop an empowered minority community and enlist its support in changing behavior that fosters institutionalized racism.

William Harmon noted that one of ACOT's first recommendations to the Secretary was to support research into ethnic disparities.

Turrisi said that, in Charleston, it has been her experience that many African Americans have not been managed aggressively for hypertension and diabetes. That may be an early factor. We are starting to look at those disparities. Callender observed that we are not treating post-transplant hypertension properly either. Right now we have abject ignorance. We need a strategic plan to address it.

Roger Evans asked why Callender is using the word "disparities" instead of "inequities." Callender said that it is the same thing. Evans replied that the word "inequities" implies a cause. Disparities is just politically correct. We all want all Americans to have successful transplants. What helps one group helps the others.

Fritz Port made the point that three disadvantaged antigens are more common in the African Americans than in Whites. When we combine dialysis and transplantation and adjust for diabetes, hypertension, and age, we find that blacks have better outcomes. It is a profound observation, which we need to analyze further.

Recent Congressional Action

Emily Marcus Levine

The Organ Donation and Recovery Improvement Act (formerly the Frist Bill, now Public Law 108-216, an amendment of the National Organ Transplant Act (NOTA) passed Congress overwhelmingly and was signed into law by the President on April 5, 2004.

The Act expands the Secretary's authority to improve donation and transplant system and symbolizes Congress's recognition of the importance of these issues.

Section 3 of the Act may be of particular interest to ACOT. By way of background, Section 301 of NOTA makes it illegal for any person to "...knowingly acquire, receive, or otherwise transfer any human organ for valuable consideration..." Statutory exclusions include "...expenses of travel, housing, and lost wages incurred by the donor of a human organ in connection with the donation of the organ." The Organ Donation and Recovery Improvement Act authorizes the U.S. Department of Health and Human Services (HHS) to disburse grants ($5 million per year for 2005–2009) to reimburse living donors for allowed expenses. This is payment of last resort. The Secretary may also pay such expenses for up to two people to assist the donor. Preference is to be extended to people whom the Secretary determines are least likely to otherwise meet expenses.

Section 4 deals with public awareness; studies and demonstrations. This section establishes new grant/contract authorities and provides for a public awareness program to be overseen by the Secretary directly or administered through grants/contracts. This section also addresses the need to educate the public and generate awareness about the need for donors. Some programs already exist, but this provision will be supplementary. Also included in this section is authority for issuing peer-reviewed grants/contracts with the intent to conduct studies and demonstration projects for both deceased and living donors.

Section 4 also gives new authority to issue grants to OPOs and hospitals (must be trauma hospitals and those serving populations of 200,000 people) for the purpose of establishing programs to coordinate organ donation activities to increase donation rates. This measure will help states in their efforts to increase donation. Finally, there is an educational activity section. HHS will develop educational materials to inform health care and other professionals on donation issues. These programs must coordinate with OPTN and other organizations.

Section 5 confers new authority on the Secretary, through the Agency for Healthcare Research and Quality, to develop scientific evidence in support of efforts to increase donation and improve the recovery, preservation, and transportation of organs. The Secretary is authorized to conduct or support research, carry out a review of the scientific literature, develop and adopt proven practices. Other activities mentioned include research and dissemination of findings, development of a uniform clinical vocabulary for organ recovery and so forth, enhancement of skills in the workforce, and assessment of technologies.

Section 6 directs the Secretary to report to Congress on transplant-related activities under NOTA. The report is to discuss which activities have affected rates of organ donation and recovery and must include an analysis to evaluate the effectiveness of activities. The practices to be covered are to include those of the states, organizations, and other countries. The initial report is due in 2005, and subsequent reports every 2 years thereafter. The 2005 report must:

• Address donation practices for most effective practices and existing barriers
• Evaluate living donation practices
• Evaluate federally supported and conducted efforts
• Evaluate state registries
• Include a plan to improve federally supported and conducted activities.

Section 7 authorizes the Secretary to establish and maintain mechanisms to evaluate the long-term effects associated with living organ donation.

Section 8 is likely to involve ACOT in meaningful ways. This section directs the Secretary to evaluate proposals to increase cadaveric donation and report to Congress on those proposals. The Secretary must consult with the community (advocacy groups representing populations likely to be disproportionately affected by proposals). The report is due by 12/31/2004. Kress noted that there is likely to be a role for ACOT in the development of this report, which he referred to as the "Section 8 Study." He reminded the group that this meeting will result in direction and guidance to the Subcommittees. The recommendations coming out of the November meeting will then have to be addressed quickly in order to roll those recommendations into the Section 8 Study.

Section 9 repeals section 371(a)(3) of the Public Health Service Act (part of NOTA), which gave grant/contract authority for special projects designed to increase the number of donors. It had been relied upon by HRSA's Division of Transplantation but has now been replaced with more expansive authorities and a larger pool of eligible entities.

Levine noted that the new law does not address the controversial valuable consideration issues under section 301, nor does it appropriate any funds. (Funds were only authorized.) Language was struck from Frist's original bill about demonstration projects to test incentives that otherwise might be barred under NOTA section 301.

Progress Report on the HHS Breakthrough Collaborative and the Latest Secretarial Organ Initiative

Dennis Wagner
Virginia McBride

Dennis Wagner told the story of the Breakthough Collaborative and shared the broad outline of the YIELD initiative, which is aimed at increasing the number of organs transplanted per donor.

The Organ Donation Breakthrough Collaborative is "committed to saving or enhancing thousands of lives a year by spreading known best practices to the Nation's largest hospitals to achieve organ donation rates of 75% or higher in these hospitals." Wagner noted that the involvement of the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) in the Collaborative is largely due to ACOT's work.

A collaborative is an intensive, full-court press to facilitate breakthrough transformations in the performance of organizations, based on what already works. The methodology can be implemented in a variety of issues and arenas. In particular, the goals of the Organ Donation Breakthrough Collaborative are to:

• Increase the average conversion rate of eligible donors from the current average of 43 percent to 75 percent in the Nation's 300 largest hospitals
• Increase donations by up to 1,900 donors per year
• Increase the number of transplantations by 6,000 per year
• Help save the lives of thousands of people each year and prevent up to 17 deaths per day.

Wagner noted that 50% of eligible deceased donors are found in 223 hospitals; 90% are found in 953 hospitals. When one examines 1-year conversion rates among the largest 300 hospitals, conversion rates range from 10% to more than 90%. Most cluster around the national average of 40% to 50%.

The Collaborative has conducted site visits at six top-performing OPOs to develop a menu of practices that generate high conversion rates. Wagner showed a slide of conversion rates by donation service area (DSA). The average rate goes from more than 80% to 30% or less. This is not a case of being clumped around the average.

The Collaborative team consists of about 500 people at 95 large hospitals and 42 organ procurement organizations. The faculty includes 13 leading practitioners from OPOs and hospitals that have high conversion rates. Also, a leadership coordinating council supports the Collaborative. (Several council members were present in the room, including several members of ACOT.)

The Collaborative functions within a framework of learning sessions. Learning Session 1 (LS1) is dedicated to the study of change concepts and the Deming PDSA model (Plan, Do, Study, Act). LS2 encompasses more PDSA cycles. LS3 is dedicated to sustaining progress. The LS4 meeting will probably be held in November. Each team reports monthly. The learning sessions were also broadcast via satellite to large hospitals across the county to enable remote participation.

Susan Gunderson shared some of her insights gained as a result of her experience with the Collaborative. She said it has been very helpful to get hospital people together with OPOs so we are looking at the common problem and seeing how we can work together. The other real benefit is information sharing. The information is really used to bring about practice change. It is timely and helpful. She also spoke about the benefits gained by bringing the other players to the table (e.g., JCAHO, American Hospital Association) to hear their views on organ donation. She admitted that the Collaborative is an enormous amount of work.

Michael Williams spoke about attending the first Collaborative: "We learned that our effort was designed to bring together transplant coordinators, nurses, and physicians to work together." He cautioned, however, that it may be difficult to isolate effects of the Collaborative versus other interventions, perhaps confounding data collection and analysis for other studies.

Mike Seely said that the energy generated by the Collaborative is infectious. "Everyone is coming together to solve problems." He attended the learning session in Dallas and was struck by the size of the group. He observed that, historically, all these groups have been working in silos. "It is an eye-opening experience for OPOs to be at a table with their hospital peers." The Collaborative makes very effective use of the open space technique.

Virginia McBride then spoke about the results of the Collaborative's Action Period 2. She noted that the Collaborative in many respects carries out Acot Recommendations 12-16. Specifically, for example, ACOT's recommendation 16 states that "the regulatory framework provided by the Center for Medicare & Medicaid Services (CMS) for transplant center and OPO certification should be based on principles of continuous qua