Remy Aronoff announced that five ACOT members could not attend this meeting. He announced that Mary Kelleher-Crabtree is a new member on the committee. Ms. Kelleher-Crabtree is a pancreas recipient and is currently also a candidate. She works in the DC area with MMG, a health communications company, in the health care practices division. She also develops written guides and educational programs for individuals who are considering enrolling in clinical research studies. She has served as a consultant to clinical studies seeking to recruit potentially vulnerable subjects. Ms. Kelleher-Crabtree has also worked at NIH, for NIAID.
In another announcement, he said that this may or may not be Gail Agrawal’s last meeting. Papers have been submitted extending her position as Chair, but approval has not yet been received to do so. This is, however, Mr. Aronoff’s last meeting as the Executive Secretary because he will be the Executive Secretary of the Advisory Council on Blood Stem Cell Transplantation. Dr. Gregory Fant will replace him as Executive Secretary of ACOT.
Dr. Fant is a health statistician in the Health Resources and Services Administration’s Division of Transplantation (DoT). Dr. Fant serves as the project officer for the Scientific Registry of Transplant Recipients (SRTR). He joined the Federal Civil Service in 1997 and has served as a Federal statistician for the HIV/AIDS Bureau, Walter Reed Army Medical Center, U.S. Department of Defense, and the Bureau of the Census. Dr. Fant earned his PhD at the University of Nebraska. Mr. Aronoff will work with Dr. Fant in preparation for the next ACOT meeting.
The meeting agenda was rearranged due to presenters’ scheduling needs.
Tissue Regulation Update
Sam Holtzman confirmed that everyone had received a copy of the documents. His workgroup held a conference call and has been discussing tissue regulation issues. The workgroup members concluded that it is hard to make any suggestions to ACOT about a direction it should take in terms of making a recommendation to the Secretary because the industry itself needs to sort through these issues before ACOT can act. The Association of Organ Procurement Organizations (AOPO) convened a task force on public trust and tissue recovery. This task force has been meeting and is in the process of formulating its final recommendations. The American Association of Tissue Banks (AATB) and the Eye Bank Association of America (EBAA) have been engaged in the process, as have been a number of the major U.S. processors. The workgroup determined that it is premature to come up with a recommendation until ACOT members have a better idea of what the industry itself is recommending in terms of internal practices and regulations. It was Mr. Holtzman’s suggestion to invite representatives from these groups to come to the meeting today to present to the ACOT.
This group of presenters included Tracy Schmidt, past president of AOPO, who spoke to the group by telephone because of another commitment. Robert Rigney from the American Association of Tissue Banks (AATB) talked about AATB’s involvement in the process. Lastly, ACOT heard from Dr. Laura St. Martin with the Food and Drug Administration (FDA) about the new things FDA has been doing for the last year.
P. Robert Rigney, Jr., JD – The American Association of Tissue Banks (AATB)
Mr. Rigney’s stated that his goal is to address the ACOT’s concerns raised at other meetings. He presented on what the AATB has been doing, and also discussed the safety of tissue transplants in the U.S.
At the November 2, 2006, and on May 15, 2007, ACOT meetings, comments were made that: “When something untoward occurs concerning tissue in the United States, it affects organ donation rates as well.” In theory, if this is true, then the reverse is also true; tissue donation is affected by negative publicity on organ transplantation. In the last few days, the tissue community has had to answer questions about the Chicago case (e.g., HIV transmission) and other issues about organ transplantations. California Kaiser, St. Vincent’s, U.C. Irvine – all of these places have had problems with organ transplantation. We know that organ and tissue donations are increasing in number. Negative publicity is not, in fact, having a dampening effect on transplantation.
The statement has been made that there is: “a lack of information about tissue and recovery in the United States. It is not clear what organizations are doing recovery…” This is not true at all. The FDA requires regulation of all tissue transplant facilities. There is a very searchable system on the FDA’s webpage. There are three times more tissue donors than there are organ donors. The Human Cell and Tissue Establishment Registration System (HCTERS) indicates that there are 138 active establishments that recover and/or distribute ocular tissues; and there are 102 establishments that process ocular grafts. Among active tissue establishments that work with other tissues, the numbers are 158 that recover musculoskeletal (MS) tissues; 95 that process bone and soft tissue (MS, OA); 75 that process skin (S); 47 that process heart valves (C); and 580 that distribute conventional tissues.
Another quote has been made about standards, namely that: “…it is relatively easy to enter the field, which is not well-regulated (e.g., there are no mandatory guidelines).” This is also not true. Organizations might be able to register, but the FDA will show up at their doors very soon. The FDA has regulated tissue banks since 1993. Both Federal and State statutory regulations apply to tissue organizations, and private accreditation is provided by the AATB and EBAA.
Legal and regulatory oversight includes Federal statutes, such as the National Organ Transplant Act (NOTA) and the Public Health Service Act, and regulations by the Food and Drug Administration (FDA). The FDA’s 21 CFR 1270 & 1271 provide a comprehensive system of regulations that includes registration and product listing, donor eligibility, good tissue practices, and guidance documents. Legal and regulatory oversight on the part of the States include statutes such as the Uniform Anatomical Gift Act (UAGA); registration and/or licensing requirements; and other state-imposed requirements (e.g., New York). Private accreditation is handled by AATB and EBAA.
Federal regulations have three basic elements: 1) registration, 2) donor eligibility requirements, and 3) good tissue practices. There are 14 guidance documents and an Standard Operating Procedure (SOP) manual issued by the FDA on adverse reaction reports. Mr. Rigney displayed the binders of FDA regulations and guidance documents for tissue banks. FDA regulations in 21 CFR 1271 et seq. describe registration requirements (Subparts A and B [1271.1 – 1271.37]; donor eligibility requirements (Subpart C [1271.45 – 1271.90]); and good tissue practice requirements (Subparts D [1271.145 – 1271.320]).
In fact, tissue banking is heavily regulated clinically. Published AATB standards include four guidance documents and seven changes to standards that have been made just in 2007 alone. Administrative and clinical regulations are both issues. Mr. Rigney noted that the field is not highly regulated administratively; it is, however, more clinically regulated than organ procurement organizations.
The AATB started as the Navy Tissue Bank, which had as its mission: “To facilitate the provision of safe transplantable tissues of uniform high quality in quantities sufficient to meet national needs.” It establishes standards to prevent disease transmission and to ensure optimum clinical performance of transplanted cells and tissues. It also accredits tissue banks in order to ensure compliance with AATB Standards. Certification includes training and certifying tissue banking personnel.
The AATB Standards Committee meets on a monthly basis and the 12th edition of its standards will be published in 2008. The first edition, in 1984, predated FDA regulation of tissues by 10 years. The AATB standards address all aspects of tissue banking, including institutional requirements; records; informed consent; donor suitability; retrieval; processing; containers; storage; labeling; distribution; packaging; recalls; SOPs; staff; facilities; equipment; QA; QC; testing; and release. The over 100 pages include 55 Sections, 275 Subsections, and 3 Appendixes. The AATB Standards Committee includes liaisons with many organizations including the FDA, CDC, NY State Department of Health, EBAA, ASTM, AAMI, AORN, and Health Canada. Twenty States cite AATB in their State laws and/or regulations.
AATB Standards are universally accepted industry standards. They are referenced in statutes and/or regulations in more than 20 States. Six States and the District of Columbia require AATB accreditation. One State requires either AATB accreditation or FDA registration. Two States have incorporated AATB Standards by reference (burn centers may only obtain tissue from AATB-accredited banks). In two States, recovery agencies must be AATB-accredited; in two, tissue regulations must be based on AATB Standards. One State requires that AATB Standards be followed, and one State decrees the suitability of the gift is to be based on criteria established by the AATB. In four States, technicians must be AATB/CTBS or be certified by a tissue organization that is accredited by AATB. In two States, tissue donations must be tested for HIV and other communicable diseases as specified by the AATB.
AATB’s Standards have served as a model for many regulations and other standards, including FDA’s CGTPs regulations; Health Canada’s Cells, Tissues and Organs Regulations; New York Department of Health’s Tissue and Cell Standards; the European Union’s Commission Directives; the European Association of Tissue Banks Standards; the Latin American Association of Tissue Banks Standards; and the British Association for Tissue Banking Standards.
The AATB has four guidance documents and several others are being developed right now. AATB guidance documents in development include those on the following topics:
Many organizations recommend AATB accreditation. For example, the American Academy of Orthopaedic Surgeons has a policy that it will use tissue only from banks accredited by AATB. The American Burn Association requires that burn center hospitals’ policies and procedures for the use of allograft tissues must be in compliance with all Federal, State, and JCAHO requirements and, when feasible and appropriate, with standards of the American Association of Tissue Banks. A Philadelphia Grand Jury Report issued a recommendation to: “Require all tissue agencies to be licensed by the State and accredited by the American Association of Tissue Banks…Accreditation by the AATB should be required for a license. This would automatically subject the agencies to the most comprehensive standards for safe tissue practices, including qualifications and training of staff, procedures for donor consent, and donor eligibility screening by medical professionals.”
There are issues relating to tissue regulation. With Biomedical Tissue Services (BTS), for example, there were charges of allegedly forged consent forms, and allegedly falsified medical records. BTS is not AATB-accredited. Donor Referral Services (DRS) allegedly falsified medical records and is not AATB-accredited, either. In response to the BTS case, the AATB appointed an investigative task force of experts who conducted fact finding and analysis, and made recommendations. The overall findings of the task force were that AATB accreditation is important. The problems centered on non-accredited tissue banks and, in fact, it was AATB-accredited banks that reported the discrepancies to the FDA and led to these (and other) disclosures. Another finding was that AATB standards are critical – the tissue banks in question had violated AATB standards and compliance with the standards would have prevented the negative outcomes. Finally, the task force noted that changes are needed to prevent re-occurrence and potential criminal activity.
The AATB decided to make changes to its standards to prevent this sort of thing from happening again. With BTS, we realized that good practices that one ought to be able to take for granted cannot, in fact, be assumed to happen. Many changes in standards, accreditation policies, and CTBS programs have stemmed from this case. For example, around consent, AATB Bulletin No. 07-36, dated 4/24/07, requires the recording of all telephone consents. It requires a sampling plan that verifies consent documentation, requires an audit plan to compare content of recording to paper documentation, and mandates that inspections and audits include sampling requirement. These requirements exceed the consent laws in every State.
Changes were also made in AATB standards with respect to medical records.
AATB Bulletin No. 07-02, dated 1/9/07, requires information-sharing of donor records. Changes include requiring that a certified copy of the death certificate be included in donor records if the death did not occur in a hospital; if no third-party records are available to establish cause of death; or if an autopsy was not performed (see AATB Bulletin No. 07-04, 1/22/07). AATB now requires that only authorized and trained personnel can obtain consent and perform risk assessment interviews. In terms of recovery and collection, new standards require that tissue recovery sites must be qualified using 12 AATB suitability parameters (see AATB Bulletin No. 07-46, 7/10/07).
Additional changes include that AATB inspectors must be allowed to inspect non-AATB-accredited tissue banks that work with an accredited facility. AATB’s Guidance Document No. 4 (Providing Service to Tissue Donor Families), dated 3/10/07, requires substantial proof of tissue donor family services program. Additional Guidance documents are in process, as noted earlier.
There is a new code of conduct in place that organizations have to sign. The AATB can revoke their certification if this does not happen. We argue often to colleague organizations, including to the ACOT, in favor of supporting criminal sanctions in this area. Anyone who falsifies medical records or falsifies consent should be subject to criminal sanctions. This was added to the UAGA in revision.
Turning to the issue of the safety of tissue transplants, in the last 20 years there have been 10 million tissue transplants. The last viral transmission was in 2002; the last case of HCV was in the early 1990s; the last case of TB; and HBV was 50 years ago. The last case of HIV transmission was 20 years ago and was in a person within the “window period” for identifying the disease. There have been no reported cases of LCMV, Chagas Disease, Rabies, or West Nile Virus among tissue transplantation – these have only occurred in organ transplantation. For NAT (HIV/1 and HCV), the AATB requires NAT testing and has done so since 2005 (the FDA started requiring this last summer). However, NAT testing is not yet required for organ transplantation.
The bacterial contamination death in 2001 occurred with a non-accredited recovery agency/processor, the same one that was responsible for the 14 cases of Clostridium. This processor is now accredited by the AATB. There has been only one case of fungal contamination, and no cancer transmissions from tissue transplantation. The Human Tissue Task Force (HTTF) conducted a blitz and inspected 153 tissue recovery agencies in the first quarter of fiscal year 2007. They found no “major inaccuracies or deficiencies in records that could put tissue recipients at risk for transmission of relevant communicable disease agents or diseases.” To ensure safety, all of the following are required: safety of tissue transplants; screening (we have extensive standards); testing (NAT); donor eligibility (Medical Director); processing (Validation); and final terminal sterilization (Irradiation).
In conclusion, we know that donation rates are increasing for both organs and tissues.
We do know a great deal about tissue banks both in terms of their numbers and their activities. Tissue banking is heavily regulated, and AATB-accredited banks distribute virtually all of the tissue for transplant in the U.S. The field has a 23-year history of proven standards -- with a mechanism for continuous updating of these standards that are more detailed and extensive than the FDA. The AATB has a 22-year-old accreditation program to ensure compliance with its standards. These programs have produced a remarkable safety record and are recognized nationally and internationally. AATB accreditation is recommended by medical organizations and others, and serves as an additional check on safety.
In closing, the tissue transplantation community asks the ACOT to include them in any activities around tissues.
Ms. Agrawal asked ACOT members to hold their questions because Mr. Schmidt was on the telephone and the speakers would address questions jointly after he spoke.
Tracy Schmidt – Intermountain Recovery Systems
Tracy Schmidt was asked to follow up on the efforts that began in November 2006, to coordinate among organizations that are involved with tissue transplantation. The goal of this effort was to look at ways to improve trust in the tissue recovery process and field. Many organ recovery agencies are involved, as well.
In November 2006, a meeting was held that included organ recovery agencies, the AATB, the EBAA, and others. This group prioritized areas in which they can coordinate and improve public trust issues. There is a lot of really great support for this effort. Mr. Schmidt noted that handouts are available in the ACOT meeting room. Areas of focus for the group include the following:
The group worked on these areas. The group met three times and is looking forward to doing more cross-organizational work in the future. Mr. Schmidt’s colleague added that this was a good opportunity for tissue processors and key agencies to talk about shared issues. It’s not just about the single issue of tissue recovery and public trust, but also includes issues connected to donation as well. There are a lot of resources available if ACOT members have questions.
Ms. Agrawal thanked the speakers and asked for questions from the ACOT members.
Mr. Holtzman asked Mr. Rigney about his statement that the FDA had inspected 153 recovery agencies. He also said that the AATB has accredited over 100 and asked whether Mr. Rigney would describe the difference. Are the 53 not accredited eye banks? In response, Mr. Rigney said that his association accredits processing, storage, distribution, recovery or any combination of those. The FDA tissue task force was composed only of tissue recovery agencies. The extra places visited were probably multiple sites and/or non-accredited agencies. There are 59 OPOs and 58 are registered as tissue establishments, but only 20 are accredited by AATB.
A participant asked the FDA how many agencies that are recovering tissues are not AATB-accredited. The answer was that they would have to look it up. If Dr. St. Martin had to guess, she would say it’s about 50. A suggestion was made to print the list off of the FDA page and match it to the AATB-accredited list. The speakers offered to do that and get back to ACOT members.
Mr. Holtzman asked, given the presentation of the value of accreditation, why ACOT should not recommend that every recovery agency be accredited by the AATB? Mr. Schmidt responded that it’s not a bad recommendation. He commented that there should be an effort to improve coordination so that only one organization has to do the accrediting, rather than multiple organizations. Mr. Rigney added that he has made the same recommendation before and the AATB would welcome it. It would go a long way to ensuring the safety of tissue transplantation in the U.S.
Ms. Anita Principe said she applauded the presentations. She commented that she had spoken at an AATB meeting in the 1970s as part of an effort to try to foster dialogue between organ and tissue communities. She is confident that -- with this initiative – this will be achieved. It’s important because they are the same issues to the public. The difference between administrative and clinical oversight is a good point to make. It is her hope that coordination proceeds so that there is, ultimately, oversight and regulatory accreditation for all tissue banks. To the point that Mr. Rigney made about how it is easy for an organization to register but it is hard for them to do the work, in New York there have been problems arising from the length of time it takes for non-accredited tissue banks to be identified. Finally, it should be mandated that these organizations be accredited from groups like the AATB or the EBAA. She applauded these efforts and looks forward to future progress.
Dr. Matthew Kuehnert, ex officio member from the CDC, clarified a point about rabies. The tissue that was transplanted was considered “organ” not “tissue.” From the CDC standpoint, however, it’s not really an organ, and they are unsure what to call it. Rabies has been transmitted through corneas, but it is important to recognize that it’s hard to communicate risks to the public if experts themselves do not understand what those risks are. Most tissues are processed, so the risk is low. But the number of tissues being used is high, which is where problems with tissue come from. For organs, on the other hand, the risk is higher, but there are smaller numbers being used. Thus, the risks between the two become equivalent.
Dr. Jim Burdick stated that he would like to quibble with the previous speaker. To clarify, there is a HRSA regulation that vessels removed with an organ for transplantation are to be used only for organ transplantation. These vessels are regulated as organs, as specified by Secretary. There is a clear process for monitoring this, and a clear policy that specifies following the vessels and determining where they go and ensuring that they are discarded if not used in the organ transplant setting. Whether there are cracks in the system – if tissues are retrieved that are not at least secondarily covered, as by AATB accreditation – that is another question. The ACOT may not be the right place for this discussion but there is some disquiet on this area and requiring accreditation would make a big difference.
Dr. Laura St. Martin – The Food and Drug Administration (FDA)
Dr. St. Martin provided an FDA update on Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps). She commented that some of the presentation might be redundant after Mr. Rigney’s presentation.
The FDA has been regulating tissues since 1993 – limited scope, limited spectrum of diseases. The interim tissue rule (21 CFR 1270) was published in December 1993, and finalized in July 1997. It addressed donor suitability and included a limited scope of tissues and diseases. The proposed approach was published in February 1997 and opened for public comment. Input was provided from other Federal agencies, including HRSA and the CDC. The current “Tissue Rules” (21 CFR 1271) became effective May 25, 2005. It takes a tiered, risk-based approach and includes a broad scope of cells and tissues.
The regulations on HCT/Ps cover: “Articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient. This includes musculoskeletal tissue, skin, ocular tissue, human heart valves, dura mater, reproductive tissue, hematopoietic stem/progenitor cells, other cellular therapies, and tissue/device and other combination therapies.” The regulation has several specific subparts, including Subpart A (scope and definitions); Subpart B (procedures for registration and listing); Subpart C (donor eligibility); Subpart D (current good tissue practice); Subpart E (reporting and labeling); and Subpart F (inspection and enforcement). Dr. St. Martin described each in turn.
Subpart A’s general provisions are to provide a purpose and scope for all parts of the regulation. It also includes important definitions.
Subpart B is the procedures for registration and listing. Subpart B has the force of law; it is a requirement. Any entity that does the following activities must register: performs recovery, processing, storage, labeling, or distribution of HCT/Ps, or donor screening or testing. Organizations must register and be listed within five days. They must also re-register annually and update the registration if there are any changes in location or ownership. All foreign establishments importing HCT/Ps to the U.S. must register and list such HCT/Ps. As of August 2007, there were 2,650 establishments registered, of which 531 were inactive. Musculoskeletal/ocular was 1,286; hematopoietic stem cell was 654; and reproductive organizations were 685 of those registered. The number also includes 186 international establishments (mostly stem cell entities).
Subpart C concerned donor eligibility and sets forth procedures for eligibility determination including the need for an interview for high-risk behaviors, a physical exam, and screening and testing for relevant communicable diseases. HCT/P must not be administered until the donor has been determined to be eligible, with some exceptions. Sub-part C is very specific about what is required and also includes detailed recommendations on how to conduct donor eligibility activities. These must be completed before tissue is used, with only some exceptions.
Subpart D describes current good tissue practice, specifically the methods, facilities, and controls for manufacturing to prevent communicable disease transmission. It includes broad goals that are applicable to the wide range of HCT/Ps. It requires a quality program to prevent, detect, and correct deficiencies that could increase communicable disease risk.
Additional requirements are set forth in Subpart E, including adverse reaction reporting, and labeling requirements. Organizations must report significant adverse reactions for their products. The FDA then determines if further action is necessary. The FDA may also issue more recommendations based on reporting.
Subpart F describes inspection and enforcement activities. Establishments must permit the FDA to inspect all manufacturing locations, and the inspections are usually unannounced. The frequency of inspections is at the FDA’s discretion. Enforcement actions include an untitled letter, a warning letter, an Order of Retention and Recall, and an Order of Cessation of Manufacturing. Enforcement actions will depend on the violations. Dr. St. Martin showed a slide indicating the number of inspections conducted by the FDA. The number inspected has increased over time; the FDA is looking at ways to improve its inspection capabilities.
The FDA’s Human Tissue Task Force was formed in August 2006 to evaluate and strengthen the FDA’s risk-based system for regulating HCT/Ps; to assess the challenges that had occurred in implementation of the new system; and to identify additional steps to further protect the public health by preventing the transmission of communicable disease while assuring the availability of safe products. The Task Force report issued in June 2007 is available at the FDA website.
In terms of inspections and compliance activities, from October 1, 2006 through March 31, 2007, the FDA conducted 153 inspections of domestic musculoskeletal recovery establishments. Although deviations from the regulations were noted during some of the inspections, no major inaccuracies or deficiencies were observed. None of the inspections resulted in regulatory action.
Some guidances have been issued, and others are in the works. A draft CGTP guidance is in progress. The FDA published a guidance for the industry to aid with compliance with 21 CFR 1271.150(c)(1), in September 2006. Cord Blood Guidance was released in January 2007. A guidance on HCT/Ps from Donors Tested Using Pooled Specimens or Diagnostic Tests, was also released in January 2007. A Donor Eligibility Guidance was reposted in August 2007.
The Advisory Committee on Blood Safety and Availability has a new charter as of October 2006, which broadens the Committee’s scope to include blood, blood products, tissues, and organs. It will focus on issues related to transfusion and transplantation safety and availability. Federal agency representation and the committee composition also will change to encompass expertise in both tissue and organs as well. The committee will be renamed to reflect that change. It is hoped that these changes may help to address cross-agency concerns.
Dr. Yilang Zhu asked what triggers an FDA inspection? Dr. St. Martin responded that some are done routinely while others are triggered by an adverse reaction report or through other channels. The FDA may learn there are non-compliance issues, or something that needs to be clarified. Dr. Zhu commented that Dr. St. Martin had said there are 2,000 agencies, but the FDA only had 153 inspections over 6 months. This amounts to one inspection every seven years, is that right? The answer was that there is a staffing issue at the FDA; it is ramping up capacity for the new regulations. The Task Force mentions consideration of prioritizing inspections, so those with higher risks are inspected more often.
Dr. Ruth Solomon from the FDA clarified how the estimate of “over 2,000” establishments that have been registered was arrived at. It includes not only those that recover and process, but also distributors -- of which there are many. The number includes testing labs that conduct donor screening, and microbiology labs that conduct screening and testing. It seems like an inflated number, but it includes any entity that performs any step in the manufacturing of tissues. The FDA cannot inspect them all, so it prioritizes. For example, a processor would be inspected more often than a small lab would be. The FDA prioritizes every year and instructs the field offices about the places on which to focus.
Dr. Solomon asked the speakers to talk about regulations around informed consent, and specifically about international donor sources. What’s known about the source of those donors? The answer was that the tissue rules do not address informed consent, just donor screening and eligibility. Dr. Solomon said there was an AATB note about documenting consent and understanding the source of the tissues. Is that not about the need to attend to the source of tissues and informed consent for them? The FDA response was that it is interested in donor protections but authorized to protect the public from communicable diseases. Tissue organizations have to meet FDA regulations and there are a host of other organizations that have standards as well.
Mr. Rigney said that the AATB has been in top World Health Organization (WHO) conferences to discuss specifications for consent around tissues. AATB standards note that if a bank gets tissues from another country, even if these tissues are just being processed and then returned to that original country, the banks have to be sure that they follow AATB standards as well as those of the member states (like the European Union). There is a global movement to improve tissue safety and to develop regulations. The consent issue is different in different countries. A country without its own regulations has to follow WHO guidance. This is inserted into AATB standards.
Dr. Russell Wiesner asked if the FDA inspections pertain to sperm and egg banks as well. He was told they do.
Dr. Wiesner asked if any products are coming into the U.S. from executed prisoners from China? The answer was that this is not known, but they would have to meet lab standards. Dr. St. Martin is not aware that this is happening, but it would have to be regulated. Dr. Wiesner pointed out that this does not affect where the tissue comes from; FDA standards can be met and still come from an executed prisoner. Those are not excluded. Dr. Burdick clarified that the National Marrow Donor Program is in the process of creating an arrangement with China for the exchange of blood stem cells for transplantation with all of the criteria that you have been hearing about. It’s the beginning of a process for international aspects of this.
Mr. Holtzman asked if the FDA was confident that it is aware of all of those who are recovering tissues for transplantation. Dr. St. Martin said that these entities are required to register and the FDA believes that there is better diligence about this and that things have improved. Mr. Holtzman asked if that was a “yes”; and Dr. St. Martin said that it was.
Mr. Holtzman asked if medical examiners who recover dura mater/eye tissue are subject to FDA inspection. Dr. St. Martin said that the regulations are specific. If they have an agreement or contract with an establishment, then the parent company registers and makes sure its contractors comply. There are also requirements for individuals. All entities are included in the regulations. Mr. Holtzman asked if individuals recovering any tissue for any reason are subject to FDA inspection. The answer was that these individuals are required to register and subject to inspection.
Dr. Zhu asked what the major international sources of cell tissues are, and Dr. St. Martin said she could look this up and get back to him. Dr. Ruth Solomon noted that the FDA has import regulations on any product that comes into the country. They have to be passed by the FDA, and they cannot come into the U.S. until there has been a review. In terms of prisoners, any potential donor who has been incarcerated for more than 3 consecutive days may not be a donor in the U.S. So, executed prisoners are not eligible.
Ms. Agrawal asked why the FDA did not require AATB accreditation as part of the new regulatory oversight. The response was that the statutes under which the FDA operates (PHS Act) do not give them the authority to require accreditation by any private organizations.
Quality of Life: Organ Donors and Recipients – Dr. Hong
Dr. Barry Hong from the Washington University School of Medicine presented on quality of life (QOL) of organ donors and recipients. If one looks at the first (identical twin) transplant, in 1952, the donor is still alive today and has stated he would make the donation again. He responded in the way that donors do today. A book on this transplant, by Joseph Murray, included entries from the clinical record. From the recipient’s psychiatric background, it seems like his QOL was shaky on the front-end. He might have had a psychotic reaction – it’s important to remember there were different criteria for assessing people back then. He was restless, and tried to cancel the operation the night before (his brother refused). Dr. Hong noted that with that behavior, in 2007, no one would operate on him.
“Quality of life” was first used in cancer studies – it is really about functional adjustments. Later, it was broadened to include mental health and satisfaction issues.
The Karnofsky scale (Karnofsky & Burchenal, 1949) was one of the first QOL measures. It is mainly about functionality and if the person is functioning as he or she was before.
What is “quality of life”? It is one of those things that everyone thinks they know, but the specific definitions vary. It is a very abstract idea, and a lot of domains are covered by it, including medical, psychological, and personal domains. It is extremely subjective, and hard to measure. There is the notion that QOL is more than just the burden of illness (i.e., it also includes the person’s perceptions and meanings assigned to the experience). These domains are almost as important as functional or symptom outcome.
The term started in sociology, after World War II, and concerned material affluence and things like the home and one’s possessions. It came to medicine later and primarily in three “flavors”: disease-specific measures, health-related QOL, and global life quality. There is an effort to measure health more broadly. Multi-dimensional measures (like OARS) were created, and now we traditionally talk about dimensions that end up in a single score (the SF-36, for example).
In 2007, there are agreed-upon categories for the various domains, although they may be measured differently: the recipient’s physical functional status; his/her mental health and cognitive status; and social functioning, meaning whether the recipient is working, if his/her social life is active again; and global QOL.
There has been a change in how models or measures are seen -- biomedical models were more linear. Now, researchers see QOL as being more interactive; the domains feed into each other, and include non-medical factors, rather than being linearly driven. (Wilson & Cleary, 1995.)
More complex modes include the work of the PROMIS Domain Framework, which stands for the “Patient-Reported Outcomes Measurement Information System” and which has tried to collect a databank of agreed-upon and validated QOL measures. Dr. Hong showed a slide illustrating the very complicated system. He pointed out that the third column contains the usual things about functioning, but that there are many subgroups enumerated in addition to those. Uses of QOL indicators include assessing general populations and for planning individual care. It is often used by health economists to plead for more resources for a community or region.
Dew has noted that there are 218 studies involving over 14,000 patients, so there is a fair amount of information available on this subject. Studies (see Dew et al, 1997) report that improvements in transplanted patients’ QOL are better than in other disease groups. Outcome differs by organ groups, however (e.g., renal vs. heart); and it may be that these patients’ primary illness or long-term complications are very different. It’s also noted that one does not see uniform improvement in all four domains – some will go up and some will not. Thus, the improvements seen may not be due to individuals, but could result from treatment effects (such as the use of different immunosuppressant -- cyclosporine vs. FK506).
Methodological problems with QOL indicators are that they are subjective; objective; and have not always separated psychopathology and well-being. Measurements vary in terms of scales, domains, and global measures, and the relationship among these measures is an issue. It is hard to explain how they are connected and interact. The search for valid and reliable measures continues.
One issue is about QOL stability. A 1995 study conducted 5-year follow-ups with transplant recipients found that, after about 5 years, they stayed stable. The study controlled for age and rejection. QOL was not influenced by age, rejection episodes, or pre-operative medical parameters. Generally, one’s perceptions about oneself stabilize over time.
A Spanish study tried to answer this interesting question through a large, randomized survey. The sample was of 210 transplants, 170 hemodialysis patients, and 402 people from the general population (random). Instruments used included Karnofsky, SF-36, and the SIP (Sick Impact Profile). Results indicated that transplant patients were similar to the general population. Co-morbid illness was similar in transplant patients and the general population, while hemodialysis patients had more co-morbid illness. (Rebollo, et al, 2000.)
The field has moved into other areas, including subjective ones. Researchers are now trying to look at beliefs, experiences, expectations, and perceptions of illness – all of which affect QOL. The gap between expectation and experience is important; patients have to understand that they are not getting a new organ. Often, patients have mistaken notions about how healthy they will be after the transplant and get annoyed when these expectations are not met. We may create expectations about what a person will feel like after the donation. It is also vexing that changes in health (biological) may not be reflected in QOL assessments. A person’s perception of QOL is dynamic within the individual, and equal clinical conditions do not yield the same QOL measures. There is no clear association between physical changes and QOL. (Burra, et al, 2007.)
Dr. Hong has conducted a study about perceptions that looked retrospectively at donors, recipients, and a third party who is connected to the donor (e.g., a spouse). There were 174 donor triads and an assessment was conducted pre- and post-transplant about their perceptions and concerns and how they differed. Dr. Hong showed a slide with columns indicating the respondent’s endorsement for specific items and noted that the third party and the donors are clearly aligned in their concerns. The recipients have very different concerns, though they are less concerned about death or the painfulness of surgery. There are marked differences in measures. (Burroughs, Waterman & Hong, 2003.)
There will be a specific presentation later on the NIH study, RELIVE, and QOL; but Dr. Hong noted that RELIVE has a dedicated QOL committee. It’s like the United Nations. There are people from all sorts of disciplines working on this. It is the biggest effort by the Federal Government to study this. There are specific QOL measures for each organ and measures that are common among groups. We measure traditional domains (function, mental, social, global) as well as some limited subjective appraisals. We also include some newer QOL measures, i.e., sense of community, positive psychology. An attempt is made to address concerns raised by the literature.
The methodology for RELIVE is to avoid asking medical status questions that have been asked elsewhere, and to avoid asking duplicate questions. This reduces the response burden (shortlist instrument) but keeps the use of validated measures intact. Questions that emphasize subjective recall also are avoided. The instrument can be given through in-person interview, over the phone or paper/pencil format.
The limitations are that the kidney and lung groups may not be comparable, but the researchers will combine findings, if that’s possible. Not every QOL is given, so this is not comprehensive for some measures. The mental health measures are not equivalent to criterion symptom-based diagnoses.
It is a matter of discussion if they can find appropriate controls/comparisons. No illness control group is possible. Another possible problem with controls is the fact that controls for kidney and lung differ. Dr. Hong stated that he likes the concept of “yoked control.” Friends are not good controls for many things, but they might work for living donors. Problems with using friends as controls include the fact that people often choose someone slightly better than themselves; it may be difficult to motivate them for participation in the study; they have only been used this way in a small number of studies; they may be better at measuring objective events from donation time until the present; and the meaning of donation may have an unintended effect on them.
Dr. Hong closed by talking about three psychological theories that might throw all of our findings into concern. First, cognitive dissonance (Festinger); second, positive and health illusions (Taylor); and third, positive psychology (Seligman).
Ms. Agrawal thanked Dr. Hong for an interesting presentation.
Mrs. Rhonda Boone said that she was excited to see this subject on the agenda and asked where Dr. Hong had gotten the information presented. She noted that quality of life is something that is often ignored in living donors and asked if this was this from published studies about recipients. Dr. Hong replied that the published studies (e.g., Dew) are mostly about organ recipients. There is a misconception that nothing has been done in this area, but this is not the case. In fact, much work has been done -- but no one knows what it means. The literature is confusing and conflicting. Mrs. Boone asked if the study he is conducting includes any items to determine the high number of complications that affect donors and recipients. The response was that the researchers are very much aware of the limitations; there are lots of analytic models to use. We can look at complications and see if the variables predict QOL. It’s hard, though, to see how they influence one another. It will give us better answers, but they may not be perfect.
Dr. Mildred Solomon said that this was a very interesting presentation. She is puzzled, however, that one would have to defend the subjective nature of QOL assessments. She mentioned pain measurements and commented that researchers in that field have embraced the subjectivity of those measurements. Dr. Hong responded that it depends on “who you hang out with.” Measurement folks hammer him on this all the time, while QOL people often say it’s all subjective. Folks line up all over the place. There is a lot of debate about this and if you use validated measures, then what are the constructs? Dr. Solomon asked if he was saying that there is a difference in QOL assessment between people in pain and organ donation. Dr. Hong answered that it’s tipped to a positive direction; you can’t get away from that.
Ms. Principe asked about cultural issues. Dr. Hong said that when there is a family member who is a potential donor, with White families, there are few people in the room and one person (like the father) makes the final decision. With African American families, however, the waiting rooms tend to be too small; the families have 50-60 people present. It can be hard to make a decision that way and, if one person doesn’t want to do the donation, other family members will not override that person. Such cultural issues may feed into lower approval rates for organ donations among certain minorities. There may also be QOL variations by cultural groups. If it emphasizes something different, it will impact the QOL assessment. He referred Ms. Principe to “PROMIS,” which has a lot of details. Since Ms. Principe is from New York, she stated she is thinking in terms of the live donors and the QOL for them based on cultural diversity issues. There is a lack of data on this. Dr. Hong agreed that this is very complex and that he hopes to get to it at some point. He wants common measures right now. The goal is to define QOL better so it can be used as a measure across the various groups.
Dr. Jorge Reyes said that, as a clinician, they deal with outcomes to affect initiatives. Where might this be going in terms of impact and the field? And, is there another area of medicine where QOL has impacted practice? The answer was that cancer seems to be doing better – the cancer field can say if a treatment is better or worse in terms of QOL domains (e.g., getting the person back to work). It’s complicated. Memories are distorted in every aspect of life.
Dr. David Vega asked if Dr. Hong thinks QOL measures are sophisticated enough to impact allocation decisions among deceased donors. The short answer is no. For some patients, some things will be better. We have a terrible dilemma of trying to have global goods and an individual patient with a specific disease and a prior quality of life.
Dr. Zhu asked about promoting positive psychology as a way to promote donation. Dr. Hong responded that he is very interested in living, altruistic donors. They are very different, and special; it’s about their personality and not about education. They may have a gene for altruism and be wired differently. Our research is showing there seems to be a different type of person, different from relatives and from the general public. The MMPI has a scale (the S scale) that is based on airline pilots – they tend to be sociable, self-directed, to work well with others, and to make their own decisions. Altruistic organ donors look the same. They have strong views, are firm, and are socially proactive.
National Institutes of Health (NIH) Studies of Living Donors – Dr. Odim
Dr. Jonah Odim began by noting that 15 years ago his stepsister, who was newly married and had just relocated to Texas from West Africa, was in kidney failure from unknown causes. She approached her twin brother (who was living in Chicago) about donating one of his kidneys. Although they were fraternal twins, the two had not grown up together and had been separated during the Biafran Civil War in the late 1960s. Despite pleas from the family, the brother ultimately decided against undergoing a donor medical and psychosocial evaluation. The stepsister went on to dialysis and eventually received a renal transplantation from a deceased donor, but is now back on dialysis.
This scenario shows the rollercoaster, emotional ride surrounding living donor transplantation. Dr. Odim stated that he will briefly review NIH’s research initiatives to look at outcomes among living organ donors. Specifically, he will describe the five protocols that are currently in various stages of development and some of the factors that affect the time and pipeline of new information regarding research of this nature.
We all know that there is a chronic shortage of organs, and that there are deaths among those who are on the waiting lists. The push to meet the demand has fueled debates in the lay press. For example, this week the Wall Street Journal published an article on sales of organs. Issues related to live organ donation also recently have been discussed in the New England Journal of Medicine.
What do living donors need to know? The Wall Street Journal has published articles noting the need for long-term outcome studies in living donors of solid organs. It is important to recognize that live organ donation is a relatively young science. There is a mere 13-year history for lung donation, 20-year history for liver transplants, and a little more than 50-year history for kidney donation. So, no one knows precisely what the time-dependent, natural history is for a particular individual live donor.
The rising number of donors suggests that there are benefits to becoming a donor – for the donor, the recipient, and the health care field. The potential benefits for the living donor include respect for autonomy, a psychological benefit from the altruistic act, and (in other parts of the world) financial benefits. The recipient usually benefits from reduction in the time they have to wait, reduced chance of dying on the waiting list, reduced down time “in the ice bucket” that reduces organ ischemia, and improved graft and recipient survival (in most instances).
Looking at outcomes for living donation, it’s clear that, for kidney at least, mortality rates associated with living kidney donation are very low. No early mortality has been reported for lung transplantation cases. Morbidity rates for liver donation are all over the map. Only three centers do live liver donations and their mortality ranges from 20-50 percent. Early mortality after living kidney donation is about three deaths in 10,000 (this is similar to the risk from general anesthesia), with morbidities reported around 1-10 per 100 cases.
Living lung and liver transplantation are technically and physiological more stressful procedures. About two in 1,000 donors of a liver segment die early in the short-term. Short-term morbidity is appreciable in 10 out of 100 of the cases. Donor lobar transplantation involves a pair of donors per recipient. There have been no reported deaths in the short (13 years) experience at the few U.S. centers that offer this service. On the other hand, minor and major complications are seen.
The ACOT recommended, and the Secretary agreed, that NIH should support a research program on the outcomes for, and health care needs of, living donors. The NIH responded by funding two consortia of investigators. The “Adult to Adult Living Liver” (A2ALL) donor study, supported by NIDDK, was initiated in 2002 with funding for seven years. It is a consortium of nine U.S. clinical liver transplantation sites.
The second, and more recent, is the “RELIVE” study, which stands for REnal and Lung LIVing donors Evaluation study. This got underway last fall with three kidney and two lung sites. The three clinical kidney sites are the University of Minnesota, the Mayo Clinic, and the University of Alabama. Together, they provide long-standing expertise and regional and ethnic diversity. The two lung sites are U.S.C. and Washington University (in Ohio) that, together, have performed over 80 percent of all the living lung transplants in the U.S. since the technique was initiated 13 years ago. The consortium of investigators is funded by predominantly by NIAID with supplemental support from NHLBI and HRSA. The data coordinating center for RELIVE also coordinates the A2ALL group.
If one looks at the race distribution of living donors and living donors on the waiting list, among donors who need a kidney graft, almost half are African American. Risks may be variable based on a number of predictors: socioeconomic status, ethnicity. This raises issues for the field. (Gibney, 2007.) Looking at donors, there were over 62,000 living donations made between 1993 and 2005. While only 14 percent of this group was African Americans, African Americans represented almost 50 percent of living donors going on the ESRD and wait listed for a new kidney. What is the age-gender and race-adjusted risk of ESRD after living kidney donation?
The RELIVE study is doing a chart review to explore the status of all live kidney donors in their catchment area. Information about donors will be linked with a variety of databases the researchers will identify. Comparisons will be made with control groups. The next phase on kidneys is a cross-sectional protocol with the primary endpoints being: (1) Hypertension, proteinuria, renal disease, and anemia; (2) Risk for cardiovascular disease; and (3) Quality of life and insurance risk. Secondary endpoints include differences in primary endpoints (race, surgical technique, ECD vs. SD, time from donation, donor family history); and accuracy of GFR vs. measured GFR.
For live liver donation a similar strategy is being used. A retrospective analysis will be conducted to determine the status of all of the patients, looking at endpoints about death as well as other milestones (e.g., cause of death). Also, we will assess if any of them are on the lung transplant lists. Dr. Odim described the methodology for the RELIVE studies.
The few studies conducted on informed consent are all retrospective and are subject to limitations that include “recall bias.” There are no prospective studies of the donor’s understanding of the process at the time of their donation. “Informed consent” is the act of an individual exercising an autonomous choice about whether to undergo a living donation. Non-control (or “voluntariness”) is fundamental to autonomous actions. Control can be exerted through influences that undermine the voluntary (or non-controlled) nature of the actions. These influences include persuasion, manipulation, and coercion.
The informed consent portion of the study will be a short-term prospective survey for kidney and lung donors. Primary endpoints include their understanding of pressure to donate; the process of donation; medical and psychosocial consequences of donation; and center and ethnic/racial variability. Secondary endpoints include the understanding of short- and long-term medical risks; psychological risks; and variable recipient outcomes.
QOL focus will have the goal of assessing the long-term quality of life in living kidney and lung donors compared with matched control subjects, and identifying predictors/correlates of long-term quality of life following living kidney and lung donation. Dr. Hong’s presentation covered this issue.
The data coordinating center is taking the data sets from the individual centers and trying to make linkages with a variety of databases to fill in gaps and create a complete data set. The ultimate database will be similar to the A2ALL one.
We do have some preliminary data from a dry run that looks at kidney donors by site and the year of donation. We have data from 70 percent of these donors (for lungs, we have about 80 percent of cases). Data do not include cases from before 1980s, when SRTR was launched. In terms of deaths per year among the kidney group, there is only one that was reported to the SRTR; but when linkages were made with other databases (e.g., Social Security), more instances are found. The cause of death is unknown, however. It is the same with lungs -- there is one from the SRTR data.
Study wide design issues include: HRQoL (validated tools, disease-specific tools); selection of controls (disease-free; comparable time at risk; age, race and gender-matched); and ascertainment of donor outcomes (standardized definition, uniform ascertainment method; practical, adjudication mechanism).
A JAMA article on the impact of HIPAA on health care research is interesting and notes that when the researchers looked at the impact of the rule (which went into effect in 1993), they determined that it has made it significantly more difficult to do research. The consensus also was that HIPAA has not strengthened the public’s trust in the process.
In conclusion, living organ donation is perhaps one of the remarkable success stories of modern medicine. We have witnessed the heroism and compassion of well-motivated individuals who take risks to help others. The generation of new knowledge (especially patient-oriented research) involving multiple investigators and researchers, and encompassing the impact of IRB and HIPAA requirements, impairs the speed at which the information is generated.
The NIH wishes to thank HRSA and other agencies for sharing with NIH in trying to get this research underway.
Mrs. Boone asked if there are safeguards in place for this and/or for the liver study to ensure that the transplant center information is complete and accurate. Dr. Odim asked if she meant, are there safeguards that it’s safe and accurate, then to the extent possible, yes. It’s retrospective information, however, and it will depend on what the safeguards were in place when the donor was in the specific facility. Mrs. Boone asked if the information from Social Security and the centers can be compared to determine why the patients died and to see the discrepancy. Dr. Odim said most definitely this can occur. But, not everyone has a Social Security number, so even this is not a failsafe method. NIH is going to do other things to help the group get that information.
Dr. Low commented that the mortality figures presented seemed low. Do they cover the whole time period, because they seem lower even than would be seen among the general population? If the rates are that low, he joked that he wanted to get a transplant. Dr. Odim said the rates do cover the whole time period of 20 years. He stated that Dr. Low’s points are excellent and cautioned that these are preliminary data. There are plans to look at this more closely.
Dr. Velma Scantlebury thanked Dr. Odim for the presentation. She asked for clarification about the statement that there were 13 deaths, but only one was in the SRTR? Dr. Odim stated that this was correct for kidney donor deaths; that is the number or reported deaths for that institution among donors. Dr. Burdick commented that SRTR data are collected by OPTN, which does not collect long-term data. Because these are deaths that come from any cause, they have no way to track them. There’s no discrepancy; it’s just what SRTR collects. The OPTN didn’t exist before 1987 so that would have been voluntary reporting before then. Dr. Odim agreed and said that RELIVE wanted to look and see who is alive, and then they can be contacted for follow-up.
Dr. Wiesner reminded the group that the processes have evolved too. We now take hypertensive or older people; the donors over time are not comparable. Dr. Odim agreed that it’s a moving target; we are taking more donors who are obese, old, medicated and that was not the case 10 years ago. The role of the consortium is to see if all 8,000 living donors are alive or dead, and to collect circumstances of death for all who are not alive.
Reports from Workgroups: Discussion & Recommendations
Ms. Agrawal announced that the ACOT would hear reports from workgroups and get their recommendations. The workgroups will present in the order listed on the agenda.
Tommy Frieson -- Transplant Tourism Workgroup
Mr. Frieson began by noting that the demand for donations in the U.S. exceeds supply. As a result of that and the length of the waiting list, people are seeking organs outside of the United States. Countries such as India, Thailand, China, and South America (to name just a few) are getting involved in “transplant tourism.” Issues include: where the transplanted organs come from; the quality of care received by the recipient; the recipient’s ability to get follow-up after the donation; levels of care for live organ donors; the recipient’s lack of ability to litigate, if needed; and possible threats to insurance coverage for the transplant and/or for any needed follow-up?
Dr. Frank Delmonico spoke to the ACOT about this issue in May 2007. His talk described how the poor and vulnerable are being victimized. They are frequently paid very small amounts for organs and not being properly taken care of afterwards. Also, there are questions about U.S. surgeons who go to these countries to perform transplant operations.
Two articles are provided in the ACOT member packets relevant to this topic. Mr. Frieson tried to contact insurance companies. He contacted United Health Group Programs, U.S. Health, and Blue Cross Blue Shield (BCBS) of South Carolina. The first two did not return his call. BCBS did and he learned that BCBS transplant patients are leaving the country because of monetary issues. Mr. Frieson was assured that the international facilities were monitored. The BCBS representative said that this was happening because people were not able to wait or to pay for organs. In fact, BCBS saves a lot of money because of this sort of “medical travel.” When a person goes to Thailand, he/she brings his own living donor. BCBS then takes care of them as a patient. The conversation did not address issues of prisoners’ organs.
Mr. Frieson asked why someone would have to wait for a transplant in the U.S. if this individual was on the waiting list and had an identified living donor. The BCBS representative did not answer this point. Ms. Agrawal noted that the costs would be primarily either BCBS’ own or Medicare’s, not the patient’s. Mr. Frieson said he had mentioned that and the BSBC representative responded, “This is what we do.” Then, no future calls from Mr. Frieson were answered by BSBC. The workgroup has discussed this issue and also talked to Dr. Delmonico about Chinese prisoners being killed for their organs.
Proposed Recommendation: Transplant Tourism Workgroup
For waitlisted patients removed from the waiting list because of transplant, the ACOT recommends that the OPTN create a unique code for transplants that occur outside the U.S. That code will lead to the collection of follow-up information on those patients, e.g., where the transplant occurred, type of transplant, basic post-transplant health condition information. The patient would be followed at the hospital(s) where post-transplant treatment is provided in the same manner as other transplant recipients.
For non-waitlisted patients who receive a transplant outside the U.S., the ACOT recommends that the OPTN seek the cooperation of transplant programs in identifying those non-U.S. transplant patients they are treating, and then in collecting the same type of information as for those patients who had been waitlisted.
Dr. Alan Leichtman from SRTR noted that the OPTN has been collecting some of this information although they have not conducted an audit on this. A more systematic tracking of this is beginning. It’s important to recognize that some of these foreign operations result from transplant tourism, but others are because people have roots in other countries and may be having the operation in their native lands. While there is a sizable concern about exploitation, not all of these operations are exploitive.
Mr. Frieson agreed that this is an important point. The BCBS representative did also say that some of them are elective. There is a person in Alabama who was from Israel and went home to have the transplantation. The U.S. company paid for it, though. BCBS did not want to talk about this, although it was stated that the company monitors hospitals they recommend and have criteria on where they make recommendations.
Mrs. Boone asked, in instances where someone takes his own donor with him, who is responsible for caring for the living donor? Mr. Frieson said that BCBS did not provide any information on that situation.
Dr. Reyes said that the ACOT is trying to define inappropriate transplant tourism. “We have lots of people who come to the U.S. for this sort of procedure too, so this country is also part of the issue.”
Dr. Solomon noted that she serves on an ethics committee for an insurer and has had a long conversation with the company about their responsibility for this sort of thing. It’s helpful to decide the types of operations that are happening. One of the major motivations for those who choose go elsewhere for care (not necessarily for organs) is to get something that’s not on the approved list of things that their insurer covers. Then, there are the uninsured who do this because it’s cheaper for them. She asked why someone who has a living donor would go outside the country. They are either buying an organ elsewhere, or the insurer is saving money and it’s collusion between the two. It’s helpful to tease out what’s acceptable and what’s not. If the transaction is not about purchasing, then the transplant tourist actually helps those patients who are here on the U.S. wait list. It’s just about where the organ came from. Mr. Frieson agreed that this does not make any sense. BCBS did not answer his questions about that later on.
Dr. Zhu said that the ACOT is charged with helping to promote an equitable and fair system for everyone. It’s our obligation to speak out about the very real risks of, and concerns about, exploitation. We have to create a statement on this. But, he has been hearing many allegations about Chinese prisoners being executed for their organs and commented that it is dangerous to repeat this sort of charge without any solid evidence. We do not know this is happening and should be more neutral and not politicize the issue.
Dr. Reyes commented that while SRTR is collecting data, it is not made clear in the recommendation (in terms of data). Mr. Frieson said that this is a beginning. We have some data; but if it’s required, then we will start seeing what the real numbers are.
Dr. Low asked if the statement was too long and should be condensed. Ms. Emily Levine, Office of General Counsel, cautioned that it needs to be clear that ACOT recommends to the Secretary. There are different ways to do it in terms of the structure. In the past, ACOT has had a one-sentence recommendation, then provided background for the concerns raised.
Ms. Agrawal asked if the group should edit it or not, and the group decided that she and Ms. Levine would prepare the recommendation with the appropriate language and format and present it in the morning.
Dr. Burdick expressed concern about the second recommendation for several reasons. HRSA has been thinking about this, in fact. How do we identify the recipients when they come back to the U.S? How we would we do it is a difficult question, although it’s very reasonable to try to do. Is there a way to get at the patient who isn’t in the system? Ms. Levine noted that the Secretary has oversight in this area. ACOT can make clear what it recommends to be collected and the Department would think about how to achieve that. OPTN only gets data from members; therefore, CMS might be a better avenue for capturing data outside the transplant programs.
Ms. Kelleher–Crabtree stated that the origin of the organs being received is a critical issue to include.
Ms. Principe asked if the person who is not transplanted in a Medicare-certified center is eligible for Medicare coverage for the immunosuppressant drugs. The answer is that they are covered by Medicare Part D.
Ms. Principe commented that she felt lost in what ACOT should do. She appreciates the fact that the group needs to work through this, but is not sure what it is trying to achieve.
Ms. Agrawal said that she felt that the group was trying to do get a handle on the scope of the problem. These recommendations are insufficient, in that case, because the group might actually need more data to even know what the scope is. Mr. Frieson agreed that, until there are more data, we do not really know. Are American doctors doing this? What is the effect? We are trying to pinpoint what’s happening, as a beginning.
Dr. Zhu suggested adding a third recommendation, that the ACOT encourages the U.S. government to work with international foreign governments and companies to look into potential risk of transplant tourism in terms of exploitation. Dr. Scantlebury commented that this is what Dr. Delmonico is doing.
Ms. Agrawal asked if the committee would accept that suggestion and the members agreed. She then asked the committee members to vote in principle that the ACOT recommends that the Secretary use the data sources available on transplants occurring outside of the U.S., and that the Secretary use the resources available to work with international organizations that can provide additional information especially about the exploitation of living donors in international countries where transplant tourism is occurring.
Dr. Low asked if the recommendations could be projected before the vote, and Ms. Agrawal agreed.
Dr. Low -- Informed Consent Workgroup
Dr. Lewis Low noted that one of the ACOT’s first actions was to make informed consent recommendations and read ACOT recommendations 1-3 (see the ACOT website for specific language). At the May 2007 meeting, Ms. Marcia Newton from CMS updated the group on recommendations 1-2. She described new requirements that transplant donors have a living donor advocate and for new informed consent requirements. At that meeting, ACOT members discussed other guidelines about informed consent and described concerns about variability in actual practice.
The ACOT workgroup was formed for that reason. The workgroup knew that the OPTN meeting in September would address informed consent issues and members decided not to do anything specific until that body had met. The OPTN Board approved two important informed consent documents for living donors, and these are in the ACOT member packets. The first is a resource document. This is a summary that is not binding but aids organizations in developing their consent forms. The second is a modification to the OPTN program criteria for UNOS bylaws (section 13, paragraph D), which is on page four of the handout on background papers.
Specifically, the ACOT workgroup would like members to consider whether this language is sufficient? Are we satisfied in light of Dr. Odim’s study and other informed consent protections for living donors? Is this strong enough? We talked about developing a standard informed consent form for the whole country – is this good enough. Also, what is UNOS/OPTN doing if someone doesn’t adhere (enforcement)?
Ms. Principe noted that conditions of participation will be released shortly which will support appropriate consent processes for live donors. She feels that UNOS has done a good job of delineating the process to follow. She supports the efforts of the OPTN and CMS regulations as appropriate. She would not support the ACOT doing anything additional.
Dr. Solomon asked if there is any language about informed consent that would require a private conversation in order to ensure there is an opportunity for privacy? The answer is that there is a lot of language about opting out, but there is nothing specifically about a private (one-on-one) conversation. Dr. Low said that he would think that the donor advocate would play that role, but this is not specified. Mr. Aronoff read the language about conversations being confidential, but Dr. Solomon felt that this was not the same thing. Mrs. Boone reported that North Carolina’s rules are very specific. There has to be a conversation without anyone else present, including the recipient. That’s what happened in her husband’s case. She felt the language around this needed to be more specific because we cannot assume everything happens as it should.
Ms. Agrawal summarized by saying that the ACOT members support and endorse the works that have been done. Perhaps ACOT could recommend that the Secretary should clarify that conversations with a potential living donor be conducted in private. Ms. Kelleher–Crabtree expressed the opinion that that component is part of the donation not being acquired under coercion. Dr. Low agreed that most will interpret it that way.
Mrs. Boone stated that she wanted to go on the record as saying that the discussion of potential risk cannot be achieved when there is no long-term follow-up on living donors.
Dr. Reyes asked if it is the transplant center’s responsibility to assess donors’ ability to access long-term benefits (e.g., disability) and who is responsible for the follow-up? Mr. Aronoff read the informed consent document (for livers). It indicates that several elements should be included, the fourth of which is about the impact of the potential donor’s ability to obtain health, life and disability insurance.
Ms. Agrawal asked if ACOT has not already recommended that coverage be provided. Mr. Aronoff agreed that this was covered in Recommendation #44, which addresses standards of coverage for living organ donors.
Mr. Holtzman commented that the lungs are not addressed here. Dr. Burdick clarified that the organ-specific committees addressed this, and it may be that the lung committee has not taken it up because there are so few live donors. With more organs becoming available, living donor lung donation is almost zero now, although it’s worth keeping this on the table. Dr. Low asked for follow up on that issue and Dr. Burdick agreed that HRSA could provide that.
Ms. Agrawal sought the group’s sense of whether there is a recommendation that requires ACOT’s action? Possibilities included (1) to endorse the work that’s been done; (2) to recommend more specificity about informed consent conditions and privacy; or (3) to suggest more specificity about the availability of insurance coverage for the living donor. Dr. Low stated that none of those would necessitate another informed consent recommendation on the ACOT’s part and suggested, since these issues are so important, that the committee work through OPTN to address them.
Ms. Agrawal closed by saying that the group needed to come back to this issue, as it wasn’t resolved. ACOT will return to this issue the following morning with the other workgroup recommendations.
Organ Allocation: Geographic Boundaries & Disparities – Dr. Orlowski
Dr. Janis Orlowski commented that her discussion was about the need to do something about geography. She intended to give some insights into what the OPTN Policy Oversight Committee is doing and also ask for the ACOT members’ help. Issues include policy oversight, and how the question of geography evolved. She acknowledged and thanked the staff of the SRTR, who helped with the slide set and these issues. Mr. Aronoff asked her to also talk about the regions, so she will talk about what SRTR is doing to review this and set the agenda.
The OPTN Policy Oversight Committee (POC) was created to support and improve the efficiency of the OPTN policy development and process for deliberation. It is to ensure that allocation policies meet certain performance improvement standards; support the on-going operation and improvement of data collection systems; and review proposed research projects to ensure the continued understanding of organ donation and transplantation issues that will ultimately improve the performance of the national transplantation system.
The POC also advises the OPTN Board of Directors about how effectively OPTN policies comport with HHS Organ Transplantation Program performance goals and the expectations for policies outlined in the OPTN Policy Development Checklist. Specifically, the POC reviews existing and proposed policies to determine if the OPTN policy goals are objective and measurable; that the goals further the mission, strategic plan, and long-term goals of the OPTN and HHS Organ Transplantation performance goals; and that the goals are scientifically based.
Membership is composed of the incoming chairs of the Liver and Intestinal Organ Transplantation Committee, the Pancreas Committee, the Kidney Committee, the Thoracic Organ Transplantation Committee, the Organ Procurement Organization Committee, the Minority Affairs Committee, the Pediatric Committee, and the Patient Affairs Committee. Dr. Orlowski described the other members of the POC in addition to these chairs.
The POC comments on all OPTN policies that come forward. POC is charged with going back and looking at all of the policies and evaluating them. When one reads these policies from the beginning to the end, what’s happened is that good intentions and good people have created a confusing situation. The policies have to be understandable to the public and those who the transplant community serves. We also have to assess if the specific policy gets us to where we want to go. Dr. Orlowski described the policy-making process and requirements contained in the Final Rule.
Distribution of organs over broad geographic areas is part of POC’s charge. The issue of geography arose because of the POC charge to review all existing policies, to develop methodologies for policy development, and to review new policies that are being developed. Geography is a component of the issue of equity allocation. At the February 2007 meeting, POC reviewed the current liver policies; and concerns were raised over regional differences in the MELD/PELD guidelines. In some regions, a patient may require several extensions, with increases in their score, before being transplanted while, in other regions, patients are transplanted earlier and with lower PELD/MELD scores. The POC looked at the policy and the metrics of the policy, in order to see why these regional differences existed.
The Board of Directors met in June 2007 and passed a resolution that the OPTN undertake a study to address geographic differences in organ allocation (not just for livers). The Board gave the work of the resolution back to the POC to complete and POC has started this process.
Dr. Orlowski was asked to speak about how the regions were developed to begin with, as background to her comments. She commented that, when she retires, she plans to do an oral history about this because she has talked about this issue with many people and everyone has a little bit of the history. She does not have the whole picture yet, and has yet to find the actual documentation of how this began. She noted that she has asked OPTN to search their records but she does not have anything yet.
Dr. Orlowski described the creation of the OPO regions, and the NOTA requirements for Medicare payment through HCFA. For administrative reasons, UNOS originally divided the country into eight geographic regions. As a result of size discrepancy and organ sharing concerns, several of these OPTN regions were re-formed to carve out regions 9, 10, and 11 in late 1989. Dr. Orlowski expressed the opinion that it’s not clear what the basis was for the first eight regions.
Before continuing, Dr. Orlowski expressed appreciation to SRTR for aiding the POC in assessing and analyzing geographic issues. SRTR has reported on geographic differences in access to transplantation many times over the year (a list of reports was provided) and SRTR has developed useful metrics for describing access to transplantation. Information is available at The Scientific Registry of Transplant Recipients website .
Geography can be considered in many “units,” each of which leads to an extensive discussion about the role of geography. Units could be created based on CMS or OPTN region, DSA, OPOs, State, county, zip code, transplant centers, hospitals, donor hospitals, distance or time traveled, population, disease rate, or by provider (e.g., dialysis units or physicians).
The POC also had to consider the measurement of differences. Possibilities include outcomes, access to the list, access to transplant after being listed (waiting time, transplant rate, fraction dying on the waiting list, fraction inactive); recipient characteristics (MELD, LAS, LYFT); donor characteristics (DPU, DRI); and/or transplant characteristics (e.g., CIT, HLA size). POC is wrestling with these issues.
In terms of access, there are differences that appear when one looks at insurance, race, and geography. If one looks at these characteristics that explain the variances, then geography becomes a bigger factor than race or insurance. We know there are differences in waiting list/death ratios with respect to age, race, and geography. Looking at the relative rate of wait listing among ESRD patients versus the deceased donor transplantation rate, it’s clear that some States have higher rates and some are much lower. Relative rates differ and one has to specify which the important questions are with respect to geography.
If one looks at the percent of living kidney donors, it varies significantly by program. Questions to consider include if access to transplant altered by this, and which may be altered by access to deceased donations. In terms of unrelated living donors, some programs have a very high rate; others have a very small rate for this.
Dr. Orlowski described other metrics that the POC has looked at, essentially to make the point that there are a lot of data, and that the issue of geography’s importance in allocation is affected by the question one asks and looks at in the data.
In conclusion, Dr. Orlowski summarized that differences exist in access to both the waiting list and to transplantation. Many, but not all, of these differences can be measured and characterized with existing SRTR metrics. Some differences will be highly dependent on existing geographic boundaries, while others will be dependent on practice patterns. The dilemma is how to begin studying the geographic question in current policies. The POC has to consider which piece to do first. In the context of a well-defined question, policy recommendations must be created that lead to equitable distribution across location. Dr. Orlowski closed by asking for ACOT members’ thoughts and input and direction as the POC tackles this question.
Ms. Agrawal thanked Dr. Orlowski and noted that this is a lot of information to process.
Mr. Holtzman reported that he gets a lot of these questions at his OPO. He assumes that the OPTN committee is looking at donation rates as well, and at the business aspects of it, such as how centers are listing patients and how aggressive they are in transplantation. Dr. Orlowski corrected him and said that they were not. She asked for clarification if he meant whether they are looking at the centers’ ability to have different insured populations. Mr. Holtzman clarified. One OPO he knows double-lists 100 percent in two locations. This makes them more efficient and they get their patients transplanted faster. It’s a business model and some centers are more aggressive than others. Dr. Orlowski said that they know there are more aggressive centers (this is clear from the discard rate and unrelated living donors’ data). These are differences in the character of a program.
Mr. Holtzman said that he serves nine kidney centers. Half of them are urban and half of them are rural. The latter argue that they are isolated and geographic reallocation will threaten them. Also, Medicare reimbursement for kidney transplantation encourages centers to perform low volumes of these operations, and shift the overhead costs to their transplantation program. Dr. Orlowski said there are important reimbursement questions that affect programs’ existence, and which may impact (and be impacted by) geography. She does not know if there is a single answer to the geography question. She believes that the impact is so large, however, that we cannot fail to talk about it. She stated a belief that there are important access issues related to some small programs and also that there are no access reasons for other small programs to exist.
Dr. Wiesner asked what the goal is of “equitable allocation.” Dr. Orlowski stated that this is exactly what the Committee is trying to ask. Are the differences seen in the regions that result from policy acceptable? Or, are there factors that can be modified to improve some of these metrics? We cannot say that every time Chicago gets an organ, New York City gets one too. But we have to ask if any of our boundaries influence outcomes, or whether this is just about distribution? The MELD/PELD data suggest there are regional differences that are unintended and which result from the policy. This raises the question of why the regional differences exist at all. It may be that they are within the standard deviation and are acceptable. Could they stem from variations in diseases or some other regional differences? She feels this is unlikely, but possible. For whatever reason, do our policies make access/outcome unfair, just because of some geographic boundary?
Ms. Principe said she was very happy that this is being addressed. She said she was saddened that the liver community, once again, drove the issue of equity allocation She sat on UNOS’ first Board for two terms and can report that the eight regions were created to handle UNOS administratively, not for allocation per se. It probably came out of what was available, in terms of the active OPOs at the time. A lot of this was the OPO process, and some of it was politics that occurred behind closed doors. In terms of the liver community, thousands and thousands of real patients have not benefited “equitably” over the years. We have States’ rights -- every State handles things differently and people have different advantages and disadvantages from living in different States. One would think that the data should not drive the policy, but it’s a Catch 22 and is self-fulfilling. Ms. Principe stated her support for what was said about rural vs. urban locations. We have to consider how people live, not just how organs are currently shared. Finally, the members of the committee should be multi-disciplinary and should include, for example, an ethicist.
Dr. Orlowski thanked Ms. Principe for her comments and emphasized that the question of “what do we know about geography” was considered. As a result, we determined that we cannot have data and just catalogue what we know. We have to step back and ask what we’re asking about and use the data to drive that. The Committee members informed themselves about models and metrics for the various organs. We have to not be driven by the data, but ask the question and make sure we understand the questions and then look at the data.
Dr. Reyes cautioned that, if the Committee is going down that path, it will take years to come up with usable data. It will come down to a foregone conclusion, namely, that there are geographic disparities that don’t make sense. So why do it? Second, he asked for Dr. Orlowski’s thoughts about pediatric livers? His organization wanted to minimize these mortality rates so they eliminated geography. It is the same with heart and lung; for better outcomes one needs to focus on the time from place of donor. There will always be disparities if there is geography in the allocation scheme. Dr. Orlowski agreed that the committee should not study this for 10 years, but should instead tackle a piece of this. Looking at access with respect to a geographic metric enables them to look at more novel ideas, e.g., miles from donor hospital, pediatric issues. This is not intended to be a study as a grand thesis, but rather one that impacts policy. Should minimizing death on the wait list be the issue? Geography then becomes a factor and there are ways to do allocation within the regions and also to do miles from a donor hospital. Management regions are being used for allocation, and she feels that there are clever ways to look at donor hospitals and find quick things to do once they have an end point.
Dr. Vega commented that it is not a surprise that allocation varies across the U.S. because everything varies across the States. The difference is that it’s the transplant field and so it is highly scrutinized. It is hard to look just at geography because when one changes one thing there may be other, negative consequences. There has to be a balance depending on the organ and cold ischemia time, and geography does matter. It just cannot be a stand-alone variable. Dr. Orlowski said she agreed with Dr. Vega. There are two things that she hopes the POC is doing to help. First, we look at unintended consequences early on; second, medicine is local. We have a limited resource, however. She recently interviewed a transplant surgeon coming to take a look at her institution. He was well trained, and she asked how many surgeries he had performed of various types. He responded that he had not done a living/related in 2 years. The wait list time is so short they do not have to. The supply and the demand impact the process. When there is a scarce resource, one should look at variances in medical practice that lead to potential differences that can be ameliorated.
Dr. Wiesner commented that he was sure that Dr. Orlowski had seen “Death by Geography”; there are a lot of people looking at this. There are blatant areas where across a river or a bay there are MELDs of 10-11 in one place and, in the other, they are doing them at 30. We know the outcomes of the scores, and they are good tools for looking at the data. It should be reasonably easy to do this in a short amount of time. Dr. Orlowski agreed and said this is intended to have an impact. They are also interested in discards for non-ECD kidneys.
Dr. Leffell issued a caveat to underscore that the data are not driving the conclusions. If one looks at renal, for example, there are differences in listing criteria and allocation by waiting time. These variables have to be taken into account. Dr. Orlowski agreed.
Ms. Agrawal stated that the ACOT members look forward to talking and working with the POC Committee. Dr. Orlowski said that if ACOT members want to send her and the Committee any information, they would be delighted to receive it.
Xenotransplantation -- Dr. Sachs
Dr. David Sachs announced he would like to persuade ACOT members that xenotransplantation deserves more attention and more funding. Nothing leads him to think that this cannot work with the benefits of modern technology, and it will have a huge benefit. Dr. Sachs provided background and described the hurdles involved with xenotransplantation.
While allotransplantation is transplantation of tissue or organ between members of the same species, xenotransplantation is transplantation of tissue or organ from one species to another. The potential for xenotransplantation is enormous. It can overcome the current severe shortage of organs for allogeneic transplantation and overcome the problem that less than one-third of the waiting list is transplanted per year, and that there is an increasing use of living donors. We are currently doing everything we can to increase donations and to use all organs.
What are the other options? Mechanical solutions have the limitation of portability and energy supply. Stem cells have biological and technological limitations. Tissue engineering has technology limitations.
Xenotransplantation has the potential to treat diseases causes by human-specific viruses (CMV, HIV) and to deliver genes in tissues from genetically engineered animals (insulin, deficient enzymes, cytokinesis, growth factors). Xenotransplantation has the potential to avoid the risk of occult tumors and infections (because one can screen and get an animal cleaner than a dead human), to simplify coordination, to lower costs, and to make re-transplantation an available option.
Given that, what animal is most appropriate for xenotransplantation? Non-human primates have several disadvantages around size and availability. Chimps and Great Apes are endangered and baboons are too small. Plus, viruses can be readily transmitted between closely related species. Ethics presents a huge problem.
For this reason, most xenotransplantation programs have worked with the pig as the most appropriate donor species. The availability is limitless, and there are many fewer ethical questions. The major disadvantage has been the natural antibodies that are present and which have held the field back. Over 10 years of research indicate that most antibodies are directed against one antigen. More than 85 percent are anti-GAL antibodies. It’s natural, however, so it’s hard to turn off.
Dr. Sachs has been breeding pigs for 30 years. They are continuously inbred and are histocompatible without immunosuppressant drugs. They will accept any transplantation without rejection. They started as miniature wild-caught swine and are about 200-300 pounds (compared to domestic pigs, which can weigh 1,000 pounds), which makes them the right size for humans. They have the potential for transgenics and knockouts. Inbred animals can incorporate a variety of genes for various reasons: kidney, lung, or liver donor.
There are two approaches to xenotransplantation: chronic immunosuppression (involves drugs and monoclonal antibodies) and the induction of immunologic tolerance (involves mixed chimerism, thymic transplantation). Dr. Sachs uses the second approach. Results with normal and transgenic pigs in the 1990’s indicated that chronic immunosuppression did not prevent the return of natural antibodies to GAL. Also, the tolerance approach diminished T-cell immunity but did not prevent the return of natural antibodies to GAL, either. It was clear that they needed a GalT-KO pig. The first GalT-KO miniature swine was born in 2002.
What happens when the cells are put into a baboon? Tolerance by thymus transplantation puts the thymokidney into the donor beforehand. This was a major breakthrough because it does not take unless it’s vascularized. With the pig-to-baboon thymokidney and the serum creatinine, the baboon lived on the pig’s kidney and it died with a normal kidney. When you use GAL knockout, we are seeing much longer survivals of up to four months, but then the animals die of infection or CMV. These things can be addressed, however. We also have a reversal of diabetes in monkeys by xenogeneic islets. This is long-term primate reversal of diabetes by islets.
The hurdles that remain now are four-fold: scientific, public perception, infections, and funding. The progress that has occurred in pig-to-primate transplants is continuous and is currently at an exciting stage. Scientific problems can be solved, potentially, through genetic engineering. Problems around public perception include false expectations that have been raised and which lead to public disappointment.
Risks from infections and ethical issues also come into play with public perceptions. The solution to these hurdles is honesty, openness, vigilance, and guidelines. Screening, breeding and antibiotics can help with bacterial and viral infections. We can control infection by making the pigs cleaner. That would not aid in the case of a retrovirus, but vigilance would help. Also, the FDA now has guidelines on retrovirus, which can help protect against unknown problems (as with PERV). With PERV, there were a lot of studies after the scare and everything seems all right now. PERV was only transmissible to one cell line, which is a problem, but not an overriding one.
The final hurdle is funding. There is a need for more funding to take this to the next level. Support from private companies is needed. For example, Novartis got out of this because of PERV and the liability issues. However, there have been major advances. Dr. Sachs is hopeful that new groups will enter the field. The success of clinical trials may encourage them to do so. The government could help here by indemnifying these companies for the good of the public.
Dr. Sachs concluded by stating that xenotransplantation offers the most promising near-term solution to the current critical organ shortage. Enormous progress has been made in this field, although additional hurdles remain. All in all, there are unprecedented opportunities for success.
Mrs. Boone asked if they had now, or expected to get in the future, opposition from animal rights groups. Dr. Sachs said absolutely, yes. He commented that thousands of pigs are slaughtered for bacon, and people do not seem to mind that. Objections are expected although there have not been any problems yet.
Dr. Low asked how ACOT can support these efforts. Is this a question of political sensitivity and someone being willing to make a statement in a public forum? If this could work, it would make a big difference. Dr. Sachs said that both awareness and funding promotion would be helpful, although he was not sure specifically what ACOT could do.
Dr. Wiesner asked if there were problems with vascular rejection at 12-15 days. Dr. Sachs said that one of the biggest problems with transplantation is the need for immunosuppressant drugs and induction of tolerance. One has to avoid the production of antibodies rather than address them after they have been produced. Infectious issues are manageable, but we have to figure out how to do it.
Gail Agrawal thanked Dr. Sachs for his presentation.
Reports from Workgroups: Discussion and Recommendations (continued)
Dr. Leffell -- Live Donation Long-term Follow-up Workgroup
Dr. Susie Leffell said that her workgroup had two recommendations on long-term follow up of live donors, based on two issues the group had identified. These are, first, that sufficient long-term data on the outcomes of live donation must be collected to assess the risks incurred by donation and to provide prospective donors appropriate information to be able to make informed decisions about donation. Second, mechanisms must be developed to ensure that live donors have access to and funding for appropriate long-term medical treatment of any complications resulting from their donation.
To address the first issue, which is readily achievable and could be implemented at relatively low cost, the workgroup proposes the following resolution:
Proposed Recommendations: Long Term Follow-up for Living Donors Workgroup
- A registry for long-term follow-up should (shall?) be established by the OPTN to provide annual reporting of general health status criteria of registered live donors for a minimum of ten years post-donation. The registry should (shall?) also provide a central location for donors to obtain information and assistance in obtaining referrals for medical treatment in the event of post-donation complications.
- Annual reporting of the heath status of donors and the cost of maintaining this donor registry shall be the responsibility of all transplant centers performing live donor transplants. The funding for the registry will be generated through annual donor registration fees. Alternative reimbursement strategies may be investigated to offset the costs to transplant centers for maintenance of the registries and might include, for example, having the annual registration fee payable by the recipient’s insurer.
The committee noted that an alternative approach could be to amortize the cost of maintaining the donor registry among all transplant candidates, since all candidates benefit when some come forward with potential living donors by decreasing the number competing for deceased donation. In this case, the annual registry cost could be divided among all transplant candidates by a relatively small increase in the annual candidate registration fee with the OPTN.
Dr. Leffell commented that addressing the second issue requires further study and additional data on the incidence of post-donation complications.
The recommendations need to be edited, but the consensus was that a registry should be established, and run through OPTN.
Ms. Agrawal thanked the Live Donation Long-term Follow-up Workgroup members for their work.
Dr. Solomon said that data will help improve access to good treatment, but these issues should be considered separately. It’s just right that there be coverage for costs if there are complications so putting this on the back burner doesn’t seem right. Dr. Leffell agreed and said that the workgroup would not object to separating the two. Members felt that, without data on incidence, they could not make a reasonable recommendation on the referral center, which is why the language was structured this way.
Dr. Scantlebury asked if Donate Life America could be used to help with this process and goal. Dr. Wiesner suggested that it should be the transplant center’s job to maintain the donor registry, but one of the push-backs has been that there is no reimbursement for this collection. With 200 donors, the follow-up would take a lot of time. It needs to be funded by CMS or by some other mechanism. It cannot just be a burden that is added to the transplant center. Registration fees are a major funding source for OPTN and might work here.
Ms. Principe agreed with Dr. Wiesner. If this occurs through the OPTN, we have to supply information going ahead so that it is all part of the process that’s already in place and will have to be done. We are doing a registry, so it’s not a change in what organizations are obliged to do going ahead for either the OPTN or the regulatory bodies. We’re not married to any way of doing it in particular. The concept is what the workgroup wanted to bring forward. A registry is familiar to the transplant world, but the issues of cost and staffing are real. Dr. Wiesner suggested that the registry could be added to SRTR and be web-based.
Dr. Vega asked what “health status of the donor” means. Does it mean are they alive or is about their creatinine levels? This has to be more specific. Dr. Leffell agreed. This proposal is just to establish a registry, but it would have to include the sorts of things outlined earlier in the day. Dr. Vega responded that more requirements, however, means less follow-up. Most donors are all right, and they are not very likely to be compliant with a lot of follow-up. He agrees with the thought, but it’s going to be hard to accomplish. Dr. Leffell raised the issue of a live donor who ends up as a transplant candidate. There are no data on this, and there should be. Data collection is a problem, but it is one that we have to address in the interests of promoting live donation.
Dr. Burdick commented that the hope is that the NIH studies will help answer some of this. That’s one of HRSA’s goals and an explicit reason for HRSA being involved. He also urged the group to remember that there are things we can and cannot do with reimbursement. The ACOT can make suggestions, but there are restrictions on what we can pay for and how we do so. There are thoughts about how to go forward, however; and he is hopeful that in 6-12 months there will be an improved way to have better, long-term living donor information.
Ms. Agrawal suggested that what the group is trying to say is that the ACOT recommends that the Secretary cause the formation of a registry or other mechanism to acquire and maintain appropriate clinical information about living donors. The other ideas can be handled as background or suggestions, such as by saying: “included but not limited to.”
Dr. Wiesner cautioned that the NIH is using four of the best centers in the country and their data may not be representative. Dr. Burdick said there are areas of concern for living donors. First, the long-term outcome of having part of the liver or one of the kidneys removed. We know that practice patterns at the centers make a difference, and we do not have to study all donors to know this. Second is to gather information on every donor and every center, and we need to get this information through the OPTN. Mr. Aronoff stated that the Gift for Life Act of 2007 includes a provision for a living donor database to be housed at HHS but has not been acted on yet by Congress. Dr. Scantlebury added that we also have to realize that donors are not perfect people any more. We now accept donations from those who are obese or hypertensive.
Ms. Agrawal asked what the group wanted to do about the recommendations. The group wanted to vote to agree in principle; and then finalize the language for review, discussion, and vote on the second day of the meeting.
Dr. Low asked if it was necessary to specify how a registry would be funded. Mr. Aronoff responded that the ACOT can request government funding. Dr. Leffell said that this had been discussed in May when the issue was raised that funding was a roadblock to doing a registry. That’s why the workgroup included the recommendations about funding and location. It’s also fine by the members to make a statement and provide examples of how it can be funded.
Ms. Agrawal led the group through each recommendation in turn. She asked, for a registry for long-term follow-up, whether the OPTN part of the recommendation was necessary, or should the ACOT recommendation just say “registry”? Dr. Leffell responded that the issue of the registry is key, and that it be centralized is also key. The gist of the first bullet is to recommend a mechanism to capture data on long-term follow-up on living donors, for a period of at least 10 years post-donation. The ACOT members voted on whether they accepted this recommendation in principle. The vote was unanimous.
The second recommendation is about a central location. Ms. Agrawal commented that if it’s at OPTN, assistance can be provided to donors that way. It could also be independent of a registry also. They do not have to be linked. The issue is that donors need a mechanism to get assistance if needed, i.e., less data collection and more of a donor advocacy office. The ACOT members voted on whether they accepted this recommendation in principle. The vote was unanimous.
Ms. Principe asked, if there is a place where a donor can call for help from the registry/data location, how the center would know there are issues with the donor? She suggested there should be a connection back to transplant center so it knows what is happening. Dr. Scantlebury suggested that this could be included in the details of how it’s set up, as through a forum or a telephone call.
Ms. Agrawal turned to the next recommendation, for an annual reporting of the health status of donors and cost of maintaining registry. The group agreed that how this would be paid for should be included as background. Dr. Leffell said the key is that right now, follow-up is for 2 years and it should be longer. Dr. Scantlebury added that the goal is to emphasize that it is the centers’ responsibility to provide information on the donors for some time, in order for follow-up to occur. Ms. Kelleher–Crabtree said the ACOT members also need to accept that the donor has a right not to be bugged about it 10 years later.
Mr. Aronoff asked, in terms of the registration fee, why an entity would want to pay a fee and do the work, too. Ms. Levine pointed out that if this process goes through OPTN, the cost of OPTN is specified and, thus, there is not a lot of discretion in funding levels, if it’s housed in OPTN. Ms. Agrawal asked if the annual reporting component needed to be retained. Dr. Solomon said that there were three key things in the language: that the donor be followed for 10 years, that the registry be centralized, and that there be an annual reporting to the central mechanism. It makes more sense that the center where the donation was made should make the report on an annual basis. Ms. Agrawal clarified that the center either does the reporting, or it gets some other entity to do it. One could delegate the reporting, but it is the center’s charge to get it done. Ms. Principe said that if there is a new and larger body of patients to follow, the registration fees will have to increase because there will be more work to be done. The ACOT members voted on whether they accepted this recommendation in principle. The vote was unanimous.
Mrs. Boone commented that a central location to provide assistance to donors, through a living donor advocate program, has been in existence for some time. The women who operate the program fund it out of their own pockets. If they can do it on their own, the Federal government can find a way to finance it.
Film: History of Organ Transplantation – Ms. Ganikos
Ms. Ganikos thanked the group for allowing her to show the film. This is the 50th anniversary of first successful transplant, and the Division of Transplantation wanted to create a historical treatise on this in both the U.S. and internationally. PBS has 2-year rights to air the documentary, and stations will choose when they want to air it. She suggested that OPOs talk to stations and conduct outreach around it. The producers of this film also produced an earlier film on transplantation that won an Emmy. Four of the early pioneers in the film have died since it was created, so this is in many respects an oral history of the transplantation field.
Copies of the movie will be available in early 2008 and will be distributed widely. Staff is currently adding more information to the DVD and the packaging. Ms. Ganikos thanked Dr. Scantlebury for being part of the movie.
Public Comment and Adjournment
Ms. Agrawal reported that any members of the public who would like to testify are invited to do so.
Kimberly Tracy –Living Organ Donor Advocate Program
Ms. Tracy said that she wanted to thank the ACOT members for their work. Five years ago, she came before the ACOT as both a living donor and registered nurse. The progress that has been made since then is phenomenal. She is also on the OPTN Living Donor Committee; and it is great to see what extent people have realized there is a lot to learn from living donors.
Ms. Tracy continued that, in terms of informed consent, there is nothing that addresses informed consent when living donors donate to a recipient who is involved in a study. It could be an NIH study or something else. She hoped that ACOT can address this situation. She knows of one recipient who was in a study, but her mother and her donor did not know that. Transplant centers do a lot of transplants and are on top of this. However, there are places where there are fewer transplants conducted, and these things can fall through the cracks. When something goes wrong, people may not know where to network.
Ms. Tracy continued. In terms of a registry with a central location, it’s not just for living donors. It’s also for when they go home and for their general practitioner. She was contacted by someone who was looking for information to help a donor; it was a small institution and they didn’t know what to do. They sent a doctor’s lecture about how this particular type of problem was treated. They keep the papers so they can give them out. If a person has a problem and their general practitioner does not know what do it, a registry is a place for both donors and providers to get information. She personally went to a surgeon who did not know what to do about a particular complication. Two years later, he called her to see if she had found anything out about it. She still did not know the answer. He told her that he had a new situation which was similar; and he hoped she had the answer.
Finally, the ACOT has influenced conditions of participation and such, but there is a group that isn’t being influenced: the Veterans Administration (VA) system. She urged ACOT members to talk to their colleagues so that these proposals are required to be followed by the VA, as well. There are not that many living donors, but we need to be informed about their outcomes. This is very important if the ACOT recommends the OPTN proposal for a registry. She thanked the members for everything they have done.
Donna. Luebke – Living Organ Donor Advocate Program
Ms. Luebke said that Ms. Tracy is doing the living donor program. They are not catching everyone, but have had a lot of calls from donors who need help and information. It might only be 10-20 percent who experience complications, but it is an important issue to address. Please do not abandon the donors. Please “discard” them to someone who can take care of them. Her organization knows of a potential donor who had not been told about the risks from anesthesia and she walked out; then was criticized for doing so. We hear profound stories from donors. As a nurse, Ms. Luebke would like to thank Kimberly Tracy; and as a donor, she thanked the ACOT members. Ms. Luebke reported that it’s the 10-year anniversary of her sister’s transplant, and she’s doing great.
Ms. Agrawal thanked Ms. Tracy and Ms. Luebke for their comments.
The meeting adjourned at 6:15 pm.
Reports from Workgroups: Discussion and Recommendations (continued)
Ms. Agrawal led the group through a discussion of the revised recommendations from November 15, 2007.
Revised Transplant Tourism Recommendations
The ACOT recommends that the Secretary use the resources available to or within HHS to cause the collection of data concerning transplants on patients who are United States citizens or residents who received their organ transplants outside of the United States.
Background to Recommendation 1: The processes could include, without limitation, data collection by the OPTN and/or CMS on matters such as where the transplant occurred, type of transplant, information about the donor, and basic post-transplant health condition information.
The ACOT recommends that the Secretary facilitate cooperation with international organizations and/or foreign governments to identify and address risks of exploitation to, and risks to the health of, unrelated living donors to United States recipients.
The ACOT members voted on each in turn. The vote was unanimous for both recommendations.
Revised Data Registry Recommendations
The ACOT recommends that the Secretary take actions to ensure that data on the general health status of living donors is collected on a nationwide basis by a centralized entity. The ACOT recommends that such data be collected, at a minimum, on an annual basis for a period of 10 years post-donation. The ACOT further recommends that the transplant program that performed a donor's transplant be principally responsible for the data submissions (insofar as the transplant program should be required to collect and submit such data or ensure that another institution providing ongoing medical care to, or follow-up on, the donor collect and submit such data).
Ms. Kelleher-Crabtree said that the parentheses are confusing because the text states that they should be “principally” responsible, but then adds “to the extent required.”
Dr. Richard Migliori commented that this might well be the third time the ACOT has made this recommendation. Gail Agrawal clarified that it’s a variation on a theme. She referred members to ACOT’s recommendations numbered in the 30s and early 40s. Ms. Principe noted that there are now the new Conditions of Participation and additional UNOS requirements that are in sync with this. Ms. Agrawal quipped that advisory committees are like lawyers, they can give advice but they cannot make anyone take it.
The ACOT members voted on this recommendation. The vote was unanimous.
The ACOT recommends that the Secretary take actions to ensure that a centralized resource is available to living donors post-donation for information, medical assistance, and referrals for medical help in the event of post-donation complications.
Dr. Solomon said that the term “medical assistance” is vague and seems like we are providing care. Has the ACOT previously recommended covering costs of complications? Dr. Migliori said that it had. Dr. Wiesner asked what the group was talking about, specifically. Ms. Agrawal clarified that what was under discussion was specifying the form that the centralized resource should take. Dr. Wiesner suggested using an 800-number with a doctor or a nurse practitioner answering it, or a website. People want someone to talk to when they have a complication. Dr. Migliori said that a live agent is a good idea. However, if we get too specific, it becomes about operations and not about recommendations. In terms of “medical assistance,” we could use the term “patient advocacy” instead so it’s an active process regardless of how it is done specifically. Ms. Principe suggested that the group stay away from the details, although her recommendation was that the mechanism be more than a website. It needs to be multi-lingual, for example. It’s also important to have the advocacy entity connect to the transplant centers as well. The Secretary needs to know the ACOT wants this to be connected back to the transplant center or caregiver so they can learn their donors are seeking assistance and need help.
Ms. Agrawal asked if the group wanted to add language that the resource entity has to inform the transplant center where the transplant occurred so that it knows about the contact. Ms. Principe said that the dots have to be connected or the data that will be submitted will not be in sync with what’s happening with the donor. Ms. Agrawal pointed out that the person could call the hotline for something other than a health concern, such as that their insurance has been cancelled or for general information. Not every call will be a medical problem. Ms. Principe agreed but reiterated that, if the call concerns a medical problem that relates to required data submission, there has to be a connection made with the center. Ms. Principe said that the care of the live donor should be equal to the care of the recipient, in terms of our responsibility to the person.
Dr. Solomon suggested that it’s not necessary to include details so long as the recommendation preserves the concept. The background provided can include the point about making linkages to the extent permissible given HIPAA. Mr. Frieson suggested removing “centralized” and making it a resource. Ms. Agrawal summarized that there are regulations now that talk about the requirement to have a living donor advocate within a transplant program so we could take out centralized, and it’s already captured. Dr. Migliori stressed that the issue is not just one of centralization. The entity should also report events to a national database so that the centers can track the data. This is an issue for the disclosure of the recipient, and he believed that the recipient can block this from happening. Dr. Reyes said the data go to UNOS, and there are no disclosure issues there. Ms. Kelleher–Crabtree said the goal is to capture the need for a source of assistance for those who are disenfranchised, to provide another resource that they would feel alright about going to. Ms. Agrawal stated that “centralized” should stay because it’s something that is different from current regulations.
Mrs. Boone suggested the addition of “additional,” which might protect the on-site donor advocate and clarify that this is something different. Dr. Wiesner objected that, realistically, 3 years later on, that person is going to be gone. Dr. Zhu asked what the scope is of the recommendation if someone is not a physician. That person cannot refer the caller anywhere but back to their transplant center. Ms. Principe suggested leaving the specifics to the experts who can work out the process. ACOT should just recommend whatever is needed to take care of the patient. Ms. Agrawal suggested keeping the parts about information, advocacy, and referrals and removing the part about medical help. In fact, the caller might get a referral to Social Security, a social worker, or somewhere else. There are a lot of places they might need to be sent. Dr. Zhu agreed with the suggestion to take out “medical help” and keeping the concepts of advocacy and creating an information center.
Ms. Kelleher–Crabtree suggested adding something about potential living donors so these individuals have a resource in case they have are questions beforehand. Dr. Wiesner pointed out that UNOS already does this.
Dr. Low asked, if someone does not want to go back to his or her transplant center, whether enough of a database exists to refer the person somewhere else that is appropriate. His community has problem doing that just locally, so how will this be possible on a national level? Referring patients is going to be really hard, and what happens if the place the person is referred to does not want to take that patient on? Ms. Principe reiterated that there is a new system going forward in response to CMS, COPs and UNOS changes. ACOT cannot be seen as not supporting the process with which the centers are going forward. Dr. Migliori said that databases are possible and exist already. Referral and triage systems have been honed over the years and he is not worried about this. It’s a wonderful idea for the donor and candidate alike.
Ms. Agrawal summarized by saying that the sense is to table recommendation two as it is stated, and to reassign it and continue to thing about what is needed, in terms of what already exists, and how we can move ahead. What we have been discussing was not the main focus of the workgroup. The group agreed to send it back, with the benefit of this conversation, for refinement and discussion at the next meeting. A new workgroup will be formed on this (as neither the workgroup leader nor the person who presented yesterday was present). Mr. Aronoff said that the staff will ask for volunteers among ACOT members.
Tissue Regulation Workgroup Recommendations
The ACOT recommends that the Secretary seek the statutory authorities to: (1) require HHS Accreditation of all entities that recover, process, or distribute tissue for human transplantation in the U.S.; and (2) to accept accreditation by a national accreditation body (including, but not limited to, the American Association of Tissue Banks) as an alternative to HHS accreditation as satisfying HHS standards.
Background to Recommendation 1 -- This requirement is intended to supplement and not supplant existing requirements imposed by HHS on entities that recover, process, or distribute tissue. The Joint Commission on Accreditation of Healthcare Organizations’ model is limited to entities reimbursed by HHS.
Ms. Agrawal said that she had a conversation with Ms. Levine and Mr. Aronoff about this. At the core of this is the recommendation that the Secretary require all the agencies that are now registered with FDA also to be accredited by the AATB or another appropriate group. Legal issues exist around this, however, because the Secretary would need new statutory authority in order to do so. There are some legal doctrines that prevent this, also.
Mr. Holtzman said he had talked to representatives from the AATB and AOPO, and there is not consensus on how to accredit an organization. There is consensus that organizations’ need to be accredited in order to be in the business of recovering, processing, and/or distributing tissues. His suggestion is that ACOT leaves this to the Secretary and merely recommend that HHS require accreditation of “any and all entities that recover, process or distribute tissues for transplantation.” In other words, let the staff decide how to do it. Ms. Agrawal clarified that Mr. Holtzman was suggesting deletion of everything after the semi-colon (and  to accept accreditation by a national accreditation body (including, but not limited to, the American Association of Tissue Banks) as an alternative to HHS accreditation as satisfying HHS standards).
Mr. Holtzman agreed that this was what he meant and asked if that alone would require statutory authority, or if the language should just be to require HHS accreditation? Ms. Levine answered that it probably would require new authority, but that this can certainly be vetted. Mr. Holtzman asked if it was appropriate for the ACOT to ask the FDA to beef up the process. Ms. Levine responded that she had thought the ACOT wanted everyone to get AATB accreditation. As an alternative, however, the Secretary could have the accreditation process go through the FDA. There could still be issues with this, but she promised to look into it. This would be a Government accreditation requirement and what goes along with that. Ms. Principe said that it should be complicated. We are looking to see that sort of change, even if it requires statutory authority.
A comment was made from the floor by Mr. Kelly from the Eye Bank Association of America that Federal regulations on tissues encompass many things, including eyes. The way that the recommendation is worded, however, eye banks would have to be accredited by the AATB and that doesn’t make sense. Ms. Agrawal disagreed with this reading, but thanked Mr. Kelly for his comment.
Mr. Holtzman added that there is a difference in the AOPA and AATB accreditation standards. One is more about clinical matters, and the other is about governance and compliance issues. They need to be blended in order to be effective. Ms. Agrawal asked him if he was withdrawing the recommendation. Mr. Holtzman responded that, as it is written now, it would create problems; but he did not have an alternative.
Dr. Low commented that everyone agrees that accreditation is the goal and asked why it was necessary for the ACOT to work out the details. We should just say it’s important. It’s too big for us to handle it, but we should make a statement. Dr. Reyes reminded the group that the issue was the lack of oversight. This recommendation, however, is overly encompassing. He echoed Dr. Low’s idea that the group could just describe its intent. Dr. St. Martin added that a small number of States have regulations. ACOT could recommend that the Secretary work with States to implement accreditation requirements.
Ms. Agrawal suggested that the language be that the ACOT recommends that the Secretary require accreditation and how that’s done would be up to the Secretary (it could be through HHS, the FDA, or by working with States).
Mr. Rigney from the AATB commented from the floor that what he had heard in yesterday’s discussion, and what AATB has proposed before, is that in addition to FDA regulations there be the requirement for accreditation by the appropriate entity. He offered language yesterday that the ACOT could recommend that the Secretary take action to require that every entity registered with the FDA as a tissue establishment be accredited by AATB and/or EBAA (if it is working with ocular tissue).
Ms. Agrawal said that it is fine to say that all agencies registered should be accredited, but she felt that stepping in with specific suggested agencies is beyond the ACOT’s purview.
The ACOT recommends that the Secretary take action to require accreditation of those entities that are registered under with the FDA.
Ms. Agrawal said that she and Ms. Levine would work on this recommendation and circulate it to the group by email, because they need time to hone this recommendation. It will be brought before the next meeting for a vote (it could also be done by conference call but that has to be open to the public and it’s complicated to do that process).
Revised Informed Consent Recommendations
Dr. Low said that everyone agrees that the informed consent work that the OPTN has done is great and is consistent with ACOT’s recommendations. The only concern is that it is not detailed enough. The discussion of potential risks (including medical and psychological) needs to be more detailed. The OPTN resource document is more specific, but it’s not clear if the ACOT members think that’s enough or if it needs to be expanded.
Mrs. Boone said that she was pushing to make it more specific. This would protect the potential donor and should be worded as “potential but not limited to.” This also protects the doctor. You can’t ever tell what people hear; but if it’s on paper and they have copies, it’s better protection for everyone. Ms. Principe noted that the group has not received the final CMS conditions of participation requirements yet. ACOT should not delay taking action, but her expectation is that these requirements will specifically address this problem.
Dr. Low asked if, as it stands, members are satisfied or if ACOT should go back and hash this out some more in a workgroup. Dr. Scantlebury said that she felt that members could wait to see what CMS does and then address it at the next meeting after there has been time to review it with respect to our concerns about statements about protecting the donor. Ms. Principe reminded the group that individual practitioners can speak with CMS, although the ACOT may not be able to do so as a body.
Dr. Low recommended that ACOT members monitor the CMS actions. Ms. Agrawal said the next meeting would include participation by an OPTN representative who can tell us where they are, as well as a CMS representative, who can describe their thinking.
Dr. Wiesner -- Reimbursement for Data Collection in Organ Transplantation
Dr. Wiesner reported that he wanted to raise this issue, although there will not be any recommendations made today. There are questions about who uses the data and who pays for the data. There has been pushback from AST, and one-third of data collection has been eliminated, cancer registry and long-term follow up.
The OPTN was created in 1987. SRTR collects information about transplant candidates and recipients of all transplant organs. This data collection has influenced hundreds of publications in peer-reviewed journals and has influenced policy decisions on allocation.
SRTR’s yearly reports are used extensively by CMS, insurance companies, administrators, institutions, pharmaceutical industry, and the public. Dr. Wiesner described the various types of findings from analysis of the data and how the data have been used to affect allocation.
There is an increasing demand for data collection at all transplant centers. There is a major concern about increasing costs and decreasing reimbursement for data. The cost of data collection is, at present, shouldered exclusively by transplant centers. This is becoming burdensome at large transplant centers. In the future, there will be more of a need for more data with increasing complexity. Policy decisions must be evidence-based, where possible, and this also depends on data. The accuracy of data is a continued concern and hence there is an increased need for oversight.
Dr. Wiesner proposed that, since the data are important and utilized by a variety of entities, the cost should be borne by these entities. His initial suggestion was to add a charge for each data form filled out on the patient, a charge that would be applied to third-party payers. Since the institution also needs these data (as do CMS, pharmaceutical industry, and the public), it is his view that all of these entities should contribute to the cost associated with this data collection.
Because of the burden and costs of data collection, a year ago, both the ASTS and AST formed a committee that has drastically reduced the amount of data that are collected. This included data on long-term follow-up that are desperately needed, as well as data for a tumor registry. The cause of death related to specific immunosuppressive therapy is an important parameter that should also be followed closely. At the present time, the University of Cincinnati has a voluntary data collection on cancer data, but this in no way encompasses the major population of patients transplanted in the United States.
Ms. Principe said it was a very powerful presentation and thanked Dr. Wiesner for making it. Dr. Wiesner touched on reimbursement of costs, but there are also data issues around accuracy, use, and what’s left out of data requirements. This has been discussed for a decade but efforts to address it get tabled or fail to go anywhere. Data are here to stay. There has to be an improvement in the data process and there’s no oversight. Can UNOS make charging for data use occur? The government cannot make that happen, but a private enterprise might be able to. There should be a recommendation on all data issues, including reimbursement. Dr. Reyes said that he liked that suggestion and suggested the ACOT focus on this aspect of it. He noted that private payers will follow CMS’ lead. He is glad that the committee is talking about this and believes that it requires further study.
Dr. Migliori added that this is worthy of real academic study. Questions include how much we spend on data collection per case; what proportion of total revenue is it (e.g., it is a major component or not); is compliance with reporting threatened because of it? As an insurer, his organization is paying for the service. Are the data cost considered to be a part of that or is it captured as a separate step?
Dr. Solomon agreed that this is worth further study and suggested making a recommendation that ties quality with cost. Second, she has heard a lot about DCD and its potential negatives and wonders if this is an area that should also be looked at. The IOM encouraged DCD, but there may be a role for calling for more study. Dr. Wiesner agreed that this is an example of data that should be collected and concurred that, if DCD was being pushed, it would be important to know why these organs failed, what the risk factors are, and how it can be improved. Only a few centers do DCD, and there is a need to look both globally and at best practices. Why do some places do better at this?
Ms. Ginny McBride who works with the Breakthrough Collaboratives made a comment from the floor to clarify the OPTN data collection in DCD cases. She said that data collection for donors is identical for all donors regardless of whether they are cardiac or brain death donors. It’s not that there are no DCD data. It may be that there are other variables that are not being collected that impact donation after cardiac death. But, for every donor, all of the information collected is identical regardless of whether they are cardiac or brain death. Dr. Solomon clarified that she was merely asking if it should be looked at, in terms of analysis. There are opportunity costs for a DCD who might have become brain dead at a later point and more organs might have been available in the latter case. She is happy for this to be tabled, however.
Dr. Zhu noted that there are long-term needs for data that can be available in 10-20 years. We also need topical data (condition-specific) but maybe not for that long a time period. When the ACOT advocates for any data collection needs, we should consider that long-term need, for 50 years versus 5 years.
Ms. Agrawal suggested that the workgroup members might want to talk about this between meetings. Mr. Aronoff said that the workgroup could be continued.
Pediatric Transplantation – Dr. Reyes
Dr. Reyes noted that the donor shortage is familiar to us all. Over the last 15 years the number of people on the waiting list has risen exponentially because (due to technological advances in transplantation methods and immunosuppressive therapies) transplantation continues to become a method of treatment for a greater population of patients. Of the over 98,000 people on the waiting list, 2,004 are children.
Almost 30,000 organs have been transplanted into children. Segmental cadaver organ transplantation involves using the left lateral segment for pediatric cases, and the whole right lobe for adult cases. Reduced size organ transplant allows reduction from a large donor to a small recipient (i.e., adult donor to pediatric recipient). It can work for both liver and lung transplantation. Split organ transplants involve the anatomic split of an organ for the purpose of transplantation into more than one recipient. It can be done with lung and liver.
This process impacts outcome and survival and can have a significant impact on both the waiting list and survival. Graphs can be separated out to various components.
The question is, who gets what organ? Allocation involves many different factors such as donor (age, size, blood type, risk factors), geography (where is the donor), urgency (how sick is the recipient), fairness (equivalent access to transplant), waiting time, and organ-specific policies and other considerations. Kidney allocation, for example, involves factors such as sensitization (which is time-dependent).
In 1998, the OPTN Pediatric Committee reviewed the impact the additional points had on pediatric transplantation rates and the rates were felt to be unacceptably low. It was therefore recognized that children should be transplanted within the following time frames, based on age: age at listing < 6 years: 6 months; age at listing 6–10 years: 12 months; and age at listing 11–17 years: 18 months. If they were not, then they would move to the “top of the list.” These goals were chosen as a best estimate compromise. It was hoped that they would be long enough to give the child a chance at a well-matched kidney while not being so long that his or her growth and development were severely compromised.
The percent transplanted after four months at “top priority” post-goal has gone up slightly in those under age 6, decreased in the 6-10 age group, and gone up somewhat in the 11-17 age group. The Pediatric Committee looked at the characteristics of the patients who where not transplanted within 4 months of passing their time goal and found that the majority were waiting for their first transplant, had a low PRA, and were getting offers. The most common reason for donor turndown was poor organ quality.
The number of children entering the waiting list, per year, is stable at about 600 per year. The greatest increases in those entering the list are among those over age 50. Dr. Reyes described increases in available organs and patients per age, and expanded the projections into the future.
Why change the system? The current pediatric point/time goal policies are not effective. Children do not contribute to the problem of increasing donor/recipient imbalance. The number of children on the list is stable (700-800 children on the list), compared to the growing number of adults (70,000+ adults). Thus prioritizing children would have a minimal impact, if any, on adult transplantation. Moreover, the system should be changed for the following reasons: children have a longer life expectancy with opportunity for subsequent transplants; young children have the best long-term graft survival; adolescents have worse long-term outcomes, but they are improving; and NOTA mandates that the policy needs to address the health care issues that are unique to children.
Dr. Reyes showed another analysis that looked at the effect of donor age on pediatric recipients. Again, there was a trend of higher RR of graft failure with increasing donor age, although this difference is not statistically significant. Previous studies have shown that there is an advantage for younger donors in terms of graft survival; so given the small numbers here, this difference is probably clinically significant.
The new pediatric policy should be that children listed before age 18 receive priority for kidneys from donors under the age of 35 (after 0 HLA mismatch, highly sensitized, kidney + other organ, prior living organ donors). It should occur before paybacks. The Kidney Allocation Review Subcommittee (KARS) was charged by the Board of Directors to review and recommend changes to the current system.
There is an advantage to being transplanted for kids at all age groups. In terms of expected remaining lifetime years of dialysis, there are significant long-term advantages for these patients when transplanted. Survival is just as good in children when compared to adults. We are doing well with kidney transplantation and we hope to eliminate deaths on the waiting list for kidney groups. With liver, we also are doing well. The wait list is relatively stable for children. Dr. Reyes shows the survival rates and allocation algorithms for various organs.
Status 1 is the most acute status, intended for patients who are likely to die in a matter of days. Dr. Reyes noted that Status 1B does not exist for adults and that prioritization is different for children than for adults. One can ask for exceptions but cannot get Status 1 by exception (There had been some problems on the West Coast in which 30-40 percent of West Coast patients were listed as Status 1. This was unacceptable to the transplant community.)
Looking at reported pediatric deaths among those who are waiting for livers, the biggest problem is among patients less than one year old. The other death rates are pretty stable. There has been a persistent effort to split livers in order to address this need. We could have a policy that certain livers are split, regardless, and that would address the need even better. Most pediatric livers transplants are deceased donors. Living donation has decreased because the split liver process has been successful.
Looking at intestines, the growth in the waiting list stems from the awareness that it is possible to do the transplant at all. The risk of dying is highest for intestine, then heart.
Improvements stem from earlier transplantation with better organs. Looking at heart, we are doing well at all ages. Children do not do worse than adults.
In summary, the waiting list and the transplant numbers for children are not clearly increasing over the decade. The proportion of all transplants carried out in children is declining. The waiting list mortality figures remain unacceptable because there are a small number of patients; and we could eliminate the mortality entirely, if we focused on it. Pediatric donors make a significant contribution to donor pool overall. Post-transplant survival is improving for all organs. Immunosuppressants have improved.
He showed slides illustrating improvement in children’s outcomes. Achieving survival was the endpoint of medical and surgical management during the early years of intestine transplantation. The vast majority of pediatric recipients are now surviving that first year and beyond, with a 1-year survival rate of greater than 90 percent being reported at some centers. The outlook is overall optimistic but still there is work to be done.
In terms of quality of life, Dr. Reyes said that he knows it when he sees it; and he also knows it when he doesn’t see it. Non-compliance is an issue; and it is important to help children have a better QOL. There will be an international consensus meeting in January 2008 about this issue.
Dr. Reyes described some of his patients and showed pictures of patients who had gone on to get married, become parents, have good QOL. Dr. Reyes has been thinking about how QOL impacts a person. He showed a picture of an intestine transplant patient who, he joked, has a better QOL than Dr. Reyes. With Thanksgiving coming up, “The Wizard of Oz” is being aired. Dr. Reyes pointed out that none of the characters received their transplants; the change all came from inside. He suggested that transplantation is somewhat the same. We give them organs but people remain who they are and we try to help them do that.
Dr. Migliori was struck that the 11-17-year-old kidney survival was the lowest of all the cohorts and asked if that had to do with compliance. Dr. Reyes said that it was. While he is a “hard ass” and finds it intolerable when people are non-compliant, there is a problem with transitioning between pediatric programs and kids. We have to do better.
Mr. Holtzman said that, a year ago, he had thought it was time to mandate that livers which could be should be split. At the time, a doctor told him that deaths on the list were not a problem. That’s not what he is hearing today, however. He suggested that the ACOT recommend a national policy to split livers to reduce deaths on the waiting list for pediatric patients.
Ms. Agrawal remembered that there was an early conversation about this. The concern had been whether all centers were equally competent to handle split livers. That was years ago, however, and maybe things have changed. Perhaps ACOT should talk about it again. Dr. Wiesner noted that, when one looks at the donor risk index in terms of split livers, it is one of the highest factors associated with decreased graph survival. Dr. Reyes agreed that was correct. However, the center-affect is tremendous. Some centers are taking 5 hours to split a liver so you know they are doing a bad job. Centers should be certified to be able to do it. The only reason we do not have this as requirement is because it doesn’t have to do with living donors, so there is less scrutiny. There is a role for optimizing this. In terms of mortality, Dr. Reyes has heard that adults die at a greater rate. But he shudders to assume that it’s ever acceptable for children to die at a similar rate to adults. It’s not acceptable when there are 100 liver kids dying a year, and we could fix it.
Dr. Vega thanked Dr. Reyes for the presentation. For pediatric heart and lung donors, they are allocated preferentially to pediatric recipients first. The thoracic community recognizes that the pediatric cases have precedence. What impact has this had on wait list mortality? Dr. Reyes reported that heart mortality among those on the waiting list has decreased for 10 years, mainly due to management in heart failure. For lung it has changed due to allocation changes, and there are only two years of data. We do not know specifically but expect to see decrease as well.
Dr. Scantlebury asked how we can prioritize children to get potentially splitable livers before an adult does? Dr. Reyes suggested that we focus on the 300-400 adolescent donors and mandate they are to be allocated as splitable organs (left lateral segment) if there is a willing recipient. Focus on the donors.
Mr. Holtzman said that they worked on this in Region 4. All of the liver surgeons agreed that, if a liver were splitable, the centers and surgeons who were willing to split it would get priority. As a result, the waiting list in San Antonio was eliminated and the deaths on the list at Children’s in Houston were eliminated. We have to have the will to do this.
Ms. Agrawal thanked Dr. Reyes for his presentation.
Transplantation Growth and Management Collaborative: Getting to 35,000 – Ms. McBride and Dr. Tuttle-Newhall
Dr. Betsy Tuttle-Newhall began by commenting she will provide an update on the Collaborative under the leadership of Ms. McBride. We have to plan ahead for success. The goal of the Transplant Growth and Management Collaborative is to: “Save or enhance thousands of lives a year by maximizing the number of organs transplanted from each and every donor and building the necessary capacity within the Nation’s transplant programs to transplant 35,000 deceased donor organs annually.”
If we have a 75 percent conversion rate, and 3.75 organs transplanted per donor, and a 10 percent increase in DCD in each DSA, we need 35,000 DCD annually (the Collaborative does not include living donors). This is achievable and we have made strides towards it. We only need 10,500 organs to get to the goal. Dr. Tuttle-Newhall showed a slide illustrating the number of transplanted organs and how that has increased since the Collaborative’s conception.
The Third Annual Learning Congress was held in October to look at best practices evaluation. Representatives from the OPO community, transplant centers, senior hospital leadership, and many others participated. Dr Reyes was at the meeting and reported that it was great; there were a huge number of people (1,300); and the breakouts were great, too. It was very informative.
The purpose of the best practices evaluation study was to (1) learn about transplant center best practices that influence high organ transplantation rates and efficiency in recovered organ use, while maintaining expected or higher than expected patient and graft survival outcomes; and (2) study transplant centers’ policies, procedures, management, administrative and other clinical, behavioral, cultural, organizational and financial practices associated with high performance in organ acceptance, transplantation and outcomes.
The study design adopted a qualitative, case study approach. Eight site visits were conducted to a sample of 15 high performing transplant centers and 34 organ transplant programs. More than 450 transplant center staff were interviewed (including surgeons, physicians, nurses, and other clinical, administrative, financial, and allied health staff). Researchers synthesized and analyzed findings from the eight site visits to identify best practices, which were reviewed and clarified at the Expert Panel Meeting.
Four criteria were used to select the high performing transplant centers and organ programs:
Additional criteria that were considered when selecting the high performing centers and programs included: donor information (percent SCD/ECD/DCD); whether the center performs pediatric transplants; geographic diversity; percent of imported organs; waitlist mortality; and organ type representation.
The programs are:
Study limitations include that there was a small sample and some practices may not be generalizable. This was not a controlled study, and they did not compare practices of higher- to lower-performers. The perspectives gathered were limited (e.g., the researchers did not hear the perspectives of transplant recipients and families involved in the organ transplant process). There may be risks of the Halo effect. (At centers labeled as “higher performers,” more practices may have been identified as “best” than would have been without such a label). There also are risks of a Hawthorne-like effect. (As a result of site visits many interviewees have noted that some “routine” activities are now recognized as likely best practices. This may enable centers to codify and track these practices and share them with others. Some interviewees noted that feedback on their centers’ performance and reflection prompted by interview process has led to changes.)
The strategies or drivers for growth, volume and/or quality were: institutional vision and commitment; having a dedicated team; having an aggressive clinical style; offering patient- and family-centered care; having financial intelligence; and having an aggressive management of performance outcomes. These were described in turn.
Strategy or driver #1: institutional vision and commitment. Hospital leadership demonstrates a commitment to making transplantation an institutional priority and to assuring the necessary resources to make this vision a reality. Key change concepts were:
Strategy or driver #2: dedicated team. Create and support a collaborative and rewarding work environment to attract and retain highly dynamic, committed and skilled specialists in transplantation. Key change concepts were:
Strategy or driver #3: aggressive clinical style. Assure program growth through advanced clinical practices in organ and patient acceptance and waitlist management and collaborate with referring physicians and OPOs on optimal care for donors and patients. Key change concepts were:
Strategy or driver #4: Patient- and family-centered care. Establish institution-wide practices, systems and mechanisms to organize care around the needs of patients and families in an effort to provide the best possible care to every patient and family everyday. Key change concepts were:
Strategy or driver #5: financial intelligence. Achieve transplant program financial strength through a detailed understanding of program finances, sound financial management, and excellent payer relations. Key change concepts were:
Strategy or driver #6: aggressive management of performance outcomes. Optimize transplant program performance through the implementation and use of protocols, research and innovation, and data-driven quality improvement/ performance.
Key change concepts were:
Ms. McBride asked the ACOT members what their best insights were, and are the best opportunities to succeed. Dr. Migliori said that he’s said it before: if this were a normal industry, people would be getting raises. It’s phenomenal. The benchmarking, sharing of best practices implementation. It also is clear that high-performing programs are the most profitable. They know how to run their business well. Payers are seeing the difference and it helps us too. They are more economical for us too. He asked if it’s possible to see an improvement in the discard/wastage rates. The answer was no, these are still going up for liver and kidneys, perhaps because of the increased aggressiveness in seeking consent for organs that eventually can’t be used. However, there is variability in how donors are managed clinically and we can do better. There is variability in quality improvement at both OPOs and transplant centers.
Dr. Reyes commented that a positive impact in one place will always have a negative impact elsewhere. For example, increased utilization of DCD may lead to worse outcomes. The response was that there has not been a negative impact in terms of patient/graph survival. It’s clear that there is at least one liver DCD program that is doing amazing work. They have been on a non-stop road show about their good results. This is generating some interest. It is our hope that this will help people to look at the institutional level and think about streamlining, not just their transplant services but other service lines too. Transplant care will also improve other service lines as well. This is increasing OPO operations, which will help centers and payers.
Ms. Principe congratulated the Collaborative on a successful effort. She would like to stress the importance of working with administrative groups to affect what needs to happen and to continue trying to make this happen.
Ms. McBride said that almost half of the centers participated. They are currently in “Action Period 1.” They will regroup in March 2008 and have the second learning session, which will focus on what new centers have been doing to adopt best practices and their results. Then the group will return together in October 2008, which should be about 1,500 people.
Action Period 1 involves setting and clarifying the team aims; developing a “home team;” identifying and testing changes; generating senior leader and data reports; collaborating with OPO partners; and participating in monthly “All Collaborative Call.” We want them to increase their volume by 20 percent. Collaborating with OPO partners is happening and we are seeing great outcomes. The level of collaboration with staff and sharing among staff has really increased. Partnerships can become deeper.
Ms. McBride described the data being collected. She noted that a lot of data is being collected on volume; and the participating organizations get data back, too, so everyone can see what all of the centers are doing.
Interesting points include the “donor management goals” which includes things like the person’s glucose and urine. When the OPO sets the goals in collaboration with other stakeholders, the goals improve. What the OPO does affects what the centers can do.
Our goal is to close the gap. Right now, we are sitting on a new plateau and we have to figure out how to get beyond it to the next plateau. The OPOs have variable infrastructures, but we need them to be consistent and successful in quality. Last month, the conversion rate was 69 percent, with 11,000 donors a year. We are getting close.
Mrs. Boone said that she has a special appreciation for this work because she knows of no better way to protect the living donors.
Ms. Agrawal thanked the speakers for their presentation.
Public Comment and Adjournment
Ms. Luebke – Living Organ Donor Advocate Program
Ms. Luebke stated that she would like to speak to ACOT members as a generic donor advocate. In talking with other donors, there are some themes that emerge, many of which ACOT has addressed. In speaking with donors and families, the main thing they need is education in the pre-donation period. Transplant Living has great information on their website, as does Livingdonorsonline.org , which is a moderated site. The Kidney Foundation also has a great website that includes live organ donor education and a protection project, too. They can help with issues after the donation while donor advocates would play a key role in doing work before the donation, such as ensuring informed consent and proper evaluation.
Ms. Luebke said that her advocacy program sees issues around what happens after the transplant, when the donor needs support and resources. They operate a 24-hours-per-day, seven-days-per-week. The organization may spend an hour with a person, including going back to the center and finding someone there who can help them. It does take a lot of energy and resources, but we embrace them as part of the family, the transplant community.
In terms of informed consent, it would be good to make clear to donors that there is no allocation priority for a prior donor, other than the four points given for kidneys. People are told they will be number one on the list, but this is not true. Ms. Luebke has talked to both OPTN and the Liver Committee about this. Donors need to know what the situation is, and they should also be given priority if they have a need later. The volume is small but issues can be profound. She closed by personally thanking Mrs. Boone who has made great efforts on this issue during her time on ACOT.
Ms. Agrawal thanked Ms. Luebke for her comments.
Dr. Reyes proposed a pediatric workgroup that would focus on developing ACOT recommendations around eliminating pediatric deaths on the list. Mr. Aronoff agreed to take names of volunteers for this workgroup.
Ms. Agrawal closed the meeting by asking the committee to thank Remy Aronoff, as this is his last meeting. She knows that everyone has an enormous amount of appreciation for what he’s done behind the scenes, certainly no one more than herself. The ACOT members applauded Mr. Aronoff.
Mr. Aronoff thanked the committee and said that he had enjoyed working with them all. Mrs. Boone thanked Ms. Agrawal for her contribution to ACOT and thanked Mr. Aronoff as well, noting that both individuals have been a great friend to the living donors and have done a great job.
Ms. Agrawal stated that this might be her last ACOT meeting. She has served on the ACOT since its initiation, and was originally appointed by Secretary Shalala 7 years ago. She has learned that you can give good advice but you cannot make anyone take it. Even though ACOT cannot make anyone take its advice, we should act anyway because one never knows what will happen afterwards. It can be frustrating to come here, work hard, and not see magic and instantaneous results. But even over 7 years, which is not a lot of time, there have been results. For instance, the UAGA has been amended, largely in response to ACOT recommendations. There is a lot left to do around living donors, but there has been much progress from CMS, OPTN, and other private and public groups, to address ACOT’s concerns in this area. She wanted to say that, if she is not here the next time ACOT meets and if members are ever tempted to wonder why they are doing this, think about the long view. Think about the Supreme Court justice who is writing a dissent in an 8-1 decision. She’s not writing it to change the results of the decision but so, the next time, the wisdom will be available and can influence the next group considering the question. Please give yourself a pat on the back. It’s been a pleasure working with you all. Ms. Agrawal closed by saying that, if she sees everyone in May 2008, it will be great and, if not, it’s been wonderful working with everyone.
The meeting adjourned at 12:00 noon.