Bone Marrow Transplants: Despite Recruitment Successes, National Program May Be Underutilized
Published: 2002-10-18T00:00:00

Fast Facts:

Highlights:
section_title: What GAO Found
paragraphs: More than 30,000 people are diagnosed annually with leukemia or other blood, metabolic, or immune system disorders, many of whom may die without stem cell transplants, using stem cells from bone marrow or another source. When a patient needs a transplant of donated stem cells and no genetically compatible related donor is available, the National Bone Marrow Donor Registry may help the patient search for compatible stem cells from unrelated donors. The National Bone Marrow Registry Reauthorization Act of 1998 required, among other things, that the Registry carry out a donor recruitment program giving priority to minority and underrepresented donor populations, ensure efficiency of operations, and verify compliance with standards by organizations that participate in the Registry. From 1998, when the National Bone Marrow Registry Reauthorization Act was enacted, through 2001, the number of stem cell donors on the Registry increased for all racial and ethnic groups. Although the exact number of patients in need of transplants is not known, estimates suggest that about one-third of them use the Registry to search for donors. The organizations that are involved in transplantation and participate in the National Marrow Donor Program (NMDP) network generally adhere to NMDP's standards and procedures. In 2001, NMDP required 24 centers to take corrective actions because they did not meet its standards.

section_title: Letter
paragraphs: More than 30,000 people are diagnosed annually with leukemia or other  blood, metabolic, or immune system disorders, many of whom may die  without stem cell transplants, using stem cells from bone marrow or  another source. When a patient needs a transplant of donated stem cells  and no genetically compatible related (family) donor is available, the  National Bone Marrow Donor Registry (Registry) may help the patient  search for compatible stem cells from unrelated donors. Founded in 1986,  the Registry is the largest and most diverse list of potential donors in the  world. This list currently includes more than 4 million donors. The  Registry is operated by the nonprofit National Marrow Donor Program  (NMDP) under contract to the Department of Health and Human Services’  (HHS) Health Resources and Services Administration (HRSA), with  additional support from the U.S. Navy. NMDP coordinates stem cell  transplants through its network of more than 400 participating  organizations, domestic and foreign, involved in transplantation, including  donor centers, which recruit and manage donors; laboratories; blood  sample repositories; bone marrow collection centers; and transplant  centers. NMDP has facilitated more than 14,000 transplants since 1987.
Concerns about the Registry have been raised by the HHS Office of the  Inspector General (OIG) and in our own work. These include the extent to  which the Registry provides equality of opportunity for patients of all  racial and ethnic groups to find compatible (matched) unrelated donors,  the extent to which it is utilized by those in need of stem cell  transplantation, and the effectiveness of the management of the donor  centers. We reported in 1992 that the proportions of African American and  Hispanic donors on the Registry were less than their proportions in the  U.S. population. This imbalance results in a decreased likelihood of an  individual from a minority group finding a match and eventually receiving  a transplant because matches are more likely to be found from among  donors of one’s own group. In an effort to address these concerns, a 1996  OIG report recommended that HRSA and NMDP reexamine the method  used to finance the donor centers that recruit volunteers to join the  Registry. It recommended a performance-based method to pay donor  centers for specific activities including monetary incentives tied to  performance indicators and emphasizing recruitment and retention of  donors, especially those from racial and ethnic minority groups.
The National Bone Marrow Registry Reauthorization Act of 1998 required,  among other things, that the Registry carry out a donor recruitment  program giving priority to minority and underrepresented donor  populations, ensure efficiency of operations, and verify compliance with  standards by organizations that participate in the Registry. In addition, the  act required that we conduct a study of the Registry, including an  examination of the extent to which it has increased representation of  racial and ethnic minority groups so that a member of such a group has a  probability of finding a match comparable to that of a person who is not a  member of such a group. In conducting this study, we addressed the  following questions: (1) To what extent have the program’s recruitment  efforts increased the enrollment of donors, including those from racial and  ethnic minority groups, since the 1998 act took effect, and has the chance  of finding a suitable match increased? (2) To what extent is the Registry  utilized to search for and obtain transplants? (3) Are the donor centers and  other organizations in the NMDP network complying with its standards  and procedures?
To answer these questions, we analyzed NMDP data on racial and ethnic  representation on the Registry from 1998 through 2001 and, to provide a  broader context for examining these changes, also analyzed data on racial  and ethnic representation in relation to the patients who searched the  Registry from 1988 through 2001. In addition, we analyzed data provided  by the International Bone Marrow Transplant Registry (IBMTR) on  transplants from related donors from 1997 through 2000, which enabled us  to estimate the demand for unrelated donor transplants in the United  States and relate this estimate to Registry utilization by patients searching  for donors during this period; analyzed NMDP data on matches, canceled  searches, and transplants obtained for patients needing donors during this  period; reviewed NMDP’s standards for participating in the Registry; and  reviewed evidence of compliance with the standards and procedures by  the organizations that participate. We also interviewed officials of NMDP;  HRSA; the Department of the Navy; the American Red Cross; and selected  donor, stem cell collection, and transplant centers. We did not  independently verify the accuracy of the data provided by NMDP. We  conducted our work from June 2001 through June 2002 in accordance with  generally accepted government auditing standards.
subsections: section_title: Background
paragraphs: Most of the diseases treated by stem cell transplantation involve  abnormalities of the blood, metabolic, or immune systems. These diseases  include several forms of cancer as well as certain nonmalignant diseases.  They strike all races, although one racial group or another may have a  higher incidence rate for a particular disease. Not all patients with  diseases that may be cured by stem cell transplants necessarily pursue  them. Depending on a number of donor and patient characteristics, from  about 10 to 50 percent of patients are alive 5 years after transplants. The  patients who do not survive may succumb either to their diseases or to the  consequences of transplantation. Because of these low survival rates,  some patients and physicians may be reluctant to select this stressful  treatment under most or all circumstances. For most of the diseases  involved, other therapies are available that may be less invasive, carry  lower risk, or be the medically preferred initial treatment. Nevertheless,  some of these diseases are best treated by stem cell transplantation, either  initially or after other treatments have failed.
Prior to stem cell transplantation, the patient’s bone marrow and,  consequently, immune system are destroyed with radiation or  chemotherapy. The patient’s bloodstream is then infused with healthy  stem cells from a donor. Healthy stem cells can be therapeutic because  they can develop into all the components of blood, including those needed  to replace the patient’s immune system. In an “autologous” transplant,  these cells come from the patient’s own marrow. In a “syngeneic”  transplant, the cells come from an identical twin. For many diseases, the  most common type of transplant is an “allogeneic” transplant, which  consists of stem cells from a genetically compatible donor.
subsections: section_title: Bone Marrow and Other Sources of Stem Cells for Transplantation
paragraphs: Although bone marrow was initially the only source of stem cells for  transplantation, in recent years two other sources of stem cells, umbilical  cord blood and peripheral blood stem cells (PBSC), have also been used.  In 2001, 1,215 of the transplants facilitated by NMDP (70 percent) involved  marrow, 42 (2 percent) involved cord blood, and 491 (28 percent) involved  PBSC. Umbilical cord blood is collected from the placenta and umbilical  cord of a newborn and then preserved in a cord blood bank until needed  by a matched patient. The number of stem cells typically obtained from  cord blood is relatively small but is often adequate for pediatric patients.  For transplantation from cord blood, the blood is volunteered when the  blood is banked, not when it is used. The Registry began an umbilical cord  blood stem cell program in 1998. Stem cells from peripheral blood may be  obtained in numbers sufficient for transplantation when the donor is  treated with a drug that causes the cells to leave the marrow and enter the  bloodstream where they can be extracted using a process where the stems  cells are removed and the remaining components of the blood are returned  to the donor. A donor, matched to a patient, may be asked to donate either  bone marrow or PBSC, depending on the preference of the patient’s  physician. The Registry has offered PBSC to patients since 1999.
section_title: Matching Donor and Patient
paragraphs: In addition to its dependence on such common determinants of treatment  success as patient age and disease severity, the outcome of a transplant  depends on the degree of match between donor and patient with respect  to particular blood cell proteins—the human leukocyte antigens (HLA)— that are part of a person’s genetic makeup. Each person has three  primary pairs (one set of three from each parent) of these antigens that  play a major role in the compatibility of a transplant. A matched donor is  defined as one for whom each of these six antigens has the same kind of  HLA. If a matched donor cannot be found, then a donor with certain types  of mismatch may be used, depending on the transplant center’s  preferences, although usually with poorer results. In general, the more  closely related two people are, the more likely it is that their HLA will  match. At one extreme, identical twins always match, and, in fact, match  on all antigens, not just the six ordinarily focused upon. At the other  extreme, members of separate racial groups are relatively unlikely to  match one another. Full siblings can provide a six out of six match,  resulting in what is called an “HLA-identical sibling transplant,” but only  about 30 to 40 percent of patients can be expected to have a matched  sibling donor. As a result, unrelated donors with matched HLA are sought  from the registries in which their HLA type has been recorded.
The definition of a match has been refined over time as scientific  understanding of HLA increases. HLA are being typed more precisely, so  more types of HLA can now be distinguished. Thus, some of today’s  matches may be judged as mismatches in the future because better  matches are possible. This increasing refinement does not mean, however,  that finding a suitable match for transplantation is inevitably becoming  more difficult. Some kinds of mismatch may be less dangerous than  others. As a result, as research continues, there may be fewer matches by  today’s standards, but relatively harmless mismatches will be recognized  as such and used. Further, there is evidence that cord blood may not  require as exact an HLA match as is usually sought.
section_title: The NMDP Network
paragraphs: In support of the Registry, NMDP manages a worldwide network  consisting of more than 400 donor centers, recruitment groups, contract  laboratories where tissue is typed, apheresis centers, cord blood banks,  collection centers where marrow is harvested, blood sample repositories,  and transplant centers. More than half of these organizations are donor  (91) or transplant centers (149). The relationship of these network  components to NMDP varies. Some, such as the recruitment groups, were  designed to be parts of the network and work with NMDP, whereas others,  such as the transplant centers, exist separately from the network and  function independently of NMDP except where specified by contract.
The NMDP network includes donor centers and other organizations in  foreign countries. The foreign donor centers merge their files with the  Registry, contributing more than one million donors. These centers are  required to comply with NMDP policies, program standards, and other  criteria, although fees for recruiting donors and other financial incentives  and payments that go to U.S. centers are not paid to foreign centers.  NMDP has also signed cooperative agreements with national registries in  13 foreign countries. Although certain data on donors recruited into these  registries are not entered into the Registry’s computer system, these  foreign registries will search their donor files on behalf of a U.S. patient  searching the Registry. In addition, 6 foreign apheresis centers, 18 foreign  bone marrow collection centers, and 36 foreign transplant centers are  affiliated with the Registry. NMDP’s affiliations with foreign donor and  transplant centers result in its facilitation of both foreign-to-U.S. and U.S.- to-foreign donations.
The existence of these international affiliations with the Registry does not  prevent U.S. transplant centers from obtaining stem cells through foreign  registries directly, that is, without going through Registry channels. Even  domestically, the Registry is not a monopoly; other U.S. registries also  maintain lists of donors, conduct searches for stem cells, or perform both  of these functions. These other registries, however, are relatively small;  often specialize in donors from particular racial or ethnic groups; and are  private, with no national requirements.
section_title: Operation of the NMDP Registry
paragraphs: The Registry serves two groups of people, donors and patients. The  Registry’s donor centers and recruitment groups recruit donors, who are  then managed by the donor centers. The Registry pays these centers and  groups for signing up donors. In view of the past underrepresentation of  minorities in the Registry, NMDP has initiated several recruitment efforts  to increase its racial and ethnic diversity. For example, it provides free or  low-cost minority-specific educational materials to donor centers and  recruitment groups. Probably the most important aspects of managing  donors are to maintain their commitment to donation so that they are  locatable and willing to donate when their stem cells are requested, to  keep records of how to contact them, and to drop from the list any  individuals who are too old or no longer able or willing to donate.
A patient’s first contact with the Registry occurs when his or her physician  or a transplant center conducts a free, preliminary search of the Registry  for stem cell donors and cord blood units. The preliminary search, which  takes about 24 hours, produces a list of donors and cord blood units that  are potentially suitable for that patient. However, many patients for whom  such searches are conducted are not necessarily good candidates for stem  cell transplants. For example, some searches may be conducted for  patients who are too sick for transplantation or who are good candidates  for less invasive therapies.
If the physician and patient decide to continue a search for an unrelated  donor (or unrelated cord blood) on the Registry, then more information  about the matching stem cells is required and a formal search is begun.  Only a physician affiliated with a transplant center in the NMDP network  may conduct a formal search of the Registry. The Registry bills the  transplant center a one-time activation fee of $600. It also bills the center  for the cost of the four or five testing components of the search process,  each of which costs more than $100. Since several donors may have to be  tested before one is selected for the patient, these component charges may  be made repeatedly, resulting in a search costing thousands of dollars to  the transplant center, and more to the patient when the center adds its  markups. Relatively few insurance plans pay for searches; however, plans  often pay for the actual transplantation including the procurement of stem  cells. The details of the formal search and the subsequent steps in the  process possibly leading to transplantation depend on the additional  information needed; the results of laboratory tests; and the kind of stem  cells sought, whether stored blood from an umbilical cord or blood or  marrow from a living donor.
If a suitable donor or suitable cord blood unit is found, and if other  requirements in the process toward transplantation are fulfilled, then  either (1) the marrow is harvested from the donor at a collection center,  (2) PBSC are collected from the donor at an apheresis center, or (3) the  cord blood is shipped from a cord blood bank. The stem cells are  transported to the transplant center, often by courier. The final step is the  infusing of the patient’s bloodstream with the selected marrow, PBSC, or  cord blood. The entire process—from the initiation of the formal search to  the transplant (infusion)—typically requires many months and sometimes  more than 1 year. However, some patients cannot wait this long for  transplants because their medical conditions are deteriorating.
During the search process, NMDP offers patient advocacy services  through two channels. Its Office of Patient Advocacy (OPA) provides  several services, including education, support, case management  intervention, financial assistance, and special advocacy projects. For  example, OPA publishes the Transplant Center Access Directory, a  patient guide listing all transplant centers in the NMDP network. The  directory describes each center’s HLA matching criteria and lists the  diseases each typically treats with unrelated donor marrow transplants.  The directory also provides information on comparable search charges  and risk-adjusted patient survival data. In addition to the services provided  through OPA, NMDP requires that each transplant center have a patient  advocate on staff. The patient advocate must be familiar with the center’s  transplant program and with issues of unrelated donor stem cell  transplantation and must not be a member of the transplant team.
section_title: OIG Review
paragraphs: A 1996 OIG review raised concerns about donor center costs and  performance. Before the review, NMDP used two methods to finance  donor centers. NMDP paid for services at some donor centers through  cost-based contracts for direct expenses, such as labor and fringe benefits  and donor expenses. Other donor centers received payments from NMDP  for specified activities, such as donor recruitment and donor search  activities. The OIG recommended that HRSA and NMDP develop a  payment approach for all donor centers that more directly linked funding  to performance and emphasize recruitment and retention of donors,  particularly donors from racial and ethnic minority groups. Further, the  OIG recommended that HRSA and NMDP develop procedures to monitor  the performance of donor centers and other organizations in the NMDP  network.
section_title: NMDP Has Succeeded in Increasing Recruitment of Donors, Including Minorities, but May Not Be Able to Equalize Access to Matches
paragraphs: The program’s recruitment efforts have apparently increased the number  of donors on the Registry since 1998 for all racial and ethnic groups, and  the theoretical probability of finding a match has increased steadily over  the life of the Registry. By 2001, the number of donors from each minority  group on the Registry had grown by at least 30 percent and was either  greater than or no more than 2 percentage points below its representation  in the general population. However, when viewed as a percentage of each  group’s population, African Americans and Hispanics are still substantially  underrepresented. For all racial and ethnic groups, the theoretical  probability of finding a match has grown as the Registry size has  increased, but equal access to a match may not be attainable. Differences  among racial and ethnic groups in the rarity and variability of the genes  responsible for compatibility in transplants may mean that the Registry  cannot achieve equal probability for all groups. Further, the goal of equal  access to a match conflicts to some extent with attempts to maximize the  overall numbers of matches and transplants for the Registry.
subsections: section_title: Number of Donors on Registry Has Increased for All Groups
paragraphs: The size of the Registry has increased since 1998 by 36 percent, and no  minority group increased by less than 30 percent. NMDP’s efforts to  recruit minorities may have substantially increased the number of donors  from these populations. Percentage increases for minorities ranged from  30 percent for Native Americans to 53 percent for Hispanics. Caucasian  donors increased 28 percent. (See table 1.) The multiple race category had  the largest increase, 123 percent, but this may result in part from an  increase in the use of that category by those to whom it applies, rather  than solely from an increase in the availability of donors of that group.
The total of more than 1,000,000 minority donors listed in 2001 contrasts  with the approximately 80,000 we reported in 1992. As can be seen in table  1, by 2001, the proportions of both African Americans and Hispanics on  the Registry were within 2 percentage points of their proportions in the  2000 U.S. population. The proportions of other minorities on the Registry  were either approximately equal to or exceeded their proportions in the  population. While the differences between Registry and population levels  of representation for African Americans and Hispanics reflect improved  representation of these groups, the 2-percentage point differences still  indicate a substantial underrepresentation in comparison with their  proportions in the U.S. population. Specifically, in 1992, the proportions of  African Americans and Hispanics, both at 4 percent of the Registry, were 8  and 5 percentage points lower, respectively, than their proportions in the  U.S. population (which were 12 and 9 percent, respectively). This  translated to a 67 percent underrepresentation for African Americans and  a 56 percent underrepresentation for Hispanics. The current 2-percentage  point differences on the Registry for these groups translate to a 17 percent  underrepresentation for African Americans and a 15 percent  underrepresentation for Hispanics.
section_title: Theoretical Probability of Finding a Match Has Increased over Life of Registry
paragraphs: For all racial and ethnic groups the theoretical probability of a patient’s  finding at least one matched donor has increased every year since 1988 but  has leveled off somewhat since 1998. The increase in theoretical  probability represents significant progress in raising the likelihood of a  match. It reflects inclusion in the Registry of the most common genetic  types over the period when the Registry was small and new, and  recruitment efforts were beginning. The leveling off likely reflects the fact  that for all groups, after years of recruitment activity, improvement now  occurs mainly when rare types are added. (See fig. 1.)
Nevertheless, the theoretical probability of finding a match varies by race,  ranging in 2001 from under 60 percent for African Americans to over 80  percent for Caucasians. This probability has always been higher for  Caucasian patients than for patients in any minority group, in part,  perhaps, because of Caucasians’ greater numbers and level of  representation on the Registry. The theoretical probability of finding a  matched donor has been lowest for African American patients. This is  because, in addition to their smaller numbers and lower level of  representation on the Registry, their rarer and more varied HLA  combinations make matching harder.
section_title: Equal Access for All Groups May Be Unattainable
paragraphs: Because of genetic differences among racial and ethnic groups, there is  reason to believe that patients from some minority groups, notably African  Americans, may never have the same probability of finding matches, and  therefore of access to transplants, as Caucasian patients, regardless of the  efforts made to recruit them. Any patient is more likely to find a match in  his or her own racial and ethnic group than in another group, so patient  matching rates depend, to some extent, on the number of people in the  patient’s group on the Registry. All minorities are at a disadvantage for this  reason. Further, some minority groups, such as African Americans, are  known to have more rare and more varied HLA combinations than do  Caucasians. The likelihood of finding a match from among a group of  racially or ethnically defined donors declines with the rarity and number  of possible genetic types found among the members of that group.
In addition to these factors related to finding a match, there are other  factors that may contribute to differences in access to a transplant. Some  of these depend on the characteristics of those who volunteer for the  Registry. For example, donors from different groups may differ in their  tendency to be available (locatable, willing, and physically able) when  called upon to actually donate. Other possible factors involve the  attitudes, health, medical care, resources, and preferences of the patients.  Patients of different groups may differ in their tendency to engage the  health care system at all, to seek help early enough in their illnesses, or to  search the Registry as opposed to pursuing other options. It may be  possible to effect changes in these factors, thereby moving closer to the  goal of equal opportunity for all racial and ethnic groups.
However, not only is the goal of equal access to transplants for all groups  difficult to attain, but it also may conflict with the statutory goal of  maximizing the number of patients who find a match and thereby  maximizing the number of transplants facilitated. Recruiting donors with  the rare HLA combinations that may be needed for minorities is difficult.  Large numbers of donors must be recruited and retained in the Registry in  order to identify and add each rare genetic type to the donor pool, so the  cost of recruiting such donorsthe incremental cost of adding these rare  genetic types to the donor poolis large. Thus, devoting many resources  in pursuit of a small number of rare genetic types may divert resources  from other efforts, such as recruiting Caucasians and other groups with  more common genetic types, which might more readily increase the  number of matches.
Because of the difficulty encountered in finding matches for minority  patients, NMDP engages in a number of initiatives to increase the  Registry’s diversity. It conducts outreach, recruitment, and educational  efforts directed towards minorities. In addition, NMDP has initiated a  program to pay the full costs of HLA tissue typing for minority donors.
Although the difficulty in finding matches for minority patients may be  unavoidable, it may be mitigated somewhat by the efforts of the Registry  to increase the number of donors on whom it has complete HLA typing.  The vast majority of actual donations are obtained from by donors whose  HLA is fully typed. When only these donors are considered, each minority  constitutes a larger portion of the Registry than its representation in the  population. Therefore, because access to a match depends upon, for the  most part, the fully typed donors on the Registry, access for minorities  may be somewhat better than might be assumed by looking at the Registry  as a whole.
section_title: National Registry May Be Underutilized
paragraphs: Although the exact number of patients in need of transplants from  unrelated donors is not known, the number of patients utilizing the  Registry to search for matches is about one-third of the estimated number  of patients in need of unrelated donor transplants. About one-tenth of the  number of patients estimated to be in need of unrelated donor transplants  obtain transplants facilitated by NMDP. These figures suggest that the  Registry may be underutilized for both searching and facilitating  transplants. Physicians for approximately 15,000 U.S. patients requested  preliminary searches of the Registry from 1997 through 2000. This number  represents 34 percent of the 44,740 U.S. patients estimated to be in need of  stem cell transplants from unrelated donors in that 4-year period. About  4,000, or 27 percent, of the patients whose physicians searched the  Registry eventually received transplants facilitated by NMDP. However, a  significant proportion of searches were not completed because stem cells  were obtained from donors or organizations without the involvement of  NMDP.
subsections: section_title: Estimates Suggest about One-Third of Patients in Need Search the Registry and about One-Tenth Receive Transplants
paragraphs: From 1997 through 2000, physicians carried out preliminary searches for  34 percent of the number of U.S. patients estimated to be in need of  transplantation from unrelated donors at any time during that period. The  number of transplants facilitated by NMDP for all U.S. patients was 9  percent of the number estimated to be in need. The precise number of  patients in need of unrelated donor transplants is not known. However,  there is a greater than 10 to 1 ratio between the number of such patients  estimated to be in need and the number of transplants facilitated by  NMDP. This suggests that the Registry may be underutilized, as many  more U.S. patients may need unrelated donor transplants than obtain them  through the Registry. The ratio of the number of preliminary searches to  the number of patients in need varied by race and ethnicity. Among  specific racial and ethnic groups, the percentage of preliminary searches  was highest for Caucasian patients (35 percent), and was lowest for  Hispanic patients (24 percent) and Native American patients (24 percent).  (See table 2.) We do not know why these apparent disparities in search  rates exist.
About one-fifth of the number of patients estimated to be in need formally  searched the Registry (9,623 out of 44,740). Less than one-tenth of those  estimated to be in need ultimately received NMDP-facilitated transplants.  The numbers and percentages of preliminary searches that progressed to  formal searches from 1997 through 2000 are presented by racial and ethnic  group in table 2. The overall rate of progression from preliminary to formal  search is 63 percent. Further, 4,056 of the 15,231 U.S. patients (27 percent)  for whom preliminary searches were conducted from 1997 through 2000  eventually received NMDP-facilitated transplants. This number  corresponds to 9 percent of the number of patients estimated to be in need  of unrelated transplants during that period.
section_title: Reasons for Cancellation Vary and Include Obtaining Stem Cells from a Provider Other than NMDP
paragraphs: Reasons for cancellation of preliminary searches or formal searches vary.  Although clinical reasons, such as a change in medical condition, are the  most commonly cited explanations for cancellation of both preliminary  and formal searches, another relatively frequent reason is that stem cells  are obtained from a provider other than NMDP, such as a related donor or  another registry. (See tables 3 and 4.) We do not know the proportion of  these cases that used a related donor, and some cases may not have been  able to find a potential match at NMDP. However, it is likely that in at least  some of these cases, NMDP might have facilitated a transplant if the  patient’s transplant center had not selected another registry to provide the  stem cells, thus representing another kind of possible underutilization of  NMDP. Lack of donor availability—not finding any potential matches— and financial reasons are not commonly cited as reasons for cancellation  of either kind of search, although it is possible that patients with limited  financial resources or insurance may not be encouraged to make  preliminary searches.
Several factors may influence a decision to obtain stem cells from a  provider outside the NMDP network, including the source of stem cells  preferred by the physician, the costs involved, and the timeliness of the  response. Outside providers may need to be used when the physician sees  cord blood as a viable alternative source to bone marrow or PBSC because  some cord blood banks do not list their cord blood units with NMDP.
Search and procurement costs can also be a factor. Administrators of  transplant centers that have done non-NMDP-affiliated transplants told us  that other registries charge less for searches than NMDP does. For  example, we were told that only a few other registries worldwide charge a  search activation fee in addition to their charges for the specific medical  procedures needed to confirm that a particular donor is healthy and  matched to the patient. In addition, the cost of stem cell procurement at  NMDP tends to be higher. One transplant center director told us that the  center pays about $13,000 for stem cells obtained directly from overseas  registries and about $21,000 for NMDP stem cells. However, even when  NMDP is not paid for a formal search or for stem cells, it may still have  been utilized. An official at NMDP informed us that it is possible for a  transplant center to determine the NMDP-affiliated registry at which a  foreign (but not domestic) potential match is registered on the basis of a  preliminary search and to contact the foreign registry directly to obtain the  stem cells. Moreover, that official stated that some transplant centers may  do this regularly. Thus, although NMDP may not be recorded as having  facilitated the transplants that result, its role in helping to locate donors in  such cases means that its utilization is somewhat greater than the record  suggests.
Timeliness can be another factor. A few center administrators mentioned  that NMDP takes longer to provide stem cells than do other registries. For  example, one administrator told us that the time it takes to obtain a donor  sample for testing at the transplant center—an important component of  the overall search process—can be a week longer for NMDP than for a  foreign registry, depending on whether NMDP judges the search to be  urgent. Waiting this additional week can be frustrating for those at the  transplant center who are anxious to determine whether they have a  confirmed match or will have to continue searching. Another director told  us that stem cells from non-NMDP providers are more likely to be received  by the date the transplant center requests them than are stem cells from  NMDP. NMDP has attempted to shorten its time from formal search  initiation to transplant and reports that its median time has decreased  from 4.8 months from 1992 through 1993 to 3.7 months in 2000. The  optimal time frames for patients vary. Some may not be urgent, but NMDP  has shown that it is possible to complete urgent searches in less than a  month and reports that it expects to begin offering urgent searches as an  option to transplant centers.
section_title: Organizations in the NMDP Network Generally Comply with Its Standards and Procedures
paragraphs: Organizations that participate in the NMDP network generally comply with  the standards and procedures it has established. In order to encourage  adherence, NMDP uses various mechanisms to monitor compliance and  performance. These include site visits, the Continuous Process  Improvement (CPI) program, and incident reports, as well as a financial  incentive system designed to improve the performance of donor centers.  The results of the selected site visits, analysis of CPI measures, and  incident report summaries we reviewed show that the organizations in the  NMDP network generally adhere to NMDP’s standards and procedures. In  general, NMDP ensures compliance by taking action against noncompliant  organizations. (See app. II for examples of how NMDP uses these systems  to achieve compliance with respect to selected activities.) In 2001, NMDP  required 24 donor and transplant centers to take corrective actions  because they did not meet its standards. The incentive system encourages  compliance by linking donor center reimbursement to performance.
subsections: section_title: NMDP Monitors Network Compliance and Performance
paragraphs: NMDP uses several mechanisms to encourage the compliance and  performance of the participating organizations in its network. NMDP staff  members conduct site visits to donor centers to monitor the centers’  compliance with NMDP’s standards and procedures and to provide  feedback about the results. It also employs the CPI program to assess and  provide feedback at donor, transplant, and bone marrow collection  centers. Further, NMDP monitors incident reports from donor, transplant,  and collection centers and may take corrective action including, in serious  cases, suspension or termination.
According to NMDP officials, NMDP staff members conduct site visits at  donor centers approximately every 2 years to assess donor center  compliance with program standards and procedures. NMDP staff members  review the organization of the program (such as its support and staffing  structure), recruitment activities (such as performance against goals and  donor drive compliance), donor management activities (such as  management of patient-related donor search requests, confidentiality  procedures, and records management), and billing and reimbursement to  determine adherence to NMDP’s standards and procedures. They also  compare performance against goals for various recruitment activities.  Upon completion of these visits, NMDP staff members discuss the results  with the center staff and provide a summary report. Centers that are  noncompliant are advised of the problems and are required to submit  corrective action plans to NMDP that address the problems. Our review of  donor center site visit reports indicates that the reports identified  problems and the corrective actions required of the centers to meet NMDP  criteria.
Since 1998, NMDP has conducted additional site visits at transplant  centers to verify the accuracy of the data that the transplant centers  submit electronically to NMDP. NMDP staff members compare the data  from the centers’ records with the data from NMDP’s computer system.  During these visits, NMDP staff members may also review other activities,  such as the signing of patient consent forms. The site visits are scheduled  for each transplant center every 4 years. NMDP plans to issue its first  annual report on the results of the first cycle of site visits in September  2002.
NMDP monitors the operations and performance of its centers through the  CPI program. The program includes nine goals to increase the efficiency of  key activities in the search and donation process and measures  performance against these goals. For example, at donor centers, NMDP  measures the timeliness of registering new donors, resolving search- related requests, and processing requests for HLA blood typing. At  transplant centers, NMDP measures the time it takes to resolve and report  confirmatory testing results. NMDP also monitors post-transplant data  submission through CPI. These outcome data are used in research studies  to analyze outcomes for donors and patients. NMDP also monitors the  accuracy and timeliness with which donor and transplant centers submit  donor and patient blood samples to NMDP’s research repository. NMDP  provides regular feedback to donor and transplant centers concerning  their performance on CPI measures. For example, each center receives a  monthly report summarizing the results of its activities, along with those  of all other centers, in the previous month. The reports allow centers to  analyze how consistently they perform and to compare their results to  those of other centers in the network. NMDP also conducts a year-end  analysis to provide feedback to centers.
Through its CPI program, NMDP monitors whether organizations in its  network meet goals for timeliness and may recommend corrective actions  for centers that do not meet these goals. A year-end analysis of the CPI  program shows that during 2001 almost half (44 of 91) of donor centers  met all nine CPI goals for the search process. In addition, 20 more donor  centers met eight of nine goals, and 9 others met seven of nine goals.  According to NMDP, the remaining 18 donor centers (20 percent) that met  six or fewer goals were the focus of technical assistance to improve their  performance. Our analysis shows that 5 of the 91 donor centers (5  percent) were placed on review or probation for failing to meet CPI goals  in 2001.
Our analysis also shows that NMDP placed 18 of the 129 transplant centers  (14 percent) on probation. Eight of these were placed on probation for  failure to meet CPI goals for the search process, seven for failure to meet  CPI measures concerned with timely submission of recipient follow-up  information, and three for problems related to the accuracy and timeliness  of submissions of donor and patient research blood samples.
NMDP supplements these activities with incident reports, which are  written accounts of deviations from policies and standards that are  categorized by the nature of a deviation and include, but are not limited to,  categories such as confidentiality concerns, customer service, and product  transport. NMDP uses incident reports to track deviations from its  standards by recording the specifics of incidents. NMDP staff members  follow up and investigate incidents. In addition, an NMDP committee  reviews a summary report of incidents twice a year to identify developing  trends that may affect an individual center or the entire network. Since  NMDP reviews center participation annually, the committee may follow up  on deviations from NMDP’s standards or take action such as probation,  suspension, or termination during the reapplication process. We reviewed  a summary of incidents categorized by type of problem and the corrective  actions taken to resolve them. For example, one incident involved an  operating room staff member administering less appropriate blood, rather  than the donor’s own blood, which was available for that purpose, during a  marrow harvest. NMDP monitored an investigation at the hospital to  ensure that the problem would be addressed.
section_title: Donor Center Reimbursement Is Linked to Performance
paragraphs: To improve the operation of its donor centers, NMDP ties their  reimbursement to their performance. In 1997, NMDP instituted a new  reimbursement system that links payment to performance on CPI goals for  all donor centers. NMDP pays donor centers a fee for each activity to  recruit donors for the Registry, such as signing up donors, typing their  tissues, maintaining their files, and other activities related to confirming  that the donors identified as potential matches for a searching patient  actually match and are medically cleared for donation. NMDP pays each  donor center a recruitment fee of $28 and $10 for every minority and  Caucasian donor, respectively, recruited up to the number specified in its  recruitment goal. NMDP establishes annual recruitment goals for each  donor center based on the demographics of the local population. When  donors are recruited, the donor centers that do not register a specific  percentage of the new donors within a certain period incur financial  penalties. For example, the CPI goal for registering new donors is to  register at least 85 percent of them within 35 days of the date on which  they volunteer. NMDP would reduce the total recruitment fee it pays to  donor centers that register less than 85 percent of new donors within this  time frame. NMDP data show that in May 2001, 98 percent of all donor  centers met this goal. In addition, NMDP pays incentives to donor centers  for retaining donors at various points in the donation process.
section_title: Concluding Observations
paragraphs: In spite of progress in recruiting minority donors, racial and ethnic  disparities in the Registry remain, due in part to differences in the genetic  variability within groups. Thus, differences among racial and ethnic groups  in the probability of obtaining transplants will likely continue. Many in  need of transplants may not search the Registry; those that do often do not  obtain them, and for those that obtain them, the transplants may not be  facilitated by NMDP. Although NMDP enhances the quality of its network  by actively monitoring the compliance and performance of the component  organizations, it has not attained the level of utilization that might be  expected.
section_title: Agency Comments
paragraphs: In its written comments on a draft of this report, HRSA stated that the  report provides an accurate and helpful overview of the status of the  National Bone Marrow Donor Registry. HRSA agreed that recruitment of  donors cannot be the sole strategy for improving access to unrelated  donor transplants for minority patients or those with unusual antigens,  and cited the need for other efforts to supplement recruitment activities.  However, HRSA noted that the Registry consists of two distinct groups of  donors, those who are fully HLA typed and those who are less than fully  typed. Since the vast majority of actual donors are selected from the fully  typed portion, minority racial and ethnic groups therefore make up a  larger proportion of the Registry than their representation in the U.S.  population. We have noted in the report that, because of this, access for  minorities may be somewhat better than might be assumed by looking at  the Registry as a whole.
With regard to underutilization of the Registry, HRSA agreed that many  patients who could benefit from unrelated donor transplants never consult  the Registry or do so too late in the course of their illnesses. HRSA  suggested a slightly modified method for estimating the number of patients  in need. We modified table 2 in accordance with its suggestions, but note  that both approaches produce virtually identical estimates of overall  utilization. (See app. I.)
Finally, HRSA noted that many factors affect the time required to complete  a search of the Registry. While searches frequently take many months and  the median search time has decreased, NMDP has completed medically  urgent searches in less than a month, on a pilot basis, and reports that it  expects to begin offering urgent searches as an option to transplant  centers. We have revised the report to include this clarification. HRSA also  provided technical comments, which we incorporated as appropriate.  HRSA’s comments are reprinted in appendix III.
We are sending this report to the Administrator of HRSA, the NMDP Chief  Executive Officer, and other interested persons. We will also make copies  available to others upon request. In addition, the report will be available at  no charge on the GAO Web site at http://www.gao.gov.
If you or your staff members have any questions about this report, please  call me at (202) 512-7119. Key contributors to this assignment are listed in  appendix IV.
section_title: Appendix I: Methods of Assessing Registry Utilization
paragraphs: Registry utilization is the extent to which patients in need of unrelated  stem cell transplants search the Registry or obtain NMDP-facilitated  transplants. In determining utilization, it is necessary to use indirect  methods to calculate the number of patients in need because it is  impossible to determine this number directly. For example, although we  may be able to obtain data on the number of patients who have been  diagnosed with certain blood and immune system diseases, we are unable  to determine the number for whom stem cell transplants are the best  treatment.
One measure of the utilization of the Registry is the extent to which the  number of patients obtaining transplants facilitated by the Registry is as  high as it could be. The maximum possible utilization of the Registry  would be indicated if the number of U.S. patients conducting preliminary  searches was approximately equal to the estimated number of patients  needing unrelated donor transplants. A second measure of utilization is  the extent to which patients search the Registry.
The method we used to assess the two aspects of utilization—searching  the Registry and obtaining an NMDP-facilitated transplant—is also used by  NMDP. It involves estimating the number of patients in need of unrelated  donor transplants by using data on the number of HLA-identical sibling  transplants obtained from IBMTR. This method and two alternative  methods that are also used by NMDP to assess utilization by U.S. patients,  one based on the number of preliminary searches conducted and the other  based on the incidence of disease, are described here.
subsections: section_title: Method Based on Number of HLA- Identical Sibling Transplants
paragraphs: For the years from 1997 through 2000, we estimated the number of  Caucasian patients in need of unrelated donor transplants based on the  average annual number of Caucasian HLA-identical sibling transplants  performed during those years. To obtain this estimate, we multiplied the  number of HLA-identical sibling transplants, for Caucasians, by the  number of patients of that group that genetic theory predicts—on the basis  of the average number of children born to the women of that group—are  in need of unrelated donor transplants for every Caucasian HLA-identical  sibling transplant in the United States.
The average number of children born to Caucasian women over a lifetime  during the years from 1989 through 1995 was 1.7925. Subtracting the  individual who is in need of a transplant gives n = 0.7925 as the number of  siblings available to be transplant donors. The likelihood of a match  between two siblings is 25 percent because each child inherits one-half of  each parent’s HLA genes, resulting in a one out of four chance of having  the same HLA genes as a sibling has. Therefore, the probability that no  sibling HLA identically matches the one in need is P = (0.75) . For a  Caucasian patient, P = (0.75)0.7925 = 0.796134.
The number of patients in need of unrelated stem cell transplants is equal  to the number of sibling donor transplants multiplied by P/(1 − P).
Therefore, for every HLA-identical sibling transplant recorded for a  Caucasian patient, there will be 0.796134/(1 − 0.796134) = 3.90518 patients  in need of unrelated donor transplants. Because there were 7,920 sibling  transplants performed for Caucasian patients from 1997 through 2000, we  estimate that 3.90518(7,920) = 30,929 Caucasian patients were in need of  stem cell transplants during that period. The estimates for other racial and  ethnic groups are presented in table 2. Because minorities generally have  less access to health care and may therefore have less access to sibling  transplants specifically, these estimates were obtained by assuming that  each minority group’s need for unrelated donor transplants is proportional  to the Caucasian group’s need. The estimates were obtained by multiplying  the number of persons in the minority group by the proportion of  Caucasians in need of unrelated donor transplants. This approach  implicitly assumes that differences across groups in fertility rates are of  negligible importance in computing the numbers of patients in need of  unrelated donor transplants.
An alternative approach assumes that minorities and Caucasians have  equal access to HLA-identical sibling transplants. Based on this  assumption, this approach derives the needs of minorities for unrelated  donor transplants directly from their observed numbers of HLA-identical  sibling transplants. In doing so, it allows for the possibility that each group  has its own disease incidence rates and that the differences among groups  in their relative levels of sibling donations reflect these rates, not  differences in access. (See table 5.) This approach, while utilizing  somewhat different assumptions from the method above, produces a  virtually identical estimate of the underutilization of the Registry (10  percent versus 9 percent).
section_title: Method Based on Number of Preliminary Searches
paragraphs: The second method used by NMDP to assess Registry utilization is based  simply on the annual number of patients conducting preliminary searches.  In order to use this method, one must assume that this number directly  represents those in need of unrelated donor transplants. One cannot  assess the extent to which those in need search the Registry on the basis  of this number since the number itself is the number of patients searching.  However, one can assess the extent to which those in need obtain NMDP- facilitated transplants by considering the annual percentage of patient  searches that result in NMDP-facilitated transplants. This method yields an  estimate of the patients searching who obtain NMDP-facilitated  transplants of 27 percent. (See table 5.)
Although this approach has been used by NMDP as a way of assessing  utilization, officials at NMDP observe that the validity of this approach to  utilization assessment is limited by the freedom with which patients can  choose whether to search. These officials point out that preliminary  searches are performed for some patients who are not good candidates for  transplant and that other patients who should submit preliminary searches  probably do not. Because of the lack of correspondence between the  number of patients in need and the number performing preliminary  searches, this estimate is not likely to be as accurate as the other two.
section_title: Method Based on Incidence of Disease
paragraphs: The third method used by NMDP is based on an estimate of the annual  number of U.S. patients newly diagnosed from 1997 through 2000 with  selected diseases that might benefit from unrelated stem cell transplants.  The estimated number of potential recipients for each disease is obtained  from disease incidence estimates, with adjustments for the likelihood that  (1) the patient is young enough to benefit from transplantation, (2) disease  severity is not so great as to make transplantation futile, and (3) an HLA- identical sibling donor is available, thereby making unrelated donor  transplant unnecessary. The ratio of the annual number of NMDP- facilitated transplants for U.S. patients diagnosed with these selected  diseases during this period to the estimated number of new U.S. patients  with the diseases is used to assess utilization. (See table 6.) The ratio, for  all patients with the selected diseases, corresponds to an estimated  percentage of candidates obtaining transplants—10 percent—that is very  close to the estimate obtained by the first method. The validity of this third  method is constrained by the limited number of diseases for which data  are available.
section_title: Appendix II: How NMDP Achieves Network Compliance with Selected Standards and Procedures
paragraphs: NMDP requires that the organizations participating in its network comply  with its standards and procedures. This appendix discusses how NMDP  achieves the compliance by network organizations with standards and  procedures for obtaining the informed consent of donors and patients,  donor selection criteria, confidentiality of records, collection and  transportation of marrow, laboratory standards, and maintenance of donor  files in the Registry.
subsections: section_title: Informed Consent of Donors and Patients
paragraphs: At each stage of the search process, NMDP requires donors to sign  informed consent statements for procedures performed at the donor and  transplant centers. A volunteer must sign an informed consent form  before being listed as a donor on the Registry, and also before the  collection of blood for initial and follow-up testing, infectious disease  testing, and participation in research. In addition, consent must be  obtained before notifying the transplant center that a donor is willing to  proceed to marrow donation and before the administration of anesthesia.  Consent must also be obtained before collecting blood specimens for  research and before any proposed procedure for which the donor has not  previously given consent.
According to NMDP officials, during each donor center site visit, NMDP  staff members review about 35 randomly selected donor files. NMDP staff  members check that each donor has signed all appropriate consent forms  for the stages of the recruitment and search process the donor has  completed. According to an NMDP official, since NMDP began performing  site visits in 1998, missing or unsigned donor consent forms occurred in  only a few cases, indicating that a high level of compliance has been  achieved. The number of missing consent forms is not readily available  because cumulative data are not permanently stored. Transplant centers  are responsible for obtaining informed consent from each transplant  patient, for collecting research blood samples that are sent to the NMDP  repository, and for submitting baseline and follow-up data to the Registry.  Some of the centers have separate consent forms specifically for the  research samples and clinical data, whereas others incorporate consent  for the research samples and clinical data into the informed consent  document the patient signs for the transplant.
NMDP is currently collecting information on how transplant centers are  handling the informed consent process for the research samples and  clinical data submitted to NMDP. This information will be analyzed, and  NMDP will evaluate whether changes in policies or procedures should be  made to the consent process for obtaining NMDP data and research blood  samples.
section_title: Criteria for Donor Selection
paragraphs: In order to be considered for stem cell donation, donors must be from age  18 through 60 and in good health. Individuals with serious illness or those  who are significantly overweight are disqualified. The donor must provide  a medical history and acknowledge in writing that the history is accurate.  Pertinent donor medical information is evaluated for acceptance or  deferral according to NMDP medical eligibility standards and criteria set  by the medical director at the local donor center.
NMDP monitors whether registered donors have filled out the appropriate  medical history questionnaires, but NMDP does not store cumulative data  on the number of missing medical history questionnaires. During each  donor center site visit, NMDP staff members check a random number of  health history questionnaires. However, NMDP is limited in how it  monitors the donor selection process. Although NMDP tracks the number  of donors who are unavailable for medical reasons, it cannot determine  whether an unavailable donor’s medical condition was preexisting, and  therefore should have been caught in the health screening at the time the  donor volunteered, or whether the donor’s health changed during the  period between registration and a request for testing prior to donation.
section_title: Methods to Protect Confidentiality
paragraphs: NMDP requires that each participating donor center have a system for  safeguarding donor confidentiality. The Registry identifies donors by code  number only. Donor centers maintain donor identity and location and limit  access to this information by using locked file cabinets and locked rooms.
NMDP also requires that each participating transplant center have a  system of confidentiality in place to protect the privacy of patients. It  provides that transplant patient identification should not appear on papers  or publications, and the patient’s name and location should not be  disclosed to the donor(s).
section_title: Marrow Collection and Transport
paragraphs: Organizations responsible for marrow collection and transport must meet  certain participation criteria in order to be affiliated with NMDP. Among  other things, participating cord blood banks must be accredited and  licensed or registered by the Food and Drug Administration for collection  of autologous blood. Marrow collection centers must provide emergency  and intensive care services and must be accredited by the Joint  Commission on Accreditation of Healthcare Organizations. In addition,  each collection center must have a licensed medical director, an  experienced marrow collection team that regularly collects bone marrow,  and a designated site for management of collection activities.
NMDP has established standards to ensure the proper collection and  transportation of marrow. These require that bone marrow collection  centers have experienced personnel to collect marrow and adequate  resources to support collection and management activities. In addition,  NMDP requires that collection centers maintain written standard operating  procedures and policies for collecting, testing, labeling, and transporting  marrow.
section_title: Laboratory Standards
paragraphs: Laboratories responsible for HLA tissue typing must meet certain criteria  in order to be affiliated with NMDP. Participating HLA typing laboratories  must be accredited by the American Society for Histocompatibility and  Immunogenetics (ASHI) or the European Foundation for Immunogenetics  for techniques required by NMDP. Laboratories must also comply with all  state and federal regulations, including the Clinical Laboratory  Improvements Amendments of 1988 (or their non-U.S. equivalent) for  infectious disease testing, blood typing, red cell antibody screening, and  other tests required by NMDP.
As part of NMDP’s quality control program, participating laboratories must  type blind samples provided by NMDP. The laboratories must maintain  monthly error rates less than or equal to 1.5 percent. If a laboratory fails to  meet quality control and quality assurance standards established by ASHI  or NMDP, NMDP may require that laboratory to submit a corrective action  plan. After the period allowed for corrective action, the laboratory’s  contract with NMDP may be terminated if it still does not meet the  standards.
From February 2000 through April 2002, NMDP suspended five  laboratories responsible for HLA tissue typing. The length of suspension  ranged from 1 to 9 weeks, and reasons for suspension were related to  electronic communication problems, overdue samples, and poor  turnaround time.
section_title: Donor File Maintenance and Updates
paragraphs: NMDP’s central database is updated when new donors are recruited and  when information on existing donors changes or donors are deleted from  the Registry. Information about newly recruited donors includes donor  identification numbers, demographic data, and the donors’ HLA types.  According to NMDP procedures, domestic donor centers submit data on  donors daily through NMDP’s central database.
section_title: Appendix III: Comments from the Health Resources and Services Administration
section_title: Appendix IV: GAO Contact and Staff Acknowledgments
subsections: section_title: GAO Contact
section_title: Acknowledgments
paragraphs: The following staff members made important contributions to this work:  Donna Bulvin, Charles Davenport, Donald Keller, Kelly Klemstine, Behn  Miller, and Roseanne Price.