The term “tissue” covers a wide range of products used for many medical purposes. Traditionally, most human tissue used in medicine comprised such body components as skin, bone, corneas, and heart valves that were transplanted for replacement purposes as well as semen and ova implanted for reproductive purposes. In recent years, scientists have developed innovative methods of manipulating and using human cells and tissues for therapeutic purposes. For example, in what is known as somatic cell therapy, scientists are studying the use of human cells that have been manipulated in the laboratory to treat viral infections, Parkinson’s disease, diabetes, and other diseases and conditions. Other tissue research includes the use of blood from the placenta and umbilical cord to treat leukemia and other diseases. Two events in the early 1990s initiated concern about the safety of human tissue recovered for transplantation. The first was the transmission of the human immunodeficiency virus from a donor to a number of recipients of the donor’s organs and fresh-frozen bone tissue. The other event was the importation from foreign countries of human tissue for which there was no record of source or testing for infectious diseases. As a result of these events, FDA issued interim regulations on December 14, 1993, to help prevent the transmission of HIV and hepatitis B and C. This action was taken under section 361 of the Public Health Service (PHS) Act (42 U.S.C. 264), which authorizes the secretary of HHS to make and enforce regulations necessary to prevent the introduction, transmission, or spread of communicable diseases from foreign countries into the United States or from state to state. The interim regulations provided for donor screening, documentation of testing, FDA inspections of tissue facilities, and the recall of potentially unsafe tissue, but they were limited in the types of tissue they covered. On July 29, 1997, FDA issued a final rule (to become effective January 26, 1998) for the regulation of human tissue intended for transplantation. The rule requires facilities engaged in the recovery, screening, testing, processing, storing, or distributing of human tissues to ensure that specified minimum required medical screening and infectious disease testing are performed and that records documenting screening and testing for each human tissue are available for FDA’s inspection. The rule also contains provisions for retaining, recalling, or destroying human tissue for which appropriate documentation is not available. However, the rule does not cover reproductive tissue and stem cells. In concert with the final rule, FDA issued guidance for industry for screening and testing donors of human tissue intended for transplantation. This document represents FDA’s current thinking on screening and testing donors and does not bind FDA or the public to its recommendations. Tissue facilities can choose to follow this guidance or alternatives. The document outlines recommended tests and algorithms for accepting donors and gives information pertaining to screening donors to determine their acceptability. CDC has also set forth voluntary guidelines for screening and testing for HIV and hepatitis B and C. In 1994, CDC published a guideline on preventing the transmission of HIV through the transplantation of human tissues and organs. The guideline outlined recommendations on donor screening, donor testing for infectious diseases, laboratory and other medical exclusionary criteria for donors, record keeping for tracking recipients and tissues, testing recipients, and recalling stored tissue. In 1991, a Public Health Service interagency guideline was published covering issues relating to the screening of donors of blood, plasma, tissues, organs, and semen for evidence of hepatitis B and C that included information on screening, testing, medical evaluations, and counseling. Several industry associations are also involved in standard setting, and some conduct inspections. These include the American Association of Blood Banks (AABB), the American Association of Tissue Banks (AATB), the American Society for Reproductive Medicine (ASRM), the Eye Bank Association of America (EBAA), and the Foundation for the Accreditation of Hematopoietic Cell Therapy (FAHCT). FDA has also circulated for public comment a proposed approach to the regulation of human cellular and tissue-based products that would provide oversight for the wide spectrum of cellular and tissue-based products that are marketed now or envisioned for the future. FDA plans to implement this approach iteratively, so it may be many years until the entire framework has the force of law. Broad in scope and ambitious in intent, the proposed approach is still in its formative stages and its final form is uncertain. Below we present information on the different processes between when a prospective donor is identified and when human tissue can be transplanted. (More detail is given in appendix I.) We also outline the role of industry associations and state regulations relating to human tissue. CDC has estimated that more than 400 facilities bank or process several hundred different types of human tissue. Some tissue facilities procure their own tissue and process it themselves. Other tissue facilities procure their own tissue but have it processed by an outside entity and then receive the tissue back from the processor for distribution to their clients (that is, hospitals and dentists). Some facilities receive tissue from other facilities for processing. An assessment of tissue suitability is based on an extensive medical, sexual, and social history completed by the next of kin of a cadaveric donor. Living donors complete their own histories. The tissue of donors who meet all acceptance requirements is retrieved under aseptic or otherwise clean techniques and quarantined until a blood sample sent for infectious disease testing for HIV and hepatitis B and C shows that the tissue is safe. Table 1 outlines the infectious diseases that have been transmitted by human tissue. Each donor is assigned a unique identification number to facilitate tracing tissues during processing and distribution. Processing procedures vary by tissue type. Some tissues undergo procedures to remove or inactivate viruses; others do not. Tissues that can be processed and sterilized include bone, tendons and cartilage, and fascia. These procedures can be employed on such tissues because they can function even though they are rendered acellular and nonviable. Cornea, skin, stem cells, and semen cannot undergo such processing because they contain viable cells that could be damaged. All tissues are stored in containers capable of withstanding appropriate storage conditions and are labeled with the tissue identification number, tissue facility name and address, expiration date (if applicable), acceptable storage conditions, disinfection or sterilization procedure and preservatives or potential residues of processing (if applicable), and an instruction to “see the package insert.” The package insert supplies additional information for the health professional, including possible contraindications and adverse reactions. Distribution information is recorded for tracking in the event that transplanted tissue is found to have come from a donor who is later identified as positive for an infectious disease. AATB has standards and an accreditation program for its members. AATB currently accredits 60 tissue facilities, while another 40 to 60 are not accredited. AATB inspects its member institutions for compliance with the standards. AATB has recently hired an inspector to inspect its member institutions, and this inspector has no affiliation with any tissue facility. Before this, tissue facilities inspected one another for accreditation purposes. AATB standards outline procedures for tissue facilities in the areas of record management, screening, tissue retrieval, processing, quarantine, labeling, storage, and distribution. Also, AATB standards have specific information relating to musculoskeletal, skin, semen, and cardiovascular facilities. EBAA has an accreditation program and standards for its members, and the American Academy of Ophthalmology independently reviews EBAA’s standards. These standards cover such issues as training and certification of eye-banking personnel, donor screening, procurement and preservation procedures, tissue evaluation, storage, labeling, and distribution. EBAA has 110 members; some eye banks are not members. As with AATB, EBAA inspects its member institutions. The approximately 315 individual members of ASRM are mostly reproductive medicine practitioners. ASRM is a professional organization but it does not certify or accredit sperm banks. There are about 150 assisted reproductive technology programs in the United States. CDC estimates that there are about 100 semen banks and an undetermined number of smaller semen banks based in hospitals or the offices of individual physicians. ASRM, in conjunction with the College of American Pathologists, sets standards for the accreditation of reproductive laboratories that include requirements for laboratory personnel, resources and facilities, and quality control and assurance. Approximately one-third of the reproductive laboratories in the United States are accredited. ASRM also has draft guidelines for therapeutic donor insemination and a guideline for oocyte donation. The latter includes appendixes on the minimal genetic screening for gamete donors and psychological assessments for anonymous and known oocyte donors. Guidelines for gamete donation were made final in 1993. FAHCT has initiated a voluntary standard-setting inspection and accreditation program that encompasses all phases of hematopoietic stem cell collection, processing, and transplantation. It is a nonprofit organization developed by the International Society of Hematotherapy and Graft Engineering (ISHAGE) and the American Society for Blood and Marrow Transplantation (ASBMT) for self-assessment and accreditation in the field of hematopoietic cell therapy. FAHCT has established quality standards for medical and laboratory practice in hematopoietic cell transplantation. They cover topics such as donor evaluation and selection, collection procedures, processing, cryopreservation, labeling, storage, transportation, and records management. FAHCT plans in the near future to conduct inspections and accredit programs that will encourage health institutions and facilities performing hematopoietic cell transplantation to voluntarily meet its standards. Recognition of compliance with the standards will result in certificates of accreditation. Additionally, AABB has standards on hematopoietic progenitor cells (that is, stem cells) that cover issues relating to donor selection, collection, cell processing, laboratory testing, labeling, storage, and distribution. The National Marrow Donor Program (NMDP) compiles statistics on the number of transplants from bone marrow, peripheral stem cells, and cord blood stem cells. The International Bone Marrow Transplant Registry collects data on allogeneic transplants performed worldwide. Information on peripheral and cord blood stem cell transplants has been collected since 1990. Transplants that NMDP facilitates must be reported to this registry; otherwise, reporting is voluntary. About 40 to 50 percent of the transplants are reported. In October 1996, NHLBI announced the first multicenter study of umbilical cord blood stem cell transplants from unrelated, newborn donors. The 5-year $30 million study is designed to show whether cord blood transplantation is a safe and effective alternative to bone marrow transplantation for children and adults who have a variety of cancers, blood diseases, and genetic disorders. The cord blood units will be collected at three facilities. The transplants will be conducted at seven centers using standard protocols for enrolling patients, preparing them for transplant, and treating them after transplant. A data-coordinating center will identify the units for transplant as well as collect the data from the study. Table 2 provides an overview of the relevant facts and figures associated with tissue banking in the United States today. Several states have promulgated regulations on specific standards required at particular types of tissue facilities. For instance, some states require sperm banks to register and to be inspected by state health departments, while other states have guidelines on the interpretation of tissue donor screening test results and the processing and storage of stem cells. CDC is currently establishing prototype regulations from which states could model their own regulations on reproductive tissues. CDC was mandated to do this by the Fertility Clinics Success Rate and Certification Act of 1992. CDC officials stated that the model laboratory certification program will closely mirror existing laboratory accreditation procedures formulated by the College of American Pathologists laboratory accreditation program. In addition to requiring CDC to establish model regulations, the act required assisted reproductive technology programs that assist infertile couples to report pregnancy success rates to CDC. Presently, California, Florida, Minnesota, and New York have regulatory programs or are working on legislation for reproductive tissue. Several states have also enacted three categories of corneal removal laws: (1) implied consent, in which corneas may be released to an eye bank when it is a medical examiner’s or coroner’s case, an autopsy is required, release would not interfere with a subsequent investigation, and there is no known objection by next of kin; (2) diligent or reasonable search, in which an effort must be made to contact next of kin within a specific time period before release of corneas; and (3) consent only, in which release is possible only when authorized next of kin consent has been obtained. According to EBAA, 12 states and Puerto Rico have implied-consent laws, 9 states have diligent search laws, and 6 states have consent-only laws. FDA’s current regulation on human tissue intended for transplantation covers several areas of tissue collection, processing, and storage, all relating to the control of hepatitis B and C and HIV transmission. These include (1) donor screening and testing; (2) requirements for written procedures for testing for infectious disease and obtaining, reviewing, and assessing the medical records of donors; (3) record keeping; (4) quarantining requirements; (5) FDA authority to inspect tissue facilities; (6) importation of human tissue; and (7) retention, recall, and destruction of human tissue. The proposed approach to the regulation of tissue and cellular-based therapies represents a move toward forward-thinking regulation of a diverse and rapidly advancing field. It is less prescriptive than traditional FDA regulation and it has generally been well received by industry. Although it is clearly open to broad interpretation, it would expand the current FDA oversight to include reproductive tissues and stem cells. The approach would focus on three main areas: (1) preventing unwitting use of contaminated tissues with the potential for transmitting infectious diseases, (2) preventing improper handling and processing that might contaminate or damage tissues, and (3) ensuring that clinical safety and efficacy are demonstrated for tissues that are highly processed (more than minimally manipulated), used for other than their normal function (nonhomologous), combined with nontissue components, or used for metabolic purposes. We have three concerns about omissions in the current regulation that FDA has identified and plans to address under its proposed approach: (1) lack of registration of tissue facilities, (2) some types of tissue facilities not covered under the current regulation, and (3) misleading and false advertising in cord blood banking. However, because the proposal will be promulgated iteratively, these omissions may remain for the foreseeable future. Unlike in other industries that FDA regulates, such as blood and implantable medical devices, FDA does not have an accurate list of tissue facilities in the United States because these facilities have not been and are not now required to register with FDA. Therefore, FDA can neither notify all tissue facilities as potential public health threats arise nor plan inspections from a complete registration of tissue facilities. FDA recognizes this deficiency and is drafting a regulation that would require registration. FDA previously inspected tissue facilities “for cause” but now intends to conduct a small number of routine inspections. According to data obtained from FDA on its inspection activities, the agency conducted 14 inspections in 1997. With resources of 2.8 full-time staff equivalents, the agency expects in fiscal year 1998 to inspect 44 of the approximately 200 known tissue facilities now covered by the current regulation. Adding reproductive and stem cell facilities and others currently not identified would increase FDA’s inspection burden. FDA officials have stated publicly that they will also rely on industry associations to monitor their members. However, among the approximately 400 known tissue facilities, fewer than half, or about 170, are accredited by industry associations. A complete registry of facilities would include nonmembers of industry associations and those that failed accreditation. While industry associations recommend standards for their member institutions, some facilities do not abide by them. For example, AATB standards state that anonymous semen donors should be younger than 40 years of age. However, some sperm banks collect donations from men older than 40. AATB standards also state that semen is not to be distributed to private individuals without a physician’s written order, but according to some in the industry, some sperm banks do, in fact, sell semen samples directly to private individuals. Furthermore, officials from ASRM stated that each semen donor is limited to 10 resulting pregnancies to limit the possibility of genetic offspring unknowingly intermarrying. However, some sperm banks do not abide by this limit. To date, FDA has inspected approximately 80 tissue banks and has issued 15 notices for the recall of tissues at 10 tissue facilities. FDA has also issued letters of opportunity for voluntary corrective action. For example, in a December 1996 letter, FDA notified one EBAA-accredited eye bank that it had procured eye tissues from 43 donors between December 1993 and January 1994 that were subsequently processed, distributed, and transplanted without any testing for anti-HIV 2. FDA has also performed an initial analysis of 30 Form 483s issued to 27 tissue facilities between January 1994 and June 1996 that resulted in 216 observations.Approximately half of these observations were related to section 1270.5(e) of the interim rule, which stated that it should be determined that a donor of tissue intended for transplantation is suitable, including ascertaining the donor’s identity and adequately completing and recording relevant medical histories to ensure freedom from risk factors for or clinical evidence of hepatitis B, hepatitis C, or HIV infection. Potential problems among association nonmembers and those that do not abide by industry standards, as well as clear problems identified in FDA initial inspections, illustrate that FDA inspection is necessary to maintain the safety of human tissue intended for transplantation. Only through registration of all tissue facilities will FDA have an adequate means by which to plan its inspection activities. Furthermore, while industry inspections can augment this process, only FDA has the legal authority, under the Federal Food, Drug, and Cosmetic Act, to impose actions such as injunctions and seizures of certain products. The current regulation does not cover facilities that collect, store, process, or distribute reproductive tissues or stem cells. Specifically, these facilities are not required to adhere to the requirement for infectious disease testing nor does FDA have direct authority to inspect these facilities for compliance with the current regulation. Reproductive tissues and stem cells can transmit hepatitis, HIV, human T-cell lymphotropic virus (HTLV), cytomegalovirus, and sexually transmitted diseases. Because work in both kinds of tissue is expanding, this represents a significant gap in FDA oversight. FDA recognizes the safety implications of this omission and would begin its oversight of these tissue facilities by including them in registration requirements. Little is known about the type and level of information that private cord blood facilities present to expecting parents, either in writing or orally. FDA has periodically monitored but not regulated this industry’s advertising practices. Techniques to collect, process, store, and transfuse cord blood are not well established, but this fact is not emphasized to prospective parents. If provided at all, the extremely low probability of ever requiring the cord blood unit for transplantation into the child or a family member is rarely, if ever, completely portrayed. Nor are parents always told of other sources of stem cells, such as peripheral blood and bone marrow, that can be collected and transplanted when they are needed. Current scientific knowledge suggests that umbilical cord blood stem cells are less likely to initiate graft versus host disease (GVHD) in a recipient than bone marrow and, perhaps, peripheral stem cells. However, new techniques and immune suppression therapies are constantly improving GVHD rates, thus increasing the likelihood that the future transplant needs of a family could be met without the costly collection and storage fees associated with cord blood. Moreover, because GVHD rates associated with the transplantation of unrelated—even highly genetically mismatched—cord blood stem cells from public banks appear to be so low, the need for a highly genetically matched family member is not the gravely important issue that it is in the transplantation of bone marrow stem cells. Table 3 illustrates the type of misleading and false information that prospective parents can find on the Internet as they research decisions to store their unborn child’s cord blood. For example, while one company claims that “autologous transplants are the most common type of transplant performed,” there have not, in fact, been any published reports of autologous cord blood transplants in patients for treatment of a malignant disease. Moreover, scientific controversy surrounds the use of a young child’s own stem cells to reconstitute a diseased immune system. We found unsubstantiated and exaggerated claims, both implied and explicit, in four areas relating to umbilical cord blood: its safety relative to bone marrow transplantation, scientific research establishing the feasibility and efficacy of transplanting it, the number and type of transplants to date, and the state of the art of collecting, processing, and storing it. Clearly, consumers have the right to collect and store umbilical cord blood for personal use. However, they should also be protected from misleading or inaccurate information, and the risks and benefits of other therapies should be made known to them. FDA officials are concerned about the types of information being provided to the public regarding umbilical cord blood and have engaged in discussions with the Federal Trade Commission regarding the regulation and monitoring of this industry. Under the proposed approach, FDA would provide some regulation of product claims for umbilical cord blood. We have two concerns about omissions in the current regulation that are not addressed in the proposed approach: (1) issues surrounding informed consent for cord blood and (2) the lack of requirements for the disclosure of genetic testing of reproductive tissues. The largest public cord blood facility that collects umbilical cord blood stem cells for use in unrelated allogeneic recipients usually obtains informed consent from the mother after the cord blood has been collected. This facility follows this practice because obtaining consent in advance can be highly problematic. For instance, some mothers do not receive prenatal care and, thus, do not afford the cord blood facility the opportunity to obtain informed consent before delivery. An FDA official stated that since the placenta and umbilical cord are normally discarded following delivery, these tissues typically become the property of the hospital. For other tissues removed and discarded (as in surgery), consent to collect portions for other uses is not generally required. Therefore, an argument can be made that consent is needed for umbilical cord blood testing and use but not collection. Two safety concerns are raised when informed consent is not obtained until after collection. First, the health implications to recipients of umbilical cord blood from mothers who may not have received prenatal care are currently unknown. Second, an essential safety control is to ask the mother a series of screening questions regarding her behavior and exposure to disease. A new mother might not answer truthfully questions on high-risk behavior (such as illicit drug use) that could otherwise result in removing her newborn from her care. The public cord blood bank that obtains consent after collection is operating under an FDA-approved investigational new drug (IND) protocol and has obtained institutional review board approval from the hospital where the cord blood is collected. The current cord blood banking protocols under FDA-approved INDs will provide the opportunity through data collection to assess the safety and risks of seeking informed consent after cord blood has been collected. Until these analyses have been conducted, the safety of seeking consent after delivery remains unknown. There is also an ethical concern in obtaining consent after collection. A recent consensus statement from the Working Group on Ethical Issues in Umbilical Cord Blood Banking noted that informed consent should be obtained before procuring placental blood for transplantation because not obtaining consent runs counter to the explicit reasoning behind informed consent—that is, providing an individual with the information and opportunity to make a decision before a procedure is performed. Obtaining consent before delivery affords the mother the opportunity to deliberate more fully on the decision before the birth. The National Heart, Lung, and Blood Institute (NHLBI) multicenter study examining cord blood transplantation will require consent before delivery. AABB’s accreditation requirements state that the informed consent of a blood, apheresis, or marrow donor must be obtained and documented before donation. However, FAHCT has provided for flexibility in obtaining informed consent after cord blood has been collected. FDA recommendations for blood donation note that informed consent should be obtained before each donation in language relating to potentially high-risk behavior. This allows the donor an opportunity to notify collection personnel and health care professionals with information that could protect them from infectious diseases. Neither FDA’s current regulation nor its proposed approach has language on disclosure of genetic tests that have been performed on donors of reproductive tissues that, when transplanted, could result in the transmission of genetic anomalies. Without such disclosure, recipients of these tissues lack vital information that, if available, might alter their decision to use tissues from such donors. Genetic anomalies in donated sperm or eggs can cause serious or fatal diseases. Donors may be unaffected carriers of these anomalies with no family history of such disease. Such genetic diseases arise when a child inherits an affected gene from both the mother and father. While some genetic diseases are more prevalent in certain ethnic and racial populations, the rise of interracial and mixed ethnic marriages makes these population distinctions less valuable as a screening tool (see table I.1). Studies conducted to determine, retrospectively, whether new tests to detect cystic fibrosis would find previous donors to be carriers found that of 149 actual donors, 5 were heterozygous carriers of the mutation for cystic fibrosis. Also, 1 of 100 donor applicants was found to be a heterozygous carrier. The researchers determined that the chance was 1 in 16,100 that an individual who had no family history of cystic fibrosis and who used a DNA-tested donor would bear a child with the disease. They concluded that it is important for donor banks to perform genetic screening for cystic fibrosis and that such screening “is a responsible policy that will eliminate most high-risk carriers.” AATB standards state that donors should be tested for Tay-Sachs disease, thalassemia, sickle cell trait, or cystic fibrosis if indicated by their family history or ethnic background. However, since AATB accredits only six reproductive facilities, it is not known how often such testing is performed. Genes for some diseases, such as those discussed above, are determinative when both parents pass them on and their offspring have the disease. Other genes are not determinative, such as the recently discovered gene for breast cancer; scientists still do not know what it means to carry this gene. Some reproductive tissue facilities go beyond the AATB standards and perform chromosomal analyses and testing for the gene that has been implicated in breast cancer. Genetic testing is an emerging science, none of these tests are 100-percent accurate, and FDA has not approved or cleared them for the intended use of screening reproductive donors; therefore, FDA does not plan to require that such tests be performed. However, we believe that consumers should know, for informed decision making, which facilities conduct such testing to maximize the safety of their products and which do not. Four issues not addressed in the current regulation are addressed in the proposed approach but in a manner that does not adequately eliminate potential safety problems: (1) the lack of error and accident reporting to FDA, (2) inadequate tracking systems, (3) the lack of safety and efficacy data on specific stem cell therapies, and (4) inadequate tissue-processing techniques. There are presently no federal requirements that tissue facilities maintain records for the reporting of errors and accidents or adverse events to FDA, even though this practice is required for similar types of industries such as blood banking. For example, the distribution of quarantined tissues or the inadvertent transplantation of tissue testing positive for infectious disease might go unreported. The proposed approach would require the reporting of adverse events associated with infectious disease transmission but not errors and accidents. FDA officials believe that requiring facilities to record and investigate errors and accidents without reporting to the agency even a subset of the most serious ones is sufficient to monitor the industry. In fact, FDA interprets section 361 of PHS (which authorizes regulations to control the spread of communicable disease) as authorizing regulations requiring the reporting of tissue failures based on problems associated with processing, among other events, because repeated tissue failures may require repeated tissue transplants, thereby increasing potential exposure to communicable disease. But because errors and accidents are often early warning signals of noncompliance or poor practices, FDA is missing an opportunity to identify tissue facilities that would benefit from additional FDA oversight. One recent FDA inspection found that a firm had distributed corneas before receiving test results showing that one cornea had tested positive for HIV. The proposed approach, if implemented as written, would not require the reporting of incidents such as this one. We found that FDA’s tracking system for identifying recipients of transplants that may have been virally infected is incomplete. For example, when attempting to track recipients of a donor who tested negative on the first-generation hepatitis C test but positive on the second-generation test, researchers found that 1 of 16 grafts released for distribution from this donor was sent to a hospital that had no record of the graft. This made it impossible to notify the recipient of this graft of his or her potential exposure to hepatitis C. Additionally, a study conducted in 1993 by one tissue facility found that 23 percent of the hospitals that it surveyed had no tracking system. Another facility had only a 65-percent compliance rate for reporting the final disposition of tissues that it distributed. A 1994 survey of 54 tissue facilities reported that only 34 percent of the respondents were always capable of identifying the patient who received their tissues, and only 10.5 percent routinely received feedback on tissue use from hospitals. AATB standards state that the records management system of a facility should permit the reciprocal tracing of tissues from donors to those who receive them and back. Also, the standards state that upon discovering the need for recalling tissues, facilities should promptly notify all entities to whom affected tissue was distributed or dispensed. For this reason, some within the tissue industry have called for regulations requiring that receiving institutions or clinicians be responsible for keeping records of the final disposition of tissues so that tissue facilities can identify recipients of tissues that might be contaminated. Moreover, a CDC guideline for preventing the transmission of HIV through the transplantation of human tissue and organs recommends that all facilities involved in the acquisition of tissues or organs from a single donor be able to communicate among themselves for the purpose of tracking tissues and organs to recipients who should be notified when HIV transmission is confirmed. Imposing tracking requirements is not without precedent within FDA. Presently, the Center for Devices and Radiological Health has a tracking requirement for approximately 20 percent of the devices it regulates that is based on the potential for serious adverse health consequences. Specifically, section 519(e) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360i) requires that manufacturers track certain devices from the manufacturer through the distribution chain to the patient. Devices covered under this section include heart valves, vascular grafts, breast and penile implants, and pacemakers. This tracking permits manufacturers to directly notify patients of a recall when a problem has been identified. Similarly, blood facilities are required to track units from donors who subsequently test positive for HIV to the recipients of those units (C.F.R. 610.47(b)). To date, however, a significant gap remains in the tracing of tissues. FDA officials stated that the proposed approach addresses this problem, but tissue tracking is mentioned in the proposed approach only as an example of good tissue practices and its role in the transmission of communicable diseases. Under the proposed approach, tissues transplanted from one person to another for their normal function (homologous use) without undergoing extensive processing (minimal manipulation) would be subject to infectious disease screening and testing, and to requirements for good tissue practices, but would not need FDA review or premarket approval.Thus, most processors of conventional and reproductive tissues would not be required to submit information about their products to FDA or to seek its permission to market those products. The proposed approach would require premarket approval for tissues that were processed extensively (more than minimally manipulated), combined with nontissue components, used for purposes other than their normal function (nonhomologous use), or contained a metabolic mode of action. This latter category would include stem cells that were obtained for allogeneic use, defined in the proposed approach as unrelated allogeneic transplants. Stem cells that were obtained for autologous use or from a close blood relative (related allogeneic) would not require FDA approval. A current moratorium on the requirement for IND and premarket approval applications allows the stem cell community time to collect information that may provide FDA with adequate data to promulgate standards. If sufficient data do not become available to establish processing and product standards after a specified period of time, stem cell products will be subject to IND and marketing application requirements. The approach notes that FDA intends to invite professional groups and individuals to submit data and standards that they believe would ensure the safety and effectiveness of stem cell transplantation. FDA intends to list in the Federal Register questions relevant for collecting data on volume, storage temperature limits, limits on microbial or other contamination, viable cell number, and functionality. In addition, FDA will request information on procedures for handling, transporting, storing, and thawing materials and for when and how contamination and viability testing should be carried out. For several reasons, we are concerned about the demarcation that the proposed approach makes between unrelated allogeneic and related allogeneic donations. Efficacious collection, processing, and storing methods are not yet well characterized within the cord and peripheral blood stem cell community. The mitigation of this problem is not related to the source of stem cells (autologous, family-related, or unrelated allogeneic), even though the proposed approach makes a demarcation between the source of the stem cells and whether premarket approval should be required. Furthermore, the academic medical community considers the collection of data on the safety and efficacy of umbilical cord blood transplantation to be at the investigational phase. For example, a 1996 scientific research report of 18 allogeneic transplantations described its research as “a phase I clinical trial.” Stem cells from umbilical cord blood are typically collected by attending obstetricians or nurses during delivery. Most collections are performed by medical personnel who have had no formal collection training and, indeed, may be collecting cord blood for the first time. Meanwhile, research has shown that different collection and processing techniques affect levels of bacterial contamination and the viability of cells. For example, the rate of bacterial contamination was 3.3 percent for collections that used closed systems and 12.5 percent for collections that used open systems. Cord-clamping time was also found to influence the volume of cord blood collection and, therefore, the potential to obtain more stem cells. However, many facilities instruct obstetricians to “clamp the cord as you normally would.” Additionally, the efficacy of separation procedures to obtain stem cells from the cord blood was markedly reduced when the cord blood samples were stored for more than 12 hours before separation. Cord blood collected for private banking is usually not processed before 24 or even 48 hours. The investigators also questioned the validity of some traditional methods of determining the potential for the collected cells to engraft sufficiently to restore a patient’s immune system. Similarly, much is still not known about the optimal collection and assessment of viable stem cells from peripheral blood. Because the pluripotent hematopoietic stem cell has not yet been isolated, all current methods of measuring the efficacy of the collection and quality of peripheral or cord blood progenitor cells are indirect. Some studies have examined collection and processing methods to determine which ones yield more viable stem cells for transplantation, but investigators have noted that the protocols and procedures used to collect peripheral blood cells have not been standardized. While some information points to greater success in transplants from related donors, the factors that influence the success of cord blood transplants are just emerging. For example, recent research has pointed out that patients who received cord blood from an unrelated donor had significantly lower estimates of survival at 1 year—29 percent versus 63 percent for recipients of related donors. As with bone marrow transplants, greater success was achieved with a donor with identical human leukocyte antigen (HLA), which is more likely to occur with a related donor. GVHD was different between HLA-matched and unmatched donors and recipients. GVHD occurred in 9 percent of 60 recipients of HLA-matched cord blood and in 50 percent of 18 recipients of mismatched cord blood. However, none of the GVHD cases were life-threatening. This study also found that for the 143 transplants examined at 45 participating centers, methods of collecting, cryopreserving, storing, and thawing cord blood varied widely. For example, the number of cells infused after thawing ranged from 7 million to 300 million. This factor was a significant predictor of successful outcomes. Other important factors included a recipient’s age and weight, diagnosis, and cytomegalovirus-negative test results. As a result of the issues raised above, some experts in the field of stem cell transplantation have noted that FDA should require premarket approval for cord and peripheral blood stem cell transplantation, whether or not the cells were obtained from a close blood relative or a stranger, because such transplants are not yet well characterized. Other experts in stem cell transplantation from both academia and industry, including FACHT and the American Society for Clinical Oncology, have opposed such an approach. Private cord blood banks also disagree, stating that they would be put out of business by premarket approval requirements because federal statutes forbid profitmaking when a product has premarket approval status. In sum, several safety issues arise when transplanting metabolic cells. Stem cells and other products characterized by a metabolic mode of action usually rely on viable, functioning cells. They are therefore sensitive to collection, processing, and storage perturbations and may not retain normal function after transplantation. Because transplantation therapy is routinely used to reconstitute the blood of patients whose own defective blood cells have been completely destroyed by chemotherapy or irradiation, the failure or improper functioning of such products could end in a broad variety of systemically adverse events, including death. We are concerned that the state of knowledge about these tissue therapies is not well characterized and poses equivalent risks to recipients whether the source of stem cells is a relative or an anonymous donor. The proposed approach considers the processing of cells and nonstructural tissues to be more than minimal manipulation when it alters the biological characteristics (and, thus, potentially the function or integrity) of the cells or tissues or when it is unknown whether it will alter them. Examples include cell expansion, activation, and genetic modification. More than minimally manipulated cells or tissues would be subject to processing controls and to premarket requirements to determine safety and effectiveness. FDA would evaluate the processing techniques in the course of reviewing premarket applications and would inspect firms to assess their operations and review their processing techniques before granting marketing approval. The proposal is different for minimally manipulated tissues. For these tissues, FDA would require that the validation of the procedures be documented and available when FDA inspects a facility but would not require the submission of any information on processing. The proposed approach considers the processing of cells and tissues to be minimal manipulation when it does not alter their original relevant characteristics, such as those relating to the ability of cells or tissues to carry out the function of reconstruction or repair. Examples include cutting, grinding, and shaping; soaking in antibiotic solution; sterilization by ethylene oxide or gamma irradiation; cell separation; and cryopreservation. Tissues that were processed with minimal manipulation would be subject to good tissue practices relating to contamination, integrity, and function that FDA would establish in future rulemaking. However, FDA currently has limited information on which to base criteria for these practices, and we found few processing techniques that had been validated by tissue facilities and evaluated by FDA for safety and effectiveness. In several interviews, we obtained information regarding processes some facilities use that may be harmful to the efficacy of tissues or that have no established safety or efficacy record (for example, the use of bleach and peroxide or “air drying”). We did not independently verify what we were told. Below, we present information we gathered from these interviews and from the scientific research that highlights potential safety and efficacy issues. Some procedures that remove or destroy bacteria hamper the ability of tissue to remain viable. For instance, sterilization can destroy the viability of grafts, and irradiation and freeze-drying both reduce biomechanical strength. Therefore, cryopreserved skin, heart valve, and osteochondral bone grafts cannot be treated with these methods. Furthermore, chemical sterilization by exposure to ethylene oxide or demineralization techniques may adversely affect the regenerating properties of bone, although the evidence is controversial. Similarly, although many tissue facilities use dimethyl sulfoxide in their cryopreservation practices, FDA has not approved this product for such purposes. Ethylene oxide has been used with fluorocarbon (or freon) in an inactivation technique for tendons. However, it has been shown to result in residuals that were carcinogenic and deteriorated the tendons. Some tissue facilities use bleach and peroxide on bones, although this causes structural weaknesses. Also, other facilities have advertised the use of “air drying,” although this technique is unfamiliar to some tissue facility officials as an efficacious tool for inactivation. Gamma radiation is also used to process bone. For weight-bearing transplants, this process has been found to increase susceptibility to fracture (not all processors use this technique, but some do). Irradiation may be a good viral inactivation procedure, but it can cause mechanical problems in the processed bone. Although some physical and chemical agents have been shown to reduce the likelihood of isolating virus from treated solid tissues, we found no conclusive evidence that those processes render solid tissue completely safe and structurally intact. In a case of HIV transmission through the use of fresh-frozen bone allografts from a donor who was negative on HIV screening but who infected four organ recipients and three of four recipients of fresh-frozen bone, it was found that more than 25 other recipients of tissue from this donor did not become infected. The latter group were transplanted with tissues that were relatively avascular; thus, it is unclear whether HIV transmission was absent because of processing or vascularity or both. Although processes used to clean, sterilize, and render infectious agents harmless may affect the safety and efficacy of the tissue being processed, FDA officials agree that they have little information about the types of techniques currently in use and that they have not specified the processes that can be used safely and efficaciously. The proposed approach would require that facilities validate their procedures for safety and efficacy and make this information available to FDA upon inspection. However, the proposed approach would not require facilities to notify FDA of processing techniques defined as minimal manipulation, nor would facilities be required to submit safety and efficacy data on those processes. Submitting this information to FDA would provide the agency with a baseline understanding of industry practice. In its proposed approach, FDA addresses three problems we identified as not covered in the current regulation: registration of tissue banks, oversight of reproductive and stem cell facilities, and false product claims. However, the proposed approach is still in its formative stages and will be codified over a number of years. Until then, these concerns will remain. We identified two problems that are not addressed in either FDA’s current regulation or its proposed approach. We found that some public umbilical cord blood banks obtain informed consent after collecting the blood. The safety implications of using units from mothers who may not have received prenatal care or who are called upon to answer questions postcollection about high-risk behavior are unknown. Requesting informed consent before delivery provides the mother with the information and opportunity to make a decision before a procedure is performed. Second, the lack of disclosure of genetic testing for donated reproductive tissues limits vital information that, if otherwise available, might alter a recipient’s decision to use tissues from donors who could introduce genetic anomalies. In four instances, we found that the proposed approach addresses issues that are not covered in the current regulation but does so in a manner that is inadequate to eliminate potential safety problems. First, the proposed approach would not require the reporting of any errors or accidents, even those that could have serious consequences. Without such reporting, FDA will miss an opportunity to provide warranted oversight. Second, FDA has an inadequate system for tracking tissues to recipients from donors who are later determined to have been virally infected or whose tissues should otherwise not have been transplanted. The inability to trace potentially infectious or otherwise hazardous tissues could have serious public health consequences. Third, FDA plans to require premarket approval for therapies using stem cells if the cells are obtained from an unrelated allogeneic donor. As a matter of policy, FDA will waive this requirement if the cells are obtained from oneself (autologous) or from a close blood relative (related allogeneic). However, the scientific community has not determined optimal collection, separation, processing, and storage procedures for these cellular-based tissues. Because these products are used to reconstitute a patient’s entire immune system, the treatment poses great risk, regardless of whether the source is a relative or an anonymous donor. Fourth, we found that facilities have validated and FDA has evaluated few processing procedures. Some procedures currently in use may, in fact, harm the viability of grafts, reduce their biomechanical strength, and negatively affect the regenerating properties of bone. Without baseline knowledge of industry practice, FDA is hampered in its ability to fully monitor the safety of this aspect of human tissue banking. We believe that steps that would generally incur minimal additional cost to the tissue-banking industry could be taken to address these concerns. Many of these steps, requiring little change in the majority of tissue-banking facilities, would correct practices that are not up to industry standards. Two areas could require that additional, more costly, steps be taken: the creation of a system for tracking tissues to recipients and the imposition of premarket controls upon related allogeneic stem cell therapies if FDA determines that adequate safety and efficacy data are not available after the moratorium it has proposed. However, we believe that actions should be taken if risks outweigh costs, as we believe is likely. We recommend that the Secretary of the Department of Health and Human Services direct FDA to take action in several areas to improve the safety and efficacy of donated human tissue and to increase FDA’s ability to regulate tissue facility activities. FDA should move ahead with its plan to require tissue facilities, including reproductive and stem cell facilities, to register with FDA; reproductive and stem cell facilities to adhere to all requirements of the current regulation; facilities that collect and store cord blood to provide accurate oral and written communication to consumers with regard to the state of knowledge of collection, processing, and storage techniques, as well as the likelihood of requiring cord blood transplantation, and to portray the risks and benefits relative to other therapies. FDA should also add to its oversight plans provisions that would require tissue facilities to obtain informed consent before procuring any tissues intended for transplantation from living donors; disclosure of genetic tests that have been performed on donated reproductive tissues; tissue facilities to report serious error and accidents to FDA (“serious” to be defined in consultation with industry representatives); facilities that collect, store, process, distribute, or transplant human tissues to establish validated systems to track tissues to consignees and recipients; tissue facilities that collect, store, process, or distribute allogeneic peripheral stem cells or any cord blood stem cells to make premarket submissions if FDA determines that adequate safety and efficacy data are not available to license such products; and tissue facilities to inform FDA of the types of processing techniques used on tissues and to supply information on the safety and efficacy of these techniques. In commenting on a draft of this report, FDA generally concurred with our recommendations to require (1) the registration of all tissue facilities with FDA, (2) adherence of reproductive and stem cell facilities to all the requirements in the current regulation, (3) accurate labeling and promotion by facilities that collect and store cord blood, (4) disclosure to recipients of genetic tests performed on reproductive tissues, and (5) validation of systems to track tissues to consignees and recipients. The agency partly concurred with our recommendations on (1) reporting errors and accidents to FDA, (2) requirements for premarket submissions by peripheral and cord blood stem cell facilities, and (3) tissue facilities’ informing FDA of the types of processing techniques they use and the safety and efficacy data of these techniques. FDA agreed that adverse events should be reported to the agency but pointed out that reviewing error and accident reports would cost resources for both FDA and the industry and that current budgeting constraints would not allow FDA to review and evaluate such reports. We understand the fiscal ramifications of requiring error and accident reporting, and it is for this reason that we recommended that only “serious” errors and accidents be reported to FDA. FDA noted that it intends to require premarket applications for unrelated allogeneic cord blood stem cells but would not require such submissions for family-related allogeneic transplants because FDA was trying to accommodate the needs and concerns of families. However, we are unaware of safety issues that would be relevant only for unrelated allogeneic cord blood transplants. For this reason, we recommended that facilities that collect, store, process, or distribute peripheral or cord blood stem cells make premarket submissions if FDA determines that adequate safety and efficacy data are not available to license such products. FDA also pointed out that while it intends to review the processes tissue facilities use before approving highly manipulated tissue products, it will require validation to be documented and available during FDA inspections for procedures involving only “minimal” tissue manipulation. However, we are concerned about the time that could elapse before the agency learns about the safety and efficacy of these processes. Because FDA does not plan to conduct routine inspections of tissue facilities, the agency may not have the opportunity for many years to evaluate the documentation. FDA did not concur with our recommendation that informed consent be obtained from living donors before procuring tissues intended for transplantation. The agency believes that seeking informed consent for the use of cord blood after collection does not raise any additional safety concerns, but it states that current investigational protocols will provide the opportunity to assess this. We point out that obtaining informed consent before infant delivery affords mothers sufficient time to deliberate decisions before procedures are performed. FDA’s comments and our response are provided in greater detail in appendix II. The agency provided a number of technical comments that we have not reprinted but did incorporate into the report as appropriate. As we arranged with your office, unless you publicly announce the report’s contents earlier, we plan no further distribution until 15 days after it is issued. We will then send copies to the Secretary of the Department of Health and Human Services, the Commissioner of FDA, and others who are interested. We will also make copies available to others upon request. If you have any questions or would like additional information, please call me at (202) 512-7119 or Marcia Crosse, Assistant Director, at (202) 512-3407. Major contributors to this report are listed in appendix III. Ideally, each potential tissue or organ donor encounters only one organization capable of performing all aspects of the donation process, but this rarely occurs. Indeed, donors of multiple tissues or organs may encounter as many as 10 different transplant-related programs. Tissue donors who also donate organs are coordinated by the federally designated organ procurement organization (OPO) in the area. Organs are almost always recovered from heart-beating donors, but they may also be collected from nonheart-beating donors. In the case of organ donation, the OPO is usually the main point of contact for the many steps between contacting the family of a potential donor and tissue or organ recovery. While the screening requirements and procedures of OPOs and tissue banks are basically the same, they do sometimes differ. Moreover, while OPOs are generally required by law to establish agreements with tissue facilities operating within the same service area, the coordination between an OPO and its associated tissue facility is determined without definitive method by individual facilities. Tissue brokers may procure tissue and distribute it but do not track it after they have sent it to other tissue banks or organ procurement organizations. Even these brokers will be considered tissue facilities under FDA’s proposed approach. Tissue processors obtain tissue from different sources (OPOs, medical examiners, and tissue facilities) and are charged with processing the tissue. Some processors procure and process their own tissue as well as process tissue for other facilities; others work through contractual agreements with OPOs, medical examiners, and tissue facilities. Tissues that are procured from donors include musculoskeletal tissues (bones, tendons, and cartilage), corneas, skin, reproductive tissues, and stem cells. Tissues are recovered from two types of donors and the procedures for accepting these donors vary slightly. Living persons can donate reproductive tissue in the form of sperm or eggs, stem cells from circulating blood or placenta or umbilical cord blood, eye tissue, and surgical bone recovered incidentally to a medical procedure. Bone, connective tissue, eye tissue, skin, and heart valves can be taken from cadavers. Private cord blood banks collect and store cord blood for use in the event of disease in the infant or family members. These facilities have emerged in recent years in response to some scientific evidence suggesting the benefits of cord blood transplantation over traditional bone marrow transplantation. Consumers pay about $300 to $1,700 for the collection, processing, and testing of the unit and an annual storage fee of about $100. Public cord blood facilities also collect and store umbilical cord blood stem cells for allogeneic use in unrelated recipients. While there are no storage fees at these facilities, they charge transplant centers a fee (approximately $15,000) for obtaining, processing, and storing the cord blood. While policies and procedures vary by institution, the American Association of Tissue Banks (AATB) has clear standards for the acquisition of tissues. If a prospective cadaveric donor meets basic acceptance requirements for time and cause of death, the family is approached for consent. Foundation for the Accreditation of Hematopoietic Cell Therapy (FAHCT) standards require informed consent from maternal donors of umbilical cord blood before or within 7 days of the delivery of the child. Screening questions focus mainly on risk behaviors for infectious disease, genetic abnormalities, and degenerative neurological disease. The importance of following all screening steps is underscored by research at one tissue facility that found that 9.8 percent of 1,000 donors whose families provided a medical history negative for risk factors were rejected on disease testing or autopsy. Table I.1 outlines the suitability criteria established by AATB. Significant active infection (septicemia, systemic viral disease, untreated syphilis, active tuberculosis, systemic mycosis) (continued) History of receiving pituitary-derived human growth hormone History of dementia or degenerative neurological disorders of viral or unknown etiology HIV or hepatitis risk factor Current malignancy (except as noted above) History of leprosy (Hansen’s disease) In addition to these AATB criteria, standards the Eye Bank Association of America (EBAA) has established for eye donors include the rejection of donors with an unknown cause of death, active encephalitis, progressive encephalopathies, congenital rubella, Reyes syndrome, rabies, and intrinsic eye disease or certain prior eye surgeries. A physical examination checks for signs of intravenous drug use, recent tattoos or body piercing, swollen glands, and other indications of possible infection. The tissue facility’s medical examiner reviews autopsy findings. Donors who have received blood or fluid transfusions may have blood that is too diluted to detect infection, and a pretransfusion or infusion sample is then sought. If none is available, the donor’s medical records should be examined to determine the acceptability of postransfusion or postinfusion blood specimens. Each tissue facility is also to develop a procedure for determining whether a postransfusion or postinfusion specimen can be used. This plasma dilution algorithm is to be used to determine if the amount of blood loss and fluid replacement is below the threshold that renders a postransfusion or postinfusion blood sample invalid for accurate testing of the donor’s own blood for infectious diseases. If the results are above the threshold and no pretransfusion or preinfusion sample exists, the donor is rejected. After death, cells in the blood system burst, creating a state known as hemolysis. Hemolyzed blood samples can lead to false positive test results, which is why test kit manufacturers caution against using such samples. False positive tests result in the destruction of donated tissue that is probably not infected and is, therefore, safe for use; they also cause undue concern among relatives who are notified of the donor’s test results. Confirmatory tests often indicate noninfectivity, but these results cannot be used to invalidate possible false positives on initial tests. FDA is currently working with viral test kit manufacturers to validate these kits for use on cadaveric samples. However, because the number of donors is so few, the economic motivation for manufacturers to do so is low. Current regulations require that currently licensed test kits are to be used until FDA has given its approval and labeling of the test kits has been modified to specifically indicate their use for cadaveric blood specimens. Processing musculoskeletal tissue varies but tends to follow certain procedures to ensure its safety. Processing occurs in clean, aseptic rooms. Single-donor processing uses air filtration and the tissue is cleaned with high-pressure lavage and ultrasonic techniques. It is also soaked in antibiotic and ethanol solutions and irradiated at low doses. It is then cut and shaped to certain specifications and is preserved by freezing or freeze-drying. Grafts are also cultured for microbiological testing. Tendons and ligaments do not go through an alcohol-processing step as bone does (alcohol is used as a defatter). Skin is either cryopreserved or processed nonfrozen. Cryopreservation often begins within 72 hours of procurement, although AATB standards allow 96 hours. Skin is placed in a preservation solution that is then replaced with 10-percent to 15-percent glycerol and allowed to incubate 20 to 60 minutes before freezing. Standards from AATB state that final cultures should be performed for specific organisms (for example, serratia, yeast or fungi, or proteus). AABB standards note that refrigerated skin is to be stored no longer than 14 days. Corneas are excised and placed in a culture medium that is an FDA-approved medical device (there is only one manufacturer of this medium). A cornea can stay in the medium for up to 1 week but the usual time is 3 days. Corneas can also be cryopreserved, although this is rarely done. They are stored in liquid nitrogen with a cryoprotective agent, such as dimethyl sulfoxide, to prevent the formation of damaging intracellular ice crystals. Donated semen can be used for both intrauterine and intracervical insemination. Processing donated semen for intrauterine insemination involves washing the ejaculate specimen to remove the seminal plasma contents before freezing. Specimens are then resuspended and frozen with a buffer (such as egg yolk citrate). Motility and total motile cells/ml are the same for both types of insemination. Semen that is shipped is usually kept in liquid nitrogen containers that keep the semen frozen for 7 to 10 days. Cord blood is preserved in the short term in a liquid state in FDA-approved CPD anticoagulant for 24 hours at 1 to 6 degrees Celsius. It can also be stored after being cryopreserved in liquid nitrogen with dimethyl sulfoxide for 3 to 5 years at –85, –135, or –185 degrees Celsius. The frozen cells are thawed in a water bath, a dextran-albumin mixture is added, and the cells are then centrifuged. The supernatant, which contains the dimethyl sulfoxide, is then removed, and the cells are resuspended in more detran and albumin and are transfused. This results in an increase in viable cells and an increase in colony-forming unit recovery over time. It also allows for the manipulation of the cells after thawing. The following are GAO’s comments on FDA’s October 23, 1997, letter. 1. We believe that the current umbilical cord blood banking protocols, operating under FDA-accepted INDs, will be worthwhile in ascertaining the safety consequences of obtaining informed consent for cord blood collection after delivery. This information should be used to determine the manner and time at which collection is to take place. However, it should be noted that a working group on ethical issues in cord blood banking concluded that informed consent should be obtained before procuring placental blood for transplantation because not obtaining consent before delivery does not allow mothers to make decisions before collection.Additionally, obtaining consent before birth accords mothers sufficient time to deliberate any decisions they might have made before the collection began. 2. We believe that FDA’s requirement that facilities maintain records of error and accidents and make them available for FDA review during inspections is worthwhile. However, we believe that serious errors and accidents, such as the distribution of unacceptable tissues, should be reported to FDA so that the agency may take immediate action if such problems threaten the public health. Presently, FDA might not learn of such incidents until after it has performed an inspection. FDA officials have noted that they do not plan to conduct routine inspections of tissue facilities. Furthermore, FDA’s present authority to seize tissue products and enjoin tissue facilities is available only for products that are more than minimally manipulated, nonhomologous, and so on. By requiring tissue facilities to report serious errors and accidents, FDA would be able to obtain information pertinent to activities that might compromise human tissue safety or effectiveness. 3. We understand that FDA intends to allow the cord blood stem cell community time to collect information that would provide the agency with adequate data to promulgate standards. FDA officials have stated that if they cannot determine that adequate safety and effectiveness data are available, unrelated allogeneic cord blood stem cell transplants would require an IND. These officials have also noted that an IND would not be required for family-related allogeneic stem cell transplants because FDA is trying to accommodate the concerns and needs of families. However, as we point out in our report, different collection and processing techniques can affect levels of bacterial contamination and the viability of the stem cells, and collection, processing, and storing methods are not yet well characterized within the cord and peripheral blood stem cell communities. The mitigation of these problems is not related to where one obtains these stem cells (autologous, family-related, or unrelated allogeneic). As a result, there is no scientific basis on which to make a demarcation for premarket submissions based on the source of the stem cell, and we believe that patients whose source of stem cells is a family member should be afforded the same safety considerations as those who obtain stem cells from someone unrelated. 4. We agree with FDA’s position that certain products should require premarket review (for example, more than minimally manipulated or not homologous) that would also include an evaluation of their manufacturing processes. We also agree with FDA’s position that tissue facilities should be required to validate processing procedures for products that do not fall under such categories and have documentation available for FDA inspection. However, we have provided information in our report on processing techniques that may result in only minimal manipulation but may destroy the viability of grafts, affect biomechanical strength, and hamper the regenerating properties of bone. Thus, we are concerned about these processes still being employed before the codification of a requirement to maintain validation studies. Additionally, since FDA does not intend to conduct routine inspections of tissue facilities, the agency will not have adequate opportunity to evaluate the documentation of these validation studies. Once facilities are required to document the validation of their procedures, it would pose little burden to ask that the documentation be submitted to FDA rather than waiting for inspections. For these reasons, we believe that information on these processing techniques should be provided to FDA so that the agency can ascertain their safety and efficacy in a timely manner. Marcia Crosse, Assistant Director Jacqueline D’Alessio, Project Manager Kurt Kroemer, Senior Social Science Analyst David Michaels, Evaluator Roy Hogberg, Adviser The first copy of each GAO report and testimony is free. Additional copies are $2 each. 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Summary: Pursuant to a congressional request, GAO evaluated the Food and Drug Administration's (FDA) oversight of transplanted human tissue as well as potential safety problems, focusing on: (1) gaps in the current regulation; and (2) whether and how FDA plans to address them in the approach it has proposed for regulating tissue banking. GAO noted that: (1) FDA is just now expanding its oversight to improve tissue-banking safeguards in the growing field of tissue-based therapies; (2) FDA has proposed a regulatory approach that is much broader in scope than the current regulation; (3) still in its formative stages, the regulatory approach describes a risk-based approach that industry has generally received well; (4) FDA's proposed approach would alleviate three safety problems not covered by the current regulation: (a) FDA has no universal registry of tissue facilities currently operating in the United States; (b) the current regulation does not cover reproductive tissue or stem cell facilities; and (c) there are numerous instances of misleading and false advertising in private cord blood banking; (5) two problems that FDA does not address in the current regulation or in the proposed approach are: (a) some facilities obtain informed consent after infant delivery, raising safety and ethical concerns about cord blood; and (b) FDA has no current or proposed requirements for disclosing to recipients whether genetic tests have been performed on reproductive tissues and stem cells; and (6) four instances in which FDA's proposed approach inadequately addresses potential safety problems not covered in the current regulation are: (a) facilities would be required to record and investigate errors and accidents but not to report them to FDA; (b) the proposed approach only minimally mentions tracking tissues as good tissue practices and then only in respect to controlling disease transmission; (c) FDA will not require premarket submissions when cells or tissues are to be used in the person from whom they are obtained or in a close blood relative; and (d) FDA has proposed that certain tissue products be subject to premarket approval and that it evaluate processing techniques used on those products, but, for minimally manipulated tissue products, would require only that the validation of the procedure be documented and available when FDA inspects facilities.