Hematopoietic stem and progenitor cell transplants: regulation and accreditation

Pediatr Transplantation 2003: 7 (Suppl. 3): 101 108 Printed in UK. All rights reserved Copyright Ó 2003 Blackwell Munksgaard Pediatric Transplantation ISSN 1398-2265 Hematopoietic stem and progenitor cell transplants: regulation and accreditation Warkentin PI. Hematopoietic stem and progenitor cell transplants: regulation and accreditation. Pediatr Transplantation 2003: 7 (Suppl. 3): 101 108. Ó2003 Blackwell Munksgaard Phyllis I. Warkentin University of Nebraska Medical Center, Omaha, NE, USA Phyllis I. Warkentin, University of Nebraska Medical Center, 982168 Nebraska Medical Center, Omaha, NE 68198-2168, USA Tel.: +1 402 5597257 Fax: +1 402 5596782 E-mail: pwarkent@unmc.edu This is an era of increasing and rapidly evolving regulation in the field of hematopoietic stem and progenitor cell therapies. This is occurring, in part at least, because of serious issues raised in the early 1990s about the safety of human tissue used for transplantation. The primary concern at that time was the potential for transmission of HIVand/or one of the hepatitis viruses through transplantation from an infected donor. Interim federal regulations regarding donor infectious disease screening were implemented in 1993 and finalized in 1997, with the intent to add more extensive requirements in the future (1, 2). At the same time, there is considerable debate concerning the appropriateness and necessity of governmental regulation, as well as the effectiveness, Abbreviations: AABB, American Association of Blood Banks; ASBMT, American Society for Blood and Marrow Transplantation; CBER, Center for Biologics Evaluation and Research; CDRH, Center for Devices and Radiological Health; CFR, Code of Federal Regulations; cgtp Current Good Tissue Practices; CJD, Creutzfeldt Jakob disease; FACT, Foundation for the Accreditation of Cellular Therapy; FAHCT, Foundation for the Accreditation of Hematopoietic Cell Therapy; FDA, Food and Drug Administration; HCT/Ps, human cells, tissues, and cellular and tissue-based products; HIV, human immunodeficiency virus; HPCs, hematopoietic stem and progenitor cell products; HRSA, Health Resources and Services Administration; ICCBBA, International Committee for Commonality in Blood Banking Automation; ISBT, International Society of Blood Transfusion; ISHAGE, International Society for Hematotherapy and Graft Engineering; ISCT, International Society for Cellular Therapy; NMDP, National Marrow Donor Program; PHS, Public Health Service. benefit and burden of voluntary accreditation. The purpose of this review is to provide an overview of the current governmental regulatory requirements, the accreditation requirements of voluntary professional organizations and insurance carriers, and those federal and professional requirements that are reasonably expected within the next months. The value and goals of both regulation and accreditation will also be presented, along with the incentives to compliance. This review will be limited to collection, processing and transplantation of fairly routine HPCs, and will not include those products regulated as drugs, medical devices or products involved in gene therapy. It is important to understand the fundamental difference between regulation and accreditation. Governmental regulation is universal and mandatory; it applies to all persons and facilities engaged in the relevant activities. Governmental regulation occurs at the federal and state levels. At the federal level, the FDA regulates HCT/Ps under the authority of the PHS Act and the FDCA. Within FDA, the CBER and the CDRH have oversight of various activities that involve HCT/Ps. CBER regulates human tissues intended for transplantation that is recovered, processed, stored, or distributed by methods that do not change tissue function or characteristics and that is not currently regulated as a human drug, biological product, or medical device. Regulations require registration of the facility with the FDA, compliance with all applicable regulations, and cooperation with periodic on-site inspections. 101

Warkentin In contrast, accreditation by professional organizations is voluntary. Persons, programs and facilities have the choice whether or not to participate in the accreditation process. Accredited programs are required to follow the Standards; those who chose not to participate are not required to follow the Standards. Accreditation requires documented compliance with applicable Standards of the accrediting organization. Once the decision has been made to participate, the standards are no longer optional. This distinction between regulation and voluntary accreditation is one of the limitations of voluntary self-monitoring within an industry. There is no assurance that all who engage in an activity will choose to participate in the voluntary accreditation process, and hence, follow the professional standards. In the field of hematopoietic stem and progenitor cell transplantation, there are three professional organizations that set standards and accredit various aspects. These three are the FACT, formerly the FAHCT, the AABB, and the NMDP. Governmental regulation Federal Federal oversight of HCT/Ps has been highly fragmented, resulting in inconsistencies and confusion. In 1997, the FDA published a new proposed approach to the regulation of cellular and tissue-based products (3). This new regulatory framework proposed to provide 1) a unified, tiered approach to the regulation of both traditional and new products, including hematopoietic stem and progenitor cells; 2) a process for harmonized review of applications within FDA; and 3) only the amount of governmental oversight necessary to protect the public health. Products that are expected to be at a higher risk for transmission of common diseases or at risk for contamination, such as allogeneic cells or cells highly manipulated ex vivo, would be subject to more regulation than those with less risk, such as autologous products. The proposal also announced the formation of the Tissue Reference Group, comprised of representatives of CBER and CDRH, to provide a single reference point within FDA for all regulatory questions about HCT/Ps. Formation of the Tissue Reference Group has been accomplished; the development and implementation of the regulations has begun. In proposing regulation, the FDA considered five overarching public health and regulatory concerns. These are 1) prevention of the transmission of communicable disease; 2) assurance that necessary processing controls exist to prevent contamination of cells and tissues and to preserve their integrity and function; 3) assurance of clinical safety and effectiveness; 4) assurance of necessary product labeling, including permissible promotion for proper product use; and 5) establishment of a mechanism for FDA to communicate with the cell and tissue industry (3). The proposed regulations have been published in the Federal Register for public comment and will create a new section of the Code of Federal Regulations, Title 21, part 1271 that will contain cell and tissue regulations. The regulations and their current status are listed in Table 1. The proposed site for future publication of these proposed regulations as final rules is shown in Table 2. For the purposes of these regulations, HCT/Ps are defined as those human cells or tissues intended for implantation, transplantation, infusion or transfer into human recipients, at all stages of manufacture from recovery through distribution, including donor screening (4). In addition to hematopoietic stem and progenitor cells derived from peripheral blood or umbilical cord, HCT/Ps include bone, ligament, skin, dura mater, heart valves, cornea, manipulated autologous chondrocytes, epithelial cells, and some reproductive tissue. HCT/Ps do not include minimally manipulated bone marrow, regulated by the HRSA through its administration of the national bone marrow donor registry program; or whole blood, blood components and derivatives, animal-derived tissues, or secreted tissue-related products, all of which are extensively regulated elsewhere. The FDA registration rule, published in January 2001, was effective from 4 April 2001 (4). This regulation requires that any establishment that manufactures HCT/Ps regulated under section 361 of the PHS Act must register with the FDA using FDA form 3356, available on-line at http://forms.psc.gov/forms/fda/fda.html (4). Establishments such as tissues banks or processing laboratories that are already registered because of other activities should have registered within 30 days of the effective date of the regulation. All other HCT/Ps are required to register by January 2003, the date that the remainder of these HCT/P regulations are expected to be final. In addition, registration must be updated annually and product listings must be updated every 6 months. HCT/Ps are regulated solely under section 361 of the PHS Act if they are minimally manipulated, are intended for homologous function, are not combined with a drug or device, except for sterilization, preserving or storage agent, and do not have a systemic effect or are 102

Hemopoietic stem and progenitor cell transplants Table 1. FDA Regulation of HCT/Ps, 21 CFR part 1271 Title Reference Publication date Status Human Cells, Tissues, and Cellular and Tissue-Based 66FR 5447 19January Final rule effective Products; Establishment Registration and Listing 2001 4 April 2001 Suitability Determination for Donors of Human 64FR 52696 30 September Proposed Cellular and Tissue-Based Products 1999 Current Good Tissue Practice for Manufacturers of 66FR 1508 8 January Proposed Human Cellular and Tissue-Based Products; Inspection and Enforcement 2001 FR ¼ Federal Register. Table 2. FDA Regulation of Human Cells, Tissues, and Cellular and Tissue- Based Products, 21 CFR part 1271 Subpart A B C D E F Reference: (4). Title General Provisions, Scope, Definitions Procedures for Registration Listing (`Registration Rule') final Donor Suitability (`Donor Suitability Rule') proposed Current Good Tissue Practice (cgtp) (`cgtp Rule') proposed cgtp Labeling and Reporting proposed Inspection and Enforcement proposed not dependent upon metabolic activity of living cells for their primary function and are autologous or intended for transplantation into a first or second-degree blood relative. For purposes of this regulation, manufacture means any or all of the steps in the recovery, processing, storage, labeling, packaging, or distribution of any human cell or tissue, including the screening and testing of the donor. Minimal manipulation includes processing that does not alter the relevant biological characteristics of cells or tissues, including density gradient separation, selective removal of B cells, T cells, malignant cells, red blood cells, or platelets, cell separation or cryopreservation. The FDA intends to reclassify products over time based on data and experience. Under the proposed donor suitability rule, the FDA considers communicable disease screening and testing to be part of manufacturing, and therefore subject to regulation (5). Donor screening refers to the review of relevant medical records for indication of past or present infection and for risk factors for a relevant communicable disease. Donor testing refers to performing laboratory tests on a specimen, generally a blood specimen, collected from the donor to determine if the donor has been exposed to or infected with a relevant communicable disease or its agent. Except in certain specified circumstances, HCT/Ps may not be infused, implanted, transplanted or transferred until the donor has been found to be suitable, based on donor screening and testing. Under the proposed tiered approach, the infectious disease screening and testing requirements will be based on risk. For example, the allogeneic donor will be required to be screened for high risk factors for HIV, hepatitis B and C and CJD. In contrast, it would be recommended that the autologous donor be screened for high risk factors for HIVand hepatitis B and C. The allogeneic donor would be required to be tested for evidence of infection by HIV1 and 2, hepatitis B virus, hepatitis C virus, human T lymphotropic virus I and II, cytomegalovirus, and Treponema pallidum (the syphilis agent). Recommended testing for the autologous donor would include only evidence of infection by HIV 1 and 2, hepatitis B virus, hepatitis C virus, and human T lymphotropic virus I and II. For both types of donors, however, the FDA would expect that as new infectious diseases arise, screening and testing would be required as appropriate. The proposed cgtp rule is a set of regulations intended to prevent the introduction, transmission, and spread of communicable disease by helping to ensure that products do not contain relevant communicable disease agents, products are not contaminated during manufacturing, and the function and integrity of products are not impaired through improper processing (6). GTP regulations include requirements for adequate organizational structure; sufficient personnel; adequate facilities; environmental control and monitoring; adequate equipment supplies and reagents for the processes carried out in the facility; proper processing, including process change and process validation; proper labeling, claims and labeling controls; storage; receipt, distribution and other records; maintenance of complaint files; reporting adverse reactions and product deviations; and the establishment of a quality plan. For facilities and programs unfamiliar with regulation and particularly with on-site inspections, the establishment of an adequate quality plan often proves to be difficult. The following quality plan functions, taken from the FDA proposed cgtp should assist facilities in 103

Warkentin preparation of such a plan (6). The functions of a quality plan are 1) to ensure that required procedures are established and maintained, that appropriate analysis and sharing of information that could affect the integrity and function of the HCT/Ps occurs, that appropriate corrective actions are taken and documented, and that there is proper education and training of personnel; 2) to establish and maintain a system of record maintenance, document control and appropriate monitoring systems; 3) to investigate and document product deviations; 4) to make required reports; and 5) to conduct evaluations, investigations, audits, and other actions necessary to ensure compliance with regulations. Along with these guidelines, a quality plan requires development of institutional protocols and procedures that may be highly individualized. The abundant use of terminology such as appropriate, adequate and sufficient indicates the importance of an individualized quality plan that has complete institutional support. Governmental regulation state and local In proposing federal regulation in the field of hematopoietic progenitor cell transplantation, the FDA has expressed its opinion that the state regulation is piecemeal, often voluntary, and inadequate to prevent the transmission of disease. Many states have little specific regulation. Some states have adopted mechanisms of qualifying hematopoietic stem and progenitor cell transplant programs and facilities, such as the certificate of need process. Other states have developed a licensure process, often heavily dependent on the standards established by professional societies. Some states have identified the public health concerns in cellular transplantation, and have adopted direct and specific regulations for HCT/P processing and storage facilities. For example, New York first enacted regulations for hematopoietic progenitor cell banks in 1988, revised these regulations in 1992 to reflect the rapid evolution of the field of hematopoietic cellular transplantation, and later added guidelines for cord blood banks (7, 8). These regulations are primarily related to public health concerns for the transmission of communicable diseases, but also include issues such as informed consent, proper storage, handling, labeling, and records. Since the enactment of the New York State Transplant Law in 1990, licensure has been required to operate a collection, transfusion, processing or storage facility for hematopoietic progenitor cells within the state. The licensure process includes an on-site inspection, the documentation of qualified medical leadership and staff, and written standard operating procedures. Other states have adopted a mechanism of approval for transplantation that requires accreditation by a professional organization. At the present time, both Massachusetts and Maryland require FACT accreditation to perform hematopoietic progenitor cell transplantation within those states. Insurance company issues Improvements in hematopoietic stem and progenitor cell transplantation outcomes have resulted in the classification of such therapies as standard of care for many malignant and serious non-malignant disorders. Most insurers have mechanisms in place to cover transplant services; however, there is considerable variability in the extent of coverage, the services covered, and the diseases that are considered reimbursable. When unrelated volunteer donors are utilized for hematopoietic progenitor cells grafts, there is also variation in the extent to which insurance coverage is available for both donor search expenses and graft procurement expenses. Increasingly, insurers seek contracts with specific transplant facilities or programs, variously known as centers of excellence or preferred providers, to perform all hematopoietic progenitor cell transplants for their clients. Insurance companies seek independent measures of excellence on which to base the designation of Center of Excellence. There is an important role for professional organizations in this process of development of criteria of excellence. Presently, most insurance contract applications ask if the transplant program is accredited by FACT, and use this to a greater or lesser extent in selecting programs to participate in their network. Some insurance companies have indicated that they may require FACT accreditation when a sufficient number of programs have been accredited. Voluntary accrediting organizations In the field of hematopoietic stem and progenitor cell transplantation, there are three professional organizations that set standards and accredit HPC facilities. These three are FACT, AABB and NMDP. The FAHCT was founded in 1996 to establish standards for high quality medical and laboratory practice and to develop and implement a voluntary inspection and accreditation program. The two parent organizations, the ASBMT and 104

Hemopoietic stem and progenitor cell transplants the ISCT, formerly ISHAGE, merged their clinical and laboratory standards, respectively, to form the first edition of standards, in the belief that a valid accreditation process committed to high quality patient care and laboratory practice must assess both aspects. Reflecting the expansion of the field of cellular therapy, and following the lead of ISCT, FAHCT changed its name to FACT, effective from 7 December 2001. To date, there are 101 transplant programs in North America that have been accredited by FACT, with an additional 100 applicant programs in the accreditation process. FACT Standards are unique in hematopoietic progenitor cell therapy in the detail and the breadth of covered services (9). FACT Standards cover all phases of collection, processing and administration of hematopoietic cells obtained from bone marrow or from the peripheral blood of allogeneic or autologous donors. FACT Standards also apply to the transplantation of umbilical cord blood cells under the clinical standards for transplantation of allogeneic or autologous hematopoietic progenitor cells, as appropriate. The collection, processing and banking of cord blood cells are not covered in FACT Standards, but are separately covered in the NETCORD/FAHCT International Standards for Cord Blood Collection, Processing, Testing, Banking, Selection and Release (10). FACT Standards are designed to provide minimum guidelines for facilities and individuals performing hematopoietic cell transplantation and therapy or providing support services for such procedures. FACT Standards require that all accredited programs have in place a Quality Management Program that includes at least quality audits, a system for detecting, evaluating and reporting errors, accidents, suspected adverse reactions and biological product deviations, corrective actions, documentation, review and reporting, and safety provisions. All clinical, collection and laboratory processing facilities must evaluate and report clinical outcomes, especially engraftment of hematopoietic cells. FACT Standards require an accredited clinical program to utilize a collection service and a cell processing laboratory that meet FACT Standards. No specific program structure is required, however, functional coordination and cooperation are required. At the present time, the only two mechanisms available to demonstrate compliance with FACT Standards is either FACT accreditation or successful completion of an on-site inspection by FACT inspectors using the FACT process without accreditation. A detailed description of all FACT Standards is beyond the scope of this review; however, the following are topics covered in each section clinical, collection and laboratory. In addition to the quality management requirements, each section contains minimal standards for facility components and space, personnel requirements, requirements for written standard operating procedures and policies, and data management and records requirements. The clinical section contains the standards for minimal program size; donor evaluation, selection and management; therapy administration; and clinical research, including informed consent. The collection section contains standards for the collection procedure, donor evaluation and management during donations, and labels to be applied to hematopoietic cell products at the end of collection. The laboratory section contains standards for cell processing, cryopreservation, storage, transportation and disposal; numerous product labels; and the issue of products for infusion. There are some significant differences between requirements of the first edition of FACT Standards and the second edition, which was effective from 1 June 2002. Most noticeable is the change in organizational structure. Relevant standards have been moved to each section as applicable. The topics in each section have been moved to be generally parallel. For example, Quality Management can be found in B4.000, C4.000, and D4.000. Labeling requirements have been simplified and clarified by movement of the collection label to the collection section and display of all label requirements on a simple table. There is a change in the proper nomenclature for hematopoietic cell products. The new names are consistent with the proposals of the ICCBBA for ISBT 128 product codes (11). This change is based on the importance of international cooperation in hematopoietic cell therapies, the value of common terminology, and the recent support of the FDA for the use of ISBT product codes. In the Clinical section, there is now a requirement for the transplantation of an annual minimum of 10 new patients of each type (allogeneic or autologous) for which accreditation is sought. There are new requirements for pediatric transplantation, including a minimum number of children to be transplanted per year by combined adult and pediatric programs, the requirement for specific pediatric expertise as demonstrated by physicians and nurses trained in pediatrics, at least one physician Board-certified in Pediatric Hematology/Oncology, and consultants qualified 105

Warkentin to treat pediatric recipients. Donor evaluation and selection has been moved from the collection section to the clinical section, reflecting usual practice. There are stricter requirements for administration of high dose chemotherapy. Data required by each program has been expanded to the specific Transplant Essential Data forms of the International Bone Marrow Transplant Registry and the Autologous Blood and Marrow Transplant Registry. Additional informed consent requirements are detailed, including required disclosure of financial interests and potential conflicts. The FACT Standards for cell collection now include the specific collection label requirements. Although the standards for donor selection have been moved to the clinical section, personnel involved in collection are still responsible for the interim evaluation of donors and their management during the collection period. The AABB is the professional society of 8500 individuals involved in blood banking and transfusion medicine. It also represents over 2200 institutional members, including community and Red Cross blood collection centers, hospitalbased blood banks, transfusion services and cell processing laboratories that collect, process, distribute, and transfuse blood components and hematopoietic progenitor cell products (12). The AABB has a long history of standard-setting activity, having published its first edition of Standards for a Transfusion Service in 1958, the same year that it began its program of on-site inspections and accreditation. Approximately 160 programs involved in hematopoietic cell therapy worldwide have been accredited by the AABB. The AABB has current standards for hematopoietic progenitor cell services and a separate volume dedicated to cord blood services (13, 14). The third edition of Standards for Hematopoietic Progenitor Cell Services was effective from 1 May 2002; and the first edition of Standards for Cord Blood Services is the current version. All Standards documents of the AABB are based upon a quality management framework. All standards within the documents are of equal importance. Each standard is stated once, then it applies throughout. The quality management standards, combined with the technical requirements, form the total requirements of AABB. Although very different in structure, the content of AABB Standards for hematopoietic progenitor cell services parallels the FACT Standards for cell collection and processing as published in the first edition. AABB Standards do not include clinical transplantation standards. The NMDP was founded in 1987 as a cooperative effort of the AABB, the American Red Cross, the Council of Community Blood Centers, and the US Navy to facilitate volunteer unrelated donor marrow transplantation. It is comprised of a network of cooperating facilities, including transplant centers, donor centers, marrow collection centers, apheresis centers, cord blood banks, recruitment groups, cooperative donor registries, contract laboratories, and cell and serum repositories. The NMDP itself has regulatory oversight by the Health Resources and Services Administration (HRSA). Since its inception, NMDP has established standards for membership participation; and a standards committee composed of experts in various aspects of transplantation has been charged with continuous review and revision of these standards. NMDP Standards cover cells obtained from marrow, peripheral blood, and umbilical cord blood. Included are standards for participating centers and groups, personnel qualifications, required support services, policy and procedure requirements, confidentiality, recruitment of the unrelated donor, donor medical and laboratory screening and testing, the informed consent process, the donation and transplant process, progenitor cell packaging, labeling and transportation, quality control, patient rights, and records. Standards for laboratory processing are not as detailed as those of AABB or FACT, as most of the processing laboratories and the cell processing procedures performed there are an integral part of the recipient s transplant program. Oversight of investigational procedures is from the Institutional Review Board, the FDA if applicable, and FACT or AABB if the program participates. NMDP Standards are intended to serve the discrete function of qualifying groups, centers, and banks for participation in the registry. NMDP Standards include standards for quality assessment and improvement, and are generously supplemented by operational policies and procedures of the registry. How much regulation? The questions of how much regulation is necessary and how much is too much is controversial. Because not all practitioners in the field of hematopoietic therapy choose to be voluntarily accredited and to comply with established professional standards, some regulation in this area is probably needed. It is the responsibility of the FDA to regulate as needed to prevent the transmission of communicable disease. Examples of this type of regulation are donor screening and 106

Hemopoietic stem and progenitor cell transplants testing for transmissible diseases, product quarantine regulations, and processing controls to prevent the contamination of cells and tissues. Also reasonable are labeling regulations that require certain standard information be prominently displayed, and that all promotional materials about the cellular product be clear, accurate, balanced, and non-misleading. There have been examples of product promotions that were viewed by many professionals in the field to be potentially misleading to patients, encouraging the vulnerable patient to purchase services in the false belief that the service would be live saving. Conversely, regulation that adds no value or quality to the service is too much regulation. That amount of oversight is burdensome and costly. Regulation of the practice of medicine would also be excessive. Examples of issues that many would consider to be the practice of medicine include regulation of the cell dose for an HPC graft, regulation of the histocompatibility match criteria for allogeneic transplantation, or regulation of the clinical disorders for which hematopoietic grafts could be used. Voluntary accreditation in a regulated field There are numerous roles for voluntary accreditation in a regulated environment. First, the purpose of voluntary accreditation is to improve the quality of medical and laboratory care in the field of hematopoietic cell therapies. This occurs regardless of the presence of governmental regulation. In any such setting, the voluntary standards must meet, but certainly can exceed, the governmental regulation. Second, to achieve the goal of raising the overall quality of care, a major role played by the voluntary accreditation programs is to educate the practitioners in the field. The voluntary accreditation programs also serve to educate the regulators, and thereby influence the depth and breadth of regulation. For example, in January, 1998, the FDA published in the Federal Register a request for input regarding standards for hematopoietic cells (13). FACT, NMDP and AABB were all among the respondents to this request. In the proposed regulation that followed, many of these voluntary standards were obvious throughout. In its analysis of the burden of compliance, the FDA stated in the background to the proposed current Good Tissue Practices, that it expected compliance with FDA regulations would be easier and cheaper for those programs and facilities that were accredited by FACT or AABB than for non-accredited facilities (5). The agency estimated that FACT or AABB accredited facilities would already be nearly 100% compliant with the proposed donor suitability rule. Relative to the cgtp rule, FDA estimated FACT-accredited facilities were approximately 80% compliant with proposed FDA regulations; and further estimated the annual cost of compliance for a FACT-accredited facility to be $27 291, as compared with a nonaccredited facility, for whom the estimated annual cost would be $79 437 (6). Finally, the effort of on-site inspection of all facilities and programs involved in hematopoietic stem and progenitor cell therapy is enormous. While it is clear that the FDA has the right to inspect any regulated facility, the Agency intends a tiered inspection process, taking into account professional accreditation (4). Some have raised the question of the purpose of regulations, when there is transplantation activity occurring in uncertified centers. Where there is voluntary accreditation, there will always be non-participants and nonaccredited programs. However, when there is federal regulation, there will not be regulated activities in non-compliant centers. The Public Health Services Act gives authority for enforcement of regulations to the FDA. Any establishment that performs any step in manufacturing (recovery, donor screening, donor testing, processing, storage, labeling, packaging, distribution including contract services) is required to permit inspection by FDA at any time. Section 368 of the PHS Act allows the following consequences for noncompliance with Section 361 regulations. 1) Persons who violate these regulations may be imprisoned up to 1 yr and fined up to $100 000 (if no death occurred) or $250 000 if a death resulted from the violation. 2) Organizations out of compliance with these regulations may be ordered to cease operation and fined up to $200 000 per violation if no death occurred, and up to $500 000 per violation if a death occurred (4). Such potential consequences should serve as a powerful incentive to compliance. In summary, federal regulations have been formally proposed to include all aspects of hematopoietic stem and progenitor cell manufacturing, including donor screening, testing, cell collection, packaging, processing, labeling, storage, and distribution. The proposed schema is a tiered, risk-based regulation, where the amount of regulation increases as does the risk of transmission of communicable disease and/or product contamination or functional impairment. The first portion of these regulations, requiring all establishments engaged in manufacturing to register with the FDA, is already in 107

Warkentin effect. The remainder of the regulatory schema is expected by early 2003. There are also some state regulations; however, these are non-uniform. Several professional organizations have published standards for hematopoietic stem and progenitor cell therapies, including FACT, AABB, and the NMDP. These are voluntary accreditation programs that have a large role in improving the quality of medical care and laboratory practice. References 1. Food and Drug Administration Interim Rule for Human Tissue Intended for Transplantation. Federal Register 1993: 58: 65514. 14 December. 2. Food and Drug Administration HHS. Human tissue for transplantation. Final Rule Federal Register 1997: 62: 40429. 29 July. 3. Food and Drug Administration HHS. A proposed approach to the regulation of cellular and tissue-based products. Federal Register 1997: 62: 9721. 4 March. 4. Food and Drug Administration HHS. Human cells, tissues, and cellular and tissue-based products; establishment registration and listing. Final Rule Federal Register 2001: 66: 5447. 19 January. 5. Food and Drug Administration HHS. Suitability determination for donors of human cellular and tissue-based products. Federal Register 1999: 64: 52696. 30 September. 6. Food and Drug Administration HHS. Current good tissue practice for manufacturers of human cellular and tissue-based products; inspection and enforcement. Federal Register 2001: 66: 1508. 8 January. 7. Ciavarella D, Linden JV. The regulation of hematopoietic stem cell collection and storage: The New York State approach. J Hematother 1992: 1: 201 214. 8. Linden JV, Preti RA, Dracker R. New York State guidelines for cord blood banking. J Hematother 1997: 6: 535 541. 9. Foundation for the Accreditation of Cellular Therapy (FACT). Standards for Hematopoietic Progenitor Cell Collection, Processing and Transplantation, 2nd edn. Omaha, NE: FACT, 2002. 10. NETCORD and FACT. International Standards for Cord Blood Collection, Processing, Testing, Banking, Selection and Release, 2nd edn. Omaha, NE: NETCORD/FACT, 2002. 11. International Committee for Commonality in Blood Banking Automation. ISBT 128 Product Code Database Progenitor Cells [HPC] (including Lymphocytes and T Cells): Structure and Definitions, version 1.1.0. York, PA: ICCBBA Inc., 2001. 12. Warkentin PI. Regulations and standards for hematopoietic progenitor cell facilities. In: Snyder EL, Haley NR, eds. Hematopoietic Progenitor Cells: A Primer for Medical Professionals. Bethesda, MD: AABB Press, 2000. 13. Food and Drug Administration HHS. Request for proposed standards for unrelated allogeneic peripheral and placental/ umbilical cord blood hematopoietic stem/progenitor cell products; request for comments. Federal Register 1998: 63: 2985. 108