oversight

Human Tissue Banks: FDA Taking Steps to Improve Safety, but Some Concerns Remain

Published by the Government Accountability Office on 1997-12-05.

Below is a raw (and likely hideous) rendition of the original report. (PDF)

                 United States General Accounting Office

GAO              Report to the Ranking Minority Member,
                 Committee on Commerce, House of
                 Representatives


December 1997
                 HUMAN TISSUE
                 BANKS
                 FDA Taking Steps to
                 Improve Safety, but
                 Some Concerns
                 Remain




GAO/HEHS-98-25
      United States
GAO   General Accounting Office
      Washington, D.C. 20548

      Health, Education, and
      Human Services Division

      B-275822

      December 5, 1997

      The Honorable John D. Dingell
      Ranking Minority Member
      Committee on Commerce
      House of Representatives

      Dear Mr. Dingell:

      Each year human tissue transplants allow approximately 600,000
      Americans to live fuller and healthier lives. These transplants aid burn
      victims, the visually impaired, and persons living with cancer, heart
      defects, and various other illnesses and injuries. Additionally,
      transplanting reproductive tissue allows infertile couples to bear children.

      Notwithstanding the benefits of tissue transplantation, some are
      concerned about the potential transmission of infectious diseases from
      donor to recipient and about certain tissue-processing techniques that may
      affect the usefulness of tissues or leave them with harmful residues.
      Because of these concerns, you asked us to evaluate the Food and Drug
      Administration’s (FDA) oversight of transplanted human tissue as well as to
      evaluate potential safety problems. Specifically, we sought to identify gaps
      in the current regulation, determining whether and how FDA plans to
      address them in the approach it has proposed for regulating tissue
      banking. In this report, we provide our findings and recommendations on
      these topics for musculoskeletal tissue, skin, corneas, reproductive tissue,
      and peripheral and umbilical cord blood stem cells.1

      Our examination of the tissue industry was limited to human tissues that
      are under FDA oversight. We did not examine transfusable blood products
      or other more specialized FDA-regulated tissue-related products, such as
      tissues derived from animals, products used to propagate cells or tissues,
      or products that are extracted from cells or tissues. We also did not
      examine FDA’s regulation of highly manipulated cellular techniques, such
      as those used in somatic cell therapies.




      1
       We do not discuss solid organs such as hearts, livers, kidneys, pancreatic tissue, and lungs or bone
      marrow. The National Organ Transplant Act of 1984 provides for federal oversight of the organ
      transplant system. The Health Resources and Services Administration (HRSA) and the Health Care
      Financing Administration (HCFA) within the Department of Health and Human Services (HHS)
      currently administer programs related to organ transplantation. HRSA also administers the contract
      for the National Marrow Donor Program for which the Transplant Amendments Act of 1990
      established standards.



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                   We examined FDA’s regulation of human tissue intended for
                   transplantation, the agency’s December 1995 draft document on the
                   regulation of placental and umbilical cord blood stem cell products
                   intended for transplantation, and the agency’s proposed approach for the
                   regulation of cellular and tissue-based products, as well as guidance from
                   FDA and the Centers for Disease Control and Prevention (CDC) on screening
                   donors of human tissues.2 We obtained information on FDA’s guidance on
                   inspections for human tissue, summaries of findings on inspections, and
                   memoranda relating to tissue donation and viral testing of donors. We met
                   with officials from FDA and all the relevant industry associations to obtain
                   their views on the regulation of tissue banking. We also collected
                   information on state regulations and trade association standards and
                   reviewed them for variations and gaps between federal, state, and private
                   entities in the oversight of human tissue.

                   We interviewed representatives of and made site visits to the full
                   complement of the types of tissue facilities within the scope of our study,
                   including musculoskeletal facilities and processors, eye facilities,
                   reproductive facilities, and facilities that collect, process, store, or
                   transplant peripheral and umbilical cord blood stem cells. We observed
                   tissue processing and infectious disease controls and reviewed documents
                   relating to donor screening and standard operating procedures. We
                   attended technical conferences and examined the scientific literature on
                   the collection and processing of tissues, infectious and noninfectious
                   complications from tissue transplantation, and variations in human tissue
                   practices in order to obtain information on generally accepted practices
                   and potential safety problems from tissue transplantation.

                   We conducted our review from November 1996 to September 1997 in
                   accordance with generally accepted government auditing standards.


                   FDA is just now expanding its oversight to improve tissue-banking
Results in Brief   safeguards in the growing field of tissue-based therapies. FDA’s regulation,
                   part of which will not be fully effective until January 26, 1998, specifies
                   minimum medical screening and infectious disease testing and the
                   maintenance of documentation for these activities and provides for
                   retaining, recalling, or destroying human tissue for which such
                   documentation is not available. FDA has also proposed a regulatory
                   approach that is much broader in scope than the current regulation. Still in

                   2
                    The December 1995 draft document was superseded by the proposed approach for tissue and
                   cellular-based products.



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its formative stages, it describes a risk-based approach that industry has
generally received well. FDA plans to codify it iteratively over a period of
years. Meanwhile, FDA’s regulatory authority is limited to the requirements
relating to the transmission of human immunodeficiency virus (HIV) and
hepatitis B and C.

We found a number of safety problems that are not controlled under the
current regulation and that will remain unsolved until future regulations
are put into effect. Some of these problems are addressed in FDA’s
proposed approach, others are not addressed, and still others are
addressed but not adequately.

FDA’s proposed approach would alleviate three safety problems not
covered by current regulation. First, because the current regulation does
not require facilities to register with FDA, the agency has no universal
registry of tissue facilities currently operating in the United States. As a
result, FDA could not disseminate to all tissue banks critical information in
a public health emergency that might affect the safety of transplanted
tissues. FDA officials have stated that their agency does not plan to conduct
routine annual inspections of tissue facilities for lack of resources, but the
agency does plan to conduct some inspections.3 Without requirements for
registration, FDA cannot identify the universe of tissue facilities that may
warrant inspection or need to be notified. Second, the current regulation
does not cover reproductive tissue or stem cell facilities. Although such
tissues can transmit infectious diseases, these facilities are not required to
abide by the current regulation for infectious disease control that covers
musculoskeletal facilities and eye banks, nor will FDA be routinely
inspecting these facilities. Third, we found numerous instances of
misleading and false advertising in private cord blood banking; FDA is not
currently regulating such product claims but would do so under the
proposed approach.

We also found two problems that FDA does not address in the current
regulation or in the proposed approach. First, some facilities obtain
informed consent after infant delivery, raising safety and ethical concerns
about cord blood from mothers who may not have received prenatal care
and who are screened for high-risk behavior postcollection. Requesting
consent after collection also does not provide expectant mothers with
information and opportunity to make a decision before a procedure is
performed. Second, although reproductive tissues and stem cells could

3
 For fiscal year 1998, FDA has planned 44 inspections of tissue facilities using a total of 2.8
full-time-equivalent staff.



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introduce genetic diseases to recipients, FDA has no current or proposed
requirements for disclosing to recipients whether genetic tests have been
performed on these products.

We also found four instances in which FDA’s proposed approach
inadequately addresses potential safety problems not covered in the
current regulation. First, facilities are not currently required to report
errors or accidents that result in the distribution of unacceptable tissues
or to report adverse events associated with the transplantation of human
tissue.4 The proposed approach would require recording and investigating
errors and accidents but no reporting to FDA. Without a requirement to
report serious errors and accidents, FDA is missing an opportunity to target
facilities that may need additional oversight.

Second, the current tissue-tracking system is inadequate to notify
recipients who receive tissues later deemed to have been unsuitable for
transplantation. Yet, the proposed approach only minimally mentions
tracking tissues as good tissue practices and then only in respect to
controlling disease transmission. Third, the proposed approach would
require premarket submissions to FDA for certain tissues and
cellular-based therapies that are to be used in an unrelated recipient
(unrelated allogeneic). As a matter of policy, FDA would not require
premarket submissions when cells or tissues were to be used in the person
from whom they were obtained or in a close blood relative of that person
(related allogeneic). This dichotomy ignores the similar risks from
unrelated and related allogeneic transplantation.

Fourth, we found few processing techniques that tissue facilities had
validated and FDA had evaluated; some nonvalidated processing techniques
are known to adversely affect the safety and effectiveness of tissues. FDA
has proposed that certain tissue products (for example, those that are
more than minimally manipulated or nonhomologous) be subject to
premarket approval and that FDA evaluate processing techniques used on
these products in the course of reviewing premarket applications. But for
the minimally manipulated tissue products that were the focus of our

4
 Presently, FDA regulations require licensed manufacturers of biological products to promptly notify
FDA of errors or accidents that may affect the safety, purity, or potency of any product (21 C.F.R.
600.14). These regulations do not apply to tissue banks because no licensing is required. However,
FDA has published a proposed rule that would require unlicensed blood facilities to report all errors
and accidents. Adverse events that are serious or unexpected must be reported to FDA by the licensed
manufacturer of biological products within 15 days of initial receipt of information. “Serious” means an
adverse experience associated with the use of a biological product that is fatal or life-threatening, is
permanently disabling, requires inpatient hospitalization, or is a congenital anomaly, cancer, or
overdose. “Unexpected” means an adverse biological product experience that is not listed in the
current labeling of the product (21 C.F.R. 600.80).



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             review, the proposal would require only that the validation of the
             procedure be documented and available when FDA inspects facilities
             engaged in such activities. Because FDA does not plan to conduct routine
             inspections of tissue facilities, inspectors may have few opportunities to
             evaluate the different procedures that tissue facilities use.


             The term “tissue” covers a wide range of products used for many medical
Background   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.5

             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,


             5
              Human blood contains a variety of cells tailored to specific functions. Erythrocytes, or red blood cells,
             transport life-sustaining oxygen throughout the body. Platelets arrest bleeding by promoting clotting.
             White blood cells, which include lymphocytes, monocytes, and neutrophils, form the immune system
             that guards an individual against attack by foreign tissue, viruses, and other microorganisms. All these
             cells develop from a “master cell,” the hematopoietic stem cell, which is found in the bone marrow and
             circulates in blood vessels throughout the body and in umbilical cord blood. Stem cells can divide to
             form more stem cells or they can go through a series of divisions by which they become fully mature
             blood cells. Most blood cells mature in the bone marrow. However, some white blood cells
             (lymphocytes) complete their maturation in the thymus, spleen, or lymph nodes. Injury to the stem
             cells—from chemotherapy, radiation, or disease, for example—can cripple the immune and blood
             production systems. The transplantation of stem cells can be used to treat people who have sustained
             such damage, such as those with cancer, aplastic anemia, and autoimmune disorders.



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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.6

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.7 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.8

6
 FDA, “Guidance for Industry: Screening and Testing of Donors of Human Tissue Intended for
Transplantation,” Washington, D.C., July 1997.
7
 CDC, “Guidelines for Preventing Transmission of Human Immunodeficiency Virus Through
Transplantation of Human Tissue and Organs,” Morbidity and Mortality Weekly Report, Vol. 43
(RR-8) (1994), pp. 1-17.
8
 CDC, “Public Health Service Inter-Agency Guidelines for Screening Donors of Blood, Plasma, Organs,
Tissues, and Semen for Evidence of Hepatitis B and Hepatitis C,” Morbidity and Mortality Weekly
Report, Vol. 40 (RR-4) (1991), pp. 1-23.



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            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.9 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.


Processes   CDC  has estimated that more than 400 facilities bank or process several
            hundred different types of human tissue.10 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

            9
             FDA’s notice regarding its proposed approach to regulation of cellular and tissue-based products was
            published in the March 4, 1997, Federal Register. The approach does not encompass whole organs or
            minimally manipulated bone marrow (both of which are regulated by HRSA) or transfusable blood
            products (for example, whole blood, red blood cells, platelets, and plasma), which FDA already
            regulates under the Food, Drug, and Cosmetic Act and the Public Health Service Act. The approach
            also does not encompass other FDA-regulated tissue-related products, such as tissues derived from
            animals, products used in the propagation of cells or tissues, or products extracted from cells or
            tissues (such as human milk, collagen, or growth factors).
            10
             A tissue bank is any facility that engages in recovering, screening, testing, processing, storing, or
            distributing human tissue intended for transplantation.



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                                     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.11 Table 1 outlines the infectious diseases that have been
                                     transmitted by human tissue.

Table 1: Infectious Diseases
Transmissible Through Human Tissue   Tissue                                 Infectious disease
                                     Bone                                   Hepatitis, HIV, bacteria, tuberculosis
                                     Skin                                   HIV (?) , bacteria, cytomegalovirus (?)a
                                     Cornea                                 Hepatitis, bacteria, rabies, Creutzfeldt-Jakob disease,b
                                                                            fungus, herpes
                                     Reproductive tissuec                   Hepatitis, HIV, cytomegalovirus, human T-cell
                                                                            lymphotropic virus,d sexually transmitted diseases
                                     Stem cellse                            Hepatitis, HIV, cytomegalovirus,a human T-cell
                                                                            lymphotropic virus,d syphilis
                                     a
                                      Cytomegalovirus belongs to the herpes virus group and is acquired by respiratory or sexual
                                     contact or from blood component or tissue or organ allografts. At this time, it is unclear as to
                                     whether HIV or cytomegalovirus can be transmitted by skin.
                                     b
                                      Creutzfeldt-Jakob disease leads to a degenerative neurologic disease that manifests as
                                     progressive dementia and death.
                                     c
                                      Diseases denoted in this table for reproductive tissue are based on those that ASRM testing
                                     standards require. Bacteria are likely transmissible.
                                     d
                                       Human T-cell lymphotropic virus (HTLV) is similar to HIV in the manner in which it replicates
                                     itself. It has been associated with adult T-cell leukemia and tropical spastic paraparesis, or
                                     HTLV-I-associated myelopathy.
                                     e
                                      Diseases denoted in this table for stem cells are based on those that FAHCT testing standards
                                     require. Bacteria are likely transmissible.

                                     Source: Adapted from T. Eastlund, “Infectious Disease Transmission Through Cell, Tissue, and
                                     Organ Transplantation: Reducing the Risk Through Donor Selection,” Cell Transplantation, Vol. 4
                                     (1995), p. 457.



                                     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.12 These procedures can be

                                     11
                                       AATB also recommends testing for human T-lymphotropic virus, syphilis, and bacteria. In addition,
                                     living donors are tested at the time of donation and 6 months later to ensure catching any infection too
                                     new to be detected by the first test. EBAA does not require testing for human T-lymphotropic disease
                                     or syphilis. Semen donors and donors of umbilical cord blood are tested for hepatitis B core antibody,
                                     an indication of past hepatitis B infection and potential high-risk behavior. Maternal umbilical cord
                                     blood donors are tested for cytomegalovirus, a highly prevalent and usually benign virus that is
                                     particularly dangerous for the immunocompromised patients who receive cord blood.
                                     12
                                         Fascia is a sheet of connective tissue covering or binding together body structures.



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                       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.


The Role of Industry   AATB  has standards and an accreditation program for its members. AATB
Associations           currently accredits 60 tissue facilities, while another 40 to 60 are not
                       accredited.13 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.



                       13
                        There are also about 110 eye banks, 100 reproductive tissue banks, and about 100 surgical bone
                       banks. This latter group has declined recently as these banks were usually in hospitals that stored
                       bone from surgical bone procedures, such as from living donors who had hip replacement surgery,
                       whereby the extracted femoral head could be used for other patients.



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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.14 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.15 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.16


14
  Assisted reproductive technology programs are involved in such practices as in vitro fertilization,
gamete intrafallopian transfer, and zygote intrafallopian transfer. These are procedures performed to
assist couples who have infertility problems to conceive children. For example, embryology
laboratories are an integral part of in vitro fertilization, gamete intrafallopian transfer, tubal embryo
transfer, and zygote intrafallopian transfer programs. These are collectively known as assisted
reproductive technologies. Embryology laboratories are not referral laboratories but maintain specific
affiliation with a physicians’ group. They perform some of the following activities: examination of
follicular aspirates with oocyte identification; oocyte quality and maturity grading; sperm preparation;
insemination of oocytes; determination of fertilization and zygote quality evaluation; and oocyte,
embryo, and sperm cryopreservation. Andrology laboratories, in contrast, perform activities such as
semen analysis, semen biochemical tests, tests for sperm survival, sperm viability and integrity, sperm
antibody testing, preparation of sperm for intrauterine insemination, and sperm cryopreservation.
15
  A single anonymous semen donation can be divided into several (four to eight) samples, and,
industrywide, about one of every eight potential donors is accepted. Some sperm banks accept only 3
to 5 percent of the applicants, and even those that are accepted as donors often produce donations
that are not acceptable (at one sperm bank, only 33 percent of the donations are accepted).
16
  ISHAGE was formed in 1992 as a professional society representing scientists and physicians working
in the area of hematopoietic stem cell graft manipulation. It has more than 900 members representing
all the major bone marrow and stem cell transplant centers in the world. It developed the first draft of
the Standards for Hematopoietic Cell Collection and Processing. ASBMT was formed in 1993 as a
professional organization representing physicians and investigators involved in the clinical conduct of
hematopoietic progenitor cell transplantation. It has more than 800 members and developed the first
draft of the Clinical Standards for Hematopoietic Cell Transplantation.



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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.




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Table 2: Tissue Banking Facts and Figures
                            Number of donors            Estimated number of           Estimated number of
Types of tissue             annually                    banks                         recipients annually           Industry association
Musculoskeletal: bone        5,500                      About 100; 2 largest          350,000                       AATB
(whole, crushed, chips,                                 collect 50-55%; 6 others
demineralized powder),                                  collect 30-45%
cardiovascular, cartilage,
skin, tendon
Eye tissue: cornea, sclera   40,000-45,000              110                           40,000-45,000                 EBAA and American
                                                                                                                    College of Opthalmology
Reproductive: embryo,        Unknown                    100 semen banks, 150          Semen = 200,000;              ASRM and American
oocyte, semen                                           assisted reproductive         embryo= 2,500                 College of Pathology
                                                        technology facilities, 300
                                                        laboratories
Stem cells                   Unknown                    20-50 collect umbilical       250 (U.S.),                   AABB, ASBMT, FACHT,
  Umbilical cord blood                                  cord blood; 6 private         500 (worldwide);              ISHAGE
                                                        banks; 6 public banksa;       75% are unrelated
                                                        about 15 facilities have      allogeneicb
                                                        performed cord blood
                                                        transplants

  Peripheral                                            Unknown number                700 (U.S.), 2,000
                                                                                      (worldwide);
                                                                                      most are related
                                                                                      allogeneic
                                             a
                                              The number given for private banks is based on those that have advertised through the Internet
                                             as of August 22, 1997. An unknown number of private physicians may be collecting and storing
                                             cord blood stem cells. The number given for public banks is based on information obtained from
                                             NHLBI.
                                             b
                                             Total transplants to date.




State Regulations                            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



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                      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
Overview of Current   covers several areas of tissue collection, processing, and storage, all
Regulation and        relating to the control of hepatitis B and C and HIV transmission. These
Proposed Approach     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.




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                             We have three concerns about omissions in the current regulation that FDA
The Proposed                 has identified and plans to address under its proposed approach: (1) lack
Approach Addresses           of registration of tissue facilities, (2) some types of tissue facilities not
Certain Omissions in         covered under the current regulation, and (3) misleading and false
                             advertising in cord blood banking. However, because the proposal will be
Current Regulation           promulgated iteratively, these omissions may remain for the foreseeable
                             future.


Facilities Not Required to   Unlike in other industries that FDA regulates, such as blood and
Register                     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.17 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

                             17
                               Identification techniques that FDA has employed include (1) asking known tissue banks about others
                             that they compete with for donors, (2) receiving assistance from a local coroner or medical examiner
                             to identify tissue facilities that procure tissue, and (3) consulting local telephone directories.



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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.18 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.19
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.20


18
  The purpose of such correspondence is to provide facilities with the opportunity to implement
voluntary corrective action to bring a facility and its operations into compliance with the current
regulation. Such action may include, but is not limited to, notifying physicians of medical risks
involved with the tissues that are referenced in the letter.
19
  Form 483 allows FDA inspectors to attach inspection observations to an establishment inspection
report that is thought to violate an FDA regulation.
20
  This applies only to tissue products that are more than minimally manipulated, are for
nonhomologous use, are combined with noncellular or nontissue components, or are for metabolic use
other than reproduction except when used autologously or in a close family member. For other
minimally manipulated tissues that are regulated solely under section 361 of PHS, the authorities for
injunctions under section 302 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 332) and
seizures under section 304 of that act are not available.



Page 15                                                      GAO/HEHS-98-25 Human Tissue Banks
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Some Facilities Are Not   The current regulation does not cover facilities that collect, store, process,
Covered by Current        or distribute reproductive tissues or stem cells. Specifically, these facilities
Regulation                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.21 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.


Some Umbilical Cord       Little is known about the type and level of information that private cord
Blood Banks Use           blood facilities present to expecting parents, either in writing or orally. FDA
Misleading and False      has periodically monitored but not regulated this industry’s advertising
                          practices.
Advertising
                          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.22 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.


                          21
                            FDA’s regulation requiring facility registration, currently in draft, will include reproductive and stem
                          cell facilities. Subsequent regulations will cover good tissue practices and infectious disease testing for
                          these facilities.
                          22
                            In GVHD, donor lymphocytes engraft and multiply in the recipient, reacting against the “foreign”
                          tissues of the recipient. When donors and recipients are highly “matched” for antigens, GVHD is
                          lessened.



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                                                 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.


Table 3: Misleading and False Information About Umbilical Cord Blood on the Internet
Informationa                                                         Correction
“It has the added advantage of being ‘privileged’ or unexposed to most            Cord blood is at risk for any disease of the mother, who, as
diseases.”                                                                        an adult, has risks equal to those of any other adult who
                                                                                  might donate bone marrow.
“Cord blood is rarely contaminated by viruses such as cytomegalovirus or
Epstein-Barr virus that can cause serious problems for the transplant
patient.”

“Cord blood stem cells are not infected by HIV . . . .”

“Because they are captured immediately after birth, they are much less
likely than stem cells found in an adult’s bone marrow to contain
contaminating viruses.”

“very low risk of transmissible infectious diseases”
“As a result of numerous preclinical and clinical studies supporting the          The feasibility and efficacy of umbilical cord blood
feasibility and efficacy of umbilical cord transplantation . . .”                 transplantation have not been scientifically established.
                                                                                  The National Institutes of Health is just beginning to
“Cord blood can be used to treat any cancer or genetic disease that is            conduct the first true clinical trial, which will be completed
currently treatable by bone marrow transplantation.”                              in 5 years. Cord blood has been used to treat a very limited
                                                                                  number of diseases. Its comparability to bone marrow has
Compared to bone marrow recipients, “cord blood transplant recipients             not been clinically established.
have a higher survival rate, a higher quality of life after transplant and less
frequent hospitalization due to complications such as graft vs host
disease.”

“it has been found that cord blood stem cells are much more proliferative
than bone marrow stem cells . . . .”
“Already, cord blood stem cells have been used in hundreds of cancer,             We are unaware of any data supporting this statement.
blood and immune system treatments with a success rate of 85%.”
                                                                                                                                    (continued)




                                                 Page 17                                                 GAO/HEHS-98-25 Human Tissue Banks
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Informationa                                                                     Correction
“an individual’s own cord blood offers an appropriate source of                  To date, no autologous cord blood transplants have been
transplantable cells, furthermore, autologous transplants are the most           conducted to treat a malignant disease.
common type of transplant performed.”
“There is no risk to the mother or baby from collection.”                        While risks are probably extremely low, the collection and
                                                                                 specimen preparation require the attention of the attending
                                                                                 physician or nurse when his or her attention is normally on
                                                                                 the mother and baby.
“All reagents used in processing are FDA approved.”                              FDA has not approved any processing reagents for use in
                                                                                 preparing stem cells.
“Stem cells can be cryogenically frozen or stored for an indefinite period       Cord blood stem cells have been stored for 15 years;
of time.”                                                                        however, the oldest unit used in a transplant was stored for
                                                                                 less than 5 years. It is not currently known how long
                                                                                 cryogenically frozen stem cells remain viable.
“1 in 100 blood recipients [receiving 5 units] will contract various forms of    The risk of hepatitis B to a recipient of 5 units of blood is
hepatitis transmitted through blood.”                                            about 1 in 12,000; it is 1 in 1,800 to 1 in 20,000 for hepatitis
                                                                                 C.b

                                                a
                                                  Such information has been provided to prospective parents by private firms advertising on the
                                                Internet as recently as August 21, 1997.
                                                b
                                                 G. Schreiber and others, “The Risk of Transfusion-Transmitted Viral Infections,” New England
                                                Journal of Medicine, Vol. 334 (1996), pp. 1685-90, and Blood Supply: Transfusion-Associated
                                                Risks (GAO/PEMD-97-2, Feb. 25, 1997). The range for the risk estimate for hepatitis C is based
                                                on the possibility that there may be individuals with chronic infections who do not produce
                                                detectable seropositivity.



                                                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
The Proposed                                    not addressed in the proposed approach: (1) issues surrounding informed
Approach Does Not                               consent for cord blood and (2) the lack of requirements for the disclosure
Address Certain                                 of genetic testing of reproductive tissues.

Omissions in Current
Regulation


                                                Page 18                                                   GAO/HEHS-98-25 Human Tissue Banks
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Obtaining Informed          The largest public cord blood facility that collects umbilical cord blood
Consent After Collecting    stem cells for use in unrelated allogeneic recipients usually obtains
Umbilical Cord Blood        informed consent from the mother after the cord blood has been collected.
                            This facility follows this practice because obtaining consent in advance
Raises Safety and Ethical   can be highly problematic. For instance, some mothers do not receive
Concerns                    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.23



                            23
                             J. Sugerman and others, “Ethical Issues in Umbilical Cord Blood Banking,” Journal of the American
                            Medical Association, Vol. 278 (1997), pp. 938-43.



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                            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.


Genetic Testing on          Neither FDA’s current regulation nor its proposed approach has language
Reproductive Tissues That   on disclosure of genetic tests that have been performed on donors of
Might Limit Transmission    reproductive tissues that, when transplanted, could result in the
                            transmission of genetic anomalies. Without such disclosure, recipients of
of Genetic Anomalies Is     these tissues lack vital information that, if available, might alter their
Not Disclosed               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




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                            screening for cystic fibrosis and that such screening “is a responsible
                            policy that will eliminate most high-risk carriers.”24

                            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           proposed approach but in a manner that does not adequately eliminate
Does Not Adequately         potential safety problems: (1) the lack of error and accident reporting to
Address Certain             FDA, (2) inadequate tracking systems, (3) the lack of safety and efficacy
                            data on specific stem cell therapies, and (4) inadequate tissue-processing
Issues                      techniques.


Error and Accident          There are presently no federal requirements that tissue facilities maintain
Reporting Is Not Required   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

                            24
                             E. F. Fugger, Anne Maddalena, and J. D. Schulman, “Results of Retroactive Testing of Human Semen
                            Donors for Cystic Fibrosis and Human Immunodeficiency Virus by Polymerase Chain Reaction,”
                            Human Reproduction, Vol. 8 (1993), pp. 1435-37.



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                             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.25 The proposed approach, if implemented as written,
                             would not require the reporting of incidents such as this one.


Current Tracking Systems     We found that FDA’s tracking system for identifying recipients of
Cannot Identify Recipients   transplants that may have been virally infected is incomplete. For
of Tissue Transplants        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.26 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.27 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.28

                             AATBstandards state that the records management system of a facility
                             should permit the reciprocal tracing of tissues from donors to those who

                             25
                               This cornea was later recalled and destroyed.
                             26
                              E. Conrad and others, “Transmission of the Hepatitis-C Virus by Tissue Transplantation,” Journal of
                             Bone and Joint Surgery, Vol. 77-A (1995), pp. 214-24.
                             27
                              Information presented at the June 20-21, 1995, FDA Workshop on Tissue for Transplantation and
                             Reproductive Tissue: Scientific and Regulatory Issues and Perspectives, Bethesda, Md.
                             28
                              J. Prottas, “A Study of the Tissue Procurement and Distribution System of the United States,” draft,
                             FDA contract #240-09-0048, October 1995.



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                             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.29

                             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.30


Stem Cell Therapies Are      Under the proposed approach, tissues transplanted from one person to
Not Yet Well Characterized   another for their normal function (homologous use) without undergoing
                             extensive processing (minimal manipulation) would be subject to

                             29
                              CDC, “Guidelines for Preventing Transmission of Human Immunodeficiency Virus Through
                             Transplantation of Human Tissue and Organs.”
                             30
                               See FDA’s proposed approach, table 1.



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infectious disease screening and testing, and to requirements for good
tissue practices, but would not need FDA review or premarket approval.31
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.32

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

31
  Premarket approval includes an IND, or request for authorization from FDA to administer an
investigational drug or biological product to humans. Such authorization must be secured before the
interstate shipment and administration of any new drug or biological product that is not the subject of
an approved new drug application or product license.
32
 Close blood relative is defined in the proposed approach as a first-degree blood relative (that is,
parent, child, or sibling).



Page 24                                                       GAO/HEHS-98-25 Human Tissue Banks
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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.”33

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.34 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




33
  A phase I clinical trial is the earliest experimental stage for testing in humans. J. Wagner and others,
“Successful Transplantation of HLA-Matched and HLA-Mismatched Umbilical Cord Blood From
Unrelated Donors: Analysis of Engraftment and Acute Graft-versus-Host Disease,” Blood, Vol. 88
(1996), pp. 795-802.
34
 F. Bertolini and others, “Comparative Study of Different Procedures for the Collection and Banking
of Umbilical Cord Blood,” Journal of Hematotherapy, Vol. 4 (1995), pp. 29-36.



Page 25                                                        GAO/HEHS-98-25 Human Tissue Banks
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peripheral or cord blood progenitor cells are indirect.35 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.36

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.37 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.38 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


35
  Stem cells have varying degrees of “stemness”—that is, the range of more specialized cells that they
can create. Some stem cells can replicate extensively but have only a limited capacity for
differentiation. Thus, some stem cells can become only red blood cells while others may be able to
form red or white blood cells or platelets. The most fundamental stem cell is the totipotent cell. In
principle, one of these cells could reconstitute the entire blood producing and immune system.
Pluripotent cells are less general but they can still differentiate into several “lines” that form different
types of blood cells.
36
 I. Webb and others, “Kinetics of Peripheral Blood Mononuclear Cell Mobilization with Chemotherapy
and/or Granulocyte-Colony Stimulating Factor: Implications for Timing and Yield of Hematopoietic
Progenitor Cell Collections,” Transfusion, Vol. 36 (1996), pp. 160-67.
37
 E. Gluckman and others, “Outcome of Cord-Blood Transplantation from Related and Unrelated
Donors,” New England Journal of Medicine, Vol. 337 (1997), pp. 373-81.
38
  The HLA system includes a complex array of genes and their molecular products that are important
in immune regulation, transplantation, and transfusion. It is second in importance to the ABO antigens
in influencing the survival of transplanted solid organs, and immunologic recognition of differences in
HLA antigens is probably the first step in the rejection of transplanted tissue.


Page 26                                                         GAO/HEHS-98-25 Human Tissue Banks
                        B-275822




                        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.


Some Processing         The proposed approach considers the processing of cells and
Techniques May Affect   nonstructural tissues to be more than minimal manipulation when it alters
Safety and Efficacy     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



                        Page 27                                       GAO/HEHS-98-25 Human Tissue Banks
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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.39 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.



39
 E. Conrad and others, “Transmission of the Hepatitis-C Virus by Tissue Transplantation,” Journal of
Bone and Joint Surgery, Vol. 77A (1995), pp. 214-24.



Page 28                                                    GAO/HEHS-98-25 Human Tissue Banks
              B-275822




              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.40 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.41 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
Conclusions   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

              40
                CDC, “Guidelines for Preventing Transmission of Human Immunodeficiency Virus.”
              41
               T. Eastlund, “Infectious Disease Transmission Through Cell, Tissue, and Organ Transplantation:
              Reducing the Risk Through Donor Selection,” Cell Transplantation, Vol. 4 (1995), pp. 455-77.



              Page 29                                                   GAO/HEHS-98-25 Human Tissue Banks
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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.



Page 30                                      GAO/HEHS-98-25 Human Tissue Banks
                       B-275822




                       We recommend that the Secretary of the Department of Health and Human
Recommendations        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.42 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
Agency Comments        recommendations to require (1) the registration of all tissue facilities with
and Our Response       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

                       42
                         We define tissue facilities in these recommendations as covering both tissue and stem cell facilities.



                       Page 31                                                       GAO/HEHS-98-25 Human Tissue Banks
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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



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consent before infant delivery affords mothers sufficient time to deliberate
decisions before procedures are performed.

FDA’scomments 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.

Sincerely yours,




Bernice Steinhardt
Director, Health Services Quality
  and Public Health Issues




Page 33                                      GAO/HEHS-98-25 Human Tissue Banks
Contents



Letter                                                                                           1


Appendix I                                                                                      36
                        Procurement                                                             36
Additional              Screening                                                               37
Information on          Testing                                                                 39
                        Processing                                                              39
Tissue-Banking
Processes
Appendix II                                                                                     41

Comments From the
Food and Drug
Administration
Appendix III                                                                                    48

Major Contributors to
This Report
Tables                  Table 1: Infectious Diseases Transmissible Through Human                 8
                          Tissue
                        Table 2: Tissue Banking Facts and Figures                               12
                        Table 3: Misleading and False Information About Umbilical Cord          17
                          Blood on the Internet
                        Table I.1: Donor Suitability Criteria                                   37




                        Page 34                                   GAO/HEHS-98-25 Human Tissue Banks
Contents




Abbreviations

AABB       American Association of Blood Banks
ASBMT      American Society for Blood and Marrow Transplantation
AATB       American Association of Tissue Banks
ASRM       American Society for Reproductive Medicine
CDC        Centers for Disease Control and Prevention
EBAA       Eye Bank Association of America
FAHCT      Foundation for the Accreditation of Hematopoietic Cell
                 Therapy
FDA        Food and Drug Administration
GVHD       graft versus host disease
HCFA       Health Care Financing Administration
HHS        Department of Health and Human Services
HIV        human immunodeficiency virus
HLA        human leukocyte antigen
HRSA       Health Resources and Services Administration
HTLV       human T-cell lymphotropic virus
IND        investigational new drug
ISHAGE     International Society of Hematotherapy and Graft
                 Engineering
NHLBI      National Heart, Lung, and Blood Institute
NMDP       National Marrow Donor Program
OPO        organ procurement organization
PHS        Public Health Service


Page 35                                  GAO/HEHS-98-25 Human Tissue Banks
Appendix I

Additional Information on Tissue-Banking
Processes

               Ideally, each potential tissue or organ donor encounters only one
Procurement    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.43 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

               43
                 OPOs are responsible for recovering organs from donors. The National Organ Transplant Act requires
               that OPOs also arrange to cooperate with tissue facilities for the retrieval, processing, preservation,
               storage, and distribution of tissues as may be appropriate to ensure that all usable tissues are obtained
               from potential donors.



               Page 36                                                      GAO/HEHS-98-25 Human Tissue Banks
                                        Appendix I
                                        Additional Information on Tissue-Banking
                                        Processes




                                        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,
Screening                               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.44 Table I.1 outlines the suitability criteria
                                        established by AATB.

Table I.1: Donor Suitability Criteria
                                        Donor suitability criterion                                 Action
                                        Excised, healed localized skin cancer,                      Accept donor
                                        carcinoma-in-situ of the uterine cervix, or proven
                                        nonmetastatic primary brain tumor
                                        History of other malignancies treated by surgery      Base decision on medical
                                        alone with no evidence of recurrence or spread for at director’s evaluation
                                        least 5 years
                                        History of autoimmune disease                               Base decision on medical
                                                                                                    director’s evaluation
                                        Ingestion or exposure to toxic substances                   Base decision on medical
                                                                                                    director’s evaluation
                                        Significant active infection (septicemia, systemic viral Reject donor
                                        disease, untreated syphilis, active tuberculosis,
                                        systemic mycosis)
                                                                                                                             (continued)
                                        44
                                         Information provided by B. Buck at FDA workshop on human tissue intended for transplantation,
                                        Bethesda, Maryland, June 1994.



                                        Page 37                                                  GAO/HEHS-98-25 Human Tissue Banks
Appendix I
Additional Information on Tissue-Banking
Processes




Donor suitability criterion                                    Action
History of receiving pituitary-derived human growth            Reject donor
hormone
History of dementia or degenerative neurological               Reject donor
disorders of viral or unknown etiology
HIV or hepatitis risk factor                                   Reject donor
Current malignancy (except as noted above)                     Reject donor
Rheumatoid arthritis, systemic lupus erythematosus,            Reject as musculoskeletal tissue
polyarteritis nodosa, sarcoidosis, myasthenia gravis,          donor
metabolic bone disease
History of leprosy (Hansen’s disease)                          Reject as skin donor
Family history of genetic disorders that may affect            Reject as umbilical cord blood
recipient                                                      donor
Positive genetic tests for cystic fibrosis, sickle cell        Reject as semen donor
trait, Tay-Sachs disease, or thalassemiaa
Positive tests for Neisseria gonorrhea and Chlamydia Reject as semen donor
trachomatisb
Inadequate sperm quality and quantityb                         Reject as semen donor
Age criteria established by facilities’ standard               Reject as semen donor
operating procedures except as noted below                     Reject as cardiovascular tissue
— Older than 40                                                donor
— Older than 60
History of bacterial endocarditis, rheumatic fever, or         Reject as cardiovascular tissue
semilunar valvular disease                                     donor

a
 Cystic fibrosis is the most common recessive disease in the Caucasian population and usually
results in severe lung disease and other problems leading to early death. Sickle cell is found
mostly in individuals of African ancestry. It results in a number of medical problems such as pain,
increased risk of infection, and stroke. Tay-Sachs is a recessive disorder in which the activity of
an important enzyme is deficient. The results are neurological complications and death before
age 5. Thalassemia is found primarily in Asian, African, Middle Eastern, and Mediterranean
groups. It results in a variety of medical problems and a need for lifelong blood transfusions and
other complications.
b
Not performed for musculoskeletal, skin, eye, or stem cell donors.



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.




Page 38                                                     GAO/HEHS-98-25 Human Tissue Banks
             Appendix I
             Additional Information on Tissue-Banking
             Processes




             Donors who have received blood or fluid transfusions may have blood that
Testing      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
Processing   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



             Page 39                                     GAO/HEHS-98-25 Human Tissue Banks
Appendix I
Additional Information on Tissue-Banking
Processes




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.




Page 40                                       GAO/HEHS-98-25 Human Tissue Banks
Appendix II

Comments From the Food and Drug
Administration

Note: GAO comments
supplementing those in the
report text appear at the
end of this appendix.




                             Page 41   GAO/HEHS-98-25 Human Tissue Banks
Appendix II
Comments From the Food and Drug
Administration




Page 42                           GAO/HEHS-98-25 Human Tissue Banks
                 Appendix II
                 Comments From the Food and Drug
                 Administration




See comment 1.




See comment 2.




                 Page 43                           GAO/HEHS-98-25 Human Tissue Banks
                 Appendix II
                 Comments From the Food and Drug
                 Administration




See comment 3.




                 Page 44                           GAO/HEHS-98-25 Human Tissue Banks
                 Appendix II
                 Comments From the Food and Drug
                 Administration




See comment 4.




                 Page 45                           GAO/HEHS-98-25 Human Tissue Banks
               Appendix II
               Comments From the Food and Drug
               Administration




               The following are GAO’s comments on FDA’s October 23, 1997, letter.


               1. We believe that the current umbilical cord blood banking protocols,
GAO Comments   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.45
               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

               45
                The Working Group on Ethical Issues in Umbilical Cord Blood Banking was supported by the Cannon
               Foundation, Concord, North Carolina, and the Kenan Program in Ethics at Duke University, Durham,
               North Carolina.



               Page 46                                                 GAO/HEHS-98-25 Human Tissue Banks
Appendix II
Comments From the Food and Drug
Administration




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.




Page 47                                      GAO/HEHS-98-25 Human Tissue Banks
Appendix III

Major Contributors to This Report


               Marcia Crosse, Assistant Director
               Jacqueline D’Alessio, Project Manager
               Kurt Kroemer, Senior Social Science Analyst
               David Michaels, Evaluator
               Roy Hogberg, Adviser




(108306)       Page 48                                   GAO/HEHS-98-25 Human Tissue Banks
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