Human Tissue Banks: FDA Taking Steps to Improve Safety, but Some Concerns
Remain (Letter Report, 12/05/97, GAO/HEHS-98-25).

Pursuant to a congressional request, GAO evaluated the Food and Drug
Administration's (FDA) oversight of transplanted human tissue as well as
potential safety problems, focusing on: (1) gaps in the current
regulation; and (2) whether and how FDA plans to address them in the
approach it has proposed for regulating tissue banking.

GAO noted that: (1) FDA is just now expanding its oversight to improve
tissue-banking safeguards in the growing field of tissue-based
therapies; (2) FDA has proposed a regulatory approach that is much
broader in scope than the current regulation; (3) still in its formative
stages, the regulatory approach describes a risk-based approach that
industry has generally received well; (4) FDA's proposed approach would
alleviate three safety problems not covered by the current regulation:
(a) FDA has no universal registry of tissue facilities currently
operating in the United States; (b) the current regulation does not
cover reproductive tissue or stem cell facilities; and (c) there are
numerous instances of misleading and false advertising in private cord
blood banking; (5) two problems that FDA does not address in the current
regulation or in the proposed approach are: (a) some facilities obtain
informed consent after infant delivery, raising safety and ethical
concerns about cord blood; and (b) FDA has no current or proposed
requirements for disclosing to recipients whether genetic tests have
been performed on reproductive tissues and stem cells; and (6) four
instances in which FDA's proposed approach inadequately addresses
potential safety problems not covered in the current regulation are: (a)
facilities would be required to record and investigate errors and
accidents but not to report them to FDA; (b) the proposed approach only
minimally mentions tracking tissues as good tissue practices and then
only in respect to controlling disease transmission; (c) FDA will not
require premarket submissions when cells or tissues are to be used in
the person from whom they are obtained or in a close blood relative; and
(d) FDA has proposed that certain tissue products be subject to
premarket approval and that it evaluate processing techniques used on
those products, but, for minimally manipulated tissue products, would
require only that the validation of the procedure be documented and
available when FDA inspects facilities.

--------------------------- Indexing Terms -----------------------------

 REPORTNUM:  HEHS-98-25
     TITLE:  Human Tissue Banks: FDA Taking Steps to Improve Safety, but 
             Some Concerns Remain
      DATE:  12/05/97
   SUBJECT:  Testing
             Product safety
             Infectious diseases
             Health hazards
             Health resources utilization
             Safety standards
             Safety regulation
             Reporting requirements
             Quality assurance
             Health care facilities
IDENTIFIER:  National Marrow Donor Program
             AIDS
             
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Cover
================================================================ COVER


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

Human Tissue Banks

(108306)


Abbreviations
=============================================================== ABBREV

  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

Letter
=============================================================== LETTER


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. 

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. 


--------------------
\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. 

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


   RESULTS IN BRIEF
------------------------------------------------------------ Letter :1

FDA is just now expanding its oversight to improve tissue-banking
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 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 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 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. 


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

\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). 


   BACKGROUND
------------------------------------------------------------ Letter :2

The term "tissue" covers a wide range of products used for many
medical purposes.  Traditionally, most human tissue used in medicine
comprised such body components as skin, bone, corneas, and heart
valves that were transplanted for replacement purposes as well as
semen and ova implanted for reproductive purposes.  In recent years,
scientists have developed innovative methods of manipulating and
using human cells and tissues for therapeutic purposes.  For example,
in what is known as somatic cell therapy, scientists are studying the
use of human cells that have been manipulated in the laboratory to
treat viral infections, Parkinson's disease, diabetes, and other
diseases and conditions.  Other tissue research includes the use of
blood from the placenta and umbilical cord to treat leukemia and
other diseases.\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, 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

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. 


--------------------
\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. 

\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. 

\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). 


      PROCESSES
---------------------------------------------------------- Letter :2.1

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 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        Hepatitis, HIV, cytomegalovirus, human T-cell
tissue\c            lymphotropic virus,\d sexually transmitted
                    diseases

Stem cells\e        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 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. 


--------------------
\10 A tissue bank is any facility that engages in recovering,
screening, testing, processing, storing, or distributing human tissue
intended for transplantation. 

\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. 


      THE ROLE OF INDUSTRY
      ASSOCIATIONS
---------------------------------------------------------- Letter :2.2

AATB has standards and an accreditation program for its members. 
AATB 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. 

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

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. 



                                         Table 2
                         
                             Tissue Banking Facts and Figures

                    Number of                          Estimated number
                    donors          Estimated number   of recipients     Industry
Types of tissue     annually        of banks           annually          association
------------------  --------------  -----------------  ----------------  ----------------
Musculoskeletal:    5,500           About 100; 2       350,000           AATB
bone (whole,                        largest collect
crushed, chips,                     50-55%; 6 others
demineralized                       collect 30-45%
powder),
cardiovascular,
cartilage, skin,
tendon

Eye tissue:         40,000-45,000   110                40,000-45,000     EBAA and
cornea, sclera                                                           American College
                                                                         of Opthalmology

Reproductive:       Unknown         100 semen banks,   Semen = 200,000;  ASRM and
embryo, oocyte,                     150 assisted       embryo= 2,500     American College
semen                               reproductive                         of Pathology
                                    technology
                                    facilities, 300
                                    laboratories

Stem cells          Unknown         20-50 collect      250 (U.S.),       AABB, ASBMT,
Umbilical cord                      umbilical cord     500               FACHT, ISHAGE
blood                               blood; 6 private   (worldwide);
                                    banks; 6 public    75% are
                                    banks\a; about 15  unrelated
                                    facilities have    allogeneic\b
                                    performed cord
                                    blood
Peripheral                          transplants
                                                       700 (U.S.),
                                    Unknown number     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. 


--------------------
\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. 

\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. 


      STATE REGULATIONS
---------------------------------------------------------- Letter :2.3

Several states have promulgated regulations on specific standards
required at particular types of tissue facilities.  For instance,
some states require sperm banks to register and to be inspected by
state health departments, while other states have guidelines on the
interpretation of tissue donor screening test results and the
processing and storage of stem cells. 

CDC is currently establishing prototype regulations from which states
could model their own regulations on reproductive tissues.  CDC was
mandated to do this by the Fertility Clinics Success Rate and
Certification Act of 1992.  CDC officials stated that the model
laboratory certification program will closely mirror existing
laboratory accreditation procedures formulated by the College of
American Pathologists laboratory accreditation program.  In addition
to requiring CDC to establish model regulations, the act required
assisted reproductive technology programs that assist infertile
couples to report pregnancy success rates to CDC.  Presently,
California, Florida, Minnesota, and New York have regulatory programs
or are working on legislation for reproductive tissue. 

Several states have also enacted three categories of corneal removal
laws:  (1) implied consent, in which corneas may be released to an
eye bank when it is a medical examiner's or coroner's case, an
autopsy is required, release would not interfere with a subsequent
investigation, and there is no known objection by next of kin; (2)
diligent or reasonable search, in which an effort must be made to
contact next of kin within a specific time period before release of
corneas; and (3) consent only, in which release is possible only when
authorized next of kin consent has been obtained.  According to EBAA,
12 states and Puerto Rico have implied-consent laws, 9 states have
diligent search laws, and 6 states have consent-only laws. 


   OVERVIEW OF CURRENT REGULATION
   AND PROPOSED APPROACH
------------------------------------------------------------ Letter :3

FDA's current regulation on human tissue intended for transplantation
covers several areas of tissue collection, processing, and storage,
all relating to the control of hepatitis B and C and HIV
transmission.  These include (1) donor screening and testing; (2)
requirements for written procedures for testing for infectious
disease and obtaining, reviewing, and assessing the medical records
of donors; (3) record keeping; (4) quarantining requirements; (5) FDA
authority to inspect tissue facilities; (6) importation of human
tissue; and (7) retention, recall, and destruction of human tissue. 

The proposed approach to the regulation of tissue and cellular-based
therapies represents a move toward forward-thinking regulation of a
diverse and rapidly advancing field.  It is less prescriptive than
traditional FDA regulation and it has generally been well received by
industry.  Although it is clearly open to broad interpretation, it
would expand the current FDA oversight to include reproductive
tissues and stem cells.  The approach would focus on three main
areas:  (1) preventing unwitting use of contaminated tissues with the
potential for transmitting infectious diseases, (2) preventing
improper handling and processing that might contaminate or damage
tissues, and (3) ensuring that clinical safety and efficacy are
demonstrated for tissues that are highly processed (more than
minimally manipulated), used for other than their normal function
(nonhomologous), combined with nontissue components, or used for
metabolic purposes. 


   THE PROPOSED APPROACH ADDRESSES
   CERTAIN OMISSIONS IN CURRENT
   REGULATION
------------------------------------------------------------ Letter :4

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


      FACILITIES NOT REQUIRED TO
      REGISTER
---------------------------------------------------------- Letter :4.1

Unlike in other industries that FDA regulates, such as blood and
implantable medical devices, FDA does not have an accurate list of
tissue facilities in the United States because these facilities have
not been and are not now required to register with FDA.  Therefore,
FDA can neither notify all tissue facilities as potential public
health threats arise nor plan inspections from a complete
registration of tissue facilities.\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 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


--------------------
\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. 

\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. 


      SOME FACILITIES ARE NOT
      COVERED BY CURRENT
      REGULATION
---------------------------------------------------------- Letter :4.2

The current regulation does not cover facilities that collect, store,
process, or distribute reproductive tissues or stem cells. 
Specifically, these facilities are not required to adhere to the
requirement for infectious disease testing nor does FDA have direct
authority to inspect these facilities for compliance with the current
regulation.\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. 


--------------------
\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. 


      SOME UMBILICAL CORD BLOOD
      BANKS USE MISLEADING AND
      FALSE ADVERTISING
---------------------------------------------------------- Letter :4.3

Little is known about the type and level of information that private
cord blood facilities present to expecting parents, either in writing
or orally.  FDA has periodically monitored but not regulated this
industry's advertising practices. 

Techniques to collect, process, store, and transfuse cord blood are
not well established, but this fact is not emphasized to prospective
parents.  If provided at all, the extremely low probability of ever
requiring the cord blood unit for transplantation into the child or a
family member is rarely, if ever, completely portrayed.  Nor are
parents always told of other sources of stem cells, such as
peripheral blood and bone marrow, that can be collected and
transplanted when they are needed.  Current scientific knowledge
suggests that umbilical cord blood stem cells are less likely to
initiate graft versus host disease (GVHD) in a recipient than bone
marrow and, perhaps, peripheral stem cells.\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. 

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

Information\a                                     Correction
------------------------------------------------  ------------------------------
"It has the added advantage of being              Cord blood is at risk for any
`privileged' or unexposed to most diseases."      disease of the mother, who, as
                                                  an adult, has risks equal to
"Cord blood is rarely contaminated by viruses     those of any other adult who
such as cytomegalovirus or Epstein-Barr virus     might donate bone marrow.
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          The feasibility and efficacy
clinical studies supporting the feasibility and   of umbilical cord blood
efficacy of umbilical cord transplantation . .    transplantation have not been
."                                                scientifically established.
                                                  The National Institutes of
"Cord blood can be used to treat any cancer or    Health is just beginning to
genetic disease that is currently treatable by    conduct the first true
bone marrow transplantation."                     clinical trial, which will be
                                                  completed in 5 years. Cord
Compared to bone marrow recipients, "cord blood   blood has been used to treat a
transplant recipients have a higher survival      very limited number of
rate, a higher quality of life after transplant   diseases. Its comparability to
and less frequent hospitalization due to          bone marrow has not been
complications such as graft vs host disease."     clinically established.

"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    We are unaware of any data
in hundreds of cancer, blood and immune system    supporting this statement.
treatments with a success rate of 85%."

"an individual's own cord blood offers an         To date, no autologous cord
appropriate source of transplantable cells,       blood transplants have been
furthermore, autologous transplants are the most  conducted to treat a malignant
common type of transplant performed."             disease.

"There is no risk to the mother or baby from      While risks are probably
collection."                                      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          FDA has not approved any
approved."                                        processing reagents for use in
                                                  preparing stem cells.

"Stem cells can be cryogenically frozen or        Cord blood stem cells have
stored for an indefinite period of time."         been stored for 15 years;
                                                  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]    The risk of hepatitis B to a
will contract various forms of hepatitis          recipient of 5 units of blood
transmitted through blood."                       is 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. 


--------------------
\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. 


   THE PROPOSED APPROACH DOES NOT
   ADDRESS CERTAIN OMISSIONS IN
   CURRENT REGULATION
------------------------------------------------------------ Letter :5

We have two concerns about omissions in the current regulation that
are not addressed in the proposed approach:  (1) issues surrounding
informed consent for cord blood and (2) the lack of requirements for
the disclosure of genetic testing of reproductive tissues. 


      OBTAINING INFORMED CONSENT
      AFTER COLLECTING UMBILICAL
      CORD BLOOD RAISES SAFETY AND
      ETHICAL CONCERNS
---------------------------------------------------------- Letter :5.1

The largest public cord blood facility that collects umbilical cord
blood stem cells for use in unrelated allogeneic recipients usually
obtains informed consent from the mother after the cord blood has
been collected.  This facility follows this practice because
obtaining consent in advance can be highly problematic.  For
instance, some mothers do not receive prenatal care and, thus, do not
afford the cord blood facility the opportunity to obtain informed
consent before delivery.  An FDA official stated that since the
placenta and umbilical cord are normally discarded following
delivery, these tissues typically become the property of the
hospital.  For other tissues removed and discarded (as in surgery),
consent to collect portions for other uses is not generally required. 
Therefore, an argument can be made that consent is needed for
umbilical cord blood testing and use but not collection. 

Two safety concerns are raised when informed consent is not obtained
until after collection.  First, the health implications to recipients
of umbilical cord blood from mothers who may not have received
prenatal care are currently unknown.  Second, an essential safety
control is to ask the mother a series of screening questions
regarding her behavior and exposure to disease.  A new mother might
not answer truthfully questions on high-risk behavior (such as
illicit drug use) that could otherwise result in removing her newborn
from her care. 

The public cord blood bank that obtains consent after collection is
operating under an FDA-approved investigational new drug (IND)
protocol and has obtained institutional review board approval from
the hospital where the cord blood is collected.  The current cord
blood banking protocols under FDA-approved INDs will provide the
opportunity through data collection to assess the safety and risks of
seeking informed consent after cord blood has been collected.  Until
these analyses have been conducted, the safety of seeking consent
after delivery remains unknown. 

There is also an ethical concern in obtaining consent after
collection.  A recent consensus statement from the Working Group on
Ethical Issues in Umbilical Cord Blood Banking noted that informed
consent should be obtained before procuring placental blood for
transplantation because not obtaining consent runs counter to the
explicit reasoning behind informed consent--that is, providing an
individual with the information and opportunity to make a decision
before a procedure is performed.\23 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. 


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


      GENETIC TESTING ON
      REPRODUCTIVE TISSUES THAT
      MIGHT LIMIT TRANSMISSION OF
      GENETIC ANOMALIES IS NOT
      DISCLOSED
---------------------------------------------------------- Letter :5.2

Neither FDA's current regulation nor its proposed approach has
language on disclosure of genetic tests that have been performed on
donors of reproductive tissues that, when transplanted, could result
in the transmission of genetic anomalies.  Without such disclosure,
recipients of these tissues lack vital information that, if
available, might alter their decision to use tissues from such
donors. 

Genetic anomalies in donated sperm or eggs can cause serious or fatal
diseases.  Donors may be unaffected carriers of these anomalies with
no family history of such disease.  Such genetic diseases arise when
a child inherits an affected gene from both the mother and father. 
While some genetic diseases are more prevalent in certain ethnic and
racial populations, the rise of interracial and mixed ethnic
marriages makes these population distinctions less valuable as a
screening tool (see table I.1). 

Studies conducted to determine, retrospectively, whether new tests to
detect cystic fibrosis would find previous donors to be carriers
found that of 149 actual donors, 5 were heterozygous carriers of the
mutation for cystic fibrosis.  Also, 1 of 100 donor applicants was
found to be a heterozygous carrier.  The researchers determined that
the chance was 1 in 16,100 that an individual who had no family
history of cystic fibrosis and who used a DNA-tested donor would bear
a child with the disease.  They concluded that it is important for
donor banks to perform genetic screening for cystic fibrosis and that
such screening "is a responsible policy that will eliminate most
high-risk carriers."\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. 


--------------------
\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. 


   PROPOSED APPROACH DOES NOT
   ADEQUATELY ADDRESS CERTAIN
   ISSUES
------------------------------------------------------------ Letter :6

Four issues not addressed in the current regulation are addressed in
the proposed approach but in a manner that does not adequately
eliminate potential safety problems:  (1) the lack of error and
accident reporting to FDA, (2) inadequate tracking systems, (3) the
lack of safety and efficacy data on specific stem cell therapies, and
(4) inadequate tissue-processing techniques. 


      ERROR AND ACCIDENT REPORTING
      IS NOT REQUIRED
---------------------------------------------------------- Letter :6.1

There are presently no federal requirements that tissue facilities
maintain records for the reporting of errors and accidents or adverse
events to FDA, even though this practice is required for similar
types of industries such as blood banking.  For example, the
distribution of quarantined tissues or the inadvertent
transplantation of tissue testing positive for infectious disease
might go unreported. 

The proposed approach would require the reporting of adverse events
associated with infectious disease transmission but not errors and
accidents.  FDA officials believe that requiring facilities to record
and investigate errors and accidents without reporting to the agency
even a subset of the most serious ones is sufficient to monitor the
industry.  In fact, FDA interprets section 361 of PHS (which
authorizes regulations to control the spread of communicable disease)
as authorizing regulations requiring the reporting of tissue failures
based on problems associated with processing, among other events,
because repeated tissue failures may require repeated tissue
transplants, thereby increasing potential exposure to communicable
disease.  But because errors and accidents are often early warning
signals of noncompliance or poor practices, FDA is missing an
opportunity to identify tissue facilities that would benefit from
additional FDA oversight.  One recent FDA inspection found that a
firm had distributed corneas before receiving test results showing
that one cornea had tested positive for HIV.\25 The proposed
approach, if implemented as written, would not require the reporting
of incidents such as this one. 


--------------------
\25 This cornea was later recalled and destroyed. 


      CURRENT TRACKING SYSTEMS
      CANNOT IDENTIFY RECIPIENTS
      OF TISSUE TRANSPLANTS
---------------------------------------------------------- Letter :6.2

We found that FDA's tracking system for identifying recipients of
transplants that may have been virally infected is incomplete.  For
example, when attempting to track recipients of a donor who tested
negative on the first-generation hepatitis C test but positive on the
second-generation test, researchers found that 1 of 16 grafts
released for distribution from this donor was sent to a hospital that
had no record of the graft.\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

AATB standards state that the records management system of a facility
should permit the reciprocal tracing of tissues from donors to those
who receive them and back.  Also, the standards state that upon
discovering the need for recalling tissues, facilities should
promptly notify all entities to whom affected tissue was distributed
or dispensed.  For this reason, some within the tissue industry have
called for regulations requiring that receiving institutions or
clinicians be responsible for keeping records of the final
disposition of tissues so that tissue facilities can identify
recipients of tissues that might be contaminated. 

Moreover, a CDC guideline for preventing the transmission of HIV
through the transplantation of human tissue and organs recommends
that all facilities involved in the acquisition of tissues or organs
from a single donor be able to communicate among themselves for the
purpose of tracking tissues and organs to recipients who should be
notified when HIV transmission is confirmed.\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


--------------------
\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. 

\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. 


      STEM CELL THERAPIES ARE NOT
      YET WELL CHARACTERIZED
---------------------------------------------------------- Letter :6.3

Under the proposed approach, tissues transplanted from one person to
another for their normal function (homologous use) without undergoing
extensive processing (minimal manipulation) would be subject to
infectious disease screening and testing, and to requirements for
good tissue practices, but would not need FDA review or premarket
approval.\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 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 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 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. 


--------------------
\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). 

\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. 

\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. 


      SOME PROCESSING TECHNIQUES
      MAY AFFECT SAFETY AND
      EFFICACY
---------------------------------------------------------- Letter :6.4

The proposed approach considers the processing of cells and
nonstructural tissues to be more than minimal manipulation when it
alters the biological characteristics (and, thus, potentially the
function or integrity) of the cells or tissues or when it is unknown
whether it will alter them.  Examples include cell expansion,
activation, and genetic modification.  More than minimally
manipulated cells or tissues would be subject to processing controls
and to premarket requirements to determine safety and effectiveness. 
FDA would evaluate the processing techniques in the course of
reviewing premarket applications and would inspect firms to assess
their operations and review their processing techniques before
granting marketing approval. 

The proposal is different for minimally manipulated tissues.  For
these tissues, FDA would require that the validation of the
procedures be documented and available when FDA inspects a facility
but would not require the submission of any information on
processing.  The proposed approach considers the processing of cells
and tissues to be minimal manipulation when it does not alter their
original relevant characteristics, such as those relating to the
ability of cells or tissues to carry out the function of
reconstruction or repair.  Examples include cutting, grinding, and
shaping; soaking in antibiotic solution; sterilization by ethylene
oxide or gamma irradiation; cell separation; and cryopreservation. 
Tissues that were processed with minimal manipulation would be
subject to good tissue practices relating to contamination,
integrity, and function that FDA would establish in future
rulemaking.  However, FDA currently has limited information on which
to base criteria for these practices, and we found few processing
techniques that had been validated by tissue facilities and evaluated
by FDA for safety and effectiveness. 

In several interviews, we obtained information regarding processes
some facilities use that may be harmful to the efficacy of tissues or
that have no established safety or efficacy record (for example, the
use of bleach and peroxide or "air drying").  We did not
independently verify what we were told.  Below, we present
information we gathered from these interviews and from the scientific
research that highlights potential safety and efficacy issues.  Some
procedures that remove or destroy bacteria hamper the ability of
tissue to remain viable.  For instance, sterilization can destroy the
viability of grafts, and irradiation and freeze-drying both reduce
biomechanical strength.  Therefore, cryopreserved skin, heart valve,
and osteochondral bone grafts cannot be treated with these methods. 
Furthermore, chemical sterilization by exposure to ethylene oxide or
demineralization techniques may adversely affect the regenerating
properties of bone, although the evidence is controversial.\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. 

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. 


--------------------
\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. 

\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. 


   CONCLUSIONS
------------------------------------------------------------ Letter :7

In its proposed approach, FDA addresses three problems we identified
as not covered in the current regulation:  registration of tissue
banks, oversight of reproductive and stem cell facilities, and false
product claims.  However, the proposed approach is still in its
formative stages and will be codified over a number of years.  Until
then, these concerns will remain. 

We identified two problems that are not addressed in either FDA's
current regulation or its proposed approach.  We found that some
public umbilical cord blood banks obtain informed consent after
collecting the blood.  The safety implications of using units from
mothers who may not have received prenatal care or who are called
upon to answer questions postcollection about high-risk behavior are
unknown.  Requesting informed consent before delivery provides the
mother with the information and opportunity to make a decision before
a procedure is performed.  Second, the lack of disclosure of genetic
testing for donated reproductive tissues limits vital information
that, if otherwise available, might alter a recipient's decision to
use tissues from donors who could introduce genetic anomalies. 

In four instances, we found that the proposed approach addresses
issues that are not covered in the current regulation but does so in
a manner that is inadequate to eliminate potential safety problems. 
First, the proposed approach would not require the reporting of any
errors or accidents, even those that could have serious consequences. 
Without such reporting, FDA will miss an opportunity to provide
warranted oversight.  Second, FDA has an inadequate system for
tracking tissues to recipients from donors who are later determined
to have been virally infected or whose tissues should otherwise not
have been transplanted.  The inability to trace potentially
infectious or otherwise hazardous tissues could have serious public
health consequences.  Third, FDA plans to require premarket approval
for therapies using stem cells if the cells are obtained from an
unrelated allogeneic donor.  As a matter of policy, FDA will waive
this requirement if the cells are obtained from oneself (autologous)
or from a close blood relative (related allogeneic).  However, the
scientific community has not determined optimal collection,
separation, processing, and storage procedures for these
cellular-based tissues.  Because these products are used to
reconstitute a patient's entire immune system, the treatment poses
great risk, regardless of whether the source is a relative or an
anonymous donor.  Fourth, we found that facilities have validated and
FDA has evaluated few processing procedures.  Some procedures
currently in use may, in fact, harm the viability of grafts, reduce
their biomechanical strength, and negatively affect the regenerating
properties of bone.  Without baseline knowledge of industry practice,
FDA is hampered in its ability to fully monitor the safety of this
aspect of human tissue banking. 

We believe that steps that would generally incur minimal additional
cost to the tissue-banking industry could be taken to address these
concerns.  Many of these steps, requiring little change in the
majority of tissue-banking facilities, would correct practices that
are not up to industry standards.  Two areas could require that
additional, more costly, steps be taken:  the creation of a system
for tracking tissues to recipients and the imposition of premarket
controls upon related allogeneic stem cell therapies if FDA
determines that adequate safety and efficacy data are not available
after the moratorium it has proposed.  However, we believe that
actions should be taken if risks outweigh costs, as we believe is
likely. 


   RECOMMENDATIONS
------------------------------------------------------------ Letter :8

We recommend that the Secretary of the Department of Health and Human
Services direct FDA to take action in several areas to improve the
safety and efficacy of donated human tissue and to increase FDA's
ability to regulate tissue facility activities.\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. 


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


   AGENCY COMMENTS AND OUR
   RESPONSE
------------------------------------------------------------ Letter :9

In commenting on a draft of this report, FDA generally concurred with
our recommendations to require (1) the registration of all tissue
facilities with FDA, (2) adherence of reproductive and stem cell
facilities to all the requirements in the current regulation, (3)
accurate labeling and promotion by facilities that collect and store
cord blood, (4) disclosure to recipients of genetic tests performed
on reproductive tissues, and (5) validation of systems to track
tissues to consignees and recipients. 

The agency partly concurred with our recommendations on (1) reporting
errors and accidents to FDA, (2) requirements for premarket
submissions by peripheral and cord blood stem cell facilities, and
(3) tissue facilities' informing FDA of the types of processing
techniques they use and the safety and efficacy data of these
techniques. 

FDA agreed that adverse events should be reported to the agency but
pointed out that reviewing error and accident reports would cost
resources for both FDA and the industry and that current budgeting
constraints would not allow FDA to review and evaluate such reports. 
We understand the fiscal ramifications of requiring error and
accident reporting, and it is for this reason that we recommended
that only "serious" errors and accidents be reported to FDA. 

FDA noted that it intends to require premarket applications for
unrelated allogeneic cord blood stem cells but would not require such
submissions for family-related allogeneic transplants because FDA was
trying to accommodate the needs and concerns of families.  However,
we are unaware of safety issues that would be relevant only for
unrelated allogeneic cord blood transplants.  For this reason, we
recommended that facilities that collect, store, process, or
distribute peripheral or cord blood stem cells make premarket
submissions if FDA determines that adequate safety and efficacy data
are not available to license such products. 

FDA also pointed out that while it intends to review the processes
tissue facilities use before approving highly manipulated tissue
products, it will require validation to be documented and available
during FDA inspections for procedures involving only "minimal" tissue
manipulation.  However, we are concerned about the time that could
elapse before the agency learns about the safety and efficacy of
these processes.  Because FDA does not plan to conduct routine
inspections of tissue facilities, the agency may not have the
opportunity for many years to evaluate the documentation. 

FDA did not concur with our recommendation that informed consent be
obtained from living donors before procuring tissues intended for
transplantation.  The agency believes that seeking informed consent
for the use of cord blood after collection does not raise any
additional safety concerns, but it states that current
investigational protocols will provide the opportunity to assess
this.  We point out that obtaining informed consent before infant
delivery affords mothers sufficient time to deliberate decisions
before procedures are performed. 

FDA's comments and our response are provided in greater detail in
appendix II.  The agency provided a number of technical comments that
we have not reprinted but did incorporate into the report as
appropriate. 


---------------------------------------------------------- Letter :9.1

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


ADDITIONAL INFORMATION ON
TISSUE-BANKING PROCESSES
=========================================================== Appendix I


   PROCUREMENT
--------------------------------------------------------- Appendix I:1

Ideally, each potential tissue or organ donor encounters only one
organization capable of performing all aspects of the donation
process, but this rarely occurs.  Indeed, donors of multiple tissues
or organs may encounter as many as 10 different transplant-related
programs.  Tissue donors who also donate organs are coordinated by
the federally designated organ procurement organization (OPO) in the
area.\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 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. 


--------------------
\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. 


   SCREENING
--------------------------------------------------------- Appendix I:2

Screening questions focus mainly on risk behaviors for infectious
disease, genetic abnormalities, and degenerative neurological
disease.  The importance of following all screening steps is
underscored by research at one tissue facility that found that 9.8
percent of 1,000 donors whose families provided a medical history
negative for risk factors were rejected on disease testing or
autopsy.\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      Accept donor
cancer, carcinoma-in-situ of the
uterine cervix, or proven
nonmetastatic primary brain tumor

History of other malignancies       Base decision on medical
treated by surgery alone with no    director's evaluation
evidence of recurrence or spread
for at least 5 years

History of autoimmune disease       Base decision on medical
                                    director's evaluation

Ingestion or exposure to toxic      Base decision on medical
substances                          director's evaluation

Significant active infection        Reject donor
(septicemia, systemic viral
disease, untreated syphilis,
active tuberculosis, systemic
mycosis)

History of receiving pituitary-     Reject donor
derived human growth hormone

History of dementia or              Reject donor
degenerative neurological
disorders of viral or unknown
etiology

HIV or hepatitis risk factor        Reject donor

Current malignancy (except as       Reject donor
noted above)

Rheumatoid arthritis, systemic      Reject as musculoskeletal tissue
lupus erythematosus, polyarteritis  donor
nodosa, sarcoidosis, myasthenia
gravis, metabolic bone disease

History of leprosy (Hansen's        Reject as skin donor
disease)

Family history of genetic           Reject as umbilical cord blood
disorders that may affect           donor
recipient

Positive genetic tests for cystic   Reject as semen donor
fibrosis, sickle cell trait, Tay-
Sachs disease, or thalassemia\a

Positive tests for Neisseria        Reject as semen donor
gonorrhea and Chlamydia
trachomatis\b

Inadequate sperm quality and        Reject as semen donor
quantity\b

Age criteria established by         Reject as semen donor
facilities' standard operating      Reject as cardiovascular tissue
procedures except as noted below    donor
--Older than 40
--Older than 60

History of bacterial endocarditis,  Reject as cardiovascular tissue
rheumatic fever, or semilunar       donor
valvular disease
----------------------------------------------------------------------
\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. 


--------------------
\44 Information provided by B.  Buck at FDA workshop on human tissue
intended for transplantation, Bethesda, Maryland, June 1994. 


   TESTING
--------------------------------------------------------- Appendix I:3

Donors who have received blood or fluid transfusions may have blood
that is too diluted to detect infection, and a pretransfusion or
infusion sample is then sought.  If none is available, the donor's
medical records should be examined to determine the acceptability of
postransfusion or postinfusion blood specimens.  Each tissue facility
is also to develop a procedure for determining whether a
postransfusion or postinfusion specimen can be used.  This plasma
dilution algorithm is to be used to determine if the amount of blood
loss and fluid replacement is below the threshold that renders a
postransfusion or postinfusion blood sample invalid for accurate
testing of the donor's own blood for infectious diseases.  If the
results are above the threshold and no pretransfusion or preinfusion
sample exists, the donor is rejected. 

After death, cells in the blood system burst, creating a state known
as hemolysis.  Hemolyzed blood samples can lead to false positive
test results, which is why test kit manufacturers caution against
using such samples.  False positive tests result in the destruction
of donated tissue that is probably not infected and is, therefore,
safe for use; they also cause undue concern among relatives who are
notified of the donor's test results.  Confirmatory tests often
indicate noninfectivity, but these results cannot be used to
invalidate possible false positives on initial tests.  FDA is
currently working with viral test kit manufacturers to validate these
kits for use on cadaveric samples.  However, because the number of
donors is so few, the economic motivation for manufacturers to do so
is low.  Current regulations require that currently licensed test
kits are to be used until FDA has given its approval and labeling of
the test kits has been modified to specifically indicate their use
for cadaveric blood specimens. 


   PROCESSING
--------------------------------------------------------- Appendix I:4

Processing musculoskeletal tissue varies but tends to follow certain
procedures to ensure its safety.  Processing occurs in clean, aseptic
rooms.  Single-donor processing uses air filtration and the tissue is
cleaned with high-pressure lavage and ultrasonic techniques.  It is
also soaked in antibiotic and ethanol solutions and irradiated at low
doses.  It is then cut and shaped to certain specifications and is
preserved by freezing or freeze-drying.  Grafts are also cultured for
microbiological testing.  Tendons and ligaments do not go through an
alcohol-processing step as bone does (alcohol is used as a defatter). 

Skin is either cryopreserved or processed nonfrozen. 
Cryopreservation often begins within 72 hours of procurement,
although AATB standards allow 96 hours.  Skin is placed in a
preservation solution that is then replaced with 10-percent to
15-percent glycerol and allowed to incubate 20 to 60 minutes before
freezing.  Standards from AATB state that final cultures should be
performed for specific organisms (for example, serratia, yeast or
fungi, or proteus).  AABB standards note that refrigerated skin is to
be stored no longer than 14 days. 

Corneas are excised and placed in a culture medium that is an
FDA-approved medical device (there is only one manufacturer of this
medium).  A cornea can stay in the medium for up to 1 week but the
usual time is 3 days.  Corneas can also be cryopreserved, although
this is rarely done.  They are stored in liquid nitrogen with a
cryoprotective agent, such as dimethyl sulfoxide, to prevent the
formation of damaging intracellular ice crystals. 

Donated semen can be used for both intrauterine and intracervical
insemination.  Processing donated semen for intrauterine insemination
involves washing the ejaculate specimen to remove the seminal plasma
contents before freezing.  Specimens are then resuspended and frozen
with a buffer (such as egg yolk citrate).  Motility and total motile
cells/ml are the same for both types of insemination.  Semen that is
shipped is usually kept in liquid nitrogen containers that keep the
semen frozen for 7 to 10 days. 

Cord blood is preserved in the short term in a liquid state in
FDA-approved CPD anticoagulant for 24 hours at 1 to 6 degrees
Celsius.  It can also be stored after being cryopreserved in liquid
nitrogen with dimethyl sulfoxide for 3 to 5 years at -85, -135, or
-185 degrees Celsius.  The frozen cells are thawed in a water bath, a
dextran-albumin mixture is added, and the cells are then centrifuged. 
The supernatant, which contains the dimethyl sulfoxide, is then
removed, and the cells are resuspended in more detran and albumin and
are transfused.  This results in an increase in viable cells and an
increase in colony-forming unit recovery over time.  It also allows
for the manipulation of the cells after thawing. 




(See figure in printed edition.)Appendix II
COMMENTS FROM THE FOOD AND DRUG
ADMINISTRATION
=========================================================== Appendix I



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)


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

GAO COMMENTS

1.  We believe that the current umbilical cord blood banking
protocols, operating under FDA-accepted INDs, will be worthwhile in
ascertaining the safety consequences of obtaining informed consent
for cord blood collection after delivery.  This information should be
used to determine the manner and time at which collection is to take
place.  However, it should be noted that a working group on ethical
issues in cord blood banking concluded that informed consent should
be obtained before procuring placental blood for transplantation
because not obtaining consent before delivery does not allow mothers
to make decisions before collection.\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 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. 


--------------------
\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. 


MAJOR CONTRIBUTORS TO THIS REPORT
========================================================= Appendix III

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


*** End of document. ***