[Federal Register Volume 63, Number 12 (Tuesday, January 20, 1998)]
[Notices]
[Pages 2985-2988]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-1171]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 97N-0497]
Request for Proposed Standards for Unrelated Allogeneic
Peripheral and Placental/Umbilical Cord Blood Hematopoietic Stem/
Progenitor Cell Products; Request for Comments
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice; request for comments.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is requesting
submission of comments proposing product standards intended to ensure
the safety and effectiveness of minimally manipulated hematopoietic
stem/progenitor cells derived from peripheral and cord blood for
unrelated allogeneic use.\1\ The comments should include supporting
clinical and nonclinical laboratory data and other relevant
information. This information will aid FDA in developing product
standards for hematopoietic stem/progenitor cell products intended for
allogeneic use in recipients unrelated to the donor (hereinafter
referred to as unrelated allogeneic), including manufacturing controls
and product specifications. FDA is also announcing its intention to
phase-in implementation of investigational new drug application (IND)
and license application requirements for minimally manipulated\2\
unrelated allogeneic hematopoietic stem/progenitor cell products 3
years after the date of issuance of this notice to permit the
development of licensing standards for those products where possible.
This action is taken in response to the agency's ``Proposed Approach to
Regulation of Cellular and Tissue-based Products,'' which fullfills the
objectives of the administration's ``Reinventing the Regulation of
Human Tissue'' initiated to streamline regulatory requirements to ease
the burden on regulated industry, while providing adequate protection
to the public health.
\1\ The term unrelated allogeneic use means the implantation,
infusion, or transfer of a human cellular or tissue-based product
from one person to another who is not a parent, sibling, or a child
of the donor.
\2\ The term minimally manipulated means processing of cells and
nonstructural tissues that does not alter the biological
characteristics and thus, potentially, the function or integrity of
the cells or tissues.
---------------------------------------------------------------------------
DATES: Submit requested standards and supporting clinical and
nonclinical laboratory data by January 20, 2000.
ADDRESSES: Submit proposed product standards and supporting data to the
Dockets Management Branch (HFA-305), Food and Drug Administration,
12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Paula S. McKeever, Center for
Biologics Evaluation and Research (HFM-17), Food and Drug
Administration, 1401 Rockville Pike, Rockville, MD 20852-1448, 301-827-
6210.
SUPPLEMENTARY INFORMATION:
I. Background
A. Use of Peripheral and Cord Blood Stem/Progenitor Cells for
Hematopoietic Reconstitution
The field of hematologic transplantation has changed substantially
during the last two decades. Improved understanding of the diverse
aspects of human hematologic precursors has facilitated their
experimental manipulation. Our knowledge of their localization in
humans during both fetal and postnatal development, growth regulation,
differentiation, homing, and of phenotypic and functional
characteristics has facilitated the development of new methods of
transplantation. Traditional bone marrow transplantation, involving the
extraction of bone marrow by aspiration from bone cavities with further
processing by density centrifugation, is increasingly being supplanted
by novel approaches that include use of hematopoietic stem/progenitor
cells and biotechnologic procedures to purify and expand hematopoietic
stem/progenitor cells. Human cord blood, which is enriched with
pluripotent hematopoietic stem/progenitor cells, and peripheral blood,
which can be enriched in hematopoietic stem/progenitor cells by a
variety of
[[Page 2986]]
interventions, have emerged as sources of hematopoietic cells
alternative to bone marrow aspirates for bone marrow reconstitution.
B. Stem/Progenitor Cell Workshops
FDA held a public workshop to discuss procedures for preparation
and storage of cord blood stem/progenitor cells on December 13, 1995
(60 FR 58088, November 24, 1995). The workshop was jointly sponsored by
FDA and the National Heart, Lung, and Blood Institute (NHLBI), National
Institutes of Health. The purpose of the workshop was to identify and
discuss steps for collection, processing, and storage of cord blood
stem/progenitor cells for transplantation and to identify what
additional post transplantation scientific data are needed in this
area. A draft document, discussing an appropriate regulatory approach
for placental/umbilical cord blood stem/progenitor cell products for
transplantation, was made available at the workshop, and a notice of
availability for comment was published in the Federal Register of
February 26, 1996 (61 FR 7087). In response to requests to extend the
comment period, a notice extending the comment period by 90 days was
published in the Federal Register of May 28, 1996 (61 FR 26473).
In the Federal Register of February 8, 1996 (61 FR 4786), FDA
announced a public workshop, jointly sponsored by FDA and NHLBI to be
held on February 22 and 23, 1996, to discuss procedures for the
preparation, processing, and characterization of human peripheral blood
stem/progenitor cells. The purpose of the workshop was to identify and
discuss the methods for the collection, processing, and storage of
peripheral blood stem/progenitor cells for transplantation and to
identify areas in need of further research. A draft document was made
available at the workshop describing FDA's proposed regulatory approach
for human peripheral blood stem/progenitor cell products for
transplantation.
Based, in part, on information presented at these meetings, FDA
recognized a need to reconsider whether the concepts and procedures
used to regulate traditional biological products were appropriate for
regulation of peripheral and cord blood hematopoietic stem/progenitor
cells and other cellular and tissue-based products which are a result
of new technologies. After consultation with representatives of the
involved public, FDA proposed a new regulatory framework for cellular
and tissue-based products, including hematopoietic stem/progenitor
cells, in February 1997, entitled ``Reinventing the Regulation of Human
Tissue,'' and ``Proposed Approach to Regulation of Cellular and Tissue-
based Products.'' On March 4, 1997, the agency announced a public
meeting, to be held on March 17, 1997, to solicit information and views
from the interested public on the agency's proposed regulatory approach
for such products, and the agency requested that written comments be
submitted to the docket (62 FR 9721).
C. New Regulatory Approach for Human Cellular and Tissue-Based Products
The proposed framework provides a tiered approach to human cellular
and tissue-based product\3\ regulation. The regulation focuses on three
general areas: (1) Preventing use of contaminated tissues with the
potential for transmitting infectious diseases; (2) preventing improper
handling or processing that might contaminate or damage tissues, or
produce cellular or tissue-based products of inadequate quality; and
(3) ensuring that clinical safety and effectiveness are demonstrated
for most tissues that are highly processed, are used for other than
their homologous use,\4\ are combined with nontissue components, or
have a systemic effect.
---------------------------------------------------------------------------
\3\ The term human cellular and tissue-based product means a
product containing human cells or tissues or any cell or tissue-
based component of such a product.
\4\ The term homologous use means the use of a cellular or
tissue-based product for a normal function that is analogous to that
of the cells or tissues being replaced or supplemented.
---------------------------------------------------------------------------
Under the tiered approach, FDA intends to impose Federal
requirements only to the extent necessary to protect the public health,
with minimal regulation for some products and with increasing degrees
of oversight as the potential risk increases. For example, tissues
transplanted from one person to another for their normal structural or
reproductive functions and without undergoing extensive processing will
be subject to requirements for infectious disease screening and
testing, and to requirements for good processing and handling
procedures, but will not need FDA marketing approval before
distribution and use. Thus, FDA expects that most processors of
reproductive tissue, tissue products currently regulated under 21 CFR
part 1270, and other minimally manipulated products will not be
required to seek FDA premarket approval of their products nor to submit
detailed clinical information about their products to FDA. The agency
intends to regulate as biological drugs or devices those tissues that
are processed extensively, combined with nontissue components, promoted
or labeled for use other than homologous use, or (with limited
exceptions) that have systemic effect on the body. Minimally
manipulated hematopoietic stem/progenitor cells derived from peripheral
and cord blood, for unrelated allogeneic use, would therefore be
regulated as biological drugs under the Public Health Service Act and
the Federal Food, Drug, and Cosmetic Act. FDA does not intend to
request clinical data to demonstrate safety and effectiveness for
cellular and tissue-based products with systemic effect that are for
autologous use\5\ or family-related allogeneic use\6\ or for
reproductive tissues for reproductive use providing such products are
minimally manipulated, for homologous use, and not combined with a
nontissue component. FDA intends to require that establishments
manufacturing such minimally manipulated hematopoietic stem/progenitor
cell products for hematopoietic reconstitution register and list their
products with FDA, comply with good tissue practice regulations, and
ensure that all labeling and promotional materials are clear, accurate,
balanced, and nonmisleading.
---------------------------------------------------------------------------
\5\ The term autologous use means the implantation,
transplantation, infusion, or transfer of a human cellular or
tissue-based product back into the individual from whom the cells or
tissue comprising such product were removed.
\6\ The term family-related allogeneic use means the
implantation, transplantation, infusion, or transfer of a human
cellular or tissue-based product into a first-degree blood relative
of the individual from whom cells or tissue comprising such product
were removed.
---------------------------------------------------------------------------
D. Application of the Proposed Regulatory Approach to Hematopoietic
Stem/Progenitor Cell Products
For unrelated allogeneic hematopoietic stem/progenitor cells
intended for hematopoietic reconstitution, provided they are not more
than minimally manipulated (i.e., processing does not alter the
biological characteristics of the cells), the agency believes that it
may be possible to develop product standards and establishment and
processing controls based on existing clinical trial data or data
developed in the near future demonstrating the safety and efficacy of
the cells. If adequate information can be developed, the agency intends
to issue guidance for establishment controls, processing controls, and
product standards in accordance with the agency's ``Good Guidance
Practices,'' issued in the Federal Register of February 27, 1997 (62 FR
8961). FDA intends to propose that, in lieu of individual applications
containing clinical data, licensure may be granted
[[Page 2987]]
for products certified as meeting issued standards. To allow sufficient
time for data and standards to be developed, the agency will phase-in
IND and license application requirements for minimally manipulated
unrelated allogeneic hematopoietic stem/progenitor cell products for
hematopoietic reconstitution 3 years following the date of issuance of
this Federal Register notice. FDA is inviting product providers,
professional groups, and other interested persons to submit to the
agency proposed standards and supporting data designed to ensure the
safety and effectiveness of minimally manipulated hematopoietic stem/
progenitor cell products for hematopoietic reconstitution. Proposed
standards should be supported by adequate data and other relevant
information. In order to permit development of useful standards within
the phase-in period for enforcement of premarket application
requirements, FDA suggests that interested parties work together to
achieve consensus on uniform standards before submission to FDA. FDA
will evaluate the information submitted. If the agency determines that
the submissions support the development of standards, FDA intends to
issue such standards through the agency's guidance documents
procedures. If FDA determines that adequate establishment and
processing controls and product standards are not available, the agency
intends to enforce IND and license application requirements at the
close of the 3 year period. FDA reminds affected parties that cells
that have been more than minimally manipulated (e.g., expanded,
activated, genetically modified or otherwise have their biological
characteristics altered) or combined with nontissue components continue
to require IND's and licensing approval, and are not subject to a
phase-in period for enforcement of these requirements.
II. Request for Product Standards with Supporting Clinical and
Nonclinical Data
A. Purpose
FDA is inviting product providers, professional groups, and other
interested persons to submit to the agency proposed product standards
with supporting clinical and nonclinical laboratory data, and other
relevant information, designed to ensure the safety and effectiveness
of minimally manipulated hematopoietic stem/progenitor cells derived
from peripheral and placental/umbilical cord blood for unrelated
allogeneic hematopoietic reconstitution. Submitted data may be specific
for a patient subset, e.g., pediatric patients, and should identify the
patient subset, if applicable.
FDA is requesting that proposed establishment controls include
standards for personnel, facilities, quality management, standard
operating procedures, staff training and competence, and process
validation. Establishment controls should also include standards for
recordkeeping regarding donors, processing, quarantine, storage,
labeling, distribution, tracking, handling of errors and accidents,
deviations from standard operating procedures, suspected adverse
reactions, and quality control processes.
FDA is requesting that proposed processing controls include
standards for donor selection, informed consent, donor testing and
screening, histocompatibility testing, collection procedures, product
testing, volume reduction methods, cryopreservation, storage conditions
in liquid and frozen state, storage monitoring, transportation within
and between facilities, temperature limits, packaging, and thawing
procedures. The processing controls should include standards for
testing for product contamination, product viability, composition, and
functionality, and include when and how such testing is to be
performed.
FDA is requesting that proposed product standards include the
criteria for acceptance of a unit of hematopoietic stem/progenitor
cells derived from peripheral or placental/umbilical cord blood.
Criteria should include volume of the product, viable cell number
(specified as nucleated or mononuclear cells), storage temperature
limits, microbial or other contamination limits, and any other
appropriate characteristics of the product, e.g., CD34 positive cell
enumeration. For peripheral blood hematopoietic stem/progenitor cell
products, information regarding the treatment regimens of the donors
with mobilizing agents should also be provided including the type of
mobilizing agent, duration of mobilization, and the number of apheresis
collections.
The agency is suggesting that evidence of hematopoietic stem/
progenitor cell engraftment for these products be consistently
expressed as the time, expressed as number of days from the day of
hematopoietic stem/progenitor cell infusion to the day that a
neutrophil count of equal to or greater than 500 cells/L is
obtained, and the time, expressed as number of days from the day of
hematopoietic stem/progenitor cell infusion to the first of 3
consecutive days in which the transfusion-independent platelet count of
equal to or greater than 20,000 platelets/L is demonstrated in
the recipient. Information relevant to sustained platelet engraftment,
such as the number of days from the day of hematopoietic stem/
progenitor cell infusion to the day in which a transfusion-independent
platelet count of equal to or greater than 50,000 platelets/L
is observed, should also be provided. Data provided should include the
extent of HLA (human leukocyte antigen) disparity, the nucleated cell
dose/kg body weight of the recipient, the weight, age, and underlying
disease of the recipient, the extent and severity of Graft-Versus-Host
Disease, the criteria utilized for evidence for allogeneic cell
engraftment, and any other important information regarding the safety
and efficacy of the infused product, e.g., incidence of infection. In
addition, a description of the methods used for data evaluation,
including statistical techniques, should be included.
B. Review and Consolidation of Submitted Information by FDA
FDA will review and assess the information submitted, and evaluate
it as to its application in issuing hematopoietic stem/progenitor cell
product standards. FDA may find it necessary to present any or all of
the aspects of the standards and/or data for public discussion. Any
public meeting held by FDA will be announced to the public prior to the
date of the meeting. Subsequent to receiving sufficient standards with
supporting data, FDA intends to adopt appropriate standards as guidance
and announce their availability in the Federal Register.
III. Submissions
Interested persons may, on or before January 20, 2000 submit to the
Dockets Management Branch (address above) written proposed standards
and supporting clinical and nonclinical laboratory data. Two copies of
standards and data should be submitted, except that individuals may
submit one copy. Standards and data should be identified with the
docket number found in brackets in the heading of this document. All
information submitted will be placed on public display and will be
subject to public disclosure. Any information that is not intended to
be made public must be deleted before submission to the Dockets
Management Branch. Trade secrets and confidential commercial
information, as well as information that could be used to identify
individual patients or others whose privacy should be maintained,
should be deleted before being submitted. All comments proposing
[[Page 2988]]
standards with supporting data will be available for public examination
in the Dockets Management Branch (address above) between 9 a.m. and 4
p..m., Monday through Friday.
Dated: January 8, 1998.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 98-1171 Filed 1-16-98; 8:45 am]
BILLING CODE 4160-01-F
