[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/<greek-m>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/<greek-m>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/<greek-m>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