Request for Proposed Standards for Unrelated Allogeneic Peripheral and Placental/Umbilical Cord Blood Hematopoietic Stem/ Progenitor Cell Products; Request for Comments

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.

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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.

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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

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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.

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\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.

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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.

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\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.

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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

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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

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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]

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