[Federal Register Volume 63, Number 93 (Thursday, May 14, 1998)]
[Proposed Rules]
[Pages 26744-26755]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-12751]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 207, 807, and 1271
[Docket No. 97N-484R]
RIN 0910-AB05
Establishment Registration and Listing for Manufacturers of Human
Cellular and Tissue-Based Products
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to require
manufacturers of certain human cellular and tissue-based products to
register with the agency and list their products. In addition, the
agency is proposing to amend the registration and listing regulations
that currently apply to human cellular and tissue-based products
regulated as drugs, devices, and/or biological products. This action is
being taken to establish a unified registration and listing program for
human cellular and tissue-based products.
DATES: Submit written comments on the proposed rule by August 12, 1998.
Submit written comments on the information collection provisions by
June 15, 1998.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,
Rockville, MD 20857. Submit written comments on the information
collection provisions to the Office of Information and Regulatory
Affairs, OMB, New Executive Office Bldg., 725 17th St. NW., Washington,
DC 20503, Attn: Desk Officer for FDA.
FOR FURTHER INFORMATION CONTACT: Dano B. Murphy or Paula S. McKeever,
Center for Biologics Evaluation and Research (HFM-17), Food and Drug
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448, 301-827-6210.
SUPPLEMENTARY INFORMATION:
I. Introduction
FDA is putting in place a comprehensive new system of regulation
for human cellular and tissue-based products. As a first step toward
accomplishing this goal, the agency is proposing regulations that will
require establishments that manufacture those products to register and
list their products with the agency.
A. Background
The term ``human cellular and tissue-based products'' encompasses
an array of medical products derived from the human body and used for
replacement, reproductive, or therapeutic purposes. Skin, tendons,
bone, heart valves, and corneas have long been used as replacements for
damaged or diseased tissues. Semen, ova, and embryos are transferred
for reproductive purposes. Currently, some human cellular and tissue-
based products are being developed for new therapeutic uses. For
example, scientists are studying the use of manipulated human cells to
treat viral infections, Parkinson's disease, and diabetes, among other
diseases.
Human cellular and tissue-based products serve a crucial role in
medicine, and they have the potential for providing important new
therapies. Yet they also raise public health concerns. With the
development of new products, and new uses for existing products, come
questions about safety and effectiveness that need to be answered
through clinical investigation. Furthermore, all human cellular and
tissue-based products, because they contain components of the human
body, pose some risk of carrying pathogens that could cause disease in
health-care personnel, other handlers of tissue, recipients, and family
members or other close contacts of recipients.
FDA has never had a single regulatory program for human cellular
and tissue-based products. Instead, it has regulated these products on
a case-by-case basis responding as it determined appropriate to the
particular characteristics of and concerns raised by each type of
product. Some tissues have been regulated as medical devices under
section 201 of the Federal Food, Drug, and Cosmetic Act (the act) (21
U.S.C. 321 et seq.). Corneal lenticules, dura mater, heart valve
allografts, and umbilical cord vein grafts fall into this category.
Other products have been considered biological products under section
351 of the Public Health Service Act (the PHS Act) (42 U.S.C. 262) and
drugs under the act (hereinafter referred to as biological drugs).
Somatic cell therapy products and some gene therapy products fall
[[Page 26745]]
into this category. (See 58 FR 53248, October 14, 1993.)
FDA has also relied on section 361 of the PHS Act (42 U.S.C. 264),
which provides the authority to issue regulations to prevent the spread
of communicable diseases, to regulate tissues that it has chosen not to
regulate as devices or biological drugs. In 1993, in response to
concerns about the safety of human tissue intended for transplantation,
FDA used this authority to require testing and screening of tissue
donors for hepatitis and human immunodeficiency viruses. (See 58 FR
65514, December 14,1993.) Until it issued those regulations (``Human
Tissues Intended for Transplantation,'' codified in title 21 of the
Code of Federal Regulations (CFR) part 1270), FDA exerted little or no
regulatory control over certain types of human cellular and tissue-
based products. Instead, human tissue for transplantation was subject
to some State regulation and to voluntary accreditation systems. Even
today, FDA's human tissue regulations do not address the infectious
disease risk of donating, processing, and storing reproductive cells
and tissue.
FDA has evaluated its approach to regulating human cellular and
tissue-based products and has determined that changes are needed. In
light of the development of new products, coupled with a growing
awareness of infectious-disease concerns, the agency believes that the
current patchwork of regulatory policies is no longer adequate and
plans to create a comprehensive regulatory program that will cover a
broad range of human cellular and tissue-based products. The agency has
considered the relevant provisions of the act and the PHS Act and has
concluded that these two statutes provide sufficiently broad authority
for the proposed regulatory program.
The agency announced its plans for reform in two documents released
in February 1997: ``Reinventing the Regulation of Human Tissue,'' and
``A Proposed Approach to the Regulation of Cellular and Tissue-Based
Products'' (hereinafter ``Proposed Approach document''). The agency
requested written comments on its proposed approach and, on March 17,
1997, held a public meeting to solicit information and views from the
interested public. (See 62 FR 9721, March 4, 1997) (Docket No.: 97N-
0068). FDA has considered the comments submitted at the public meeting
and to the docket in drafting this proposed rule. FDA welcomes comments
on the proposed rule from all interested parties.
B. The Proposed Approach
FDA seeks to achieve several goals with its new approach to
regulating human cellular and tissue-based products. Primary among them
is the improved protection of the public health without the imposition
of unnecessary restrictions on research, development, or the
availability of new products. Under the new program, the degree of
scrutiny afforded different types of products will be commensurate with
the risks presented, enabling the agency to use its resources more
effectively. Consolidating the regulation of human cellular and tissue-
based products into one regulatory program is expected to lead to
increased consistency and greater efficiency. Together, these planned
improvements should increase the safety of human cellular and tissue-
based products, and public confidence in that safety, while encouraging
the development of new products.
In developing its proposed approach, FDA examined five issues that
it considered fundamental to the proper regulation of the various types
of human cellular and tissue-based products. First, the agency asked
how the transmission of communicable disease by these products occurs
and could be prevented. Second, the agency looked at the types of
handling, processing, and manufacturing controls that are necessary to
prevent contamination and to preserve the integrity and function of
these products. Third, the agency examined concerns about the products'
clinical safety and effectiveness. Fourth, FDA considered the type of
labeling necessary for proper use of the products and the kind of
promotion that would be permissible. Finally, the agency asked how it
could best monitor and communicate with the cell and tissue industry.
Through examination of these five public-health and regulatory
concerns, FDA was able to develop a proposed comprehensive regulatory
scheme tailored to the relevant characteristics of human cellular and
tissue-based products. In order to devise an umbrella approach, the
agency first focused on the products' common attributes. Then, to
ensure appropriate levels of regulation, the agency differentiated
between the various types of products based on the public health risks
associated with them. For example, the risks posed by cells that are
extensively manipulated in a laboratory and then implanted for their
systemic effect on a patient are different from those of an
unmanipulated tissue that is transplanted into a patient to replace an
injured structural tissue.
Taking into account these differences, the agency designed a risk-
based tiered approach intended to regulate human cellular and tissue-
based products only to the extent necessary to protect public health.
Some products will be subject to little or no regulation. For example,
no regulatory requirements will be imposed on tissues transplanted into
the same patient during the same surgical procedure.
As the potential risk posed by a product increases, so will the
level of oversight afforded that product. Thus, minimally processed
tissues transplanted from one person to another for their normal
structural functions would be subject to infectious disease screening
and testing and to requirements for good handling procedures, but would
not need FDA premarket review or marketing approval. In contrast,
premarket approval would generally be required for cells and tissues
that are processed extensively, are combined with noncellular or
nontissue components, are labeled or promoted for purposes other than
their normal functions, or have a systemic effect. In addition, these
products would be subject to requirements for good tissue practices and
infectious disease screening and testing, as well as to the good
manufacturing practice requirements applicable to drugs and devices.
Although FDA's proposed regulatory approach is far more
comprehensive in scope than its present system, some products will not
be covered. Among the products not included under the approach are
vascularized organs and minimally manipulated bone marrow, both of
which fall under the purview of the Health Resources Services
Administration. FDA already comprehensively regulates transfusable
blood products (e.g., whole blood, red blood cells, platelets, and
plasma) under a different regulatory scheme and will not at this time
regulate those products as human cellular and tissue-based products.
Xenograft transplantation (transplantation using tissues derived from
animals) raises different public health issues from transplantation
with human tissue, and so will not be subject to the new regulatory
program. The new program will also exclude from coverage ancillary
products used in cell or tissue propagation, storage, or processing, as
well as products that are secreted by or extracted from cells or
tissues (e.g., human milk, collagen, urokinase, cytokines, and growth
factors), because these products often raise different manufacturing,
safety, and effectiveness
[[Page 26746]]
issues, and generally are covered by other rules, regulations, or
standards.
II. Registration of Human Cellular and Tissue-Based Products
FDA is now proposing to extend registration and listing
requirements to manufacturers of human cellular and tissue-based
products not currently subject to such requirements.
A. Need for Registration and Listing
In order to implement its new approach to the regulation of human
cellular and tissue-based products, FDA needs to be able to assess the
state of the cell and tissue industry. Although some human cellular and
tissue-based products are currently regulated by the agency as devices
or biological drugs--and thus are covered by registration and listing
requirements--others have not been subject to such regulation. As a
result, FDA does not know the full size and scope of the cell and
tissue industry and its products.
Through the current proposal to extend the requirements of
registration and product listing to members of the tissue and cell
industry not presently under such obligations, FDA seeks to accrue the
basic knowledge about the industry that is necessary for its effective
regulation. Without reliable data on the tissue and cell industry
(e.g., names and addresses of manufacturers and types of products) FDA
cannot apply appropriate oversight to a rapidly changing industry. FDA
must keep informed of the state of the industry, including developments
such as the introduction of new products, in order to understand and
respond to all relevant public health issues. Because FDA intends to
calibrate its level of regulation to the risks posed by various types
of cellular and tissue-based products, it is crucial for the agency to
have accurate information about those products.
The proposed registration requirement will facilitate communication
between the agency and industry. Once FDA has a complete list of the
cell and tissue industry and its products, the agency will be able to
reach members of the industry with educational materials and
information regarding FDA policies, guidances, and requirements.
Important information (e.g., about a newly identified public health
risk) can also be quickly disseminated to the industry. Moreover,
information obtained through the new registration and listing
regulation will permit the agency to monitor the industry more
effectively. For example, FDA will be able to identify quickly which
establishments should be inspected for compliance with applicable laws
and regulations, including those to be issued as part of the new tissue
regulation program. Required updating of industry registrations and
product lists will ensure that FDA's information about the industry
remains current.
B. How Registration Will Be Achieved
In proposing these new registration regulations, FDA seeks to
improve the way it collects and manages information about the cell and
tissue industry and its products. The agency plans to create a single,
comprehensive data base with information about human cellular and
tissue-based products, maintained by the Center for Biologics
Evaluation and Research (CBER). By requiring registration and product
listing from manufacturers not presently subject to such requirements,
and by consolidating that new information with data currently being
collected, FDA will be able to develop a less fragmented and more
efficient oversight program. Meanwhile, manufacturers already under a
registration obligation will benefit from the availability of new,
electronic procedures.
The main set of regulations being proposed, new part 1271 of title
21 of the CFR, will apply to those human cellular and tissue-based
products that the agency will regulate under section 361 of the PHS
Act. Proposed part 1271 will cover those products, including products
consisting of reproductive cells or tissue, that: (1) Are minimally
manipulated; (2) are not promoted or labeled for any use other than a
homologous use; (3) have not been combined with or modified by the
addition of any noncellular or nontissue component that is a drug or
device; and (4) do not have a systemic effect, except in cases of
autologous use, transplantation into a first-degree blood relative, or
reproductive use. For convenience these products will be referred to as
``products regulated under section 361'' or ``361 products.'' (However,
the use of these terms does not indicate that other products will not
be regulated under section 361 of the PHS Act. In fact, FDA intends to
rely in part on section 361 of the PHS Act when imposing requirements
on human cellular and tissue-based products regulated as biological
drugs or devices under the act and/or section 351 of the PHS Act.)
Examples of products to be regulated under section 361 of the PHS Act
include bone, tendons, skin, corneas, and sclera. If all other criteria
are met, products with a systemic effect that could come under section
361 of the PHS Act include peripheral and cord blood stem cells used
autologously or in first degree blood relatives and sperm, oocytes, and
embryos for reproductive use.
Establishments that manufacture human cellular or tissue-based
products that meet the criteria set out above would be required to
register and list those products under proposed part 1271. However,
certain exceptions would apply. For example, although the agency's
proposed definition of ``manufacture'' includes distribution,
commercial carriers would not need to register. Also, certain
scientific, educational, or other uses of cellular or tissue-based
products would not be covered by part 1271. These and other exceptions
are discussed in greater detail in section III of this document.
In order to unify its registration system, FDA also proposes to
amend parts 207 and 807 (21 CFR parts 207 and 807) so that information
on human cellular and tissue-based products regulated as biological
drugs or devices will be submitted to the same data base used for 361
products. Parts 207 and 807 contain the registration and listing
requirements for drugs and devices. Under the proposed amendments,
manufacturers of human cellular and tissue-based products regulated as
biological drugs or devices will be required to comply with the
registration and listing requirements in part 207 or 807, as
applicable, by following the procedures set out in proposed part 1271.
Human cellular and tissue-based products subject to regulation as
biological drugs or devices are those that do not meet the criteria set
out above for regulation under section 361 of the PHS Act. That is,
they are: (1) More than minimally manipulated; (2) are promoted or
labeled for a nonhomologous use; (3) have been combined with or
modified by the addition of a noncellular or nontissue component that
is a drug or device; or (4) have a systemic effect (except in cases of
autologous use, transplantation into a first degree blood relative, or
reproductive use). Examples include: Hematopoietic stem cells intended
for use in recipients who are not close blood relatives of the cell
donor or for uses other than to reconstitute the cellular components of
the blood; more than minimally manipulated bone marrow; hematopoietic
stem cells that have been expanded or modified as part of gene therapy;
cloned and/or activated lymphocyte therapies for cancer or infectious
diseases; bone combined with collagen or growth factors; and
manipulated cells for autologous structural use (MAS cells), such as
[[Page 26747]]
expanded chondrocytes to repair damaged knee cartilage.
Under the proposed regulatory system, some products that are
currently regulated as medical devices might be regulated as section
361 products instead. One such product under consideration is dura
mater, the collagenous connective tissue that covers the human brain
and spinal cord. Dura mater is excised from cadavers shortly after
death, washed, cut into smaller pieces, sterilized, preserved, and
reconstituted before use in neurosurgical, gynecological, oral,
otolaryngological, and general surgical procedures. This manner of
processing does not change the tissue's original characteristics
relating to its ability to carry out reconstruction, repair, or
replacement and, therefore, would be considered minimal manipulation as
defined in proposed part 1271. Moreover, dura mater does not have a
systemic effect. Thus, dura mater that is not combined with or modified
by the addition of any nontissue or noncellular component that is a
drug or device, and that is not promoted or labeled for any use other
than a homologous use, appears to meet the proposed criteria in part
1271 for regulation under section 361 of the PHS Act.
Recent reports linking the transmission of Creutzfeldt-Jakob
Disease (CJD) to several recipients of human cadaveric dura mater have
raised questions as to the controls needed to regulate dura mater.
Following discussion of data and information relating to dura mater, on
October 6 and 7, 1997, FDA's Transmissible Spongiform Encephalopathy
Advisory Committee recommended that FDA adopt measures intended to
decrease the risk of CJD transmission via dura mater. These
recommendations include specific handling procedures to reduce or
eliminate CJD infectious agents in cadaveric dura mater and
histological examinations of brain biopsies taken from donor cadavers.
In light of these recent developments and the committee's
recommendations, FDA is requesting comments on whether FDA's proposal
to regulate dura mater under the authority of section 361 of the PHS
Act will provide adequate controls, or, conversely, whether tissues
with certain risk and disease factors should be subject to premarket
submission requirements found in the act and in section 351 of the PHS
Act. The agency invites comments regarding the appropriate controls for
dura mater and like products, and whether such controls may be
appropriately addressed in ``good tissue practice'' requirements
specific to these products issued under the authority of section 361 of
the PHS Act. In the meantime, FDA will continue to regulate dura mater
as a device.
The agency intends to regulate as 361 products human heart valve
allografts that meet the criteria of proposed Sec. 1271.10, which are
now subject to regulation as medical devices. In the past, these
products were considered by FDA to be class III medical devices. In
1994, in a stipulated order of dismissal in Northwest Tissue Center v.
Shalala, No. 91-C-6515 (N.D. Ill., October 7, 1994), FDA stipulated
that it would not enforce the class III requirement of premarket
approval for human heart valve allografts. In 1995, the American Red
Cross (ARC) requested that FDA regulate human heart valve allografts as
human tissues for transplantation, rather than as medical devices.
ARC's request for jurisdictional change for the regulation of human
heart allografts was supported by the Northwest Tissue Center.
The agency now proposes to regulate, as section 361 products, heart
valve allografts that are minimally manipulated, do not a have a
systemic effect, and are not promoted for a nonhomologous use or
combined with a nontissue or noncellular component that is a drug or a
device.
C. Legal Authority
FDA is proposing to issue new regulations in part 1271 solely under
the authority of section 361 of the PHS Act. Under that section, FDA
may make and enforce regulations necessary to prevent the introduction,
transmission, or spread of communicable diseases between the States or
from foreign countries into the States. (See sec. 1, Reorg. Plan No. 3
of 1966 at 42 U.S.C. 202 for delegation of section 361 authority from
the Surgeon General to the Secretary, Health and Human Services; see 21
CFR 5.10(a)(4) for delegation from the Secretary to the Food and Drug
Administration.) Intrastate transactions may also be regulated under
section 361 of the PHS Act. (See Louisiana v. Mathews, 427 F. Supp.
174, 176 (E.D. La. 1977).
Because of their nature as derivatives of the human body, all human
cellular and tissue-based products pose a potential risk of
transmitting diseases. FDA has determined that it may appropriately and
effectively regulate certain of these products (described in section
II.B of this document) by controlling the infectious disease risks they
present rather than by requiring premarket approval or licensing under
the act or the PHS Act.
In order to prevent the spread of infectious disease, FDA must
obtain the type of basic information about the industry and its
products that these proposed regulations will require be provided to
the agency. This information will enable the agency to react swiftly to
newly discovered or understood risks by alerting members of the
industry of its concerns and, when appropriate, by conducting
establishment inspections.
Moreover, the registration regulations now being proposed lay the
foundation for a regulatory program that will further the goal of
preventing the transmission of communicable disease. FDA intends to
propose regulations to be issued at a later date that would require
such measures as the maintenance of ``good tissue practices'' and
various tests for communicable diseases. Without the information that
the agency will collect through establishment registration and product
listing, FDA cannot effectively monitor compliance with these future
regulations--and, thus, prevent the transmission of communicable
disease.
Authority for the enforcement of section 361 of the PHS Act is
provided by section 368 of the PHS Act (42 U.S.C. 271). Under section
368(a), any person who violates a regulation prescribed under section
361 of the PHS Act may be punished by imprisonment for up to 1 year, a
fine of not more than $1,000, or both (42 U.S.C. 271(a)). In addition,
Federal District Courts have jurisdiction to enjoin individuals and
organizations from violating regulations implementing section 361 of
the PHS Act. The agency intends, in a future rulemaking, to issue
regulations including requirements for testing, good tissue practices,
and enforcement under the authority of section 361 of the PHS Act.
Human cellular and tissue-based products that do not meet FDA's
criteria set forth in part 1271 for regulation solely under section 361
of the PHS Act are subject to regulation as biological drugs or
devices, and their manufacturers are required to register with the
agency under section 510 of the act. Regulations implementing section
510 are found under parts 207 and 807, among other parts. As discussed
earlier, in order to consolidate its data base on the cell and tissue
industry and thus to improve its oversight functions, FDA proposes to
amend parts 207 and 807 to require registering establishments to follow
the procedures set out in part 1271. Section 510 of the act remains the
authority for the substantive registration requirement for products
subject to parts 207 and 807. Because harmonizing the registration and
listing procedures
[[Page 26748]]
applicable to the various human cellular and tissue-based products is
intended to further the goal of preventing the spread of communicable
disease, the agency is also relying on the additional authority of
section 361 of the PHS Act for the proposed amendments to parts 207 and
807.
III. Summary of the Proposed Regulations
A. Purpose, Coverage, and Exceptions of Part 1271
1. Purpose
The purpose of part 1271, as set out in Sec. 1271.1, is to
establish a unified registration and product listing system for
establishments that manufacture human cellular and tissue-based
products.
2. Coverage
Section 1271.1 states that manufacturers of human cellular and
tissue-based products regulated under section 361 of the PHS Act are
required by part 1271 to register and list their products with CBER.
These products are further described in Sec. 1271.10, which states who
must register and submit a list. The products are those that: (1) Are
minimally manipulated; (2) are not promoted for any use other than
homologous use; (3) are not combined with or modified by the addition
of any nontissue or noncellular component that is a drug or device; and
(4) do not have a systemic effect, except in cases of autologous or
family-related allogeneic systemic use or reproductive use. Many of
these terms are defined in the definition section of the regulation,
Sec. 1271.3.
In addition, Sec. 1271.1 notes that manufacturers of products
regulated under section 351 of the PHS Act and/or the act are required
to register and list their products following the procedures in subpart
B of part 1271.
3. Exceptions
Section 1271.20 sets out exceptions to the provisions of part 1271.
These exceptions are for activities that do not raise issues the agency
currently believes warrant regulation.
a. The use of human cellular or tissue-based products solely for
nonclinical scientific or educational purposes does not trigger the
registration or listing requirements. Any use for implantation,
transplantation, infusion, or transfer into humans is considered
clinical use and would be subject to part 1271.
b. An establishment or person that removes human cellular or
tissue-based products from an individual and then implants,
transplants, infuses, or transfers those cells or tissues into the same
individual is not required to register or list with the agency, so long
as the human cellular or tissue-based product is quarantined pending
completion of the surgery. For example, a surgeon might remove a
saphenous vein from a patient for use in a later coronary bypass in the
same patient. Registration and listing would not be required unless the
saphenous vein was stored with other cellular or tissue-based products.
Storage in the same location as other human cellular or tissue-based
products gives rise to concerns about the spread of infectious disease
and would be considered beyond the bounds of the exception.
c. Carriers that accept, receive, carry, hold, or deliver human
cellular or tissue-based products in the usual course of business are
not required to register or list.
d. Establishments that receive human cellular or tissue-based
products solely for implantation, transplantation, infusion, or
transfer within the same facility do not come under the terms of part
1271. This exception is intended only for end-user establishments, that
is, establishments that do not procure, distribute, or otherwise
manufacture human cellular or tissue-based products.
B. Definitions
Section 1271.3 contains definitions of many of the terms used in
part 1271. Some of the definitions relate to the types of product
covered by part 1271, e.g., Sec. 1271.3(d) defines ``homologous use.''
Other definitions are intended to clarify the sorts of activities that
will trigger the requirements of part 1271, e.g., Sec. 1271.3(f)
defines ``manufacture.''
1. Human Cellular or Tissue-Based Product
A human cellular or tissue-based product is defined in
Sec. 1271.3(e) as a product containing human cells or tissues, or any
cell or tissue-based component of such a product.
The following products are excluded from this definition:
Vascularized human organs for transplantation; products that are
secreted or extracted from humans, such as milk, collagen, and cell
factors; minimally manipulated bone marrow; ancillary products used in
the propagation of cells or tissues, and cells, tissues, or organs
derived from animals.
Whole blood, blood components, or blood derivative products subject
to listing under 21 CFR part 607 are also excluded. Such products
include, among others, whole blood, red blood cells, cryoprecipitated
AHF, platelets, leukocytes/granulocytes, plasma, blood products for
diagnostic use, and blood bank reagents. In contrast, peripheral and
cord blood stem cells are not subject to the exception for whole blood,
blood components and blood derivative products and therefore are
subject to part 1271.
2. Minimal Manipulation
One of the criteria for regulation of a human cellular or tissue-
based product under section 361 of the PHS Act and part 1271 is that it
be minimally manipulated. Minimal manipulation is defined in
Sec. 1271.3(g). For structural tissue, minimal manipulation is defined
as processing that does not alter the original relevant characteristics
of the tissue that relate to the tissue's utility for reconstruction,
repair, or replacement. For example, separation of structural tissue
into components whose relevant characteristics relating to
reconstruction or repair are not altered would be considered minimal
manipulation, as would extraction or separation of cells from
structural tissue in which the remaining structural tissue's relevant
characteristics relating to reconstruction and repair remain unchanged.
Other examples of procedures that would be considered minimal
manipulation include: Cutting, grinding, and shaping; soaking in
antibiotic solution; sterilization by ethylene oxide treatment or
irradiation; cell separation; lyophilization; cryopreservation; and
freezing.
For cells (structural and nonstructural) and nonstructural tissues,
minimal manipulation is defined as processing that does not alter the
relevant biological characteristics and, thus potentially, the function
or integrity of the cells or tissues. For example, FDA considers cell
selection (e.g., selection of stem cells from amongst lymphocytes and
mature cells of other lineages) to be minimal manipulation.
FDA considers the processing of cells and tissue to be ``more than
minimal'' if information does not exist to show that the process meets
the definition of minimal manipulation. Examples of manipulation not
considered minimal, based on current scientific knowledge, include cell
expansion, encapsulation, activation, and genetic modification. FDA
recognizes that the subsequent accumulation of clinical data and
experience about a particular process may demonstrate that it does not
alter the original relevant characteristics of the cells or tissue, and
the agency will consider this information in determining whether a
procedure should be considered minimal as opposed to more-than-minimal
[[Page 26749]]
manipulation. For example , FDA previously considered demineralized
bone products (DMB) to be more than minimally manipulated. However, at
the March 17, 1997, public meeting, and during a July 11, 1997, meeting
between the American Association of Tissue Banks and FDA, the agency
was urged to reconsider its position regarding the regulatory status of
DMB. After reviewing information provided, the agency believes that the
relevant characteristics that relate to DMB's utility for replacement,
reconstruction and repair are not altered by processing bone specimens
into DMB. Therefore, FDA proposes to regulate DMB under section 361 of
the PHS Act provided it is used for homologous function and is not
combined with a noncellular or nontissue component that is a drug or
device because FDA believes DMB falls within the minimal manipulation
definition.
3. Homologous Use
The second criterion for regulation under part 1271 is that a human
cellular or tissue-based product not be promoted or labeled for any use
other than homologous use. Homologous use is defined in Sec. 1271.3(d)
as the use of a cellular or tissue-based product for replacement or
supplementation of a recipient's cells or tissues. Homologous use of a
structural tissue-based product occurs when the tissue is used for the
same basic structural function that it fulfills in its native state, in
a location where such structural function normally occurs. Basic
function of a structural tissue is what the tissue does from a
biological/physiological point of view, or is capable of doing when in
its native state. For example, the agency considers structural tissue
to be used for a homologous function when it is used to replace an
analogous structural tissue that has been damaged or otherwise does not
function adequately. Conversely, the agency would consider structural
tissue to be performing a nonhomologous function when it is fulfilling
a function that is different from the basic function it fulfills in its
native state.
Examples of homologous use claims for structural tissues that would
fall within the scope of part 1271 include bone allograft obtained from
a long bone but labeled for use in a vertebra; skin allograft obtained
from the arm but labeled for use as a skin graft on the face;
pericardium, a structural membranous covering of the heart, labeled for
use as a structural membranous covering for the brain; and heart valves
labeled for use as heart valves. An example of a nonhomologous use
claim for structural tissue is cartilage labeled for placement under
the submucosal layer of the urinary bladder to change the angle of the
ureter and thereby prevent backflow of urine from the bladder into the
ureter. The cartilage would be performing a structural function (adding
volume to change the angle of the ureter) which is different from the
function in its native state (to afford flexibility and provide
musculoskeletal support).
According to the definition, homologous use of nonstructural
cellular or tissue-based products occurs when the cells or tissues are
used to perform the function(s) that they performed in the donor. An
example of a homologous use claim would be hematopoietic stem cells
labeled for use for hematopoietic reconstitution. An example of a
nonhomologous use claim for the same cellular product would be a claim
for treatment of adrenal leukodystrophies (congenital metabolic
deficiencies).
In determining whether a product comes under part 1271 or is
instead required to comply with premarketing requirements, FDA has
tentatively decided to focus on whether a cellular or tissue-based
product is promoted or labeled by its manufacturer for a nonhomologous
use, rather than on the intent of the practitioner who uses the
product. Accordingly, the actual use of a cellular or tissue-based
product for a nonhomologous function would not trigger premarket review
requirements if the product was not labeled or promoted for
nonhomologous use. This change from the Proposed Approach document
comes in response to industry concerns and is expected to lead to the
more efficient use of the agency's resources. The agency specifically
requests comments on this new language.
4. Nontissue or Noncellular Component
Products combined with or modified by the addition of any nontissue
or noncellular component that is a drug or device will not be regulated
under part 1271. Because ``nontissue or noncellular component' is self-
explanatory, FDA does not consider it necessary to define the term.
However, the agency has modified the phrase ``nontissue or noncellular
component'' with the words ``that is a drug or device'' in order to
clarify that water and buffers would not ordinarily be considered
nontissue or noncellular components. In contrast, a product composed of
human cells or tissue in combination with a mechanical or synthetic
component, such as epithelial cells on a biomatrix to cover burns,
would not come under part 1271 and would be regulated under section 351
of the PHS Act and/or the act.
5. Systemic Effect
The final requirement for a product to be regulated under part 1271
is that the product not have a systemic effect. Given that ``systemic''
is a commonly used medical term, FDA is not proposing a regulatory
definition of the word. The agency would consider the insertion of
pancreatic islet cells, pituitary cells, or stem cells into an
individual to have a mainly systemic effect. In contrast, the insertion
of replacement bone would not have a mainly systemic effect; the effect
would be limited to the immediate area around the insertion. FDA
recognizes that some products may have both systemic and structural
effects but intends that a product's primary effect be determinative.
Earlier discussions of FDA's regulatory plans, including the
Proposed Approach document, used the term ``metabolic function.'' After
considering concerns raised by comments on the proposed approach, FDA
has decided that ``systemic effect'' more accurately reflects the
agency's intended meaning.
6. Autologous, Allogeneic, Family-Related Allogeneic, and Reproductive
Uses
Under Sec. 1271.10(d), there are several exceptions to the
requirement that a human cellular or tissue-based product not have a
systemic effect to be regulated under part 1271. These exceptions are
for cases of autologous or family-related allogeneic systemic use and
for reproductive use. Thus, products with a systemic effect that are
utilized for autologous, family-related allogeneic, or reproductive use
and that meet the other criteria set out in Sec. 1271.10 will be
regulated under part 1271.
Autologous use is defined in Sec. 1271.3(a) as the implantation,
transplantation, infusion, or transfer of a cellular or tissue-based
product back into the individual from whom the cells or tissue
comprising such product were removed. Several comments on the Proposed
Approach document pointed out that the agency had used ``Autologous''
in a confusing manner. With the previous definition, the agency intends
to clarify the meaning of the word. In contrast with autologous use,
allogeneic use (not defined in this regulation) is the transplantation
of cells or tissue obtained from a different individual.
FDA is using the phrase ``family-related'' for situations where the
[[Page 26750]]
recipient of cells or tissue is a biological parent, child, or sibling
of the donor. Thus, family-related allogeneic use is defined in
Sec. 1271.3(c) as 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. Some comments on the Proposed
Approach document have disagreed with FDA's definition of ``family-
related,'' arguing that its scope should be made broader to include
such relatives as cousins and grandparents. Other comments have argued
against an exception for family related allogeneic use, asserting that
the family-related allogeneic use of products with a systemic effect
should be treated no differently from any other allogeneic use. The
agency specifically requests further comment on this issue.
The third situation in which a product with a systemic effect will
be regulated under part 1271 is when the product contains human
reproductive cells or tissue and is for reproductive use. In contrast
to other tissues with a systemic effect, transfer of reproductive
tissues such as semen and ova pose less risk to the health of the
recipient from rejection, graft-versus-host disease, and compatibility.
In addition, the failure of a reproductive-tissue product will
generally cause lesser health risks to the individual than the failure
of other systemic products. FDA has decided that it is not necessary to
define ``reproductive use'' in the regulation, because the term is well
understood.
7. Transfer
Some of the definitions in Sec. 1271.3 contain the terms
implantation, transplantation, and infusion, which FDA believes are
generally understood. However, FDA is proposing to define, for the
purpose of this part, transfer, which may not be as well understood, to
mean ``the placement of human reproductive cells or tissues into a
human recipient.'' This definition, in Sec. 1271.3(k), reflects the way
the term ``transfer'' is used within the reproductive tissue industry.
8. Establishment and Manufacture
Other terms defined in Sec. 1271.3 relate to the manufacturing of
human cellular and tissue-based products. An establishment is defined
as a place of business under one management, at one general physical
location that engages in the manufacture of human cellular or tissue-
based products. The term includes facilities that engage in contract
manufacturing services for a manufacturer. The term also includes any
individual, partnership, corporation, association, or other legal
entity engaged in the manufacture of human cellular or tissue-based
products.
Under Sec. 1271.3(f), the term manufacture includes all steps in
the recovery, screening, testing, processing, storage, labeling,
packaging, or distribution of any human cellular or tissue-based
product. The agency interprets certain terms used in the definition of
``manufacture'' in the following ways. By ``recovery'' FDA means
obtaining cells or tissues from a donor that are intended for use in
human transplantation, infusion, implantation, or transfer. ``Storage''
would include holding human cells or tissue for future distribution or
use. ``Processing'' means any activity, other than recovery, performed
on a human cellular or tissue-based product, including preventing
contamination and preserving the function and integrity of the product.
Processing includes preparation, preservation for storage, removal from
storage, and any steps to inactivate and remove adventitious agents.
``Distribution'' includes any conveyance or shipment of human cellular
or tissue-based product (including importation and exportation),
whether or not such conveyance or shipment is entirely intrastate and
whether or not possession of the human cellular or tissue-based product
is taken.
Many entities and individuals that would be considered
manufacturers under part 1271 because they recover human cells or
tissues expressed concerns that they would be subject to registration
requirements. FDA anticipates that individuals engaged solely in the
procurement or recovery of cells or tissues and under contract to
organizations that coordinate procurement or recovery of human cells or
tissues will not have to independently register under part 1271.
Registration will be the responsibility of the employer or contracting
organization, which will also be required under future rulemaking to
ensure that its employees, agents, and contractors that engage in the
recovery of cells or tissues comply with applicable regulations or
procedures regarding the collection, safe handling, and proper shipment
of human cells or tissues.
C. Procedures for Registration and Listing
The procedures for complying with proposed part 1271, found in
subpart B, are designed to impose only a minimal burden on
manufacturers while providing FDA with the basic information needed to
underpin its regulatory program. Under Sec. 1271.21(a), registration
and listing are required within 5 days after the initiation of an
establishment's operations. Registration updates are required annually,
by December 31, under Sec. 1271.21(b). Section 1271.21(c) governs the
semi-annual updating of product lists. Product lists must be updated
with the following information: (1) Each human cellular or tissue-based
product introduced by the registrant for distribution that has not been
included in any list previously submitted; (2) each human cellular or
tissue-based product formerly listed for which distribution has been
discontinued; (3) each human cellular or tissue-based product for which
a notice of discontinuance was submitted and for which distribution has
been resumed; and (4) any material change in any information previously
submitted. Product list updates must be submitted each June and
December; alternatively, they may be submitted at the time the change
occurs. When no changes have occurred since the previously submitted
product list, no update is required.
Section 1271.22 requires registration, listing, and annual updates
to be submitted on Form FDA 3356. That section also tells how to obtain
the form and where to submit it, including information on obtaining the
form electronically. The agency anticipates that some firms may prefer
the ease of obtaining the registration and listing form electronically.
For this reason, an electronic version of this form is currently being
developed. It will be available by the time the final regulations go
into effect.
Section 1271.25 sets out the information required for registration
and listing, including the name and address of the establishment.
Information required for product listings includes the established and
proprietary names of each product, as well as a statement of whether
the product meets the criteria set out in Sec. 1271.10. (Any change in
whether a product meets these criteria will be considered a ``material
change'' subject to reporting under Sec. 1271.21(c)(iv).)
Under Sec. 1271.26, changes in an establishment's ownership or
location are to be submitted as an amendment to registration within 5
days of such changes. Section 1271.27 states that the agency will
provide the registrant with a permanent registration number. Section
1271.37 sets out the registration and product listing information that
will be made available to the public.
At this time, the agency is not proposing to charge a fee for
registration
[[Page 26751]]
or product listing. FDA is evaluating its authority to assess a fee and
the impacts of such a fee. If it determines that a fee it is
appropriate, the agency will make such a proposal in a future
rulemaking.
D. Amendments to Parts 207 and 807
FDA proposes to add new paragraph (f) to Sec. 207.20 and new
paragraph (e) to Sec. 807.20. These additions will state that owners
and operators of establishments that recover, screen, test, process,
store, label, package, or distribute human cellular or tissue-based
products, as defined in Sec. 1271.3(f), shall register and list those
products with CBER on Form FDA 3356, following the procedures found in
subpart B of part 1271. Thus, instead of following the procedures in
subpart C of part 207 (e.g., procedures contained in Secs. 207.21,
207.22, 207.25, 207.26, and 207.30), establishments that manufacture
human cellular or tissue-based products regulated as biological drugs
under the act and the PHS Act would follow the procedures set out in
part 1271, subpart B. Regulations that do not pertain to the procedural
requirements for registration and listing (e.g., Sec. 207.39, on
misbranding) would still apply. In addition, new Sec. 207.20(f) will
specifically state that the procedures for submitting additional
information, in Sec. 207.31, remain applicable.
With respect to human cellular or tissue-based products regulated
as devices under the act, manufacturers would follow the registration
and listing procedures of part 1271, subpart B, instead of those found
in part 807, subpart B (e.g., procedures in Secs. 807.21, 807.22,
807.25, 807.26, and 807.30). As would be the case for devices, the
requirements for additional listing information in Sec. 807.31 will
remain in place and regulations that do not pertain to registration and
listing (e.g., Sec. 807.39) would still be applicable.
IV. Analysis of Economic Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866, under the Regulatory Flexibility Act (5 U.S.C. 601-612),
and under the Unfunded Mandates Reform Act (Pub. L. 104-4). Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and, when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity).
The Regulatory Flexibility Act requires agencies to analyze whether
a rule may have a significant impact on a substantial number of small
entities and, if it does, to analyze regulatory options that would
minimize the impact. The Unfunded Mandates Reform Act requires that
agencies prepare an assessment of anticipated costs and benefits before
proposing any rule that may result in an expenditure by State, local,
and tribal governments, in the aggregate, or by the private sector, of
$100,000,000 (adjusted annually for inflation) in any 1 year. The
agency has determined that the proposed rule is a significant rule as
described in the Executive Order, but not a significant action as
defined in the Unfunded Mandates Reform Act. Aggregate impacts of the
rule, and aggregate expenditures caused by the rule, will not approach
$100 million for either the public or the private sector.
An analysis of available information suggests that costs to the
entities most affected by this rule, including small entities, are not
expected be significant, as described in the analysis below. Therefore,
the agency certifies that this rule will not have a significant impact
on a substantial number of small entities.
A. Objective and Basis of the Proposed Action.
FDA is proposing this action as a first step in the regulation of
the rapidly evolving industry of human cellular and tissue-based
products. This industry has not been previously subject to a
comprehensive regulatory program by FDA or other public health
authorities. Lack of a single regulatory approach or registration
system has prevented the agency from acquiring information regarding
the full size of the cell and tissue industry and the scope of its
products. The proposed rule will require all manufacturers of human
cellular and tissue-based products to register with the agency and to
submit to the agency a list of their products. Through registration and
listing, FDA will be able to identify industry participants and the
products manufactured. This will enable the agency to more efficiently
monitor the industry, distribute new information such as guidances,
policies, or requirements, and identify entities that may be subject to
inspection by FDA. This action is taken solely under the authority of
section 361 of the PHS Act. Section 361 is also used as authority to
amend parts 207 and 807 so that the registration data bases developed
for drugs and devices may be consolidated with the data base of the
proposed human cell and tissue registration program. Section 510 of the
act remains the substantive registration requirement for products
subject to parts 207 and 807. FDA has reviewed related Federal rules
and has not identified any rules that duplicate, overlap, or conflict
with the proposed rule.
B. Small Entities Affected
This proposal affects both entities that currently register with
FDA and submit product lists to the agency under applicable sections of
the act (parts 207 and 807), and those entities that are not presently
required to register or list with the agency. FDA has structured
registration and listing to have a minimal impact on affected entities.
However, the agency anticipates that the impact will be greater for
those entities that do not currently register or list.
The number of entities that will be required to begin registration
and listing under part 1271 is difficult to ascertain. Because the
agency has not previously regulated certain human cellular and tissue-
based products, the agency can only approximate the number of entities
that may fall under the requirements of the proposed rule. This lack of
accessible, accurate information is, in fact, a major reason behind the
agency's registration and listing initiative. In calculating the
burden, the agency has used information obtained from various trade
organizations related to the human cellular and tissue-based industry.
Several organizations also provided estimates of what portion of the
industry their membership represented, and the agency included in its
analysis the 65 manufacturers of human cellular and tissue-based device
products that are registered with the agency under part 807. The
Musculoskeletal Transplant Foundation lists approximately 25 tissue and
organ recovery members, which it estimates to be about one-third of the
tissue and organ procurement organizations in the United States. The
National Bone Marrow Donor Program, which includes establishments that
recover peripheral blood stem cells, lists approximately 101 donor
centers and 114 collection centers in the United States. The American
Association of Tissue Banks (AATB) lists approximately 60 tissue banks.
The Eye Bank Association of America represents about 112 eye banks,
which it estimates is about 95 percent of the U.S. eye banks. The
American Society for Reproductive Medicine has a membership of
approximately 7,200 physicians, researchers, and other health care
professionals, of which perhaps only 120 are fertility doctors who
would be subject to the registration and listing requirements. In
addition, it is estimated that there are about 90 semen
[[Page 26752]]
depositories in commercial operation. Any of the entities described
above that engage in manufacture (including, but not limited to,
recovery, screening, testing, processing, storage, labeling, packaging,
or distribution) of human cellular or tissue-based products would be
affected by the proposed rule. A great majority of these approximately
680 entities would be considered ``small'' under criteria established
by the Small Business Administration. FDA invites comments on this
analysis of the number of entities that may be affected by the proposed
registration and listing rule.
C. Nature of the Impact
The main cost involved in implementing the proposed rule would be
the time required to obtain the form, read the instructions, and
complete and submit the form. FDA has no precise estimate of the
initial registration and listing procedure but estimates that it should
require an average of 1 hour of staff time per registrant. This
estimate is supported by the estimates prepared for the completion of
the blood product registration on FDA Form 2830, which is similar in
length, type of information requested, and complexity to the proposed
Form FDA 3356 (62 FR 11898, March 13, 1997). In addition, the proposed
rule will require an update of the product list which is estimated to
require about 0.5 hour of staff time. Thus, registration and listing is
anticipated to require about 1.5 hours of staff time per annum. At an
estimated $38.00/hour value of staff time, most registrants are
expected to incur an annual cost of approximately $57.00 to comply with
the requirements of the proposed rule. There are no specific
educational or technical skills required to complete and submit the
registration and listing form. Similar activities are generally
completed by trained and qualified employees of an establishment who
are intimately involved with the operations of the entity.
The proposed rule is the first step in creating a tiered, risk-
based regulatory scheme that will tailor the degree of scrutiny
afforded to different products to the risks associated with each
product. Through registration and listing, FDA will acquire the
information needed to characterize the nature and extent of the human
cellular and tissue-based industry. This information will enable FDA to
efficiently and effectively respond to emerging public health concerns
related to human cellular or tissue-based products. Lists of industry
members and their products will also help FDA disseminate educational
materials and other important information regarding FDA policies,
guidances, and requirements.
D. Minimizing the Impact on Small Entities
FDA recognizes that a large number of the establishments that would
be required to register and list under the proposed rule will be small
entities with limited resources. In recognition of this, the agency is
proposing that the information to be provided during registration and
listing be only that which is necessary to achieve the agency's goals
of industry characterization and identification of its participants. To
alleviate the impact on entities, especially small entities, FDA
proposes that Form FDA 3356 be electronically retrievable. Future
development of registration and listing will consider the use of
electronic submissions (e-mail or Internet) and electronic signatures.
V. Proposed Effective Date
The agency proposes that any final rule that may issue based on
this proposed rule become effective 180 days after its date of
publication in the Federal Register.
VI. Environmental Impact
The agency has determined under 21 CFR 25.30(h) that this action is
of a type that is categorically excluded from the preparation of an
environmental assessment because these actions, as a class, will not
result in the production or distribution of any substance and therefore
will not result in the production of any substance into the
environment.
VII. The Paperwork Reduction Act of 1995
This proposed rule contains information collection requirements
that are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The
title, description, and respondent description of the information
collection requirements are shown below with an estimate of the annual
reporting burden. Included in the estimate is the time for reviewing
the instructions, gathering necessary information, and completing and
reviewing the report.
With respect to the following collection of information, FDA
invites comments on: (1) Whether the proposed collection of information
is necessary for the proper performance of FDA's functions, including
whether the information will have practical utility; (2) the accuracy
of FDA's estimate of the burden of the proposed collection of
information, including the validity of the methodology and assumptions
used; (3) ways to enhance the quality, utility, and clarity of the
information to be collected; and (4) ways to minimize the burden of the
collection of information on respondents, including through the use of
automated collection techniques, when appropriate, and other forms of
information technology.
Title: Establishment Registration and Product Listing for
Manufacturers of Human Cellular and Tissue-based Products.
Description: FDA is proposing to require establishments that
recover, screen, test, process, store, label, package, or distribute
any human cellular or tissue-based product to register with FDA and
submit lists of the manufactured products to be updated twice a year.
FDA proposes to define certain terms relevant to registration and
listing, define which manufactures will be subject to the provisions of
the proposed rule, and provide a form (Form FDA 3356) to be used for
the entry of an entity's name and location information and its product
list. FDA is proposing this action in response to the agency's public
health concerns regarding products comprised of human cells or tissues,
or that incorporate such cells or tissues. Through this initiative the
agency will improve its ability to protect the public health by
controlling the spread of communicable diseases.
Description of Respondents: Manufacturers of human cellular and
tissue-based products.
Table 1.--Estimated Annual Reporting Burden1
----------------------------------------------------------------------------------------------------------------
Annual Hours per
21 CFR Form No. No. of Frequency per Total Annual Response Total Hours
Respondents Response Responses (average)
----------------------------------------------------------------------------------------------------------------
1271 FDA 3356 680 2 1,360 0.75 1,020
207.20 FDA 3356 1 2 2 0.75 1.5
[[Page 26753]]
807.20 FDA 3356 65 2 130 0.75 97.5
TOTAL 746 2 1,492 0.75 1,119
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
Because many manufacturers of products using human cells or tissues
have not been required to register or list with FDA, the agency's
ability to predict how many entities would be affected by the proposed
rule is limited. The estimates for number of respondents are based on
the number of entities currently registered with FDA as manufacturers
of human cellular or tissue-based devices, membership information
obtained from trade organizations related to the manufacturing of
products utilizing human cells or tissues, and an estimate of entities
that are not presently registered with FDA or members of trade
organizations but that would be subject to registration under the
proposed rule. The annual frequency of responses is based on the
requirement in the proposed rule for the submission of an annual
registration and a biannual product list updating. In practice, it is
expected that the annual registration, or annual confirmation of
registration for entities that have already registered once, and the
first product list update of the biannual requirement will be completed
simultaneously on the same form. The hours for response was obtained by
averaging the estimates of 1 hour of staff time for the initial, or
confirmatory registration and 0.5 hour of staff time for the update of
the product list. The ``Total Hours'' column provides the estimated
total number of hours for registration and listing by manufacturers of
human cellular and tissue-based products under proposed part 1271,
existing Secs. 207.20 and 807.20 as they would be amended by the
proposal, and a cumulative total for registration and listing by
manufacturers of such products under all three sections.
In compliance with section 3507(d) of the Paperwork Reduction Act
of 1995 (44 U.S.C. 3507(d)), the agency has submitted a copy of this
proposed rule to OMB for review of the information collection
provisions. Interested persons are requested to submit written comments
regarding information collection by June 15, 1998, to the Office of
Information and Regulatory Affairs, OMB (address above), Attention:
Desk Officer for FDA.
VIII. Request for Comments
Interested person may, on or before August 12, 1998, submit to the
Dockets Management Branch (address above) written comments regarding
this proposal, except that comments regarding information collection
provisions should be submitted in accordance with the instructions in
section VII of this document. Two copies of any comments on issues
other than information collection are to be submitted, except that
individuals may submit one copy. Comments are to be identified with the
docket number found in brackets in the heading of this document.
Received comments may be seen in the office above between 9 a.m. and 4
p.m., Monday through Friday.
List of Subjects
21 CFR Part 207
Drugs, Reporting and recordkeeping requirements.
21 CFR Part 807
Confidential business information, Imports, Medical devices,
Reporting and recordkeeping requirements.
21 CFR Part 1271
Human cellular and tissue-based products, Reporting and
recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, it is proposed that chapter I of title
21 of the Code of Federal Regulations be amended as follows:
PART 207--REGISTRATION OF PRODUCERS OF DRUGS AND LISTING OF DRUGS
IN COMMERCIAL DISTRIBUTION
1. The authority citation for 21 CFR part 207 is revised to read as
follows:
Authority: 21 U.S.C. 331, 351, 352, 355, 356, 357, 360, 360b,
371, 374; 42 U.S.C. 262, 264, 271.
2. Section 207.20 is amended by adding new paragraph (f) to read as
follows:
Sec. 207.20 Who must register and submit a drug list.
* * * * *
(f) Owners and operators of establishments or persons engaged in
the recovery, screening, testing, processing, storage, or distribution
of human cellular or tissue-based products, as defined in
Sec. 1271.3(e) of this chapter, that are regulated under section 351 of
the Public Health Service Act and/or the Federal Food, Drug, and
Cosmetic Act shall register and list those products with the Center for
Biologics Evaluation and Research on Form FDA 3356 following the
procedures set out in subpart B of part 1271 of this chapter, except
that the additional listing information requirements in Sec. 207.31
remain applicable.
PART 807--ESTABLISHMENT REGISTRATION AND DEVICE LISTING FOR
MANUFACTURERS AND DISTRIBUTORS OF DEVICES
3. The authority citation for 21 CFR part 807 is revised to read as
follows:
Authority: 21 U.S.C. 331, 351, 352, 360, 360c, 360e, 360i, 360j,
371, 374; 42 U.S.C. 264, 271.
4. Section 807.20 is amended by adding new paragraph (e) to read as
follows:
Sec. 807.20 Who must register and submit a device list.
* * * * *
(e) Owners and operators of establishments or persons engaged in
the recovery, screening, testing, processing, storage, or distribution
of human cellular or tissue-based products, as defined in
Sec. 1271.3(e) of this chapter, that are regulated under section 351 of
the Public Health Service Act and/or the Federal Food, Drug, and
Cosmetic Act shall register and list those products with the Center for
Biologics Evaluation and Research on Form FDA 3356 following the
procedures set out in subpart B of part 1271 of this chapter, except
that the additional listing information requirements in Sec. 807.31
remain applicable.
[[Page 26754]]
5. New part 1271 is added to read as follows:
PART 1271--ESTABLISHMENT REGISTRATION AND PRODUCT LISTING FOR
MANUFACTURERS OF HUMAN CELLULAR AND TISSUE-BASED PRODUCTS
Subpart A--General Provisions
Sec.
1271.1 Purpose.
1271.3 Definitions.
1271.10 Who must register and submit a list.
1271.20 Establishments not required to register or list under this
part.
Subpart B--Procedures for Registration and Listing
1271.21 When to register and list.
1271.22 How and where to register and list.
1271.25 Information required for registration and listing.
1271.26 Amendments to registration.
1271.27 Assignment of a registration number.
1271.37 Inspection of establishment registration and product lists.
Authority: 42 U.S.C. 216, 243, 264, 271.
Subpart A--General Provisions
Sec. 1271.1 Purpose.
The purpose of this part is to create a unified registration and
product listing system for establishments that manufacture human
cellular and tissue-based products. Manufacturers of human cellular and
tissue-based products regulated under the authority of section 361 of
the Public Health Service Act are required by this part to register and
list their products with the Food and Drug Administration, Center for
Biologics Evaluation and Research. Under Secs. 207.20(f) and 807.20(e)
of this chapter, manufacturers of human cellular and tissue-based
products regulated under section 351 of the Public Health Service Act
and/or the Federal Food, Drug, and Cosmetic Act are required to
register and list their products following the procedures in subpart B
of this part.
Sec. 1271.3 Definitions.
The following definitions apply only to this part:
(a) 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.
(b) Establishment means a place of business under one management,
at one general physical location, that engages in the manufacture of
human cellular or tissue-based products. The term includes, among
others, facilities that engage in contract manufacturing services for a
manufacturer of human cellular or tissue-based products. The term also
includes any individual, partnership, corporation, association, or
other legal entity engaged in the manufacture of human cellular or
tissue-based products, except that an individual engaged solely in the
procurement or recovery of cells or tissues or under contract to a
registered establishment is not required to independently register.
(c) 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) Homologous use means the use of a cellular or tissue-based
product for replacement or supplementation and:
(1) For structural tissue-based products, occurs when the tissue is
used for the same basic function that it fulfills in its native state,
in a location where such structural function normally occurs; or
(2) For cellular and nonstructural tissue-based products, occurs
when the cells or tissue is used to perform the function(s) that they
perform in the donor.
(e) Human cellular or tissue-based product means a product
containing human cells or tissues or any cell or tissue-based component
of such a product. The following products are not considered human
cellular or tissue-based products and establishments that manufacture
only one or more of the following would not be subject to the
registration or listing provisions of this part:
(1) Vascularized human organs for transplantation;
(2) Whole blood or blood components or blood derivative products
subject to listing under part 607 of this chapter;
(3) Secreted or extracted human products, such as milk, collagen,
and cell factors;
(4) Minimally manipulated bone marrow;
(5) Ancillary products used in the propagation of cells or tissues;
or
(6) Cells, tissues or organs derived from animals.
(f) Manufacture means, but is not limited to, any or all steps in
the recovery, screening, testing, processing, storage, labeling,
packaging, or distribution of any human cellular or tissue-based
product.
(g) Minimal manipulation means:
(1) For structural tissue, processing that does not alter the
original relevant characteristics of the tissue relating to the
tissue's utility for reconstruction, repair, or replacement; and
(2) For cells and nonstructural tissues, processing that does not
alter the relevant biological characteristics of cells or tissues.
(h) Transfer means the placement of human reproductive cells or
tissues into a human recipient.
Sec. 1271.10 Who must register and submit a list.
All owners and operators of establishments, both foreign and
domestic, that manufacture human cellular and tissue-based products,
whether or not the product enters into interstate commerce, are
required under this part to register with the Food and Drug
Administration and submit to the agency a list of each human cellular
or tissue-based product manufactured, if such product is:
(a) Minimally manipulated;
(b) Not promoted or labeled for any use other than a homologous
use;
(c) Not combined with or modified by the addition of any nontissue
or noncellular component that is a drug or a device; and
(d) Does not have a systemic effect; except that a human cellular
or tissue-based product that meets the requirements in paragraphs (a),
(b), and (c) of this section may have a systemic effect if the product
is for:
(1) Autologous use;
(2) Family-related allogeneic use; or
(3) Reproductive use and contains human reproductive cells or
tissue.
Sec. 1271.20 Establishments not required to register or list under
this part.
The following establishments are not required to register or submit
product listings under this part:
(a) Establishments that use human cellular or tissue-based products
solely for nonclinical scientific or educational purposes;
(b) Establishments that remove human cellular or tissue-based
products from an individual and implant such cells or tissues into the
same individual during the same surgical procedure;
(c) Carriers who accept, receive, carry, hold, or deliver human
cellular or tissue-based products in the usual course of business as
carriers; and
(d) Establishments that only receive or store human cellular or
tissue-based products solely for pending scheduled implantation,
transplantation, infusion, or transfer within the same facility.
[[Page 26755]]
Subpart B--Procedures for Registration and Listing
Sec. 1271.21 When to register and list.
(a) Owners and operators of establishments required to register and
list under Sec. 1271.10 or required under other provisions of this
chapter to follow the procedures in subpart B of this part shall
register within 5 days after beginning operations and shall submit a
list of every product that is manufactured.
(b) Owners and operators of establishments shall update their
registration annually by December 31, except as required by
Sec. 1271.26. Annual registration may be accomplished in conjunction
with the updating of product lists under paragraph (c) of this section.
(c)(1) Owners and operators of establishments shall update their
product lists during each June and December or, at their discretion, at
the time the change occurs, with the following information:
(i) A list of each human cellular or tissue-based product
introduced by the registrant for distribution that has not been
included in any list previously submitted. The registrant shall provide
all of the information required by Sec. 1271.25(b) for each such
product.
(ii) A list of each human cellular or tissue-based product formerly
listed in accordance with paragraph (a) of this section and for which
distribution has been discontinued, including for each product so
listed, the identity by established name and proprietary name, and the
date of discontinuance. It is requested but not required that the
reason for discontinuance of distribution be included with this
information.
(iii) A list of each human cellular or tissue-based product for
which a notice of discontinuance was submitted under paragraph
(c)(1)(ii) of this section and for which distribution has been resumed,
including the identity by established name and proprietary name, the
date of resumption, and any other information required by
Sec. 1271.25(b) not previously submitted.
(iv) Any material change in any information previously submitted.
Material changes include any change in whether the product meets the
criteria set out in Sec. 1271.10.
(2) When no changes have occurred since the previously submitted
list, no report is required.
Sec. 1271.22 How and where to register and list.
(a) Establishment registration, product listing, and updates of
registration and listing shall be submitted on Form FDA 3356 to the
Center for Biologics Evaluation and Research (HFM-370), Food and Drug
Administration, 1401 Rockville Pike, Rockville, MD 20852-1448,
Attention: Tissue Establishment Registration Coordinator, or
electronically in accordance with instructions provided with Form FDA
3356.
(b) Copies of Form FDA 3356 can be obtained from the Center for
Biologics Evaluation and Research (HFM-370), Food and Drug
Administration, 1401 Rockville Pike, Rockville, MD 20852-1448,
Attention: Tissue Establishment Registration Coordinator (from any Food
and Drug Administration district office); by calling the CBER Voice
Information System at 1-800-835-4709 or 301-827-1800, or by calling the
Fax Information System at 1-888-CBER-FAX or 301-827-3844. Persons with
access to the Internet may obtain the document using the World Wide Web
(WWW) by connecting to: CBER at ``http//www.fda.gov/cber/
publication.htm''.
Sec. 1271.25 Information required for registration and listing.
(a) Registration shall include:
(1) The legal name(s) of the establishment;
(2) Each location, including the street address of the
establishment and the postal service zip code;
(3) The name, address, and title of the reporting official; and
(4) A signed and dated statement by the reporting official
affirming that all information contained in the registration and
listing form is true and accurate.
(b) Listing information shall include all human cellular or tissue-
based products (including the established name and the proprietary
name) that are recovered, screened, tested, processed, stored, labeled,
packaged, and distributed. Listing information shall also include a
statement of whether each product meets the criteria set out in
Sec. 1271.10.
(c) Copies of all contract service agreements shall be available at
the time of inspection of the establishment.
Sec. 1271.26 Amendments to registration.
Changes in the ownership or location of an establishment shall be
submitted as an amendment to registration within 5 days of such
changes.
Sec. 1271.27 Assignment of a registration number.
(a) A permanent registration number will be assigned to each
location.
(b) FDA acceptance of establishment registration and listing forms
for human cellular and tissue-based products does not constitute a
determination that an establishment is in compliance with applicable
rules and regulations.
Sec. 1271.37 Inspection of establishment registration and product
lists.
(a) A copy of the Form FDA 3356 filed by each establishment will be
available for inspection at the Office of Communication, Training, and
Manufacturers Assistance (HFM-48), Center for Biologics Evaluation and
Research, Food and Drug Administration, 1401 Rockville Pike, suite
200N, Rockville, MD 20852-1448. In addition, there will be available
for inspection at each of the Food and Drug Administration district
offices the same information for firms within the geographical area of
such district office. Upon request and receipt of a self-addressed
stamped envelope, verification of a registration number or the location
of a registered establishment will be provided. The following
information submitted under the human cellular and tissue-based product
requirements is illustrative of the type of information that will be
available for public disclosure when it is compiled:
(1) A list of all human cellular and tissue-based products;
(2) A list of all human cellular and tissue-based products
manufactured by each establishment;
(3) A list of all human cellular and tissue-based products
discontinued; and
(4) All data or information that has already become a matter of
public record.
(b) Requests for information regarding human cellular and tissue-
based product establishment registrations and product listings should
be directed to the Office of Communication, Training and Manufacturers
Assistance (HFM-48), Center for Biologics Evaluation and Research, Food
and Drug Administration, 1401 Rockville Pike, suite 200N, Rockville, MD
20852-1448.
Dated: March 10, 1998.
Michael A. Friedman,
Lead Deputy Commissioner for the Food and Drug Administration.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 98-12751 Filed 5-13-98; 8:45 am]
BILLING CODE 4160-01-F