[Printable PDF]
[Federal Register: January 19, 2001 (Volume 66, Number 13)]
[Rules and Regulations]
[Page 5447-5469]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr19ja01-4]
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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]
Human Cells, Tissues, and Cellular and Tissue-Based Products;
Establishment Registration and Listing
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule
to require human cells, tissue, and cellular and tissue-based product
establishments to register with the agency and list their human cells,
tissues, and cellular and tissue-based products. FDA is also amending
the registration and listing regulations that currently apply to human
cells, tissues, and cellular and tissue-based products regulated as
drugs, devices, and/or biological products. These actions are being
taken to establish a unified registration and listing program for human
cells, tissues, and cellular and tissue-based products.
DATES: The regulation is effective April 4, 2001, except for 21 CFR
207.20(f), 807.20(d), and 1271.3(d)(2), which are effective on January
21, 2003.
FOR FURTHER INFORMATION CONTACT: Valerie A. Butler, 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
We, FDA, are putting in place a comprehensive new system of
regulation for human cells, tissues, and cellular and tissue-based
products. The goal of the new approach is to improve protection of the
public health without imposing unnecessary restrictions on research,
development, or the availability of new products. Under the new system,
the regulation of different types of human cells, tissues, and cellular
and tissue-based products will be commensurate with the public health
risks presented, enabling us to use our resources more effectively.
Consolidating the regulation of human cells, tissues, and cellular and
tissue-based products into one regulatory program is expected to lead
to increased consistency and greater efficiency. Together, these
planned improvements will increase the safety of human cells,
[[Page 5448]]
tissues, and cellular and tissue-based products, and public confidence
in their safety, while encouraging the development of new products.
A. Background
In 1997, we announced our regulatory plans for human cells,
tissues, and cellular and tissue-based products in two documents:
``A Proposed Approach to the Regulation of Cellular and
Tissue-Based Products'' (62 FR 9721, March 4, 1997) and
``Reinventing the Regulation of Human Tissue'' (Ref. 1).
The proposed approach described a comprehensive plan for regulating
human cells, tissues, and cellular and tissue-based products that would
include establishment registration and product listing, donor-
suitability requirements, good tissue practice regulations, and other
requirements. Under this tiered, risk-based approach, we proposed to
exert only the type of government regulation necessary to protect the
public health. To accomplish this goal, we planned to issue new
regulations under the communicable disease provisions of the Public
Health Service Act (the PHS Act). Some human cellular and tissue-based
products would be regulated only under these new regulations, while
other human cellular and tissue-based products would also be regulated
as drugs, devices, and/or biological drugs. We requested written
comments on the proposed approach and, on March 17, 1997, held a public
meeting (62 FR 9721).
Since 1997, we have published three proposed rules to implement the
proposed approach. In 1998, as a first step toward accomplishing these
goals, we published the proposed rule, ``Establishment Registration and
Listing for Manufacturers of Human Cellular and Tissue-Based Products''
(63 FR 26744, May 14, 1998) (the ``registration proposed rule''). That
rule proposed to require cell and tissue establishments to register
with us and submit a list of their human cellular and tissue-based
products. We also proposed modifications to current registration and
listing requirements for drugs and devices under which cell and tissue
establishments already regulated under the Federal Food, Drug, and
Cosmetic Act (the act) and/or section 351 of the PHS Act (42 U.S.C 262)
would register and list following the new procedures.
In addition to the registration proposed rule, we published two
more proposed rules:
Suitability Determination for Donors of Human Cellular and
Tissue-Based Products (64 FR 52696, September 30, 1999) (the ``donor-
suitability proposed rule''); and
Current Good Tissue Practice for Manufacturers of Human
Cellular and Tissue-Based Products; Inspection and Enforcement (66 FR
1508, January 8, 2000) (the ``GTP proposed rule'').
Together, these three rules when finalized would establish a
comprehensive regulatory program for human cellular and tissue-based
products, to be contained in part 1271 (21 CFR part 1271).
In the three proposed rules, we used the term ``human cellular and
tissue-based products.'' In this final rule, we have changed the term
to ``human cells, tissues, and cellular and tissue-based products''
(abbreviated ``HCT/P's''). This change in terminology is a
clarification and does not affect the scope of the definition, which
continues to encompass an array of articles containing or consisting of
human cells or tissues, and intended for implantation, transplantation,
infusion, or transfer into human recipients, including investigational
products. The definition of ``human cells, tissues, or cellular or
tissue-based product'' is intended to cover HCT/P's at all stages of
their manufacture, from recovery through distribution. Some examples of
HCT/P's include skin, tendons, bone, heart valves, corneas,
hematopoietic stem cells, manipulated autologous chondrocytes,
epithelial cells on a synthetic matrix, and semen or other reproductive
tissue.
B. Implementation of the New Regulations
We had intended to finalize the registration proposed rule with the
two other rules that would make up part 1271 in its entirety, and to
implement all three rules together. However, we are now making the
registration rule final, with staggered effective dates, before
finalizing the two remaining portions of part 1271. We are taking this
action because of recent concerns raised about the safety of tissue,
which have led us to believe that accelerating the collection of basic
information about the rapidly growing tissue industry is vital. This
medical sector has grown rapidly, with a need for clearer standards and
improved accountability. The Department of Health and Human Services
met in mid-2000 with representatives of key tissue-related
organizations, who supported finalization of this regulation as quickly
as possible, instead of awaiting simultaneous publication with the
other tissue regulations. For these reasons, we are going to begin
collecting registration and listing information, while continuing to
develop the remainder of the final rules that will complete part 1271,
and we have changed the effective date of this rule from the proposed
180 days to 75 days after the date of publication in the Federal
Register. As part of completing the rulemaking for part 1271, we would
make any necessary conforming amendments to this regulation to make it
consistent with any changes made in the remainder of the rulemaking
process, and we would revoke part 1270.
Establishments that engage in the recovery, screening, testing,
processing, storage, or distribution of human tissue intended for
transplantation currently regulated under section 361 of the PHS Act
(42 U.S.C. 264) and the regulations in part 1270 (21 CFR part 1270)
(``Human Tissue Intended for Transplantation'') will be required to
begin registering with the agency and listing their HCT/P's within 30
days after the effective date of this final rule. The effective date
for all other human cells, tissues, and cellular and tissue-based
products (as described in Sec. 1271.3(d)(2)) is 2 years after
publication, by which time we expect to have completed rulemaking for
all the subparts of part 1271. (Some establishments that are not
required to register and list until the second effective date have
expressed a desire to submit registration and listing forms as soon as
possible. In response, FDA is prepared to accept registration and
listing forms submitted in advance of the second effective date.
However, FDA is not soliciting this information.) Once the entire
rulemaking is complete, the new regulatory approach would apply to a
broad range of human cells, tissues, and cellular and tissue-based
products, including reproductive cells and tissue; hematopoietic stem
cells; and tissues and cells regulated as devices, drugs, and/or
biological products.
Staggering the effective dates of this regulation permits us to
begin collecting important registration and listing information soon
from those establishments currently regulated under part 1270, while
continuing to proceed through rulemaking to develop the remainder of
part 1271. We believe that this action may prevent an unintentional gap
in the regulation of certain currently regulated HCT/P's, permit an
orderly implementation process, and avoid duplicative information
collection. If we instead implemented the regulation immediately for
all HCT/P's, this action could have the effect of shifting the
regulation of certain products (e.g., HCT/P's currently regulated as
devices
[[Page 5449]]
that meet the criteria set out in Sec. 1271.10 for regulation solely
under section 361 of the PHS Act) into the new regulatory system before
standards and enforcement provisions are in place. Staggering the
effective dates also helps permit an orderly implementation process.
Establishments that manufacture cells and tissues that will be
regulated for the first time under new part 1271 may require more time
than those currently regulated to implement the provisions of this
final rule. However, we also recognize that unanticipated delays in
completing the rulemaking for the remainder of part 1271 could occur.
Should the rulemaking proceedings be delayed past the 2-year timeframe,
we will consider whether to maintain the 2-year effective date for the
HCT/P's described in Sec. 1271.3(d)(2) or whether to extend that date
for some or all of those HCT/P's.
C. Legal Authority
We are issuing this final rule under the authority of section 361
of the PHS Act. Under section 361 of the PHS Act, we 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 of the PHS Act
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
FDA.) 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).)
HCT/P's are derivatives of the human body and thus pose a potential
risk of transmitting infectious disease. We have determined that some
HCT/P's may be effectively regulated solely by controlling the
infectious disease risks they present. The regulation now being
finalized forms the foundation for a regulatory program that will
further the goal of preventing the transmission of communicable
disease. To begin implementing this regulatory program, we are
publishing the registration final rule, with staggered effective dates
so that those HCT/P establishments not currently subject to regulation
under section 361 of the PHS Act will have adequate preparation time
and FDA can continue working towards finalizing the remainder of the
program.
For this regulatory system to be effective in preventing the spread
of disease, we must obtain basic information about the human cell and
tissue industry and its HCT/P's. The information to be submitted in
compliance with the registration and listing requirements in subpart B
will provide baseline data on establishments that will be subject to
part 1271. This information from the registration rule will assist us
in reacting swiftly to newly discovered or understood risks by alerting
members of the industry to our concerns and, when appropriate, by
conducting establishment inspections. Without this information, we
would not be able to effectively monitor compliance with the proposed
donor-suitability, GTP, and other regulations that make up the rest of
the regulatory program.
Authority for 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) of
the PHS Act, any person who violates a regulation prescribed under
section 361 of the PHS Act may be punished by imprisonment for up to 1
year. Individuals may also be punished for violating such a regulation
by a fine of up to $100,000 if death has not resulted from the
violation or up to $250,000 if death has resulted (18 U.S.C. 3559 and
3571(c)). In addition, Federal District Courts have jurisdiction to
enjoin individuals and organizations from violating regulations
implementing section 361 of the PHS Act. The regulations that we have
proposed specific to enforcement appear in the GTP proposed rule.
HCT/P's that do not meet FDA's criteria set forth in part 1271 for
regulation solely under section 361 of the PHS Act are regulated as
drugs, devices, and/or biological products under the act and/or section
351 of the PHS Act, and their manufacturers are required to register
with the agency under section 510 of the act (21 U.S.C. 360).
Regulations implementing section 510 of the act are found in parts 207
and 807 (21 CFR parts 207 and 807), among other parts. In order to
consolidate our data base on the cell and tissue industry and thus to
improve our oversight functions, we are amending parts 207 and 807 to
require registering establishments to follow the procedures set out in
part 1271; these amendments are effective in 2 years, when we project
the remaining two proposed tissue rules will be ready for
implementation. 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
applicable to the various HCT/P's is intended to further the goal of
preventing the spread of communicable disease, we are relying on the
additional authority of section 361 of the PHS Act for the proposed
amendments to parts 207 and 807.
II. Highlights of the Final Rule
A. Plain Language
On June 1, 1998, President Clinton directed Federal agencies to
begin using ``plain language'' in regulations and other documents. The
goal of the plain language initiative is to publish government
documents that are easier to understand.
In response to this initiative, we have written the registration
regulation in plain language. We have
Written the regulation in question-and-answer format,
Reorganized some regulatory sections for greater clarity,
and
Followed other plain-language conventions, such as using
``must'' instead of ``shall.''
The resulting codified language is easier to read and understand than
the proposed regulation. These editorial changes are for clarity only
and do not change the substance of the requirements.
B. Framework of the Final Regulation and Part 1271
When final, new part 1271 will be made up of six subparts. This
final regulation contains subpart A (general provisions pertaining to
the scope and applicability of part 1271; definitions); and subpart B
(registration and listing procedures). The donor-suitability proposed
rule contains subpart C of part 1271; and the GTP proposed rule
contains subparts D, E, and F.
Section 1271.10, in subpart A, sets out the criteria that form the
foundation of our tiered, risk-based approach to regulating HCT/P's.
HCT/P's that meet these criteria are subject only to regulation under
section 361 of the PHS Act. When all the proposed rules that will make
up part 1271 become effective, these HCT/P's would be subject to the
regulations in part 1271, and no premarket submissions would be
required. (We sometimes refer to these HCT/P's as ``361 HCT/P's.'' This
term replaces ``section 361 products,'' which was used in the
registration proposed rule.) HCT/P's that do not meet the criteria for
regulation as 361 HCT/P's will be regulated as drugs, devices, and/or
biological products.
In September 1999, in the donor-suitability proposed rule, we
modified proposed Secs. 1271.1, 1271.3(e), 1271.10, and 1271.20 as they
appeared in the registration proposed rule, and we added new
Sec. 1271.15. We made some of these changes to clarify our meaning.
[[Page 5450]]
We made other changes so that the provisions on scope and applicability
contained in subpart A would apply not only to the registration
procedures in subpart B but more generally to the rest of the
requirements in part 1271. These changes obviated the need for the
addition, in later rulemaking, of new sections dealing with scope and
applicability and were consistent with our original regulatory intent,
as set out in the proposed approach.
We received comments on the registration proposed rule, and we
received additional comments on subparts A and B of part 1271 in
response to the donor-suitability proposed rule. To the extent possible
we address these comments in this final rule; however, we recognize
that additional discussion may be necessary as issues arise in the
remaining rules that will makeup part 1271.
C. Staggered Effective Dates
In order to accomplish the goal of staggering the effective dates
of the registration and listing regulation for different types of HCT/
P's, we have divided the definition of ``HCT/P'' in Sec. 1271.3(d) into
two paragraphs. Paragraph (d)(1) of Sec. 1271.3 identifies the subgroup
of human tissues defined in part 1270. Paragraph (d)(2) provides the
broader definition of HCT/P based on proposed Sec. 1271.3(e). The
definition of the subgroup in paragraph (d)(1) incorporates the
definition of ``human tissue'' set out in Sec. 1270.3(j) and thus
identifies those tissues that are currently regulated under part 1270,
including, for example, such tissues as corneas, bone, and skin. This
represents the subgroup of human cells, tissues, and cellular and
tissue-based products for which this final rule will first go into
effect. Paragraph (d)(2) of Sec. 1271.3 provides the broader definition
of HCT/P and includes those HCT/P's described in paragraph (d)(1) as
well as such additional HCT/P's as reproductive cells and tissues,
hematopoietic stem cells, and cells and tissues currently regulated as
drugs, devices, and/or biological products. The definition in paragraph
(d)(2) of Sec. 1271.3 will eventually replace paragraph (d)(1), as
described below.
The effective date of Sec. 1271.3(d)(1) is 75 days after the
publication of this rule. The entire definition of HCT/P in
Sec. 1271.3(d)(2) is effective 2 years after the publication of this
final rule in the Federal Register. The effect of this action is to
make this final regulation applicable first to those HCT/P's currently
regulated under part 1270, and later to the complete range of HCT/P's
defined in Sec. 1271.3(d)(2). When all of the regulations that make up
part 1271 are final and have superseded part 1270, we will revoke
Sec. 1271(d)(1) and renumber (d)(2) as a conforming amendment. At that
time the new regulatory framework contained in part 1271 will be
instituted as a whole.
D. Other Highlights of This Final Rule
This final rule contains other changes from the proposed rule.
Among these changes are the following:
We have broadened ``family-related allogeneic use,'' as
used in proposed Sec. 1271.10, to include first-degree and second-
degree blood relatives.
We have modified the definition of ``homologous use.''
We have replaced the phrase ``combined with or modified by
the addition of a drug or a device'' in Sec. 1271.10 with new language.
We have deleted the phrase ``pending scheduled'' from the
exception in Sec. 1271.15(d) for establishments that only receive or
store HCT/P's.
We have added an exception for establishments that only
recovers reproductive cells or tissues for immediate transfer into a
sexually intimate partner of the cell or tissue donor.
(Sec. 1271.15(e)).
III. Comments on the Proposed Rule and FDA's Responses
We received 28 comments on the proposed rule as it was published in
1998. We received over 400 comments on the donor-suitability proposed
rule; many of these raised issues related to subparts A and B of part
1271.
A. General Comments
(Comment 1) Many comments expressed general approval of the rule.
One comment stated that the proposed rule addresses the public health
needs for regulation in this area, helping to assure an adequate supply
of safe and functional products without imposing unnecessary regulatory
burdens or inhibitions to progress. Another comment, in support of
registration, noted the importance of establishing a known data base of
the industry. Another comment stated that creation of an official
inventory of establishments subject to FDA regulation is important to
determine the actual level of compliance and to develop reliable
estimates of the cost of enforcement.
We acknowledge and appreciate these supportive comments. The new
regulation on registration and listing will increase our knowledge and
understanding of the HCT/P industry and will enable us to monitor
industry developments and communicate with industry members. This final
rule will enhance our compliance efforts in protecting the public from
the spread of communicable diseases, when the remaining tissue
regulations become effective.
(Comment 2) Some comments objected to the development of a
comprehensive regulatory system. One of these comments objected that
the approach is based on potential, not actual, concerns, is more
applicable to new products than to such tissues as corneal tissue
offered for transplant, and is unnecessary in light of quality
assurance programs established by professional organizations.
We believe that this new regulatory program for HCT/P's, when it is
in place, will be superior to the confusing patchwork of requirements
that it will replace. We have created a simple registration system with
uniform requirements for all HCT/P's and a one-page registration and
listing form. The procedures in subpart B of part 1271 will be followed
by all HCT/P establishments, along with those in proposed subparts C
and D of part 1271. Together, they are intended to establish a
communicable disease prevention program necessary to protect the public
health.
In developing and issuing the registration rule, we have recognized
that, because all HCT/P's are derived from the human body, they share
certain common characteristics, among other things the ability to
transmit infectious diseases. Thus, basic requirements such as
registration, communicable disease screening and testing, and GTP's may
reasonably be applied to all HCT/P's. However, we have also recognized
that within the larger group of HCT/P's, certain products may present a
greater degree of risk, and that these HCT/P's should be subject to
additional premarket requirements.
With this tiered, risk-based approach, we will be putting in place
a set of baseline requirements for all HCT/P's, while recognizing that
different HCT/P's may present different concerns. As the comment points
out, some concerns may be more applicable to new products than to such
tissues as corneal tissue offered for transplant. We have identified
criteria corresponding to the types of reduced risks that certain
products may present. HCT/P's that do not meet all of these criteria
will be regulated under the act and/or section 351 of the PHS Act
(subject to subsequent effective dates). On the other hand, most HCT/
P's, including cadaveric corneas, will be regulated solely under the
communicable disease authority of section 361 of the PHS Act
[[Page 5451]]
and the regulations that will make up part 1271.
When implemented, the registration, donor-suitability, and GTP
regulations are intended to reduce the risk of transmission of
communicable disease by HCT/P's. The donor-suitability proposed rule
incorporates and expands upon many of the requirements for human tissue
intended for transplantation in part 1270. The part 1270 requirements
were put into place to prevent the transmission of human
immunodeficiency virus and hepatitis through the transplantation of
tissue from domestic and foreign sources, ``Human Tissue Intended for
Transplantation,'' final rule (62 FR 40429, July 29, 1997).
Registration and listing are crucial components of a regulatory
program to increase the safety of HCT/P's. Indeed, the United States
General Accounting Office (GAO) has urged the agency to put a program
in place in response to the potential transmission of infectious
diseases from cell and tissue donors to recipients, GAO, ``Human Tissue
Banks, FDA Taking Steps to Improve Safety, but Some Concerns Remain''
(December 1997).
We recognize the importance of voluntary quality assurance
programs, and we respect the efforts and accomplishments of
professional organizations. We have considered the efforts of
professional organizations, and we will continue to do so as we
implement the new regulations. However, not all HCT/P establishments
belong to or are accredited by such groups, and voluntary programs are
not enforceable.
(Comment 3) Another comment stated that we should finalize the
registration rule as soon as possible, without waiting for the other
rules.
We agree that there are benefits to publishing the registration
final rule in advance of the other final rules, and we are doing so.
However, as discussed earlier in this document, we are staggering the
regulation's effective dates. Under this approach, we will be able to
promptly begin receiving registration and listing information for HCT/
P's currently subject to part 1270.
(Comment 4) One comment asserted that we should identify those
tissues and entities subject to part 1271 that are not currently
subject to part 1270, and initiate rulemaking to broaden the coverage
of the substantive regulations codified in part 1270.
Rather than broaden the scope of the regulations in part 1270, we
have earlier noted that we intend to replace part 1270 with the new
regulations in part 1271 (donor-suitability proposed rule, 64 FR
52697). Revocation of part 1270 will occur at the time the GTP final
rule becomes effective. We have earlier made clear (64 FR 52697 to
52698) that the new rules in part 1271, when complete, will be broader
in scope than those in part 1270, will impose additional testing and
screening requirements, and will cover more establishments and HCT/P's
(e.g., hematopoietic stem cells, reproductive tissue). Thus, it is not
necessary to initiate rulemaking to broaden the coverage of the
regulations in part 1270.
(Comment 5) One comment asked the agency to clarify if it intends
to require registered organizations to pass along any information the
agency disseminates. Another comment counseled against depending on a
secondary dissemination system, from those required to register to
those with whom they interact who are not required to register, to get
educational information to all of the tissue community.
We are not imposing a specific information-dissemination
requirement at this time. The only members of the tissue community who
would be subject to the rules in part 1271 and who are not required to
register are those individuals who recover cells or tissue under
contract, agreement, or other arrangement with a registered
establishment, but who perform no other manufacturing step (except for
sending the cells or tissue to the registered establishment). These
individuals would be subject to the other requirements that will be
contained in part 1271, when complete, and the establishments for whom
they perform their services would be responsible for their work. (This
exception is discussed in greater detail below.) Therefore, we believe
that if we distribute information to registered establishments, we will
be reaching the whole of the affected tissue community.
(Comment 6) One comment expressed concern that the proposed rule
failed to identify the party ultimately responsible for the tissue or
for the decisions required in the process of determining donor and
tissue suitability.
We have addressed the question of responsibility in the GTP
proposed rule.
(Comment 7) Several comments raised the issue of dispute
resolution, particularly with respect to questions about homologous use
and minimal manipulation. One of these comments urged us to develop and
follow a process for resolving disputes in a prompt and efficient
manner. One comment recommended that the Tissue Reference Group (TRG)
serve as the forum for resolving any disagreements that arise with
regard to the application of definitions.
We recognize that, as we implement this new regulation, there will
be areas in which additional guidance may be desirable or
interpretations may differ. To help answer questions about how a
particular HCT/P will be regulated, the agency developed the TRG. If an
establishment is not sure how its HCT/P may be regulated, it should
contact the TRG.
The TRG provides a single reference point and makes recommendations
to the Center Directors regarding regulation of specific HCT/P's, e.g.,
regulation solely under section 361 of the PHS Act or additionally
under the act and/or section 351 of PHS Act. The TRG is composed of:
(1) Three representatives from the Center for Biologics Evaluation and
Research (CBER), including the product jurisdictional officer; (2)
three representatives from the Center for Devices and Radiological
Health (CDRH), including the product jurisdictional officer; and (3) a
liaison from the agency's Office of the Chief Mediator and Ombudsman
(OCMO), a nonvoting member. Other FDA staff attend the TRG meetings as
needed to discuss issues related to products in their area of
expertise. Further information about the TRG can be found on CBER's
website at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cber/tissue/trg.htm.
In some cases, a product regulated under the act will fall under
the jurisdiction of more than one agency component, e.g., a combination
device and biological product. Where the agency component with primary
jurisdiction is unclear or in dispute, a sponsor may request
designation from the product jurisdiction officer, who is the FDA
Ombudsman, as detailed in 21 CFR part 3. In addition, the OCMO can
assist in resolving disputes with the agency that may arise from
decisions made by the Center Directors regarding the regulation of HCT/
P's, after consideration of TRG recommendations, as described above.
In addition, we recognize that further public discussion of how
tissue regulation would be applied to certain categories of human
cells, tissues, and cellular and tissue-based products may be warranted
due to the complexity or sensitivity of the issues. For example, we
held a public meeting on August 2, 2000, to discuss how proposed
definitions for ``minimally manipulated'' and ``homologous use'' should
be applied to human bone allograft products (65 FR 44485, July 18,
2000). We intend to provide further opportunities for public discussion
of
[[Page 5452]]
how the regulatory approach should be applied to other HCT/P's. We
anticipate that there may be additional needs for discussion through
public meetings, public hearings, or guidance as we implement the new
regulations.
(Comment 8) One comment asserted that we have published no document
describing the TRG's current composition, authoritative status,
procedures, whether its decisions are or will be made public, or how
industry is expected to communicate with the group. The comment also
suggested that we should consider making the TRG's policy decisions
routinely available to the public.
We appreciate these comments and are committed to working on the
issues raised. Among other things, the TRG is looking into mechanisms
for increasing the transparency of its functions, while still
protecting confidential information. Information about the TRG can be
found on CBER's website at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cber/tissue/trg.htm.
(Comment 9) Several comments asserted that we are proposing to
regulate the practice of medicine, especially with respect to
reproductive tissue and hematopoietic stem cells.
We disagree with this comment. This final rule sets out
registration and listing requirements for establishments that recover,
process, store, label, package, or distribute HCT/P's, or screen or
test cell and tissue donors. HCT/P's, including hematopoietic stem
cells and reproductive tissues, fall within our jurisdiction. Some HCT/
P's will be regulated under the act and/or the PHS Act, while other
HCT/P's will be effectively regulated solely by regulations issued
under our authority to prevent the spread of communicable disease. We
are not attempting to govern practitioners' use of HCT/P's, but rather
to ensure that HCT/P's that would be used by practitioners in their
treatment of patients are in compliance with applicable regulations,
including regulations designed to prevent the transmission or spread of
communicable disease.
(Comment 10) We received several comments on our proposed
regulation of hematopoietic stem cells. One comment supported the
proposal that all establishments involved with hematopoietic stem cell
therapy register with FDA. Two comments asserted that the proposed
regulation would jeopardize patient treatment, impede the development
of new therapies, and increase the costs of treatment. One comment
asserted that we lack the legal authority to regulate intrastate
hematopoietic stem cell transplants. Another comment argued that
clinical research involving the use of blood or bone marrow
transplantation for treatment of human diseases, but not involving an
investigational drug or device, should not require an investigational
new drug application or investigational device exemption. This comment
further requested the development of simplified procedures for
evaluating those investigational devices or cellular biologic products
that are more than minimally manipulated. Two comments argued that
there is no need for FDA regulation as industry standards suffice and
FDA requirements would be duplicative.
We believe that it is necessary to bring the regulation of
hematopoietic stem cells in line with the regulation of other HCT/P's,
and that we possess the legal authority to take this action. Like other
HCT/P's, hematopoietic stem cells may transmit communicable diseases;
thus, the basic communicable disease prevention requirements that will
be contained in part 1271, including these registration and listing
requirements, are as relevant to these cells as to any other HCT/P's.
Intrastate activities involving hematopoietic stem cells, as well as
other HCT/P's, can be regulated to prevent the interstate spread of
communicable diseases under section 361 of the PHS Act. (See Louisiana
v. Mathews, 427 F. Supp. 174, 176 (E.D. La. 1977).) The GAO has cited
the lack of regulation of hematopoietic stem cells as a significant gap
in our oversight, and urged us to proceed with implementing new
regulations that would cover hematopoietic stem cells. We are now
closing that gap.
Although we applaud the development of industry standards noted by
the comments received, such standards are not followed by all HCT/P
establishments. Moreover, voluntary standards differ significantly from
enforceable regulations. We cannot take enforcement actions to ensure
compliance with voluntary industry standards and thus would be limited
in our ability to protect the public health if we relied on such
standards alone. Establishments that comply with industry standards,
however, should have little trouble adapting their practices to the new
requirements. Thus, any additional burden should be minimal.
Rather than require data submission from each hematopoietic stem
cell establishment, we have considered the development of standards for
certain stem cell products. On January 20, 1998 (63 FR 2985), we
published a notice in the Federal Register requesting the submission of
proposed standards and supporting data relating to certain stem cell
products by January 20, 2000, entitled ``Request for Proposed Standards
for Unrelated Allogeneic Peripheral and Placental/Umbilical Cord Blood
Hematopoietic Stem/Progenitor Cell Products.'' Later, we extended the
deadline for submitting data to July 17, 2000 (65 FR 20825, April 18,
2000).
(Comment 11) One comment generally agreed with our proposal to
require registration for certain reproductive tissue, but requested
several clarifications and exceptions. Several comments questioned the
need for the regulation of reproductive cells and tissues, citing
current oversight from professional organizations, other Federal
agencies, and States. Comments opposed registration for programs
involved in egg donation, egg retrieval, semen processing, semen
evaluation, or in vitro fertilization (IVF) in assisted reproductive
technologies. One comment asserted that a large number of medical
practitioners who perform inseminations would not be included in this
new regulation, lessening their effectiveness. Another comment asserted
that programs that manufacture tissue culture products for the growth
of oocytes and sperm for sale should be required to register, but IVF
programs making culture medium for their own uses should be exempt.
We stand by our decision to extend regulatory requirements to
reproductive cells and tissue. Currently, FDA does not have regulations
in place to address the infectious disease risk of donating,
processing, and storing reproductive cells and tissue. Because there
has been no registration or listing requirement, we have not had
accurate information about the industry. We agree with the GAO that
extending regulation to reproductive cells and tissues will remedy a
significant gap in oversight.
Although we recognize the value of professional efforts to self-
regulate, and of regulatory efforts of other agencies and the States,
we disagree that these piecemeal, often voluntary, efforts are
adequate. Nor will the new regulations in part 1271 be duplicative.
State regulation varies from State to State and does not consistently
address our concerns about the transmission of communicable disease.
The model certification program for embryo laboratories developed by
the Centers for Disease Control and Prevention (CDC) is a voluntary
program that States may or may not choose to adopt; its primary focus
is not on preventing the transmission of communicable disease. No State
has yet adopted CDC's model certification program. Membership in
professional societies is voluntary.
[[Page 5453]]
Moreover, many establishments do not report to the Society for Assisted
Reproductive Technology. The Clinical Laboratories Improvement
Amendment of 1988 (CLIA) covers clinical laboratory testing, including
certain procedures performed in embryo laboratories; however, as
discussed later in this document, CLIA certification is not equivalent
to the requirements we are putting in place.
We disagree that establishments that only deal with egg donation,
retrieval, semen processing, or IVF should be exempt from the new
regulations. These activities are vital to the handling of reproductive
tissues. Performing these activities appropriately in order to prevent
cross-contamination and mix-ups requires proper recordkeeping, storage
practices, and accountability. Moreover, registration of these
establishments is consistent with agency practice in other areas; e.g.,
establishments where only blood donation or processing occurs are
required to register.
As discussed later in this document, however, this final rule
contains a new exception for certain reproductive tissue establishments
that perform only certain limited activities that raise limited
communicable disease concerns. Under the exception, an establishment
that only recovers reproductive cells or tissue for immediate transfer
into a sexually intimate partner of the cell or tissue donor is not
required to comply with the requirements that will be contained in part
1271, including registration and listing.
With respect to the comment about tissue culture media, these
products are not considered HCT/P's. Rather, embryo culture media and
other such products are regulated as medical devices by FDA, and
establishments that manufacture embryo culture media are subject to the
device regulations.
(Comment 12) Several comments responded to our discussion of
regulating dura mater and human heart valve allografts as 361 HCT/P's
rather than as devices, if they meet the criteria in Sec. 1271.10 (63
FR 26744 at 26747). Three comments supported the regulation of heart
valves as 361 HCT/P's. One comment suggested that, to prevent a
regulatory ``open window,'' the regulatory change should not take place
until GTP requirements are effective or other steps are taken. One
comment asked whether the transfer of heart valves would be reflected
in a codified regulation. A fourth comment supported regulating dura
mater as a 361 HCT/P and strongly suggested that ``special controls''
be included in the GTP requirements. No comments objected to regulating
heart valve allografts and dura mater as 361 HCT/P's.
We agree that we should avoid an ``open window'' where possible.
Therefore, we have staggered effective dates for this rule to prevent
such an outcome. We do not intend to begin regulating human heart valve
allografts and dura mater that meet the criteria in Sec. 1271.10 as 361
HCT/P's until the donor-suitability and GTP components of part 1271
become effective, or other appropriate steps have been taken. The GTP
proposed rule contains special requirements for dura mater intended to
address the communicable disease concerns about that product. Because
Sec. 1271.10 contains the criteria for regulation of HCT/P's as 361
HCT/P's, and we are now reiterating our view that heart valves meeting
those criteria will not be regulated as devices, we do not intend to
issue a separate regulation to change regulatory authority on that
specific point.
(Comment 13) One comment suggested that we consider voluntary
accreditation and inspection programs in implementing our regulatory
strategy. The comment further requested that we accord ``deemed
status'' to certain accredited facilities.
We are exploring various options for inspections and compliance
actions to enforce the new regulations. Among other ideas, we are
looking into those suggested by this comment, including the legal
issues raised. At present, we have in place a tiered inspection
approach to enforce the regulations in part 1270 that takes into
consideration such factors as professional accreditation. We intend to
provide a more detailed discussion of our regulatory intentions after
consideration of comments to the GTP proposed rule.
(Comment 14) One comment noted that tissue recovery is frequently
performed by organ procurement organizations, and that the requirements
with regard to the prevention of infectious disease transmission are
appropriately much less stringent for organ donation than are
comparable requirements for tissues. The comment asserted that
exempting these organizations from regulation would immeasurably weaken
the public health protection provided by this regulation.
An organ procurement organization that also recovers cells or
tissues in addition to organs is not exempt from these regulations, and
must register with the agency and follow all other regulations
applicable to its actions with respect to HCT/P's. An organ procurement
establishment is not required to submit a list of the vascularized
human organs for transplantation that it recovers, because these organs
are not covered by the definition of HCT/P (see Sec. 1271.3(d)(2)(i)).
However, such an organization must list with the agency any HCT/P's
that fall within the scope of part 1271 that the organization recovers
or otherwise manufactures.
B. Comments on Subpart A of Part 1271: Definitions
We received comments on many of the proposed definitions in
Sec. 1271.3(a) through (h). We did not receive comments on the
definitions of ``autologous'' and ``transfer.'' We address many of
these comments below. Comments on the definitions of ``homologous use''
and ``minimal manipulation'' are addressed in section III.C of this
document.
(Comment 15) The definition of establishment in proposed
Sec. 1271.3(b) reads as follows:
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 (emphasis added).
Comments raised issues about the proposed exception in the last
sentence of the definition. Some comments asserted that individuals or
organizations engaged solely in procurement under contract should be
required to register. One comment pointed to the critical role in the
suitability assessment of a cell and tissue donor that such
organizations play. Another comment asserted that registration and
listing should be applied to those who screen donors and that
procurement of tissue that is not done in an aseptic manner places
tissue recipients at risk. One comment expressed confusion about the
exception and suggested that ``or under contract'' should read ``and
under contract.'' This comment further suggested that individuals and
other legal entities engaged solely in procurement or recovery be
required to register unless contracted for that activity to a
registered establishment.
Three comments argued for an expanded exception. One comment urged
us to clarify that the ``under
[[Page 5454]]
contract to'' language can apply to other contracting individuals, not
just to contractors engaged in procurement or recovery (e.g., sales
representatives who distribute HCT/P's). Two other comments requested
clarification that clinical laboratories who perform testing are
excluded from the registration and listing requirements.
We have rewritten the exception and moved it to Sec. 1271.15(f).
The relevant language now states:
(f) You are not required to register or list your HCT/P's
independently, but you must comply with all other applicable
requirements in this part, if you are an individual under contract,
agreement, or other arrangement with a registered establishment and
engaged solely in recovering cells or tissues and sending the
recovered cells or tissues to the registered establishment.
We believe this new language addresses many of the comments'
concerns. We have replaced ``or under contract'' with ``and under
contract, agreement, or other arrangement.'' In addition, because
``procurement'' and ``recovery'' refer to the same action--the removal
of cells or tissue from a donor--we have decided that it is redundant
and possibly confusing to use both words. Instead, the exception now
uses the term ``recovery,'' the same term used in the definition of
``manufacture'' in Sec. 1271.3(e). Therefore, the exception only
applies to those individuals engaged solely in recovery of HCT/P's and
who are under contract, agreement, or other arrangement with a
registered establishment. We believe this is an appropriate way of
easing the regulatory burden on individuals while ensuring the
protection of the public health.
This exception does not extend to an individual who does more than
recover tissue and send it to the contracting establishment. (Thus, for
example, an individual engaged in any aspect of donor screening is not
covered by the exception and must register.) Further, an individual who
meets the terms of the exception would be excepted only from
registration and listing requirements and would be required to comply
with all other requirements to be contained in part 1271.
We are not extending the exception to ``other legal entities.''
Only individuals are covered. Examples of such individuals not required
to register might include certain medical examiners, morticians, or
physicians who recover hematopoietic stem cells or tissues (e.g.,
corneas, cord blood). Laboratories that perform donor testing are not
excluded from registration, listing, or other requirements in part
1271.
(Comment 16) We proposed to define family-related allogeneic use in
proposed 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.'' Under Sec. 1271.10(d),
as proposed, HCT/P's with a systemic effect that are for family-related
allogeneic use would be regulated under section 361 of the PHS Act
(provided that the HCT/P meets all other criteria set out in
Sec. 1271.10). This limited exception from the requirement for
investigational use exemptions and premarketing submissions was first
proposed in the proposed approach (62 FR 9721). In the registration
proposed rule, we specifically requested further comments on the issue
(63 FR 26744 at 26750).
We received approximately 13 comments on our proposed definition of
``family-related allogeneic use,'' most from individuals and
organizations involved in hematopoietic stem cell transplantation. One
comment praised the proposed definition as clearer and more consistent
than that used in the proposed approach, but cautioned that our
terminology might create confusion. Other comments argued that we
should expand the definition to more distantly related family members.
Several comments suggested that the term include all ancestral
relations, siblings, and collateral relations to the fourth degree by
blood, marriage, or adoption. Another comment objected to
distinguishing between family-related donors and other donors, stating
that the same principles apply in both situations. This comment argued
that the clinical use of unrelated versus related allogeneic
transplants falls within the practice of medicine and should not be
regulated by FDA.
We have decided to change the term from ``family-related allogeneic
use'' to ``allogeneic use in a first-degree or second-degree blood
relative.'' Parents, children, and siblings are considered first-degree
relatives. Aunts, uncles, nieces, nephews, first cousins, grandparents,
and grandchildren are second-degree relatives. Relations by adoption or
marriage are not included. Because we are using the phrase ``first-
degree or second-degree blood relative'' in its ordinary sense, the
final regulation does not contain a definition of this phrase.
Our decision to broaden the scope of related donors to include
second-degree blood relatives, rather than just first-degree, is based
upon several factors. In the absence of a human leukocyte antigen (HLA)
identical sibling, the search for donors in extended families is
occurring now to a very limited degree, but is likely to increase with
the continuing advances in deoxyribonucleic acid technology. The
likelihood of finding a donor with a haplotype identical to that of the
recipient is greater among blood-related individuals than among
unrelated individuals. Indeed, statistical methods have been proposed
to measure this probability (Refs. 2 and 3).
In addition, for certain ethnic groups, it is extremely difficult
to find an appropriate unrelated donor. Success at finding a match
among the extended family can be equal to or even greater than the
chance of finding a match using a single sibling search, if the
haplotype is a common one within the patient's ethnic population, and
the family members are of the same ethnic origin.
Registry outcome data for some hematologic malignancies suggest
that peripheral blood and bone marrow transplant recipients may have a
better survival rate when transplanted with hematopoietic stem cells
from related donors. One possible reason is that a related donor is
likely to share identical haplotypes with the patient (the genotypic
level), whereas an unrelated donor is matched at the phenotypic level.
Also, family donors may be better matched for minor histocompatability
loci for which testing is not routinely performed.
We initially proposed a more limited exception. Having reviewed the
comments on this issue, we believe there is some scientific merit in
expanding the exception to second-degree blood relatives. This change
is consistent with our goal of keeping regulatory burden to a minimum.
The same scientific justification does not exist for expanding the
exception to relatives by marriage or adoption, and is weaker for blood
relatives beyond the second degree. In addition, the exception in
Sec. 1271.10(a)(4)(ii)(b) for allogeneic use in a first-degree or
second-degree blood relative does not extend to those situations where
the HCT/P is more than minimally manipulated, is advertised, labeled or
otherwise objectively intended by the manufacturer for a nonhomologous
use, or is combined with a drug or device (except as described in
Sec. 1271.10(a)(3)).
(Comment 17) One of the comments on ``family-related allogeneic
use'' asserted that, in the context of reproductive medicine, the
notion of appropriate use of family-related materials must include the
close blood relatives of either partner. This
[[Page 5455]]
comment proposed that those facilities collecting or using reproductive
tissues from sexually intimate partners or close relatives should not
be required to register.
Later in this document, we address the question of registration for
reproductive tissue facilities. The change in terminology from
``family-related allogeneic use'' to ``allogeneic use in first-degree
or second-degree blood relatives'' does not affect the registration of
reproductive tissue establishments.
(Comment 18) Several comments objected to the word ``product'' in
the term human cellular or tissue-based product, defined in proposed
Sec. 1271.3(e). These comments asserted that human cells and tissues
are donations, not goods manufactured for sale. Some comments argued
that the use of the word ``product'' might have legal implications;
e.g., subjecting eye banks to inappropriate product liability
litigation. Comments also noted that the word ``product'' is
inconsistent with terms used in the tissue and eye banking field. We
also received an objection to describing embryos and germ cells as
``products.''
In choosing ``human cellular or tissue-based product,'' we were
seeking a term that would describe everything that will be subject to
the regulations in part 1271. We needed a term broad enough to cover
both cells and tissues, and one that would include within its scope
such diverse articles as unprocessed tissue, highly processed cells,
and tissues that are combined with certain drugs or devices. Although
we have considered removing the word ``product'' from the definition,
we are concerned that another term (e.g., ``human cells and tissues'')
would not be understood to include many of the highly manufactured
products to which the regulations apply, or might be misconstrued to
apply only to the cell or tissue component of such a product. Moreover,
the term ``product'' is consistent with the language of the statutes
under which we operate; for example, blood (which is also routinely
donated) is a ``biological product'' under section 351 of the PHS Act.
We do not believe that the use of the word ``product'' will affect the
manner in which state laws apply to HCT/P's; our experience with the
regulation of blood and blood products supports this view.
We recognize, however, that conceptual difficulties may arise in
calling certain cells or tissues ``products.'' Thus, as noted earlier
in this document, we have expanded the term to ``human cells, tissues,
and cellular and tissue-based products,'' abbreviated as ``HCT/P's.''
We have made appropriate substitutions throughout the regulation. The
definition itself has not changed, and the scope of the term remains
the same.
Proposed Sec. 1271.3(e) has been redesignated as Sec. 1271.3(d)(2).
(Comment 19) One comment stated that the proposed rule leaves vague
peripheral blood lymphocytes that are not cultured or manipulated, but
are used for their immunological effects for the treatment of disease.
According to the comment, the definition in proposed Sec. 1271.3(e)(2)
(finalSec. 1271.3(d)(2)(ii)) implies that these cells are subject to
regulation under 21 CFR part 607. The comment recommends that these
cells be specifically included in this proposal and not be considered
mature blood cells subject to regulation under other sections of title
21 of the CFR.
We believe that the commenter is addressing donor lymphocytes
(leukocytes) for infusion (DLI), which are the lymphocyte-rich cellular
fractions obtained by leukapheresis of the peripheral blood of donors
of bone marrow or peripheral blood hematopoietic stem/progenitor cells.
Many DLI products are not further manipulated. These minimally
manipulated products are administered to select patients to elicit a
graft-versus-leukemia effect and to treat other transplant-associated
complications.
DLI, regardless of the level of manipulation, meet the definition
of HCT/P in this rule. FDA intends to regulate all DLI as HCT/P's,
rather than as traditional blood products.
(Comment 20) One comment on proposed Sec. 1271.3(e) requested
clarification that an extract would not fall under the definition of
human cellular or tissue-based product. The comment noted that the
words ``any cell or tissue-based component of such a product'' may
imply that an extract could fall within the definition.
We do not consider extracts to be HCT/P's. When we revised the
definition of human cellular or tissue-based product in the donor-
suitability proposed rule (64 FR 52696 at 52719), we deleted the phrase
``or any cell or tissue-based component of such a product.'' Moreover,
we listed ``any secreted or extracted human products'' as an exception
to the definition of HCT/P in proposed Sec. 1271.3(e)(3). These changes
are codified in this rule at Sec. 1271.3(d)(2)(iii).
(Comment 21) One comment on proposed Sec. 1271.3(e)(4) objected to
the exclusion of bone marrow from the definition of HCT/P, since all
three sources of hematopoietic stem cells (cord, peripheral blood, bone
marrow) have the same risk of infectious disease transmission.
Minimally manipulated bone marrow falls under the purview of the
Health Resources and Services Administration (section 379 of the PHS
Act (42 U.S.C. 274(k)). For this reason, we have excepted it from the
definition of HCT/P's, and thus from the scope of this regulation
issued under section 361 of the PHS Act authority.
The exception for bone marrow in final Sec. 1271.3(d)(2)(iv)
extends only to ``minimally manipulated bone marrow for homologous use
and not combined with a drug or a device (except for a sterilizing,
preserving, or storage agent, if the addition of the agent does not
raise new clinical safety concerns with respect to the bone marrow).''
Bone marrow would meet the definition of an HCT/P if it is: More than
minimally manipulated; advertised, labeled, or otherwise objectively
intended by the manufacturer for a nonhomologous use, or combined with
certain drugs or devices.
(Comment 22) In the proposed rule, we stated in proposed
Sec. 1271.3(f) that ``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'' (63 FR 26744 at 26754). Approximately 10 comments
objected that the term ``manufacture'' is inappropriate. Some comments
asserted that fertility clinics are not ``manufacturers'' of human
tissue. Comments from the eye banks asserted that it is inaccurate to
use the word ``manufacture'' with respect to corneal tissue; along with
``product,'' the term could raise legal issues (e.g., subjecting eye
banks to inappropriate product liability litigation). Another comment
asserted that tissue banks do not manufacture tissue, but rather
process it.
We have considered substituting a different term for
``manufacture,'' but have been unable to find a satisfactory
replacement. Most of the terms that we considered (e.g., produce,
handle) were too limited in scope. Moreover, comments that objected to
the term did not suggest alternatives. For these reasons, we continue
to use the word ``manufacture'' as an umbrella term to capture the many
different actions that HCT/P establishments might take in preparing
HCT/P's for use. These steps may include, but are not limited to,
recovery, screening, testing, processing, storage, labeling, packaging,
and distribution. No comments disagreed with or objected to any of the
actions listed in the definition of manufacture.
[[Page 5456]]
Rather than list each of these activities repeatedly throughout this
preamble and the regulation, we have decided to maintain the term
``manufacture,'' as defined in this rule (proposed Sec. 1271.3(f) is
codified at Sec. 1271.3(e)).
(Comment 23) One comment on manufacture questioned the rationale
for requiring testing establishments to register. Three comments
asserted that testing laboratories should not be required to register
because CLIA certification is sufficient. One comment asked if labs
that test for other diseases or that perform bacterial cultures need to
register.
The definition of ``manufacture'' is intended to cover all steps in
the process of handling HCT/P's. Testing donors for communicable
diseases is a critical step in this process and for that reason is
included the definition of manufacture. The registration requirement
for testing laboratories enables us to have a list of all parties
involved in manufacturing activities.
Having a list of testing laboratories enables us to inspect
laboratories to ensure that testing is performed in a correct manner
according to test kit instructions. The CLIA certification referred to
in the comments is important, and in fact we are requiring CLIA
certification. However, because there are differences between
inspections under CLIA and inspections carried out by FDA, CLIA
certification alone is not adequate for our purposes. CLIA requirements
address only a limited spectrum of laboratory testing and personnel
requirements and do not focus on donor testing. Moreover, our
experience with inspecting testing laboratories indicates that
significant violations have been found. To exclude testing laboratories
from the scope of this regulation would not be consistent with our goal
of preventing the transmission of communicable diseases.
The registration requirement for testing laboratories extends to
those laboratories that test donor specimens for communicable disease.
Only laboratories that test for relevant communicable diseases as
defined in the proposed donor-suitability rule are required to
register. We have clarified the definition of ``manufacture'' to refer
to ``screening or testing of the cell or tissue donor'' rather than to
screening or testing of the cell or tissue. In the situation where
communicable disease testing to determine donor suitability might be
appropriately performed on the cells or tissues, rather than on the
donor (as might be the situation with cord blood), such testing would
be included within the meaning of donor testing.
(Comment 24) One comment noted that entities engaged only in
labeling and packaging are not explicitly within the scope of part
1270, but are covered by this new rule.
Part 1271 covers more activities than part 1270.
(Comment 25) In the preamble to the proposed rule, we noted that
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'' (63 FR 26750). We have proposed a codified definition of
``distribution'' in the GTP proposed rule.
For purposes of the regulations in part 1271 only, we have proposed
in the GTP rule to define ``distribute'' to mean the conveyance or
shipment of an HCT/P. In other contexts, FDA has defined
``distribution'' more broadly. Under the act, FDA has interpreted the
term ``distribute'' to include the delivery, transfer, and dispensing
of products. Moreover, the ordinary, dictionary meaning of the term
``distribute'' includes acts such as delivering, dispensing, supplying,
and giving out. In this rule, we do not intend the term to include the
dispensing or the transfer of an HCT/P to or in a patient.
Two comments on the registration proposed rule disagreed with the
phrase ``whether or not possession is taken.'' They asserted that
merely taking orders for a product should not be included within the
meaning of ``distribution,'' and thus should be excluded from
``manufacture.'' One of these comments described its ``service and
distribution'' agreement with a tissue processor, noting that although
it does not ship or take possession of the product, its name appears on
the product label along with that of the processor. A third comment
recommended that the term ``distributes'' be clarified to exclude
``distributors''; i.e., organizations that receive processed/
manufactured allografts and ship them to hospitals. Another comment
noted that hospitals and other establishments sometimes provide tissue
to other institutions in emergencies or in cases of special need. The
comment requested that these limited activities not be considered
distribution.
We agree that an entity that does not take possession of HCT/P's is
not distributing them for the purposes of this rule. However, we
disagree that distributors should be excluded from the terms of the
definition of ``distribution.'' We agree that the occasional provision
of HCT/P's to other institutions on an emergency basis does not fall
within the meaning of ``distribution.''
We will consider any additional comments on the definition of
``distribution'' when finalizing the other proposed rules that will
make up part 1271.
C. Comments on Subpart A: Proposed Secs. 1271.10 and 1271.15 (Final
Secs. 1271.10 and 1271.20)
In proposed Sec. 1271.10, we set out the criteria for regulating
certain HCT/P's solely under section 361 of the PHS Act and the
regulations to be contained in part 1271. An HCT/P would be subject to
this level of regulation if it: (1) Was minimally manipulated; (2) was
not promoted or labeled for any use other than a homologous use; (3)
was not combined with or modified by the addition of any component that
is a drug or a device; and (4) either does not have a systemic effect,
or has a systemic effect and is for autologous, family-related
allogeneic, or reproductive use (64 FR 52720).
Proposed Sec. 1271.15 was intended to describe the HCT/P's that did
not meet the criteria set out in Sec. 1271.10 and for which we
therefore did not consider regulation solely under section 361 of the
PHS Act to be justified (64 FR 52699). The section set out the ``mirror
images'' of the criteria in Sec. 1271.10 to assist readers in
understanding which HCT/P's would not be regulated solely under part
1271. However, rather than providing clarification, the proposed
section could have been interpreted to create an additional hurdle for
regulation of certain HCT/P's as drugs, devices, and/or biological
products.
Our ability to regulate an HCT/P as a drug, device, and/or
biological product derives from the act and section 351 of the PHS Act,
authorities that are distinct from our authority to issue regulations
to prevent the transmission of communicable disease under section 361
of the PHS Act. If an HCT/P does not meet the criteria in Sec. 1271.10
for regulation solely under section 361 of the PHS Act, and the
establishment does not qualify for any of the exceptions in final
Sec. 1271.15, the HCT/P will be regulated under the act and/or the PHS
Act and applicable regulations. As part of this rulemaking process, we
are amending certain drug and device regulations (e.g., Secs. 207.20,
807.20) to require compliance with certain subparts of part 1271.
Therefore, we have modified proposed Sec. 1271.15 and renumbered it
Sec. 1271.20. That section now refers to ``an HCT/P that does not meet
the
[[Page 5457]]
criteria set out in Sec. 1271.10(a),'' rather than setting out the
mirror images of those criteria. As before, the section contains cross-
references to those drug and device regulations (e.g., Secs. 207.20 and
807.20) that will direct establishments to follow the procedures set
out in subparts B, C, and D of part 1271. The section now also
clarifies that the referenced drug and device regulations apply if the
establishment does not qualify for any of the exceptions in
Sec. 1271.15.
We address below the comments received on proposed Sec. 1271.10 and
on the proposed definitions of ``homologous use'' and ``minimal
manipulation.''
(Comment 26) One comment requested that we schedule a public
meeting to discuss the appropriateness, legality, and practicality of
using the criteria in Sec. 1271.10 to reach jurisdictional
determinations.
We value public input on the criteria in Sec. 1271.10. In February
1997 we made available the proposed approach, which among other things
described the factors that we would consider in choosing to regulate
certain HCT/P's solely under the authority of section 361 of the PHS
Act rather than as drugs, devices, and/or biological products. On March
17, 1997, we held a public meeting to solicit information and views on
the proposed approach from the interested public, and we opened a
docket for the submission of comments (Docket No. 97N-0068).
We have published three proposed rules in the Federal Register. Two
of those rules specifically solicited comments on the criteria for
regulating certain HCT/P's solely under section 361 of the PHS Act. On
August 2, 2000, we held an open public meeting to solicit information
on current practices related to the manipulation and homologous use of
human bone allograft in the spine and other orthopedic reconstruction
and repair. Many of the comments presented at the meeting indicated
that there were misunderstandings about how the criteria set out in
Sec. 1271.10 would be applied, and about the meaning of the terms
``minimal manipulation'' and ``homologous use.'' This final rule
contains clarifications and additional examples that we believe will
clear up much of the confusion expressed at the meeting. We will
consider issuing a guidance document if establishments need additional
help in understanding the terms.
We intend to schedule additional public meetings as necessary. For
example, FDA believes that additional public discussion of how the
criteria in Sec. 1271.10 would apply to reproductive tissues would be
helpful, and further development of policy in this area may be
warranted.
(Comment 27) We received numerous comments on the definition of
minimal manipulation. The proposed definition reads as follows:
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.
One comment urged us to state in the preamble of the final rule
those activities that FDA presently considers to be minimal
manipulation. Two comments recommended that the following procedures be
considered minimal manipulation: Selective removal of B-cells, T-cells,
or malignant cells; blood or platelet depletion; centrifugation;
density gradient separation; and cryopreservation. Two comments
supported the use of clinical and scientific data to determine whether
a tissue-processing method is appropriately considered to be minimal
manipulation or more than minimal manipulation.
Eight comments asserted that ``minimal manipulation'' is vague and
open to subjective interpretation, and should be eliminated. Two
comments asserted that it is difficult to draw a meaningful distinction
between tissues that are minimally manipulated and those that are more
than minimally manipulated. One of these comments suggested that
instead of the minimal manipulation criterion, FDA should propose that
tissue products labeled or promoted for tissue replacement,
reconstruction, or restoration of function be regulated as tissue.
Another comment requested the development of guidance and noted that,
in light of future technological advances, a broader definition of
minimal manipulation may be more appropriate. One comment recommended
that the TRG serve as the liaison for communicating with manufacturers
concerning FDA's intended application of the definition of minimal
manipulation to particular tissues.
We received many comments on the regulation of bone allografts,
INCLUDING bone dowels, submitted in response to the donor-suitability
proposed rule. (The agency had previously considered regulating certain
bone dowels as medical devices.) Many of these comments addressed the
concept of minimal manipulation. Several comments supported regulating
machined bone allografts as medical devices in order to evaluate their
safety and efficacy and protect the public health. However, most
comments opposed such regulation, pointing to the long history of safe
use of bone allografts and citing concerns about decreased supply,
among other issues.
Comments did not suggest changes to the definition of minimal
manipulation, and we have not changed the regulation's wording. We
disagree that the term should be eliminated, however, as it serves as a
valid indicator of those HCT/P's that present fewer risks and that are
most appropriately regulated solely under section 361 of the PHS Act
and part 1271 (so long as other criteria are also met).
We agree that the TRG will continue to play a role in providing
recommendations for certain decisions made by the Center director
interpreting the term ``minimal manipulation.'' At this time, examples
of HCT/P's that we consider to be minimally manipulated include those
that have been subjected to the following procedures: Density gradient
separation; selective removal of B-cells, T-cells, malignant cells, red
blood cells, or platelets; centrifugation; cutting, grinding, or
shaping; soaking in antibiotic solution; sterilization by ethylene
oxide treatment or irradiation; cell separation; lyophilization;
cryopreservation; or freezing. We do not agree that the expansion of
mesenchymal cells in culture or the use of growth factors to expand
umbilical cord blood stem cells are minimal manipulation.
Most of the comments we received on the regulation of bone
allografts and bone dowels assumed that we planned to regulate all bone
allografts as medical devices. This is a misunderstanding. We are not
considering regulating all bone allografts as medical devices. Like all
other HCT/P's, the regulation of bone allografts depends on the four
factors set out in Sec. 1271.10. If the allograft is minimally
manipulated, is not advertised, labeled, or otherwise objectively
intended by the manufacturer for a nonhomologous use, and is not
combined with a drug or device (except as described in
Sec. 1271.10(a)(3)), then it will be regulated as a 361 HCT/P and
subject only to the regulations in part 1271. (Bone allografts do not
have a systemic effect, so the fourth factor is not at issue.) We
consider cutting, shaping and grinding of bone minimal manipulation.
Threading and other machining procedures that are performed to create
bone dowels, screws, and pins are also considered minimal manipulation.
[[Page 5458]]
(Comment 28) We received many comments on the term homologous use,
which we defined in proposed Sec. 1271.3(d) as follows:
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.
One comment praised the definition as reasonable, but urged us to
develop a process for resolving differences of opinion between FDA and
tissue manufacturers. Another comment supported our preamble statement
that the ``[b]asic 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'' (63 FR 26744 at 26749). As an example,
this comment pointed to surgical use of fascia lata or pericardium
allografts to replace or repair damaged dura mater or to construct a
bladder support sling from a fascia lata allograft to prevent
incontinence. Another comment questioned whether the homologous/
nonhomologous criterion is a meaningful indicator of the need for
premarket review; this comment cited fascia lata as an example of a
tissue that has been used safely and effectively for years in ways that
may be considered nonhomologous. One comment in response to our
statement (63 FR 26744 at 26749) that the use of hematopoietic stem
cells for treatment of adrenal leukodystrophy is an example of
nonhomologous use stated that logical application of hematopoietic stem
cells for their known hematologic, immunologic or metabolic effects as
treatment of human disease should be considered within the practice of
medicine and not subject to regulation by FDA.
Approximately 10 comments argued that the term ``homologous use''
should be eliminated. Many of these comments asserted that the term is
vague and open to subjective interpretation. One comment stated that
the phrase ``fulfills in its native state'' implies that tissue must be
used in the identical place and for identical purposes, which ignores
the realistic use of most tissue products. Many comments questioned the
application of the term ``homologous use'' to bone allografts. One
asserted that it is unusual for allograft tissues to be used in a
homologous location, especially with regard to the spine.
Below, in comment 29, we discuss our decision to look not at the
actual use of an HCT/P, but at the manufactuer's objective intent for a
nonhomologous use. Under this approach, a practitioner could use an
HCT/P, such as hematopoietic stem cells or fascia lata, for a
nonhomologous use in the treatment of the physician's patients. Thus,
we would not look at the surgical use of HCT/P's such as fascia lata or
pericardium allografts, but instead at whether they were advertised,
labeled, or otherwise objectively intended by the manufacturer for a
nonhomologous use. In the absence of advertising, labeling, or other
indications of the manufacturer's intent for such use, we would not
require premarket submissions. Should such review be required for a
product that has been used safely and effectively for years in
nonhomologous ways, and that is intended for a nonhomologous use, we
would expect that data would already exist to facilitate the review
process.
We disagree that the term ``homologous use'' should be eliminated
as a criterion for regulation of human cells or tissues under section
361 of the PHS Act. Regulation solely under section 361 and part 1271
is not warranted unless it is clearly demonstrated that the use of an
HCT/P in the recipient is homologous to the function the HCT/P would
carry out in the donor. We continue to consider nonhomologous use to be
a meaningful indicator that regulation solely under section 361 of the
PHS Act is not sufficient. For example, promotion of an HCT/P for an
unproven therapeutic use, such as curing cancer, would clearly make it
inappropriate to regulate the HCT/P solely under section 361 of the PHS
Act and the regulations that will be in part 1271.
We have, however, rewritten the definition of homologous use in
response to the comments' concerns. The new definition (codified at
Sec. 1271.3(c)) reads: ``Homologous use means the replacement or
supplementation of a recipient's cells or tissues with an HCT/P that
performs the same basic function or functions in the recipient as in
the donor.'' The rewording eliminates the distinction between, on the
one hand, structural tissues and, on the other, nonstructural tissues
and cells. The new wording does not include the statement that, for
structural tissues, homologous use occurs ``in a location where such
structural function normally occurs.'' This language was understood,
contrary to our intention, to limit the use of structural tissue to the
same location from which is was derived. However, a use of a structural
tissue may be homologous even when it does not occur in the same
location as it occurred in the donor. For example, the use of bone for
repair, replacement, or reconstruction anywhere in the skeleton of the
recipient (including the vertebral column) would be considered
homologous use. However, it should be understood that, for the use of a
structural tissue to be considered homologous, the HCT/P must perform
the same basic function or functions in the recipient as it did in the
donor; the use of structural tissue in a location where it does not
perform the same basic function as it did in the donor would not be
homologous.
We intend to interpret ``nonhomologous'' narrowly. Examples of uses
that would be considered nonhomologous include: The use of dermis as a
replacement for dura mater, the use of amniotic membrane in the eye,
and the use of cartilage in the bladder. As noted above, an HCT/P that
is intended by the manufacturer for one of these uses would not be
regulated solely under section 361 of the PHS Act and these
regulations, but as a drug, device, and/or biological product.
(Comment 29) We received approximately six comments agreeing with
our focus in proposed Sec. 1271.10(b) on the promotion or labeling of
HCT/P's for nonhomologous uses, rather than on their actual use. One of
these comments noted that the use of a product should be determined not
by the practice of surgeons but by the promotion, labeling, and
objective intent of the manufacturer. Another noted that the manner in
which we intend to determine homologous use is consistent with the way
we determine the intended use of other products under our jurisdiction.
Two comments interpreted proposed Sec. 1271.10(b) as relieving
clinicians from restrictions on use of tissue, and one of these
comments asserted that the exception should be extended to certain
clinical transplant programs.
Another supportive comment questioned how we will regulate the
labeling of 361 HCT/P's. Among other things, the comment asked whether
we will require 361 HCT/P's to be labeled for their homologous use. The
comment also queried whether cutting, shaping, or processing a product
in a manner that makes it amenable to nonhomologous use would be
considered promotion, in the absence of labeling or advertising.
We appreciate the comments on this issue, and we have decided to
maintain the regulation's focus on the objective intent of the HCT/P's
manufacturer for a nonhomologous use, rather than on
[[Page 5459]]
the intent of the practitioner who uses the HCT/P. We believe this
approach will lead to more efficient use of our resources. The focus on
labeling, advertising, and other indications of the manufacturer's
objective intent does not relieve clinicians from all restrictions on
the use of HCT/P's. However, it does mean that clinical use of an HCT/P
in a nonhomologous manner, whether by an individual practitioner or a
transplant program, can be consistent with regulation of the HCT/P
solely under section 361 of the PHS Act and the regulations to be
contained in part 1271. In order to clarify this provison, we are
revising proposed Sec. 1271.10(b) to read, in new Sec. 1271.10(a)(2),
as follows: ``The HCT/P is intended for homologous use only, as
reflected by the labeling, advertising, or other indications of the
manufacturer's objective intent.
By labeling, we refer to the HCT/P label and any written, printed,
or graphic materials that supplement, explain, or are textually related
to the product, and which are disseminated by or on behalf of its
manufacturer. We will address specific labeling requirements after
reviewing comments to the GTP proposed rule.
In order to be more consistent with terminology used by the rest of
the agency, we have replaced the word ``promoted'' with ``advertised.''
The terms ``advertised,'' ``advertisement,'' and ``advertising''
include information, other than labeling, that originates from the same
source as the product and that is intended to supplement, explain, or
be textually related to the product (e.g., print advertising, broadcast
advertising, electronic advertising (including the Internet),
statements of company representatives).
(Comment 30) As originally proposed, Sec. 1271.10(c) contained the
following criterion for regulation of an HCT/P solely under section 361
of the PHS Act: ``Not combined with or modified by the addition of any
nontissue or noncellular component that is a drug or a device.'' We
modified that wording in the donor-suitability proposed rule by
deleting the phrase ``nontissue or noncellular.''
Two comments questioned the meaning of Sec. 1271.10(c) and
requested additional explanation. For example, the comments asked
whether we would regard a component as being a drug or device based on
its actual function in the product, or based on how the component is
already regulated. The comments also questioned whether all products
containing a ``nontissue or noncellular component that is a drug or
device'' would automatically be subject to regulation and premarket
review as drugs or devices, and expressed concern that application of
the criterion might result in unnecessary regulation of HCT/P's as
drugs or devices. Another comment asserted that we should not regulate
a product containing a drug or device component unless it could affect
recipient safety, and that the manufacturer should make the initial
determination of whether this threshold has been crossed. One comment
stated that hematopoietic stem cell components are routinely processed
using centrifuges and other laboratory equipment, combined with
dimethylsulfoxide (DMSO) and other reagents for cryopreservation, and
separated using devices approved for the processing of hematopoietic
stem cells components, and that we have previously classified these
steps as minimal manipulation. The comment expressed concern that these
steps might be considered to combine the cells with a drug or device
component.
In response to the concerns expressed by these comments, we have
rewritten the proposed language. Proposed Sec. 1271.10(c) has been
renumbered as Sec. 1271.10(a)(3), and now reads: ``The manufacture of
the HCT/P does not involve the combination of the cell or tissue
component with a drug or a device, except for a sterilizing,
preserving, or storage agent, if the addition of the agent does not
raise new clinical safety concerns with respect to the HCT/P.''
The addition of a drug or a device to the cell or tissue component
of an HCT/P may ordinarily be expected to add a therapeutic effect and
may also raise safety concerns. For these reasons, the addition of a
drug or a device to a cell or tissue makes it no longer appropriate to
regulate the HCT/P solely under section 361 of the PHS Act. (As used,
the terms drug and device are defined in section 201(g) of the act (21
U.S.C. 321(g)).
However, we recognize that the use of certain sterilizing,
preserving, and storage agents do not raise the same concerns. For this
reason, we have excepted sterilizing, preserving, and storage agents,
but only if the addition of the agent does not raise new clinical
safety concerns with respect to the HCT/P. Examples of substances that
would generally be acceptable include: (1) Cryoprotectants (e.g.,
DMSO); (2) chemicals used for sterilization (e.g., ethylene oxide); and
(3) storage solutions. We encourage the development of industry
standards that describe the safe use of sterilization, preserving, and
storage agents.
Some drugs or devices that have as their principal purpose
sterilizing, preserving, or storage may also have a therapeutic effect
or may be claimed to have such an effect. The addition of such drugs or
devices would not fall within the exception for sterilizing,
preserving, and storage agents. We agree that the establishment that
manufactures the HCT/P should make the initial determination of whether
the addition of a drug or device that is a sterilizing, preserving, or
storage agent to an HCT/P raises new clinical safety concerns.
(Comment 31) We received one comment in response to our request for
comments on whether the term ``systemic effect'' adequately
characterizes those HCT/P's that should be regulated under section 351
of the PHS Act, such as neural-derived tissues and cells used to
replace or supplement neurons in the brain (donor suitability proposed
rule, 64 FR 52699). This comment expressed concern that the intent of
the proposed change is vague and that currently there is little or no
evidence that supports such cells or tissues having any systemic effect
when implanted in the brain.
After further consideration, we agree that the term ``systemic
effect'' may not cover all of the HCT/P's that we intended to cover.
Because the effect of implanted neurons or neural tissue into the brain
would likely be restricted to the site where the tissue/cells were
placed, this effect might not be included within the meaning of
systemic. However, as discussed in the proposed approach, HCT/P's that
rely on living cells for their primary function, such as neuronal
tissue, raise clinical safety and effectiveness concerns that are not
appropriately addressed solely under section 361 of the PHS Act. Such
concerns include viability, efficacy, malignant transformation, or
rejection after transplantation. Thus, although neuronal cells may not
be considered to have a systemic effect, they nonetheless require
regulation under the act and/or section 351 of the PHS Act.
Therefore, we have clarified Sec. 1271.10(a)(4) to indicate that an
HCT/P that either has systemic effect or depends upon the metabolic
activity of living cells for its primary function would not be
appropriately regulated solely under section 361 of the PHS Act, and
therefore will be regulated as a drug, device, and/or biological
product. Cells or tissues such as pancreatic islet cells, which have
effects on many different organs throughout the body through the
secretion of insulin, are appropriately characterized by the term
``systemic effect.'' Neurons for implantation in the brain would fall
into the category of HCT/P's that depend upon the metabolic activity of
living
[[Page 5460]]
cells for their primary function. In contrast, some HCT/P's (such as
corneas, skin, or osteochondral allografts) may contain living cells,
but do not depend on them for their primary function, which is
structural.
(Comment 32) Two comments on proposed Sec. 1271.10 suggested that
isolated human hepatocytes intended for transplantation be considered
to meet the criteria in Sec. 1271.10 and therefore be regulated as 361
HCT/P's.
We do not consider human hepatocytes, isolated in tissue culture
medium, infused into the spleen, and intended for temporary treatment
of liver failure to be suitable for regulation solely under section 361
of the PHS Act. Human hepatocytes have a systemic effect. Therefore,
regardless of the level of manipulation of the hepatocytes, these cells
would be regulated under the act and section 351 of the PHS Act.
D. Comments on Subpart A: Proposed Sec. 1271.20 (Final Sec. 1271.15)
Proposed Sec. 1271.20, as modified in the donor-suitability
proposed rule, set out four specific exceptions from the requirements
of part 1271. We address comments on these proposed exceptions below.
In this final rule, we have renumbered proposed Sec. 1271.20 as
Sec. 1271.15.
(Comment 33) We received one comment on the proposed exception in
Sec. 1271.20(b) for establishments that remove human cells or tissues
from an individual and implant such cells or tissues into the same
individual during the same surgical procedure. The comment assumed that
hospitals retaining autologous tissue, not used in a scheduled surgical
procedure, to be used in a subsequent application on the same patient,
are exempt from registration and listing because the two applications
are essentially a single continuous procedure.
We agree that, so long as the hospital does not engage in any other
activity encompassed with in the definition of ``manufacture,'' the
hospital would not be required to register or comply with the other
provisions to be codified in part 1271. For example, if the hospital
expanded the cells or tissues, it would not meet the terms of the
exception. In reaching this conclusion, we note that hospitals that
store autologous cells or tissues for subsequent application in the
same patient must follow the guidelines of the Joint Commission on
Accreditation of Healthcare Organizations (JCAHO) for tissue storage,
monitoring of storage devices, and tracking in order to obtain or
maintain accreditation.
(Comment 34) We received comments questioning the proposed
exception in Sec. 1271.20(d) for establishments that ``receive or store
human cellular or tissue-based products solely for pending scheduled
implantation, transplantation, infusion, or transfer within the same
facility.'' Approximately eight comments asserted that hospitals and
other surgical facilities keep tissue allografts on hand for future use
and suggested that the phrase ``pending scheduled'' be deleted from the
exception. One comment projected that institutions would discontinue
stocking tissue in order to avoid the registration requirement, leading
to the denial to patients of appropriate implants. Another comment
noted that thousands of hospitals and physician's offices store cells
and tissue, and argued that registration could cause an unnecessary
burden for facilities and FDA. One comment asserted that hospitals must
follow the JCAHO guidelines for storage of tissues, monitoring of
storage devices, and tracking of tissue use to provide for the safe
storage of tissue. Another comment questioned whether physicians who
receive sperm from a sperm bank and examine it for viability would be
covered by the exception.
In response to many of these comments, we have deleted the phrase
``pending scheduled.'' The exception, codified at Sec. 1271.15(d), now
reads:
You are not required to comply with the requirements of this
part if you are an establishment that does not recover, screen,
test, process, label, package, or distribute, but only receives or
stores human cells or tissue solely for implantation,
transplantation, infusion, or transfer within your facility.
As we noted in the preamble to the registration proposed rule (63 FR
26744 at 26748), this exception is intended only for end-user
establishments; that is, establishments that do not recover,
distribute, or otherwise manufacture human cells or tissue. Examples of
such establishments might include some hospitals, dental offices, and
physicians' offices. Physicians who do not recover sperm from donors
but only receive sperm from a sperm bank would fall within the
exception; examining the received sperm sample for viability would not
be considered screening.
We believe that expanding this exception will ease the regulatory
burden without posing public health concerns. To date, we have not
become aware of problems with the types of facilities that will fall
under the exception. However, should that situation change--e.g.,
should we encounter problems with tracking systems or learn of storage
problems--we will consider narrowing the exception through rulemaking
to bring these establishments within the scope of the regulation.
(Comment 35) One comment argued that registration should not be
required for facilities collecting or using reproductive tissues from
sexually intimate partners or close relatives. The comment strongly
urged us to expand proposed Sec. 1271.20(d) to include establishments
that collect reproductive materials for use between sexually intimate
partners or close relatives.
We agree with this comment, in part, and have added new paragraph
(e) to the exceptions in Sec. 1271.15. This exception is limited to
establishments that recover reproductive materials for immediate use
between sexually intimate partners. (By ``immediate use,'' we mean that
the reproductive materials are used promptly enough that
cryopreservation is not necessary and is not performed.) The exception
is intended to cover an establishment that recovers semen for use in
the artificial insemination of the donor's sexually intimate partner.
We believe that this situation raises few new infectious disease
concerns. For this reason, we are excepting these establishments from
registering and from the other requirements that will be contained in
part 1271. The exception does not extend to the recovery of cells or
tissues from close relatives who are not sexually intimate partners,
since an increased risk of communicable disease transmission exists in
this situation.
E. Comments on Subpart B of Part 1271: Procedures for Registration and
Listing
Many comments expressed general agreement with the proposed
registration and listing procedures. One comment stated that the rule
set forth a reasonable structure of requirements to be applied
uniformly.
(Comment 36) One comment expressed concern that we might impose a
registration fee.
We stated in the preamble to the registration proposed rule that we
were evaluating our authority to assess a fee and the impacts of such a
fee (63 FR 26744 at 26751). At this time, we have no plans to impose a
registration fee.
(Comment 37) Comments opposed the proposed requirement in
Sec. 1271.21 for twice yearly reporting as excessive and supported
annual listing updates instead. One comment noted that it is unlikely
that the components processed by individual laboratories will change
greatly over a 12-month period.
We disagree that the requirement for updating HCT/P lists is
excessive. Establishments are required to update
[[Page 5461]]
their listings with information on changes that have occurred since the
previously submitted list. These changes include the introduction of
new HCT/P's, the discontinuation of HCT/P's, the reintroduction of
previously discontinued HCT/P's, and material changes in information
previously submitted. However, if no such change has occurred since the
previously submitted list, the establishment is not required to submit
an update.
Those establishments that must update their lists will likely find
the task relatively simple. As discussed in section III.G of this
document, Form FDA 3356 was designed with ease of completion in mind.
Yet the information to be submitted on those updates is crucial if we
are to keep abreast of developments in the cell and tissue industry.
Without current information, we will be restricted in our ability to
understand the industry and achieve our public health goals.
In setting up a unified registration system for all HCT/P's, we
incorporated certain components from current registration and listing
regulations for drugs and devices, such as the update requirements. By
doing so, we made it possible for establishments that manufacture HCT/
P's regulated as devices, drugs, and/or biological drugs to register
and list their products with the agency using the same form as
manufacturers of 361 HCT/P's. Thus, the requirement for updating is
similar to the requirements in Secs. 207.30 and 807.30 and is
consistent with the requirements of section 510(j)(2) of the act.
We have rewritten the requirement for updates for greater clarity.
Section 1271.21(c) now contains timeframes for updating. Section
1271.25(c) lists the changes that must be reported. The listed events
to be reported have been corrected to reflect the type of information
required to be included in the initial listing. Thus, for example, just
as a listing includes the names of HCT/P's that an establishment
recovers, processes, stores, labels, packages, distributes, or for
which it performs donor screening or testing, so the updated listing
would reflect any changes in the HCT/P's for which any of these
activities are performed.
We have made an additional change to proposed Sec. 1271.25(c),
which would have required that copies of all contract service
agreements be available at the time of inspection of the establishment.
In order to avoid duplicating a similar requirement proposed in the GTP
regulations, we have deleted the requirement from Sec. 1271.25(c).
(Comment 38) We earlier stated that we were developing an
electronic version of Form FDA 3356 (registration proposed rule, 63 FR
26750). One comment strongly supported these efforts and asserted that
manufacturers should also be able to submit registration and listing
information electronically.
We understand that it would be convenient to submit registration
and listing information electronically over the Internet. We intend to
rely on our experience in developing electronic submission capability
in other areas (e.g., biological product deviations in manufacturing
reports) to develop an electronic submission process for HCT/P
registration and listing. When electronic submissions of Form FDA 3356
are possible, we will make an announcement to that effect.
(Comment 39) Two comments disagreed with the requirement proposed
in Sec. 1271.25(a)(4) for a statement affirming the truth and accuracy
of all information in the registration and listing form. The comments
argued that no similar requirement exists in the registration and
listing regulations for drugs and devices, parts 207 and 807. The
comments proposed that, if the requirement is maintained, the statement
be qualified with a phrase such as ``to the best of my knowledge.''
To be of use, information submitted on the registration and listing
form must be truthful and accurate. Moreover, the reporting official
who completes and signs the form should be aware of the obligation to
report truthfully and accurately. Although, as the comment points out,
the registration and listing regulations for drugs and devices do not
contain a similar statement, the act specifically prohibits the
submission of false or misleading reports with respect to any device
(section 301(q)(2) of the act (21 U.S.C. 331(q)(2)). Furthermore, a
willfully false statement to a Federal agency is a criminal offense,
and it is not uncommon for forms submitted to the agency to so note (18
U.S.C. 1001).
For these reasons, we are maintaining the requirement for a
statement affirming the truth and accuracy of the information submitted
on the registration and listing form. However, the reporting official
may reasonably obtain the reported information from reliable sources
rather than firsthand. For this reason, we believe it is reasonable to
modify the required statement with the language ``to the best of my
knowledge.'' We have made this change to the regulation and to the
form.
(Comment 40) Two comments questioned the requirement proposed in
Sec. 1271.25(b) for a statement of whether each listed product meets
the criteria set out in Sec. 1271.10. One comment queried whether we
plan to regard this statement as an admission that a product is or is
not a 361 HCT/P. This comment suggested the addition of language
consistent with that of other product registration and listing
regulations clarifying that registration and listing under part 1271
does not constitute such an admission of product regulatory status.
Both comments noted that only the statement is required, not an
explanation or summary of why a product does or does not meet the
criteria or which criteria are not met.
The categorization of HCT/P's as 361 HCT/P's or as drugs, devices,
and/or biological products is a fundamental component of the new
tiered, risk-based system. We are requiring this information for each
HCT/P type to help us understand the HCT/P industry. Establishments
need to know how their products are regulated in order to comply with
appropriate requirements; therefore, the information required should be
readily available. We understand that there may be instances where an
establishment is unsure into which category its HCT/P falls; the
establishment should contact the executive secretariat of the TRG in
these situations. (For more information on the TRG, see CBER's website
at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cber/tissue/trg.htm.)
The requirement in Sec. 1271.25(b) is for a statement only, not an
explanation. The statement will inform the agency of the manufacturer's
opinion, but will not be an ``admission'' with respect to how an HCT/P
will be regulated. To be regulated solely under section 361 of the PHS
Act and part 1271, an HCT/P must meet the criteria set forth under
Sec. 1271.10.
(Comment 41) Two comments requested that we clarify whether
individual sizes or configurations of tissues should be listed
separately, or instead under more general headings. One of these
comments questioned whether a ``new'' product would include a new size
of a product.
The information currently required on the registration and listing
form is of a more general nature. Because the form does not ask for
sizes, a new product would not include a new product size.
(Comment 42) One comment encouraged the use of standard product
names for hematopoietic progenitor cell therapies in order to make
product listing consistent.
We encourage the development of standard names. However, at this
point we are requesting more general information on Form FDA 3356. In
the
[[Page 5462]]
future, we may ask for more detailed information.
(Comment 43) One comment recommended that required listing
information include, with respect to each listed type of tissue, the
specific manufacturing activities conducted at each registered
establishment.
To simplify the registration and listing form, we are not asking
for specific manufacturing information for each product but for the
establishment in general. If there is a need, we may possibly ask for
more specific information in the future.
(Comment 44) One comment questioned whether the addition of an
adjacent building with a different address would be considered a new
location, requiring an amendment to registration under Sec. 1271.26.
No. Adding an adjacent building would not require an amendment to
registration.
(Comment 45) No comments were received on proposed Sec. 1271.27,
which deals with the assignment of a registration number. We wish,
however, to note that establishments that are currently registered
under the drug or device registration and listing requirements, and who
would in the future register and list using the procedures in part
1271, when that part is fully effective, would keep the same
registration number that was issued previously. Those establishments
should provide that number to us when registering for the first time
using the new procedures.
(Comment 46) One comment supported the release of registration and
listing information under Sec. 1271.37, but questioned how we would
determine which information to disclose to the public.
The information submitted on Form FDA 3356 is not proprietary or
confidential in nature and may be released to the public. Section
1271.37(a)(4) notes that the agency may also release all data or
information that has already become a matter of public record. The
agency will follow the procedures and requirements set out in 21 CFR
part 20 to determine which information has become a matter of public
record and may be released.
F. Comments on the Proposed Amendments to Secs. 207.20 and 807.20
(Comment 47) No comments were submitted on the proposed amendments
to Secs. 207.20 and 807.20.
We have modified the language proposed for Secs. 207.20(f) and
807.20(e) to clarify that establishments that manufacture HCT/P's
regulated as devices, drugs, and/or biological products will register
and list their products following the procedures in part 1271 instead
of the procedures in parts 207 and 807. Thus, when this rule is
effective for HCT/P's regulated as devices, drugs, and or biological
products, these establishments will submit Form FDA 3356 according to
the procedures set out in subpart B of part 1271, at the same time as
other cell and tissue establishments, and will no longer have to submit
other registration and listing forms. We have also renumbered proposed
Sec. 807.20(e) as Sec. 807.20(d).
The effective date of Secs. 207.20(f) and 807.20(d) is 2 years
after the publication of this rule.
G. Comments on the Registration and Listing Form (Form FDA 3356)
We asked nine manufacturers to participate in a pilot study to
evaluate FDA Form 3356 in draft form, as allowed by the Office of
Management and Budget (OMB) before we finalized the paperwork burden
analysis. The pilot study had two purposes: To evaluate the ease of use
of Form FDA 3356, and to validate the data base software developed for
FDA under contract. The pilot study took place in May 1998, and in
August 1998 we submitted to the docket a summary of the results of the
study.
Six of the participating establishments noted that the draft form
was easy to use and required less than 1 hour to complete. Other
comments on the form noted several areas of potential confusion. We
have addressed many of these issues elsewhere in this document, in
response to comments submitted to the docket. We have addressed other
issues by modifying the instructions for completing the form.
We have made minimal changes to Form FDA 3356 and its instructions
to conform to the revised requirements in part 1271, subpart B. We have
not added any additional information requirements.
IV. Analysis of Economic Impacts
FDA has examined the impacts of the rule under Executive Order
12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612) as amended
by subtitle D of the Small Business Regulatory Fairness Act of 1996
(Public Law 104-121) and under the Unfunded Mandates Reform Act of 1995
(Public Law 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 agency believes the final rule is consistent with the
regulatory philosophy and principles identified in the Executive Order.
OMB has determined that the final rule is a significant action as
defined in Executive Order 12866.
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 one year. We have
also determined that this rule will not result in aggregate
expenditures for State, local, and tribal governments, or the private
sector of $100 million in any one year (adjusted for inflation).
An analysis of available information suggests that costs to the
entities most affected by this rule, including small entities, are not
expected to 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 Action
This action is a first step in the regulation of the rapidly
evolving industry of human cells and tissue. The entire industry has
not been previously regulated under a single 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 human cells, tissues, and cellular and
tissue-based products (HCT/P's) that are used by the industry. The rule
will require all manufacturers of HCT/P's to register with the agency
and to submit to the agency a list of their HCT/P's. Through
registration and listing, FDA will be able to identify industry
participants and the scope of the HCT/P's produced. 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 FDA oversight. This action is taken
solely under the authority of section 361 of the PHS Act. Section 361
of the PHS
[[Page 5463]]
Act is also used as authority to amend parts 207 and 807 so that the
registration and data bases for all human cells, tissues, and cellular
and tissue-based products may be consolidated. FDA has reviewed related
Federal rules and has not identified any rules that duplicate, overlap,
or conflict with the rule.
B. Small Entities Affected
This rule affects both establishments that currently register with
FDA and submit product lists to the agency under applicable sections of
the act (parts 207 and 807), and those establishments that are not
presently required to register or list with the agency. FDA has
structured registration and listing for HCT/P's to have a minimal
impact on affected establishments. However, the agency anticipates that
the impact will be greater for those establishments that do not
currently register or list. Because the final rule is effective 75 days
after publication of this document for those establishments currently
regulated under part 1270, and is effective in 2 years for all other
HCT/P establishments, the economic impact on the industry will be
staggered.
The total number of establishments that are required to register
and list under part 1271 in 2 years after the publication of this rule
is estimated to be 1,225. The registration and listing initiative will,
in part, help the agency obtain more accurate numbers of HCT/P's
establishments. In calculating the burden, the agency has relied on
information obtained from trade organizations related to the human
cells, tissue, and cellular and tissue-based products industry, several
of which also provided estimates of what portion of the industry their
membership represented. Along with this information and from our own
research, we determined that 65 manufacturers of human cells, tissue,
and cellular and tissue-based products are registered with the agency
as required by part 807. The agency also determined that one
manufacturer of an HCT/P drug is registered as required by part 207
According to the U.S. Small Business Administration, a tissue bank
is a small entity if it has annual revenues less than $5 million. FDA
estimates that 110 tissue banks are involved in the manufacture of
conventional tissue and that approximately 77.5 percent (or 85) of
these banks are small entities. FDA estimates that there are 425 stem
cell facilities (400 peripheral blood stem cell facilities and 25 cord
blood facilities), and that all are small entities. FDA estimates that
approximately 114 eye banks are currently operating in the United
States, and industry experts estimate that virtually all facilities
would be classified as small. FDA estimates that there are
approximately 400 assisted reproductive technology (ART) facilities.
This estimate is consistent with industry comments. Consultants
estimate that two-thirds of all ART facilities (or 267 establishments)
would be classified as small entities. In addition, the American
Society of Reproductive Medicine (ASRM) has a 1996 list of
approximately 110 sperm banks operating in the U.S. Information about
sperm banks from a report by Eastern Research Group (ERG) indicates
that 95 percent (or 105) of these sperm banks are small. Thus,
approximately 996 (85 + 425 + 114 + 267 + 105) of all 1,225
establishments would be considered small entities. In addition, 66
establishments are currently regulated as drugs, devices, or biological
products under parts 207 and 807. Approximately 90 percent of these (or
60 establishments) are small entities. Therefore, we estimate that a
total 1,056 establishments (996 + 60) are small entities.
C. Nature of the Impact
The main cost in implementing this final rule is staff time, which
we estimate to cost $38.00 per hour, based on 1997 Bureau of Labor
Statistics estimates.
Out of a total 1,225 establishments affected by this rule, 66 HCT/P
drug and device establishments currently submit registration and
product listing information under parts 207 and 807. In the proposed
rule, we incorrectly estimated both the time and the scope of annual
information collection for these establishments. Our estimate
inaccurately lumped the submission of all required information into one
year and concluded that 2 hours would be needed annually to register
and list initially, submit a subsequent annual registration, update
HCT/P listings, and amend ownership or location information.
As proposed, however, this final rule requires that HCT/P drug and
device manufacturers use a new, single form to register and list their
HCT/P products. This rule does not impose any new registration or
listing requirements for establishments regulated under parts 207 and
807. To avoid duplication, the rule provides HCT/P drug and device
manufacturers a single, new form to replace the multiple forms
currently required under parts 207 and 807. Therefore, we now estimate
only the time needed to transition from the use of multiple forms to
the use of the one form. Based on results from the pilot study
described above in section III.G of this document, we estimate that
establishments will need approximately 0.5 hour to transition to Form
FDA 3356 at a one-time transition cost of approximately $19 [$38 x
0.5]. We estimate that the total impact for all 66 establishments will
be approximately $1,254 [66 x $38 x 0.5].
For the 1,159 HCT/P manufacturers not regulated under parts 207 and
807, the costs are based upon the staff time needed to obtain the form,
read the instructions, and complete and submit the form for the initial
registration and HCP/T listing, subsequent annual registration, and, as
needed, listing updates and location/ownership amendments. Based on the
pilot study described above, FDA estimates that it will take an average
of 0.75 hour of staff time per establishment for the initial
submission. At $38.00 per hour of staff time, each establishment is
expected to incur an initial one-time cost of approximately $28 [$38 x
0.75]. We estimate the total impact for all 1,159 establishments for
the submission of initial registration and HCT/P listing to be
approximately $33,032 [1,159 x $38 x 0.75].
After the initial registration, the final rule requires annual
registration, which we estimate will take 0.5 hour to complete and
submit to FDA. We estimate that the annual cost of these submissions
will be approximately $22,021 [1,159 x $38 x 0.5] or $19 per
establishment.
The final rule also requires HCT/P listing updates twice a year, a
submission that is required only when a change has been made since the
previous listing submission. FDA assumes that in any given year, 5
percent or 58 of the 1,159 establishments [1,159 x 0.05] will submit
one listing. The listing update is estimated to take about 0.5 hours to
complete and submit to FDA. We estimate that each establishment will
incur an annual cost of approximately $19 [$38 x 0.5], for a total of
$1,102 for all 58 establishments.
The rule also requires changes in ownership or location to be
reported as an amendment within 5 days of such changes. FDA expects
that this will be a rare event and that in any given year, no more than
5 percent or 58 of the 1,159 establishments [1,159 x 0.05] will change
location or ownership and submit an amendment. This amendment is
estimated to take 0.25 hours of staff time. We estimate that each
establishment will incur a cost of approximately $10 [$38 x 0.25],
totaling $580 for all 58 establishments.
[[Page 5464]]
In sum, we estimate the total annual for all submissions subsequent
to the initial registration and listing (annual registration and, as
needed, listing updates and location/ownership amendments) to be
$23,702 [$22,021 + $1,101 + $580].
There are no specific educational or technical skills required to
complete and submit the registration and listing form. Trained and
qualified employees of an establishment who are involved with its
operations generally complete similar activities.
This final rule is the first step in creating a tiered, risk-based
regulatory scheme that will tailor the degree of scrutiny afforded to
different HCT/P's to the risks associated with each of them. Through
registration and listing, FDA will acquire the information needed to
characterize the nature and extent of HCT/P's. This information will
enable FDA to efficiently and effectively respond to emerging public
health concerns related to human cells or tissue. Lists of industry
members and their HCT/P's 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 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 will consider
the use of electronic submissions (e-mail or Internet) and electronic
signatures.
V. 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.
VI. Federalism
FDA has analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. FDA has determined that the rule
does not contain policies that have substantial direct effects on the
States, on the relationship between National Government and the States,
or on the distribution of power and responsibilities among the various
levels of government. Accordingly, the agency has concluded that the
rule does not contain policies that have federalism implications as
defined in the order and, consequently, a federalism summary impact
statement is not required.
VII. The Paperwork Reduction Act of 1995
This final 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 (PRA) (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 initial
one-time reporting burden and the annual reporting burden. Included in
the estimate is the time for reviewing the instructions, searching
existing data sources, gathering and maintaining the data needed,
completing and reviewing each collection of information.
Title: Establishment Registration and Listing Requirements for
Human Cells, Tissues, and Cellular and Tissue-Based Products.
Description: The final rule requires establishments that recover,
process, store, label, package, or distribute any human cell, tissue,
and cellular and tissue-based product (HCT/P), or that perform donor
screening or testing, to submit an initial establishment registration
and HCT/P list to FDA. Subsequently, establishments must submit an
annual update to their establishment registration. In addition,
establishments are required to submit HCT/P list updates, if any, and
amendments whenever an establishment changes ownership or locations.
FDA provides a registration and listing form (Form FDA 3356) to
facilitate the ease and speed of submissions. Form FDA 3356 is an
approved information collection format under OMB control number 0910-
0372. The approval expires July 31, 2001.
Description of Respondents: Establishments that recover, process,
store, label, package, or distribute any human cells, tissue, and
cellular and tissue-based product.
As required by section 3506(c)(2)(B) of the PRA, FDA provided an
opportunity for public comment on May 14, 1998 (63 FR 26744), on the
information collection requirements of the proposed rule.
Table 1 of this document lists the estimated one-time reporting
burden for the initial establishment registration and HCT/P listing,
which is required under Sec. 1271.10(b). Section 1271.25(a) and (b)
identify the initial establishment and HCT/P listing information
required. Sections 207.20(f) and 807.20(d) require HCT/P establishments
to use Form FDA 3356 for providing registration and listing information
required under parts 207 and 807.
Table 2 of this document provides the estimate of the ongoing
annual reporting burden for establishment registration. In addition,
table 2 of this document sets out estimated reporting burdens for HCT/P
listing updates and establishment location or ownership amendments that
would occur during any given year. If there is no change to an HCT/P
listing, establishment location or ownership, a submission is not
required.
Sections 1271.21(b) and 1271.10(b) require the annual establishment
registration by domestic and foreign HCT/P establishments that are
solely regulated under section 361 of the PHS Act and this part.
Sections 1271.21(c)(ii), 1271.25(c), and 1271.10(b) require
domestic and foreign HCT/P establishments to submit HCT/P listing
updates only when an HCT/P is changed, added, or discontinued, and when
there has been a material change to information submitted previously to
the agency. If no change has occurred since the previous submission, an
update is not required.
Sections 1271.26 and 1271.10(b) require domestic and foreign HCT/P
establishments to submit an amendment, but only when the establishment
makes a change in location or ownership.
Sections 207.20, 207.26, 207.30, 807.20, 807.26, and 807.30 already
require establishments that manufacture drug or device products to
submit initial establishment registration and product listing, as well
as annual establishment registration, product listing updates, and
location and ownership amendments. This final rule adds Secs. 207.20(f)
and 807.20(d), which require that manufacturers of HCT/P drugs and
devices submit this registration and listing information using Form FDA
3356 instead of the multiple forms identified under parts 207 and 807.
Therefore, these establishments will incur only a one-time burden to
transition from the use of several forms to the use of one form (see
table 1 above). This rule adds no new registration and listing
requirements.
[[Page 5465]]
This final rule is implemented according to the staggered effective
dates. Human tissues intended for transplantation that are currently
regulated under section 361 of the PHS Act and part 1270 are required
to register with the agency and list their HCT/P's within 5 days of the
first effective date. The effective date for all other HCT/P's is 2
years after publication of this rule in the Federal Register, about
which time we expect that the remaining subparts of part 1271 will
become effective.
In the proposed rule, FDA underestimated the number of respondents.
Based on additional information provided to FDA by industry
representatives, trade organizations, and professional societies, we
have revised our estimate of establishments to approximately 1,225
(i.e., approximately 110 conventional tissue, 114 eye tissue banks, 400
peripheral blood stem cells, 25 stem cell products from cord blood, 400
reproductive tissue, 110 sperm banks, and 66 licensed biological
products and approved devices).
Our burden estimates for the annual frequency per response and
average hours per response are based on institutional experience with
comparable reporting provisions for drugs, including biological
products, and devices, information from industry representatives and
trade organizations, and data provided by the Eastern Research Group
(ERG), a consulting firm hired by FDA to prepare an economic analysis
of the potential economic impact on sperm banks and other reproductive
tissue facilities.
In the final rule, we have separated the initial, one-time
reporting requirements (table 1 of this document) from the subsequent
ongoing annual establishment registration, HCT/P updates and amendment
requirements (table 2 of this document).
Table 1 of this document provides the initial, one-time estimated
burden for HCT/P establishment registration and HCT/P listing. This
information may be submitted simultaneously on the same form, Form FDA
3356. We estimate that 0.75 hour of staff time will be needed for each
initial submission. This estimate is based on a pilot program described
above in section III.G of this document conducted to evaluate Form FDA
3356.
In table 1 of this document we also include the one-time burden for
HCT/P drug and device manufacturers regulated under parts 207 and 807.
Parts 207 and 807 require that drug and device manufacturers submit
initial establishment registration and product listing, annual
establishment registration, product listing updates, and location/
ownership amendments. New Secs. 207.20(f) and 807.20(d) change only the
reporting format and require use of only one form, new Form FDA 3356,
in place of the multiple forms currently required, i.e., Forms FDA-2656
and FDA-2657 for drug manufacturers, and Forms FDA-2891, FDA-2891(a),
and FDA-2892 for device manufacturers. Therefore, the one-time
reporting burden estimate for Secs. 207.20(f) and 807.20(d) in table 1
of this document reflects only the time necessary to transition from
the use of current multiple forms to the use of Form FDA 3356. In the
proposed rule, we incorrectly included the time needed to submit the
registration and listing information already required under parts 207
and 807. As revised here, the reporting burden under new
Secs. 207.20(f) and 807.20(d) reflects only the time necessary to
transition from the use of current multiple forms to the use of Form
FDA 3356.
Table 2 of this document shows more accurately than in the proposed
rule that on-going annual registration, updates and amendments require
0.50 hour, while the initial submission requires on average 0.75 hour.
In addition, table 2 of this document shows that the average hours per
response is less for the HCT/P listing updates and location/ownership
amendments, which are required only when a change is made, than for the
annual registration, which must be submitted every year. In table 2 of
this document, we also estimate that approximately 5 percent of the
1,159 establishments, or 58 establishments, will make changes to HCT/
P's, location, or ownership in any one year after the initial
registration and listing. Based on additional information from industry
representatives and from our own experiences, we estimate that annual
registration, HCT/P listing updates, and location/ownership amendments
will require 0.5, 0.5, and 0.25 hours, respectively, as opposed to the
full hour estimated for every establishment submission in the proposed
rule. The greater precision afforded by this breakout shows that,
despite the increased number of total estimated respondents, the
estimated total burden hours is lower than in the proposed rule. In
table 2 of this document, the total annual burden of 623 hours for
ongoing reporting is slightly less than the initial, one-time reporting
burden total of 902.25 hours in table 1 of this document.
FDA estimates the burden of this collection of information as
follows:
Table 1.--Estimated Initial (One-Time) Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
Annual Hours per
21 CFR No. of frequency per Total annual response Total hours
respondents response responses (average)
----------------------------------------------------------------------------------------------------------------
207.20(f) 1 1 1 0.5 0.5
807.20(d) 65 1 65 0.5 32.50
Initial Registration and HCT/P 1,159 1 1,159 0.75 869.25
Listing 1271.25(a), with
1271.25(b) and 1271.10(b)
TOTAL 902.25
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
Table 2.--Estimated Annual Reporting Burden \2\
----------------------------------------------------------------------------------------------------------------
Annual Hours per
21 CFR No. of frequency per Total annual response Total hours
respondents response responses (average)
----------------------------------------------------------------------------------------------------------------
Annual Registration 1,159 1 1,159 0.5 579.50
1271.21(b) and 1271.10(b)
HCT/P Listing Update 58 1 58 0.5 29.00
1271.21(c), 1271.25(c), and
1271.10(b)
[[Page 5466]]
Location/Ownership Amendment 58 1 58 0.25 14.50
1271.26 and 1271.10(b)
TOTAL 623
----------------------------------------------------------------------------------------------------------------
\2\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
Individuals and organizations may submit comments on these burden
estimates or on any other aspect of these information collection
requirements, including suggestions for reducing the burden. Comments
should be directed to the Food and Drug Administration, Center for
Biologics Evaluation and Research, Tissue Establishment Registration
Coordinator (HFM-305), 1401 Rockville Pike, suite 200N, Rockville, MD
20852.
The information collection requirements of the final rule have been
submitted to OMB for review. Prior to the effective date of the final
rule, FDA will publish a document in the Federal Register announcing
OMB's decision to approve, modify, or disapprove the information
collection requirements in the final rule. An agency may not conduct or
sponsor, and a person is not required to respond to, a collection of
information unless it displays a currently valid OMB control number.
VIII. References
The following references have been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
1. Vice President's National Performance Review report,
``Reinventing the Regulation of Human Tissue,'' February 1997.
2. Schipper, R. F., D'Amaro, J., and Oudshoorn, M., ``The
Probability of Finding a Suitable Related Donor for Bone Marrow
Transplantation in Extended Families,'' Blood, 87:800-804, 1996.
3. Kaufman, R., ``A Generalized HLA Prediction Model for Related
Donor Matches,'' Bone Marrow Transplantation, 17:1013-1020, 1996.
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 cells, Reporting and recordkeeping requirements, tissue-based
products.
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, chapter I of title 21 of the Code of
Federal Regulations is 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, 360, 360b, 371,
374; 42 U.S.C. 262, 264, 271.
2. Section 207.20 is amended by revising the heading and adding
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 cells, tissues, and cellular and tissue-based products, as
defined in Sec. 1271.3(d) of this chapter, that are regulated under
section 351 of the Public Health Service Act and/or the Federal Food,
Drug, and Cosmetic Act must register and list those human cells,
tissues, and cellular and tissue-based 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, instead
of the procedures for registration and listing contained in this part,
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 revising the heading and adding
paragraph (d) to read as follows:
Sec. 807.20 Who must register and submit a device list?
* * * * *
(d) Owners and operators of establishments or persons engaged in
the recovery, screening, testing, processing, storage, or distribution
of human cells, tissues, and cellular and tissue-based products, as
defined in Sec. 1271.3(d) of this chapter, that are regulated under the
Federal Food, Drug, and Cosmetic Act must register and list those human
cells, tissues, and cellular and tissue-based 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, instead
of the procedures for registration and listing contained in this part,
except that the additional listing information requirements of
Sec. 807.31 remain applicable.
5. Part 1271 is added to read as follows:
PART 1271--HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED
PRODUCTS
Subpart A--General Provisions
Sec.
1271.1 What are the purpose and scope of this part?
1271.3 How does FDA define important terms in this part?
1271.10 Are my HCT/P's regulated solely under section 361 of the
PHS Act and the regulations in this part, and if so what must I do?
1271.15 Are there any exceptions from the requirements of this
part?
1271.20 If my HCT/P's do not meet the criteria in Sec. 1271.10, and
I do not qualify
[[Page 5467]]
for any of the exceptions in Sec. 1271.15, what regulations apply?
Subpart B--Procedures for Registration and Listing
1271.21 When do I register, submit an HCT/P list, and submit
updates?
1271.22 How and where do I register and submit an HCT/P list?
1271.25 What information is required for establishment registration
and HCT/P listing?
1271.26 When must I amend my establishment registration?
1271.27 Will FDA assign me a registration number?
1271.37 Will establishment registrations and HCT/P listings be
available for inspection, and how do I request information on
registrations and listings?
Authority: 42 U.S.C. 216, 243, 264, 271.
Subpart A--General Provisions
Sec. 1271.1 What are the purpose and scope of this part?
(a) Purpose. The purpose of this part, in conjunction with
Secs. 207.20(f), 210.1(c), 210.2, 807.20(d), and 820.1(a) of this
chapter, is to create a unified registration and listing system for
establishments that manufacture human cells, tissues, and cellular and
tissue-based products (HCT/P's) and to establish donor-suitability,
current good tissue practice, and other procedures to prevent the
introduction, transmission, and spread of communicable diseases by HCT/
P's.
(b) Scope. (1) If you are an establishment that manufactures HCT/
P's that are regulated solely under the authority of section 361 of the
Public Health Service Act (the PHS Act), this part requires you to
register and list your HCT/P's with the Food and Drug Administration's
(FDA's) Center for Biologics Evaluation and Research and to comply with
the other requirements contained in this part, whether or not the HCT/P
enters into interstate commerce. Those HCT/P's that are regulated
solely under the authority of section 361 of the PHS Act are described
in Sec. 1271.10.
(2) If you are an establishment that manufactures HCT/P's that are
regulated as drugs, devices and/or biological products under section
351 of the PHS Act and/or the Federal Food, Drug, and Cosmetic Act,
Secs. 207.20(f) and 807.20(d) of this chapter require you to register
and list your HCT/P's following the procedures in subpart B of this
part. Sections 210.1(c), 210.2, 211.1(b), and 820.1(a) of this chapter
require you to comply with the donor-suitability procedures in subpart
C of this part and the current good tissue practice procedures in
subpart D of this part, in addition to all other applicable
regulations.
Sec. 1271.3 How does FDA define important terms in this part?
The following definitions apply only to this part:
(a) Autologous use means the implantation, transplantation,
infusion, or transfer of human cells or tissue back into the individual
from whom the cells or tissue were recovered.
(b) Establishment means a place of business under one management,
at one general physical location, that engages in the manufacture of
human cells, tissues, and cellular and tissue-based products.
``Establishment'' includes:
(1) Any individual, partnership, corporation, association, or other
legal entity engaged in the manufacture of human cells, tissues, and
cellular and tissue-based products; and
(2) Facilities that engage in contract manufacturing services for a
manufacturer of human cells, tissues, and cellular and tissue-based
products.
(c) Homologous use means the replacement or supplementation of a
recipient's cells or tissues with an HCT/P that performs the same basic
function or functions in the recipient as in the donor.
(d)(1) Human cells, tissues, or cellular or tissue-based products
(HCT/P's) means any human tissue derived from a human body and intended
for transplantation into another human, as defined under
Sec. 1270.3(j). Examples of HCT/P's include, but are not limited to,
bone, ligament, skin, and cornea.
(2) Human cells, tissues, or cellular or tissue-based products
(HCT/P's) means articles containing or consisting of human cells or
tissues that are intended for implantation, transplantation, infusion,
or transfer into a human recipient. Examples of HCT/P's include, but
are not limited to, bone, ligament, skin, dura mater, heart valve,
cornea, hematopoietic stem cells derived from peripheral and cord
blood, manipulated autologous chondrocytes, epithelial cells on a
synthetic matrix, and semen or other reproductive tissue. The following
articles are not considered HCT/P's:
(i) Vascularized human organs for transplantation;
(ii) Whole blood or blood components or blood derivative products
subject to listing under parts 607 and 207 of this chapter,
respectively;
(iii) Secreted or extracted human products, such as milk, collagen,
and cell factors; except that semen is considered an HCT/P;
(iv) Minimally manipulated bone marrow for homologous use and not
combined with a drug or a device (except for a sterilizing, preserving,
or storage agent, if the addition of the agent does not raise new
clinical safety concerns with respect to the bone marrow);
(v) Ancillary products used in the manufacture of HCT/P;
(vi) Cells, tissues, and organs derived from animals other than
humans; and
(vii) In vitro diagnostic products as defined in Sec. 809.3(a) of
this chapter.
(e) Manufacture means, but is not limited to, any or all steps in
the recovery, processing, storage, labeling, packaging, or distribution
of any human cell or tissue, and the screening or testing of the cell
or tissue donor.
(f) 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 or nonstructural tissues, processing that does not
alter the relevant biological characteristics of cells or tissues.
(g) Transfer means the placement of human reproductive cells or
tissues into a human recipient.
Sec. 1271.10 Are my HCT/P's regulated solely under section 361 of the
PHS Act and the regulations in this part, and if so what must I do?
(a) An HCT/P is regulated solely under section 361 of the PHS Act
and the regulations in this part if it meets all of the following
criteria:
(1) The HCT/P is minimally manipulated;
(2) The HCT/P is intended for homologous use only, as reflected by
the labeling, advertising, or other indications of the manufacturer's
objective intent;
(3) The manufacture of the HCT/P does not involve the combination
of the cell or tissue component with a drug or a device, except for a
sterilizing, preserving, or storage agent, if the addition of the agent
does not raise new clinical safety concerns with respect to the HCT/P;
and
(4) Either:
(i) The HCT/P does not have a systemic effect and is not dependent
upon the metabolic activity of living cells for its primary function;
or
(ii) The HCT/P has a systemic effect or is dependent upon the
metabolic activity of living cells for its primary function, and:
(a) Is for autologous use;
(b) Is for allogeneic use in a first-degree or second-degree blood
relative; or
(c) Is for reproductive use.
[[Page 5468]]
(b) If you are a domestic or foreign establishment that
manufactures an HCT/P described in paragraph (a) of this section:
(1) You must register with FDA;
(2) You must submit to FDA a list of each HCT/P manufactured; and
(3) You must comply with the other requirements contained in this
part.
Sec. 1271.15 Are there any exceptions from the requirements of this
part?
(a) You are not required to comply with the requirements of this
part if you are an establishment that uses HCT/P's solely for
nonclinical scientific or educational purposes.
(b) You are not required to comply with the requirements of this
part if you are an establishment that removes HCT/P's from an
individual and implants such HCT/P's into the same individual during
the same surgical procedure.
(c) You are not required to comply with the requirements of this
part if you are a carrier who accepts, receives, carries, or delivers
HCT/P's in the usual course of business as a carrier.
(d) You are not required to comply with the requirements of this
part if you are an establishment that does not recover, screen, test,
process, label, package, or distribute, but only receives or stores
HCT/P's solely for implantation, transplantation, infusion, or transfer
within your facility.
(e) You are not required to comply with the requirements of this
part if you are an establishment that only recovers reproductive cells
or tissue and immediately transfers them into a sexually intimate
partner of the cell or tissue donor.
(f) You are not required to register or list your HCT/P's
independently, but you must comply with all other applicable
requirements in this part, if you are an individual under contract,
agreement, or other arrangement with a registered establishment and
engaged solely in recovering cells or tissues and sending the recovered
cells or tissues to the registered establishment.
Sec. 1271.20 If my HCT/P's do not meet the criteria in Sec. 1271.10,
and I do not qualify for any of the exceptions in Sec. 1271.15, what
regulations apply?
If you are an establishment that manufactures an HCT/P that does
not meet the criteria set out in Sec. 1271.10(a), and you do not
qualify for any of the exceptions in Sec. 1271.15, your HCT/P will be
regulated as a drug, device, and/or biological product under the act
and/or section 351 of the PHS Act, and applicable regulations in title
21, chapter I. Applicable regulations include, but are not limited to,
Secs. 207.20(f), 210.1(c), 210.2, 211.1(b), 807.20(d), and 820.1(a) of
this chapter, which require you to follow the procedures in subparts B,
C, and D of this part.
Subpart B--Procedures for Registration and Listing
Sec. 1271.21 When do I register, submit an HCT/P list, and submit
updates?
(a) You must register and submit a list of every HCT/P that your
establishment manufactures within 5 days after beginning operations or
within 30 days of the effective date of this regulation, whichever is
later.
(b) You must update your establishment registration annually in
December, except as required by Sec. 1271.26. You may accomplish your
annual registration in conjunction with updating your HCT/P list under
paragraph (c) of this section.
(c)(i) If no change described in Sec. 1271.25(c) has occurred since
youpreviously submitted an HCT/P list, you are not required to update
your listing.
(ii) If a change described in Sec. 1271.25(c) has occurred, you
must update your HCT/P listing with the new information:
(a) At the time of the change, or
(b) Each June or December, whichever month occurs first after the
change.
Sec. 1271.22 How and where do I register and submit an HCT/P list?
(a) You must use Form FDA 3356 for:
(i) Establishment registration,
(ii) HCT/P listings, and
(iii) Updates of registration and HCT/P listing.
(b) You may obtain Form FDA 3356:
(i) By writing to the Center for Biologics Evaluation and Research
(HFM-305), Food and Drug Administration, 1401 Rockville Pike,
Rockville, MD 20852-1448, Attention: Tissue Establishment Registration
Coordinator;
(ii) By contacting any Food and Drug Administration district
office;
(iii) By calling the CBER Voice Information System at 1-800-835-
4709 or 301-827--1800;
(iv) By calling the Fax Information System at 1-888-CBER-FAX or
301-827-3844; or
(v) By connecting to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://forms.psc.gov/forms/FDA/fda.html on the
Internet.
(c)(i) You may submit Form FDA 3356 to the Center for
BiologicsEvaluation and Research (HFM-305), Food and Drug
Administration, 1401 Rockville, Pike, Rockville, MD 20852-1448,
Attention: Tissue Establishment Registration Coordinator; or
(ii) You may submit Form FDA 3356 electronically in accordance with
the instructions provided with the form.
Sec. 1271.25 What information is required for establishment
registration and HCT/P listing?
(a) Your establishment registration Form FDA 3356 must 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 dated signature by the reporting official affirming that all
information contained in the establishment registration and HCT/P
listing form is true and accurate, to the best of his or her knowledge.
(b) Your HCT/P listing must include all HCT/P's (including the
established name and the proprietary name) that you recover, process,
store, label, package, distribute, or for which you perform donor
screening or testing. You must also state whether each HCT/P meets the
criteria set out in Sec. 1271.10.
(c) Your HCT/P listing update must include:
(1) A list of each HCT/P that you have begun recovering,
processing, storing, labeling, packaging, distributing, or for which
you have begun donor screening or testing, that has not been included
in any list previously submitted. You must provide all of the
information required by Sec. 1271.25(b) for each new HCT/P.
(2) A list of each HCT/P formerly listed in accordance with
Sec. 1271.21(a) for which you have discontinued recovery, processing,
storage, labeling, packaging, distribution, or donor screening or
testing, including for each HCT/P so listed, the identity by
established name and proprietary name, and the date of discontinuance.
We request but do not require that you include the reason for
discontinuance with this information.
(3) A list of each HCT/P for which a notice of discontinuance was
submitted under paragraph (c)(2) of this section and for which you have
resumed recovery, processing, storage, labeling, packaging,
distribution, or donor screening or testing, 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.
(4) Any material change in any information previously submitted.
Material changes include any change in information submitted on Form
FDA 3356, such as whether the HCT/P meets the criteria set out in
Sec. 1271.10.
[[Page 5469]]
Sec. 1271.26 When must I amend my establishment registration?
If the ownership or location of your establishment changes, you
must submit an amendment to registration within 5 days of the change.
Sec. 1271.27 Will FDA assign me a registration number?
(a) FDA will assign each location a permanent registration number.
(b) FDA acceptance of an establishment registration and HCT/P
listing form does not constitute a determination that an establishment
is in compliance with applicable rules and regulations or that the HCT/
P is licensed or approved by FDA.
Sec. 1271.37 Will establishment registrations and HCT/P listings be
available for inspection, and how do I request information on
registrations and listings?
(a) A copy of the Form FDA 3356 filed by each establishment will be
available for public 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 HCT/P requirements is
illustrative of the type of information that will be available for
public disclosure when it is compiled:
(1) A list of all HCT/P's;
(2) A list of all HCT/P's manufactured by each establishment;
(3) A list of all HCT/P's discontinued; and
(4) All data or information that has already become a matter of
public record.
(b) You should direct your requests for information regarding HCT/P
establishment registrations and HCT/P listings 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: January 2, 2001.
Jane E. Henney,
Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 01-1126 Filed 1-18-01; 8:45 am]
BILLING CODE 4160-01-F