[Federal Register Volume 66, Number 13 (Friday, January 19, 2001)]
[Rules and Regulations]
[Pages 5447-5469]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-1126]


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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:
    <bullet> ``A Proposed Approach to the Regulation of Cellular and 
Tissue-Based Products'' (62 FR 9721, March 4, 1997) and
    <bullet> ``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:
    <bullet> Suitability Determination for Donors of Human Cellular and 
Tissue-Based Products (64 FR 52696, September 30, 1999) (the ``donor-
suitability proposed rule''); and
    <bullet> 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
    <bullet> Written the regulation in question-and-answer format,
    <bullet> Reorganized some regulatory sections for greater clarity, 
and
    <bullet> 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:
    <bullet> We have broadened ``family-related allogeneic use,'' as 
used in proposed Sec. 1271.10, to include first-degree and second-
degree blood relatives.
    <bullet> We have modified the definition of ``homologous use.''
    <bullet> 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.
    <bullet> 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.
    <bullet> 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://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://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://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://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