Federal Register / Vol. 66, No. 13 / Friday, January 19, 2001 / Rules and Regulations 5447

involved in nuclear, missile, or military

activities included in Supplement No. 4

to part 744 (Entity List). All license

applications for exports and reexports to

India and Pakistan not meeting these

criteria for presumption of denial will

be considered on a case-by-case basis

under other licensing policies set forth

in the EAR applicable to such

computers.

(iv) Post-shipment verification. This

section outlines special post-shipment

reporting requirements for exporters of

certain computers to destinations in

Computer Tier 3. Post-shipment reports

must be submitted in accordance with

the provisions of this paragraph

(b)(3)(iv), and all relevant records of

such exports must be kept in accordance

with part 762 of the EAR.

(A) Exporters must file post-shipment

reports for computer exports, as well as

exports of items used to enhance

previously exported or reexported

computers, according to the following

schedule:

(1) For exports occurring prior to

February 26, 2001, where the CTP is

greater than 12,500 MTOPS;

(2) For exports on or after February

26, 2001, but before March 20, 2001

where the CTP is greater than 28,000

MTOPS; and

(3) For exports on or after March 20,

2001 where the CTP is greater than

85,000 MTOPS.

(B) Information that must be included

in each post-shipment report. No later

than the last day of the month following

the month in which the export takes

place, the exporter must submit the

following information to BXA at the

address listed in paragraph (b)(3)(iv)(C)

of this section:

(1) Exporter name, address, and

telephone number;

(2) License number;

(3) Date of export;

(4) End-user name, point of contact,

address, telephone number;

(5) Carrier;

(6) Air waybill or bill of lading

number;

(7) Commodity description,

quantities—listed by model numbers,

serial numbers, and CTP level in

MTOPS; and

(8) Certification line for exporters to

sign and date. The exporter must certify

that the information contained in the

report is accurate to the best of his or

her knowledge.

(C) Mailing address. A copy of the

post-shipment report[s] required under

paragraph (b)(3)(iv)(A) of this section

shall be delivered to one of the

following addresses. Note that BXA will

not accept reports sent C.O.D.

(1) For deliveries by U.S. postal service:

U.S. Department of Commerce,

Bureau of Export Administration, P.O.

Box 273, Washington, D.C. 20044,

Attn: Office of Enforcement Analysis

HPC Team, Room 4065.

(2) For courier deliveries: U.S.

Department of Commerce, Office of

Enforcement Analysis HPC Team,

14th Street and Constitution Ave.,

NW, Room 4065, Washington, DC

20230.

* * * * *

PART 748—[AMENDED]

6. Section 748.10 is amended by

revising paragraph (b)(3) as follows:

§ 748.10 Import and end-user certificates.

* * * * *

(b) * * *

(3) Your transaction involves an

export to the People’s Republic of China

(PRC) of a computer. You must obtain

a PRC End-User Certificate, regardless of

dollar value, as follows:

(i) For exports of computers as

described by § 740.7(d)(2) of the EAR,

regardless of value, to the People’s

Republic of China. (See paragraph (c) of

this section for information on obtaining

the PRC End-User Certificate.) Exporters

are required to obtain a PRC End-User

Certificate before exporting computers

to the PRC. In addition, exporters are

required to provide the PRC End-User

Certificate Number to BXA as part of

their post-shipment report (see

§ 740.7(d)(5)(v) of the EAR). When

providing the PRC End-User Certificate

Number to BXA, you must identify the

transaction in the post shipment report

to which that PRC End-User Certificate

Number applies. The original PRC EndUser Certificate shall be retained in the

exporter’s files in accordance with the

recordkeeping provisions of § 762.2 of

the EAR.

(ii) For exports of computers that

require license applications.

* * * * *

Dated: January 16, 2001.

Matthew S. Borman,

Acting Deputy Assistant Secretary for Export

Administration.

[FR Doc. 01–1623 Filed 1–16–01; 4:49 pm]

BILLING CODE 3510–33–P

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.

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 tissuebased 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,

5448 Federal Register / Vol. 66, No. 13 / Friday, January 19, 2001 / Rules and Regulations

tissues, and cellular and tissue-based

products, and public confidence in their

safety, while encouraging the

development of new products.

A. Background

In 1997, we announced our regulatory

plans for human cells, tissues, and

cellular and tissue-based products in

two documents:

• ‘‘A Proposed Approach to the

Regulation of Cellular and Tissue-Based

Products’’ (62 FR 9721, March 4, 1997)

and

• ‘‘Reinventing the Regulation of

Human Tissue’’ (Ref. 1).

The proposed approach described a

comprehensive plan for regulating

human cells, tissues, and cellular and

tissue-based products that would

include establishment registration and

product listing, donor-suitability

requirements, good tissue practice

regulations, and other requirements.

Under this tiered, risk-based approach,

we proposed to exert only the type of

government regulation necessary to

protect the public health. To accomplish

this goal, we planned to issue new

regulations under the communicable

disease provisions of the Public Health

Service Act (the PHS Act). Some human

cellular and tissue-based products

would be regulated only under these

new regulations, while other human

cellular and tissue-based products

would also be regulated as drugs,

devices, and/or biological drugs. We

requested written comments on the

proposed approach and, on March 17,

1997, held a public meeting (62 FR

9721).

Since 1997, we have published three

proposed rules to implement the

proposed approach. In 1998, as a first

step toward accomplishing these goals,

we published the proposed rule,

‘‘Establishment Registration and Listing

for Manufacturers of Human Cellular

and Tissue-Based Products’’ (63 FR

26744, May 14, 1998) (the ‘‘registration

proposed rule’’). That rule proposed to

require cell and tissue establishments to

register with us and submit a list of their

human cellular and tissue-based

products. We also proposed

modifications to current registration and

listing requirements for drugs and

devices under which cell and tissue

establishments already regulated under

the Federal Food, Drug, and Cosmetic

Act (the act) and/or section 351 of the

PHS Act (42 U.S.C 262) would register

and list following the new procedures.

In addition to the registration

proposed rule, we published two more

proposed rules:

• Suitability Determination for

Donors of Human Cellular and TissueBased Products (64 FR 52696,

September 30, 1999) (the ‘‘donorsuitability proposed rule’’); and

• Current Good Tissue Practice for

Manufacturers of Human Cellular and

Tissue-Based Products; Inspection and

Enforcement (66 FR 1508, January 8,

2000) (the ‘‘GTP proposed rule’’).

Together, these three rules when

finalized would establish a

comprehensive regulatory program for

human cellular and tissue-based

products, to be contained in part 1271

(21 CFR part 1271).

In the three proposed rules, we used

the term ‘‘human cellular and tissuebased 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 tissuebased products (as described in

§ 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

Federal Register / Vol. 66, No. 13 / Friday, January 19, 2001 / Rules and Regulations 5449

that meet the criteria set out in

§ 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

§ 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 donorsuitability, GTP, and other regulations

that make up the rest of the regulatory

program.

Authority for enforcement of section

361 of the PHS Act is provided by

section 368 of the PHS Act (42 U.S.C.

271). Under section 368(a) of the PHS

Act, any person who violates a

regulation prescribed under section 361

of the PHS Act may be punished by

imprisonment for up to 1 year.

Individuals may also be punished for

violating such a regulation by a fine of

up to $100,000 if death has not resulted

from the violation or up to $250,000 if

death has resulted (18 U.S.C. 3559 and

3571(c)). In addition, Federal District

Courts have jurisdiction to enjoin

individuals and organizations from

violating regulations implementing

section 361 of the PHS Act. The

regulations that we have proposed

specific to enforcement appear in the

GTP proposed rule.

HCT/P’s that do not meet FDA’s

criteria set forth in part 1271 for

regulation solely under section 361 of

the PHS Act are regulated as drugs,

devices, and/or biological products

under the act and/or section 351 of the

PHS Act, and their manufacturers are

required to register with the agency

under section 510 of the act (21 U.S.C.

360). Regulations implementing section

510 of the act are found in parts 207 and

807 (21 CFR parts 207 and 807), among

other parts. In order to consolidate our

data base on the cell and tissue industry

and thus to improve our oversight

functions, we are amending parts 207

and 807 to require registering

establishments to follow the procedures

set out in part 1271; these amendments

are effective in 2 years, when we project

the remaining two proposed tissue rules

will be ready for implementation.

Section 510 of the act remains the

authority for the substantive registration

requirement for products subject to

parts 207 and 807. Because harmonizing

the registration and listing procedures

applicable to the various HCT/P’s is

intended to further the goal of

preventing the spread of communicable

disease, we are relying on the additional

authority of section 361 of the PHS Act

for the proposed amendments to parts

207 and 807.

II. Highlights of the Final Rule

A. Plain Language

On June 1, 1998, President Clinton

directed Federal agencies to begin using

‘‘plain language’’ in regulations and

other documents. The goal of the plain

language initiative is to publish

government documents that are easier to

understand.

In response to this initiative, we have

written the registration regulation in

plain language. We have

• Written the regulation in questionand-answer format,

• Reorganized some regulatory

sections for greater clarity, and

• Followed other plain-language

conventions, such as using ‘‘must’’

instead of ‘‘shall.’’

The resulting codified language is easier

to read and understand than the

proposed regulation. These editorial

changes are for clarity only and do not

change the substance of the

requirements.

B. Framework of the Final Regulation

and Part 1271

When final, new part 1271 will be

made up of six subparts. This final

regulation contains subpart A (general

provisions pertaining to the scope and

applicability of part 1271; definitions);

and subpart B (registration and listing

procedures). The donor-suitability

proposed rule contains subpart C of part

1271; and the GTP proposed rule

contains subparts D, E, and F.

Section 1271.10, in subpart A, sets out

the criteria that form the foundation of

our tiered, risk-based approach to

regulating HCT/P’s. HCT/P’s that meet

these criteria are subject only to

regulation under section 361 of the PHS

Act. When all the proposed rules that

will make up part 1271 become

effective, these HCT/P’s would be

subject to the regulations in part 1271,

and no premarket submissions would be

required. (We sometimes refer to these

HCT/P’s as ‘‘361 HCT/P’s.’’ This term

replaces ‘‘section 361 products,’’ which

was used in the registration proposed

rule.) HCT/P’s that do not meet the

criteria for regulation as 361 HCT/P’s

will be regulated as drugs, devices, and/

or biological products.

In September 1999, in the donorsuitability proposed rule, we modified

proposed §§ 1271.1, 1271.3(e), 1271.10,

and 1271.20 as they appeared in the

registration proposed rule, and we

added new § 1271.15. We made some of

these changes to clarify our meaning.

5450 Federal Register / Vol. 66, No. 13 / Friday, January 19, 2001 / Rules and Regulations

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

§ 1271.3(d) into two paragraphs.

Paragraph (d)(1) of § 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 § 1271.3(e). The definition

of the subgroup in paragraph (d)(1)

incorporates the definition of ‘‘human

tissue’’ set out in § 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 § 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 § 1271.3 will eventually replace

paragraph (d)(1), as described below.

The effective date of § 1271.3(d)(1) is

75 days after the publication of this rule.

The entire definition of HCT/P in

§ 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 § 1271.3(d)(2). When all of

the regulations that make up part 1271

are final and have superseded part 1270,

we will revoke § 1271(d)(1) and

renumber (d)(2) as a conforming

amendment. At that time the new

regulatory framework contained in part

1271 will be instituted as a whole.

D. Other Highlights of This Final Rule

This final rule contains other changes

from the proposed rule. Among these

changes are the following:

• We have broadened ‘‘family-related

allogeneic use,’’ as used in proposed

§ 1271.10, to include first-degree and

second-degree blood relatives.

• We have modified the definition of

‘‘homologous use.’’

• We have replaced the phrase

‘‘combined with or modified by the

addition of a drug or a device’’ in

§ 1271.10 with new language.

• We have deleted the phrase

‘‘pending scheduled’’ from the

exception in § 1271.15(d) for

establishments that only receive or store

HCT/P’s.

• We have added an exception for

establishments that only recovers

reproductive cells or tissues for

immediate transfer into a sexually

intimate partner of the cell or tissue

donor. (§ 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 onepage 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

Federal Register / Vol. 66, No. 13 / Friday, January 19, 2001 / Rules and Regulations 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

5452 Federal Register / Vol. 66, No. 13 / Friday, January 19, 2001 / Rules and Regulations

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.

Federal Register / Vol. 66, No. 13 / Friday, January 19, 2001 / Rules and Regulations 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 mixups 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 § 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

§ 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

§ 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

§ 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 § 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 § 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 tissuebased 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

5454 Federal Register / Vol. 66, No. 13 / Friday, January 19, 2001 / Rules and Regulations

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 § 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

§ 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 § 1271.3(c) as ‘‘the

implantation, transplantation, infusion,

or transfer of a human cellular or tissuebased product into a first-degree blood

relative of the individual from whom

cells or tissue comprising such product

were removed.’’ Under § 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 § 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 ‘‘firstdegree 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 firstdegree, 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 seconddegree 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 § 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 § 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

Federal Register / Vol. 66, No. 13 / Friday, January 19, 2001 / Rules and Regulations 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 ‘‘familyrelated 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

§ 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 tissuebased 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 § 1271.3(e) has been

redesignated as § 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

§ 1271.3(e)(2) (final§ 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-versusleukemia 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 § 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 tissuebased 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 § 1271.3(e)(3). These

changes are codified in this rule at

§ 1271.3(d)(2)(iii).

(Comment 21) One comment on

proposed § 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 § 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 § 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.

5456 Federal Register / Vol. 66, No. 13 / Friday, January 19, 2001 / Rules and Regulations

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

§ 1271.3(f) is codified at § 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 tissuebased 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

§§ 1271.10 and 1271.15 (Final

§§ 1271.10 and 1271.20)

In proposed § 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, familyrelated allogeneic, or reproductive use

(64 FR 52720).

Proposed § 1271.15 was intended to

describe the HCT/P’s that did not meet

the criteria set out in § 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 § 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 § 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 § 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., §§ 207.20, 807.20) to

require compliance with certain

subparts of part 1271.

Therefore, we have modified

proposed § 1271.15 and renumbered it

§ 1271.20. That section now refers to

‘‘an HCT/P that does not meet the

Federal Register / Vol. 66, No. 13 / Friday, January 19, 2001 / Rules and Regulations 5457

criteria set out in § 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., §§ 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 § 1271.15.

We address below the comments

received on proposed § 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 § 1271.10 to reach

jurisdictional determinations.

We value public input on the criteria

in § 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 § 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

§ 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 § 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

§ 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.

5458 Federal Register / Vol. 66, No. 13 / Friday, January 19, 2001 / Rules and Regulations

(Comment 28) We received many

comments on the term homologous use,

which we defined in proposed

§ 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 tissuebased 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

§ 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 § 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 § 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

Federal Register / Vol. 66, No. 13 / Friday, January 19, 2001 / Rules and Regulations 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 § 1271.10(b) to

read, in new § 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,

§ 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 donorsuitability proposed rule by deleting the

phrase ‘‘nontissue or noncellular.’’

Two comments questioned the

meaning of § 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

§ 1271.10(c) has been renumbered as

§ 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

§ 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

5460 Federal Register / Vol. 66, No. 13 / Friday, January 19, 2001 / Rules and Regulations

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 § 1271.10 suggested that

isolated human hepatocytes intended

for transplantation be considered to

meet the criteria in § 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

§ 1271.20 (Final § 1271.15)

Proposed § 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 § 1271.20 as

§ 1271.15.

(Comment 33) We received one

comment on the proposed exception in

§ 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

§ 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 § 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 § 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 § 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 § 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

Federal Register / Vol. 66, No. 13 / Friday, January 19, 2001 / Rules and Regulations 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 §§ 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 § 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 § 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 § 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

§ 1271.25(b) for a statement of whether

each listed product meets the criteria set

out in § 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 § 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

§ 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

5462 Federal Register / Vol. 66, No. 13 / Friday, January 19, 2001 / Rules and Regulations

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 § 1271.26.

No. Adding an adjacent building

would not require an amendment to

registration.

(Comment 45) No comments were

received on proposed § 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 § 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 §§ 207.20 and 807.20

(Comment 47) No comments were

submitted on the proposed amendments

to §§ 207.20 and 807.20.

We have modified the language

proposed for §§ 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 § 807.20(e) as

§ 807.20(d).

The effective date of §§ 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 tissuebased 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

Federal Register / Vol. 66, No. 13 / Friday, January 19, 2001 / Rules and Regulations 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 tissuebased 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.

5464 Federal Register / Vol. 66, No. 13 / Friday, January 19, 2001 / Rules and Regulations

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

§ 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

§§ 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 onetime 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.

Federal Register / Vol. 66, No. 13 / Friday, January 19, 2001 / Rules and Regulations 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 §§ 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

§§ 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 §§ 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

21 CFR No. of

respondents

Annual

frequency per

response

Total annual

responses

Hours per

response

(average)

Total hours

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 Listing 1271.25(a),

with 1271.25(b) and 1271.10(b) 1,159 1 1,159 0.75 869.25

TOTAL 902.25

1There are no capital costs or operating and maintenance costs associated with this collection of information.

TABLE 2.—ESTIMATED ANNUAL REPORTING BURDEN 2

21 CFR No. of

respondents

Annual

frequency per

response

Total annual

responses

Hours per

response

(average)

Total hours

Annual Registration 1271.21(b) and 1271.10(b) 1,159 1 1,159 0.5 579.50

HCT/P Listing Update 1271.21(c), 1271.25(c),

and 1271.10(b) 58 1 58 0.5 29.00

5466 Federal Register / Vol. 66, No. 13 / Friday, January 19, 2001 / Rules and Regulations

TABLE 2.—ESTIMATED ANNUAL REPORTING BURDEN 2—Continued

21 CFR No. of

respondents

Annual

frequency per

response

Total annual

responses

Hours per

response

(average)

Total hours

Location/Ownership Amendment 1271.26 and

1271.10(b) 58 1 58 0.25 14.50

TOTAL 623

2There 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, tissuebased 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:

§ 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

§ 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 § 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:

§ 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

§ 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 § 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 § 1271.10, and I do not qualify

Federal Register / Vol. 66, No. 13 / Friday, January 19, 2001 / Rules and Regulations 5467

for any of the exceptions in § 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

§ 1271.1 What are the purpose and scope

of this part?

(a) Purpose. The purpose of this part,

in conjunction with §§ 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 tissuebased 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 § 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, §§ 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.

§ 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 § 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 § 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.

§ 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 firstdegree or second-degree blood relative;

or

(c) Is for reproductive use.

5468 Federal Register / Vol. 66, No. 13 / Friday, January 19, 2001 / Rules and Regulations

(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.

§ 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.

§ 1271.20 If my HCT/P’s do not meet the

criteria in § 1271.10, and I do not qualify for

any of the exceptions in § 1271.15, what

regulations apply?

If you are an establishment that

manufactures an HCT/P that does not

meet the criteria set out in § 1271.10(a),

and you do not qualify for any of the

exceptions in § 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,

§§ 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

§ 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

§ 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

§ 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

§ 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.

§ 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.

§ 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 § 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 § 1271.25(b) for each new HCT/P.

(2) A list of each HCT/P formerly

listed in accordance with § 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 § 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 § 1271.10.

Federal Register / Vol. 66, No. 13 / Friday, January 19, 2001 / Rules and Regulations 5469

§ 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.

§ 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.

§ 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 selfaddressed 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

DEPARTMENT OF THE TREASURY

Bureau of Alcohol, Tobacco and

Firearms

27 CFR Parts 17 and 18

[T.D. ATF–436]

RIN 1512–AB99

Delegation of Authority for Parts 17

and 18

AGENCY: Bureau of Alcohol, Tobacco

and Firearms (ATF), Treasury.

ACTION: Treasury decision, final rule.

SUMMARY: Authority delegation. This

final rule places most ATF authorities

contained in parts 17 and 18, title 27

Code of Federal Regulations (CFR), with

the ‘‘appropriate ATF officer’’ and

requires that persons file documents

required by parts 17 and 18, title 27

Code of Federal Regulations (CFR), with

the ‘‘appropriate ATF officer’’ or in

accordance with the instructions on the

ATF form. Also, this final rule removes

the definitions of, and references to,

specific officers subordinate to the

Director. Concurrently with this

Treasury Decision, ATF Order 1130.13

is being published. Through this order,

the Director has delegated most of the

authorities in 27 CFR parts 17 and 18 to

the appropriate ATF officers and

specified the ATF officers with whom

applications, notices and other reports,

which are not ATF forms, are filed.

EFFECTIVE DATE: January 19, 2001.

FOR FURTHER INFORMATION CONTACT:

Robert Ruhf, Regulations Division,

Bureau of Alcohol, Tobacco and

Firearms, 650 Massachusetts Avenue

NW, Washington, DC 20226 (202–927–

8210).

SUPPLEMENTARY INFORMATION:

Background

Pursuant to Treasury Decision 120–01

(formerly 221), dated June 6, 1972, the

Secretary of the Treasury delegated to

the Director of the Bureau of Alcohol,

Tobacco and Firearms (ATF), the

authority to enforce, among other laws,

the provisions of chapter 51 of the

Internal Revenue Code of 1986 (IRC).

The Director has subsequently

redelegated certain of these authorities

to appropriate subordinate officers by

way of various means, including by

regulation, ATF delegation orders,

regional directives, or similar delegation

documents. As a result, to ascertain

what particular officer is authorized to

perform a particular function under

chapter 51, each of these various

delegation instruments must be

consulted. Similarly, each time a

delegation of authority is revoked or

redelegated, each of the delegation

documents must be reviewed and

amended as necessary.

ATF has determined that this

multiplicity of delegation instruments

complicates and hinders the task of

determining which ATF officer is

authorized to perform a particular

function. ATF also believes these

multiple delegation instruments

exacerbate the administrative burden

associated with maintaining up-to-date

delegations, resulting in an undue delay

in reflecting current authorities.

Accordingly, in this final rule, the

Director of ATF is rescinding all

authorities of the Director in parts 17

and 18 which were previously delegated

to a specified ATF officer and placing

all authorities of the Director with the

‘‘appropriate ATF officer.’’ Along with

this final rule, ATF is publishing ATF

Order 1130.13, Delegation Order—

Delegation of the Director’s Authorities

in parts 17 and 18, in which certain of

these authorities are then delegated

down to the appropriate organizational

level. The effect of these changes is to

consolidate all delegations of authority

in parts 17 and 18 into one delegation

instrument. This action both simplifies

the process for determining what ATF

officer is authorized to perform a

particular function and facilitates the

updating of delegations in the event of

a change in delegation or in the event

of a restructuring. As a result,

delegations of authority will be reflected

in a more timely and user-friendly

manner.

In addition to the above, this final

rule also eliminates all references in the

regulations which identify the ATF

officer with whom an ATF form is filed.

Thus, in lieu of identifying the

authorized officer in the regulations, the

form itself will indicate the officer with

whom it shall be filed. Similarly, this

final rule also amends parts 17 and 18

to provide that documents other than

ATF forms (such as letterhead

applications, notices and reports) will

be filed with the ‘‘appropriate ATF

officer.’’ The ‘‘appropriate ATF officer’’

is the Director’s delegate and will be

identified in the accompanying ATF

Order (ATF Order 1130.13, Delegation

Order—Delegation of the Director’s