26744 Federal Register / Vol. 63, No. 93 /Thursday, May 14, 1998 / Proposed Rules

failure of the hydraulic extension system,

accomplish the following:

(a) Within 600 flight hours after the

effective date of this AD, perform a one-time

operational test of the free fall control

mechanism of the landing gear to ensure

proper release of the MLG for extension by

free fall, in accordance with Airbus Industrie

All Operator Telex (AOT) 32–14, dated

February 3, 1997, or Revision 01, dated

March 13, 1997. If any discrepancy is

detected in the functioning of the free fall

control mechanism of the landing gear, prior

to further flight, readjust the mechanism, and

repeat the operational test in accordance with

the AOT. If any discrepancy is detected in

the second operational test, prior to further

flight, rerig the free fall control mechanism

in accordance with the AOT, and accomplish

the actions required by paragraph (b) of this

AD.

(b) Within 10 months after the effective

date of this AD, perform a functional test of

the free fall control mechanism of the landing

gear to ensure proper release of the MLG for

extension by free fall, in accordance with

AOT 32–14, dated February 3, 1997, or

Revision 01, dated March 13, 1997.

Thereafter, repeat the functional test of the

free fall control mechanism of the landing

gear at intervals not to exceed 12 months,

until the modification required by paragraph

(c) of the AD has been accomplished. During

any test performed in accordance with

paragraph (b) of this AD, if the free fall

control mechanism of the landing gear fails

to fully extend the MLG, prior to further

flight, readjust or rerig the mechanism in

accordance with the AOT.

(c) Within 66 months after the effective

date of this AD, modify the free fall control

mechanism of the landing gear in accordance

with Airbus Industrie Service bulletin A300–

32–0425, Revision 01 (for Model A300 series

airplanes); A310–32–2111, Revision 01 (for

Model A310 series airplanes): or A300–32–

6072, Revision 01 (for Model A300–600

series airplanes); all dated October 10, 1997;

as applicable. Accomplishment of the

modification constitutes terminating action

for the repetitive functional tests required by

paragraph (b) of this AD.

(d) An alternative method of compliance or

adjustment of the compliance time that

provides an acceptable level of safety may be

used if approved by the Manager,

International Branch, ANM–116, FAA,

Transport Airplane Directorate. Operators

shall submit their requests through an

appropriate FAA Principal Maintenance

Inspector, who may add comments and then

send it to the Manager, International Branch,

ANM–116.

Note 2: Information concerning the

existence of approved alternative methods of

compliance with this AD, if any, may be

obtained from the International Branch,

ANM–116.

(e) Special flight permits may be issued in

accordance with sections 21.197 and 21.199

of the Federal Aviation Regulations (14 CFR

21.197 and 21.199) to operate the airplane to

a location where the requirements of this AD

can be accomplished.

Note 3: The subject of this AD is addressed

in French airworthiness directive 97–113–

221(B)R1, dated December 3, 1997.

Issued in Renton, Washington, on May 7,

1998.

John J. Hickey,

Acting Manager, Transport Airplane

Directorate, Aircraft Certification Service.

[FR Doc. 98–12807 Filed 5–13–98; 8:45 am]

BILLING CODE 4910–13–U

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 207, 807, and 1271

[Docket No. 97N–484R]

RIN 0910–AB05

Establishment Registration and Listing

for Manufacturers of Human Cellular

and Tissue-Based Products

AGENCY: Food and Drug Administration,

HHS.

ACTION: Proposed rule.

SUMMARY: The Food and Drug

Administration (FDA) is proposing to

require manufacturers of certain human

cellular and tissue-based products to

register with the agency and list their

products. In addition, the agency is

proposing to amend the registration and

listing regulations that currently apply

to human cellular and tissue-based

products regulated as drugs, devices,

and/or biological products. This action

is being taken to establish a unified

registration and listing program for

human cellular and tissue-based

products.

DATES: Submit written comments on the

proposed rule by August 12, 1998.

Submit written comments on the

information collection provisions by

June 15, 1998.

ADDRESSES: Submit written comments

to the Dockets Management Branch

(HFA–305), Food and Drug

Administration, 12420 Parklawn Dr.,

rm. 1–23, Rockville, MD 20857. Submit

written comments on the information

collection provisions to the Office of

Information and Regulatory Affairs,

OMB, New Executive Office Bldg., 725

17th St. NW., Washington, DC 20503,

Attn: Desk Officer for FDA.

FOR FURTHER INFORMATION CONTACT:

Dano B. Murphy or Paula S. McKeever,

Center for Biologics Evaluation and

Research (HFM–17), Food and Drug

Administration, 1401 Rockville Pike,

suite 200N, Rockville, MD 20852–1448,

301–827–6210.

SUPPLEMENTARY INFORMATION:

I. Introduction

FDA is putting in place a

comprehensive new system of

regulation for human cellular and

tissue-based products. As a first step

toward accomplishing this goal, the

agency is proposing regulations that will

require establishments that manufacture

those products to register and list their

products with the agency.

A. Background

The term ‘‘human cellular and tissuebased products’’ encompasses an array

of medical products derived from the

human body and used for replacement,

reproductive, or therapeutic purposes.

Skin, tendons, bone, heart valves, and

corneas have long been used as

replacements for damaged or diseased

tissues. Semen, ova, and embryos are

transferred for reproductive purposes.

Currently, some human cellular and

tissue-based products are being

developed for new therapeutic uses. For

example, scientists are studying the use

of manipulated human cells to treat

viral infections, Parkinson’s disease,

and diabetes, among other diseases.

Human cellular and tissue-based

products serve a crucial role in

medicine, and they have the potential

for providing important new therapies.

Yet they also raise public health

concerns. With the development of new

products, and new uses for existing

products, come questions about safety

and effectiveness that need to be

answered through clinical investigation.

Furthermore, all human cellular and

tissue-based products, because they

contain components of the human body,

pose some risk of carrying pathogens

that could cause disease in health-care

personnel, other handlers of tissue,

recipients, and family members or other

close contacts of recipients.

FDA has never had a single regulatory

program for human cellular and tissuebased products. Instead, it has regulated

these products on a case-by-case basis

responding as it determined appropriate

to the particular characteristics of and

concerns raised by each type of product.

Some tissues have been regulated as

medical devices under section 201 of

the Federal Food, Drug, and Cosmetic

Act (the act) (21 U.S.C. 321 et seq.).

Corneal lenticules, dura mater, heart

valve allografts, and umbilical cord vein

grafts fall into this category. Other

products have been considered

biological products under section 351 of

the Public Health Service Act (the PHS

Act) (42 U.S.C. 262) and drugs under the

act (hereinafter referred to as biological

drugs). Somatic cell therapy products

and some gene therapy products fall
Federal Register / Vol. 63, No. 93 /Thursday, May 14, 1998 / Proposed Rules 26745

into this category. (See 58 FR 53248,

October 14, 1993.)

FDA has also relied on section 361 of

the PHS Act (42 U.S.C. 264), which

provides the authority to issue

regulations to prevent the spread of

communicable diseases, to regulate

tissues that it has chosen not to regulate

as devices or biological drugs. In 1993,

in response to concerns about the safety

of human tissue intended for

transplantation, FDA used this authority

to require testing and screening of tissue

donors for hepatitis and human

immunodeficiency viruses. (See 58 FR

65514, December 14,1993.) Until it

issued those regulations (‘‘Human

Tissues Intended for Transplantation,’’

codified in title 21 of the Code of

Federal Regulations (CFR) part 1270),

FDA exerted little or no regulatory

control over certain types of human

cellular and tissue-based products.

Instead, human tissue for

transplantation was subject to some

State regulation and to voluntary

accreditation systems. Even today,

FDA’s human tissue regulations do not

address the infectious disease risk of

donating, processing, and storing

reproductive cells and tissue.

FDA has evaluated its approach to

regulating human cellular and tissuebased products and has determined that

changes are needed. In light of the

development of new products, coupled

with a growing awareness of infectiousdisease concerns, the agency believes

that the current patchwork of regulatory

policies is no longer adequate and plans

to create a comprehensive regulatory

program that will cover a broad range of

human cellular and tissue-based

products. The agency has considered

the relevant provisions of the act and

the PHS Act and has concluded that

these two statutes provide sufficiently

broad authority for the proposed

regulatory program.

The agency announced its plans for

reform in two documents released in

February 1997: ‘‘Reinventing the

Regulation of Human Tissue,’’ and ‘‘A

Proposed Approach to the Regulation of

Cellular and Tissue-Based Products’’

(hereinafter ‘‘Proposed Approach

document’’). The agency requested

written comments on its proposed

approach and, on March 17, 1997, held

a public meeting to solicit information

and views from the interested public.

(See 62 FR 9721, March 4, 1997) (Docket

No.: 97N–0068). FDA has considered

the comments submitted at the public

meeting and to the docket in drafting

this proposed rule. FDA welcomes

comments on the proposed rule from all

interested parties.

B. The Proposed Approach

FDA seeks to achieve several goals

with its new approach to regulating

human cellular and tissue-based

products. Primary among them is the

improved protection of the public

health without the imposition of

unnecessary restrictions on research,

development, or the availability of new

products. Under the new program, the

degree of scrutiny afforded different

types of products will be commensurate

with the risks presented, enabling the

agency to use its resources more

effectively. Consolidating the regulation

of human cellular and tissue-based

products into one regulatory program is

expected to lead to increased

consistency and greater efficiency.

Together, these planned improvements

should increase the safety of human

cellular and tissue-based products, and

public confidence in that safety, while

encouraging the development of new

products.

In developing its proposed approach,

FDA examined five issues that it

considered fundamental to the proper

regulation of the various types of human

cellular and tissue-based products. First,

the agency asked how the transmission

of communicable disease by these

products occurs and could be

prevented. Second, the agency looked at

the types of handling, processing, and

manufacturing controls that are

necessary to prevent contamination and

to preserve the integrity and function of

these products. Third, the agency

examined concerns about the products’

clinical safety and effectiveness. Fourth,

FDA considered the type of labeling

necessary for proper use of the products

and the kind of promotion that would

be permissible. Finally, the agency

asked how it could best monitor and

communicate with the cell and tissue

industry.

Through examination of these five

public-health and regulatory concerns,

FDA was able to develop a proposed

comprehensive regulatory scheme

tailored to the relevant characteristics of

human cellular and tissue-based

products. In order to devise an umbrella

approach, the agency first focused on

the products’ common attributes. Then,

to ensure appropriate levels of

regulation, the agency differentiated

between the various types of products

based on the public health risks

associated with them. For example, the

risks posed by cells that are extensively

manipulated in a laboratory and then

implanted for their systemic effect on a

patient are different from those of an

unmanipulated tissue that is

transplanted into a patient to replace an

injured structural tissue.

Taking into account these differences,

the agency designed a risk-based tiered

approach intended to regulate human

cellular and tissue-based products only

to the extent necessary to protect public

health. Some products will be subject to

little or no regulation. For example, no

regulatory requirements will be imposed

on tissues transplanted into the same

patient during the same surgical

procedure.

As the potential risk posed by a

product increases, so will the level of

oversight afforded that product. Thus,

minimally processed tissues

transplanted from one person to another

for their normal structural functions

would be subject to infectious disease

screening and testing and to

requirements for good handling

procedures, but would not need FDA

premarket review or marketing

approval. In contrast, premarket

approval would generally be required

for cells and tissues that are processed

extensively, are combined with

noncellular or nontissue components,

are labeled or promoted for purposes

other than their normal functions, or

have a systemic effect. In addition, these

products would be subject to

requirements for good tissue practices

and infectious disease screening and

testing, as well as to the good

manufacturing practice requirements

applicable to drugs and devices.

Although FDA’s proposed regulatory

approach is far more comprehensive in

scope than its present system, some

products will not be covered. Among

the products not included under the

approach are vascularized organs and

minimally manipulated bone marrow,

both of which fall under the purview of

the Health Resources Services

Administration. FDA already

comprehensively regulates transfusable

blood products (e.g., whole blood, red

blood cells, platelets, and plasma) under

a different regulatory scheme and will

not at this time regulate those products

as human cellular and tissue-based

products. Xenograft transplantation

(transplantation using tissues derived

from animals) raises different public

health issues from transplantation with

human tissue, and so will not be subject

to the new regulatory program. The new

program will also exclude from coverage

ancillary products used in cell or tissue

propagation, storage, or processing, as

well as products that are secreted by or

extracted from cells or tissues (e.g.,

human milk, collagen, urokinase,

cytokines, and growth factors), because

these products often raise different

manufacturing, safety, and effectiveness
26746 Federal Register / Vol. 63, No. 93 /Thursday, May 14, 1998 / Proposed Rules

issues, and generally are covered by

other rules, regulations, or standards.

II. Registration of Human Cellular and

Tissue-Based Products

FDA is now proposing to extend

registration and listing requirements to

manufacturers of human cellular and

tissue-based products not currently

subject to such requirements.

A. Need for Registration and Listing

In order to implement its new

approach to the regulation of human

cellular and tissue-based products, FDA

needs to be able to assess the state of the

cell and tissue industry. Although some

human cellular and tissue-based

products are currently regulated by the

agency as devices or biological drugs—

and thus are covered by registration and

listing requirements—others have not

been subject to such regulation. As a

result, FDA does not know the full size

and scope of the cell and tissue industry

and its products.

Through the current proposal to

extend the requirements of registration

and product listing to members of the

tissue and cell industry not presently

under such obligations, FDA seeks to

accrue the basic knowledge about the

industry that is necessary for its

effective regulation. Without reliable

data on the tissue and cell industry (e.g.,

names and addresses of manufacturers

and types of products) FDA cannot

apply appropriate oversight to a rapidly

changing industry. FDA must keep

informed of the state of the industry,

including developments such as the

introduction of new products, in order

to understand and respond to all

relevant public health issues. Because

FDA intends to calibrate its level of

regulation to the risks posed by various

types of cellular and tissue-based

products, it is crucial for the agency to

have accurate information about those

products.

The proposed registration

requirement will facilitate

communication between the agency and

industry. Once FDA has a complete list

of the cell and tissue industry and its

products, the agency will be able to

reach members of the industry with

educational materials and information

regarding FDA policies, guidances, and

requirements. Important information

(e.g., about a newly identified public

health risk) can also be quickly

disseminated to the industry. Moreover,

information obtained through the new

registration and listing regulation will

permit the agency to monitor the

industry more effectively. For example,

FDA will be able to identify quickly

which establishments should be

inspected for compliance with

applicable laws and regulations,

including those to be issued as part of

the new tissue regulation program.

Required updating of industry

registrations and product lists will

ensure that FDA’s information about the

industry remains current.

B. How Registration Will Be Achieved

In proposing these new registration

regulations, FDA seeks to improve the

way it collects and manages information

about the cell and tissue industry and

its products. The agency plans to create

a single, comprehensive data base with

information about human cellular and

tissue-based products, maintained by

the Center for Biologics Evaluation and

Research (CBER). By requiring

registration and product listing from

manufacturers not presently subject to

such requirements, and by consolidating

that new information with data

currently being collected, FDA will be

able to develop a less fragmented and

more efficient oversight program.

Meanwhile, manufacturers already

under a registration obligation will

benefit from the availability of new,

electronic procedures.

The main set of regulations being

proposed, new part 1271 of title 21 of

the CFR, will apply to those human

cellular and tissue-based products that

the agency will regulate under section

361 of the PHS Act. Proposed part 1271

will cover those products, including

products consisting of reproductive

cells or tissue, that: (1) Are minimally

manipulated; (2) are not promoted or

labeled for any use other than a

homologous use; (3) have not been

combined with or modified by the

addition of any noncellular or nontissue

component that is a drug or device; and

(4) do not have a systemic effect, except

in cases of autologous use,

transplantation into a first-degree blood

relative, or reproductive use. For

convenience these products will be

referred to as ‘‘products regulated under

section 361’’ or ‘‘361 products.’’

(However, the use of these terms does

not indicate that other products will not

be regulated under section 361 of the

PHS Act. In fact, FDA intends to rely in

part on section 361 of the PHS Act when

imposing requirements on human

cellular and tissue-based products

regulated as biological drugs or devices

under the act and/or section 351 of the

PHS Act.) Examples of products to be

regulated under section 361 of the PHS

Act include bone, tendons, skin,

corneas, and sclera. If all other criteria

are met, products with a systemic effect

that could come under section 361 of

the PHS Act include peripheral and

cord blood stem cells used autologously

or in first degree blood relatives and

sperm, oocytes, and embryos for

reproductive use.

Establishments that manufacture

human cellular or tissue-based products

that meet the criteria set out above

would be required to register and list

those products under proposed part

1271. However, certain exceptions

would apply. For example, although the

agency’s proposed definition of

‘‘manufacture’’ includes distribution,

commercial carriers would not need to

register. Also, certain scientific,

educational, or other uses of cellular or

tissue-based products would not be

covered by part 1271. These and other

exceptions are discussed in greater

detail in section III of this document.

In order to unify its registration

system, FDA also proposes to amend

parts 207 and 807 (21 CFR parts 207 and

807) so that information on human

cellular and tissue-based products

regulated as biological drugs or devices

will be submitted to the same data base

used for 361 products. Parts 207 and

807 contain the registration and listing

requirements for drugs and devices.

Under the proposed amendments,

manufacturers of human cellular and

tissue-based products regulated as

biological drugs or devices will be

required to comply with the registration

and listing requirements in part 207 or

807, as applicable, by following the

procedures set out in proposed part

1271.

Human cellular and tissue-based

products subject to regulation as

biological drugs or devices are those

that do not meet the criteria set out

above for regulation under section 361

of the PHS Act. That is, they are: (1)

More than minimally manipulated; (2)

are promoted or labeled for a

nonhomologous use; (3) have been

combined with or modified by the

addition of a noncellular or nontissue

component that is a drug or device; or

(4) have a systemic effect (except in

cases of autologous use, transplantation

into a first degree blood relative, or

reproductive use). Examples include:

Hematopoietic stem cells intended for

use in recipients who are not close

blood relatives of the cell donor or for

uses other than to reconstitute the

cellular components of the blood; more

than minimally manipulated bone

marrow; hematopoietic stem cells that

have been expanded or modified as part

of gene therapy; cloned and/or activated

lymphocyte therapies for cancer or

infectious diseases; bone combined with

collagen or growth factors; and

manipulated cells for autologous

structural use (MAS cells), such as
Federal Register / Vol. 63, No. 93 /Thursday, May 14, 1998 / Proposed Rules 26747

expanded chondrocytes to repair

damaged knee cartilage.

Under the proposed regulatory

system, some products that are currently

regulated as medical devices might be

regulated as section 361 products

instead. One such product under

consideration is dura mater, the

collagenous connective tissue that

covers the human brain and spinal cord.

Dura mater is excised from cadavers

shortly after death, washed, cut into

smaller pieces, sterilized, preserved,

and reconstituted before use in

neurosurgical, gynecological, oral,

otolaryngological, and general surgical

procedures. This manner of processing

does not change the tissue’s original

characteristics relating to its ability to

carry out reconstruction, repair, or

replacement and, therefore, would be

considered minimal manipulation as

defined in proposed part 1271.

Moreover, dura mater does not have a

systemic effect. Thus, dura mater that is

not combined with or modified by the

addition of any nontissue or noncellular

component that is a drug or device, and

that is not promoted or labeled for any

use other than a homologous use,

appears to meet the proposed criteria in

part 1271 for regulation under section

361 of the PHS Act.

Recent reports linking the

transmission of Creutzfeldt-Jakob

Disease (CJD) to several recipients of

human cadaveric dura mater have raised

questions as to the controls needed to

regulate dura mater. Following

discussion of data and information

relating to dura mater, on October 6 and

7, 1997, FDA’s Transmissible

Spongiform Encephalopathy Advisory

Committee recommended that FDA

adopt measures intended to decrease the

risk of CJD transmission via dura mater.

These recommendations include

specific handling procedures to reduce

or eliminate CJD infectious agents in

cadaveric dura mater and histological

examinations of brain biopsies taken

from donor cadavers. In light of these

recent developments and the

committee’s recommendations, FDA is

requesting comments on whether FDA’s

proposal to regulate dura mater under

the authority of section 361 of the PHS

Act will provide adequate controls, or,

conversely, whether tissues with certain

risk and disease factors should be

subject to premarket submission

requirements found in the act and in

section 351 of the PHS Act. The agency

invites comments regarding the

appropriate controls for dura mater and

like products, and whether such

controls may be appropriately addressed

in ‘‘good tissue practice’’ requirements

specific to these products issued under

the authority of section 361 of the PHS

Act. In the meantime, FDA will

continue to regulate dura mater as a

device.

The agency intends to regulate as 361

products human heart valve allografts

that meet the criteria of proposed

§ 1271.10, which are now subject to

regulation as medical devices. In the

past, these products were considered by

FDA to be class III medical devices. In

1994, in a stipulated order of dismissal

in Northwest Tissue Center v. Shalala,

No. 91–C–6515 (N.D. Ill., October 7,

1994), FDA stipulated that it would not

enforce the class III requirement of

premarket approval for human heart

valve allografts. In 1995, the American

Red Cross (ARC) requested that FDA

regulate human heart valve allografts as

human tissues for transplantation,

rather than as medical devices. ARC’s

request for jurisdictional change for the

regulation of human heart allografts was

supported by the Northwest Tissue

Center.

The agency now proposes to regulate,

as section 361 products, heart valve

allografts that are minimally

manipulated, do not a have a systemic

effect, and are not promoted for a

nonhomologous use or combined with a

nontissue or noncellular component

that is a drug or a device.

C. Legal Authority

FDA is proposing to issue new

regulations in part 1271 solely under the

authority of section 361 of the PHS Act.

Under that section, FDA may make and

enforce regulations necessary to prevent

the introduction, transmission, or

spread of communicable diseases

between the States or from foreign

countries into the States. (See sec. 1,

Reorg. Plan No. 3 of 1966 at 42 U.S.C.

202 for delegation of section 361

authority from the Surgeon General to

the Secretary, Health and Human

Services; see 21 CFR 5.10(a)(4) for

delegation from the Secretary to the

Food and Drug Administration.)

Intrastate transactions may also be

regulated under section 361 of the PHS

Act. (See Louisiana v. Mathews, 427 F.

Supp. 174, 176 (E.D. La. 1977).

Because of their nature as derivatives

of the human body, all human cellular

and tissue-based products pose a

potential risk of transmitting diseases.

FDA has determined that it may

appropriately and effectively regulate

certain of these products (described in

section II.B of this document) by

controlling the infectious disease risks

they present rather than by requiring

premarket approval or licensing under

the act or the PHS Act.

In order to prevent the spread of

infectious disease, FDA must obtain the

type of basic information about the

industry and its products that these

proposed regulations will require be

provided to the agency. This

information will enable the agency to

react swiftly to newly discovered or

understood risks by alerting members of

the industry of its concerns and, when

appropriate, by conducting

establishment inspections.

Moreover, the registration regulations

now being proposed lay the foundation

for a regulatory program that will

further the goal of preventing the

transmission of communicable disease.

FDA intends to propose regulations to

be issued at a later date that would

require such measures as the

maintenance of ‘‘good tissue practices’’

and various tests for communicable

diseases. Without the information that

the agency will collect through

establishment registration and product

listing, FDA cannot effectively monitor

compliance with these future

regulations—and, thus, prevent the

transmission of communicable disease.

Authority for the enforcement of

section 361 of the PHS Act is provided

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

271). Under section 368(a), any person

who violates a regulation prescribed

under section 361 of the PHS Act may

be punished by imprisonment for up to

1 year, a fine of not more than $1,000,

or both (42 U.S.C. 271(a)). In addition,

Federal District Courts have jurisdiction

to enjoin individuals and organizations

from violating regulations implementing

section 361 of the PHS Act. The agency

intends, in a future rulemaking, to issue

regulations including requirements for

testing, good tissue practices, and

enforcement under the authority of

section 361 of the PHS Act.

Human cellular and tissue-based

products that do not meet FDA’s criteria

set forth in part 1271 for regulation

solely under section 361 of the PHS Act

are subject to regulation as biological

drugs or devices, and their

manufacturers are required to register

with the agency under section 510 of the

act. Regulations implementing section

510 are found under parts 207 and 807,

among other parts. As discussed earlier,

in order to consolidate its data base on

the cell and tissue industry and thus to

improve its oversight functions, FDA

proposes to amend parts 207 and 807 to

require registering establishments to

follow the procedures set out in part

1271. Section 510 of the act remains the

authority for the substantive registration

requirement for products subject to

parts 207 and 807. Because harmonizing

the registration and listing procedures
26748 Federal Register / Vol. 63, No. 93 /Thursday, May 14, 1998 / Proposed Rules

applicable to the various human cellular

and tissue-based products is intended to

further the goal of preventing the spread

of communicable disease, the agency is

also relying on the additional authority

of section 361 of the PHS Act for the

proposed amendments to parts 207 and

807.

III. Summary of the Proposed

Regulations

A. Purpose, Coverage, and Exceptions of

Part 1271

1. Purpose

The purpose of part 1271, as set out

in § 1271.1, is to establish a unified

registration and product listing system

for establishments that manufacture

human cellular and tissue-based

products.

2. Coverage

Section 1271.1 states that

manufacturers of human cellular and

tissue-based products regulated under

section 361 of the PHS Act are required

by part 1271 to register and list their

products with CBER. These products are

further described in § 1271.10, which

states who must register and submit a

list. The products are those that: (1) Are

minimally manipulated; (2) are not

promoted for any use other than

homologous use; (3) are not combined

with or modified by the addition of any

nontissue or noncellular component

that is a drug or device; and (4) do not

have a systemic effect, except in cases

of autologous or family-related

allogeneic systemic use or reproductive

use. Many of these terms are defined in

the definition section of the regulation,

§ 1271.3.

In addition, § 1271.1 notes that

manufacturers of products regulated

under section 351 of the PHS Act and/

or the act are required to register and list

their products following the procedures

in subpart B of part 1271.

3. Exceptions

Section 1271.20 sets out exceptions to

the provisions of part 1271. These

exceptions are for activities that do not

raise issues the agency currently

believes warrant regulation.

a. The use of human cellular or tissuebased products solely for nonclinical

scientific or educational purposes does

not trigger the registration or listing

requirements. Any use for implantation,

transplantation, infusion, or transfer

into humans is considered clinical use

and would be subject to part 1271.

b. An establishment or person that

removes human cellular or tissue-based

products from an individual and then

implants, transplants, infuses, or

transfers those cells or tissues into the

same individual is not required to

register or list with the agency, so long

as the human cellular or tissue-based

product is quarantined pending

completion of the surgery. For example,

a surgeon might remove a saphenous

vein from a patient for use in a later

coronary bypass in the same patient.

Registration and listing would not be

required unless the saphenous vein was

stored with other cellular or tissuebased products. Storage in the same

location as other human cellular or

tissue-based products gives rise to

concerns about the spread of infectious

disease and would be considered

beyond the bounds of the exception.

c. Carriers that accept, receive, carry,

hold, or deliver human cellular or

tissue-based products in the usual

course of business are not required to

register or list.

d. Establishments that receive human

cellular or tissue-based products solely

for implantation, transplantation,

infusion, or transfer within the same

facility do not come under the terms of

part 1271. This exception is intended

only for end-user establishments, that is,

establishments that do not procure,

distribute, or otherwise manufacture

human cellular or tissue-based

products.

B. Definitions

Section 1271.3 contains definitions of

many of the terms used in part 1271.

Some of the definitions relate to the

types of product covered by part 1271,

e.g., § 1271.3(d) defines ‘‘homologous

use.’’ Other definitions are intended to

clarify the sorts of activities that will

trigger the requirements of part 1271,

e.g., § 1271.3(f) defines ‘‘manufacture.’’

1. Human Cellular or Tissue-Based

Product

A human cellular or tissue-based

product is defined in § 1271.3(e) as a

product containing human cells or

tissues, or any cell or tissue-based

component of such a product.

The following products are excluded

from this definition: Vascularized

human organs for transplantation;

products that are secreted or extracted

from humans, such as milk, collagen,

and cell factors; minimally manipulated

bone marrow; ancillary products used in

the propagation of cells or tissues, and

cells, tissues, or organs derived from

animals.

Whole blood, blood components, or

blood derivative products subject to

listing under 21 CFR part 607 are also

excluded. Such products include,

among others, whole blood, red blood

cells, cryoprecipitated AHF, platelets,

leukocytes/granulocytes, plasma, blood

products for diagnostic use, and blood

bank reagents. In contrast, peripheral

and cord blood stem cells are not

subject to the exception for whole

blood, blood components and blood

derivative products and therefore are

subject to part 1271.

2. Minimal Manipulation

One of the criteria for regulation of a

human cellular or tissue-based product

under section 361 of the PHS Act and

part 1271 is that it be minimally

manipulated. Minimal manipulation is

defined in § 1271.3(g). For structural

tissue, minimal manipulation is defined

as processing that does not alter the

original relevant characteristics of the

tissue that relate to the tissue’s utility

for reconstruction, repair, or

replacement. For example, separation of

structural tissue into components whose

relevant characteristics relating to

reconstruction or repair are not altered

would be considered minimal

manipulation, as would extraction or

separation of cells from structural tissue

in which the remaining structural

tissue’s relevant characteristics relating

to reconstruction and repair remain

unchanged. Other examples of

procedures that would be considered

minimal manipulation include: Cutting,

grinding, and shaping; soaking in

antibiotic solution; sterilization by

ethylene oxide treatment or irradiation;

cell separation; lyophilization;

cryopreservation; and freezing.

For cells (structural and

nonstructural) and nonstructural

tissues, minimal manipulation is

defined as processing that does not alter

the relevant biological characteristics

and, thus potentially, the function or

integrity of the cells or tissues. For

example, FDA considers cell selection

(e.g., selection of stem cells from

amongst lymphocytes and mature cells

of other lineages) to be minimal

manipulation.

FDA considers the processing of cells

and tissue to be ‘‘more than minimal’’

if information does not exist to show

that the process meets the definition of

minimal manipulation. Examples of

manipulation not considered minimal,

based on current scientific knowledge,

include cell expansion, encapsulation,

activation, and genetic modification.

FDA recognizes that the subsequent

accumulation of clinical data and

experience about a particular process

may demonstrate that it does not alter

the original relevant characteristics of

the cells or tissue, and the agency will

consider this information in

determining whether a procedure

should be considered minimal as

opposed to more-than-minimal
Federal Register / Vol. 63, No. 93 /Thursday, May 14, 1998 / Proposed Rules 26749

manipulation. For example , FDA

previously considered demineralized

bone products (DMB) to be more than

minimally manipulated. However, at the

March 17, 1997, public meeting, and

during a July 11, 1997, meeting between

the American Association of Tissue

Banks and FDA, the agency was urged

to reconsider its position regarding the

regulatory status of DMB. After

reviewing information provided, the

agency believes that the relevant

characteristics that relate to DMB’s

utility for replacement, reconstruction

and repair are not altered by processing

bone specimens into DMB. Therefore,

FDA proposes to regulate DMB under

section 361 of the PHS Act provided it

is used for homologous function and is

not combined with a noncellular or

nontissue component that is a drug or

device because FDA believes DMB falls

within the minimal manipulation

definition.

3. Homologous Use

The second criterion for regulation

under part 1271 is that a human cellular

or tissue-based product not be promoted

or labeled for any use other than

homologous use. Homologous use is

defined in § 1271.3(d) as the use of a

cellular or tissue-based product for

replacement or supplementation of a

recipient’s cells or tissues. Homologous

use of a structural tissue-based product

occurs when the tissue is used for the

same basic structural function that it

fulfills in its native state, in a location

where such structural function normally

occurs. Basic function of a structural

tissue is what the tissue does from a

biological/physiological point of view,

or is capable of doing when in its native

state. For example, the agency considers

structural tissue to be used for a

homologous function when it is used to

replace an analogous structural tissue

that has been damaged or otherwise

does not function adequately.

Conversely, the agency would consider

structural tissue to be performing a

nonhomologous function when it is

fulfilling a function that is different

from the basic function it fulfills in its

native state.

Examples of homologous use claims

for structural tissues that would fall

within the scope of part 1271 include

bone allograft obtained from a long bone

but labeled for use in a vertebra; skin

allograft obtained from the arm but

labeled for use as a skin graft on the

face; pericardium, a structural

membranous covering of the heart,

labeled for use as a structural

membranous covering for the brain; and

heart valves labeled for use as heart

valves. An example of a nonhomologous

use claim for structural tissue is

cartilage labeled for placement under

the submucosal layer of the urinary

bladder to change the angle of the ureter

and thereby prevent backflow of urine

from the bladder into the ureter. The

cartilage would be performing a

structural function (adding volume to

change the angle of the ureter) which is

different from the function in its native

state (to afford flexibility and provide

musculoskeletal support).

According to the definition,

homologous use of nonstructural

cellular or tissue-based products occurs

when the cells or tissues are used to

perform the function(s) that they

performed in the donor. An example of

a homologous use claim would be

hematopoietic stem cells labeled for use

for hematopoietic reconstitution. An

example of a nonhomologous use claim

for the same cellular product would be

a claim for treatment of adrenal

leukodystrophies (congenital metabolic

deficiencies).

In determining whether a product

comes under part 1271 or is instead

required to comply with premarketing

requirements, FDA has tentatively

decided to focus on whether a cellular

or tissue-based product is promoted or

labeled by its manufacturer for a

nonhomologous use, rather than on the

intent of the practitioner who uses the

product. Accordingly, the actual use of

a cellular or tissue-based product for a

nonhomologous function would not

trigger premarket review requirements if

the product was not labeled or

promoted for nonhomologous use. This

change from the Proposed Approach

document comes in response to industry

concerns and is expected to lead to the

more efficient use of the agency’s

resources. The agency specifically

requests comments on this new

language.

4. Nontissue or Noncellular Component

Products combined with or modified

by the addition of any nontissue or

noncellular component that is a drug or

device will not be regulated under part

1271. Because ‘‘nontissue or noncellular

component’ is self-explanatory, FDA

does not consider it necessary to define

the term. However, the agency has

modified the phrase ‘‘nontissue or

noncellular component’’ with the words

‘‘that is a drug or device’’ in order to

clarify that water and buffers would not

ordinarily be considered nontissue or

noncellular components. In contrast, a

product composed of human cells or

tissue in combination with a mechanical

or synthetic component, such as

epithelial cells on a biomatrix to cover

burns, would not come under part 1271

and would be regulated under section

351 of the PHS Act and/or the act.

5. Systemic Effect

The final requirement for a product to

be regulated under part 1271 is that the

product not have a systemic effect.

Given that ‘‘systemic’’ is a commonly

used medical term, FDA is not

proposing a regulatory definition of the

word. The agency would consider the

insertion of pancreatic islet cells,

pituitary cells, or stem cells into an

individual to have a mainly systemic

effect. In contrast, the insertion of

replacement bone would not have a

mainly systemic effect; the effect would

be limited to the immediate area around

the insertion. FDA recognizes that some

products may have both systemic and

structural effects but intends that a

product’s primary effect be

determinative.

Earlier discussions of FDA’s

regulatory plans, including the

Proposed Approach document, used the

term ‘‘metabolic function.’’ After

considering concerns raised by

comments on the proposed approach,

FDA has decided that ‘‘systemic effect’’

more accurately reflects the agency’s

intended meaning.

6. Autologous, Allogeneic, FamilyRelated Allogeneic, and Reproductive

Uses

Under § 1271.10(d), there are several

exceptions to the requirement that a

human cellular or tissue-based product

not have a systemic effect to be

regulated under part 1271. These

exceptions are for cases of autologous or

family-related allogeneic systemic use

and for reproductive use. Thus,

products with a systemic effect that are

utilized for autologous, family-related

allogeneic, or reproductive use and that

meet the other criteria set out in

§ 1271.10 will be regulated under part

1271.

Autologous use is defined in

§ 1271.3(a) as the implantation,

transplantation, infusion, or transfer of

a cellular or tissue-based product back

into the individual from whom the cells

or tissue comprising such product were

removed. Several comments on the

Proposed Approach document pointed

out that the agency had used

‘‘Autologous’’ in a confusing manner.

With the previous definition, the agency

intends to clarify the meaning of the

word. In contrast with autologous use,

allogeneic use (not defined in this

regulation) is the transplantation of cells

or tissue obtained from a different

individual.

FDA is using the phrase ‘‘familyrelated’’ for situations where the
26750 Federal Register / Vol. 63, No. 93 /Thursday, May 14, 1998 / Proposed Rules

recipient of cells or tissue is a biological

parent, child, or sibling of the donor.

Thus, family-related allogeneic use is

defined in § 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. Some comments on the

Proposed Approach document have

disagreed with FDA’s definition of

‘‘family-related,’’ arguing that its scope

should be made broader to include such

relatives as cousins and grandparents.

Other comments have argued against an

exception for family related allogeneic

use, asserting that the family-related

allogeneic use of products with a

systemic effect should be treated no

differently from any other allogeneic

use. The agency specifically requests

further comment on this issue.

The third situation in which a

product with a systemic effect will be

regulated under part 1271 is when the

product contains human reproductive

cells or tissue and is for reproductive

use. In contrast to other tissues with a

systemic effect, transfer of reproductive

tissues such as semen and ova pose less

risk to the health of the recipient from

rejection, graft-versus-host disease, and

compatibility. In addition, the failure of

a reproductive-tissue product will

generally cause lesser health risks to the

individual than the failure of other

systemic products. FDA has decided

that it is not necessary to define

‘‘reproductive use’’ in the regulation,

because the term is well understood.

7. Transfer

Some of the definitions in § 1271.3

contain the terms implantation,

transplantation, and infusion, which

FDA believes are generally understood.

However, FDA is proposing to define,

for the purpose of this part, transfer,

which may not be as well understood,

to mean ‘‘the placement of human

reproductive cells or tissues into a

human recipient.’’ This definition, in

§ 1271.3(k), reflects the way the term

‘‘transfer’’ is used within the

reproductive tissue industry.

8. Establishment and Manufacture

Other terms defined in § 1271.3 relate

to the manufacturing of human cellular

and tissue-based products. An

establishment is defined as a place of

business under one management, at one

general physical location that engages in

the manufacture of human cellular or

tissue-based products. The term

includes facilities that engage in

contract manufacturing services for a

manufacturer. The term also includes

any individual, partnership,

corporation, association, or other legal

entity engaged in the manufacture of

human cellular or tissue-based

products.

Under § 1271.3(f), the term

manufacture includes all steps in the

recovery, screening, testing, processing,

storage, labeling, packaging, or

distribution of any human cellular or

tissue-based product. The agency

interprets certain terms used in the

definition of ‘‘manufacture’’ in the

following ways. By ‘‘recovery’’ FDA

means obtaining cells or tissues from a

donor that are intended for use in

human transplantation, infusion,

implantation, or transfer. ‘‘Storage’’

would include holding human cells or

tissue for future distribution or use.

‘‘Processing’’ means any activity, other

than recovery, performed on a human

cellular or tissue-based product,

including preventing contamination and

preserving the function and integrity of

the product. Processing includes

preparation, preservation for storage,

removal from storage, and any steps to

inactivate and remove adventitious

agents. ‘‘Distribution’’ includes any

conveyance or shipment of human

cellular or tissue-based product

(including importation and exportation),

whether or not such conveyance or

shipment is entirely intrastate and

whether or not possession of the human

cellular or tissue-based product is taken.

Many entities and individuals that

would be considered manufacturers

under part 1271 because they recover

human cells or tissues expressed

concerns that they would be subject to

registration requirements. FDA

anticipates that individuals engaged

solely in the procurement or recovery of

cells or tissues and under contract to

organizations that coordinate

procurement or recovery of human cells

or tissues will not have to

independently register under part 1271.

Registration will be the responsibility of

the employer or contracting

organization, which will also be

required under future rulemaking to

ensure that its employees, agents, and

contractors that engage in the recovery

of cells or tissues comply with

applicable regulations or procedures

regarding the collection, safe handling,

and proper shipment of human cells or

tissues.

C. Procedures for Registration and

Listing

The procedures for complying with

proposed part 1271, found in subpart B,

are designed to impose only a minimal

burden on manufacturers while

providing FDA with the basic

information needed to underpin its

regulatory program. Under § 1271.21(a),

registration and listing are required

within 5 days after the initiation of an

establishment’s operations. Registration

updates are required annually, by

December 31, under § 1271.21(b).

Section 1271.21(c) governs the semiannual updating of product lists.

Product lists must be updated with the

following information: (1) Each human

cellular or tissue-based product

introduced by the registrant for

distribution that has not been included

in any list previously submitted; (2)

each human cellular or tissue-based

product formerly listed for which

distribution has been discontinued; (3)

each human cellular or tissue-based

product for which a notice of

discontinuance was submitted and for

which distribution has been resumed;

and (4) any material change in any

information previously submitted.

Product list updates must be submitted

each June and December; alternatively,

they may be submitted at the time the

change occurs. When no changes have

occurred since the previously submitted

product list, no update is required.

Section 1271.22 requires registration,

listing, and annual updates to be

submitted on Form FDA 3356. That

section also tells how to obtain the form

and where to submit it, including

information on obtaining the form

electronically. The agency anticipates

that some firms may prefer the ease of

obtaining the registration and listing

form electronically. For this reason, an

electronic version of this form is

currently being developed. It will be

available by the time the final

regulations go into effect.

Section 1271.25 sets out the

information required for registration and

listing, including the name and address

of the establishment. Information

required for product listings includes

the established and proprietary names

of each product, as well as a statement

of whether the product meets the

criteria set out in § 1271.10. (Any

change in whether a product meets

these criteria will be considered a

‘‘material change’’ subject to reporting

under § 1271.21(c)(iv).)

Under § 1271.26, changes in an

establishment’s ownership or location

are to be submitted as an amendment to

registration within 5 days of such

changes. Section 1271.27 states that the

agency will provide the registrant with

a permanent registration number.

Section 1271.37 sets out the registration

and product listing information that will

be made available to the public.

At this time, the agency is not

proposing to charge a fee for registration
Federal Register / Vol. 63, No. 93 /Thursday, May 14, 1998 / Proposed Rules 26751

or product listing. FDA is evaluating its

authority to assess a fee and the impacts

of such a fee. If it determines that a fee

it is appropriate, the agency will make

such a proposal in a future rulemaking.

D. Amendments to Parts 207 and 807

FDA proposes to add new paragraph

(f) to § 207.20 and new paragraph (e) to

§ 807.20. These additions will state that

owners and operators of establishments

that recover, screen, test, process, store,

label, package, or distribute human

cellular or tissue-based products, as

defined in § 1271.3(f), shall register and

list those products with CBER on Form

FDA 3356, following the procedures

found in subpart B of part 1271. Thus,

instead of following the procedures in

subpart C of part 207 (e.g., procedures

contained in §§ 207.21, 207.22, 207.25,

207.26, and 207.30), establishments that

manufacture human cellular or tissuebased products regulated as biological

drugs under the act and the PHS Act

would follow the procedures set out in

part 1271, subpart B. Regulations that

do not pertain to the procedural

requirements for registration and listing

(e.g., § 207.39, on misbranding) would

still apply. In addition, new § 207.20(f)

will specifically state that the

procedures for submitting additional

information, in § 207.31, remain

applicable.

With respect to human cellular or

tissue-based products regulated as

devices under the act, manufacturers

would follow the registration and listing

procedures of part 1271, subpart B,

instead of those found in part 807,

subpart B (e.g., procedures in §§ 807.21,

807.22, 807.25, 807.26, and 807.30). As

would be the case for devices, the

requirements for additional listing

information in § 807.31 will remain in

place and regulations that do not pertain

to registration and listing (e.g., § 807.39)

would still be applicable.

IV. Analysis of Economic Impacts

FDA has examined the impacts of the

proposed rule under Executive Order

12866, under the Regulatory Flexibility

Act (5 U.S.C. 601–612), and under the

Unfunded Mandates Reform Act (Pub.

L. 104–4). Executive Order 12866

directs agencies to assess all costs and

benefits of available regulatory

alternatives and, when regulation is

necessary, to select regulatory

approaches that maximize net benefits

(including potential economic,

environmental, public health and safety,

and other advantages; distributive

impacts; and equity).

The Regulatory Flexibility Act

requires agencies to analyze whether a

rule may have a significant impact on a

substantial number of small entities

and, if it does, to analyze regulatory

options that would minimize the

impact. The Unfunded Mandates

Reform Act requires that agencies

prepare an assessment of anticipated

costs and benefits before proposing any

rule that may result in an expenditure

by State, local, and tribal governments,

in the aggregate, or by the private sector,

of $100,000,000 (adjusted annually for

inflation) in any 1 year. The agency has

determined that the proposed rule is a

significant rule as described in the

Executive Order, but not a significant

action as defined in the Unfunded

Mandates Reform Act. Aggregate

impacts of the rule, and aggregate

expenditures caused by the rule, will

not approach $100 million for either the

public or the private sector.

An analysis of available information

suggests that costs to the entities most

affected by this rule, including small

entities, are not expected be significant,

as described in the analysis below.

Therefore, the agency certifies that this

rule will not have a significant impact

on a substantial number of small

entities.

A. Objective and Basis of the Proposed

Action.

FDA is proposing this action as a first

step in the regulation of the rapidly

evolving industry of human cellular and

tissue-based products. This industry has

not been previously subject to a

comprehensive regulatory program by

FDA or other public health authorities.

Lack of a single regulatory approach or

registration system has prevented the

agency from acquiring information

regarding the full size of the cell and

tissue industry and the scope of its

products. The proposed rule will

require all manufacturers of human

cellular and tissue-based products to

register with the agency and to submit

to the agency a list of their products.

Through registration and listing, FDA

will be able to identify industry

participants and the products

manufactured. This will enable the

agency to more efficiently monitor the

industry, distribute new information

such as guidances, policies, or

requirements, and identify entities that

may be subject to inspection by FDA.

This action is taken solely under the

authority of section 361 of the PHS Act.

Section 361 is also used as authority to

amend parts 207 and 807 so that the

registration data bases developed for

drugs and devices may be consolidated

with the data base of the proposed

human cell and tissue registration

program. Section 510 of the act remains

the substantive registration requirement

for products subject to parts 207 and

807. FDA has reviewed related Federal

rules and has not identified any rules

that duplicate, overlap, or conflict with

the proposed rule.

B. Small Entities Affected

This proposal affects both entities that

currently register with FDA and submit

product lists to the agency under

applicable sections of the act (parts 207

and 807), and those entities that are not

presently required to register or list with

the agency. FDA has structured

registration and listing to have a

minimal impact on affected entities.

However, the agency anticipates that the

impact will be greater for those entities

that do not currently register or list.

The number of entities that will be

required to begin registration and listing

under part 1271 is difficult to ascertain.

Because the agency has not previously

regulated certain human cellular and

tissue-based products, the agency can

only approximate the number of entities

that may fall under the requirements of

the proposed rule. This lack of

accessible, accurate information is, in

fact, a major reason behind the agency’s

registration and listing initiative. In

calculating the burden, the agency has

used information obtained from various

trade organizations related to the human

cellular and tissue-based industry.

Several organizations also provided

estimates of what portion of the

industry their membership represented,

and the agency included in its analysis

the 65 manufacturers of human cellular

and tissue-based device products that

are registered with the agency under

part 807. The Musculoskeletal

Transplant Foundation lists

approximately 25 tissue and organ

recovery members, which it estimates to

be about one-third of the tissue and

organ procurement organizations in the

United States. The National Bone

Marrow Donor Program, which includes

establishments that recover peripheral

blood stem cells, lists approximately

101 donor centers and 114 collection

centers in the United States. The

American Association of Tissue Banks

(AATB) lists approximately 60 tissue

banks. The Eye Bank Association of

America represents about 112 eye

banks, which it estimates is about 95

percent of the U.S. eye banks. The

American Society for Reproductive

Medicine has a membership of

approximately 7,200 physicians,

researchers, and other health care

professionals, of which perhaps only

120 are fertility doctors who would be

subject to the registration and listing

requirements. In addition, it is

estimated that there are about 90 semen
26752 Federal Register / Vol. 63, No. 93 /Thursday, May 14, 1998 / Proposed Rules

depositories in commercial operation.

Any of the entities described above that

engage in manufacture (including, but

not limited to, recovery, screening,

testing, processing, storage, labeling,

packaging, or distribution) of human

cellular or tissue-based products would

be affected by the proposed rule. A great

majority of these approximately 680

entities would be considered ‘‘small’’

under criteria established by the Small

Business Administration. FDA invites

comments on this analysis of the

number of entities that may be affected

by the proposed registration and listing

rule.

C. Nature of the Impact

The main cost involved in

implementing the proposed rule would

be the time required to obtain the form,

read the instructions, and complete and

submit the form. FDA has no precise

estimate of the initial registration and

listing procedure but estimates that it

should require an average of 1 hour of

staff time per registrant. This estimate is

supported by the estimates prepared for

the completion of the blood product

registration on FDA Form 2830, which

is similar in length, type of information

requested, and complexity to the

proposed Form FDA 3356 (62 FR 11898,

March 13, 1997). In addition, the

proposed rule will require an update of

the product list which is estimated to

require about 0.5 hour of staff time.

Thus, registration and listing is

anticipated to require about 1.5 hours of

staff time per annum. At an estimated

$38.00/hour value of staff time, most

registrants are expected to incur an

annual cost of approximately $57.00 to

comply with the requirements of the

proposed rule. There are no specific

educational or technical skills required

to complete and submit the registration

and listing form. Similar activities are

generally completed by trained and

qualified employees of an establishment

who are intimately involved with the

operations of the entity.

The proposed rule is the first step in

creating a tiered, risk-based regulatory

scheme that will tailor the degree of

scrutiny afforded to different products

to the risks associated with each

product. Through registration and

listing, FDA will acquire the

information needed to characterize the

nature and extent of the human cellular

and tissue-based industry. This

information will enable FDA to

efficiently and effectively respond to

emerging public health concerns related

to human cellular or tissue-based

products. Lists of industry members and

their products will also help FDA

disseminate educational materials and

other important information regarding

FDA policies, guidances, and

requirements.

D. Minimizing the Impact on Small

Entities

FDA recognizes that a large number of

the establishments that would be

required to register and list under the

proposed rule will be small entities with

limited resources. In recognition of this,

the agency is proposing that the

information to be provided during

registration and listing be only that

which is necessary to achieve the

agency’s goals of industry

characterization and identification of its

participants. To alleviate the impact on

entities, especially small entities, FDA

proposes that Form FDA 3356 be

electronically retrievable. Future

development of registration and listing

will consider the use of electronic

submissions (e-mail or Internet) and

electronic signatures.

V. Proposed Effective Date

The agency proposes that any final

rule that may issue based on this

proposed rule become effective 180 days

after its date of publication in the

Federal Register.

VI. Environmental Impact

The agency has determined under 21

CFR 25.30(h) that this action is of a type

that is categorically excluded from the

preparation of an environmental

assessment because these actions, as a

class, will not result in the production

or distribution of any substance and

therefore will not result in the

production of any substance into the

environment.

VII. The Paperwork Reduction Act of

1995

This proposed rule contains

information collection requirements that

are subject to review by the Office of

Management and Budget (OMB) under

the Paperwork Reduction Act of 1995

(44 U.S.C. 3501–3520). The title,

description, and respondent description

of the information collection

requirements are shown below with an

estimate of the annual reporting burden.

Included in the estimate is the time for

reviewing the instructions, gathering

necessary information, and completing

and reviewing the report.

With respect to the following

collection of information, FDA invites

comments on: (1) Whether the proposed

collection of information is necessary

for the proper performance of FDA’s

functions, including whether the

information will have practical utility;

(2) the accuracy of FDA’s estimate of the

burden of the proposed collection of

information, including the validity of

the methodology and assumptions used;

(3) ways to enhance the quality, utility,

and clarity of the information to be

collected; and (4) ways to minimize the

burden of the collection of information

on respondents, including through the

use of automated collection techniques,

when appropriate, and other forms of

information technology.

Title: Establishment Registration and

Product Listing for Manufacturers of

Human Cellular and Tissue-based

Products.

Description: FDA is proposing to

require establishments that recover,

screen, test, process, store, label,

package, or distribute any human

cellular or tissue-based product to

register with FDA and submit lists of the

manufactured products to be updated

twice a year. FDA proposes to define

certain terms relevant to registration and

listing, define which manufactures will

be subject to the provisions of the

proposed rule, and provide a form

(Form FDA 3356) to be used for the

entry of an entity’s name and location

information and its product list. FDA is

proposing this action in response to the

agency’s public health concerns

regarding products comprised of human

cells or tissues, or that incorporate such

cells or tissues. Through this initiative

the agency will improve its ability to

protect the public health by controlling

the spread of communicable diseases.

Description of Respondents:

Manufacturers of human cellular and

tissue-based products.

TABLE 1.—ESTIMATED ANNUAL REPORTING BURDEN1

21 CFR Form No. No. of

Respondents

Annual

Frequency per

Response

Total Annual

Responses

Hours per

Response

(average)

Total Hours

1271 FDA 3356 680 2 1,360 0.75 1,020

207.20 FDA 3356 1 2 2 0.75 1.5
Federal Register / Vol. 63, No. 93 /Thursday, May 14, 1998 / Proposed Rules 26753

TABLE 1.—ESTIMATED ANNUAL REPORTING BURDEN1—Continued

21 CFR Form No. No. of

Respondents

Annual

Frequency per

Response

Total Annual

Responses

Hours per

Response

(average)

Total Hours

807.20 FDA 3356 65 2 130 0.75 97.5

TOTAL 746 2 1,492 0.75 1,119

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

Because many manufacturers of

products using human cells or tissues

have not been required to register or list

with FDA, the agency’s ability to predict

how many entities would be affected by

the proposed rule is limited. The

estimates for number of respondents are

based on the number of entities

currently registered with FDA as

manufacturers of human cellular or

tissue-based devices, membership

information obtained from trade

organizations related to the

manufacturing of products utilizing

human cells or tissues, and an estimate

of entities that are not presently

registered with FDA or members of

trade organizations but that would be

subject to registration under the

proposed rule. The annual frequency of

responses is based on the requirement

in the proposed rule for the submission

of an annual registration and a biannual

product list updating. In practice, it is

expected that the annual registration, or

annual confirmation of registration for

entities that have already registered

once, and the first product list update of

the biannual requirement will be

completed simultaneously on the same

form. The hours for response was

obtained by averaging the estimates of 1

hour of staff time for the initial, or

confirmatory registration and 0.5 hour

of staff time for the update of the

product list. The ‘‘Total Hours’’ column

provides the estimated total number of

hours for registration and listing by

manufacturers of human cellular and

tissue-based products under proposed

part 1271, existing §§ 207.20 and 807.20

as they would be amended by the

proposal, and a cumulative total for

registration and listing by manufacturers

of such products under all three

sections.

In compliance with section 3507(d) of

the Paperwork Reduction Act of 1995

(44 U.S.C. 3507(d)), the agency has

submitted a copy of this proposed rule

to OMB for review of the information

collection provisions. Interested persons

are requested to submit written

comments regarding information

collection by June 15, 1998, to the Office

of Information and Regulatory Affairs,

OMB (address above), Attention: Desk

Officer for FDA.

VIII. Request for Comments

Interested person may, on or before

August 12, 1998, submit to the Dockets

Management Branch (address above)

written comments regarding this

proposal, except that comments

regarding information collection

provisions should be submitted in

accordance with the instructions in

section VII of this document. Two

copies of any comments on issues other

than information collection are to be

submitted, except that individuals may

submit one copy. Comments are to be

identified with the docket number

found in brackets in the heading of this

document. Received comments may be

seen in the office above between 9 a.m.

and 4 p.m., Monday through Friday.

List of Subjects

21 CFR Part 207

Drugs, Reporting and recordkeeping

requirements.

21 CFR Part 807

Confidential business information,

Imports, Medical devices, Reporting and

recordkeeping requirements.

21 CFR Part 1271

Human cellular and tissue-based

products, Reporting and recordkeeping

requirements.

Therefore, under the Federal Food,

Drug, and Cosmetic Act and the Public

Health Service Act, and under authority

delegated to the Commissioner of Food

and Drugs, it is proposed that chapter I

of title 21 of the Code of Federal

Regulations be amended as follows:

PART 207—REGISTRATION OF

PRODUCERS OF DRUGS AND LISTING

OF DRUGS IN COMMERCIAL

DISTRIBUTION

1. The authority citation for 21 CFR

part 207 is revised to read as follows:

Authority: 21 U.S.C. 331, 351, 352, 355,

356, 357, 360, 360b, 371, 374; 42 U.S.C. 262,

264, 271.

2. Section 207.20 is amended by

adding new paragraph (f) to read as

follows:

§ 207.20 Who must register and submit a

drug list.

* * * * *

(f) Owners and operators of

establishments or persons engaged in

the recovery, screening, testing,

processing, storage, or distribution of

human cellular or tissue-based

products, as defined in § 1271.3(e) of

this chapter, that are regulated under

section 351 of the Public Health Service

Act and/or the Federal Food, Drug, and

Cosmetic Act shall register and list

those products with the Center for

Biologics Evaluation and Research on

Form FDA 3356 following the

procedures set out in subpart B of part

1271 of this chapter, except that the

additional listing information

requirements in § 207.31 remain

applicable.

PART 807—ESTABLISHMENT

REGISTRATION AND DEVICE LISTING

FOR MANUFACTURERS AND

DISTRIBUTORS OF DEVICES

3. The authority citation for 21 CFR

part 807 is revised to read as follows:

Authority: 21 U.S.C. 331, 351, 352, 360,

360c, 360e, 360i, 360j, 371, 374; 42 U.S.C.

264, 271.

4. Section 807.20 is amended by

adding new paragraph (e) to read as

follows:

§ 807.20 Who must register and submit a

device list.

* * * * *

(e) Owners and operators of

establishments or persons engaged in

the recovery, screening, testing,

processing, storage, or distribution of

human cellular or tissue-based

products, as defined in § 1271.3(e) of

this chapter, that are regulated under

section 351 of the Public Health Service

Act and/or the Federal Food, Drug, and

Cosmetic Act shall register and list

those products with the Center for

Biologics Evaluation and Research on

Form FDA 3356 following the

procedures set out in subpart B of part

1271 of this chapter, except that the

additional listing information

requirements in § 807.31 remain

applicable.
26754 Federal Register / Vol. 63, No. 93 /Thursday, May 14, 1998 / Proposed Rules

5. New part 1271 is added to read as

follows:

PART 1271—ESTABLISHMENT

REGISTRATION AND PRODUCT

LISTING FOR MANUFACTURERS OF

HUMAN CELLULAR AND TISSUEBASED PRODUCTS

Subpart A—General Provisions

Sec.

1271.1 Purpose.

1271.3 Definitions.

1271.10 Who must register and submit a

list.

1271.20 Establishments not required to

register or list under this part.

Subpart B—Procedures for

Registration and Listing

1271.21 When to register and list.

1271.22 How and where to register and list.

1271.25 Information required for

registration and listing.

1271.26 Amendments to registration.

1271.27 Assignment of a registration

number.

1271.37 Inspection of establishment

registration and product lists.

Authority: 42 U.S.C. 216, 243, 264, 271.

Subpart A—General Provisions

§ 1271.1 Purpose.

The purpose of this part is to create

a unified registration and product listing

system for establishments that

manufacture human cellular and tissuebased products. Manufacturers of

human cellular and tissue-based

products regulated under the authority

of section 361 of the Public Health

Service Act are required by this part to

register and list their products with the

Food and Drug Administration, Center

for Biologics Evaluation and Research.

Under §§ 207.20(f) and 807.20(e) of this

chapter, manufacturers of human

cellular and tissue-based products

regulated under section 351 of the

Public Health Service Act and/or the

Federal Food, Drug, and Cosmetic Act

are required to register and list their

products following the procedures in

subpart B of this part.

§ 1271.3 Definitions.

The following definitions apply only

to this part:

(a) Autologous use means the

implantation, transplantation, infusion,

or transfer of a human cellular or tissuebased product back into the individual

from whom the cells or tissue

comprising such product were removed.

(b) Establishment means a place of

business under one management, at one

general physical location, that engages

in the manufacture of human cellular or

tissue-based products. The term

includes, among others, facilities that

engage in contract manufacturing

services for a manufacturer of human

cellular or tissue-based products. The

term also includes any individual,

partnership, corporation, association, or

other legal entity engaged in the

manufacture of human cellular or

tissue-based products, except that an

individual engaged solely in the

procurement or recovery of cells or

tissues or under contract to a registered

establishment is not required to

independently register.

(c) Family-related allogeneic use

means the implantation,

transplantation, infusion, or transfer of

a human cellular or tissue-based

product into a first-degree blood relative

of the individual from whom cells or

tissue comprising such product were

removed.

(d) Homologous use means the use of

a cellular or tissue-based product for

replacement or supplementation and:

(1) For structural tissue-based

products, occurs when the tissue is used

for the same basic function that it

fulfills in its native state, in a location

where such structural function normally

occurs; or

(2) For cellular and nonstructural

tissue-based products, occurs when the

cells or tissue is used to perform the

function(s) that they perform in the

donor.

(e) Human cellular or tissue-based

product means a product containing

human cells or tissues or any cell or

tissue-based component of such a

product. The following products are not

considered human cellular or tissuebased products and establishments that

manufacture only one or more of the

following would not be subject to the

registration or listing provisions of this

part:

(1) Vascularized human organs for

transplantation;

(2) Whole blood or blood components

or blood derivative products subject to

listing under part 607 of this chapter;

(3) Secreted or extracted human

products, such as milk, collagen, and

cell factors;

(4) Minimally manipulated bone

marrow;

(5) Ancillary products used in the

propagation of cells or tissues; or

(6) Cells, tissues or organs derived

from animals.

(f) Manufacture means, but is not

limited to, any or all steps in the

recovery, screening, testing, processing,

storage, labeling, packaging, or

distribution of any human cellular or

tissue-based product.

(g) Minimal manipulation means:

(1) For structural tissue, processing

that does not alter the original relevant

characteristics of the tissue relating to

the tissue’s utility for reconstruction,

repair, or replacement; and

(2) For cells and nonstructural tissues,

processing that does not alter the

relevant biological characteristics of

cells or tissues.

(h) Transfer means the placement of

human reproductive cells or tissues into

a human recipient.

§ 1271.10 Who must register and submit a

list.

All owners and operators of

establishments, both foreign and

domestic, that manufacture human

cellular and tissue-based products,

whether or not the product enters into

interstate commerce, are required under

this part to register with the Food and

Drug Administration and submit to the

agency a list of each human cellular or

tissue-based product manufactured, if

such product is:

(a) Minimally manipulated;

(b) Not promoted or labeled for any

use other than a homologous use;

(c) Not combined with or modified by

the addition of any nontissue or

noncellular component that is a drug or

a device; and

(d) Does not have a systemic effect;

except that a human cellular or tissuebased product that meets the

requirements in paragraphs (a), (b), and

(c) of this section may have a systemic

effect if the product is for:

(1) Autologous use;

(2) Family-related allogeneic use; or

(3) Reproductive use and contains

human reproductive cells or tissue.

§ 1271.20 Establishments not required to

register or list under this part.

The following establishments are not

required to register or submit product

listings under this part:

(a) Establishments that use human

cellular or tissue-based products solely

for nonclinical scientific or educational

purposes;

(b) Establishments that remove human

cellular or tissue-based products from

an individual and implant such cells or

tissues into the same individual during

the same surgical procedure;

(c) Carriers who accept, receive, carry,

hold, or deliver human cellular or

tissue-based products in the usual

course of business as carriers; and

(d) Establishments that only receive or

store human cellular or tissue-based

products solely for pending scheduled

implantation, transplantation, infusion,

or transfer within the same facility.
Federal Register / Vol. 63, No. 93 /Thursday, May 14, 1998 / Proposed Rules 26755

Subpart B—Procedures for

Registration and Listing

§ 1271.21 When to register and list.

(a) Owners and operators of

establishments required to register and

list under § 1271.10 or required under

other provisions of this chapter to

follow the procedures in subpart B of

this part shall register within 5 days

after beginning operations and shall

submit a list of every product that is

manufactured.

(b) Owners and operators of

establishments shall update their

registration annually by December 31,

except as required by § 1271.26. Annual

registration may be accomplished in

conjunction with the updating of

product lists under paragraph (c) of this

section.

(c)(1) Owners and operators of

establishments shall update their

product lists during each June and

December or, at their discretion, at the

time the change occurs, with the

following information:

(i) A list of each human cellular or

tissue-based product introduced by the

registrant for distribution that has not

been included in any list previously

submitted. The registrant shall provide

all of the information required by

§ 1271.25(b) for each such product.

(ii) A list of each human cellular or

tissue-based product formerly listed in

accordance with paragraph (a) of this

section and for which distribution has

been discontinued, including for each

product so listed, the identity by

established name and proprietary name,

and the date of discontinuance. It is

requested but not required that the

reason for discontinuance of

distribution be included with this

information.

(iii) A list of each human cellular or

tissue-based product for which a notice

of discontinuance was submitted under

paragraph (c)(1)(ii) of this section and

for which distribution has been

resumed, including the identity by

established name and proprietary name,

the date of resumption, and any other

information required by § 1271.25(b) not

previously submitted.

(iv) Any material change in any

information previously submitted.

Material changes include any change in

whether the product meets the criteria

set out in § 1271.10.

(2) When no changes have occurred

since the previously submitted list, no

report is required.

§ 1271.22 How and where to register and

list.

(a) Establishment registration, product

listing, and updates of registration and

listing shall be submitted on Form FDA

3356 to the Center for Biologics

Evaluation and Research (HFM–370),

Food and Drug Administration, 1401

Rockville Pike, Rockville, MD 20852–

1448, Attention: Tissue Establishment

Registration Coordinator, or

electronically in accordance with

instructions provided with Form FDA

3356.

(b) Copies of Form FDA 3356 can be

obtained from the Center for Biologics

Evaluation and Research (HFM–370),

Food and Drug Administration, 1401

Rockville Pike, Rockville, MD 20852–

1448, Attention: Tissue Establishment

Registration Coordinator (from any Food

and Drug Administration district office);

by calling the CBER Voice Information

System at 1–800–835–4709 or 301–827–

1800, or by calling the Fax Information

System at 1–888–CBER–FAX or 301–

827–3844. Persons with access to the

Internet may obtain the document using

the World Wide Web (WWW) by

connecting to: CBER at ‘‘http//

www.fda.gov/cber/publication.htm’’.

§ 1271.25 Information required for

registration and listing.

(a) Registration shall include:

(1) The legal name(s) of the

establishment;

(2) Each location, including the street

address of the establishment and the

postal service zip code;

(3) The name, address, and title of the

reporting official; and

(4) A signed and dated statement by

the reporting official affirming that all

information contained in the

registration and listing form is true and

accurate.

(b) Listing information shall include

all human cellular or tissue-based

products (including the established

name and the proprietary name) that are

recovered, screened, tested, processed,

stored, labeled, packaged, and

distributed. Listing information shall

also include a statement of whether

each product meets the criteria set out

in § 1271.10.

(c) Copies of all contract service

agreements shall be available at the time

of inspection of the establishment.

§ 1271.26 Amendments to registration.

Changes in the ownership or location

of an establishment shall be submitted

as an amendment to registration within

5 days of such changes.

§ 1271.27 Assignment of a registration

number.

(a) A permanent registration number

will be assigned to each location.

(b) FDA acceptance of establishment

registration and listing forms for human

cellular and tissue-based products does

not constitute a determination that an

establishment is in compliance with

applicable rules and regulations.

§ 1271.37 Inspection of establishment

registration and product lists.

(a) A copy of the Form FDA 3356 filed

by each establishment will be available

for inspection at the Office of

Communication, Training, and

Manufacturers Assistance (HFM–48),

Center for Biologics Evaluation and

Research, Food and Drug

Administration, 1401 Rockville Pike,

suite 200N, Rockville, MD 20852–1448.

In addition, there will be available for

inspection at each of the Food and Drug

Administration district offices the same

information for firms within the

geographical area of such district office.

Upon request and receipt of a selfaddressed stamped envelope,

verification of a registration number or

the location of a registered

establishment will be provided. The

following information submitted under

the human cellular and tissue-based

product requirements is illustrative of

the type of information that will be

available for public disclosure when it

is compiled:

(1) A list of all human cellular and

tissue-based products;

(2) A list of all human cellular and

tissue-based products manufactured by

each establishment;

(3) A list of all human cellular and

tissue-based products discontinued; and

(4) All data or information that has

already become a matter of public

record.

(b) Requests for information regarding

human cellular and tissue-based

product establishment registrations and

product listings should be directed to

the Office of Communication, Training

and Manufacturers Assistance (HFM–

48), Center for Biologics Evaluation and

Research, Food and Drug

Administration, 1401 Rockville Pike,

suite 200N, Rockville, MD 20852–1448.

Dated: March 10, 1998.

Michael A. Friedman,

Lead Deputy Commissioner for the Food and

Drug Administration.

Donna E. Shalala,

Secretary of Health and Human Services.

[FR Doc. 98–12751 Filed 5–13–98; 8:45 am]

BILLING CODE 4160–01–F