Suitability Determination for Donors of Human Cellular and Tissue-Based Products

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 210, 211, 820, and 1271

[Docket No. 97N-484S]

Suitability Determination for Donors of Human Cellular and

Tissue-Based Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing new

regulations to require manufacturers of human cellular and tissue-based

products to screen and test the donors of cells and tissue used in

those products for risk factors for and clinical evidence of relevant

communicable disease agents and diseases. Human cellular and tissue-

based products are products that contain or consist of human cells or

tissues and that are intended for implantation, transplantation,

infusion, or transfer. As part of this regulatory action, the agency is

proposing to amend the current good manufacturing practice (CGMP)

regulations that apply to human cellular and tissue-based products

regulated as drugs, medical devices, and/or biological products to

incorporate the new donor-suitability procedures into existing good

manufacturing practice (GMP) regulations. The agency is taking this

action to provide more appropriate oversight for the wide spectrum of

human cellular and tissue-based products that are marketed now or may

be marketed in the future. The agency's action would improve protection

of the public health and increase public confidence in new

technologies, while permitting significant innovation and keeping

regulatory burden to a minimum.

DATES: Submit written comments on the proposed rule on or before

December 29, 1999. Submit written comments on the information

collection provisions on or before November 1, 1999.

the future. The agency's action would improve protection

of the public health and increase public confidence in new

technologies, while permitting significant innovation and keeping

regulatory burden to a minimum.

DATES: Submit written comments on the proposed rule on or before

December 29, 1999. Submit written comments on the information

collection provisions on or before November 1, 1999.

ADDRESSES: Submit written comments to the Dockets Management Branch

(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,

Rockville, MD 20852. 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: Wendy Taylor, Desk Officer for FDA.

FOR FURTHER INFORMATION CONTACT: 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 in the process of establishing a comprehensive new system

of regulating human cellular and tissue-based products. The term

``human cellular and tissue-based products'' encompasses an array of

medical products derived from the human body and used for repair,

reproductive, replacement, or other 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 conditions and diseases. FDA's new regulatory

program will cover all of these products, including those currently

regulated as ``human tissue intended for transplantation'' under part

1270 (21 CFR part 1270)

eing 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 conditions and diseases. FDA's new regulatory

program will cover all of these products, including those currently

regulated as ``human tissue intended for transplantation'' under part

1270 (21 CFR part 1270). (The proposed regulatory definition of a human

cellular or tissue-based product, and exceptions from the definition,

will be discussed in greater detail later in this document.)

In February 1997, the agency announced its regulatory plans in two

documents: ``Reinventing the Regulation of Human Tissue'' and ``A

Proposed Approach to the Regulation of Cellular and Tissue-Based

Products'' (hereinafter referred to as the ``proposed approach

document''). FDA 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 (62 FR 9721, March 4, 1997).

In the Federal Register of May 14, 1998 (63 FR 26744), FDA

proposed an establishment registration and product listing system for

manufacturers of human cellular and tissue-based products (hereinafter

referred to as the ``proposed registration rule.'') The proposed

registration rule was the first in a series of rules that the agency

intends to propose to implement its new approach to these products. The

proposed registration rule would require manufacturers of human

cellular and tissue-based products to register with the agency, to list

their products, and to submit regular updates. The rule defines ``human

cellular and tissue-based product,'' sets out exceptions to this

definition, e.g., vascularized human organs and certain minimally

manipulated bone marrow, and describes certain types of establishment

that would not be subject to the registration and listing requirement

-based products to register with the agency, to list

their products, and to submit regular updates. The rule defines ``human

cellular and tissue-based product,'' sets out exceptions to this

definition, e.g., vascularized human organs and certain minimally

manipulated bone marrow, and describes certain types of establishment

that would not be subject to the registration and listing requirement.

In addition, the rule proposes criteria for regulation of a human

cellular or tissue-based product solely under section 361 of the Public

Health Service Act (the PHS Act) (42 U.S.C. 264), rather than as a

drug, device, and/or biological product. Relevant portions of the

proposed registration rule are discussed in this proposed rule as

necessary, and the definitions contained in the proposed registration

rule are reprinted in their entirety in section III.B.1 of this

document.

As another step toward accomplishing its regulatory objectives,

the agency recently issued a request for proposed standards and

supporting data relating to certain stem-cell products (63 FR 2985,

January 20, 1998).

FDA now proposes to require manufacturers of certain human

cellular and tissue-based products to screen and test the donors of

cells and tissues used in those products for risk factors for and

clinical evidence of relevant communicable disease agents and diseases.

The proposed regulations are intended as safeguards to prevent the

transmission of communicable diseases that may occur with the use of

cells and tissues from infected donors.

In acting to increase the safety of the nation's supply of human

cellular and tissue-based products, FDA is also seeking to avoid

unnecessary regulation. Thus, consistent with the proposed approach

document, the agency has tailored the proposed testing and screening

requirements to the degree of communicable disease risk associated with

the various types of human cellular and tissue-based products

ting to increase the safety of the nation's supply of human

cellular and tissue-based products, FDA is also seeking to avoid

unnecessary regulation. Thus, consistent with the proposed approach

document, the agency has tailored the proposed testing and screening

requirements to the degree of communicable disease risk associated with

the various types of human cellular and tissue-based products. The

testing and screening for donors of cells and tissues that pose a high

degree of communicable disease risk will be more extensive than for

donors of cells and tissues with lesser risk. Where the risk is quite

low (e.g., cells or tissues used autologously), FDA will recommend

testing and screening, but will not require them; however, certain

labeling will be required.

As outlined in the proposed approach document, the agency is

implementing its regulatory plan for human cellular and tissue-based

products in a step-by-step fashion. Following the publication of this

proposed rule, the agency intends to propose current good tissue

practice ``CGTP'' regulations to address concerns about the proper

handling, storage, and processing of human cellular and tissue-based

products. The donor-suitability regulations now being proposed would be

placed in new part 1271, along with the regulations covering

registration, CGTP, and other areas, e.g., establishment inspection and

enforcement. Proposed part 1271 will eventually supersede part 1270,

which contains current regulations governing infectious-disease

testing, donor screening, and recordkeeping for human tissue intended

for transplantation. At the completion of the rulemaking process, FDA

intends to revoke part 1270.

II. Donor Suitability

A. Part 1270 and the Need for Expanded Donor-Suitability Requirements

enforcement. Proposed part 1271 will eventually supersede part 1270,

which contains current regulations governing infectious-disease

testing, donor screening, and recordkeeping for human tissue intended

for transplantation. At the completion of the rulemaking process, FDA

intends to revoke part 1270.

II. Donor Suitability

A. Part 1270 and the Need for Expanded Donor-Suitability Requirements

In the early 1990's, serious issues arose about the safety of

human tissue used for transplantation. Concern focused on the potential

for disease transmission through the transplantation of tissues from

donors infected with the human immunodeficiency virus (HIV) or one of

the hepatitis viruses. In 1993, FDA acted in response to this immediate

need to protect the public health by issuing an interim rule requiring

the donors of human tissue intended for transplantation to be screened

and tested for HIV types 1 and 2, hepatitis B (HBV), and hepatitis C

(HCV) (58 FR 65514, December 14, 1993). That rule, codified at part

1270, covered human tissue that was not regulated as a human drug,

biological product, or medical device; reproductive tissue and several

other categories of products were also excluded (Sec. 1270.3(j)). In

response to comments submitted on the interim rule, FDA modified and

clarified the requirements. In the Federal Register of July 29, 1997

(62 FR 40429), FDA issued a final rule replacing the interim rule

(hereinafter referred to as the ``tissue final rule'').

When it issued the regulations in part 1270, FDA envisioned

replacing them, at a future date, with more extensive requirements with

respect to infectious-disease control (58 FR 65514 at 65516).

Consistent with these intentions, the agency is now proposing

regulations that would expand on the current testing and screening

requirements in two ways. First, the proposed regulations would

increase the number of products covered by the screening and testing

requirements

, at a future date, with more extensive requirements with

respect to infectious-disease control (58 FR 65514 at 65516).

Consistent with these intentions, the agency is now proposing

regulations that would expand on the current testing and screening

requirements in two ways. First, the proposed regulations would

increase the number of products covered by the screening and testing

requirements. Second, the proposed regulations would require screening

and testing for additional diseases. (The present rulemaking affects

only the screening and testing

components of part 1270. Other requirements will be the subject of

future rulemaking, e.g., the requirement in Sec. 1270.31 for written

procedures and the enforcement provisions in part 1270 subpart D.)

Because of their nature as derivatives of the human body, all

human cellular and tissue-based products pose a potential risk of

transmitting communicable diseases. For example, HIV, HBV, and HCV have

been detected in human tissue, including bone, skin, corneas, and

semen. In proposing to establish a unified regulatory approach for

human cellular and tissue-based products, the agency is responding to

the concern about communicable disease transmission that is common to

all such products. The proposed testing and screening provisions would

be applicable to human cellular and tissue-based products that are

regulated under section 201 of the Federal Food, Drug, and Cosmetic Act

(the act) (21 U.S.C. 321 et. seq.) and/or section 351 of the PHS Act

(42 U.S.C. 262) as medical devices, drugs, and/or biological products.

The proposed testing and screening provisions would also apply to human

cellular products and products containing human reproductive cells or

tissues, including some products not currently subject to Federal

regulation. In addition, tissues currently regulated under part 1270

would be brought under the scope of the new regulations

C. 262) as medical devices, drugs, and/or biological products.

The proposed testing and screening provisions would also apply to human

cellular products and products containing human reproductive cells or

tissues, including some products not currently subject to Federal

regulation. In addition, tissues currently regulated under part 1270

would be brought under the scope of the new regulations.

When part 1270 was issued as an interim rule, FDA was acting

swiftly to counter the transmission of three serious disease agents,

HIV, HBV, and HCV, by the transplantation of human tissue. In this

rulemaking, the agency seeks to establish a more comprehensive system

for preventing the spread of those and other diseases transmissible by

implantation, transplantation, infusion, or transfer of human cellular

and tissue-based products. The proposed regulation would require,

except in certain limited situations, screening and testing for all

``relevant'' communicable disease agents and diseases. (The criteria

for considering a disease to be ``relevant'' are discussed later in

section III.C.1 of this document.) For example, FDA is now proposing to

require that donors of tissue and cells be tested for syphilis and

screened for transmissible spongiform encephalopathies (TSE) including

Creutzfeldt-Jakob Disease (CJD). In addition, donors of viable,

leukocyte-rich cells or tissues would be tested for human T-cell

lymphotrophic virus type I and type II (HTLV-I/II) and Cytomegalovirus

(CMV), which are considered ``cell-associated viruses.'' FDA is

proposing to require that donors of reproductive cells and tissue be

tested for Neisseria gonorrhea and Chlamydia trachomatis, which have

been transmitted through artificial insemination, and screened for

sexually transmitted and genitourinary diseases that could contaminate

reproductive cells and tissue during recovery and then be transmitted

to the recipient of those cells or tissues and/or to the fetus.

B. Legal Authority

reproductive cells and tissue be

tested for Neisseria gonorrhea and Chlamydia trachomatis, which have

been transmitted through artificial insemination, and screened for

sexually transmitted and genitourinary diseases that could contaminate

reproductive cells and tissue during recovery and then be transmitted

to the recipient of those cells or tissues and/or to the fetus.

B. Legal Authority

FDA is proposing to issue these new regulations 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 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).)

Certain diseases are transmissible through the implantation,

transplantation, infusion, or transfer of human cellular or tissue-

based products derived from donors infected with those diseases. In

order to prevent the introduction, transmission, and spread of such

diseases, FDA considers it necessary to take appropriate measures to

prevent the use of cells or tissues from infected donors. Thus, the

agency is proposing that, prior to the use of most human cellular or

tissue-based products, the manufacturer would be required to determine

the suitability of the donor of cells or tissues based on the results

of screening and testing for relevant communicable diseases

DA considers it necessary to take appropriate measures to

prevent the use of cells or tissues from infected donors. Thus, the

agency is proposing that, prior to the use of most human cellular or

tissue-based products, the manufacturer would be required to determine

the suitability of the donor of cells or tissues based on the results

of screening and testing for relevant communicable diseases. Under the

proposed regulations, a donor who tests repeatedly reactive for a

particular disease agent, or who possesses clinical evidence of or risk

factors for such a disease, would be considered unsuitable, and cells

and tissues from that donor would not ordinarily be used.

FDA's directive, under section 361 of the PHS Act, is to prevent

the introduction, transmission, and spread of communicable diseases.

Specifically, these regulations are intended to prevent the

transmission of communicable disease through the implantation,

transplantation, infusion, or transfer of human cellular or tissue-

based products. However, as discussed in the proposed registration

rule, all human cellular and tissue-based products pose some risk of

carrying pathogens that could cause disease in recipients and family

members or other close contacts of recipients, health care personnel,

and other handlers of tissue. This broader concern for the spread of

communicable disease is reflected in certain labeling requirements

proposed in these regulations and in the criteria for identifying a

relevant communicable disease. Although FDA recognizes that regulations

exist that are specifically designed to protect employees who may come

in contact with infectious materials (see 29 CFR 1910.1030, 42 CFR

72.6, and 49 CFR 171.180), the agency does not consider its proposed

regulations to be in conflict with those other regulations currently in

effect. However, the agency has made an effort to be consistent with

the terminology used in these other regulations, e.g., ``Infectious

Substances'' and Biohazard legend

es who may come

in contact with infectious materials (see 29 CFR 1910.1030, 42 CFR

72.6, and 49 CFR 171.180), the agency does not consider its proposed

regulations to be in conflict with those other regulations currently in

effect. However, the agency has made an effort to be consistent with

the terminology used in these other regulations, e.g., ``Infectious

Substances'' and Biohazard legend.

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.

Under sections 501(a)(2)(B) and (h) and 520(f)(1) of the act (21

U.S.C. 351(a)(2)(B) and (h) and 360j(f)(1)), drugs and devices are

subject to CGMP requirements designed to ensure, among other things,

product safety. Currently, no specific CGMP regulations exist with

respect to human cellular and tissue-based products regulated as drugs

or devices that delineate testing and screening procedures for

communicable diseases. (See parts 210 et seq. and 820 (21 CFR parts 210

and 820).) Nevertheless, FDA considers communicable disease testing and

screening to be steps in the manufacturing process that are crucial to

the safety of such products. As a result, FDA proposes to amend the

existing CGMP regulations for drugs in parts 210 and 211 (21 CFR part

211) and the quality system regulations for devices in part 820 (21 CFR

part 820), which include CGMP requirements, to incorporate the testing

and screening provisions of proposed part 1271 subpart C

be steps in the manufacturing process that are crucial to

the safety of such products. As a result, FDA proposes to amend the

existing CGMP regulations for drugs in parts 210 and 211 (21 CFR part

211) and the quality system regulations for devices in part 820 (21 CFR

part 820), which include CGMP requirements, to incorporate the testing

and screening provisions of proposed part 1271 subpart C. In proposing

these amendments, FDA is relying on the authority provided by section

361 of the PHS Act to issue regulations to prevent the spread of

communicable disease, as well as its authority under the act to

issue CGMP regulations (21 U.S.C. 351(a)(2)(B) and (h) and 360j(f)(1)).

Under proposed Sec. 210.1(c), the manufacturer of a human cellular

or tissue-based product regulated as a drug or biological drug would be

required to comply with the donor-suitability procedures in proposed

part 1271, subpart C. Likewise, under proposed Sec. 820.1, the

manufacturer of a human cellular or tissue-based product regulated as a

device would be required to comply with the same procedures. (Existing

regulations and policy determine whether a product is a drug,

biological product, and/or device). If the manufacturer failed to

follow the CGMP or quality system requirements, including the testing

and screening procedures in proposed part 1271, the product would be

adulterated under the act.

Section 375 of the PHS Act provides for Federal oversight of the

nation's Organ Procurement and Transplantation Network and section 379

of the PHS Act authorizes the National Bone Marrow Donor Registry. The

Health Resources and Services Administration (HRSA) currently

administers both of these programs. Given HRSA oversight in these

areas, vascularized human organs and minimally manipulated bone marrow

(as defined in proposed Sec. 1271.3(e)) for unrelated allogeneic use

are specifically excluded from the proposed and final regulations on

human cellular and tissue-based products.

III. Summary of the Proposed Regulation

ices Administration (HRSA) currently

administers both of these programs. Given HRSA oversight in these

areas, vascularized human organs and minimally manipulated bone marrow

(as defined in proposed Sec. 1271.3(e)) for unrelated allogeneic use

are specifically excluded from the proposed and final regulations on

human cellular and tissue-based products.

III. Summary of the Proposed Regulation

A. Purpose and Scope (Proposed Sec. 1271.1)

FDA is proposing that donor-suitability regulations would apply to

all establishments covered by the proposed registration rule. In the

proposed registration rule, FDA discussed its proposed system for

regulating human cellular and tissue-based products. In particular, the

agency proposed to distinguish between two groups of human cellular and

tissue-based products: those that would be regulated solely under the

authority of section 361 of the PHS Act (``361 products''), and those

regulated under the act and/or section 351 of the PHS Act as drugs,

medical devices and/or biological products as well as section 361 of

the PHS Act.

Section 1271.1 of the proposed registration rule states that

manufacturers of both 361 products and products regulated as drugs or

devices and/or biological products under the act and/or section 351 of

the PHS Act would be required to comply with the proposed registration

and listing procedures. The criteria for regulation of a human cellular

or tissue-based product as a 361 product are set out in Sec. 1271.10 of

the proposed registration rule. Section 1271.20 of the proposed

registration rule sets out exceptions from the registration and listing

requirements.

FDA is now making several modifications to proposed Secs. 1271.1,

1271.10, and 1271.20 as they appeared in the proposed registration rule

and is proposing a new Sec. 1271.15. To improve clarity, FDA has

divided section 1271.1 into separate paragraphs on scope and purpose

and has added cross-references to other pertinent regulations

t exceptions from the registration and listing

requirements.

FDA is now making several modifications to proposed Secs. 1271.1,

1271.10, and 1271.20 as they appeared in the proposed registration rule

and is proposing a new Sec. 1271.15. To improve clarity, FDA has

divided section 1271.1 into separate paragraphs on scope and purpose

and has added cross-references to other pertinent regulations. FDA has

also changed the heading of proposed Sec. 1271.10 to ``Establishments

subject to this part; criteria for regulation of human cellular and

tissue-based products solely under section 361 of the PHS Act.'' The

phrase ``nontissue or noncellular'' has been removed from proposed

Sec. 1271.10(c). Proposed Sec. 1271.10(d) has been reorganized,

although its meaning has not changed. Proposed Sec. 1271.10 now

describes human cellular and tissue-based products regulated solely

under section 361 of the PHS Act as those products that: Are minimally

manipulated, are not promoted or labeled for any use other than a

homologous use, are not combined with or modified by the addition of

any component that is a drug or a device; and either do not have a

systemic effect or have a systemic effect and are for autologous use,

are for a family-related allogeneic use, or are for reproductive use.

FDA expects that comments on the four criteria in proposed Sec. 1271.10

will be submitted in response to the proposed registration rule, and

foresees that each of the four criteria will be modified for greater

clarity. For example, the agency is considering clarifying or modifying

the term ``systemic effect'' in proposed Sec. 1271.10(d) because of

potential ambiguities. FDA is concerned that products that have local

metabolic effects, e.g., neurons used to replace or supplement neurons

in the brain, warrant regulation under the act and/or section 351 of

the PHS Act

ria will be modified for greater

clarity. For example, the agency is considering clarifying or modifying

the term ``systemic effect'' in proposed Sec. 1271.10(d) because of

potential ambiguities. FDA is concerned that products that have local

metabolic effects, e.g., neurons used to replace or supplement neurons

in the brain, warrant regulation under the act and/or section 351 of

the PHS Act. The agency invites comments on whether ``systemic effect''

adequately characterizes those products that warrant the more stringent

level of regulation or whether another term or terms would more

accurately describe such products.

FDA is proposing a new Sec. 1271.15 to describe those products

that would be regulated under the act and/or section 351 of the PHS Act

and to reference the subparts of part 1271 that will be applicable to

those products.

FDA is also modifying proposed Secs. 1271.1, 1271.10, and 1271.20

so that they refer not simply to registration and product listing

requirements but to all of the requirements that will be contained in

part 1271 when rulemaking for the entire part is complete. With these

changes, the regulatory framework that was described in the proposed

approach document and developed in the proposed registration rule would

be extended, as intended, to cover donor-suitability requirements now

being proposed as well as other requirements to be proposed later. The

agency is seeking to craft the modifications to these sections to

obviate the need for further adjustments in later rulemaking. To that

end, the new language refers to compliance ``with the other

requirements contained in this part.''

FDA intends that the procedures in part 1271 that would apply to

human cellular and tissue-based products regulated as drugs, devices

and/or biological products are the proposed registration and listing

procedures, the donor-suitability procedures now being proposed, and

the CGTP procedures to be proposed in the future

ers to compliance ``with the other

requirements contained in this part.''

FDA intends that the procedures in part 1271 that would apply to

human cellular and tissue-based products regulated as drugs, devices

and/or biological products are the proposed registration and listing

procedures, the donor-suitability procedures now being proposed, and

the CGTP procedures to be proposed in the future. Therefore, the agency

is now proposing to modify proposed Sec. 1271.1 to add the statement

that manufacturers of human cellular and tissue-based products

regulated under the act and/or section 351 of the PHS Act are required

to comply with the donor-suitability procedures and the CGTP procedures

in part 1271 in addition to all other applicable regulations.

B. Definitions (Proposed Sec. 1271.3)

1. Definitions Contained in the Proposed Registration Rule

Section 1271.3(a) through (h) of the proposed registration rule

contain definitions of terms used in the registration and listing

regulations. Because some of the terms defined in the proposed

registration rule are used in the donor-suitability regulations now

being proposed, the agency is reprinting proposed Sec. 1271.3(a)

through (h) as follows to facilitate understanding of the rule now

being proposed.

(a) Autologous use means the implantation, transplantation,

infusion, or transfer of a human cellular or tissue-based product

back into the individual from whom the cells or tissue comprising

such product were removed.

uitability regulations now

being proposed, the agency is reprinting proposed Sec. 1271.3(a)

through (h) as follows to facilitate understanding of the rule now

being proposed.

(a) Autologous use means the implantation, transplantation,

infusion, or transfer of a human cellular or tissue-based product

back into the individual from whom the cells or tissue comprising

such product were removed.

(b) Establishment means a place of business under one

management, at one general physical location, that engages in the

manufacture of human cellular or tissue-based products. The term

includes, among others, facilities that engage in contract

manufacturing services for a manufacturer of human cellular or

tissue-based products. The term also includes any individual,

partnership, corporation, association, or other legal entity engaged

in the manufacture of human cellular or tissue-based products,

except that an individual engaged solely in the procurement or

recovery of cells or tissues or under contract to a registered

establishment is not required to independently register.

(c) Family-related allogeneic use means the implantation,

transplantation, infusion, or transfer of a human cellular or

tissue-based product into a first-degree blood relative of the

individual from whom cells or tissue comprising such product were

removed.

(d) Homologous use means the use of a cellular or tissue-based

product for replacement or supplementation and:

(1) For structural tissue-based products, occurs when the

tissue is used for the same basic function that it fulfills in its

native state, in a location where such structural function normally

occurs; or

(2) For cellular and nonstructural tissue-based products,

occurs when the cells or tissue is used to perform the function(s)

that they perform in the donor.

lacement or supplementation and:

(1) For structural tissue-based products, occurs when the

tissue is used for the same basic function that it fulfills in its

native state, in a location where such structural function normally

occurs; or

(2) For cellular and nonstructural tissue-based products,

occurs when the cells or tissue is used to perform the function(s)

that they perform in the donor.

(e) Human cellular or tissue-based product means a product

containing human cells or tissues or any cell or tissue-based

component of such a product. The following products are not

considered human cellular or tissue-based products and

establishments that manufacture only one or more of the following

would not be subject to the registration or listing provisions of

this part:

(1) Vascularized human organs for transplantation;

(2) Whole blood or blood components or blood derivative

products subject to listing under part 607 of this chapter;

(3) Secreted or extracted human products, such as milk,

collagen, and cell factors;

(4) Minimally manipulated bone marrow;

(5) Ancillary products used in the propagation of cells or

tissues; or

(6) Cells, tissues or organs derived from animals.

(f) Manufacture means, but is not limited to, any or all steps

in the recovery, screening, testing, processing, storage, labeling,

packaging, or distribution of any human cellular or tissue-based

product.

(g) Minimal manipulation means: (1) For structural tissue,

processing that does not alter the original relevant characteristics

of the tissue relating to the tissue's utility for reconstruction,

repair, or replacement; and

(2) For cells or nonstructural tissues, processing that does

not alter the relevant biological characteristics of cells or

tissues.

man 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 or 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.

Since proposing the previous definitions, FDA has reconsidered the

definition in proposed Sec. 1271.3(e) of ``human cellular or tissue-

based product,'' and has determined that it is too broad. For example,

the definition might be construed to include many in vitro diagnostic

products. The agency is adding language to the proposed definition to

clarify that the products covered by the definition (and thus by these

proposed regulations) are those that are intended for implantation,

transplantation, infusion, or transfer into a human recipient. The

agency is also adding language to specifically exclude in vitro

diagnostic products as defined in 21 CFR 809.3(a) from the definition

of human cellular or tissue-based product. In addition, the agency is

deleting the reference in Sec. 1271.3(e) to the registration and

listing provisions of part 1271. Minimally manipulated bone marrow has

been clarified by adding ``for homologous use and not combined with or

modified by the addition of any component that is a drug or a device.''

Also, the agency is clarifying that, although secreted or extracted

human products such as milk, collagen, and cell factors are not

considered to meet the definition of human cellular or tissue-based

product, semen is considered a human cellular or tissue-based product

because it contains germ cells. The definition also contains several

other minor clarifications and corrections.

2. New Definitions

The agency is now proposing to define additional terms and to list

them in Sec

h as milk, collagen, and cell factors are not

considered to meet the definition of human cellular or tissue-based

product, semen is considered a human cellular or tissue-based product

because it contains germ cells. The definition also contains several

other minor clarifications and corrections.

2. New Definitions

The agency is now proposing to define additional terms and to list

them in Sec. 1271.3(i) through (ee). The agency intends to place all

definitions relevant to proposed part 1271 in proposed Sec. 1271.3.

Thus, in subsequent rulemakings, the agency may propose to define more

terms in that section.

Many of the terms now proposed to be defined in proposed

Sec. 1271.3 are currently defined in Sec. 1270.3. In several instances,

the definition now being proposed is the same as that in Sec. 1270.3 or

is only modified slightly for clarity, e.g., ``donor'' and

``responsible person'' in proposed Sec. 1271.3(n) and (w),

respectively. Although the proposed definitions of colloid and

crystalloid remain substantially the same as in Sec. 1270.3(c) and (e),

the agency specifically requests comments on the appropriateness of

these definitions, including whether it is appropriate to define these

terms in the regulations.

The definitions of some other terms (e.g., donor medical history

interview and physical assessment) have been significantly modified to

accommodate the broader range of infectious diseases covered by this

proposed regulation. Additional terms are newly defined in proposed

Sec. 1271.3 (Biohazard legend, directed donor, embryo, gamete, relevant

communicable disease agent or disease, urgent medical need,

xenotransplant, and close contact). Where relevant, proposed

definitions are discussed as follows, with the requirements to which

the defined terms relate.

The definition of ``summary of records'' in proposed

Sec. 1271.3(x) is a modification of the definition of the same term in

Sec. 1270.3(w). As in Sec

r, embryo, gamete, relevant

communicable disease agent or disease, urgent medical need,

xenotransplant, and close contact). Where relevant, proposed

definitions are discussed as follows, with the requirements to which

the defined terms relate.

The definition of ``summary of records'' in proposed

Sec. 1271.3(x) is a modification of the definition of the same term in

Sec. 1270.3(w). As in Sec. 1270.3(w), the agency proposes to define

``summary of records'' as containing a list of all tests performed for

relevant communicable disease agents and the results of those tests,

and the name and address of the establishment that made the donor-

suitability determination. However, FDA has recently received comments

from manufacturers of human tissue intended for transplantation on

other aspects of the definition of ``summary of records'' in

Sec. 1270.3(w). These comments assert that, because a processor or

distributor may use multiple testing laboratories, the requirement in

Sec. 1270.3(w) that a summary of records contain the identity of the

testing laboratory is unduly burdensome; similar objections were raised

to the requirement for listing all relevant medical records reviewed.

Such information, it was asserted, would be available from the

establishment that made the donor-suitability determination. FDA has

considered these concerns, and is proposing a new, less burdensome

definition. Under the proposed definition, the summary of records would

be redefined as: (1) A statement that communicable disease testing was

performed by a laboratory or laboratories certified under the Clinical

Laboratory Improvement Amendments of 1988 (CLIA); (2) a listing and

interpretation of the results of all communicable disease tests

performed; (3) a statement describing the types of records which may

have been reviewed as part of the relevant medical records; and (4) the

name and address of the establishment determining the suitability of

the donor of cells or tissues

ied under the Clinical

Laboratory Improvement Amendments of 1988 (CLIA); (2) a listing and

interpretation of the results of all communicable disease tests

performed; (3) a statement describing the types of records which may

have been reviewed as part of the relevant medical records; and (4) the

name and address of the establishment determining the suitability of

the donor of cells or tissues. Upon request by FDA, or other interested

persons, the establishment that made the donor-suitability

determination will be expected to promptly furnish the name and address

of the testing laboratory and a list of all relevant medical records

reviewed.

C. General Requirements

1. Determination of Donor Suitability (Proposed Sec. 1271.50)

Proposed Sec. 1271.50 sets out the fundamental requirement of

these proposed regulations: The donor-suitability determination. Except

in certain specified situations, a human cellular or tissue-based

product may not be implanted, transplanted, infused, or

transferred until the donor of the cells or tissue for the product has

been determined to be suitable.

The determination of whether a donor is suitable or unsuitable

would be made by a responsible person, as defined in proposed

Sec. 1271.3(w), and would be based on the results of required donor

screening and testing. ``Donor screening'' refers to a review of the

donor's relevant medical records, as defined in proposed

Sec. 1271.3(v), for information about the donor that might indicate

past or present infection or risk factors for a relevant communicable

disease agent or disease. ``Donor testing'' refers to performing

laboratory tests on a specimen collected from the donor, generally a

blood sample, to determine whether the donor has been exposed to or is

infected with a relevant communicable disease agent.

Both aspects of the donor-suitability determination are vital

cate

past or present infection or risk factors for a relevant communicable

disease agent or disease. ``Donor testing'' refers to performing

laboratory tests on a specimen collected from the donor, generally a

blood sample, to determine whether the donor has been exposed to or is

infected with a relevant communicable disease agent.

Both aspects of the donor-suitability determination are vital. A

donor may be determined to be suitable only if test results are

negative or nonreactive and screening shows the donor to be free from

risk factors for and clinical evidence of infection due to relevant

communicable disease agents and diseases. Conversely, if either donor

screening or donor testing indicates the presence of a relevant

infectious agent, or risk factors therefor, then the potential donor

must be determined to be unsuitable.

Proposed Sec. 1271.3(y) contains a two-part definition of the term

``relevant communicable disease agent or disease.'' Section

1271.3(y)(1) lists those disease agents and diseases that are

specifically identified in Secs. 1271.75 and 1271.85 as relevant

communicable disease agents and diseases for which the agency is

proposing to require donor screening and/or testing. These are: HIV,

types 1 and 2; HBV; HCV; TSE; Treponema pallidum; HTLV, types I and II;

CMV; Chlamydia trachomatis and Neisseria gonorrhea. In some instances,

FDA has identified a disease agent or disease as relevant for a

particular type of cells or tissue-based product; this distinction is

reflected in the proposed testing and screening requirements in

proposed Secs. 1271.75 and 1271.85.

The second part of the definition describes the criteria for a

communicable disease agent or disease to be considered ``relevant,''

and covers diseases not specifically listed in Sec. 1271.3(y)(1).

First, for a communicable disease agent or disease to be ``relevant,''

its prevalence among donors would have to be sufficient to warrant

screening or testing of all donors

s. 1271.75 and 1271.85.

The second part of the definition describes the criteria for a

communicable disease agent or disease to be considered ``relevant,''

and covers diseases not specifically listed in Sec. 1271.3(y)(1).

First, for a communicable disease agent or disease to be ``relevant,''

its prevalence among donors would have to be sufficient to warrant

screening or testing of all donors. Second, there would need to be a

risk of transmission of the disease agent or disease by a human

cellular or tissue-based product, either to the recipient of the

product or to those people who may handle or otherwise come in contact

with the product, such as medical personnel. Third, the health risks,

measured by morbidity and mortality, posed by the disease would need to

be significant. For example, HIV, HBV, HCV, and Treponema pallidum,

which are listed in Sec. 1271.3(y)(1), all pose significant health

risks. In contrast, although Ureaplasma urealyticum, Mycoplasma

hominis, and Streptococci are organisms that have been transmitted

through artificial insemination procedures, they exist in a great

number of healthy, sexually active adults and their pathogenicity to

the recipient of reproductive cells or tissue is of questionable

clinical significance. Thus, FDA does not consider them to be relevant

communicable diseases or disease agents at this time for the purpose of

this regulation. Finally, for a disease or disease agent to be

considered ``relevant,'' appropriate screening measures would need to

have been developed and/or an appropriate FDA-licensed, approved, or

cleared screening test for donor specimens would need to be available.

Should a new relevant communicable disease agent or disease arise

or be identified, the agency would consider manufacturers to be

required, under proposed Sec. 1271.75(a), to screen donors for the

disease and, under proposed Sec. 1271.80(a), to test donor specimens

for the disease agent, even if the disease agent or disease is not

specified in proposed Secs

cimens would need to be available.

Should a new relevant communicable disease agent or disease arise

or be identified, the agency would consider manufacturers to be

required, under proposed Sec. 1271.75(a), to screen donors for the

disease and, under proposed Sec. 1271.80(a), to test donor specimens

for the disease agent, even if the disease agent or disease is not

specified in proposed Secs. 1271.3(y), 1271.75, or 1271.85. The agency

intends to issue guidance in the future to interpret the term

``relevant communicable disease agent or disease,'' when additional

agents or diseases arise or are identified that meet the definition

under proposed Sec. 1271.3(y).

2. Records of Donor Suitability Determination (Proposed Sec. 1271.55)

Proposed Sec. 1271.55 incorporates requirements that are now found

in (Secs. 1270.21(e) and 1270.33(d) and (f)). Additional recordkeeping

requirements based on other regulations in part 1270 will be proposed

in the future, as part of CGTP's.

Under proposed Sec. 1271.55, manufacturers would be required to

ship a human cellular or tissue-based product accompanied by

documentation of the donor-suitability determination. This requirement

would apply to a human cellular or tissue-based product from a donor

determined to be suitable as well as to a product from a donor

determined to be unsuitable and made available for use under the

provisions of proposed Sec. 1271.65(b), (c), or (d). Manufacturers

would be required to include in the documentation a copy of the donor's

relevant medical records, as defined in proposed Sec. 1271.3(v),

results of testing required under Secs. 1271.80 and 1271.85, and the

name and address of the establishment that made the donor-suitability

determination. Alternatively, the documentation may consist of a

summary of records, as defined in proposed Sec. 1271.3(x)

ld be required to include in the documentation a copy of the donor's

relevant medical records, as defined in proposed Sec. 1271.3(v),

results of testing required under Secs. 1271.80 and 1271.85, and the

name and address of the establishment that made the donor-suitability

determination. Alternatively, the documentation may consist of a

summary of records, as defined in proposed Sec. 1271.3(x). Additional

required documentation would include a statement whether, based on a

review of the results of donor screening and testing, the donor has

been determined to be suitable or unsuitable. In the interest of

confidentiality, the agency is proposing to require that the donor's

name be deleted from the documentation of the donor's suitability

determination that accompanies the product.

FDA recognizes the potentially sensitive nature of information

about a human cell or tissue donor that may be contained in the donor's

relevant medical records. Nothing in this proposed rule is intended to

modify any currently applicable Federal, State, or local regulations

regarding confidentiality. With respect to the agency's handling of

personal medical information, the regulations in part 20 (21 CFR part

20) will continue to apply (see Sec. 20.63).

Proposed Sec. 1271.55(b) would impose record-retention

requirements on the establishment that generates records used in

determining donor suitability and on the establishment that makes the

donor-suitability determination. These records must be made available

for authorized inspection by or upon request from FDA. Records that can

be readily retrieved from another location by electronic means would be

considered ``retained.'' FDA envisions that various methods of

recordkeeping could be employed to meet the terms of Sec. 1271.55(b),

so long as suitable reader and photocopying equipment were readily

available. For example, records might be retained electronically, as

original paper records, or as true copies, such as photocopies,

microfiche, or microfilm

ocation by electronic means would be

considered ``retained.'' FDA envisions that various methods of

recordkeeping could be employed to meet the terms of Sec. 1271.55(b),

so long as suitable reader and photocopying equipment were readily

available. For example, records might be retained electronically, as

original paper records, or as true copies, such as photocopies,

microfiche, or microfilm.

Proposed Sec. 1271.55(b) would require that records be retained at

least 10 years after the date of implantation, transplantation,

infusion, or transfer of the product. If that date is not known,

however, then records would be retained at least 10 years after the

product's distribution, disposition, or expiration, whichever is

latest.

The agency notes that, given concerns about TSE transmission from

dura

mater, it may be prudent to hold records relating to donations of dura

mater for longer than 10 years, although the optimal period is not

known at this time. The latency period between receipt of a dura mater

graft and onset of TSE has been reported to be as long as 16 years

(Morbidity and Mortality Weekly Report, 46:1066, November 14, 1997). If

new information should be obtained in the future about TSE, then review

of the original screening and testing information about dura mater

donors could be invaluable. The agency requests comments on whether

records relating to donors of dura mater should be required to be held

for a period longer than 10 years and what that period should be.

3. Quarantine Pending Determination of Donor Suitability (Proposed

Sec. 1271.60)

In order to prevent the use of human cellular and tissue-based

products prior to a donor-suitability determination, Sec. 1271.60

proposes requirements for quarantine. ``Quarantine'' is defined in

proposed Sec

a mater should be required to be held

for a period longer than 10 years and what that period should be.

3. Quarantine Pending Determination of Donor Suitability (Proposed

Sec. 1271.60)

In order to prevent the use of human cellular and tissue-based

products prior to a donor-suitability determination, Sec. 1271.60

proposes requirements for quarantine. ``Quarantine'' is defined in

proposed Sec. 1271.3(t) as ``the storage or identification of a human

cellular or tissue-based product, in order to prevent improper release,

in a physically separate area clearly identified for such use, or

through use of other procedures, such as automated designation.''

As provided in proposed Sec. 1271.60, manufacturers would be

required to keep human cellular and tissue-based products in

quarantine, and clearly identify such products as being in quarantine,

until completion of the donor-suitability determination. A manufacturer

who ships a product before it is available for release or distribution

(as in the case of shipment by the procurer to the processor) would be

required to ship the product under quarantine and accompanied by

records identifying the donor, indicating that the donor-suitability

determination has not been completed, and stating that the product may

not be implanted, transplanted, infused, or transferred until

completion of the donor-suitability determination. Donor identification

may be accomplished by assigning a donor number.

4. Quarantine and Disposition of Human Cellular or Tissue-based

Product From an Unsuitable Donor (Proposed Sec. 1271.65)

If a donor is determined to be unsuitable, then under proposed

Sec. 1271.65 the manufacturer would be required to keep in quarantine

any human cellular or tissue-based product from that donor. In this

situation, quarantine would require physical separation of the product

from all other products until it is destroyed, or until it is used

under the provisions of proposed Sec. 1271.65(b), (c), or (d).

Proposed Sec

ined to be unsuitable, then under proposed

Sec. 1271.65 the manufacturer would be required to keep in quarantine

any human cellular or tissue-based product from that donor. In this

situation, quarantine would require physical separation of the product

from all other products until it is destroyed, or until it is used

under the provisions of proposed Sec. 1271.65(b), (c), or (d).

Proposed Sec. 1271.65 (b) sets out the limited circumstances in

which the proposed regulations would not bar the implantation,

transplantation, infusion, or transfer of human cellular and tissue-

based products from unsuitable donors. In three situations, the agency

is proposing that the recipient and his or her physician may decide

whether to use the human cellular or tissue-based product.

The first exception is for family-related allogeneic use. Family-

related allogeneic use is defined in Sec. 1271.3(c) of the proposed

registration rule as the implantation, transplantation, infusion, or

transfer of a human cellular or tissue-based product into a first-

degree blood relative of the individual from whom cells or tissue

comprising such product were removed. Under the second exception, a

person could choose to receive a product containing reproductive tissue

from a directed donor who had been determined to be unsuitable.

(Proposed Sec. 1271.3(m) defines ``directed donor'' as a living person

who is the source of cells or tissue designated for a specific

potential recipient of a human cellular or tissue-based product.) The

third exception is for cases where an urgent medical need exists and is

documented. Urgent medical need is defined in proposed Sec. 1271.3(z)

as the situation where no comparable human cellular or tissue-based

product from a suitable donor is available and, without the product,

the recipient is likely to suffer serious morbidity.

However, use in each of these circumstances is conditioned on

compliance with certain safeguards

an urgent medical need exists and is

documented. Urgent medical need is defined in proposed Sec. 1271.3(z)

as the situation where no comparable human cellular or tissue-based

product from a suitable donor is available and, without the product,

the recipient is likely to suffer serious morbidity.

However, use in each of these circumstances is conditioned on

compliance with certain safeguards. First, in order to protect those

people who may handle the product, the manufacturer would be required

to label such products with a Biohazard legend. (A Biohazard legend is

shown in proposed Sec. 1271.3(i) and is used to mark products that

present ``a known or suspected relevant communicable disease risk.'')

Second, the manufacturer of the product would be responsible for

documenting that: (1) The physician using the product was notified of

the results of testing and screening, (2) the physician authorized the

use of the product, (3) the physician agreed to explain the

communicable disease risks associated with the product to the recipient

or the recipient's legally authorized representative, and (4) the

physician agreed to obtain from the recipient or the recipient's

legally authorized representative consent to use the product. In

proposing these exceptions that would not prohibit, in certain cases,

the use of products from an unsuitable donor, it is FDA's intention to

delegate to the potential recipient and his or her physician the

responsibility for comparing the relative risks and benefits. The

agency specifically seeks comment on the scope of the exceptions and

the proposed safeguards that FDA has crafted

duct. In

proposing these exceptions that would not prohibit, in certain cases,

the use of products from an unsuitable donor, it is FDA's intention to

delegate to the potential recipient and his or her physician the

responsibility for comparing the relative risks and benefits. The

agency specifically seeks comment on the scope of the exceptions and

the proposed safeguards that FDA has crafted. For example, does the

exception for directed reproductive tissue donors provide a reasonable

accommodation for a woman who wishes to choose the genetic father of

her child? Should the exception be further broadened to permit a woman

to select an anonymous donor with a known high risk behavior or,

conversely, does the exception provide sufficient protection for the

woman and her potential child?

FDA recognizes that, just as there may be urgent medical

situations that might justify the use of a human cellular or tissue-

based product from an unsuitable donor, so the need may arise to use a

human cellular or tissue-based product before the donor-suitability

determination has been completed. Proposed Sec. 1271.65(c) sets out the

limited, emergency circumstances in which the proposed regulations

would not prohibit the implantation, transplantation, infusion, or

transfer of such a product. The emergency provisions of Sec. 1271.65(c)

are similar to those in Sec. 1271.65(b), with some modifications

appropriate to the different characteristics of the situation. In

particular, a product made available for use pending completion of the

donor-suitability determination must be accompanied by information on

the status of the required screening and testing. In addition,

Sec. 1271.65(c) includes the requirement that the donor-suitability

determination be completed during or after the use of the product, and

that the manufacturer inform the physician of the results of that

determination.

Under proposed Sec

ing completion of the

donor-suitability determination must be accompanied by information on

the status of the required screening and testing. In addition,

Sec. 1271.65(c) includes the requirement that the donor-suitability

determination be completed during or after the use of the product, and

that the manufacturer inform the physician of the results of that

determination.

Under proposed Sec. 1271.65(d), nonclinical uses of a human

cellular or tissue-based product from an unsuitable donor would not be

prohibited, e.g., use for educational or research purposes. A

manufacturer would be required to label a product used under the

provisions of Sec. 1271.65(c) as ``For Nonclinical Use Only'' and with

the Biohazard legend shown in proposed Sec. 1271.3(i).

D. Donor Screening (Proposed Sec. 1271.75)

The determination of donor-suitability is based on the results of

two different evaluations: Screening and testing. Donor screening

involves the review of a variety of possible sources

of information about the donor that might indicate that the donor is at

risk for or exhibits clinical evidence of infection due to a relevant

communicable disease.

1. General Requirements

The requirements for donor screening are in proposed Sec. 1271.75.

Under proposed Sec. 1271.75(a), the manufacturer would be required to

review the relevant medical records of a donor of cells or tissue for a

human cellular or tissue-based product for risk factors for and

clinical evidence of relevant communicable disease agents and diseases.

Relevant medical records are defined in proposed Sec. 1271.3(v) as a

collection of documents that includes a current donor medical history

interview as defined in proposed Sec. 1271.3(o); a current report of

the physical assessment as defined in proposed Sec

human cellular or tissue-based product for risk factors for and

clinical evidence of relevant communicable disease agents and diseases.

Relevant medical records are defined in proposed Sec. 1271.3(v) as a

collection of documents that includes a current donor medical history

interview as defined in proposed Sec. 1271.3(o); a current report of

the physical assessment as defined in proposed Sec. 1271.3(r) of a

cadaveric donor or a physical examination of a living donor; and, if

available, laboratory test results, medical records, coroner and

autopsy reports, and records or other information received from any

source pertaining to risk factors for relevant communicable disease.

(The proposed definitions for ``relevant medical records,'' ``donor

medical history interview,'' and ``physical assessment'' have been

broadened to refer not only to HIV and hepatitis but instead to

``relevant communicable disease;'' in other respects, except as

otherwise noted, these definitions are substantially the same as those

currently in Sec. 1270.3.)

Under proposed Sec. 1271.3(v), risk factors for communicable

disease may include social behavior, clinical signs and symptoms of a

relevant communicable disease, and treatments related to medical

conditions suggestive of risk for a relevant communicable disease.

Consistent with the approach taken in part 1270, the proposed

regulations do not specify risk factors, as these may change as

knowledge of communicable diseases grows. FDA, together with CDC, is

reviewing the risk factors for transmission of relevant communicable

diseases in light of current scientific knowledge. Based on the results

of the review, FDA plans to specifically describe in a guidance

document risk factors and screening information to assist manufacturers

in complying with the regulation. A notice announcing the availability

of a draft guidance document for public comment will be published in

the Federal Register

of relevant communicable

diseases in light of current scientific knowledge. Based on the results

of the review, FDA plans to specifically describe in a guidance

document risk factors and screening information to assist manufacturers

in complying with the regulation. A notice announcing the availability

of a draft guidance document for public comment will be published in

the Federal Register. The notice will provide instructions for

obtaining copies of the draft guidance document by mail, facsimile, and

the Internet using the World Wide Web. FDA plans to issue a final

guidance document on or about the time of issuance of the final rule.

Under proposed Sec. 1271.75(d), an abbreviated screening procedure

may be used for a living donor who returns to make subsequent donations

and who has already been screened under Sec. 1271.75(a) and (b). This

abbreviated screening would determine whether any changes had occurred

in the donor's medical history since the previous donation that would

make the donor unsuitable, and would require documentation of those

changes. A complete donor-suitability determination procedure would be

required at least once every 6 months.

Under proposed Sec. 1271.3(o), a ``donor medical history

interview'' means a documented dialogue with the donor, if the donor is

living. If the donor is not living or is unable to participate in the

interview, the interview takes place with an individual or individuals

who are knowledgeable about the donor's medical history and relevant

social behavior, such as the donor's next of kin, the nearest available

relative, a member of the donor's household, an individual with an

affinity relationship, and/or the primary treating physician. With

respect to relevant social behavior, the definition states that the

interview includes questions about whether or not the donor met certain

descriptions or engaged in activities or behaviors considered to place

the donor at increased risk for a relevant communicable disease

ember of the donor's household, an individual with an

affinity relationship, and/or the primary treating physician. With

respect to relevant social behavior, the definition states that the

interview includes questions about whether or not the donor met certain

descriptions or engaged in activities or behaviors considered to place

the donor at increased risk for a relevant communicable disease.

The current regulations on human tissue intended for

transplantation contain an exception from the requirement for a donor

medical history interview for corneas obtained under legislative

consent; i.e., in accordance with a State law that allows the medical

examiner or coroner to procure corneal tissue without the consent of

the donor's next of kin (Sec. 1270.21(g)). In response to numerous

comments and discussions about the tissue interim rule, FDA

acknowledged the need for flexibility in the procurement of corneal

tissue under legislative consent, and modified the regulations to

accept as sufficient a physical assessment of the donor in the absence

of a donor medical history interview (62 FR 40429 at 40437).

The regulations now being proposed do not contain an exception

from the donor medical history interview for corneas procured under

legislative consent. FDA recognizes that, when corneal tissue is

procured without the consent of the donor's next of kin, a donor

medical history interview with the donor's next of kin does not

necessarily occur. However, the agency notes that the proposed

definition of donor medical history interview would permit the

interview to be conducted with an individual knowledgeable about the

donor's medical history and relevant social behavior (e.g., primary

treating physician) and would not require an interview with the next of

kin. For this reason, FDA considers that the proposed regulation and

State laws on legislative consent may coexist, and does not intend at

this time to preempt those laws

uld permit the

interview to be conducted with an individual knowledgeable about the

donor's medical history and relevant social behavior (e.g., primary

treating physician) and would not require an interview with the next of

kin. For this reason, FDA considers that the proposed regulation and

State laws on legislative consent may coexist, and does not intend at

this time to preempt those laws. The agency requests that affected

parties submit specific, detailed comments on any potential conflicts

that might make it impossible to comply with both this regulation and

State laws on legislative consent.

Requiring a donor medical history interview for corneas obtained

under legislative consent is necessary to ensure that the risk of

communicable disease transmission is appropriately assessed. To prevent

the transmission of communicable disease, adequate donor screening

measures are necessary, even when approved tests are available.

The necessity of adequate screening for TSE illustrates the

importance of the donor medical history interview. The regulations now

being proposed would require TSE screening for all cell and tissue

donors and, in the case of dura mater donors, a post-mortem physical

assessment for TSE. (In contrast, current regulations on human tissue

intended for transplantation contained in part 1270 do not require

screening or testing for TSE.) Two recent possible transmissions of TSE

by corneal tissue have been reported in Japan and Germany. In addition,

three potential CJD transmissions have been reported in the United

Kingdom, where corneas and sclera from a donor subsequently determined

to have CJD were transplanted into, and then removed from, three

recipients (Ref. 20). Recent cognitive changes and abnormalities in

speech and gait are possible indications of TSE

TSE

by corneal tissue have been reported in Japan and Germany. In addition,

three potential CJD transmissions have been reported in the United

Kingdom, where corneas and sclera from a donor subsequently determined

to have CJD were transplanted into, and then removed from, three

recipients (Ref. 20). Recent cognitive changes and abnormalities in

speech and gait are possible indications of TSE. These and other

behavioral changes that a cell or tissue donor might exhibit prior to

donation would be expected to be uncovered in the donor medical history

interview, but would be less likely to turn up during other parts of

the screening process.

2. Specific Communicable Disease Screening Requirements

Proposed Sec. 1271.75(a)(1) states that the relevant medical

records for a cell or tissue donor shall be reviewed for risk factors

for and clinical evidence of infection due to relevant communicable

disease agents and diseases. Proposed Sec. 1271.75(a)(1) specifically

lists HIV, HBV, HCV, and TSE as relevant communicable disease agents

and

diseases for which such screening is required. These four disease

agents and diseases are listed as the ``minimum'' for which screening

would be required; should a new relevant communicable disease arise or

be identified, the agency would consider manufacturers to be required,

under proposed Sec. 1271.75(a)(1), to screen for the new disease as

well.

Special concerns arise with respect to donors of reproductive

cells or tissue, when those cells or tissue are recovered through

methods that could lead to the transmission of sexually transmitted and

genitourinary diseases. Accordingly, under proposed Sec. 1271.75(b), if

those methods are used, donor screening would be required for risk

factors for and clinical evidence of infection due to sexually

transmitted and genitourinary diseases

of reproductive

cells or tissue, when those cells or tissue are recovered through

methods that could lead to the transmission of sexually transmitted and

genitourinary diseases. Accordingly, under proposed Sec. 1271.75(b), if

those methods are used, donor screening would be required for risk

factors for and clinical evidence of infection due to sexually

transmitted and genitourinary diseases. Certain methods of recovery,

e.g., laparoscopy to recover oocytes, are not directly connected with

the transmission of sexually transmitted and genitourinary diseases,

and would not trigger this requirement.

Special concerns also arise with respect to potential donors who

have received xenotransplants. Xenotransplantation is the

transplantation of live cells, tissues, and/or organs between different

species, such as from a baboon or pig to a human. Because

transplantation necessitates disruption of the recipient's usual

protective physical immunologic barriers, xenotransplantation may

facilitate transmission of known and as yet unrecognized agents to

humans. These can include unknown retroviruses, which may remain latent

for a period of time before causing clinically recognized disease.

Concerns about the potential infectious disease and public health risks

associated with xenotransplantation have been discussed at two recent

FDA meetings (Xenotransplantation Advisory Subcommittee of the Biologic

Response Modifier Advisory Committee, December 17, 1997, and Blood

Products Advisory Committee, March 19, 1998).

Cells or tissue from a xenotransplant recipient could potentially

contain infectious agents transmitted by the xenotransplant. In

addition, the cells or tissues of a person who has been a close contact

of a xenotransplant recipient could contain infectious agents

originating from the xenotransplant. Because of the potential severity

of the risk associated with these situations, the agency is proposing

to require, in Sec

ansplant recipient could potentially

contain infectious agents transmitted by the xenotransplant. In

addition, the cells or tissues of a person who has been a close contact

of a xenotransplant recipient could contain infectious agents

originating from the xenotransplant. Because of the potential severity

of the risk associated with these situations, the agency is proposing

to require, in Sec. 1271.75(a)(2), that medical records be reviewed to

determine whether a potential donor of cells or tissue has received a

xenotransplant or has been a close contact of a xenotransplant

recipient. If so, the donor would be determined to be unsuitable under

proposed Sec. 1271.75(c).

FDA is proposing to define ``xenotransplantation'' in

Sec. 1271.3(aa) as any procedure that involves the use of live cells,

tissues, or organs from a nonhuman animal source, transplanted or

implanted into a human, or used for ex vivo contact with human body

fluids, cells, tissues, or organs that are subsequently given to a

human recipient. Nonliving biological products or materials from

animals, such as porcine heart valves, porcine insulin, and bovine

serum albumin, have been used clinically for decades and would not be

considered xenotransplantation products for purposes of these

regulations. ``Close contacts'' of a xenotransplant recipient would be

defined in proposed Sec. 1271.3(bb) as household members and others

with whom the recipient participates in activities that could result in

exchanges of bodily fluids.

E. Donor Testing

vine

serum albumin, have been used clinically for decades and would not be

considered xenotransplantation products for purposes of these

regulations. ``Close contacts'' of a xenotransplant recipient would be

defined in proposed Sec. 1271.3(bb) as household members and others

with whom the recipient participates in activities that could result in

exchanges of bodily fluids.

E. Donor Testing

In addition to donor screening, the analysis of donor test results

is necessary for a donor-suitability determination. Laboratory tests

conducted on specimens collected from a cell or tissue donor can

indicate whether the donor has evidence of infection due to a relevant

communicable disease agent or disease. Proposed Sec. 1271.80 sets out

the general requirements for donor testing. Disease- and product-

specific requirements are in proposed Sec. 1271.85.

FDA notes that the proposed regulations employ the word

``screening'' in two different contexts. In proposed Secs. 1271.80 and

1271.85, ``screening test'' refers to a laboratory test to determine

exposure to or presence of a relevant communicable disease agent. The

agency has used the term ``screening test'' in the past, e.g.,

Sec. 1270.21, and considers it to be the generally recognized term in

the industry and medical community for this type of initial test. Other

sections of the proposed regulations, e.g., proposed Sec. 1271.75, use

the term ``donor screening'' to refer to the review of the donor's

relevant medical records, as defined in proposed Sec. 1271.3(v). This

use of ``donor screening'' is consistent with part 1270 and with usage

by the industry and medical community.

1. General Requirements (Proposed Sec. 1271.80)

FDA proposes in Sec. 1271.80(a) to require that a donor specimen

be tested for evidence of infection due to relevant communicable

disease agents and diseases, which would include, at a minimum, those

specified in proposed Sec. 1271.85. Proposed Sec

or screening'' is consistent with part 1270 and with usage

by the industry and medical community.

1. General Requirements (Proposed Sec. 1271.80)

FDA proposes in Sec. 1271.80(a) to require that a donor specimen

be tested for evidence of infection due to relevant communicable

disease agents and diseases, which would include, at a minimum, those

specified in proposed Sec. 1271.85. Proposed Sec. 1271.80(a) states

that a specimen from the mother of a fetal or neonatal donor would be

acceptable for testing. The proposed regulation also specifically notes

that the purpose of testing is to adequately and appropriately reduce

the risk of transmission of relevant communicable diseases.

Proposed Sec. 1271.80(b) addresses the timing of the collection of

a donor specimen for testing. The agency proposes to require that the

donor specimen be collected at the time of recovery of cells or tissue

from the donor or within 48 hours after recovery. The agency is

concerned that a specimen collected prior to donation may not

accurately reflect the donor's actual exposure to a relevant

communicable disease at the time of donation. However, the agency

recognizes that there may be certain instances in which it would be

preferable to analyze a donor specimen to determine donor suitability

in advance of recovery of cells or tissue. For that reason, the agency

proposes that, for living donors, a specimen may be collected up to 7

days prior to recovery if: (1) Recovery of the cells or tissue involves

invasive procedures or substantial risk to the donor; (2) implantation,

transplantation, infusion, or transfer of the recovered cells or tissue

is necessary before results of testing performed on a specimen

collected at the time of recovery or post recovery would be available;

or (3) extensive processing of the recovered cells or tissue is

necessary before results of testing performed on a specimen collected

at the time of recovery or post recovery would be available

splantation, infusion, or transfer of the recovered cells or tissue

is necessary before results of testing performed on a specimen

collected at the time of recovery or post recovery would be available;

or (3) extensive processing of the recovered cells or tissue is

necessary before results of testing performed on a specimen collected

at the time of recovery or post recovery would be available.

The agency recognizes that its proposed requirement on the timing

of collection of donor specimens differs from testing practices

currently followed by various industry members, and specifically

requests comments on this proposal. Any comments that propose an

alternative time period should explain how the proffered alternative

balances the agency's concern about the spread of communicable disease

with the practical concerns relating to the coordination of donor

testing and donation.

Under proposed Sec. 1271.80(c), testing would be required to be

performed using FDA-licensed, approved, or cleared donor screening

tests in accordance with the manufacturer's instructions, to adequately

and appropriately reduce the risk of

transmission of relevant communicable disease agents or diseases.

Proposed Sec. 1271.80(c) contains a proviso with respect to Chlamydia

trachomatis and Neisseria gonorrhea, for which testing of certain

donors of reproductive cells and tissues would be required under

proposed Sec. 1271.85(c). At this time there are no FDA-licensed,

approved, or cleared donor screening tests available for those two

disease agents. However, the agency considers that testing for the

disease agents is essential to prevent their spread, and that the use

of tests labeled for the detection of those organisms in an

asymptomatic, low-prevalence population would be adequate and

appropriate until screening tests are available

are no FDA-licensed,

approved, or cleared donor screening tests available for those two

disease agents. However, the agency considers that testing for the

disease agents is essential to prevent their spread, and that the use

of tests labeled for the detection of those organisms in an

asymptomatic, low-prevalence population would be adequate and

appropriate until screening tests are available. Thus, until such time

as appropriate FDA-licensed, approved, or cleared donor screening tests

are available for these disease agents, the required testing would be

performed using tests labeled for detection of the organisms.

Under proposed Sec. 1271.80(d), a donor whose specimen tests

repeatedly reactive or positive on a test required under proposed

Sec. 1271.85 must be determined to be unsuitable. (Repeatedly reactive

means initially reactive, then reactive in at least one of two

duplicate tests with the same manufacturer's test kit.) Proposed

Sec. 1271.80(d)(1)(i) and (d)(1)(ii) set out two exceptions to this

general rule. Under the first exception, a repeatedly reactive test for

CMV will not make a donor unsuitable unless additional testing shows

the presence of an active infection. This exception is being proposed

because, although a donor with active CMV poses a risk of CMV

transmission, a donor's past infection with the virus does not

necessarily present such a risk. The results of CMV testing would

accompany the product, under proposed Sec. 1271.55(a)(1)(i), or would

be contained in the summary of records that accompanies the product,

and should be reviewed by the physician prior to use of the product.

The agency believes that the provision of information on CMV status in

the materials accompanying the product will be sufficient to allow

physicians to make informed decisions about the use of the product in

particular patients' circumstances. The agency specifically requests

comments on this approach

companies the product,

and should be reviewed by the physician prior to use of the product.

The agency believes that the provision of information on CMV status in

the materials accompanying the product will be sufficient to allow

physicians to make informed decisions about the use of the product in

particular patients' circumstances. The agency specifically requests

comments on this approach.

The second exception is for a donor whose specimen has tested

repeatedly reactive on a non-Treponemal screening test for syphilis and

negative on a specific Treponemal confirmatory test. FDA is proposing

this exception because it recognizes that non-Treponemal screening

tests, which do not test directly for the disease agent, frequently

provide false-positive results. Negative results from a Treponemal

confirmatory test, which is more specific and, thus, more accurate,

will be considered to override an initial false positive.

Blood loss from a potential donor, followed by transfusion or

infusion, may result in plasma dilution that affects test results.

Plasma dilution is defined in proposed Sec. 1271.3(s) as a decrease in

the concentration of the donor's plasma proteins and circulating

antigens or antibodies resulting from the transfusion of blood or blood

components and/or infusion of fluids. Proposed Sec. 1271.80(d)(2) sets

out the requirements for assessing whether a specimen from a donor from

whom blood loss has occurred is acceptable. (In the absence of an

acceptable specimen, a donor must be determined to be unsuitable.) A

specimen taken after blood loss but before the transfusion or infusion

is acceptable. In addition, in certain instances an established

procedure to calculate dilution (an algorithm) may be used. Proposed

Sec. 1271.80(d)(2) is based closely on Sec. 1270.20(h)(2) and (h)(3).

FDA discussed the provisions of Sec

e absence of an

acceptable specimen, a donor must be determined to be unsuitable.) A

specimen taken after blood loss but before the transfusion or infusion

is acceptable. In addition, in certain instances an established

procedure to calculate dilution (an algorithm) may be used. Proposed

Sec. 1271.80(d)(2) is based closely on Sec. 1270.20(h)(2) and (h)(3).

FDA discussed the provisions of Sec. 1270.20(h)(2) and (h)(3) in the

tissue final rule (see 62 FR 40429 at 40435 through 40436), and the

guidance document that accompanied that rule contains information on

plasma dilution and algorithms.

2. Specific Requirements (Proposed Sec. 1271.85)

Proposed Sec. 1271.85 sets out specific requirements with respect

to donor testing. Proposed Sec. 1271.85(a), (b), and (c) identify the

minimum relevant communicable disease agents for which testing is

required. Proposed Sec. 1271.85(d) contains retesting requirements for

donors of certain reproductive cells or tissues.

The proposed requirements in Sec. 1271.85(a) cover all cells and

tissues that are not subject to a regulatory exception from the testing

requirement. Under proposed Sec. 1271.85(a), a specimen from a donor of

viable or nonviable cells or tissue would be required to be tested for

evidence of infection due to: HIV type 1, HIV type 2, HBV, HCV, and

Treponema pallidum.

In addition to the testing required under proposed

Sec. 1271.85(a), a donor of viable, leukocyte-rich cells or tissues

would be required under proposed Sec. 1271.85(b) to be tested for

evidence of infection due to: HTLV types I and II, and CMV. The agency

is proposing to make the distinction between cells and tissues that are

rich in leukocytes and those that are not, because the transmission of

certain disease agents, such as HTLV types I and II, and CMV, depends

on the presence of viable leukocytes. Stem cells and reproductive cells

and tissue, e.g., semen, are examples of leukocyte-rich cells or

tissue

V types I and II, and CMV. The agency

is proposing to make the distinction between cells and tissues that are

rich in leukocytes and those that are not, because the transmission of

certain disease agents, such as HTLV types I and II, and CMV, depends

on the presence of viable leukocytes. Stem cells and reproductive cells

and tissue, e.g., semen, are examples of leukocyte-rich cells or

tissue. In contrast, FDA does not consider corneas, skin, heart valves,

dura mater, bone, tendons, ligaments, or cartilage to be leukocyte-

rich. The agency specifically requests comments on whether the term

``leukocyte-rich'' needs additional clarification.

Proposed Sec. 1271.85(c) would require testing for donors of

reproductive cells or tissue, in addition to those required by proposed

Sec. 1271.85(a) and (b). Proposed Sec. 1271.85(c)(1) identifies

Chlamydia trachomatis and Neisseria gonorrhea as relevant genitourinary

disease agents for which testing would be required. However, testing

for Chlamydia trachomatis and Neisseria gonorrhea would not be required

if the reproductive cells or tissue are procured by a method that

ensures freedom from contamination of the cells or tissue by infectious

disease organisms that may be present in the genitourinary tract. FDA

is requesting comments and supporting data on whether other

genitourinary disease agents should be considered relevant.

Proposed Sec. 1271.85(a), (b), and (c) specify that the purpose of

testing is to adequately and appropriately reduce the risk of

transmission of relevant communicable diseases. Thus, any test

performed under proposed Sec. 1271.85 must be chosen with this purpose

in mind. The regulation specifies that testing shall be performed using

FDA-licensed, approved, or cleared screening tests in accordance with

the manufacturers' instructions

cify that the purpose of

testing is to adequately and appropriately reduce the risk of

transmission of relevant communicable diseases. Thus, any test

performed under proposed Sec. 1271.85 must be chosen with this purpose

in mind. The regulation specifies that testing shall be performed using

FDA-licensed, approved, or cleared screening tests in accordance with

the manufacturers' instructions.

The following list represents FDA's current thinking on the

appropriate FDA-licensed, approved, or cleared screening tests that

should be used to adequately and appropriately reduce the risk of

transmission of relevant communicable disease agents or diseases:

(1) HIV, type 1: FDA-licensed screening test for anti-HIV-1:

(2) HIV, type 2: FDA-licensed screening test for anti-HIV-2:

(3) HBV: FDA-licensed screening test for hepatitis B surface

antigen (HBsAg);

(4) HCV: FDA-licensed screening test for anti-HCV;

(5) Treponema pallidum: FDA-cleared serological test for syphilis;

(6) Human T-lymphotropic virus, types I and II: FDA-licensed

screening test for anti-HTLV I/II; and

(7) Cytomegalovirus: FDA-cleared test for anti-CMV.

In the case of HBV, there are two types of screening test: A test

for the surface antigen and a test for the core antibody. Currently,

the appropriate test to reduce the possibility of transmission of HBV

to a recipient is the surface antigen test because it is a marker of

infectivity. Thus, ``FDA-licensed screening test for HBsAg'' appears on

the previous list as an example of a test to be performed for the HBV

virus. Testing for the core antibody alone would not accurately

evaluate the donor for the possibility of transmission, because the

core antibody test could be negative and the donor could still be

infectious. Active infection at the time of donation can only be

adequately evaluated with the use of the surface antigen screening

test, which, if repeatedly reactive, indicates early or chronic HBV

infection

g for the core antibody alone would not accurately

evaluate the donor for the possibility of transmission, because the

core antibody test could be negative and the donor could still be

infectious. Active infection at the time of donation can only be

adequately evaluated with the use of the surface antigen screening

test, which, if repeatedly reactive, indicates early or chronic HBV

infection.

It should be noted that, if the establishment determining the

suitability of the donor is aware of any repeatedly reactive screening

test for a relevant communicable disease agent that indicates the

possible presence of a relevant communicable disease, whether or not

the test is the one best suited to adequately and appropriately reduce

the risk of disease transmission, then the donor of the cellular or

tissue-based product must be determined to be unsuitable under proposed

Sec. 1271.80(d)(1). For example, a repeatedly reactive core antibody

test for HBV, although not required, would make the donor unsuitable.

Proposed Sec. 1271.80(d) would require retesting of the donor at

least 6 months after the date of donation of reproductive cells or

tissues that can reliably be stored. Cells or tissues that can reliably

be stored are those that maintain function and integrity during

storage; some examples include spermatozoa and sperm progenitor cells.

The retesting requirement is designed to address the ``window period''

between the time of infection and the presence of detectable levels of

antibodies to communicable diseases and agents such as HCV. Testing

would not be complete, and thus a donor-suitability determination could

not be made, until the completion of the second round of tests. Under

proposed Sec. 1271.60(a), quarantine for these products would last a

minimum of 6 months, until completion of testing. For donors of

reproductive cells and tissues that can be reliably stored, FDA

considers HBV core antibody screening test to be the most adequate and

appropriate retest for HBV

itability determination could

not be made, until the completion of the second round of tests. Under

proposed Sec. 1271.60(a), quarantine for these products would last a

minimum of 6 months, until completion of testing. For donors of

reproductive cells and tissues that can be reliably stored, FDA

considers HBV core antibody screening test to be the most adequate and

appropriate retest for HBV.

For all other banked tissue and cells from living donors, FDA

recommends but does not propose to require that, where appropriate and

feasible, all donors (or mothers of fetal or neonatal donors) be

retested 6 months after donation and that the banked cells and tissue

be kept in quarantine pending retesting.

3. Dura Mater

CJD, a type of TSE, is a rare, but invariably fatal, degenerative

disease of the central nervous system characterized by progressive

dementia. Recent reports link the transmission of CJD to recipients of

human cadaveric dura mater, particularly allografts manufactured by one

company prior to 1987. Thus, FDA proposes to require, in

Sec. 1271.85(e), that an assessment be performed for donors of dura

mater to detect evidence of TSE.

On March 27, 1997, the World Health Organization (WHO) recommended

a ban on the use of human dura mater as an implant because of reports

of CJD in a limited number of recipients. Since FDA had established

safeguards and guidelines in 1990 to minimize the possibility of such

infections, the agency announced on March 31, 1997, that it would not

restrict the distribution of FDA-cleared dura mater allografts.

On October 6, 1997, FDA's Transmissible Spongiform Encephalopathy

Advisory Committee (TSEAC) discussed the existing safeguards and

additional safeguards that needed to be in place to prevent the

transmission of CJD by human cadaveric dura mater. The TSEAC's

recommendations were transmitted to industry through an FDA letter to

manufacturers on March 6, 1998. After comments were received, FDA

revisited the issues with TSEAC on April 16, 1998

m Encephalopathy

Advisory Committee (TSEAC) discussed the existing safeguards and

additional safeguards that needed to be in place to prevent the

transmission of CJD by human cadaveric dura mater. The TSEAC's

recommendations were transmitted to industry through an FDA letter to

manufacturers on March 6, 1998. After comments were received, FDA

revisited the issues with TSEAC on April 16, 1998. Based upon the

recommendations of the TSEAC at this meeting, the following represent

proposed procedures for complying, at the present time, with the

testing requirements of proposed Sec. 1271.85(e) and the screening

requirements of proposed Sec. 1271.75(a)(4).

After the dura mater has been removed, a full brain autopsy of the

donor of dura mater, including gross and histological examination,

should be performed by a qualified neuropathologist, to identify

evidence of TSE changes. Testing to detect protease-resistant prion

protein (PrP-RES) either by immunohistochemistry or Western Blot, is

currently a research (investigational use) tool, as there is no FDA-

approved or validated test for screening TSE in brain tissue. However,

a negative test is considered significant in increasing the level of

confidence that the brain and the dura mater are free of TSE. FDA

encourages validation of this test. Manufacturers should continue to

monitor scientific developments and should incorporate this test if and

when it becomes approved for this intended use.

Donors of dura mater should be subject to a consistent screening

protocol, including a donor medical history interview that includes

questions relevant to TSE risk, as mentioned in the human tissue

guidance.

FDA intends to address other recommendations of the TSEAC in

future proposed regulations on CGTP's

nd should incorporate this test if and

when it becomes approved for this intended use.

Donors of dura mater should be subject to a consistent screening

protocol, including a donor medical history interview that includes

questions relevant to TSE risk, as mentioned in the human tissue

guidance.

FDA intends to address other recommendations of the TSEAC in

future proposed regulations on CGTP's. These include a standard

protocol for procuring dura mater, prevention of cross-contamination,

use of either a NaOH protocol or other procedure that has been

validated to reduce infectivity while preserving clinical utility,

archiving of a sample of brain and dura mater tissues, and

recordkeeping and tracking requirements.

4. Corneal Tissue

The possibility that corneal tissue may transmit TSE is discussed

in section III.D.1 of this document. Although the agency is proposing

to require that, for donors of dura mater, an assessment designed to

detect evidence of TSE be performed, the recommended method of

accomplishing this assessment involves a full brain autopsy, including

gross and histological examination, and definitive results are not

available for several weeks. At present, this type of testing does not

appear feasible for cornea donors, because under present conditions of

storage in the United States, corneas must be transplanted within days

of procurement in order to maintain their integrity and function. The

agency requests comment on the feasibility of testing for TSE in donors

of corneal tissue.

F. Exceptions (Proposed Sec. 1271.90)

ral weeks. At present, this type of testing does not

appear feasible for cornea donors, because under present conditions of

storage in the United States, corneas must be transplanted within days

of procurement in order to maintain their integrity and function. The

agency requests comment on the feasibility of testing for TSE in donors

of corneal tissue.

F. Exceptions (Proposed Sec. 1271.90)

1. Exceptions From the Requirement for a Donor Suitability

Determination

Proposed Sec. 1271.90(a) identifies two situations in which a

determination of donor suitability would not be required. In the case

of banked cells and tissues for autologous use, cells and tissues are

removed from a patient and stored for later use in the same patient.

Because the risk of the patient's contracting a new communicable

disease from cells or tissues taken from his or her own body is

extremely low, FDA is not requiring communicable disease testing or

screening. (Any handling and storage requirements for such cells or

tissue may be addressed later, in the proposed CGTP regulation.)

However, as a general safety measure, FDA recommends that

autologous donors be subjected to the same testing and screening as

proposed under Secs. 1271.75, 1271.85, and 1271.90 for allogeneic

donors of comparable human cellular or tissue-based products.

The second situation in which FDA is recommending but not

requiring testing is for reproductive cells or tissue donated by a

sexually intimate partner of the recipient. In this case, the recipient

will likely have been routinely exposed to the donor's semen or other

body fluids. Although some screening and testing of the donor and

recipient may be appropriate, FDA believes that this should be the

responsibility of the attending physician and the donor and the

recipient.

2. Labeling Requirements

Although screening and testing would not be required in the two

above situations, FDA is proposing certain labeling requirements

d to the donor's semen or other

body fluids. Although some screening and testing of the donor and

recipient may be appropriate, FDA believes that this should be the

responsibility of the attending physician and the donor and the

recipient.

2. Labeling Requirements

Although screening and testing would not be required in the two

above situations, FDA is proposing certain labeling requirements.

In order to protect those people who may handle the human cellular

or tissue-based product, the manufacturer would be required to label a

product as ``NOT EVALUATED FOR INFECTIOUS SUBSTANCES'' unless all donor

screening and testing applicable to a comparable human cellular or

tissue-based product under proposed Secs. 1271.75, 1271.80, and 1271.85

are performed. Thus, if screening and testing results are negative, but

not all of the testing and screening that would be required under

proposed Secs. 1271.75, 1271.80, and 1271.85 are performed, then the

product would be labeled ``NOT EVALUATED FOR INFECTIOUS SUBSTANCES.''

However, if any screening or testing is performed, and the results

indicate the presence of relevant communicable disease agents, or risk

factors for and/or clinical evidence of relevant communicable disease,

then the product would be labeled with the Biohazard legend shown in

proposed Sec. 1271.3(i).

In addition, the manufacturer would be required to label

autologous banked cells and tissues as ``FOR AUTOLOGOUS USE ONLY.''

Such a label would help prevent inadvertent allogeneic administration.

G. Drug and Device Amendments (Secs. 210.1, 210.2, 211.1, 820.1)

te the product. (References to the

requirements in proposed part 1271 are also proposed to be added to

Secs. 210.2 and 211.1, to bring those regulations in conformity with

the changes in Sec. 210.1.) Comparable amendments are being proposed

for Sec. 820.1 to achieve the same result with respect to human

cellular and tissue-based products regulated as devices.

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 (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 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 a written

statement under section 202(a) 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 million (adjusted annually for inflation in any one year).

The agency believes that this final rule is consistent with the

principles identified in Executive Order 12866. OMB has determined that

the final rule is a significant regulatory action as defined by the

Executive Order and so is subject to review

ate, local,

and tribal governments, in the aggregate, or by the private sector, of

$100 million (adjusted annually for inflation in any one year).

The agency believes that this final rule is consistent with the

principles identified in Executive Order 12866. OMB has determined that

the final rule is a significant regulatory action as defined by the

Executive Order and so is subject to review. Because the rule does not

impose mandates on State, local, or tribal governments, or the private

sector, that will result in an expenditure in any one year of $100

million or more, FDA is not required to perform a cost-benefit analysis

according to the Unfunded Mandates Reform Act.

The Regulatory Flexibility Act requires agencies to prepare a

Regulatory Flexibility Analysis for each rule unless the agency

certifies that the rule will not have a significant economic impact on

a substantial number of small entities. As explained in section IV.C of

this document, the agency believes that most of the facilities would

not be significantly affected by the proposed rule because they are

already performing the infectious disease screening and testing and

recordkeeping that is being proposed. However, FDA does not have

sufficient data to characterize the size distribution and other

relevant features of small entities involved in reproductive tissue and

the impact on these entities is uncertain. FDA has therefore prepared

an Initial Regulatory Flexibility Analysis.

A. Objectives and Basis of the Proposed Action

sease screening and testing and

recordkeeping that is being proposed. However, FDA does not have

sufficient data to characterize the size distribution and other

relevant features of small entities involved in reproductive tissue and

the impact on these entities is uncertain. FDA has therefore prepared

an Initial Regulatory Flexibility Analysis.

A. Objectives and Basis of the Proposed Action

FDA is proposing this action as the next step in the regulation of

the rapidly evolving industry of human cellular and tissue-based

products. This proposed rule focuses on the first of three general

areas of regulation proposed in the approach to cellular and tissue-

based products, i.e., preventing unwitting use of contaminated tissues

with the potential for transmitting infectious diseases such as AIDS

and hepatitis. While acting to increase the safety of the nation's

supply of human cellular and tissue-based products, FDA is proposing

regulations that would avoid unnecessary requirements. The agency has

designed the screening and testing regulations for the specific type

and use of each cellular or tissue-based product that would minimize

regulatory burden while maintaining safety.

In this rulemaking, the agency is proposing to broaden its

regulatory oversight over all human cellular and tissue-based products,

including reproductive cells and tissue. This action is focused on the

prevention of diseases transmitted by specific cellular or tissue-based

products by implantation, transplantation, infusion, or transfer of any

cellular or tissue-based product. For example, FDA is

his rulemaking, the agency is proposing to broaden its

regulatory oversight over all human cellular and tissue-based products,

including reproductive cells and tissue. This action is focused on the

prevention of diseases transmitted by specific cellular or tissue-based

products by implantation, transplantation, infusion, or transfer of any

cellular or tissue-based product. For example, FDA is

now proposing to require cell and tissue donors to be tested for

syphilis and screened for TSE. Donors of viable, leukocyte-rich cells

or tissue would also be tested for HTLV types I and II, and CMV.

Because communicable disease agents can be transmitted by semen and

other genitourinary secretions, FDA is proposing to require that donors

of reproductive cells and tissue be screened and tested for sexually

transmitted diseases. FDA proposes to amend the existing CGMP

regulations for drugs and devices to incorporate the screening and

testing requirements in proposed part 1271 subpart C. FDA is relying on

the authority provided by section 361 of the PHS Act to issue

regulations to prevent the spread of communicable disease, as well as

its authority under the act to issue CGMP regulations (21 U.S.C.

351(a)(2)(B) and (h) and 360j(f)(1)). FDA has reviewed related Federal

rules and has not identified any rules that duplicate, overlap, or

conflict with the proposed rule.

B. The Type and Number of Entities Affected

vided by section 361 of the PHS Act to issue

regulations to prevent the spread of communicable disease, as well as

its authority under the act to issue CGMP regulations (21 U.S.C.

351(a)(2)(B) and (h) and 360j(f)(1)). FDA has reviewed related Federal

rules and has not identified any rules that duplicate, overlap, or

conflict with the proposed rule.

B. The Type and Number of Entities Affected

The proposed rule would require manufacturers of human cellular

and tissue-based products, including human tissue intended for

transplantation, to screen and test donors of cells and tissue used in

those products. The rule would require that donors be screened and

tested for risk factors for and clinical evidence of relevant

communicable disease agents and diseases. The proposed rule would apply

to a range of activities conducted at facilities such as tissue banks,

blood banks, eye banks, semen banks, infertility treatment facilities,

and cord blood banks. However, the number of entities that would be

required to comply with this proposal is difficult to ascertain because

the agency has not previously regulated certain human cellular and

tissue-based products. Although the agency has proposed to require

manufacturers of human cellular and tissue-based products to register

and list their products and to identify their manufacturer steps, this

information will not be available for some time. Consequently, the

agency's estimates rely heavily on information obtained from various

trade organizations related to the human cellular and tissue-based

industry.

As shown in Table 1 of this document, the estimated numbers of

facilities affected by the proposed rule are derived from varied

industry sources. The Eye Bank Association of America (EBAA) represents

about 108 eye banks, which are estimated to be about 95 percent of eye

banks in the United States

ained from various

trade organizations related to the human cellular and tissue-based

industry.

As shown in Table 1 of this document, the estimated numbers of

facilities affected by the proposed rule are derived from varied

industry sources. The Eye Bank Association of America (EBAA) represents

about 108 eye banks, which are estimated to be about 95 percent of eye

banks in the United States. The American Association of Tissue Banks

(AATB) lists approximately 60 accredited tissue banks and projects an

additional 40 to 60 members not accredited. As of May 1998, CBER has

record of 132 registered blood bank facilities listing ``stem cell'' as

a type of product or establishment. The National Marrow Donor Program

(NMDP), which includes establishments that recover peripheral blood

stem cells, lists approximately 101 donor centers (these establishments

are associated with the American Association of Blood Banks (AABB) or

the Foundation for the Accreditation of Hematopoietic Cell Therapy

(FAHCT)). Although there is no single national organization that keeps

track of the number of facilities for umbilical cord blood banking, FDA

estimates that there are approximately 25 cord blood banks currently

operating in the United States. These facilities would also seek

accreditation through FAHCT or AABB.

In addition, the proposed rule would apply to facilities involved

with reproductive tissue, primarily fertility centers and sperm banks

that collect and process donor oocytes or donor sperm. The American

Society of Reproductive Medicine (ASRM) has a membership of

approximately 300 fertility centers, about 280 of which have provided

reports to the 1995 Society for Assisted Reproductive Technology (SART)

registry. The ASRM also has a 1996 list of approximately 110 sperm

banks operating in the United States

ters and sperm banks

that collect and process donor oocytes or donor sperm. The American

Society of Reproductive Medicine (ASRM) has a membership of

approximately 300 fertility centers, about 280 of which have provided

reports to the 1995 Society for Assisted Reproductive Technology (SART)

registry. The ASRM also has a 1996 list of approximately 110 sperm

banks operating in the United States. Although ASRM has published

guidelines for donor screening and other aspects of oocyte donation,

and for therapeutic donor insemination, ASRM does not exercise

oversight or provide accreditation of facilities that collect donor

tissue or use these tissue products in infertility treatment.

C. Nature of the Impact

The proposed rule includes requirements for donor screening, donor

testing, recordkeeping and quarantine of cells and tissue. Donor

screening would involve the review of relevant medical records to

include a medical history interview (particularly pertaining to

communicable disease risk), a current report of a physical assessment

for cadaveric donors, and a physical examination for living donors. For

living repeat donors, a complete donor-suitability determination

procedure would be required at least once every 6 months. The proposed

rule would require that a donor specimen be tested for evidence of

infection due to relevant communicable disease agents and diseases,

with testing conducted within a specified time of recovery of cells or

tissue. In general, a donor may be determined suitable if free from

risk factors for and clinical evidence of infection due to relevant

communicable disease agents and diseases, and if the required testing

is negative or nonreactive.

The proposed rule would also require recordkeeping of donor-

suitability determinations

,

with testing conducted within a specified time of recovery of cells or

tissue. In general, a donor may be determined suitable if free from

risk factors for and clinical evidence of infection due to relevant

communicable disease agents and diseases, and if the required testing

is negative or nonreactive.

The proposed rule would also require recordkeeping of donor-

suitability determinations. Manufacturers would be required to ship

human cellular and tissue-based products accompanied by documentation

of donor-suitability status, including a copy of the donor's relevant

medical records, results of required testing and the name and address

of the establishment that made the suitability determination. The

proposed rule requires that establishments that generate records used

in donor-suitability determinations retain those records for at least

10 years after the date of the product's use or distribution. The

proposed rule would also require that cell and tissue-based products be

quarantined until a determination of donor suitability is made, and

that products be clearly labeled as under quarantine during that

period. The rule would hold manufacturers responsible for the

appropriate labeling and documentation of cells or tissue from a donor

who is found to be unsuitable.

The extent of the economic impact is expected to be minor for most

of these establishments, because the leading industry associations have

already established standards for screening that, in most cases, meet

or exceed the criteria specified in the proposed rule; and because

existing FDA regulations already apply to certain human tissue intended

for transplantation (see part 1270). Table 1 of this document lists the

types of donor cells and tissue that will be affected by the proposed

rule and the associated facilities that collect and bank these tissue

products

creening that, in most cases, meet

or exceed the criteria specified in the proposed rule; and because

existing FDA regulations already apply to certain human tissue intended

for transplantation (see part 1270). Table 1 of this document lists the

types of donor cells and tissue that will be affected by the proposed

rule and the associated facilities that collect and bank these tissue

products. Table 1 also provides estimates of the number of

establishments affected by the proposed rule and the estimated

percentage of establishments already in compliance with current

industry standards for donor screening and testing. The lists of

specific donor screening and testing requirements proposed by FDA can

be compared with those currently required by the industry associations.

Table 1.--Type and Number of Establishments Affected and Percentage Already in Compliance With Industry Standards for Donor Suitability Screening and

Testing

--------------------------------------------------------------------------------------------------------------------------------------------------------

Relevant Industry Association

Type of Human Donor Tissue Type of Entities Affected (and Standards Compared to FDA Proposed Estimated Percent Entities in

Estimated Total Number) Regulations Compliance with Industry Standards

--------------------------------------------------------------------------------------------------------------------------------------------------------

Nonreproductive Tissue

--------------------------------------------------------------------------------------------------------------------------------------------------------

Eye tissue Eye banks 21 CFR part 1270 and FDA proposed 100%

108 EBAA members (114 total) (s1,s2,s3)\1\

(t1,t2,t3,t5)\2\

EBAA

(s1 through s3)\1\

(t1 through t3)\2\

Pericardium, dura mater, heart Tissue banks 21 CFR part 1270 and FDA proposed 100%

valves, skin allograft, bone 60 AATB members (110 total) (s1 through s3)\1\

allograft, other viable (t1,t2,t3,t5)\2\

AATB

(s1 throu

-------------

Eye tissue Eye banks 21 CFR part 1270 and FDA proposed 100%

108 EBAA members (114 total) (s1,s2,s3)\1\

(t1,t2,t3,t5)\2\

EBAA

(s1 through s3)\1\

(t1 through t3)\2\

Pericardium, dura mater, heart Tissue banks 21 CFR part 1270 and FDA proposed 100%

valves, skin allograft, bone 60 AATB members (110 total) (s1 through s3)\1\

allograft, other viable (t1,t2,t3,t5)\2\

AATB

(s1 through s3)\1\

(t1 through t5)\2\

Stem cells; peripheral blood Marrow donor centers FDA proposed 100%

132 FDA registered facilities (s1 through s3)\1\

donor centers (101 total) (t1 through t6)\2\

collection centers (114 total) AABB/FAHCT

(s1 through s3)\1\

(t1 through t6)\2\

Stem cells; umbilical cord blood Cord blood banks (25 total) FDA proposed 100%

(s1 through s3)\1\

(t1 through t6)\2\

AABB/FAHCT

(s1 through s3)\1\

(t1 through t6)\2\

--------------------------------------------------------------------------------------------------------------------------------------------------------

Reproductive Tissue

--------------------------------------------------------------------------------------------------------------------------------------------------------

Donor oocyte, embryos ART facilities & associated labs FDA proposed Unknown

281 in 1995 SART report (300 total) (s1 through s3)\1\

(t1,t2,t3,t5)\2\

ASRM, CAP

(s1)\1\

(t1,t2,t3,t5)\2\

Donor sperm Sperm banks FDA proposed 10% Unknown

4 in 1996 AATB survey (110 total) (s1 through s3)\1\

(t1 through t8)\2\

AATB

(s1 through s3)\1\

(t1 through t8)\2\

ASRM

(s1)\1\

(t1,t2,t3,t5,t7,t8)\2\

--------------------------------------------------------------------------------------------------------------------------------------------------------

\1\ Screening for: s1: HIV, s2: hepatitis, s3: CJD

\2\ Laboratory Tests: t1: anti-HIV-1-2, t2: anti-HCV, t3: HBsAg, t4: anti-HTLV-1, t5: syphilis, t6: CMV, t7: Neisseria gonorrhea, t8: Chlamydia

trachomatis

ASRM

(s1)\1\

(t1,t2,t3,t5,t7,t8)\2\

--------------------------------------------------------------------------------------------------------------------------------------------------------

\1\ Screening for: s1: HIV, s2: hepatitis, s3: CJD

\2\ Laboratory Tests: t1: anti-HIV-1-2, t2: anti-HCV, t3: HBsAg, t4: anti-HTLV-1, t5: syphilis, t6: CMV, t7: Neisseria gonorrhea, t8: Chlamydia

trachomatis

Based on communications with representatives of several industry

associations and facility managers, FDA estimates that the number of

facilities currently in compliance with industry standards for donor

screening and testing approaches 100 percent for several affected types

of tissue product. Facilities handling reproductive tissue are the

primary exception to this finding, and also represent the greatest area

of uncertainty for this analysis. There is currently no single reliable

source of information on fertility center or sperm bank compliance with

AATB standards or ASRM guidelines. A small percentage of sperm banks

are members of the AATB and are known to comply with that

organization's requirements for screening and testing, but little is

known about the standards for screening used at other facilities.

Because this information is essential for the estimation of economic

impact, FDA requests detailed industry comment on current donor

screening and testing practices in these facilities.

In addition to the proposed donor screening and testing, the

proposed rule is expected to require facility staff time to align

current quarantine, sample labeling and recordkeeping systems with the

requirements of the proposed rule. As shown in Table 2 of this

document, all of the industry associations already specify requirements

for these procedures. With the exception of facilities handling

reproductive tissue, the current industry standards adopted by most

facilities are at least as stringent as those included in the proposed

rule.

sample labeling and recordkeeping systems with the

requirements of the proposed rule. As shown in Table 2 of this

document, all of the industry associations already specify requirements

for these procedures. With the exception of facilities handling

reproductive tissue, the current industry standards adopted by most

facilities are at least as stringent as those included in the proposed

rule.

Table 2.--Correspondence of FDA-proposed Requirements to Current Industry Standards for Specimen Quarantine,

Labeling, and Recordkeeping

----------------------------------------------------------------------------------------------------------------

FDA-Proposed AATB Current EBAA Current AABB Current FAHCT Current ASRM Current

----------------------------------------------------------------------------------------------------------------

Quarantine X1 X1 X1 X1 Donor sperm; not

oocyte

----------------------------------------------------------------------------------------------------------------

Labeling X1 X1 X1 X1 X1

----------------------------------------------------------------------------------------------------------------

Record Retention X1 X1 X1 X1 Recommended; not

required

----------------------------------------------------------------------------------------------------------------

\1\ ``X'' means corresponds.

Due to the disparity in the amount of available information and the

potential impact of the rule on nonreproductive versus reproductive

tissue establishments, these two broad categories of tissue

establishments are treated separately in the impact analysis that

follows.

1. Impact on Nonreproductive Tissue Establishments

-------------------------------------------

\1\ ``X'' means corresponds.

Due to the disparity in the amount of available information and the

potential impact of the rule on nonreproductive versus reproductive

tissue establishments, these two broad categories of tissue

establishments are treated separately in the impact analysis that

follows.

1. Impact on Nonreproductive Tissue Establishments

(a) Impact of donor screening and testing. As summarized in Table 1

of this document, most nonreproductive tissue establishments are

already in compliance with the proposed FDA donor screening and testing

requirements, as a result of following their own industry association

standards and FDA current regulations. The cost of compliance with

these provisions will be minimal for these establishments.

(b) Impact of recordkeeping and tissue quarantine. The burden of

recordkeeping and tissue quarantine requirements will reflect the staff

time needed to compare current recordkeeping and facility procedures

with those required by the proposed standard and to make modifications

where needed in current facility procedures. Such changes are expected

to be minor for most nonreproductive tissue establishments.

FDA estimates that it would take approximately 8 to 40 hours to

compare the proposed regulations against a facility's current

standards. This process would be performed by a staff person who acts

as a regulatory reviewer, a supervisor, or a manager of quality

assurance. Assuming a labor cost of $40 per hour, this standards

reconciliation effort would result in a one-time cost per facility

ranging from $320 to $1,600. Applying this range of cost per facility

to the approximately 380 nonreproductive tissue facilities yields a

potential impact that ranges from $121,600 to $608,000.

2. Impact on Reproductive Tissue Establishments

a manager of quality

assurance. Assuming a labor cost of $40 per hour, this standards

reconciliation effort would result in a one-time cost per facility

ranging from $320 to $1,600. Applying this range of cost per facility

to the approximately 380 nonreproductive tissue facilities yields a

potential impact that ranges from $121,600 to $608,000.

2. Impact on Reproductive Tissue Establishments

(a) Impact of donor screening and testing. As indicated in Table 1

of this document, the current rate of compliance with industry

standards is unknown among reproductive tissue establishments. Thus,

FDA cannot develop a precise estimate of regulatory costs. As an upper

bound figure, however, FDA assumed that 100 percent of facilities

involved with oocyte donation and 80 percent of sperm banks would need

additional screening and testing. Although the out-of-compliance sperm

banks constitute a majority of the firms in that industry, they are

primarily small operations that are estimated to serve only 5 percent

of all sperm donors.

(i) Oocyte Donor Screening and Testing. The estimated impact of the

proposed rule on establishments involved in oocyte donation is based on

1995 data reported by SART, an organization of assisted reproductive

technology providers affiliated with ASRM. Approximately 70 percent of

ART centers reporting in 1995 had performed at least one cycle of ART

with donor eggs. In 1995, donor eggs were used in approximately 8

percent of all 59,800 ART cycles, or 4,783 cycles. (Although 78 percent

of those cycles used fresh embryos, the proposed quarantine rules would

likely necessitate the use of frozen embryos in all donor cycles, with

some potential associated reduction in the success rate per donor in

vitro fertilization (IVF) cycle (Ref. 1). FDA believes that all

infertility treatment centers already conduct medical exams and

history-taking and perform some laboratory testing prior to egg

retrieval for any potential oocyte donor

uarantine rules would

likely necessitate the use of frozen embryos in all donor cycles, with

some potential associated reduction in the success rate per donor in

vitro fertilization (IVF) cycle (Ref. 1). FDA believes that all

infertility treatment centers already conduct medical exams and

history-taking and perform some laboratory testing prior to egg

retrieval for any potential oocyte donor. Compliance with the proposed

standard, however, may entail adding some additional blood testing and

screening questions to the interview.

The cost of additional blood work (including HIV 1-2, hepatitis B,

hepatitis C, and syphilis) is estimated at about $123 per donor (Ref.

2). The additional time to interview and record information in donor

screening is estimated to cost about $37, based on the assumption that

approximately half of the required screening is already being done, and

the estimated cost of a full health history interview is $75

($37 $75/2) (Ref. 3). Thus, the additional cost per

donation is estimated at $160 ($123 + 37). Based on a reported cost of

$11,868 (Ref. 4) per donor oocyte cycle, this cost translates to a 1.3

percent increase (($160 +$11,868)/$11,868) in the cost of therapy per

cycle.

The cost of screening egg donors will depend on the number of donor

cycles attributable to each screened donor. If each donor contributes

eggs for only one cycle, and the rejection rate is low (assumed to be

0.57 percent, which is the estimated prevalence rate of HBSAG

positivity among parturient women) (Ref. 5), the number of donors to be

tested would be 4,810 (4783/(1-0.0057)). If each donor contributes eggs

for two donor cycles, the number of donors to be screened would be

2,405. These alternative assumptions imply a total cost to U.S.

facilities involved in oocyte donation of from $386,000 to $772,000 per

year, as shown in Table 3 of this document.

SAG

positivity among parturient women) (Ref. 5), the number of donors to be

tested would be 4,810 (4783/(1-0.0057)). If each donor contributes eggs

for two donor cycles, the number of donors to be screened would be

2,405. These alternative assumptions imply a total cost to U.S.

facilities involved in oocyte donation of from $386,000 to $772,000 per

year, as shown in Table 3 of this document.

Table 3.--Alternative Oocyte Donation Scenarios and Associated Donor

Screening Costs

------------------------------------------------------------------------

------------------------------------------------------------------------

Screen/Test Cost Per 2 ART Cycles Per Donor 1 ART Cycle Per Donor

Donor = 2,405 = 4,810 Donors

$123.40 + $37.00 = $386,000 ($160.40 x $772,000 ($160.40 x

$160.40 2,405 = $385,762) 4,810 =$771,524)

------------------------------------------------------------------------

(ii) Sperm donor screening and testing. The agency has conducted an

extensive search for current information on the extent of infectious

disease screening for sperm donors, but has found little current

information available. The Congressional Office of Technology

Assessment (OTA) conducted a survey of establishments involved in sperm

donation in 1987, and found that all commercial banks surveyed

performed routine screening and testing for HIV, but only 45 percent of

private physicians included this screening. The most recently available

data includes a list of approximately 110 commercial sperm banks

developed by ASRM in 1996, and a 1996 registration survey of the AATB

that includes data for 4 sperm banks. The agency is aware that some

sperm banks that have applied, but are not yet accredited members of

AATB, are nonetheless following AATB standards. It is also likely that

some other facilities have informally adopted AATB standards

ludes a list of approximately 110 commercial sperm banks

developed by ASRM in 1996, and a 1996 registration survey of the AATB

that includes data for 4 sperm banks. The agency is aware that some

sperm banks that have applied, but are not yet accredited members of

AATB, are nonetheless following AATB standards. It is also likely that

some other facilities have informally adopted AATB standards. This

analysis assumes that all sperm banks currently perform HIV screening

and testing, as reported by OTA in 1987, and a smaller percentage of

facilities additionally follow all AATB screening and testing

standards.

Based on recent conversations with sperm banking industry experts,

FDA estimates that the largest 20 sperm banks account for approximately

95 percent of the commercial production of donor sperm, and that these

facilities are compliant with AATB standards for donor screening and

testing. The agency analysis therefore assumes that the 20 largest

facilities, which account for most industry production, will experience

minimal impact; while the remaining 90 facilities, which have extremely

small volumes of production, will be more significantly affected. The

very small sperm banks are described by an industry expert as typically

functioning within a physician office practice (e.g., that of an

obstetrician or gynecologist). The sperm banking in these facilities is

generally offered as an additional service to patients receiving

fertility treatment, and is not the primary line of business within

these establishments.

The total estimated cost of the proposed screening and testing

procedures for sperm banking facilities is based on the number of sperm

donors who would require screening and testing, and their respective

unit costs. Due to the lack of data on the actual number of sperm

donors, the agency estimated the number based on projected therapeutic

donor insemination TDI demand

these establishments.

The total estimated cost of the proposed screening and testing

procedures for sperm banking facilities is based on the number of sperm

donors who would require screening and testing, and their respective

unit costs. Due to the lack of data on the actual number of sperm

donors, the agency estimated the number based on projected therapeutic

donor insemination TDI demand. The level of TDI demand has likely

changed over time, with advances in treatment for male factor

infertility. For example, the development of intracytoplasmic sperm

injection ISCI used in conjunction with in vitro fertilization has

enabled some couples to forego TDI in favor of ISCI using the male

partner's sperm (Ref. 6). In 1985, an estimated 70,000 women per year

received TDI (Ref. 7), compared to an estimated 171,000 women who

reported ever receiving artificial insemination with donor sperm, in

the National Survey of Family Growth (NSFG) conducted in 1995. If the

NSFG respondents referred only to experience over the past 5 years,

this would translate to approximately 34,200 women receiving TDI per

year. Assuming an average of three cycles of therapy per patient per

year, these data yield an estimated demand for TDI donor units of

approximately 102,600 units per year. This figure is consistent with an

industry expert estimate of current U.S. TDI production of 100,000

units per year.

Clinical literature indicates that most sperm donor attrition

occurs prior to the blood testing stage of donor screening. For

example, in one study of donor recruitment in which the clinic followed

AATB and ASRM standards, of the total of 199 potential donors initially

recruited, 174 were rejected; 172 of whom were rejected before blood

testing, with only 2 (1 percent) rejected based on the blood test

results (Ref. 8)

es that most sperm donor attrition

occurs prior to the blood testing stage of donor screening. For

example, in one study of donor recruitment in which the clinic followed

AATB and ASRM standards, of the total of 199 potential donors initially

recruited, 174 were rejected; 172 of whom were rejected before blood

testing, with only 2 (1 percent) rejected based on the blood test

results (Ref. 8). Based on these findings, the agency assumes that the

number of donors who will require infectious disease testing is

approximately equal to the number of donors needed to supply the level

of demand for TDI. Thus, FDA's estimate is based on the previous TDI

unit demand combined with the maximum number of births per donor

suggested in ASRM guidelines (Ref. 9), the average delivery rate per

cycle of intrauterine insemination, an assumed 10 donated specimens per

donor per year, and 4 donation units per donor specimen (Ref. 10).

These factors yield an estimated 2,565 donors required per year.

Assuming that the number of donors already screened and tested is

proportionate to the volume of production accounted for by facilities

compliant with AATB standards, FDA estimates that approximately 5

percent of all donors (0.05 x 2,565 = 128), or 128 donors per year, may

need to be newly screened and tested to meet the requirements of the

proposed rule.

The screening cost per donor is assumed to include an initial

medical history and physical, a 6-month followup exam, and an

abbreviated screening at the time of each donation. Based on rates

published on the Internet (Ref. 3), the agency estimates that a full

medical exam may cost $175, a less extensive followup exam will cost

approximately $75 (a published fee for a health history review), and

the abbreviated screening at the time of each donation will cost

approximately $15 (i.e., one-fifth of the time required for a full

history review). One repeat donor visit per year is assumed

lished on the Internet (Ref. 3), the agency estimates that a full

medical exam may cost $175, a less extensive followup exam will cost

approximately $75 (a published fee for a health history review), and

the abbreviated screening at the time of each donation will cost

approximately $15 (i.e., one-fifth of the time required for a full

history review). One repeat donor visit per year is assumed. Thus, the

total cost of this screening is estimated to be $265 per year per

donor.

The lab tests for prospective donors include those listed in Table

1 of this document, with 6-month followup blood tests for hepatitis B

and C, HTLV-1, and syphilis. The cost of additional testing, based on

screening test fees published on the Internet (Ref. 2), is $230.16 for

initial complete blood testing, plus $123.40 for followup blood testing

after a 6-month quarantine period, plus $113.30 for bacterial testing.

The total cost of the additional lab work is estimated to be $467 per

donor per year ($230.16 + $123.40 + $113.30 = $466.86). Because these

estimates are based on charges to facility clients, they are likely to

represent an upper bound on actual facility costs. Using these figures,

the estimated total industry cost per year is approximately $94,000

(128 x ($265 + $467) = $93,696).

(b) Impact of donor recordkeeping and tissue quarantine. The impact

of recordkeeping and tissue quarantine for reproductive tissue

establishments will reflect the staff time required for: (1) A one-time

review and modification of current recordkeeping and facility

procedures to bring them into alignment with the proposed standard, and

s approximately $94,000

(128 x ($265 + $467) = $93,696).

(b) Impact of donor recordkeeping and tissue quarantine. The impact

of recordkeeping and tissue quarantine for reproductive tissue

establishments will reflect the staff time required for: (1) A one-time

review and modification of current recordkeeping and facility

procedures to bring them into alignment with the proposed standard, and

(2) on-going, expanded practices for each donor who undergoes screening

and testing to meet the requirements of the proposed rule.

FDA estimates that the one-time review and alignment of current

facility procedures will require approximately 8 to 40 hours at each

facility. As with nonreproductive tissue facilities, this process would

be performed by a regulatory affairs analyst, a supervisor, or a

manager of quality assurance. Assuming a labor cost of $40 per hour,

this standards reconciliation effort would result in a one-time cost

per facility ranging from $320 to $1,600. This estimate corresponds to

a total one-time cost for all reproductive tissue facilities that

ranges from $131,200 ($320 x (300 + 110)) to $656,000 ($1,600 x (300 +

110)).

The recurring requirements for tissue quarantine, labeling,

recordkeeping and record retention at reproductive tissue facilities

are based on the estimated staff time needed to create and retain

records of medical history, screening information, and lab testing for

each

prospective donor from whom specimens are collected. The records must

comply with the information requirements of the proposed rule and are

estimated to require approximately 4 hours per donor per year of

clerical staff time, with an assumed labor cost of $24 per hour for

clerical staff ($96 per donor per year). Table 4 of this document

summarizes the potential range of recurring costs for all reproductive

tissue facilities. As shown, the estimated costs range from $243,000 to

$474,000, depending on the assumed number of donors.

estimated to require approximately 4 hours per donor per year of

clerical staff time, with an assumed labor cost of $24 per hour for

clerical staff ($96 per donor per year). Table 4 of this document

summarizes the potential range of recurring costs for all reproductive

tissue facilities. As shown, the estimated costs range from $243,000 to

$474,000, depending on the assumed number of donors.

Table 4.--Range of Recurring Costs for Reproductive Tissue

------------------------------------------------------------------------

------------------------------------------------------------------------

128 sperm donors $243,000

1 cycle per egg donor ((128 + 2,405) x $96 = $243,168)

------------------------------------------------------------------------

128 sperm donors $474,000

2 cycles per egg donor ((128 + 4,810) x $96 = $474,048)

------------------------------------------------------------------------

The size and range of these estimates reflects the agency's current

lack of information about typical donor practices for reproductive

tissue. If a higher rate of donation per donor is typically achieved by

facilities, compared to that assumed in this analysis, the additional

cost burden may be much lower than these estimates would indicate. More

generally, if the current level of facility donor screening and

recordkeeping is more stringent among reproductive tissue facilities

than assumed in this analysis, the overall cost of compliance with the

proposed rule will be lower than these preliminary estimates suggest.

Uncertainty about current practice and the level of compliance

results in range estimates of the cost impact of the proposed rule.

However, because most industry sectors already follow industry

standards requiring donor testing and screening, the overall impact is

expected to be small. Table 5 of this document provides a summary of

the impacts across the different industry sectors included in the

analysis

out current practice and the level of compliance

results in range estimates of the cost impact of the proposed rule.

However, because most industry sectors already follow industry

standards requiring donor testing and screening, the overall impact is

expected to be small. Table 5 of this document provides a summary of

the impacts across the different industry sectors included in the

analysis. The total annualized cost for the 380 nonreproductive tissue

facilities is estimated to range from $17,000 to $87,000, reflecting

agency uncertainty about the extent of effort devoted to one-time

review and alignment of existing standard operating procedures with the

proposed donor screening rule provisions. This translates to an average

cost of $45 to $229 per facility.

The annualized cost of compliance for the ART industry ranges from

approximately $631,000 to $1.302 million, reflecting current

uncertainty about the number of oocyte donors and the number of

donations per donor per year. These costs translate to an average cost

of approximately $2,103 ($631,000/300) to $4,340 ($1,302,000/300) per

facility per year. In general, assumed higher rates of donation per

year, or a lower number of total donor oocyte cycles per year, will

result in lower industry costs. By the same token, lower rates of

donation per donor, or higher total donor cycles performed per year,

will result in higher donor screening costs.

The total annualized cost impact on the sperm banking industry is

based on an estimated TDI demand of approximately 102 thousand units

per year, and assumed current compliance of the top 20 commercial

banks, which account for approximately 95 percent of industry

production. The total annualized costs range from approximately

$111,000 to $131,000. These industry totals yield an average annualized

cost range of $1,234 ($111,000/(110-20)) to $1,456 ($131,000/(110-20))

per facility estimated to be noncompliant with the proposed standard.

and assumed current compliance of the top 20 commercial

banks, which account for approximately 95 percent of industry

production. The total annualized costs range from approximately

$111,000 to $131,000. These industry totals yield an average annualized

cost range of $1,234 ($111,000/(110-20)) to $1,456 ($131,000/(110-20))

per facility estimated to be noncompliant with the proposed standard.

Table 5.--Donor Suitability Cost Analysis Summary Table\1\

----------------------------------------------------------------------------------------------------------------

Total Annualized

Type of Facility Total One-time Cost Total Recurring Cost Cost\2\

----------------------------------------------------------------------------------------------------------------

Nonreproductive Tissue--Eye Tissue, Conventional Tissue, and Stem Cell

----------------------------------------------------------------------------------------------------------------

(a) Donor screening and testing Minimal Minimal Minimal

(b) Recordkeeping and tissue $121,600 to $608,000 Minimal $17,000 to $87,000

quarantine

----------------------------------------------------------------------------------------------------------------

Reproductive Tissue--ART Facilities

----------------------------------------------------------------------------------------------------------------

(a) Donor screening and testing Minimal $386,000 to $772,000 $386,000 to $772,000

(b) Recordkeeping and tissue $96,000 to $480,000 $231,000 to $462,000 $245,000 to $530,000

quarantine

ART subtotal $96,000 to $480,000 $617,000 to $1,234,000 $631,000 to $1,302,000

----------------------------------------------------------------------------------------------------------------

Reproductive Tissue--Sperm Banks

----------------------------------------------------------------------------------------------------------------

(a) Donor screening and testing Minimal $94,000 $94,000

e

ART subtotal $96,000 to $480,000 $617,000 to $1,234,000 $631,000 to $1,302,000

----------------------------------------------------------------------------------------------------------------

Reproductive Tissue--Sperm Banks

----------------------------------------------------------------------------------------------------------------

(a) Donor screening and testing Minimal $94,000 $94,000

(b) Recordkeeping and tissue $35,200 to $176,000 $12,000 $17,000 to $37,000

quarantine

Sperm subtotal $35,200 to $176,000 $106,000 $111,000 to $131,000

----------------------------------------------------------------------------------------------------------------

Total Tissue Industry

----------------------------------------------------------------------------------------------------------------

Total $252,800 to $1,264,000 $723,000 to $1,340,000 $759,000 to $1,520,000

----------------------------------------------------------------------------------------------------------------

\1\ Rounded to the nearest thousand

\2\ At 7% interest rate over 10 years

D. Estimated Benefits of Proposed Rule

The proposed action would provide oversight for the full spectrum

of human cellular and tissue-based products that are now marketed and

may be marketed in the future. This action is intended to improve

protection of the public health and increase public confidence in new

technologies, while permitting significant innovation and imposing

minimal regulatory burden. An important benefit of the rule will be the

establishment of a consistent standard of safety to help ensure

equivalent protection from transmissible diseases for all recipients of

therapy involving cellular and tissue-based products, regardless of the

health condition for which they are being treated. The proposed rule

would help minimize risk to all patients of exposure to several life-

threatening, in some cases incurable, diseases including HIV, HBV, HCV,

CJD and others

of safety to help ensure

equivalent protection from transmissible diseases for all recipients of

therapy involving cellular and tissue-based products, regardless of the

health condition for which they are being treated. The proposed rule

would help minimize risk to all patients of exposure to several life-

threatening, in some cases incurable, diseases including HIV, HBV, HCV,

CJD and others. These risks would be minimized through validated

screening procedures, lab tests, and adequate labeling to avoid

unwitting use of unsafe specimens. Each of the infectious diseases

screened (see Table 1 of this document) will provide added patient

safety protection and public health benefit.

The risks of disease transmission vary by type of cellular and

tissue-based product. Donor screening, testing, and other measures to

reduce the risks of transmission for various types of tissue will

correspondingly yield a different relative reduction in disease risk.

For example, expansion of blood donor screening and improved laboratory

tests have dramatically reduced the risk of blood transfusion-

transmitted disease. The risk of HIV infection has dropped from a

reported 1 in 100 units in some U.S. cities to approximately 1 in

680,000 units. The risk of transmission of HBV has been reduced from 1

in 2,100 to 1 in 63,000 units, and the transmission risk for HCV has

been lowered from 1 in 200 units in the early 1980's to the current

level of 1 in 100,000 units (Ref. 11). These levels of risk reduction

based on blood donors, offer an illustration of the kind of

improvements in safety that might be achieved through improved and

expanded screening of donors.

As described earlier, most nonreproductive tissue establishments

are assumed to be already compliant with the proposed rule and

therefore have already achieved the level of intended risk reduction

Ref. 11). These levels of risk reduction

based on blood donors, offer an illustration of the kind of

improvements in safety that might be achieved through improved and

expanded screening of donors.

As described earlier, most nonreproductive tissue establishments

are assumed to be already compliant with the proposed rule and

therefore have already achieved the level of intended risk reduction.

The discussion of benefits resulting from the proposed rule will

therefore focus on some key areas of risk and potential benefit of the

proposed requirements for reproductive tissue recipients. The

discussion that follows will consider the risks of sexual transmission

of disease that will be reduced through expanded screening among

reproductive tissue donors, focusing on the reduced risk of two life-

threatening chronic diseases that can be transmitted through donor

tissue: HBV and HCV.

The expansion of screening among reproductive tissue donors is

expected to produce important reductions in disease risk, as evidenced

by the apparent reductions in HIV risk that have already been achieved

through screening. The risk of HIV transmission through TDI appears to

be much lower since screening for HIV was recommended by the Center for

Disease Control and Prevention (CDC) in 1985. A total of six documented

and two possible cases have been reported to the CDC as of December

1996 (Ref. 7).

The risks of transmitting HBV and HCV through reproductive tissue

should be substantially reduced as a result of donor screening, based

on the significance of self-reported risk factors as predictors of the

findings of blood screening for HBV and HCV (Ref. 12). Compared to HCV,

HBV presents a higher risk of sexual transmission. In 1991,

heterosexual activity is reported to account for 41 percent of all

cases of HBV (Ref. 13)

HCV through reproductive tissue

should be substantially reduced as a result of donor screening, based

on the significance of self-reported risk factors as predictors of the

findings of blood screening for HBV and HCV (Ref. 12). Compared to HCV,

HBV presents a higher risk of sexual transmission. In 1991,

heterosexual activity is reported to account for 41 percent of all

cases of HBV (Ref. 13). HBV transmission has also been reported by use

of TDI; in 1982 a physician used semen from an unscreened donor (later

found to carry HBsAg) to inseminate several women, one of whom later

developed HBV (Ref. 14).

HBV-infected mothers can transmit the disease to their infants.

Forty-two percent of infants born to women with HBsAg positivity

(adjusted for HBeAg status) are at risk of HBV infection, and an

additional 30 percent of infants born to HBsAg-positive mothers become

infected between 1 and 5 years of age. Prospective studies of infected

infants or young children, indicate that 25 percent will die from

primary hepatocellular carcinoma (PHC) or cirrhosis as adults. The

lifetime medical cost per case of PHC and cirrhosis is estimated to be

$96,500 (Ref. 15). An analysis of the cost-effectiveness of prenatal

screening and testing of mothers, with vaccination for positive

screens, estimates that such screening and intervention would prevent

69 percent of the chronic HBV infections acquired perinatally or later

in life (Ref. 16). This rate of effectiveness may provide an indication

of the potential benefit of HBV screening in the proposed rule.

The risk of sexual transmission is estimated to be lower for HCV,

compared to HBV. The CDC estimates the rate of transmission from female

to male partners, and the rate of transmission from mother to child, to

each be approximately 5 percent

natally or later

in life (Ref. 16). This rate of effectiveness may provide an indication

of the potential benefit of HBV screening in the proposed rule.

The risk of sexual transmission is estimated to be lower for HCV,

compared to HBV. The CDC estimates the rate of transmission from female

to male partners, and the rate of transmission from mother to child, to

each be approximately 5 percent. However, there is no vaccine

intervention available for HCV, although interferon-alpha therapy has

been found effective in eliminating the virus for at least some

patients and drug combinations (e.g., Interferon and Ribovirus) may be

even more effective. Although most patients infected with HCV are

relatively healthy during most of their lives, an estimated 30 percent

of those infected will eventually die of liver-related causes; an

estimated 8,000 patients per year (Ref. 15). The average cost of care

per year for persons with liver disease from chronic HCV is estimated

to range from $24,600 for patients without interferon-alpha therapy to

$26,500 per year for those receiving a 12-month course of therapy. The

latter is estimated to provide patients with an additional 0.37

quality-adjusted life-years (Ref. 16).

Screening third-party tissue donors is expected to significantly

reduce the excess morbidity and mortality caused by hepatitis B and C.

As noted earlier, there are an estimated 2,405 to 4,810 oocyte donors

and 2,565 sperm donors

per year for those receiving a 12-month course of therapy. The

latter is estimated to provide patients with an additional 0.37

quality-adjusted life-years (Ref. 16).

Screening third-party tissue donors is expected to significantly

reduce the excess morbidity and mortality caused by hepatitis B and C.

As noted earlier, there are an estimated 2,405 to 4,810 oocyte donors

and 2,565 sperm donors

per year. If these populations experience recently reported prevalence

rates for HVC (9.8 percent) and HBV (27.6 percent) (Ref. 12), then

screening for significant risk factors and disease markers will result

in reduced HBV and HCV exposures for the patient population at risk.

The population at risk each year is estimated to include 1,600 to 4,700

women undergoing IVF with donor eggs, and 1,300 newborns delivered as a

result of this therapy\1\; and 34,200 to 70,000 women receiving TDI,

and 8,800 newborns delivered as a result of that therapy.

---------------------------------------------------------------------------

\1\ The range of 1,600 to 4,700 IVF patients is based on a

reported 4,783 cycles of IVF with donor egg reported for 1995,

varying the assumed number of cycles of therapy per patient. The

number of newborns is based on an assumed average delivery rate of

19.6 percent per cycle.

---------------------------------------------------------------------------

E. Initial Regulatory Flexibility Analysis

1\ The range of 1,600 to 4,700 IVF patients is based on a

reported 4,783 cycles of IVF with donor egg reported for 1995,

varying the assumed number of cycles of therapy per patient. The

number of newborns is based on an assumed average delivery rate of

19.6 percent per cycle.

---------------------------------------------------------------------------

E. Initial Regulatory Flexibility Analysis

FDA's objectives and authority for issuing the proposed rule are

described in section II of this document. Based on its initial

analysis, FDA finds that a substantial number of the establishments

required to comply with this proposed rule may be small business

entities, particularly facilities involved with reproductive tissue

products. The Small Business Administration defines a small business in

this SIC industry sector to be an establishment with $5 million or less

in annual receipts (Ref. 17). The economic impact analysis presented in

section IV.C of this document includes estimates of the number of

entities to which the proposed rule will apply. Each set of facilities

involved in the tissue banking sectors includes some facilities that

would be classified as small business entities.

A 1995 study of conventional tissue banks (Ref. 18) reports average

annual revenues of $1.23 million per facility. Most nonreproductive

tissue facilities are assumed to have a comparable level of average

revenues. Reproductive tissue experts estimate that 65 percent of ART

facilities have average revenues of approximately $2.5 million per year

and the remaining 35 percent have average revenues of $11.5 million per

year. Industry experts also estimate that 19 of the 20 largest sperm

banks have average annual revenues of approximately $2 million per

year, and 1 of the 20 largest facilities has annual revenues greater

than $5 million. Thus, the majority of tissue facilities are small

entities

es of approximately $2.5 million per year

and the remaining 35 percent have average revenues of $11.5 million per

year. Industry experts also estimate that 19 of the 20 largest sperm

banks have average annual revenues of approximately $2 million per

year, and 1 of the 20 largest facilities has annual revenues greater

than $5 million. Thus, the majority of tissue facilities are small

entities. Nevertheless, as noted in the preceding cost analysis, most

of these facilities would not be significantly impacted by the proposed

rule, because they are already performing the proposed infectious

disease screening and recordkeeping.

Table 6 of this document presents estimates of the average cost per

facility as a percentage of average annual revenues. In addition to

facility revenues Table 6 presents the estimated annual practice income

for Ob/Gyn practices, because some operate a small donor sperm bank as

an additional service to patients, but may not currently comply with

the screening and testing requirements of the proposed rule. The

estimated annual revenue of $252,000 per year for individual physician

practices is based on the mean physician income of $215,000 after

expenses and before taxes for the Ob/Gyn specialty category reported in

the 1992 American Medical Association survey (Ref. 19), adjusted to

1998 assuming an average annual wage inflation of 2.7 percent, based on

yearly rates reported by the Bureau of Labor Statistics.

annual revenue of $252,000 per year for individual physician

practices is based on the mean physician income of $215,000 after

expenses and before taxes for the Ob/Gyn specialty category reported in

the 1992 American Medical Association survey (Ref. 19), adjusted to

1998 assuming an average annual wage inflation of 2.7 percent, based on

yearly rates reported by the Bureau of Labor Statistics.

Table 6.--Estimated Annualized Cost per Facility as a Percentage of

Estimated Annual Revenue

------------------------------------------------------------------------

Number of

Facilities That Average Average Annual Annualized Cost

May Be Classified Annualized Cost Revenue per as Percentage of

as Small Entities per Facility Facility Annual Revenue

--------------------------------------------

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