Federal Register / Vol. 62, No. 145 / Tuesday, July 29, 1997 / Rules and Regulations 40429

Conclusion

This action affects only certain design

features on Boeing Model 747–SP

airplanes modified by International

Aviation Services, Ltd. It is not a rule of

general applicability and affects only

the applicant who applied to the FAA

for approval of these features on the

airplane.

The substance of the special

conditions for this airplane has been

subjected to the notice and comment

procedure in several prior instances and

has been derived without substantive

change from those previously issued. It

is unlikely that prior public comment

would result in a significant change

from the substance contained herein.

For this reason, and because a delay

would significantly affect the

certification of the airplane, which is

imminent, the FAA has determined that

prior public notice and comment are

unnecessary and impracticable, and

good cause exists for adopting these

special conditions immediately.

Therefore, these special conditions are

being made effective upon issuance. The

FAA is requesting comments to allow

interested persons to submit views that

may not have been submitted in

response to the prior opportunities for

comment described above.

List of Subjects in 14 CFR Part 25

Aircraft, Aviation safety, Reporting

and recordkeeping requirements.

The authority citation for these

special conditions is as follows:

Authority: 49 U.S.C. 106(g), 40113, 44701,

44702, 44704.

The Special Conditions

Accordingly, pursuant to the

authority delegated to me by the

Administrator, the following special

conditions are issued as part of the type

certification basis for Boeing Model

747–SP airplanes modified by

International Aviation Services, Ltd.

1. Protection from Unwanted Effects

of High-Intensity Radiated Fields

(HIRF). Each electrical and electronic

system that performs critical functions

must be designed and installed to

ensure that the operation and

operational capability of these systems

to perform critical functions are not

adversely affected when the airplane is

exposed to high intensity radiated

fields.

For the purpose of these special

conditions, the following definition

applies:

Critical Functions. Functions whose

failure would contribute to or cause a

failure condition that would prevent the

continued safe flight and landing of the

airplane.

Issued in Renton, Washington, on July 17,

1997.

Gary L. Killion,

Acting Manager, Transport Airplane

Directorate, Aircraft Certification Service.

[FR Doc. 97–19858 Filed 7–28–97; 8:45 am]

BILLING CODE 4910–13–M

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 16 and 1270

[Docket No. 93N–0453]

RIN 0910–AA40

Human Tissue Intended for

Transplantation

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule.

SUMMARY: The Food and Drug

Administration (FDA) is issuing a final

rule to require certain infectious disease

testing, donor screening, and

recordkeeping to help prevent the

transmission of the human

immunodeficiency virus (HIV), and

hepatitis viruses through human tissue

used in transplantation. In response to

comments received, FDA has clarified

and modified many of the provisions of

the interim rule on human tissue

intended for transplantation which was

published in the Federal Register of

December 14, 1993. The final rule

requires facilities engaged in the

recovery, screening, testing, processing,

storing, or distributing of human tissues

to ensure that specified minimum

required medical screening and

infectious disease testing has been

performed and that records

documenting such screening and testing

for each human tissue are available for

inspection by FDA. The regulations also

contain provisions for the inspection of

such facilities and for retaining,

recalling, or destroying human tissue for

which appropriate documentation is not

available.

DATES: The regulation is effective

January 26, 1998. This effective date is

applicable to all human tissue intended

for transplantation procured on or after

this date. Written comments on the

information collection requirements

should be submitted by September 29,

1997.

ADDRESSES: Submit written comments

on the information collection

requirements to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, 12420

Parklawn Dr., rm. 1–23, Rockville, MD

20857. All comments should be

identified with the docket number

found in brackets in the heading of this

document.

FOR FURTHER INFORMATION CONTACT:

Paula S. McKeever, Center for Biologics

Evaluation and Research (HFM–630),

Food and Drug Administration, 1401

Rockville Pike, suite 200N, Rockville,

MD 20852–1448, 301–594–3074.

SUPPLEMENTARY INFORMATION:

I. Introduction

A. Background

In the Federal Register of December

14, 1993 (58 FR 65514), FDA issued an

interim rule on human tissue intended

for transplantation (hereinafter referred

to as the interim rule). These regulations

became effective upon the date of

publication in the Federal Register and

required human tissue in storage as of

that date to be in compliance. The

interim rule was issued because of

evidence indicating an immediate need

to protect the public health from the

transmission of HIV infection and

hepatitis infection through

transplantation of human tissue from

known donors infected with or at risk

for these diseases. The movement

towards regulating human tissue was

accelerated by a hearing on appropriate

oversight for human tissue banking

chaired by Senator (then Representative)

Wyden before the Subcommittee on

Regulation, Business Opportunities and

Technology of the Committee on Small

Business held on October 15, 1993. At

the hearing, representatives of persons

involved in human tissue banking

advocated that legislation setting forth

regulatory requirements for human

tissue banking be passed. There was

testimony that human tissues from

foreign sources were being offered for

sale in the United States with little

documentation as to the source of the

human tissue, the cause of death, the

medical conditions of the donor, or the

results of donor screening and testing.

This raised significant concerns about

the safety and quality of some of the

human tissue available for

transplantation. As a result of a number

of similar allegations, the agency

initiated inquiries into the possibility

that human tissues intended for

transplantation were being supplied

without appropriate infectious disease

testing and medical screening. In a

relatively brief period of time, the

agency was able to confirm the

availability for importation and

distribution to the United States of
40430 Federal Register / Vol. 62, No. 145 / Tuesday, July 29, 1997 / Rules and Regulations

human tissue that did not follow

adequate screening and testing

standards to prevent transmission of

infectious disease.

In the early 1990’s, prior to the abovementioned reports of the distribution of

imported human tissue not following

adequate screening and testing

standards, the Centers for Disease

Control and Prevention (CDC) reported

that HIV had been transmitted through

transplantation of human tissue. Based

in part on the CDC report, the Assistant

Secretary for Health convened a Public

Health Service Work Group to evaluate

the need for and type of Federal

oversight that should be developed for

human tissue. In its report on July 18,

1991, the Work Group recommended

Federal development and publication of

standards or guidance on donor

screening, testing, recordkeeping and

tracking procedures to reduce the risk of

transmission of infectious disease. The

Work Group recommended that Federal

agencies, including FDA, proceed with

pending regulations as ‘‘expeditiously

as possible.’’ The Work Group charged

FDA to ‘‘continue to assert its

jurisdiction over tissues on a productby-product basis to ensure adequate

oversight.’’ The Work Group noted that

investigation into the needed level of

mandatory oversight for human tissue

transplantation, apart from organ and

bone marrow transplantation, should

take place and recommended that FDA

evaluate this issue. Subsequently, FDA

issued the interim rule.

Since the interim rule was issued,

FDA has issued 15 orders for retention,

recall, and destruction of violative

human tissue. In March 1995, following

receipt of an order for retention, recall,

and destruction that caused shipments

of a firm’s processed allografts to be

held, a processor of human tissue filed

a complaint in Federal District Court

challenging FDA’s interim rule and the

application of internal guidance on the

interim rule issued to field investigators.

The court issued the plaintiff

preliminary injunctive relief by

enjoining FDA from detaining particular

shipments of the plaintiff’s tissue. The

plaintiff and FDA subsequently entered

into an agreement settling their dispute,

and the plaintiff’s complaint was

dismissed.

After FDA issued the interim rule,

FDA held three separate workshops to

promote continuous dialogue between

FDA and the human tissue industry.

The first workshop, which FDA

announced in the Federal Register of

June 10, 1994 (59 FR 29950), was

entitled ‘‘Public Workshop on Human

Tissue Intended for Transplantation’’

and was held on June 20, 1994

(hereinafter referred to as the June 1994

workshop). An objective of the

workshop was to give industry the

opportunity to discuss practical

concerns relating to the implementation

of the interim rule. It was the intention

of FDA to review and consider the

discussion of these topics in the

development of any future rulemaking.

The comment period on the interim rule

closed March 14, 1994, but was

reopened until August 20, 1994, to

allow interested persons additional time

to submit comments on both the interim

rule and the workshop.

In the Federal Register of February

17, 1995 (60 FR 9335), FDA announced

that the Blood Products Advisory

Committee, scheduled to meet on March

23 and 24, 1995, would participate in a

workshop entitled ‘‘Human Tissue

Intended for Transplantation and

Human Reproductive Tissue: Donor

Screening and Infectious Disease

Testing’’ (hereinafter referred to as the

March 1995 workshop). The topics

discussed at the workshop were: (1)

Recommendations for donor screening

and infectious disease testing for human

tissue intended for transplantation, (2)

draft discussion points for screening

and testing donors of human

reproductive tissue, and (3) a draft

registration form. FDA made the ‘‘Draft

Discussion Points for Screening and

Testing Donors of Human Tissue

Intended for Transplantation and

Human Reproductive Tissue,’’ and the

draft establishment registration form

available before and at the meeting.

In the Federal Register of May 24,

1995 (60 FR 27406), FDA announced a

third workshop on human tissue. This

workshop, entitled ‘‘Human Tissue for

Transplantation and Human

Reproductive Tissue: Scientific and

Regulatory Issues and Perspectives’’,

was held on June 20 and 21, 1995

(hereinafter referred to as the June 1995

workshop). The purpose of this

workshop was to provide an

opportunity for continued discussion of

the regulation of human tissue for

transplantation. The workshop

consisted of plenary and breakout

sessions that focused on the following

topics: (1) Donor screening, (2)

infectious disease testing and

inactivation methods, (3) voluntary

standards, (4) assessment of industry

practices related to tracking, (5)

interactions with organ procurement

organizations and procurement

coordination practices, and (6) State

regulatory approaches and industry

practices. FDA offered a draft discussion

document concerning the screening and

testing of donors of human tissue

intended for transplantation in advance

and at the workshop. The availability of

the draft document was announced in

the Federal Register of June 20, 1995

(60 FR 32128). FDA requested that

comments on the draft document be

sent to the Dockets Management Branch

by July 20, 1995, for consideration in

the drafting of a guidance document.

In response to industry requests for

clearer guidance on donor screening and

in an effort to consolidate and

disseminate recommendations on the

screening of donors for signs and

symptoms of infectious disease, FDA

has prepared a document entitled

‘‘Guidance for Screening and Testing of

Donors of Human Tissue Intended for

Transplantation,’’ the availability of

which is announced elsewhere in this

issue of the Federal Register. This

guidance was prepared taking into

account the issues addressed in the draft

document distributed at the workshop

and comments received.

The final rule takes into account

comments submitted to the Dockets

Management Branch, and discussions

and information obtained through

public participation in the three

workshops. The agency is taking this

action to provide clarification of the

interim rule and to finalize its

provisions.

B. Scientific and Legal Justification

The use of HIV antibody testing on

donors of human tissue makes the

human tissue inventory safer. However,

it does not eliminate the ‘‘window’’

period between the time of infection

and the presence of detectable levels of

antibodies to HIV. Therefore, as an

added safety measure FDA requires

screening for behavioral and high risk

information in addition to testing for

infection with the virus so that the

safest product will be made available.

Like the HIV virus, evidence of hepatitis

B and hepatitis C is determined by

screening and testing human tissue

donors. Since HIV and hepatitis viruses

are transmitted by parenteral and sexual

modes, exclusion of potentially infected

donations by both screening and testing

the human tissue donor has been found

to be reliable and widely accepted.

These viruses may be transmitted by a

wide range of human tissue including

solid organs, musculoskeletal and

integumentary tissue, and body fluids

(e.g., semen and breast milk).

FDA is issuing these regulatory

requirements under the legal authority

of section 361 of the Public Health

Service Act (the PHS Act, 42 U.S.C.

264). This section authorizes the

Secretary of the Department of Health

and Human Services (the Secretary), to

make and enforce such regulations as
Federal Register / Vol. 62, No. 145 / Tuesday, July 29, 1997 / Rules and Regulations 40431

judged necessary to prevent the

introduction, transmission, or spread of

communicable diseases from foreign

countries into the States or from State to

State. Intrastate transactions may be

regulated under authority of this

provision, as appropriate (see State of

Louisiana v. Mathews, 427 F. Supp. 174

(E. D. La. 1977)). Section 361 of the PHS

Act also provides for such inspection

and destruction of articles found to be

so infected or contaminated as to be

sources of dangerous infection to

humans, and other measures, as may be

deemed by the Secretary to be

necessary. Section 361 of the PHS Act

has been invoked by FDA to regulate

various activities or articles. For

example, FDA has invoked this

authority to regulate conveyance

sanitation, the source and use of potable

water, and milk pasteurization. The

agency has also acted under section 361

of the PHS Act to prevent the

transmission of communicable disease

through shellfish, turtles, certain birds,

and bristle brushes (see 21 CFR parts

1240 and 1250). FDA has also relied in

part on section 361 of the PHS Act in

issuing requirements to protect the

blood supply.

Authority for the enforcement of

section 361 of the PHS Act is provided

for in part under 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 (42 U.S.C.

271(a)). Individuals may also be

punished for violating such a regulation

by a fine of up to $100,000 if death has

not resulted from the violation or up to

$250,000 if death has resulted (18 U.S.C.

3559 and 3571(c)). In addition, Federal

District Courts have jurisdiction to

enjoin individuals and organizations

from violating regulations implementing

section 361 of the PHS Act.

II. Highlights of the Final Rule

The final rule provides clarification of

certain provisions of the interim rule

and responds to the comments and

concerns expressed. In response to

comments received on the interim rule,

definitions have been added or modified

for the following terms: Blood

component, colloid, contract services,

crystalloid, donor medical history

interview, establishment, importer of

record, legislative consent, person,

physical assessment, plasma dilution,

reconstituted blood, relevant medical

records, responsible person, and

summary of records. The final rule

further elaborates on the requirements

for: (1) Criteria for using an algorithm

when determining plasma dilution, (2)

documents to be included in the

summary of records, (3) responsibility

for maintaining the records used in

determining the suitability of the tissue

for transplantation, (4) the relevant

medical records for corneal tissue

recovered under legislative consent, and

(5) the shipment of tissue. The rule also

describes the steps to be followed when

human tissue is offered for import.

Due to the renumbering of many of

the sections in the rule the following

chart is being provided for comparison:

TABLE 1.—COMPARISON CHART OF FINAL AND INTERIM RULES

Final Rule (section) Interim Rule (section) Nature of Change

Subpart A—General Provisions

Scope

1270.1(a)(b)(c)(d) 1270.1(a)(b)

Additional exemptions added.

Definitions

1270.3(a)–(x) 1270.3(a)–(i)

Definitions added for:

(b) blood component,

(c) colloid,

(d) contract services,

(e) crystalloid,

(h) donor medical history interview,

(i) establishment,

(k) importer of record,

(l) legislative consent,

(m) person,

(n) physical assessment,

(o) plasma dilution,

(r) reconstituted blood,

(t) relevant medical records,

(u) responsible person,

(w) summary of records.

1270.5 through 1270.20 Removed.

Subpart B—Donor Screening and Testing

Human Tissue Intended for Transplantation

1270.21(a)–(h) 1270.5(a)–(f)

Renumbered. Clarification of (e) summary of

records, addition of (b) testing of neonate

donor (g) standards for corneal retrieval,

and (h) plasma dilution.

Subpart C—Procedures and Records

Written Procedures

1270.31(a)–(e) 1270.7(a)–(c)

Renumbered. Original paragraph (c) is now

paragraph (e), new paragraphs (c) and (d)

require written procedures for designating

and identifying quarantined tissue and for

preventing contamination or cross-contamination of tissue during processing.
40432 Federal Register / Vol. 62, No. 145 / Tuesday, July 29, 1997 / Rules and Regulations

TABLE 1.—COMPARISON CHART OF FINAL AND INTERIM RULES—Continued

Final Rule (section) Interim Rule (section) Nature of Change

Records, General Requirements

1270.33(a)–(h) 1270.9(a)–(e)

Renumbered. Paragraphs (c) and (d) contain

requirements for shipment of human tissue

prior to and after a determination of suitability for transplantation is made. Original

paragraphs (c),(d), and (e) are now paragraphs(f),(g), and (h), respectively. Paragraph (f) is amended to clarify who is responsible for record retention.

Specific Records

1270.35(a)–(d) 1270.11(a)–(c)

Renumbered. Original paragraphs (b) and (c)

are now paragraphs (d) and (b) respectively.

New paragraph (c) was added to require

documentation of receipt and distribution of

human tissue.

Subpart D—Inspection of Tissue Establishments

Inspection

1270.41(a)–(e) 1270.13(a)–(e)

Renumbered.

1270.42(a)–(b) none Added steps to be followed when human tissue is offered for import.

1270.43(a)–(e) 1270.15(a)–(e) Renumbered.

III. Comments on the Interim Rule and

FDA Responses

FDA received 73 comments on the

interim rule. Many comments supported

FDA’s effort to prevent transmission of

disease through transplantation and the

positive effect the interim rule had on

nationwide standardization. Other

comments, primarily from

representatives and supporters of eye

banks, objected to the interim rule. The

comments stated that implementation of

the rule temporarily halted

transplantation operations of human

tissue and argued that the industry

should be allowed to continue

regulating itself because of its excellent

record in preventing the transmission of

disease.

In general, the comments requested

clarification and modification of

selected sections of the interim rule,

presented data supporting the suggested

changes, and described burdens that

particular sections would impose, e.g.,

the effect on cornea recovery by the

requirement for a next of kin interview

in States or territories with medical

examiner laws, the retrospective review

of tissue in storage for compliance,

cadaveric specimen testing, and the

import/export of human tissue from

countries without certified laboratories

under the Clinical Laboratories

Improvement Amendments of 1988

(CLIA).

A. General Comments

1. One comment stated that the public

health was threatened by the interim

rule in that it contributed to an existing

backlog demand for processed human

tissue.

FDA recognizes that there may have

been some temporary shortages of a few

types of human tissue due to a small

amount of human tissue in storage not

being in compliance with the interim

rule, but is not aware of instances where

the public health was affected

adversely. FDA took voluntary industry

standards and State requirements into

account in issuing the rule to lessen the

impact of the implementation of the

interim rule.

2. One comment stated that organ

transplantation should be included in

the scope of the interim rule and

inquired as to why it was not covered.

The National Organ Transplant Act of

1984 provides for Federal oversight of

the human organ transplantation

system. The Health Resources Services

Administration (HRSA) within the

Department of Health and Human

Services (DHHS) currently administers

programs related to human organ

transplantation. Human organs are

specifically excluded from the interim

rule and the final rule (new

§ 1270.3(j)(4)) because they are already

regulated under existing Federal

oversight programs and FDA does not

believe that additional oversight by FDA

is needed at this time.

3. Twenty-six comments maintained

that eye banks adhere to strict internal

standards, have an excellent track

record with few documented disease

transmission cases, and should not be

regulated by the government.

The agency acknowledges that the

trade associations for eye banks, the

American Association of Tissue Banks

(AATB) and the Eye Banks Association

of America (EBAA) are recognized to

have strict internal standards and that

the eye banks have a reputation for

conscientious adherence to those

standards. The agency notes, however,

that although corneas may have a degree

of protection due to avascularity, they

can, like other tissues, carry viruses and

transmit communicable diseases.

Therefore, FDA believes that corneas

should be subject to the same regulatory

oversight as other tissues. The agency

would also note that the regulation will

impose little or no burden for eye banks

that are in compliance with the

voluntary AATB and EBAA standards

because these standards are

substantially similar to the requirements

of the regulation.

4. Two comments supported required

testing by CLIA-certified laboratories.

Under provisions of the 1988

Amendments to the Clinical

Laboratories Improvement Act of 1967

(CLIA ’88), laboratories engaged in

testing specimens in interstate

commerce must meet the requirements

of section 353 of the Public Health

Service Act (42 U.S.C. 263a) in order to

be licensed or remain licensed for

testing in interstate commerce. CLIA

applies to laboratories, including

physicians’ office laboratories, that test

human specimens. Under CLIA ’88,
Federal Register / Vol. 62, No. 145 / Tuesday, July 29, 1997 / Rules and Regulations 40433

such laboratories are subject to

regulations designed to ensure the

quality and reliability of medical tests

they perform. Therefore, the

requirement that all infectious disease

testing be performed by CLIA-certified

laboratories, helps ensure standardized

testing on all donors of human tissue

intended for transplantation.

5. One comment inquired if contract

processing is permitted under the

interim rule.

FDA realizes that not all human tissue

establishments have the facilities to

perform all manufacturing steps. It may

be more cost effective for establishments

to contract out some testing and

processing procedures. There is no

prohibition in the interim rule or final

rule concerning such contract services.

Therefore, contract services have been

added to the definitions in § 1270.3 (21

CFR 1270.3). FDA has revised

§ 1270.41(a) (21 CFR 1270.41(a)) to

clarify that such contract services are

subject to inspections conducted by

authorized representatives of FDA.

6. Two comments urged the expedited

publication of the draft guidance

document Draft USPHS Guidelines for

Preventing Transmission of Human

Immunodeficiency Virus Through

Transplantation of Human Tissue and

Organs, that provides specific questions

for use in donor behavioral and high

risk information screening.

At the time of publication of the

interim rule, the final version of the

guidance document had not been made

available. The Public Health Service

(PHS) published the final guideline on

May 20, 1994, in the Morbidity and

Mortality Weekly Report (MMWR

1994:43, 1–17). FDA considered these

guidelines and previous PHS guidelines

in the preparation of the final rule and

the guidance document that is being

announced as available by FDA

elsewhere in this issue of the Federal

Register. The guidance document

provides recommendations on

appropriate questions, clinical evidence,

and physical evidence for use in donor

screening.

7. Two comments were made on

alternative methods of preventing

transmission of HIV–1, HIV–2, hepatitis

B, and hepatitis C viruses. One

comment asked that the rule provide for

a waiver process based on alternative

methods of viral inactivation. One of the

comments added that claims of

processes that result in viral

inactivation or sterility should be

investigated for scientific accuracy prior

to exemption from any portion of these

rules.

Presently, FDA is unaware of any

alternative method of viral inactivation

that FDA believes warrants omission of

HIV and hepatitis testing. Therefore,

FDA does not believe that such a change

is warranted at this time. FDA is

interested in public comment on this

issue and will consider whether to

include in future rulemaking a process

for the agency to grant waivers from any

regulation under part 1270 (21 CFR part

1270).

8. Two comments recommended that

an expert advisory committee, to

include transplant surgeons as

members, be established as soon as

possible to review and make

recommendations for future rulemaking.

Since the time the interim rule was

published, FDA has requested the Blood

Products Advisory Committee (BPAC) to

review data and make recommendations

regarding human tissue for

transplantation in addition to blood

products. The agency recognizes the

positive contribution of experienced

professionals in providing FDA with

assistance on regulatory issues and

believes that the BPAC can serve in an

advisory role on human tissue intended

for transplantation.

On July 13, 1995, a report by the

Institute of Medicine (IOM) entitled

‘‘HIV and the Blood Supply: An

Analysis in Crisis Decisionmaking’’ was

released. The Secretary directed this

investigation in response to concerns

voiced by the hemophilia community

concerning events leading to the

transmission of HIV to individuals with

hemophilia from contaminated blood

products. FDA has made certain

changes to BPAC consistent with

recommendations in the report. In

particular, FDA has reformulated the

membership of BPAC to limit industryaffiliated representation to a single,

nonvoting representative. Additionally,

FDA has revised the BPAC charter to

expand the possibility for consumer

representation.

B. Comments on Specific Provisions in

the Interim Rule

FDA has revised the interim rule as a

result of comments submitted to the

docket. In addition, FDA on its own

initiative is making changes to clarify

the requirements of the rule and its

application to the tissue industry. The

term ‘‘banked’’ has been deleted from

the phrase ‘‘banked human tissue

intended for transplantation’’ wherever

it appears in the regulations because

FDA believes the term ‘‘banked’’ is

unnecessary with respect to human

tissues covered by this final rule

1. Scope (§ 1270.1)

Section 1270.1 defines the scope of

the regulations governing human tissue

intended for transplantation to include

human tissue and establishments or

persons engaged in the recovery,

processing, storage, or distribution of

human tissue. FDA has revised § 1270.1

by explicitly stating that screening and

testing activities are subject to

regulation. The final rule also clarifies

that at this time the regulations do not

apply to human tissue intended for

autologous use. FDA is, however,

currently conducting a review of human

tissues that includes autologous use and

is considering proposing additional

regulations in this area.

9. One comment asked that

practitioners in transplant

establishments who only store human

tissue for transplant in their own

facilities be relieved from compliance

with the provisions of the rule.

FDA recognizes that there are

instances where human tissue is

received and stored temporarily in a

hospital or other clinical facility

pending scheduled surgery within the

same facility. FDA agrees that hospitals

or other clinical facilities that only

receive and store human tissue for

transplantation within the same facility

should not be covered by the rule and

thus FDA has added this provision in

§ 1270.1(d) of the final rule. Those

hospitals or clinical facilities that

participate in the recovery, screening,

testing, processing, or distribution of

human tissue in addition to storage for

transplantation are covered by the rule.

2. Definitions (§ 1270.3)

Section 1270.3 defines various terms

used in the regulations. In the final rule

FDA has clarified, revised and

simplified the definitions. For clarity,

FDA has added the terms ‘‘shipment,’’

and ‘‘exportation’’ to the definition of

‘‘distribution’’ (§ 1270.3(f) of the final

rule). The definition of ‘‘processing’’

(§ 1270.3(p) of the final rule) has been

revised by deleting the word ‘‘potency’’

and by adding that processing includes

‘‘the inactivation or removal of

adventitious agents.’’ The phrase

‘‘human tissue that has not yet been

characterized as suitable for

transplantation’’ has been added to

clarify the definition of ‘‘quarantine’’

(§ 1270.3(q) of the final rule). The

definition of ‘‘storage’’ (§ 1270.3(v) of

the final rule) has been simplified by

deleting any reference to the facility

holding the tissue. The term ‘‘native

vasculature’’ has been replaced by the

term ‘‘original blood vessels’’ in the

definition of ‘‘vascularized’’ (§ 1270.3(x)

of the final rule).

10. One comment suggested that the

rule apply to normal human cells such
40434 Federal Register / Vol. 62, No. 145 / Tuesday, July 29, 1997 / Rules and Regulations

as hepatocytes that can be transplanted

with little or no manipulation.

The agency declines to accept the

comment’s suggestion. The rule covers

human tissue such as bone, ligament,

tendons, fascia, cartilage, corneas, and

skin. Hepatocytes and other cellular

based therapies are regulated by FDA as

biological products. (See description in

‘‘Application of Current Statutory

Authorities to Human Somatic Cell

Therapy Products and Gene Therapy

Products’’ (58 FR 53248).)

11. One comment asked for definition

of the following terms: (1) Blood

component, (2) colloid or volume

expander, (3) crystalloid, (4)

hemodilution, and (5) pretransfusion

specimen.

FDA agrees that some additional

definitions should be included and is

amending § 1270.3 to include

definitions for ‘‘blood component,’’

‘‘colloid’’ (volume expander), ‘‘contract

services,’’ ‘‘crystalloid,’’ ‘‘donor medical

history interview,’’ ‘‘establishment,’’

‘‘importer of record,’’ ‘‘legislative

consent,’’ ‘‘person,’’ ‘‘physical

assessment,’’ ‘‘plasma dilution’’ (to

replace ‘‘hemodilution’’), ‘‘relevant

medical records,’’ ‘‘reconstituted

blood,’’ ‘‘responsible person,’’ and

‘‘summary of records.’’ FDA believes

that the term ‘‘pretransfusion specimen’’

is self explanatory, therefore, a

definition has not been added.

12. One comment requested that the

definition of ‘‘vascularized’’ that

appears in § 1270.3(c) of the interim rule

be clarified.

FDA agrees that the definition of

vascularized should be clarified and has

revised the definition.

13. Two comments requested a

revision to the definition of human

tissue to specifically exclude human

organs and those human tissues that

have been chemically or biophysically

altered, such as heart valves.

The definition of human tissue found

in § 1270.3(b) of the interim rule

(§ 1270.3(j) of the final rule) contains a

specific exclusion for vascularized

organs (kidney, liver, heart, lung,

pancreas, or other vascularized human

organs). Allograft heart valves, dura

mater allografts, epikeratophakia

lenticules, preserved umbilical cord

vein grafts, and various skin and bone

products that have been chemically or

biophysically altered are currently

regulated as devices under the authority

of the Medical Device Amendments of

1976 (Pub. L. 94–295) and are therefore

excluded from this definition of human

tissue. However, FDA is considering the

regulation under part 1270 of human

heart valve allografts and certain other

tissues now regulated as devices. To

allow all interested persons to comment

on this regulatory change, FDA intends

to provide notice and request for

comment on such regulation in the

Federal Register at a future date.

Human tissues that are processed in

ways to only reduce infectivity or

preserve human tissue integrity are

regulated under part 1270.

3. Donor Testing (§ 1270.21)

Section 1270.5 of the interim rule

specifies the requirements for testing

donor blood specimens for evidence of

communicable viruses, i.e., HIV–1,

HIV–2, hepatitis B, and hepatitis C. It

requires that these tests be done using

FDA licensed test kits approved for such

use by FDA and performed in a

laboratory certified under CLIA. In the

final rule, FDA has deleted the terms

‘‘blood’’ and ‘‘serological’’ and the name

of the communicable virus has been

listed in place of a specific marker test.

This change has been made to allow for

future advancement in science and

technology which could cause a change

in the appropriate test methodology.

Section 1270.5(e) of the interim rule has

been split into § 1270.21(f) and (g) of the

final rule, in part to clarify the revised

requirements for corneal tissue retrieval.

14. One comment inquired if human

tissue would be considered suitable for

transplantation if a repeatedly reactive

screening test for any of the viral marker

tests was negative by confirmatory

testing. Some comments have

encouraged FDA to allow the use of

tissue for which blood specimens tested

repeatedly reactive for hepatitis B

surface antigen (HBsAg), if the results of

confirmatory neutralization testing do

not confirm the results of the screening.

FDA does not concur with this

suggestion. With current tests, early

HIV, hepatitis B virus, and hepatitis C

virus infections can be missed by the

respective confirmatory test due to

differences in the sensitivity of the tests,

albeit at a low frequency. The agency is

clarifying in the final rule, that

suitability of human tissue shall be

determined by the results of screening

tests for the required viral markers. The

rule requires that the donor be free of

evidence of HIV, hepatitis B, and

hepatitis C. A repeatedly reactive

screening test for any of the viral

markers indicates that the donor may

have been exposed to and infected with

the particular virus. Any indication of

the possibility of infection must be

taken into consideration when

determining the suitability of the human

tissue. The use of screening tests in

determining the suitability of the donor

of human tissue intended for

transplantation is clarified in

§ 1270.21(a) of the final rule which

specifically identifies ‘‘screening

* * *’’ as the required test. Therefore,

tissue that is repeatedly reactive is not

suitable for use even if confirmatory

tests are negative. In addition, if the

tissue establishment becomes aware of

indeterminate, repeatedly reactive, or

positive test results relative to HIV or

hepatitis, even if the tests are not

specifically required by the final rule,

then the tissue is considered not

suitable for transplantation.

15. Seven comments questioned the

validity of certain viral marker tests

using cadaveric blood specimens.

Concern was expressed over the

inadequate data that exists on the

testing of cadaveric blood specimens

using FDA licensed screening kits for

viral markers and guidance was

requested in determining the suitability

of the donor.

FDA is aware of the need to clarify the

appropriateness of using cadaveric

specimens, i.e., a blood specimen taken

from a donor whose heartbeat has

ceased, with the currently licensed test

kits. Generally, the concern is that test

results based on testing of cadaveric

blood specimens that exhibit some

degree of hemolysis and/or lipemia may

not be accurate. FDA is working with

manufacturers towards validation of

assays for cadaveric specimen use.

Screening tests that have been approved

for testing cadaveric blood are to be

used, once FDA approval has been given

and the labeling of the test kit has been

modified to specifically indicate the use

of cadaveric blood specimens.

16. One comment dealt with a letter

issued by CBER on December 28, 1993,

to the tissue industry (hereinafter

referred to as the December 1993 letter).

This letter, which was intended to

provide clarification to the industry

regarding HIV–2 testing, contained the

statement, ‘‘as long as the tissue was

tested by the best available test methods

at the time, and the newly available test

methodology was adopted in a timely

manner, the tissue continues to be

suitable for transplant.’’ The comment

said this statement may be misleading

because it could be interpreted to

include other newly licensed tests in

addition to tests for HIV–2.

Because the December 1993 letter

addresses HIV–2 testing only, FDA does

not believe the statement cited by the

comment could be easily misinterpreted

as referring to tests for other infectious

agents.

17. Three comments requested further

explanation of the approval

requirements for laboratories doing

screening tests on donor specimens.

Specifically requested, was clarification
Federal Register / Vol. 62, No. 145 / Tuesday, July 29, 1997 / Rules and Regulations 40435

of the term ‘‘registered and certified

under CLIA’’ and recognition, by the

Health Care Finance Administration

(HCFA), of accreditation by an

acceptable alternative inspection

organization.

Shortly after publication of the

interim rule, FDA provided guidance

regarding § 1270.5(b) in the December

1993 letter. Laboratories have the option

of coming under the jurisdiction of

HCFA directly, or indirectly by way of

accreditation by a private accreditation

organization approved by HCFA for

‘‘deemed status,’’ or by being located in

a State approved for exemption under

CLIA. In the December 1993 letter, FDA

recognized that many laboratories had

been registered but not yet certified

under CLIA, because: (1) They had not

yet been surveyed (inspected) by HCFA

or one of its agents; (2) they had been

surveyed but had not yet received their

certificate of compliance; or (3) the

accrediting organization performing the

survey had applied for but had not yet

received approval by HCFA for

‘‘deemed status’’ under the 1988

amendments. During this transition

period, FDA stated that its preliminary

interpretation was that a laboratory was

suitable for performing the testing

required by the interim rule provided:

(1) The laboratory had an active and

current history of being surveyed by

HCFA or one of its agents, by a private

accrediting organization, or an

organization whose approval by HCFA

was pending; (2) the laboratory was in

good standing with HCFA, and if

applicable, FDA, in that there was no

regulatory action either pending or in

effect that would limit the laboratory’s

ability to perform the types of tests that

are required in the interim rule; and (3)

the laboratory was registered with

HCFA at that time. Since the

publication of the interim rule, HCFA

has completed the first survey of

registered laboratories. All laboratories

that have met the inspection criteria

have been issued certification under

CLIA. Thus, laboratories must now be

certified under CLIA.

18. One comment on § 1270.5(a)

(§ 1270.21(a) of the final rule) urged that

tests such as those run on lymph node

tissue or vitreous humor be considered

in the absence of an appropriate blood

specimen.

In § 1270.21 of the final rule, FDA has

deleted the identification of blood as the

source of specimen required for

infectious disease testing, recognizing

advances in technology and the

possibility of future approval of viral

marker testing (used in determining

donor suitability) that may utilize

alternative specimen sources. At this

time, blood is the only specimen

approved for use with FDA licensed

viral marker tests to determine donor

suitability.

19. One comment on § 1270.5(b)

(§ 1270.21(c) of the final rule) asserted

that the rule discriminates against

importers of human tissue because they

are unable to comply with the

requirement for testing by a CLIA

certified laboratory.

During a congressional hearing held

on October 15, 1993, testimony was

given with respect to an increase of

unsuitable human tissue derived from

foreign sources being offered for sale in

the United States by individuals

unwilling to declare the actual source of

the human tissue, to provide

documentation as to the cause of death,

the medical records of the donor, the

results of donor screening and testing,

or to furnish specimens of donor serum

for testing. Human tissue imported from

outside the United States must meet the

same standards of donor screening,

testing, and tissue recovery applied to

all domestic human tissue because of

the potential for the transmission of

communicable diseases. When the

interim rule was published on

December 14, 1993, there were no CLIA

certified testing laboratories in foreign

countries. Although these facilities were

unavailable at the time, foreign

establishments were not prohibited from

using domestic CLIA certified

laboratories for performing the required

testing. Any laboratory, foreign or

domestic, may apply for certification

under CLIA. The proficiency of the

laboratory performing the required

testing is a key element in assuring the

safety of human tissue. Inspection and

regulation under CLIA helps to ensure

that the laboratory is proficient and

competent to perform the required tests

accurately. Therefore, FDA’s

requirements are not intended to

discriminate against foreign importers,

but are an attempt to help ensure that

foreign human tissue meets the same

standards as human tissue procured in

the United States for transplantation.

4. Plasma Dilution

20. Under section 1270.5(d)

(§ 1270.21(h) of the final rule), human

tissue from donors whose blood

specimen may be diluted sufficiently to

affect infectious disease test results is

unsuitable unless the specimen is

assessed for acceptability using an

established procedure to calculate

dilution (algorithm). One comment

suggested revising the term

‘‘hemodilution’’ to ‘‘plasma dilution’’ to

accurately describe the dilutional

component because it is the infused

plasma or fluid which dilutes the

donor’s plasma or serum used for

testing, not the red cell volume.

FDA agrees with the comment and is

amending § 1270.5(d)(1) § 1270.21(h)(2)

in the final rule) to use the term

‘‘plasma dilution.’’

21. Two comments on § 1270.5(d)

(§ 1270.21(h) of the final rule) proposed

revisions to include specific factors for

consideration in determining the

suitability of human tissue when the

possibility of plasma dilution exists.

The comments noted that FDA did not

address generally accepted criteria for

making the determination of plasma

dilution.

FDA recognizes that the interim rule

did not address different factors such as

amount of blood loss, renal output

versus input of fluids, time of sampling

in relation to transfusion/infusion, and

volume transfused/infused in

determining plasma dilution. Section

1270.21(h) of the final rule is revised to

recognize that an algorithm may be used

to ensure that there has not been plasma

dilution sufficient to affect test results.

Plasma dilution is further discussed in

comment 25 of this document. FDA also

notes that factors regarding the selection

of an appropriate algorithm for

determining plasma dilution are

discussed in the Guidance for Screening

and Testing of Donors of Human Tissue

Intended for Transplantation. The

notice of availability of this guidance

document may be found elsewhere in

this issue of the Federal Register.

22. One comment on § 1270.5(d)(1)

(§ 1270.21(g)(2)(i) of the final rule)

inquired if a pretransfusion/infusion

specimen was sufficient for testing or

whether a posttransfusion/infusion

specimen should also be tested.

A posttransfusion/infusion specimen

is not necessary when an adequate

pretransfusion/infusion specimen is

available. If a pretransfusion/infusion

specimen is unavailable for testing, then

for the tissue to be assessed for

suitability, a posttransfusion specimen

must be assessed for plasma dilution

using an algorithm prior to testing.

23. Five comments on § 1270.5(d)(1)

(§ 1270.21(g)(2) of the final rule)

discussed the difficulty in obtaining

pretransfusion/infusion specimens

because many potential donors arrive at

the emergency room in the process of

being transfused with blood or infused

with fluids, thus eliminating the

possibility of obtaining a

pretransfusion/infusion specimen.

The agency realizes a pretransfusion/

infusion specimen is not always

available. In those cases where the

specimen is unavailable, an algorithm to

determine if plasma dilution may affect
40436 Federal Register / Vol. 62, No. 145 / Tuesday, July 29, 1997 / Rules and Regulations

test results should be applied to

determine donor suitability. The

establishment’s standard operating

procedures (SOP’s) should outline this

algorithm and the measures for

determining donor suitability.

24. Two comments requested

clarification of specific circumstances

when plasma dilution should be

considered and what specific tests

would be affected by plasma dilution.

When a pretransfusion/infusion

specimen is unavailable, FDA believes

the following criteria should be

considered in evaluating the need for

using an algorithm to determine if

plasma dilution is sufficient to affect

infectious disease test results: (1) Blood

loss is known or suspected to have

occurred; (2) the tissue donor was

transfused or infused and an adequate

pretransfusion/infusion specimen is not

available for infectious disease testing;

(3) if preceding the collection of the

donor specimen in adult donors, more

than 2,000 milliliters (mL) of: whole

blood, reconstituted blood, red blood

cells, and/or colloids have been

administered within the previous 48

hours and/or; crystalloids have been

administered within the previous one

hour; or any combination of these has

occurred; and (4) in any donor 12 years

of age or less, any transfusion/infusion

has occurred. Once this information is

reviewed and the determination is made

that the 2,000 mL is exceeded or the

donor is 12 years of age or less, the

tissue is considered unsuitable until an

algorithm defined in the tissue

establishment’s SOP’s is used to assess

whether the dilution affected the test

results.

25. Fourteen comments on

§ 1270.5(d)(2) (§ 1270.21(h)(2)(ii) of the

final rule) requested clarification and

guidance on specific aspects of an

acceptable algorithm in evaluating

plasma dilution. One comment stated

that, in the absence of science, further

rulemaking should not include an

arbitrary cutoff. In particular, the

comments asked FDA to elaborate on:

(1) Who is responsible for determining

the parameters of the algorithm; (2) the

type of blood, blood components, and

fluids to be included or excluded; (3)

the time period that is to be taken into

consideration and the basis on which it

is calculated; (4) the unit of

measurement to be used; (5) the

maximum volume allowed; and (6) the

consideration given to output versus

input.

FDA is not prescribing who may

prepare the algorithm. It may be

prepared by any responsible person

with adequate training and

understanding of the principles of

plasma dilution. FDA discusses the

criteria for using an algorithm to

determine plasma dilution in comment

24 of this document, and is providing

additional information on a suitable

algorithm in the Guidance for Screening

and Testing Donors of Human Tissue

Intended for Transplantation announced

elsewhere in this issue of the Federal

Register. The information in the

guidance document is based on

available scientific evidence and was

the focus of the workshop held in June

1995.

The discussion of an algorithm for

determining plasma dilution in the

guidance document is based on the

calculation of blood volume and plasma

volume in relation to the donor’s body

mass. Where blood loss has occurred or

is suspected, and a pretransfusion/

infusion donor specimen is not

available,§ 1270.21(h) provides for use

of an algorithm when the transfusion/

infusion of more than 2,000 mL of

whole blood, reconstituted blood, red

blood cells, and/or colloids in the

previous 48 hours and/or crystalloids

within the previous one hour, or any

combination, has occurred in the stated

time periods prior to the collection of

the specimen. The time periods

recommended by the algorithm are

based on the safety record of voluntary

standards in the tissue industry

employing such a time period and on a

50 percent volume dilution of blood or

plasma. Transfused/infused products

have been broken into categories for the

purpose of calculating the volumes

transfused/infused. They are blood,

colloid, crystalloid, and a combination

of these categories.

FDA believes and has included in the

regulations at § 1270.21(h) that if the

following conditions are exceeded in a

circumstance of blood loss and

replacement in an adult, or transfusion/

infusion in a child 12 years of age or

less, the tissue shall be determined not

suitable for transplantation. The agency

currently believes that transfusion/

infusion of greater than one blood

volume in the case of blood replacement

or greater than one plasma volume in

the case of colloid and crystalloid

infusion, could make infectious disease

testing results unreliable due to plasma

dilution.

TABLE 2.—BLOOD AND PLASMA VOLUME CALCULATION

Category infused Product(s) included in category Hours prior to specimen collection Calculated1 volume administered

Blood Blood unit labeled as ‘‘Whole

Blood,’’ Blood unit labeled as

‘‘Red Blood Cells,’’

Reconstituted blood2

Within 48 hours > one blood volume

Colloid Plasma, platelets, albumin,

hetastarch, dextran

Within 48 hours > one plasma volume

Crystalloid Saline, dextrose in water, Ringer’s

lactate, other balanced electrolyte solutions

Within 1 hour > one plasma volume

Blood and colloids

and/or crystalloids

See all of the above Within 48 hours

and within 1 hour

> one blood volume (or if the calculated volume for colloids only,

within 48 hours of collection

and/or crystalloids within 1 hour

of collection is > one plasma

volume)

Colloids

and crystalloids

See above for colloid and crystalloidWithin 48 hours

and within 1 hour

> one plasma volume

1 Recommended methods for blood and plasma volume calculations may be found in the ‘‘Guidance for Screening and Testing of Donors of

Human Tissue Intended for Transplantation.’’
Federal Register / Vol. 62, No. 145 / Tuesday, July 29, 1997 / Rules and Regulations 40437

2 Reconstituted blood means the extracorporeal resuspension of a blood unit labeled as ‘‘Red Blood Cells’’ by the addition of colloids and/or

crystalloids to produce a hematocrit in the normal range.

5. Screening

26. Section 1270.5(e) (§ 1270.21(f) of

the final rule) requires that in order to

determine the suitability of human

tissue for transplantation, the identity of

the donor shall be ascertained and the

relevant medical records shall be

reviewed to assure freedom from risk

factors for and clinical evidence of

hepatitis B, hepatitis C, and HIV

infection. One comment requested that

the medical history include all available

medical, coroner, and autopsy records,

both written and those communicated

orally by health care practitioners.

FDA agrees that oral communications

specific to the donor’s relevant medical

history could affect donor suitability

and should be documented because they

are an integral part of the donor testing

and screening process. This information

should be recorded by a responsible

person and should serve as an adjunct

to other available information and

records required by new § 1270.21. FDA

has included a definition for ‘‘relevant

medical records’’ in § 1270.3(t) which is

consistent with the comment.

27. Twenty comments on § 1270.5(e)

(§ 1270.21(f) and (g) of the final rule)

expressed concern that the requirement

for a donor medical history interview

(formerly the Next-of-Kin interview in

the interim rule) as part of the relevant

medical records, would make it more

difficult to procure corneas under

legislative consent (formerly Medical

Examiner Law in the interim rule and

defined in § 1270.3(h) of the final rule).

The comments suggested that the donor

medical history interview for corneas

procured under legislative consent be

waived. One comment proposed using

the ‘‘all available information’’ standard

in determining suitability of corneas for

transplantation. In an opposing

viewpoint, six comments disagreed with

a waiver of donor medical history

interviews for corneas procured under

legislative consent. The latter stated that

corneas procured as a result of

legislative consent do not meet industry

standards and diminish the ability of

transplant professionals to effectively

promote the altruistic benefits of

donation. These comments endorsed

regulation of corneas because corneal

tissue does transmit disease and should

be regulated as strictly as other tissue.

After reviewing the numerous

comments on the interim rule and the

discussions at the workshops, FDA

acknowledges the need for flexibility in

the procurement of corneal tissue under

legislative consent. Where corneas are

procured under legislative consent, FDA

has modified the regulations in the final

rule to accept as sufficient a physical

assessment of the donor in the absence

of a donor medical history interview for

behavioral and high risk information.

Even though corneas may have a degree

of protection due to avascularity, FDA

notes that it is possible that viruses may

be present in donor corneal tissue.

Therefore, the agency believes that this

modification underscores the

importance of additional information

gathering in determining the suitability

of a donor. Negative viral marker test

results for HIV and hepatitis, and review

of other available information in

addition to the physical assessment,

will continue to be a requirement.

However, if additional tissue other than

cornea is recovered from the same

donor, then a donor medical history

interview is required. Based on the

recommendation of the PHS

‘‘Guidelines for Preventing

Transmission of Human

Immunodeficiency Virus Through

Transplantation of Human Tissue and

Organs’’, (MMWR, May 20, 1994) FDA

is requiring under new § 1270.21(g)

documentation in the summary of

records that corneal tissue was procured

under legislative consent so that the

transplant surgeon will be aware that:

(1) A donor medical history interview

was not obtained, (2) a physical

assessment of the donor for evidence of

high risk behavioral signs of HIV and

hepatitis infection had been made, and

(3) the tissue was determined to be

suitable in the absence of the donor

medical history interview.

28. One comment on § 1270.5(f)

(§ 1270.21(e) of the final rule) stated that

the requirement that a full set of records

physically accompany each of the

approximately 300,000 allografts

distributed annually in the United

States was superfluous as well as

unduly burdensome and expensive.

FDA believes that the comment has

misinterpreted the meaning of

§ 1270.5(f). Human tissue that is

determined to be suitable for

transplantation per § 1270.9(b)

(§ 1270.21(e) of the final rule) must be

accompanied by copies of original

records, indicating that all infectious

disease testing and screening under

§ 1270.5 (§ 1270.21 of the final rule) has

been completed, reviewed by the

responsible person, and found to be

negative. The agency has routinely

accepted completed summaries of such

records as long as the summary contains

the identity of the testing laboratory, the

listing and interpretation of all required

infectious disease tests, a listing of the

documents reviewed as part of the

relevant medical records, and the name

of the person or establishment

determining the suitability of the human

tissue for transplantation.

After review, FDA finds the

recordkeeping requirements of the rule

no more burdensome or potentially

costly than the standards established by

the American Association of Tissue

Banks or the Eye Bank Association of

America which require labeling and

package inserts to accompany a

shipment of human tissue.

6. Written Procedures (§ 1270.31)

Section 1270.7 (§ 1270.31 of the final

rule) sets forth the requirements for

written procedures for infectious

disease testing, and obtaining,

reviewing, and assessing the relevant

medical records of the donor.

The agency has added § 1270.31(c)

and (d) requiring written procedures for

the designation and identification of

quarantined tissue, and for the

prevention of contamination or crosscontamination of tissues during

processing. Because HIV and hepatitis

screening and testing of the donor may

be incomplete at the time of processing,

and to maintain the separation of

suitable tissue from that not yet

determined to be suitable or tissue that

has been determined to be unsuitable

for transplantation (which is the intent

of the concept of ‘‘quarantine’’ as it is

used in the final rule), FDA is requiring

that these written procedures be

prepared and followed. FDA is also

requiring that the written procedures for

preventing the contamination or crosscontamination by tissues during

processing be validated. These

requirements will facilitate the timely

processing of tissue when necessary

(e.g., skin and cornea) while

maintaining quarantine and continuing

current good practices performed by

industry in daily processing.

29. Two comments asked for a clearer

statement that the written procedures

and records requirement of §§ 1270.7(a)

and 1270.9(a) are the responsibility of

the laboratory where the tests are run.

FDA has amended the requirements of

§ 1270.9 (§ 1270.33 of the final rule) to

state that the person or establishment

making the determination regarding the

suitability of human tissue is

responsible for retaining all testing and

screening records used in making the
40438 Federal Register / Vol. 62, No. 145 / Tuesday, July 29, 1997 / Rules and Regulations

determination of suitability for

transplantation. FDA believes that the

person (as defined in § 1270.3(m) of the

final rule) or establishment (as defined

in § 1270.3(i) of the final rule) that has

made the determination of suitability

should have and retain the testing and

screening records used in making the

determination. The individual records

must also be retained by the

establishment performing the work

being recorded. For human tissue that is

determined to be suitable, the person or

establishment receiving the human

tissue should receive a summary of

records (as described in § 1270.1(w))

used in determining the suitability of

the donor. The summary should identify

the responsible person, in addition to

the person or establishment that made

the determination that the human tissue

is suitable for transplantation in

accordance with § 1270.21(e). Other

than having the summary, FDA does not

expect the transplant institution to

receive complete documentation

regarding the suitability of the donor. If

FDA has questions regarding donor

suitability, the person or establishment

that made the determination of donor

suitability will ordinarily be contacted.

That person or establishment is

responsible for having all records used

in making the determination. With

respect to testing records, the testing

laboratory should retain records of the

test results and the interpretation of the

test results. Copies of the interpretation

of the test results should also be

provided to, and retained by, the person

or establishment making the final

determination of donor suitability.

30. Three comments on § 1270.7(c)

(§ 1270.31 of the final rule) requested

clarification on which organization’s

SOP would be acceptable and suggested

that the agency require each facility to

have its own SOP that includes

processing, storage, and final

disposition of human tissue.

The regulations require each facility

to prepare and follow written

procedures for testing and screening of

human tissue. In § 1270.31 of the final

rule, written procedures are required for

all significant steps involved in the

infectious disease testing process which

shall conform to the manufacturers’

instructions for use contained in the

package inserts, and for all significant

steps in obtaining, reviewing, and

assessing for completeness the relevant

medical records of the donor. Any

deviation from the establishment’s

written procedures shall be recorded

and justified. FDA investigators review

an establishment’s written procedures

during an inspection, to evaluate

whether the SOP’s are consistent with

the regulations, and to determine that

the establishment is following the

procedures documented in the SOP’s. A

detailed and complete SOP ensures

uniformity and consistency for each

procedure performed. Each

establishment may develop its own

written procedures or adopt those in a

manual prepared by another

organization, as long as the procedures

satisfy the requirements set out in the

regulations. Because each establishment

differs, an establishment using

procedures developed by another

establishment or organization should

evaluate those procedures to determine

whether they are adequate or need to be

revised by that establishment. The

responsibility for ensuring adequacy of

procedures and compliance rests with

the individual establishment regardless

of the source of its procedures.

7. Records, general requirements

(§ 1270.33) and Specific records

(§ 1270.35)

Sections 1270.9 and 1270.11 of the

interim rule (§§ 1270.33 and 1270.35,

respectively of the final rule) set forth

the general and specific requirements

for the maintenance of records. Under

§ 1270.33(c), all human tissue that is to

be processed or shipped prior to the

determination of donor suitability must

be under quarantine, accompanied by

records identifying the donor, and

identifying the tissue as not determined

to be suitable for transplantation. All

human tissue found suitable for

transplantation must be accompanied by

a complete summary of records, or

copies of the original records,

documenting that all infectious disease

testing and screening has been

completed, reviewed by the responsible

person, and identified as determined to

be suitable for transplantation. The

summary of records also lists all the

available records used in determining

the suitability of the donor so that the

originals of these records can be

accessed, if necessary. These records

include the donor medical history

interview, the relationship of the person

interviewed to the donor, the physical

assessment of the donor, autopsy or

coroner records, hospital records, police

records, and any other available record

used to document the suitability of the

donor. If only corneal tissue was

procured under legislative consent in

the absence of a donor medical history

interview, the accompanying summary

of records shall document that: (1) A

donor medical history interview was not

obtained; (2) a physical assessment of

the donor for evidence of high risk

behavior and signs of HIV and hepatitis

infection had been made; and (3) the

tissue was determined to be suitable in

the absence of the donor medical history

interview. Under § 1270.9(c)

(§ 1270.33(f) of the final rule) the person

or establishment making the

determination regarding the suitability

of human tissue is responsible for

retaining the completed records and

making them available to FDA upon

their request.

Section 1270.35(c) of the final rule

has been added to complete the

accounting of the inventory between

determination of suitability

(§ 1270.35(a) and (b)) and the final

disposition of the human tissue

(§ 1270.35(d)), e.g., the destruction of

unsuitable tissue, nonclinical research

use, or distributed for transplantation.

The interim rule required the

documentation of the records used in

determining the suitability of the human

tissue, and the destruction or

disposition of unsuitable human tissue.

The final rule requires in § 1270.35(c)

documentation of the receipt and/or

distribution of human tissue.

31. One comment recommended that

the facility that made the final

determination of donor suitability and

retrieved the human tissue be required

to maintain the medical history and

testing records for each donor.

Retrieval and determination of donor

suitability are often done by separate

facilities, therefore, FDA has modified

the language in § 1270.9(c) (§ 1270.33(f)

of the final rule) to require the

maintenance of records under § 1270.5

(§ 1270.21 of the final rule), including

all testing and screening records, by the

person or establishment making the

determination regarding the suitability

of human tissue. Persons or

establishments performing operations

that would generate documentation that

has a bearing on a donor’s suitability

would retain that documentation and

make it available during an FDA

authorized inspection.

32. Two comments urged FDA to

continue to require record retention for

10 years or until the expiration date of

the human tissue, which could be

longer than 10 years, but in any event

no less than 10 years.

FDA agrees with the comments and

has modified § 1270.33(h) to require the

retention of records for a period that

extends at least 10 years beyond the

date of transplantation, if known,

distribution, disposition, or expiration

of any dating period related to the

human tissue, whichever is latest.

33. One comment stated that the

definition for required exclusions due to

the presence of risk behaviors for certain

diseases should be at all times

consonant with the recommendations of
Federal Register / Vol. 62, No. 145 / Tuesday, July 29, 1997 / Rules and Regulations 40439

the CDC and the human tissue bank

professions.

FDA has developed guidance on

behavioral and high risk information,

taking both the CDC’s recommendations

and those of the human tissue bank

professions into account. At the June

1995 workshop, FDA distributed a draft

document, which was also made

available to the general public,

discussing screening and testing issues.

Representatives from CDC participated

in all three workshops and FDA has

based its recommendations for testing

and screening on the PHS guidelines

published in the Morbidity and

Mortality Weekly Reports of April 1991,

and May 1994 and public comment

submitted in response to the workshop.

In conjunction with this rule, FDA is

issuing a guidance document

concerning the screening and testing of

donors of human tissue intended for

transplantation. FDA developed this

document taking into account the

recommendations of PHS, the Medical

Standards of the Eye Bank Association

of America, the American Association of

Tissue Banks and comments from other

interested persons.

8. Inspections (§ 1270.41)

Section 1270.13 (§ 1270.41 of the final

rule) addresses the inspectional process.

Establishments covered by the

regulations include those

establishments that recover, screen, test,

process, store, or distribute human

tissue and include those establishments

performing such activities under

contract. In large part, inspections of

tissue establishments are conducted in

the same manner as inspections of firms

dealing in other FDA regulated

commodities. FDA is presently

assessing its inspectional procedures

and the extent to which the agency can

work with other qualified organizations

to make best use of limited resources.

FDA investigators cover several major

areas during an inspection. All facilities

are subject to examination, including

any facility contracted by the primary

facility such as testing laboratories,

contract sterilizers, or off-site storage

facilities. The investigators may

examine any human tissue at the firm to

observe, for example, whether it is

appropriately quarantined, identified,

and stored. The inspections generally

will focus on a review of required

records. Employees may be interviewed

regarding their performance of regulated

activities. At the end of the inspection,

if possible violations of the regulations

are found, the FDA investigator will

issue to the responsible person at the

establishment a list of ‘‘Inspectional

Observations’’ (Form FDA–483),

describing the observations of the

investigator that represent an observed

or potential problem with the facility or

tissue. After the report of the

investigator is reviewed, FDA may issue

additional correspondence to the

establishment describing the violations

to the regulations and requesting

appropriate followup action.

FDA intends to continue to inspect

regulated establishments, both foreign

and domestic, when deemed necessary

by the agency to ensure that human

tissue is screened and tested to reduce

risk of HIV, hepatitis B, or hepatitis C.

Frequency of inspection after an initial

inspection may depend on the extent of

any violations found and will be at the

agency’s discretion.

34. One comment on § 1270.13

(§ 1270.41 of the final rule) asserted that

the provision which allows investigators

to question personnel of the

establishment as the investigator deems

necessary is inappropriate under the

governing case law. The comment cited

Donovan v. Dewey, 452 U.S. 594 (1981);

Stark v. Wickard, 321 U.S. 559 (1944),

and Ernst v. Hochfelder, 425 U.S. 185

(1976) to support this assertion.

FDA disagrees with the interpretation

of these three cases in the context of the

governing statutory authority, the PHS

Act. Section 361 of the PHS Act

authorizes the Secretary to issue and

enforce regulations to control

communicable diseases, and it provides

for such inspection and destruction of

articles found to be so infected or

contaminated as to be sources of

dangerous infection to human beings,

and other measures, that may be

necessary. These other measures

include the use of routine inspections

and the questioning of personnel during

such inspections. The FDA inspector

may question the firm’s personnel to

determine if the staff is familiar with

and following the firm’s written SOP’s.

35. One comment on § 1270.13(e)

(redesignated as § 1270.41(e) of the final

rule) asked FDA to clarify whether the

FDA investigator or a human tissue

bank official is responsible for ensuring

that records to be copied are suitably

expurgated. The comment also asked for

guidance on the scope and meaning of

‘‘suitably.’’

FDA has revised § 1270.41(e) of the

final rule to clarify that FDA will follow

its existing procedures regarding

disclosure of documents. Under these

procedures, FDA takes necessary

precautions to protect the privacy of

names of tissue donors or recipients

prior to public disclosure. These

procedures are set forth in 21 CFR part

20. See e.g., 21 CFR 20.63. FDA

recognizes the sensitive nature of the

information that would identify a

human tissue donor or recipient. FDA

may copy records containing

identification of the donors or recipients

if such records are needed for example,

to document the distribution of

potentially infectious human tissue.

9. Human Tissue Offered For Import

(§ 1270.42)

Because some human tissue used for

transplantation in the United States is

obtained from foreign sources or is

processed in foreign facilities and

because of requests for clarification of

requirements for such tissue, FDA has

added § 1270.42 to clarify the

administrative steps for the importation

of tissue into the United States. Human

tissue that has been recovered from

sources outside the United States can

enter the country, and tissue that has

been recovered from sources in the

United States that has been sent outside

the United States for processing can

reenter the country consistent with the

provisions of §§ 1270.33 and 1270.42.

For tissue imported prior to the

determination of donor suitability, the

tissue must be accompanied by records

assuring identification of the donor and

indicating that the tissue has not been

determined to be suitable for

transplantation. For tissue determined

to be suitable for transplantation, the

tissue is to be accompanied by a

summary of records, or copies of the

original records, indicating that all

infectious disease testing and screening

under § 1270.21 has been completed,

reviewed by the responsible person, and

found to be negative. Tissue that has

been determined to be suitable for

transplantation must also be identified.

As with other imports, the importer of

record (as defined in § 1270.3(k) of the

final rule) for human tissue must notify

the District Director of FDA having

jurisdiction over the port of entry when

the articles are offered for import. The

tissue must be held in quarantine until

and unless the article is released by

FDA. Human tissue that is offered for

import and is found to be in violation

of part 1270, is subject to recall and

destruction in accordance with

§ 1270.43 of the final rule.

10. Retention, Recall, and Destruction of

Human Tissue (§ 1270.43)

Section 1270.15 of the interim rule

(§ 1270.43 of the final rule) describes the

procedures for the retention, recall, and

destruction of human tissue upon a

finding that the human tissue may be in

violation of the regulations.

36. One comment on § 1270.15

(§ 1270.43 of the final rule) requested

that the rule be clarified to state that
40440 Federal Register / Vol. 62, No. 145 / Tuesday, July 29, 1997 / Rules and Regulations

when a part 16 (21 CFR part 16) hearing

has been requested, human tissues need

not be destroyed until the hearing is

held.

FDA has clarified § 1270.43(e) to state

that any possible destruction of human

tissue would be held in abeyance

pending resolution of the hearing

request. Under the provisions of

§ 16.24(d), the Commissioner of Food

and Drugs (the Commissioner) may take

action pending a hearing that is

necessary to protect the public health.

FDA is, however, sensitive to the

potential economic consequences that

would result from the immediate

destruction of potentially violative

human tissue. Any human tissue listed

in such an order must be held in

quarantine and cannot be released prior

to the resolution of a hearing request

and receipt of written notice from FDA.

If destruction is warranted, the

destruction of the human tissue is to be

conducted under the supervision of a

designated FDA official.

37. One comment asked that FDA

clarify the ‘‘may be in violation’’

language in the recall and destruction

part of the rule, particularly with

respect to what triggers the finding of a

violation.

The procedures for retention, recall,

and destruction in § 1270.43 will be

used only when the agency deems it

necessary to ensure the suitability of

human tissue for transplantation. FDA

intends to invoke § 1270.43 of the final

rule when there is evidence of a

violation related to tissue suitability,

such as the source of the human tissue,

the adequacy of the testing or screening

of the human tissue, the completeness

of the records accompanying the human

tissue, the adequacy of donor selection,

and/or the attention given to the

possibility that the donor was at a high

risk for HIV or hepatitis.

C. Comments on Legal Issues

38. Five comments objected to the

immediate effective date of the interim

rule and questioned why such a

measure was taken. Four comments

objected to the required retrospective

application of the interim rule, in that

it applied to human tissue in storage

upon the effective date, which may have

been collected and tested before the

effective date of the interim rule.

The Administrative Procedure Act

(the APA) (5 U.S.C. 551 et. seq.) governs

the issuance of rules by executive

agencies. The APA’s requirement of

notice and comment prior to the

implementation of a rule may be

dispensed with when the agency for

‘‘good cause’’ finds that the procedures

are ‘‘impracticable, unnecessary, or

contrary to the public interest.’’ (See 5

U.S.C. 553(b)(B).)

In the preamble to the interim rule (58

FR 65514 at 65518), FDA described its

good cause for proceeding directly to an

interim rule. Specifically, the agency

stated that the Commissioner found that

the use of prior notice and comment

rulemaking was ‘‘contrary to the public

interest’’ because of the ‘‘unnecessary

risk of transmission of HIV infection

and hepatitis infection from shipment

and transplantation of human tissues

derived from inadequately tested or

screened donors.’’ During an

investigation prior to the promulgation

of the interim rule, FDA investigators

learned of the availability, importation,

and distribution of musculoskeletal

tissue materials that had not been

adequately screened or tested for HIV,

hepatitis B, and hepatitis C. This

investigation illustrated the need for

swift action to reduce the risk to the

public health. Because of the public

health risk posed by the inadequately

tested or screened tissues, FDA applied

the regulations not only to tissues

screened after the effective date but also

to human tissue remaining in storage for

transplantation.

As previously stated, FDA provided

opportunities for public comment

following the promulgation of the

interim rule and has considered those

comments and the agency’s experience

in developing the final rule.

The final rule will have an effective

date of 180 days after the date of

publication and will apply to human

tissue intended for transplantation

procured on or after the effective date.

For tissue procured prior to the effective

date of the final rule, the interim rule

applies.

39. One comment urged Federal

preemption of State and local

regulations on donor suitability, testing

and labeling of human tissues.

FDA declines to take such a measure

because the agency is not aware of any

compelling reason that State regulatory

authorities should be preempted at this

time. The rule provides the minimum

criteria necessary to help ensure tissue

safety, and States are free to add

additional requirements that they

believe are warranted.

D. Comments on Economic Issues

40. Two comments on the economic

impact in the preamble to the interim

rule stated that the rule would result in

an increase in the human tissue

processing fee that the recipient must

pay. In addition, one of the two

comments stated that the number of

human tissue transplants mentioned by

the agency may be inaccurate and

human tissue banking activities generate

$59 million rather than $100 million per

year.

FDA has considered the data provided

in these comments in finalizing the

regulations. The comments did not,

however, provide the agency with

figures that would illustrate an increase

in the human tissue processing fee.

41. Three comments stated that the

implementation of the regulations will

drive the cost of corneal transplant

beyond the means of the average person.

These comments did not provide data

to support their contention. FDA’s

intention is to make tissue that is

available for transplantation safer. The

Eye Bank Association of America

Statistical Report for 1994 does not

support the premise that there has been

any decrease in the availability or

transplantation of corneal tissue. Both

the total number of donations and the

total number of transplants have

increased during 1994 under the Interim

Rule. However, as discussed in

comment 27, FDA acknowledges the

need for flexibility and has modified the

requirement for corneas procured under

legislative consent when there is no

medical history interview available.

E. Requests for Additional Regulations

42. Five comments asked FDA to

regulate all human tissue banking efforts

including musculoskeletal, skin, eye,

reproductive tissue, blood vessel, bone

marrow, heart valves, and hospital

surgical bone banks.

This rule does not apply to

reproductive tissue, bone marrow,

human milk, and heart valves under

part 1270. Heart valves are already

regulated by FDA as medical devices.

HRSA administers the program for the

National Bone Marrow Donor Registry.

As noted in comment No. 8, in the near

future, FDA is considering proposing

additional regulations governing the use

of human tissue and is considering

whether to expand the scope of the rule

to cover additional tissues.

43. Three comments stated that all

tissue banks, despite their type, should

be federally registered and subject to

inspection and accreditation. One

additional comment urged FDA to

consider the use of a nongovernmental

organization as a private accrediting

and/or inspecting entity.

FDA declines to adopt the suggestions

made by these comments as they relate

to registration and accreditation at this

time, as they are outside the scope of the

rule, but is considering addressing

registration and accreditation in future

rulemaking, at which time comments

will be solicited. Tissue facilities that

are regulated under the provisions of the
Federal Register / Vol. 62, No. 145 / Tuesday, July 29, 1997 / Rules and Regulations 40441

interim rule are subject to and will

continue to be subject to Federal

inspection under the final rule.

44. One comment suggested that

tissue banks should bank and hold

serum specimens from donors for 5

years beyond the expiration date of the

human tissue allograft for additional

testing that may become relevant to

public health in the future.

The comment did not provide any

demonstrable evidence that such a

practice is necessary for the protection

of the public health. In the absence of

such evidence, FDA declines to add

such a requirement. Complete and

careful donor screening and testing in

accordance with the provisions of the

rule, as well as maintenance of records

for the period specified in § 1270.33(h)

should provide sufficient information to

investigate possible transmission of

infectious disease. FDA is willing to

consider evidence that such a

requirement is warranted.

45. One comment urged a requirement

that records show the destination of all

human tissue released for transplant.

FDA is requiring disposition records

for human tissue (distribution for

transplantation, use for nonclinical

research, or destruction) but is not

requiring tracking to the recipient at this

time. FDA is considering requirements

for the tracking of human tissue for

inclusion in future rulemaking. FDA

discussed the tracking of human tissue

under a Federal regulatory scheme with

members of the industry at both the

March 1995 and June 1995 workshops

described earlier. FDA notes that

currently the voluntary standards of the

American Association of Tissue Banks

and the Eye Bank Association of

America include the tracking of human

tissue from the donor to the recipient,

transplanting surgeon or institution.

46. Three comments requested FDA to

consider developing requirements for

discussing donor medical history with

the Next of Kin or others who might

sign the donation consent form.

FDA recognizes the requests for

requiring a donor medical history

interview, and the need for guidance in

conducting the donor medical history

interview for assurance that the donor

did not participate in high risk behavior

for hepatitis and HIV infection. The

donor medical history interview is an

integral part of the relevant medical

records and is defined as such in the

final rule. FDA is announcing the

availability of ‘‘Guidance for Screening

and Testing of Donors of Human Tissue

Intended for Transplantation’’

elsewhere in this Federal Register to

assist those facilities involved in

determining the suitability of a donor.

47. Two comments inquired about the

mechanism used by FDA in requiring

new tests in the future and deleting

obsolete tests, and added that a careful

evaluation and decision analysis should

consider the test’s specificity,

sensitivity, and positive utility.

It is the practice of FDA to thoroughly

evaluate all data including that

accumulated by its scientists, by

industry scientists, and by academicians

when considering the use of a test or

deletion of a test for communicable

disease. When appropriate, FDA

presents such data to an advisory

committee composed of specialists and

requests their recommendation.

Therefore, FDA evaluates the need to

add or delete a test for communicable

disease taking into account the available

scientific data and the effect of the test

on the public health.

48. One comment inquired as to the

suitability of an umbilical cord blood

specimen or the mother’s blood

specimen for viral marker testing on

newborn donors.

To date, none of the viral marker test

kits address cord blood as an adequate

sample in the package insert. Cord

blood may not be acceptable for testing

if contamination of the specimen with

Wharton’s jelly occurs during

collection. If an adequate cord blood

specimen is not available, then the

mother’s blood specimen will be

considered acceptable for testing. FDA

has added § 1270.21(b) to the final rule

to clarify that in the case of a neonate,

the mother’s specimen is acceptable for

testing.

F. Comments on New Regulatory Areas

49. Forty-four comments were also

received that were beyond the scope of

this rulemaking. For example, five

comments expressed concern that FDA

would require user fees to fund the

regulation of human tissue.

This final rule does not impose a user

fee requirement for human tissue. User

fee authority to fund tissue banking

regulation was presented in legislation

introduced by Representative Wyden in

H.R. 3547 and Senator Simon in S. 1702

during the 1994 Congressional term.

Neither bill was passed.

50. One comment stated that it would

be appropriate to include recordkeeping

and tracking requirements for hospitals

and other transplant facilities.

FDA at this time declines to

incorporate tracking requirements in

this rule. Promulgation of tracking

requirements would affect transplant

facilities currently not within the scope

of the final rule, unless they are

involved in recovery, screening, testing,

processing, or distribution of human

tissue. In this rulemaking, FDA is not

expanding the recordkeeping

requirements beyond those in

§ 1270.35(c), or otherwise revising

significantly its regulatory program on

human tissue at this time. The

comments are being considered as FDA

reviews the possibility of further

developing its regulatory program and

may be the subject of future rulemaking.

IV. Analysis of Impacts

FDA has examined the impacts of the

final rule under Executive Order 12866

and the Regulatory Flexibility Act (5

U.S.C. 601–612). Executive Order 12866

directs agencies to assess all costs and

benefits of available regulatory

alternatives and, when regulation is

necessary, to select regulatory

approaches that maximize net benefits

(including potential economic,

environmental, public health and safety,

and other advantages; distributive

impacts; and equity). The agency

believes that this final rule is consistent

with the regulatory philosophy and

principles identified in the Executive

Order. The agency has also determined

that this rule is a significant regulatory

action under paragraph (f)(4) of the

Executive Order because it raises novel

policy issues.

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

below, the agency certifies that this rule

will not have a significant impact on a

substantial number of small entities.

A. The Need For the Regulation

The purpose of the final rule is to

provide clarification of the interim rule,

revise the rule in response to public

comments, and finalize its provisions.

The interim rule was promulgated as an

emergency measure to protect the public

safety against human tissue that had

incomplete or no documentation

ascertaining its freedom from

communicable diseases. This risk was

clearly demonstrated by evidence of

human tissue from foreign sources that

had been offered for sale in the United

States with little documentation of

appropriate screening and testing. The

final rule takes into account comments

submitted to the Dockets Management

Branch, and discussions and

information obtained through public

participation in three workshops held

following the promulgation of the

interim rule. The objective of the final

rule is to impose minimal requirements

for testing and screening of human
40442 Federal Register / Vol. 62, No. 145 / Tuesday, July 29, 1997 / Rules and Regulations

tissue donors, while making all human

tissue, imported and domestic, safe for

transplant needs.

B. A Description of Requirements

The interim rule requires all facilities

to ensure that specified minimum

required medical screening and

infectious disease testing has been

performed and that records

documenting such screening and testing

for each human tissue are available for

inspection by FDA. The final rule

clarifies and modifies requirements in

the interim rule and adds three

additional requirements, which are

currently voluntary industry standards:

written procedures for the designation

and identification of quarantined tissue

(§ 1270.31(c)); written and validated

procedures for the prevention of

contamination or cross-contamination of

tissues during processing (§ 1270.31(d));

and documentation of receipt and/or

distribution of human tissue determined

to be suitable for transplantation until it

is distributed to the transplanting

facility (section 1270.35(c)).

C. The Type and Number of Firms

Affected

The rule will affect any establishment

or person engaged in the recovery,

screening, testing, processing, storage or

distribution of human tissues. Because

of their small size, tissue specialty, and/

or interrelationship with other tissue

establishments, most tissue

establishments do not perform all of

these activities. Thus, the effect of this

rule will vary depending on the number

and type of functions performed.

Because tissue establishments are not

currently required to register with FDA,

the agency does not have a precise

count of the number of establishments

that will be affected by this rule. EBAA

reports 110 member eye banks. Also, an

FDA/HRSA sponsored survey projected

that in 1994, about 67 tissue banks

procured musculoskeletal tissue from

cadaveric donors. (Jeffrey Prottas, (1995)

‘‘A Study of the Tissue Procurement and

Distribution System of the United

States’’). This survey also projected an

additional 120 surgical bone banks,

entities which typically involved one or

more surgeons who save and freeze for

later use bone obtained during routine

surgical procedures. There also may

exist an unknown number of uncounted

skin banks. (Neither of these latter two

groups—surgical bone and skin banks—

are believed to account for substantial

volume of tissue.) All together,

therefore, FDA estimates that the rule

may affect a total of about 400

establishments. Since the majority of

these establishments employ fewer than

15 employees, the Small Business

Administration would define almost all

as small entities.

D. Nature of Impact

FDA finds that the final rule will have

little adverse impact on the tissue

industry. When issuing the interim rule,

FDA took voluntary industry standards

and State requirements into account to

minimize the impact on the supply of

tissue available for transplantation and

to reduce the economic burden to

industry. In its preamble to the interim

regulation (58 FR 65519), FDA

determined that the only economic

impact of the rule would be related to

the recordkeeping burdens, ‘‘because

the cost of testing for infectious disease

and the cost of screening donors has

already been assumed by the tissue

banking industry and this interim rule

imposes no additional burdens.’’ The

agency has received no new industry

comment that would alter its conclusion

that donor testing and screening are

universally accepted practice for the

industry.

The eye bank sector, however, has

questioned the need for the potential

burden associated with certain aspects

of the interim donor screening

requirements. Several comments

suggested that the agency exempt

corneas from regulations due to an

adequate safety record and adequate

internal standards (Comment 3). Some

asked that the agency exempt these

operations from the requirement for a

donor medical history interview as part

of the relevant medical record, if the

document was not available; stating that

this requirement makes it more difficult

to procure corneas under legislative

consent (Comment 27).

FDA has given great consideration to

the impact that such changes would

have on both the tissue establishments

and the public health. The agency

believes that all human tissues have the

potential to transmit communicable

diseases and that every reasonable effort

should be made to prevent disease

transmission, while ensuring the

continued availability of safe human

tissue. Keeping these elements in focus,

FDA decided to regulate all human

tissue under the same standards

(protecting the public health by

preventing disease transmission), while

permitting the procurement of corneas

under legislative consent when a donor

medical history interview is not

available. Thus, the final FDA rule

allows greater flexibility in the

procurement of corneal tissue under

legislative consent, while minimizing

any potential regulatory burden.

Similarly, the new requirements of

the final rule, (e.g., preparing two

standard operating procedures and

increased documentation for receipt

and/or distribution of human tissue)

will not add significantly to operating

costs. The final requirements are part of

industry voluntary standards and

therefore, are currently in place in most

tissue banks. The 60 tissue banks and

110 eye banks that are currently

members of the AATB and the EBAA,

respectively, are likely to account for

the great majority of tissue transactions.

For those few establishments that do not

have or must modify their existing

written procedures, FDA estimates that

they will require a one-time expenditure

of approximately 7 hours for each of

four required written SOP’s.

Furthermore, since the smaller tissue

banks would be unlikely to process

tissue (the Prottas survey projects that

only 28 percent of the 67

musculoskeletal banks process tissue),

the smaller tissue banks will need to

prepare only three written procedures.

Likewise, the new requirements for

documenting the distribution and

receipt of human tissue will impose few

costs. Prottas found that 95 percent of

the surveyed musculoskeletal banks

could track tissue to recipient

institutions. These banks presumably

already identify and document their

products. Although the smallest tissue

banks may need to expand this effort,

the associated cost would be mitigated

by the smaller number of transactions at

such establishments.

In sum, the final rule sets minimal

requirements to prevent the

transmission of communicable diseases

from human tissue used for

transplantation. The vast majority of

tissue establishments were voluntarily

complying with most of the

requirements of the interim rule before

it was issued, and are voluntarily

complying with the new requirements

in this final rule. As described in

Section V of this document, some

entities may need to prepare or modify

existing documentation procedures, but

FDA believes that very few will need to

alter actual operations. At almost no

establishment would additional

reporting and recordkeeping activities

take over 20 hours of time annually for

a nurse, physician assistant, or certified

technician. As a result, FDA expects

that very few entities will incur

significant costs due to this rule. FDA

therefore certifies that this rule will not

have a significant impact on a

substantial number of small entities.
Federal Register / Vol. 62, No. 145 / Tuesday, July 29, 1997 / Rules and Regulations 40443

V. Paperwork Reduction Act of 1995

Although the December 14, 1993,

interim rule (58 FR 65514) provided a

90-day comment period under the

Paperwork Reduction Act of 1980, and

this final rule responds to the comments

received, FDA is providing an

additional opportunity for public

comment under the Paperwork

Reduction Act of 1995, which was

enacted after the expiration of the

comment period and applies to this

final rule. Therefore, FDA now invites

comments on: (1) Whether the proposed

collection of information is necessary

for the proper performance of FDA’s

functions, including whether the

information will have practical utility;

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

burden of the proposed collection of

information, including the validity of

the methodology and assumptions used;

(3) ways to enhance the quality, utility,

and clarity of the information to be

collected; and (4) ways to minimize the

burden of the collection of information

on respondents, including through the

use of automated collection techniques,

when appropriate, and other forms of

information technology. Individuals and

organizations may submit comments on

the information collection provisions of

this final rule by September 29, 1997.

Comments should be directed to the

Dockets Management Branch (address

above).

At the close of the 60-day comment

period, FDA will review the comments

received, revise the information

collection provisions as necessary, and

submit these provisions to OMB for

review and approval. FDA will publish

a notice in the Federal Register when

the information collection provisions

are submitted to OMB, and an

opportunity for public comment to OMB

will be provided at that time. Prior to

the effective date of this final rule, FDA

will publish a notice in the Federal

Register of OMB’s decision to approve,

modify, or disapprove the information

collection provisions. An agency may

not conduct or sponsor, and a person is

not required to respond to, a collection

of information unless it displays a

currently valid OMB control number.

This final rule contains information

collection requirements which are

subject to review by the Office of

Management and Budget (OMB) under

the Paperwork Reduction Act of 1995.

The title, description, and respondents

of the information collections are shown

below with an estimate of the annual

recordkeeping and periodic reporting

burden.

Title: Human Tissue Intended for

Transplantation: 21 CFR part 1270.

Description: FDA is issuing final

regulations to prevent the transmission

of HIV, hepatitis B, and hepatitis C

through the use of human tissue for

transplantation. The final regulations

closely parallel those contained in the

interim rule on human tissue intended

for transplantation. Both the interim and

final rule provide for inspection by FDA

of persons and tissue establishments

engaged in the recovery, screening,

testing, processing, storage, or

distribution of human tissue. These

facilities are required to meet standards

intended to ensure appropriate

screening and testing of human tissue

donors and ensure that records are kept

documenting that the appropriate

screening and testing have been

completed.

Description of Respondents:

Businesses or other for-profit; nonprofit

institutions; small businesses or

organizations.

There are approximately 60 tissue

establishments with 300 employees that

are members of the American

Association of Tissue Banks. There are

an additional 600 individual members

of which 50 percent are performing a

tissue banking activity. The Eye Bank

Association of America’s membership

consists of 120 eye banks of which 110

are in the continental United States.

With the rare exceptions noted in the

preamble, FDA believes that all

respondents perform donor testing and

screening for HIV and hepatitis and

these regulations add no additional

requirements. New § 1270.31(c) and (d)

require written procedures for the

designation and identification of

quarantined tissue and to prevent the

contamination or cross-contamination of

tissue during processing. Section

1270.35(c) requires documentation of

the distribution and receipt of human

tissue, completing the accounting of

tissue between determination of

suitability, and the destruction or

disposition of the tissue.

When the interim rule was

promulgated, accredited members of the

American Association of Tissue Banks

and the Eye Bank Association of

America were already in compliance

with the regulations by adhering to the

standards established by these

organizations. The requirements added

to the Final Rule will not impose

additional burden since the members

will be complying with the current

organizations’ standards which are

comparable to the requirements in the

final rule. To account for persons or

establishments that may not be a

member of an industry organization

and, for whom therefore, the extent of

compliance with the requirements of the

final rule is unknown, FDA will be

using 1 percent as an estimation of the

information collection burden on the

tissue industry.

Industry estimates that in 1994 there

were 350,000 bone transplants, 42,000

corneal transplants, 5,000 patellar

tendon transplants, and the

transplantation of 5,000 square feet of

skin. There are approximately 300

persons and 170 tissue banks currently

operating in the United States affected

by the regulations.

TABLE 3.—ESTIMATED ANNUAL RECORDKEEPING BURDEN

21 CFR Section No. of

Recordkeepers

Annual

Frequency per

Recordkeeping

Total Annual

Records

Hours per

Recordkeeper Total Hours

1270.31(a) and 1270.31(b) and 1270.31(c) and

1270.31(d) 11 4 44 28 308

1270.35(a) and 1270.35(b) 11 420 4,620 290 3,190

1270.35(c) 11 2,893 31,823 4,782 52,602

1270.35(d) 11 17 187 17 187

Total 56,287

VI. Environmental Impact

The agency has determined under 21

CFR 25.24(a)(8) that this action is of a

type that does not individually or

cumulatively have a significant effect on

the human environment. Therefore,

neither an environmental assessment

nor an environmental impact statement

is required.
40444 Federal Register / Vol. 62, No. 145 / Tuesday, July 29, 1997 / Rules and Regulations

List of Subjects

21 CFR Part 16

Administrative practice and

procedure.

21 CFR Part 1270

Communicable diseases, HIV/AIDS,

Reporting and recordkeeping

requirements.

Therefore, under the Public Health

Service Act, and under authority

delegated to the Commissioner of Food

and Drugs, 21 CFR parts 16 and 1270 are

amended as follows:

PART 16—REGULATORY HEARING

BEFORE THE FOOD AND DRUG

ADMINISTRATION

1. The authority citation for 21 CFR

part 16 continues to read as follows:

Authority: Secs. 201–903 of the Federal

Food, Drug, and Cosmetic Act (21 U.S.C.

321–394); 21 U.S.C. 41–50, 141–149, 467f,

679, 821, 1034; secs. 2, 351, 361 of the Public

Health Service Act (42 U.S.C. 201, 262, 264);

secs. 2–12 of the Fair Packaging and Labeling

Act (15 U.S.C. 1451–1461); 28 U.S.C. 2112.

2. Section 16.1 is amended in

paragraph (b)(2) by revising the entry for

‘‘§ 1270.15(e) * * *’’ to read as follows:

§ 16.1 Scope.

* * * * *

(b) * * *

(2) * * *

§ 1270.15(e), relating to the retention,

recall, and destruction of human

tissue.

3. Part 1270 is revised to read as

follows:

PART 1270—HUMAN TISSUE

INTENDED FOR TRANSPLANTATION

Subpart A—General Provisions

Sec.

1270.1 Scope.

1270.3 Definitions.

Subpart B—Donor Screening and Testing

1270.21 Determination of donor suitability

for human tissue intended for

transplantation.

Subpart C—Procedures and Records

1270.31 Written procedures.

1270.33 Records, general requirements.

1270.35 Specific records.

Subpart D—Inspection of Tissue

Establishments

1270.41 Inspections.

1270.42 Human tissue offered for import.

1270.43 Retention, recall, and destruction

of human tissue.

Authority: Secs. 215, 311, 361, 368 of the

Public Health Service Act (42 U.S.C. 216,

243, 264, 271).

Subpart A—General Provisions

§ 1270.1 Scope.

(a) The regulations in this part apply

to human tissue and to establishments

or persons engaged in the recovery,

screening, testing, processing, storage,

or distribution of human tissue.

(b) Regulations in this chapter as they

apply to drugs, biologics, devices, or

other FDA-regulated commodities do

not apply to human tissue, except as

specified in this part.

(c) Regulations in this chapter do not

apply to autologous human tissue.

(d) Regulations in this chapter do not

apply to hospitals or other clinical

facilities that receive and store human

tissue only for transplantation within

the same facility.

§ 1270.3 Definitions.

(a) Act for the purpose of this part

means the Public Health Service Act,

section 361 (42 U.S.C. 264).

(b) Blood component means any part

of a single-donor unit of blood separated

by physical or mechanical means.

(c) Colloid means a protein or

polysaccharide solution that can be

used to increase or maintain osmotic

(oncotic) pressure in the intravascular

compartment such as albumin, dextran,

hetastarch; or certain blood

components, such as plasma and

platelets.

(d) Contract services are those

functions pertaining to the recovery,

screening, testing, processing, storage,

or distribution of human tissue that

another establishment agrees to perform

for a tissue establishment.

(e) Crystalloid means a balanced salt

and/or glucose solution used for

electrolyte replacement or to increase

intravascular volume such as saline,

Ringer’s lactate solution, or 5 percent

dextrose in water.

(f) Distribution includes any transfer

or shipment of human tissue (including

importation or exportation), whether or

not such transfer or shipment is entirely

intrastate and whether or not possession

of the tissue is taken.

(g) Donor means a human being,

living or dead, who is the source of

tissue for transplantation.

(h) Donor medical history interview

means a documented dialogue with an

individual or individuals who would be

knowledgeable of the donor’s relevant

medical history and social behavior;

such as the donor if living, the next of

kin, the nearest available relative, a

member of the donor’s household, other

individual with an affinity relationship,

and/or the primary treating physician.

The relevant social history includes

questions to elicit whether or not the

donor met certain descriptions or

engaged in certain activities or

behaviors considered to place such an

individual at increased risk for HIV and

hepatitis.

(i) Establishment means any facility

under one management including all

locations, that engages in the recovery,

screening, testing, processing, storage,

or distribution of human tissue intended

for transplantation.

(j) Human tissue means any tissue

derived from a human body, which:

(1) Is intended for transplantation to

another human for the diagnosis, cure,

mitigation, treatment, or prevention of

any condition or disease;

(2) Is recovered, processed, stored, or

distributed by methods that do not

change tissue function or

characteristics;

(3) Is not currently regulated as a

human drug, biological product, or

medical device;

(4) Excludes kidney, liver, heart, lung,

pancreas, or any other vascularized

human organ; and

(5) Excludes semen or other

reproductive tissue, human milk, and

bone marrow.

(k) Importer of record means the

person, establishment or their

representative responsible for making

entry of imported goods in accordance

with all laws affecting such importation.

(l) Legislative consent means relating

to any of the laws of the various States

that allow the medical examiner or

coroner to procure corneal tissue in the

absence of consent of the donor’s nextof-kin.

(m) Person includes an individual,

partnership, corporation, association, or

other legal entity.

(n) Physical assessment means a

limited autopsy or recent antemortem or

postmortem physical examination of the

donor to assess for any signs of HIV and

hepatitis infection or signs suggestive of

any risk factor for such infections.

(o) Plasma dilution means 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.

(p) Processing means any activity

performed on tissue, other than tissue

recovery, including preparation,

preservation for storage, and/or removal

from storage to assure the quality and/

or sterility of human tissue. Processing

includes steps to inactivate and remove

adventitious agents.

(q) Quarantine means the

identification of human tissue as not

suitable for transplantation, including

human tissue that has not yet been

characterized as being suitable for
Federal Register / Vol. 62, No. 145 / Tuesday, July 29, 1997 / Rules and Regulations 40445

transplantation. Quarantine includes the

storage of such tissue in an area clearly

identified for such use, or other

procedures, such as automated

designation, for prevention of release of

such tissue for transplantation.

(r) Reconstituted blood means the

extracorporeal resuspension of a blood

unit labeled as ‘‘Red Blood Cells’’ by the

addition of colloids and/or crystalloids

to produce a hematocrit in the normal

range.

(s) Recovery means the obtaining from

a donor of tissue that is intended for use

in human transplantation.

(t) Relevant medical records means a

collection of documents including a

donor medical history interview, a

physical assessment of the donor,

laboratory test results, medical records,

existing coroner and autopsy reports, or

information obtained from any source or

records which may pertain to donor

suitability regarding high risk behaviors,

clinical signs and symptoms for HIV

and hepatitis, and treatments related to

medical conditions suggestive of such

risk.

(u) Responsible person means a

person who is authorized to perform

designated functions for which he or

she is trained and qualified.

(v) Storage means holding tissue.

(w) Summary of records means a

condensed version of the required

testing and screening records that

contains the identity of the testing

laboratory, the listing and interpretation

of all required infectious disease tests,

and a listing of the documents reviewed

as part of the relevant medical records,

and the name of the person or

establishment determining the

suitability of the human tissue for

transplantation.

(x) Vascularized means containing the

original blood vessels which are

intended to carry blood after

transplantation.

Subpart B—Donor Screening and Testing

§ 1270.21 Determination of donor

suitability for human tissue intended for

transplantation.

(a) Donor specimens shall be tested

for the following communicable viruses,

using Food and Drug Administration

(FDA) licensed donor screening tests in

accordance with manufacturers’

instructions:

(1) Human immunodeficiency virus,

Type 1 (e.g., FDA licensed screening test

for anti-HIV-1);

(2) Human immunodeficiency virus,

Type 2 (e.g., FDA licensed screening test

for anti-HIV-2);

(3) Hepatitis B (e.g., FDA licensed

screening test for HBsAg); and

(4) Hepatitis C (e.g., FDA licensed

screening test for anti-HCV).

(b) In the case of a neonate, the

mother’s specimen is acceptable for

testing.

(c) Such infectious disease testing

shall be performed by a laboratory

certified under the Clinical Laboratories

Improvement Amendments of 1988

(CLIA).

(d) Human tissue shall be

accompanied by records indicating that

the donor’s specimen has been tested

and found negative using FDA licensed

screening tests for HIV–1, HIV–2,

hepatitis B, and hepatitis C. FDA

licensed screening tests labeled for

cadaveric specimens must be used when

available.

(e) Human tissue for transplantation

shall be accompanied by a summary of

records or copies of the original records

of the donor’s relevant medical records

as defined in § 1270.3(t) which

documents freedom from risk factors for

and clinical evidence of hepatitis B,

hepatitis C, or HIV infection. There shall

be a responsible person designated and

identified in the original record and

summary of records as having made the

determination that the human tissue is

suitable for transplantation.

(f) Determination by the responsible

person that a donor of human tissue

intended for transplantation is suitable

shall include ascertainment of the

donor’s identity, and accurately

recorded relevant medical records (as

defined in § 1270.3(t)) which documents

freedom from risk factors for and

clinical evidence of hepatitis B,

hepatitis C, and HIV infection.

(g) For corneal tissue procured under

legislative consent where a donor

medical history screening interview has

not occurred, a physical assessment of

the donor is required and other

available information shall be reviewed.

The corneal tissue shall be accompanied

by the summary of records documenting

that the corneal tissue was determined

to be suitable for transplantation in the

absence of the donor medical history

interview. Corneal tissue procured

under legislative consent shall be

documented as such in the summary of

records.

(h) Human tissue shall be determined

to be not suitable for transplantation if

from:

(1) A donor whose specimen has

tested repeatedly reactive on a screening

test for HIV, hepatitis B, or hepatitis C;

(2) A donor where blood loss is

known or suspected to have occurred

and transfusion/infusion of more than

2,000 milliliters (mL) of blood (i.e.,

whole blood, reconstituted blood, or red

blood cells), or colloids within 48 hours;

or more than 2,000 mL of crystalloids

within 1 hour; or any combination

thereof prior to the collection of a blood

specimen from the tissue donor for

testing, unless:

(i) A pretransfusion or preinfusion

blood specimen from the tissue donor is

available for infectious disease testing;

or

(ii) An algorithm is utilized that

evaluates the volumes administered in

the 48 hours prior to collecting the

blood specimen from the tissue donor to

ensure that there has not been plasma

dilution sufficient to affect test results;

or

(3) A donor who is 12 years of age or

less and has been transfused or infused

at all, unless:

(i) A pretransfusion or preinfusion

blood specimen from the tissue donor is

available for infectious disease testing;

or

(ii) An algorithm is utilized that

evaluates the volumes administered in

the 48 hours prior to collecting the

blood specimen from the tissue donor to

ensure that there has not been plasma

dilution sufficient to affect test results.

Subpart C—Procedures and Records

§ 1270.31 Written procedures.

(a) There shall be written procedures

prepared and followed for all significant

steps in the infectious disease testing

process under § 1270.21 which shall

conform to the manufacturers’

instructions for use contained in the

package inserts for the required tests.

These procedures shall be readily

available to the personnel in the area

where the procedures are performed

unless impractical. Any deviation from

the written procedures shall be recorded

and justified.

(b) There shall be written procedures

prepared and followed for all significant

steps for obtaining, reviewing, and

assessing the relevant medical records

of the donor as provided in § 1270.21.

Such procedures shall be readily

available to personnel who may perform

the procedures. Any deviation from the

written procedures shall be recorded

and justified.

(c) There shall be written procedures

prepared and followed for designating

and identifying quarantined tissue.

(d) There shall be written procedures

prepared, validated, and followed for

prevention of infectious disease

contamination or cross-contamination

by tissue during processing.

(e) In conformity with this section,

any facility may use current standard

written procedures such as those in a

technical manual prepared by another

organization, provided the procedures
40446 Federal Register / Vol. 62, No. 145 / Tuesday, July 29, 1997 / Rules and Regulations

are consistent with and at least as

stringent as the requirements of this

part.

§ 1270.33 Records, general requirements.

(a) Records shall be maintained

concurrently with the performance of

each significant step required in this

part in the performance of infectious

disease screening and testing of donors

of human tissue. All records shall be

accurate, indelible, and legible. The

records shall identify the person

performing the work, the dates of the

various entries, and shall be as detailed

as necessary to provide a complete

history of the work performed and to

relate the records to the particular tissue

involved.

(b) All human tissue shall be

quarantined until the following criteria

for donor suitability are satisfied:

(1) All infectious disease testing

under § 1270.21 has been completed,

reviewed by the responsible person, and

found to be negative; or

(2) Donor screening has been

completed, reviewed by the responsible

person, and determined to assure

freedom from risk factors for and

clinical evidence of HIV infection,

hepatitis B, and hepatitis C.

(c) All human tissue processed or

shipped prior to determination of donor

suitability must be under quarantine,

accompanied by records assuring

identification of the donor and

indicating that the tissue has not been

determined to be suitable for

transplantation.

(d) All human tissue determined to be

suitable for transplantation must be

accompanied by a summary of records,

or copies of such original records,

documenting that all infectious disease

testing and screening under § 1270.21

has been completed, reviewed by the

responsible person, and found to be

negative, and that the tissue has been

determined to be suitable for

transplantation.

(e) Human tissue shall be quarantined

until the tissue is either determined to

be suitable for transplantation or

appropriate disposition is

accomplished.

(f) All persons or establishments that

generate records used in determining

the suitability of the donor shall retain

such records and make them available

for authorized inspection or upon

request by FDA. The person(s) or

establishment(s) making the

determination regarding the suitability

of the donor shall retain all records, or

true copies of such records required

under § 1270.21, including all testing

and screening records, and shall make

them available for authorized inspection

or upon request from FDA. Records that

can be retrieved from another location

by electronic means meet the

requirements of this paragraph.

(g) Records required under this part

may be retained electronically, or as

original paper records, or as true copies

such as photocopies, microfiche, or

microfilm, in which case suitable reader

and photocopying equipment shall be

readily available.

(h) Records shall be retained at least

10 years beyond the date of

transplantation if known, distribution,

disposition, or expiration, of the tissue,

whichever is latest.

§ 1270.35 Specific records.

Records shall be maintained that

include, but are not limited to:

(a) Documentation of results and

interpretation of all required infectious

disease tests;

(b) Information on the identity and

relevant medical records of the donor,

as required by § 1270.21(e) in English

or, if in another language translated to

English and accompanied by a

statement of authenticity by the

translator which specifically identifies

the translated document;

(c) Documentation of the receipt and/

or distribution of human tissue; and

(d) Documentation of the destruction

or other disposition of human tissue.

Subpart D—Inspection of Tissue

Establishments

§ 1270.41 Inspections.

(a) An establishment covered by these

regulations in this part, including any

location performing contract services,

shall permit an authorized inspector of

the Food and Drug Administration

(FDA) to make at any reasonable time

and in a reasonable manner such

inspection of the establishment, its

facilities, equipment, processes,

products, and records as may be

necessary to determine compliance with

the provisions of this part. Such

inspections may be made with or

without notice and will ordinarily be

made during regular business hours.

(b) The frequency of inspection will

be at the agency’s discretion.

(c) The inspector shall call upon a

responsible person of the establishment

and may question the personnel of the

establishment as the inspector deems

necessary.

(d) The inspector may review and

copy any records required to be kept

pursuant to part 1270.

(e) The public disclosure of records

containing the name or other positive

identification of donors or recipients of

human tissue will be handled in

accordance with FDA’s procedures on

disclosure of information as set forth in

21 CFR part 20 of this chapter.

§ 1270.42 Human tissue offered for import.

(a) When human tissue is offered for

entry, the importer of record must notify

the director of the district of the Food

and Drug Administration having

jurisdiction over the port of entry

through which the tissue is imported or

offered for import, or such officer of the

district as the director may designate to

act in his or her behalf in administering

and enforcing this part.

(b) Human tissue offered for import

must be quarantined until the human

tissue is released by FDA.

§ 1270.43 Retention, recall, and

destruction of human tissue.

(a) Upon a finding that human tissue

may be in violation of the regulations in

this part, an authorized Food and Drug

Administration (FDA) representative

may:

(1) Serve upon the person who

distributed the tissue a written order

that the tissue be recalled and/or

destroyed, as appropriate, and upon

persons in possession of the tissue that

the tissue shall be retained until it is

recalled by the distributor, destroyed, or

disposed of as agreed by FDA, or the

safety of the tissue is confirmed; and/or

(2) Take possession of and/or destroy

the violative tissue.

(b) The written order will ordinarily

provide that the human tissue be

recalled and/or destroyed within 5

working days from the date of receipt of

the order and will state with

particularity the facts that justify the

order.

(c) After receipt of an order under this

part, the person in possession of the

human tissue shall not distribute or

dispose of the tissue in any manner

except to recall and/or destroy the tissue

consistent with the provisions of the

order, under the supervision of an

authorized official of FDA.

(d) In lieu of paragraphs (b) and (c) of

this section, other arrangements for

assuring the proper disposition of the

tissue may be agreed upon by the person

receiving the written order and an

authorized official of FDA. Such

arrangements may include providing

FDA with records or other written

information that adequately assure that

the tissue has been recovered, screened,

tested, processed, stored, and

distributed in conformance with part

1270.

(e) Within 5 working days of receipt

of a written order for retention, recall,

and/or destruction of tissue (or within 5

working days of the agency’s possession
Federal Register / Vol. 62, No. 145 / Tuesday, July 29, 1997 / Rules and Regulations 40447

of such tissue), the recipient of the

written order or prior possessor of such

tissue shall request a hearing on the

matter in accordance with part 16 of this

chapter. The order for destruction will

be held in abeyance pending resolution

of the hearing request.

Dated: July 7, 1997.

Michael A. Friedman,

Lead Deputy Commissioner for the Food and

Drug Administration.

Donna E. Shalala,

Secretary of Health and Human Services.

[FR Doc. 97–19819 Filed 7–28–97; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Part 211

[Docket No. 88N–0320]

Current Good Manufacturing Practice

in Manufacturing, Processing, Packing,

or Holding of Drugs; Revision of

Certain Labeling Controls; Partial

Extension of Compliance Date

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule; partial extension of

compliance date.

SUMMARY: The Food and Drug

Administration (FDA) is announcing a

continuation of the partial extension of

the compliance date for a provision of

the final rule, published in the Federal

Register of August 3, 1993 (58 FR

41348), revising the packaging and

labeling control provisions of the

current good manufacturing practice

(CGMP) regulations for the use of cut

labeling. FDA is extending the date for

compliance with a specific provision, as

it applies to labeling other than

immediate container labels, until the

effective date of the regulation finalizing

the proposed rule on this subject

published elsewhere in this issue of the

Federal Register.

DATES: The date for compliance with the

cut labeling provision at § 211.122(g) (21

CFR 211.122(g)), as it applies to labeling

other than immediate container labels,

is extended until the effective date of

the regulation finalizing the proposed

rule on this subject published elsewhere

in this issue of the Federal Register. The

date for compliance with all other

provisions of the August 3, 1993, final

rule remains August 3, 1994.

FOR FURTHER INFORMATION CONTACT:

Thomas C. Kuchenberg, Center for

Drug Evaluation and Research

(HFD–7), Food and Drug

Administration, 5600 Fishers Lane,

Rockville, MD 20857, 301–594–

5621 (Internet electronic mail:

kuchenbergt@cder.fda.gov), or

Paul J. Motise, Center for Drug

Evaluation and Research (HFD–

325), Food and Drug

Administration, 7500 Standish Pl.,

Rockville, MD 20855, 301–594–

1089 (Internet electronic mail:

motise@cder.fda.gov).

SUPPLEMENTARY INFORMATION: In the

Federal Register of August 3, 1993 (58

FR 41348), FDA published a final rule

amending the current good

manufacturing practice (CGMP)

regulations to require that special

control procedures be instituted if cut

labeling is used in packaging and

labeling operations. One of these

procedures requires the use of

‘‘appropriate electronic or

electromechanical equipment to

conduct a 100-percent examination for

correct labeling during or after

completion of finishing operations’’

(§ 211.122(g)(2)). The rule applied to all

types of labeling, including product

inserts, multiunit containers packaged

in individual containers, and shipping

containers.

In May 1994, FDA received two

citizen petitions from several trade

associations requesting that the agency

extend the effective date of the rule and

reopen the administrative record to

receive additional comments on the

application of § 211.122(g) to items of

labeling other than the immediate

container label. The petitions stated that

additional time was needed to obtain,

install, or validate equipment necessary

to comply with the rule. The citizen

petitions also asserted that the final rule

inappropriately expanded the scope of

§ 211.122(g) from immediate container

labels to all drug product labeling.

In the Federal Register of August 2,

1994 (59 FR 39255), FDA extended the

compliance date for § 211.122(g) as it

applies to labeling other than immediate

container labels, and opened the

administrative record through October

4, 1994, for comments on the scope of

§ 211.122(g). All other provisions of the

final rule became effective on August 3,

1994. FDA further extended the

compliance date to August 2, 1996, in

the Federal Register of April 28, 1995

(60 FR 20897), and to August 1, 1997,

in the Federal Register of July 19, 1996

(61 FR 37679).

Elsewhere in this issue of the Federal

Register, FDA is publishing a proposed

rule that would limit the scope of

§ 211.122(g) to immediate container

labels, individual unit cartons, or

multiunit cartons when immediate

containers are not packaged in

individual cartons. The proposed rule

would also permit the use of any

automated technique, including

differentiation by labeling size and

shape, that physically prevents incorrect

labeling from being processed by

labeling and packaging equipment.

In this final rule, FDA is extending

the date for compliance with

§ 211.122(g), as it applies to labeling

other than immediate container labels,

until the effective date of the regulation

finalizing the proposed rule on this

subject published elsewhere in this

issue of the Federal Register. The date

for compliance with all other provisions

of the August 3, 1993, final rule remains

August 3, 1994.

Dated: July 22, 1997.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 97–19818 Filed 7–28–97; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF THE TREASURY

Internal Revenue Service

26 CFR Part 1

[TD 8726]

RIN 1545–AT95

Requirements for Tax Exempt Section

501(c)(5) Organizations

AGENCY: Internal Revenue Service (IRS),

Treasury.

ACTION: Final regulations.

SUMMARY: This document contains final

regulations clarifying certain

requirements of section 501(c)(5). The

requirements are clarified to provide

needed guidance to organizations on the

requirements an organization must meet

in order to be exempt from tax as an

organization described in section

501(c)(5).

DATES: These regulations are effective

on December 21, 1995.

FOR FURTHER INFORMATION CONTACT:

Robin Ehrenberg, (202) 622–6080 (not a

toll-free number).

SUPPLEMENTARY INFORMATION:

Background

On December 21, 1995, the IRS

published in the Federal Register (60

FR 66228) a notice of proposed

rulemaking under section 501(c)(5). The

proposed regulations clarified that

organizations whose principal activity is

administering retirement plans are not

section 501(c)(5) organizations.