[Federal Register: July 29, 1997 (Volume 62, Number 145)]
[Rules and Regulations]               
[Page 40429-40447]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr29jy97-3]

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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.

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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

[[Page 40430]]

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 above-mentioned 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 product-by-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

[[Page 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                                                                     Additional exemptions added.        
  1270.1(a)(b)(c)(d)                  1270.1(a)(b)                                                              
----------------------------------------------------------------------------------------------------------------
  Definitions                                                               Definitions added for:              
  1270.3(a)-(x)                       1270.3(a)-(i)                         (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                                                 Renumbered. Clarification of (e)    
   Transplantation                    1270.5(a)-(f)                          summary of records, addition of (b)
  1270.21(a)-(h)                                                             testing of neonate donor (g)       
                                                                             standards for corneal retrieval,   
                                                                             and (h) plasma dilution.           
----------------------------------------------------------------------------------------------------------------
Subpart C--Procedures and Records                                                                               
----------------------------------------------------------------------------------------------------------------
  Written Procedures                                                        Renumbered. Original paragraph (c)  
  1270.31(a)-(e)                      1270.7(a)-(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.                 

[[Page 40432]]

                                                                                                                
  Records, General Requirements                                             Renumbered. Paragraphs (c) and (d)  
  1270.33(a)-(h)                      1270.9(a)-(e)                          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                                                          Renumbered. Original paragraphs (b) 
  1270.35(a)-(d)                      1270.11(a)-(c)                         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                                                                Renumbered.                         
  1270.41(a)-(e)                      1270.13(a)-(e)                                                            
----------------------------------------------------------------------------------------------------------------
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 Sec. 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,

[[Page 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 Sec. 1270.3 (21 CFR 
1270.3). FDA has revised Sec. 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 industry-affiliated 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 (Sec. 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 Sec. 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 
Sec. 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 (Sec. 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'' (Sec. 1270.3(f) 
of the final rule). The definition of ``processing'' (Sec. 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'' (Sec. 1270.3(q) of the final 
rule). The definition of ``storage'' (Sec. 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'' 
(Sec. 1270.3(x) of the final rule).
    10. One comment suggested that the rule apply to normal human cells 
such

[[Page 40434]]

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 Sec. 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 Sec. 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 Sec. 1270.3(b) of the 
interim rule (Sec. 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 (Sec. 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 Sec. 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 Sec. 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

[[Page 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 Sec. 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 Sec. 1270.5(a) (Sec. 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 Sec. 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 Sec. 1270.5(b) (Sec. 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) (Sec. 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 Sec. 1270.5(d)(1) 
Sec. 1270.21(h)(2) in the final rule) to use the term ``plasma 
dilution.''
    21. Two comments on Sec. 1270.5(d) (Sec. 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 Sec. 1270.5(d)(1) (Sec. 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 Sec. 1270.5(d)(1) (Sec. 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

[[Page 40436]]

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 Sec. 1270.5(d)(2) (Sec. 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,Sec. 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 Sec. 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             
------------------------------------------------------------------------
                       Product(s)      Hours prior to     Calculated\1\ 
 Category infused     included in         specimen           volume     
                        category         collection       administered  
------------------------------------------------------------------------
Blood              Blood unit         Within 48 hours   > one blood     
                    labeled as                           volume         
                    ``Whole Blood,''                                    
                    Blood unit                                          
                    labeled as ``Red                                    
                    Blood Cells,''                                      
                     Reconstituted                                      
                    blood\2\                                            
------------------------------------------------------------------------
Colloid            Plasma,            Within 48 hours   > one plasma    
                    platelets,                           volume         
                    albumin,                                            
                    hetastarch,                                         
                    dextran                                             
------------------------------------------------------------------------
Crystalloid        Saline, dextrose   Within 1 hour     > one plasma    
                    in water,                            volume         
                    Ringer's                                            
                    lactate, other                                      
                    balanced                                            
                    electrolyte                                         
                    solutions                                           
------------------------------------------------------------------------
Blood and          See all of the     Within 48 hours   > one blood     
 colloids           above             and within 1       volume (or if  
  and/or                               hour              the calculated 
 crystalloids                                            volume for     
                                                         colloids only, 
                                                         within 48 hours
                                                         of collection  
                                                         and/or         
                                                         crystalloids   
                                                         within 1 hour  
                                                         of collection  
                                                         is > one plasma
                                                         volume)        
------------------------------------------------------------------------
Colloids           See above for      Within 48 hours   > one plasma    
  and               colloid and       and within 1       volume         
 crystalloids       crystalloid        hour                             
------------------------------------------------------------------------
\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.''                                

[[Page 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) (Sec. 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 Sec. 1270.21. FDA has included a definition 
for ``relevant medical records'' in Sec. 1270.3(t) which is consistent 
with the comment.
    27. Twenty comments on Sec. 1270.5(e) (Sec. 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 Sec. 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 
Sec. 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 Sec. 1270.5(f) (Sec. 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 
Sec. 1270.5(f). Human tissue that is determined to be suitable for 
transplantation per Sec. 1270.9(b) (Sec. 1270.21(e) of the final rule) 
must be accompanied by copies of original records, indicating that all 
infectious disease testing and screening under Sec. 1270.5 
(Sec. 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 (Sec. 1270.31)
    Section 1270.7 (Sec. 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 Sec. 1270.31(c) and (d) requiring written 
procedures for the designation and identification of quarantined 
tissue, and for the prevention of contamination or cross-contamination 
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 cross-contamination 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 Secs. 1270.7(a) and 1270.9(a) are 
the responsibility of the laboratory where the tests are run.
    FDA has amended the requirements of Sec. 1270.9 (Sec. 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

[[Page 40438]]

determination of suitability for transplantation. FDA believes that the 
person (as defined in Sec. 1270.3(m) of the final rule) or 
establishment (as defined in Sec. 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 Sec. 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 Sec. 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 Sec. 1270.7(c) (Sec. 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 Sec. 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 (Sec. 1270.33) and Specific records 
(Sec. 1270.35)
    Sections 1270.9 and 1270.11 of the interim rule (Secs. 1270.33 and 
1270.35, respectively of the final rule) set forth the general and 
specific requirements for the maintenance of records. Under 
Sec. 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 Sec. 1270.9(c) (Sec. 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 
(Sec. 1270.35(a) and (b)) and the final disposition of the human tissue 
(Sec. 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 
Sec. 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 
Sec. 1270.9(c) (Sec. 1270.33(f) of the final rule) to require the 
maintenance of records under Sec. 1270.5 (Sec. 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 Sec. 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

[[Page 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 (Sec. 1270.41)
    Section 1270.13 (Sec. 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 Sec. 1270.13 (Sec. 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 Sec. 1270.13(e) (redesignated as Sec. 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 Sec. 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 (Sec. 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 Sec. 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 Secs. 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 Sec. 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 Sec. 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 Sec. 1270.43 of the final 
rule.
10. Retention, Recall, and Destruction of Human Tissue (Sec.  1270.43)
    Section 1270.15 of the interim rule (Sec. 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 Sec. 1270.15 (Sec. 1270.43 of the final rule) 
requested that the rule be clarified to state that

[[Page 40440]]

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 Sec. 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 
Sec. 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 
Sec. 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 Sec. 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

[[Page 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 Sec. 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 Sec. 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 
Sec. 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

[[Page 40442]]

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 (Sec. 1270.31(c)); written and validated procedures 
for the prevention of contamination or cross-contamination of tissues 
during processing (Sec. 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.

[[Page 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 
Sec. 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                                
----------------------------------------------------------------------------------------------------------------
                                                      Annual                                                    
         21 CFR Section               No. of       Frequency per   Total Annual      Hours per      Total Hours 
                                   Recordkeepers   Recordkeeping      Records      Recordkeeper                 
----------------------------------------------------------------------------------------------------------------
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.

[[Page 40444]]

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 ``Sec. 1270.15(e) * * *'' to read as follows:

Sec. 16.1  Scope.

* * * * *
    (b) * * *
    (2) * * *
Sec. 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


Sec. 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.


Sec. 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 next-of-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

[[Page 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


Sec. 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 Sec. 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 Sec. 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


Sec. 1270.31  Written procedures.

    (a) There shall be written procedures prepared and followed for all 
significant steps in the infectious disease testing process under 
Sec. 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 Sec. 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

[[Page 40446]]

are consistent with and at least as stringent as the requirements of 
this part.


Sec. 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 Sec. 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 Sec. 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 Sec. 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.


Sec. 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 Sec. 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


Sec. 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.


Sec. 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.


Sec. 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

[[Page 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