[Federal Register: October 23, 2003 (Volume 68, Number 205)]
[Page 60697-60701]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]



Food and Drug Administration

[Docket No. 2003N-0269]

Agency Information Collection Activities; Submission for Office 
of Management and Budget Review; Comment Request; Infectious Disease 
Issues in Xenotransplantation

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.


SUMMARY: The Food and Drug Administration (FDA) is announcing that a 
proposed collection of information has been submitted to the Office of 
Management and Budget (OMB) for review and clearance under the 
Paperwork Reduction Act of 1995 (the PRA).

DATES: Fax written comments on the collection of information by 
November 24, 2003.

ADDRESSES: OMB is still experiencing significant delays in the regular 
mail, including first class and express mail, and messenger deliveries 
are not being accepted. To ensure that comments on the information 
collection are received, OMB recommends that written comments be faxed 
to the Office of Information and Regulatory Affairs, OMB, Attn: Fumie 
Yokota, Desk Officer for FDA, FAX: 202-395-6974.

FOR FURTHER INFORMATION CONTACT: JonnaLynn P. Capezzuto, Office of 
Management Programs (HFA-250), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-4659.

SUPPLEMENTARY INFORMATION: In compliance with 44 U.S.C. 3507, FDA has 
submitted the following proposed collection of information to OMB for 
review and clearance.

Infectious Disease Issues in Xenotransplantation--(OMB Control Number 

    The statutory authority to collect this information is provided 
under sections 351 and 361 of the PHS Act (42 U.S.C. 262 and 264) and 
under the provisions of the Federal Food, Drug, and Cosmetic Act that 
apply to drugs (21 U.S.C. 301 et seq.). The PHS guideline recommends 
procedures to diminish the risk of transmission of infectious agents to 
the xenotransplantation product recipient and the general public. The 
PHS guideline is intended to address public health issues raised by 
xenotransplantation, through identification of general principles of 
prevention and control of infectious diseases associated with 
xenotransplantation that may pose a hazard to the public health. The 
collection of information described in this guideline is intended to 
provide general guidance to sponsors in: (1) The development of 
xenotransplantation clinical protocols, (2) the preparation of 
submissions to FDA, and (3) the conduct of xenotransplantation clinical 
trials. Also, the collection of information will help ensure that the 
sponsor maintains important information in a cross-referenced system 
that links the relevant records of the xenotransplantation product 
recipient, xenotransplantation product, source animal(s), animal 
procurement center, and significant nosocomial exposures. The PHS 
guideline describes an occupational health service program for the 
protection of health care workers involved in xenotransplantation 
procedures, caring for xenotransplantation product recipients, and 
performing associated laboratory

[[Page 60698]]

testing. The guideline also describes public health needs for: (1) A 
national xenotransplantation database, which is currently under 
development by the PHS; (2) a central PHS biologic specimen archive, 
also under consideration; and (3) the Secretary's Advisory Committee on 
Xenotransplantation, which was developed and has been implemented by 
the Department of Health and Human Services. These public health 
programs and the PHS guideline are intended to protect the public 
health and to help ensure the safety of using xenotransplantation 
products in humans by preventing the introduction, transmission, and 
spread of infectious diseases associated with xenotransplantation.
    The PHS guideline also recommends that certain specimens and 
records be maintained for 50 years beyond the date of the 
xenotransplantation. These include: (1) Records linking each 
xenotransplantation product recipient with relevant health records of 
the source animal, herd or colony, and the specific organ, tissue, or 
cell type included in or used in the manufacture of the product 
(; (2) aliquots of serum samples from randomly selected animal 
and specific disease investigations (; (3) source animal 
biological specimens designated for PHS use (3.7.1); animal health 
records (3.7.2), including necropsy results (3.6.4); and (4) 
recipients' biological specimens (4.1.2).
    The retention period is intended to assist health care 
practitioners and officials in surveillance and in tracking the source 
of an infection, disease, or illness that might emerge in the 
recipient, the source animal, or the animal herd or colony after a 
    The recommendation for maintaining records for 50 years is based on 
clinical experience with several human viruses that have presented 
problems in human to human transplantation and are therefore thought to 
share certain characteristics with viruses that may pose potential 
risks in xenotransplantation. These characteristics include long 
latency periods and the ability to establish persistent infections. 
Several also share the possibility of transmission among individuals 
through intimate contact with human body fluids. Human immunodeficiency 
virus (HIV) and Human T-lymphotropic virus are human retroviruses. 
Retroviruses contain ribonucleic acid that is reverse-transcribed into 
deoxyribonucleic acid (DNA) using an enzyme provided by the virus and 
the human cell machinery. That viral DNA can then be integrated into 
the human cellular DNA. Both viruses establish persistent infections 
and have long latency periods before the onset of disease, 10 years and 
40 to 60 years, respectively. The human hepatitis viruses are not 
retroviruses, but several share with HIV the characteristic that they 
can be transmitted through body fluids, can establish persistent 
infections, and have long latency periods, e.g., approximately 30 years 
for Hepatitis C.
    In addition, the PHS guideline recommends that a record system be 
developed that allows easy, accurate, and rapid linkage of information 
among the specimen archive, the recipient's medical records, and the 
records of the source animal for 50 years. The development of such a 
record system is a one-time burden. Such a system is intended to cross-
reference and locate relevant records of recipients, products, source 
animals, animal procurement centers, and nosocomial exposures.
    Respondents to this collection of information are the sponsors of 
clinical studies of investigational xenotransplantation products under 
investigational new drug applications (INDs) and xenotransplantation 
product procurement centers, referred to as source animal facilities. 
Currently, there are 12 respondents who are sponsors of INDs that 
include protocols for xenotransplantation in humans. Other respondents 
for this collection of information are 18 source animal facilities 
which provide source xenotransplantation product material to sponsors 
for use in human xenotransplantation procedures. These 18 source animal 
facilities keep medical records of the herds/colonies as well as the 
medical records of the individual source animal(s). The total annual 
reporting and recordkeeping burden is estimated to be approximately 156 
hours. The burden estimates are based on FDA's records of 
xenotransplantation-related INDs and estimates of time required to 
complete the various reporting and recordkeeping tasks described in the 
guideline. FDA does not expect the level of clinical studies using 
xenotransplantation to increase significantly in the next few years.
    FDA is requesting an extension of OMB approval for the following 
reporting and recordkeeping recommendations in the PHS guideline:

                   Table 1.--Reporting Recommendations
   PHS Guideline  Section                    Description
------------------------------------------------------------------------                      Notify sponsor or FDA of new archive site
                              when the source animal facility or sponsor
                              ceases operations.
3.4                          Standard operating procedures (SOPs) of
                              source animal facility should be available
                              to review bodies.
3.5.1                        Include increased infectious risk in
                              informed consent if source animal
                              quarantine period of 3 weeks is shortened.
3.5.4                        Sponsor to make linked records described in
                              section 3.2.7 available for review.
3.5.5                        Source animal facility to notify clinical
                              center when infectious agent is identified
                              in source animal or herd after
                              xenotransplantation product procurement.

                 Table 2.--Recordkeeping Recommendations
   PHS Guideline  Section                    Description
3.2.7                        Establish records linking each
                              xenotransplantation product recipient with
                              relevant records.
4.3                          Sponsor to maintain cross-referenced system
                              that links all relevant records
                              (recipient, product, source animal, animal
                              procurement center, and nosocomial
3.4.2                        Document results of monitoring program used
                              to detect introduction of infectious
                              agents which may not be apparent
------------------------------------------------------------------------                      Document full necropsy investigations
                              including evaluation for infectious
3.5.1                        Justify shortening a source animal's
                              quarantine period of 3 weeks prior to
                              xenotransplantation product procurement.

[[Page 60699]]

3.5.2                        Document absence of infectious agent in
                              xenotransplantation product if its
                              presence elsewhere in source animal does
                              not preclude using it.
3.5.4                        Add summary of individual source animal
                              record to permanent medical record of the
                              xenotransplantation product recipient.
3.6.4                        Document complete necropsy results on
                              source animals (50-year record retention).
3.7                          Link xenotransplantation product recipients
                              to individual source animal records and
                              archived biologic specimens.
------------------------------------------------------------------------                      Record base-line sera of
                              xenotransplantation health care workers
                              and specific nosocomial exposure.
------------------------------------------------------------------------ and                  Keep a log of health care workers'
4.3.2                         significant nosocomial exposure(s).
4.3.1                        Document each xenotransplant procedure.
5.2                          Document location and nature of archived
                              PHS specimens in health care records of
                              xenotransplantation product recipient and
                              source animal.

    In the Federal Register of July 10, 2003 (FR 68 41153), FDA 
published a 60-day notice requesting public comment on the information 
collection provisions. No comments were received.

             Table 3.--Estimated Annual Reporting Burden\1\
PHS Guideline      No. of      Frequency     Total    Hours per   Total
   Section      Respondents       per       Annual     Response   Hours
                               Response    Responses
------------------------------------------------------------------------\2\     18             0           0           0.5        0
------------------------------------------------------------------------\2\     2              1           2           0.5        1.0
3.4\3\         12             0.33        4           0.08       0.32
3.5.1\4\       12             0.08        (0-1) 1     0.25       0.25
3.5.4\5\       12             1           12          0.5        6.0
3.5.5\4\       18             0.06        (0-1) 1     0.2        0.2
Total                                                            7.77
\1\There are no capital costs or operating and maintenance costs
  associated with this collection of information.
\2\No animal facility and 2 sponsors have ceased operations in the last
  3 years.
\3\FDA's records indicate that an average of 4 INDs are expected to be
  submitted per year.
\4\Has not occurred in the past 3 years and is expected to continue to
  be a rare occurrence.
\5\Based on 36 patients treated over a 3 year period, the average number
  of xenotransplantation product recipients per year is estimated to be

           Table 4.--Estimated Annual Recordkeeping Burden\1\
    PHS                         Annual      Total
 Guideline       No. of     Frequency per   Annual    Hours per    Total
  Section    Recordkeepers  Recordkeeping  Records  Recordkeeper   Hours
3.2.7\2\     1              1              1        16            16.0
4.3\3\       12             1              12       0.83          9.96
3.4.2\4\     12             11             132      0.25          33.0
------------------------------------------------------------------------\5\   18             4              72       0.3           21.6
3.5.1\6\     12             0.08           (0-1) 1  0.5           0.5
3.5.2\6\     12             0.08           (0-1) 1  0.25          0.25
3.5.4        12             1              12       0.17          2.04
3.6.4\7\     12             2              24       0.25          6.0
3.7\7\       18             1.33           24       0.08          1.92
------------------------------------------------------------------------\8\   12             25             300      0.17          51.0

[[Page 60700]]\6\   12             0.08           (0-1) 1  0.17          0.17
------------------------------------------------------------------------      12             0.08           (0-1) 1  0.17          0.17
4.3.1        12             1              12       0.25          3.0
5.2\9\       12             3              36       0.08          2.88
Total                                                             148.49
\1\There are no capital costs or operating and maintenance costs
  associated with this collection of information.
\2\A one-time burden for new respondents to set up a recordkeeping
  system linking all relevant records. FDA estimates 1 new sponsor
\3\FDA estimates there is minimal recordkeeping burden associated with
  maintaining the record system.
\4\Monitoring for sentinel animals (subset representative of herd) plus
  all source animals. There are approximately 6 sentinel animals per
  herd x 1 herd per facility x 18 facilities = 108 sentinel animals.
  There are approximately 24 source animals per year (see footnote 7 of
  this table 4); 108 + 24 = 132 monitoring records to document.
\5\Necropsy for animal deaths of unknown cause estimated to be
  approximately 4 per herd per year x 1 herd per facility x 18
  facilities = 72.
\6\Has not occurred in the past 3 years and is expected to continue to
  be a rare occurrence.
\7\On average 2 source animals are used for preparing
  xenotransplantation product material for one recipient. The average
  number of source animals is 2 source animals per recipient x 12
  recipients annually = 24 source animals per year. (See footnote 5 of
  table 3 of this document.)
\8\FDA estimates there are approximately 12 clinical centers doing
  xenotransplantation procedures x approximately 25 health care workers
  involved per center = 300 health care workers.
\9\Twenty-four source animal records + 12 recipient records = 36 total

    Because of the potential risk for cross-species transmission of 
pathogenic persistent virus, the guideline recommends that health 
records be retained for 50 years. Since these records are medical 
records, the retention of such records for up to 50 years is not 
information subject to the PRA (5 CFR 1320.3(h)(5)). Also, because of 
the limited number of clinical studies with small patient populations, 
the number of records is expected to be insignificant at this time.
    Information collections in this guideline, not included in tables 1 
through 4 of this document, can be found under existing regulations and 
approved under the OMB control numbers as follows: (1) ``Current Good 
Manufacturing Practice for Finished Pharmaceuticals,'' 21 CFR 211.1 
through 211.208, approved under OMB control number 0910-0139; (2) 
``Investigational New Drug Application,'' 21 CFR 312.1 through 312.160, 
approved under OMB control number 0910-0014; and (3) information 
included in a license application, 21 CFR 601.2, approved under OMB 
control number 0910-0338. (Although it is possible that a 
xenotransplantation product may not be regulated as a biological 
product (e.g., it may be regulated as a medical device), FDA believes, 
based on its knowledge and experience with xenotransplantation, that 
any xenotransplantation product subject to FDA regulation within the 
next 3 years will most likely be regulated as a biological product.) 
However, FDA recognized that some of the information collections go 
beyond approved collections; assessments for these burdens are included 
in tables 1 through 4 of this document.
    In table 5 of this document, FDA identifies those collection of 
information activities that are already encompassed by existing 
regulations or are consistent with voluntary standards which reflect 
industry's usual and customary business practice.

 Table 5.--Collection of Information Required by Current Regulations and
                                                        21 CFR Section
    21 CFR         Description of Collection of       (unless otherwise
   Section             Information Activity                stated)
2.2.1          Document off-site collaborations      312.52
2.5            Sponsor ensure counseling patient +   312.62(c)
                family + contacts
3.1.1 and      Document well-characterized health    312.23(a)(7)(a) and
 3.1.6          history and lineage of source         211.84
3.1.8          Registration with and import permit   42 CFR 71.53
                from the Centers for Disease
                Control and Prevention
3.2.2          Document collaboration with           312.52
                accredited microbiology labs
3.2.3          Procedures to ensure the humane care  9 CFR parts 1, 2,
                of animals                            and 3 and PHS
3.2.4          Procedures consistent for             AAALAC
                accreditation by the Association      International
                for Assessment and Accreditation of   Rules of
                Laboratory Animal Care                Accreditation\2\
                International (AAALAC                 and NRC Guide\3\
                International) and consistent with
                the National Research Council's
                (NRC) Guide

[[Page 60701]]

3.2.5, 3.4,    Herd health maintenance and           211.100 and 211.122
 and 3.4.1      surveillance to be documented,
                available, and in accordance with
                documented procedures; record
                standard veterinary care
3.2.6          Animal facility SOPs                  PHS Policy\1\
3.3.3          Validate assay methods                211.160(a)
3.6.1          Procurement and processing of         211.100 and 211.122
                xenografts using documented aseptic
3.6.2          Develop, implement, and enforce SOPs  211.84(d) and
                for procurement and screening         211.122(c)
3.6.4          Communicate to FDA animal necropsy    312.32(c)
                findings pertinent to health of
3.7.1          PHS specimens to be linked to health  312.23(a)(6)
                records; provide to FDA
                justification for types of tissues,
                cells, and plasma, and quantities
                of plasma and leukocytes collected
4.1.1          Surveillance of xenotransplant        312.23(a)(6)(iii)(f
                recipient; sponsor ensures            ) and (g), and
                documentation of surveillance         312.62(b) and (c)
                program life-long (justify 2 yrs.); investigator case
                histories (2 yrs. after
                investigation is discontinued)
4.1.2          Sponsor to justify amount and type    211.122
                of reserve samples
------------------------------------------------------------------------        System for prompt retrieval of PHS    312.57(a)
                specimens and linkage to medical
                records (recipient and source
------------------------------------------------------------------------        Notify FDA of a clinical episode      312.32
                potentially representing a
                xenogeneic infection
------------------------------------------------------------------------        Document collaborations (transfer of  312.52
------------------------------------------------------------------------        Develop educational materials         312.50
                (sponsor provides investigators
                with information needed to conduct
                investigation properly)
4.3            Sponsor to keep records of receipt,   312.57 and
                shipment, and disposition of          312.62(b)
                investigative drug; investigator to
                keep records of case histories
\1\The ``Public Health Service Policy on Humane Care and Use of
  Laboratory Animals'' (http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.grants.nih.gov/grants/olaw/references/
  phspol.htm). (FDA has verified the Web site address, but is not
  responsible for subsequent changes to the Web site after this document
  publishes in the Federal Register.)
\2\AAALAC International Rules of Accreditation (http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.aaalac.org).
  (FDA has verified the Web site address, but is not responsible for
  subsequent changes to the Web site after this document publishes in
  the Federal Register.)
\3\The NRC's ``Guide for the Care and Use of Laboratory Animals''

    Dated: October 16, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-26739 Filed 10-22-03; 8:45 am]