[Federal Register: October 23, 2003 (Volume 68, Number 205)]
[Notices]
[Page 60697-60701]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr23oc03-51]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
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.
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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
0910-0456)--Extension
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
(3.2.7.1); (2) aliquots of serum samples from randomly selected animal
and specific disease investigations (3.4.3.1); (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
xenotransplantation.
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
------------------------------------------------------------------------
3.2.7.2 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.
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4.3 Sponsor to maintain cross-referenced system
that links all relevant records
(recipient, product, source animal, animal
procurement center, and nosocomial
exposures).
------------------------------------------------------------------------
3.4.2 Document results of monitoring program used
to detect introduction of infectious
agents which may not be apparent
clinically.
------------------------------------------------------------------------
3.4.3.2 Document full necropsy investigations
including evaluation for infectious
etiologies.
------------------------------------------------------------------------
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.
------------------------------------------------------------------------
4.2.3.2 Record base-line sera of
xenotransplantation health care workers
and specific nosocomial exposure.
------------------------------------------------------------------------
4.2.3.3 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\
------------------------------------------------------------------------
Annual
PHS Guideline No. of Frequency Total Hours per Total
Section Respondents per Annual Response Hours
Response Responses
------------------------------------------------------------------------
3.2.7.2\2\ 18 0 0 0.5 0
------------------------------------------------------------------------
3.2.7.2\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
12.
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
------------------------------------------------------------------------
3.4.3.2\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
------------------------------------------------------------------------
4.2.3.2\8\ 12 25 300 0.17 51.0
------------------------------------------------------------------------
[[Page 60700]]
4.2.3.2\6\ 12 0.08 (0-1) 1 0.17 0.17
------------------------------------------------------------------------
4.2.3.3 12 0.08 (0-1) 1 0.17 0.17
and
4.3.2\6\
------------------------------------------------------------------------
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
annually.
\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
records.
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
Standards
------------------------------------------------------------------------
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
animals
------------------------------------------------------------------------
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
Policy\1\
------------------------------------------------------------------------
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
conditions
------------------------------------------------------------------------
3.6.2 Develop, implement, and enforce SOPs 211.84(d) and
for procurement and screening 211.122(c)
processes
------------------------------------------------------------------------
3.6.4 Communicate to FDA animal necropsy 312.32(c)
findings pertinent to health of
recipient
------------------------------------------------------------------------
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
------------------------------------------------------------------------
4.1.2.2 System for prompt retrieval of PHS 312.57(a)
specimens and linkage to medical
records (recipient and source
animal)
------------------------------------------------------------------------
4.1.2.3 Notify FDA of a clinical episode 312.32
potentially representing a
xenogeneic infection
------------------------------------------------------------------------
4.2.2.1 Document collaborations (transfer of 312.52
obligation)
------------------------------------------------------------------------
4.2.3.1 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''
(1996).
Dated: October 16, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-26739 Filed 10-22-03; 8:45 am]
BILLING CODE 4160-01-S