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 Department of Health and Human Services Food and Drug Administration [Docket No. 96M-0311]
 AGENCY: Food and Drug Administration, HHS.
 ACTION: Notice.
 SUMMARY: The Food and Drug Administration (FDA) is announcing an opportunity for public comment on the proposed collection of certain information by the agency. Under the Paperwork Reduction Act of 1995 (the PRA), Federal agencies are required to publish notice in the 
                        **Federal Register**
                         concerning each proposed collection of information, and to allow 60 days for public comment in response to the notice. This notice solicits comments on the collection of information contained in the Public Health Service (PHS) guideline entitled “PHS Guideline on Infectious Disease Issues in Xenotransplantation.”
 DATES: Submit written comments on the collection of information by July 25, 2002.
 ADDRESSES: Submit written requests for single copies of the guideline entitled “PHS Guideline on Infectious Disease Issues in Xenotransplantation” to the Office of Communication, Training, and Manufacturers Assistance (HFM-40), Center for Biologics Evaluation and Research (CBER), Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852-1448. Send one self-addressed adhesive label to assist that office in processing your requests. The document may also be obtained by mail by calling the CBER Voice Information System at 1-800-835-4709 or 301-827-1800, or by fax by calling the FAX Information System at 1-888-CBER-FAX or 301-827-3844. Submit written comments on the collection of information to the Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number found in brackets in the heading of this document.
 FOR FURTHER INFORMATION CONTACT: Karen L. Nelson, Office of Information Resources Management (HFA-250), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-1482.


SUPPLEMENTARY INFORMATION: I. Background Under the PRA (44 U.S.C. 3501-3520), Federal agencies must obtain approval from the Office of Management and Budget (OMB) for each collection of information they conduct or sponsor. “Collection of information” is defined in 44 U.S.C. 3502(3) and 5 CFR 1320.3(c) and includes agency request or requirements that members of the public submit reports, keep records, or provide information to a third party. Section 3506(c)(2)(A) of the PRA (44 U.S.C. 3506(c)(2)(A)) requires Federal agencies to provide a 60-day notice in the 
                    **Federal Register**
                     concerning each proposed collection of information, before submitting the collection to OMB for approval. To comply with this requirement, FDA is publishing notice of the proposed collection of information set forth in this document. With respect to the following collection of information, FDA 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. PHS Guideline on Infectious Disease Issues in Xenotransplantation 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 the provisions of the Federal Food, Drug, and Cosmetic Act that apply to drugs (21 U.S.C. 301 et seq.). This PHS guideline is revised based on public comment to a previous document entitled “Draft Public Health Service (PHS) Guideline on Infectious Disease Issues in Xenotransplantation (August 1996),” which published in the 
                    **Federal Register**
                     of September 23, 1996 (61 FR 49919). 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 
                    ( print page 34197)
                    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 testing. The guideline also describes public health needs for: (1) A pilot national xenotransplant data base, which is currently under development by the PHS; (2) a central PHS biologic specimen archive; and (3) the Secretary's Advisory Committee on Xenotransplantation (SACX), which is being developed and implemented by the Department of Health and Human Services (DHHS). These public health programs and this PHS guideline are intended to protect the public health and help ensure the safety of using xenotransplantation products in humans by preventing the introduction, transmission, and spread of infectious diseases associated with xenotransplantation. Respondents to this collection of information are the sponsors of clinical studies of investigational xenotransplantation products under investigational new drug applications (IND's) and xenotransplantation product procurement centers, referred to as source animal facilities. Currently, there are 11 respondents who are sponsors of IND's, which 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 PHS guideline proposes 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. Although the draft guideline discussed holding specimens and records indefinitely, comments described this recommendation as impractical and unfeasible. 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. They contain ribonucleic acid that is reverse-transcribed into deoxyribonucleic acid (DNA) using an enzyme provided by the virus and the cell machinery. That DNA can then be integrated into the 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. If record systems are maintained in a computer data base, electronic backups should be kept in a secure office facility and backup on hard copy should be routinely performed (4.1.2.2). The development of such a record system would be a one-time burden. Such a system is intended to cross-reference and locate relevant records or recipients, source animals and facilities, and specimens of both the recipient and the source animal. Based on agency experience in establishing new, small volume, recordkeeping and tracking systems, we estimate approximately 16 hours would be necessary for each sponsor to set up the records system. The total annual reporting and recordkeeping burden is estimated to be approximately 327 hours. The burden estimates are based on FDA's records of xenotransplantation-related IND's and estimates of time required to create an appropriate record system and to complete the various reporting and recordkeeping tasks described in the guideline. A total of 22 IND's have been submitted since 1994 resulting in an average of 4 IND submissions per year. A total of 87 patients have been treated over a 3-year period indicating there are on average 29 xenotransplantation product recipients per year. FDA does not expect the level of clinical studies using xenotransplantation to increase significantly in the next few years; therefore, the agency is using these historical figures in projecting burdens for the next 3 years. FDA is requesting OMB approval for the following reporting and recordkeeping recommendations in the PHS guideline: **Table**
                         1.—
                        **Reporting Recommendations**
PHS Guideline Section
Description3.2.7.2
Notify sponsor or FDA of new archive site when source animal facility or sponsor ceases operations.3.4
Standard operating procedures (SOP's) 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.( print page 34198)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
Description3.2.7 and 4.3
Establish records linking each xenotransplantation product recipient with relevant records. 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.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 4.3.2
Keep a log of health care workers' 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.
 FDA estimates the burden for this collection of information as follows: **Table**
                         3.—
                        **Estimated Annual Reporting Burden1**
PHS Guideline Section
No. of 
                             Respondents
Annual 
                             Frequency per  
                             Response
Total Annual 
                             Responses
Hours per 
                             Response
Total Hours3.2.7.22
18
0
0
0.5
03.2.7.22
11
0
0
0.5
03.43
11
0.4
4
0.08
0.33.5.14
11
0.09
1
0.25
0.253.5.45
11
2.6
29
0.5
14.53.5.54
18
0.06
1
0.2
0.2Total




15.251
                         There are no capital costs or operating and maintenance costs associated with this collection of information.2
                         No animal facility or sponsor has ceased operations to date and none are expected to cease operation in the next several years.3
                         FDA's records indicate that an average of four IND's have been and are expected to be submitted per year.4
                         Has not occurred in the past 5 years and is expected to continue to be a rare occurrence.5
                         Based on 87 patients treated over the last 3 years, the average number of xenotransplantation product recipients per year is estimated to be 29.
 **Table**
                         4.—
                        **Estimated Annual Recordkeeping Burden1**
PHS Guideline Section
No. of 
                             Recordkeepers
Annual 
                             Frequency per  
                             Recordkeeping
Total Annual 
                             Records
Hours per 
                             Recordkeeper
Total Hours3.2.7 and 4.32
11
1
N/A
16
1723.4.23
11
15.1
166
3.77
41.53.4.3.24
18
4.0
72
1.32
23.83.5.15
11
0.09
(0-1)1
0.045
0.53.5.25
11
0.09
(0-1)1
0.023
0.253.5.4
11
2.6
29
0.45
4.93.6.46
11
5.3
58
1.32
14.53.76
18
3.2
58
0.26
4.64.2.3.27
11
27.3
300
4.64
514.2.3.25
11
0.09
(0-1)1
0.015
0.174.2.3.3 and 4.3.25
11
0.09
(0-1)1
0.015
0.174.3.1
11
2.6
29
0.66
7.255.28
11
7.9
87
0.63
6.96Total




327.61
                         There are no capital costs or operating and maintenance costs associated with this collection of information. 
                        ( print page 34199)2
                         A one-time burden for setting up a recordkeeping system which rapidly links information regarding the specimen archive, the recipient's medical records, and source animals.3
                         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 58 source animals per year (see footnote 6 of this table); 108 + 58 = 166 monitoring records to document.4
                         Necropsy for animal deaths of unknown cause estimated to be approximately 4 per herd per year x 1 herd per facility x 18 facilities = 72.5
                         Has not occurred in the past 5 years and is expected to continue to be a rare occurrence.6
                         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 29 recipients annually = 58 source animals per year. (See footnote 5 of table 3 of this document.)7
                         FDA estimates there are approximately 12 clinical centers doing xenotransplantation procedures x approximately 25 health care workers involved per center = 300 health care workers.8
                         Fifty-eight source animal records + 29 recipient records = 87 total records.
 Because xenotransplantation is a relatively new area of medical science, potential problems and adverse effects are not well known. Because of the potential risk for cross-species transmission of infectious agents from source animals to patients, their close contacts, and the general public and the latency period of known human 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 small and, therefore, the capital and operating costs are expected to be insignificant at this time. Many of the information collections described in this guideline are not new and can be found under existing regulations and, therefore, are not included in the hour burden estimates in tables 1 through 4 of this document. These information collections are included under the 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 601.1 through 601.3, approved under OMB control number 0910-0124. (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. 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 practice. **Table**
                         5.—
                        **Collection of Information Required by Current Regulations and Standards**
PHS Guideline 
                             Section
Description of Collection of Information Activity
21 CFR Section (unless otherwise
                             stated)2.2.1
Document off-site collaborations
312.522.5
Sponsor ensure counseling patient + family + contacts
312.62(c)3.1.1 and 3.1.6
Document well-characterized health history and lineage of source animals
312.23(a)(7)(a) and 211.843.1.8
Registration with and import permit from the Centers for Disease Control and Prevention
42 CFR 71.533.2.2
Document collaboration with accredited microbiology labs
312.523.2.3
Procedures to ensure the humane care of animals
9 CFR parts 1, 2, and 3 and­ PHS­ Policy1
                            ­3.2.4
Procedures consistent for accreditation by the Association for Assessment­ and­ Accreditation­ of­ Laboratory Animal Care International (AAALAC International) and consistent with the National Research Council's (NRC) Guide
AAALAC International Rules­ of­ Accreditation2
                            ­ and­ NRC­ Guide3
                            ­3.2.5, 3.4, and 3.4.1
Herd health maintenance and surveillance to be documented, available, and in­ accordance­ with­ documented procedures; record standard veterinary care
211.100 and 211.1223.2.6
Animal facility SOP's
PHS Policy13.3.3
Validate assay methods
211.160(a)3.6.1
Procurement and processing of xenografts using documented aseptic conditions
211.100 and 211.1223.6.2
Develop, implement, and enforce SOP's for­ procurement­ and­ screening processes
211.84(d) and 211.122(c)3.6.4
Communicate to FDA animal necropsy findings pertinent to health of recipient
312.32(c)3.7.1
PHS specimens to be linked to health records; provide to FDA justification for types of tissues, cells, and plasma, and quantities of plasma and leukocytes collected
312.23(a)(6)4.1.1
Surveillance of xenotransplant recipient; sponsor ensures documentation of surveillance­ program­ life-long­ (justify >2 yrs.); investigator case histories (2 yrs. after­ investigation­ is discontinued)
312.23(a)(6)(iii)(f) and (g), and 312.62(b) and (c)4.1.2
Sponsor to justify amount and type of reserve samples
211.1224.1.2.2
System for prompt retrieval of PHS specimens and linkage to medical records (recipient and source animal)
312.57(a)4.1.2.3
Notify FDA of a clinical episode potentially representing a xenogeneic infection
312.324.2.2.1
Document collaborations (transfer of obligation)
312.524.2.3.1
Develop educational materials (sponsor provides investigators with information needed to conduct investigation properly)
312.50( print page 34200)4.3
Sponsor to keep records of receipt, shipment, and disposition of investigative drug;­ investigator­ to ­ keep records of case histories
312.57 and 312.62(b)1
                         The “Public Health Service Policy on Humane Care and Use of Laboratory Animals” (http://www.grants.nih.gov/​grants/​olaw/​references/​phspol.htm).2
                         AAALAC International Rules of Accreditation (http://www.aaalac.org/​html/​rules.html).3
                         The NRC's “Guide for the Care and Use of Laboratory Animals” (1996).
 II. Electronic Access Persons with access to the Internet may obtain the guideline at http://www.fda.gov/​cber/​guidelines.htm. Dated: May 23, 2000. William K. Hubbard, Senior Associate Commissioner for Policy, Planning, and Legislation.


[FR Doc. 00-13340 Filed 5-25-00; 8:45 am] BILLING CODE 4160-01-F