[Federal Register Volume 60, Number 26 (Wednesday, February 8, 1995)]
[Notices]
[Pages 7630-7649]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-2870]
[[Page 7629]]
_______________________________________________________________________
Part II
Department of Health and Human Services
_______________________________________________________________________
National Institutes of Health
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Recombinant DNA Research; Proposed Actions Under the Guidelines; Notice
Federal Register / Vol. 60, No. 26 / Wednesday, February 8, 1995 /
Notices
[[Page 7630]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
Recombinant DNA Research: Proposed Actions Under the Guidelines
Agency: National Institutes of Health (NIH), PHS, DHHS.
Action: Notice of Proposed Actions Under the NIH Guidelines for
Research Involving Recombinant DNA Molecules (59 FR 34496).
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Summary: This notice sets forth proposed actions to be taken under the
NIH Guidelines for Research Involving Recombinant DNA Molecules (59 FR
34496). Interested parties are invited to submit comments concerning
these proposals. These proposals will be considered by the Recombinant
DNA Advisory Committee at its meeting on March 6-7, 1995. After
consideration of these proposals and comments by the Recombinant DNA
Advisory Committee, the Director of the National Institutes of Health
will issue decisions in accordance with the NIH Guidelines.
Dates: Comments received by February 27, 1995, will be reproduced and
distributed to the Recombinant DNA Advisory Committee for consideration
at its March 6-7, 1995, meeting.
Addresses: Written comments and recommendations should be submitted to
Dr. Nelson A. Wivel, Director, Office of Recombinant DNA Activities,
Suite 323, 6006 Executive Boulevard, MSC 7052, Bethesda, Maryland
20892-7052, or sent by FAX to 301-496-9839.
All comments received in timely response to this notice will be
considered and will be available for public inspection in the above
office on weekdays between the hours of 8:30 a.m. and 5 p.m.
For Further Information Contact: Background documentation and
additional information can be obtained from the Office of Recombinant
DNA Activities, Suite 323, 6006 Executive Boulevard, MSC 7052,
Bethesda, Maryland 20892-7052, Phone 301-496-9838, FAX to 301-496-9839.
Supplementary Information: The NIH will consider the following actions
under the NIH Guidelines for Research Involving Recombinant DNA
Molecules:
I. Addition to Appendix D of the NIH Guidelines Regarding a Human Gene
Transfer Protocol/Drs. Curiel and Alvarez
In a letter dated January 5, 1995, Drs. David T. Curiel and Ronald
D. Alvarez of the University of Alabama, Birmingham, Alabama, submitted
a human gene transfer protocol entitled: A Phase I Study of Recombinant
Adenovirus Vector-Mediated Delivery of an Anti-erbB-2 Single-Chain
(sFv) Antibody Gene for Previously Treated Ovarian and Extraovarian
Cancer Patients to the Recombinant DNA Advisory Committee for formal
review and approval.
II. Addition to Appendix D of the NIH Guidelines Regarding a Human Gene
Transfer Protocol/Dr. Malech
In a letter dated January 6, 1995, Dr. Harry L. Malech of the
National Institutes of Health, Bethesda, Maryland, submitted a human
gene transfer protocol entitled: Gene Therapy Approach for Chronic
Granulomatous Disease to the Recombinant DNA Advisory Committee for
formal review and approval.
III. Addition to Appendix D of the NIH Guidelines Regarding a Human
Gene Transfer Protocol/Drs. Black and Fakhrai
In a letter dated January 6, 1995, Drs. Keith L. Black and Habib
Fakhrai of the University of California, Los Angeles, California,
submitted a human gene transfer protocol entitled: Immunization of
Glioblastoma Patients with TGF-2 Antisense and Interleukin-2
(IL-2) Gene Modified Autologous Tumor Cells: A Phase I Study to the
Recombinant DNA Advisory Committee for formal review and approval.
IV. Addition to Appendix D of the NIH Guidelines Regarding a Human Gene
Transfer Protocol/Dr. Gansbacher
In a letter dated January 6, 1995, Dr. Bernd Gansbacher of the
Memorial Sloan-Kettering Cancer Center, New York, New York, submitted a
human gene transfer protocol entitled: Phase I/II Study of Immunization
with MHC Class I Matched Allogeneic Human Prostatic Carcinoma Cells
Engineered to Secrete Interleukin-2 and Interferon- to the
Recombinant DNA Advisory Committee for formal review and approval.
V. Addition to Appendix D of the NIH Guidelines Regarding a Human
Gene Transfer Protocol/Drs. Link and Moorman
In a letter dated January 6, 1995, Drs. Charles J. Link and Donald
Moorman of the Human Gene Therapy Research Institute, Des Moines, Iowa,
submitted a human gene transfer protocol entitled: A Phase I Trial of
In Vivo Gene Therapy with the Herpes Simplex Thymidine Kinase/
Ganciclovir System for the Treatment of Refractory or Recurrent Ovarian
Cancer to the Recombinant DNA Advisory Committee for formal review and
approval.
VI. Addition to Appendix D of the NIH Guidelines Regarding a Human Gene
Transfer Protocol/Drs. Morgan and Walker
In a letter dated January 9, 1995, Drs. Richard Morgan and Robert
Walker of the National Institutes of Health, Bethesda, Maryland,
submitted a human gene transfer protocol entitled: Gene Therapy for
AIDS Using Retroviral Mediated Gene Transfer to Deliver HIV-1 Antisense
TAR and Transdominant Rev Protein Genes to Syngeneic Lymphocytes in HIV
Infected Identical Twins to the Recombinant DNA Advisory Committee for
formal review and approval.
VII. Addition to Appendix D of the NIH Guidelines Regarding a Human
Gene Transfer Protocol/Drs. Economou, Glaspy, and McBride
In a letter dated April 11, 1994, Drs. James Economou, John Glaspy,
and William McBride of the University of California, Los Angeles,
California, submitted a human gene transfer protocol entitled: A Phase
I Testing of Genetically Engineered Interleukin-7 Melanoma Vaccines to
the Recombinant DNA Advisory Committee for formal review and approval.
At its June 9-10, 1994, meeting, the Recombinant DNA Advisory Committee
deferred the protocol based on insufficient toxicology studies and
failure to demonstrate biological efficacy. The Recombinant DNA
Committee required a new submission for future review of the full
Recombinant DNA Advisory Committee, not just the toxicology data.
In a letter dated January 17, 1995, Drs. James S. Economou, John A.
Glaspy, and William H. McBride submitted a revised protocol to the
Recombinant DNA Advisory Committee for formal review and approval at
its March 6-7, 1995, meeting.
VIII. Proposed Amendments to Appendix B of the NIH Guidelines Regarding
Updating the Classification of Microorganisms/Fleming
In a letter dated June 24, 1993, Dr. Diane Fleming, President of
the Mid-Atlantic Biological Safety Association requested updating
Appendix B, Classification of Microorganisms on the Basis of Hazard.
The Mid-Atlantic Biological Safety Association submitted an updated
list of the classification of microorganisms for the Committee to
review which included the latest taxonomy and agent risk group
classifications as defined by the Centers [[Page 7631]] for Disease
Control and Prevention. This request was published for public comment
in the Federal Register (August 18, 1994, 58 FR 44098).
During the September 9-10, 1993, meeting, the Recombinant DNA
Advisory Committee recommended by consensus that the current
classification of etiological agents described in the Biosafety in
Microbiological and Biomedical Laboratories, 3rd edition, May 1993,
U.S. Department of Health and Human Services, should be endorsed by the
Committee. The Committee retains the option to adopt any modification
to the CDC listing. The Committee recommended that the revised Appendix
B, Classification of Microorganisms on the Basis of Hazard, submitted
by Dr. Fleming should not be adopted until the Committee receives
letters of concurrence from both the Centers for Disease Control and
Prevention and the NIH Division of Safety.
In a telephone call on October 20, 1994, Dr. Fleming stated that
Appendix B, Classification of Microorganisms on the Basis of Hazard,
would be reviewed by experts from the Centers for Disease Control and
Prevention and the American Society for Microbiology. The revised
Appendix B was submitted to the Recombinant DNA Advisory Committee
December 1-2, 1994, meeting for review and discussion. During the
December 1994 meeting, the Committee recommended publishing the revised
Appendix B in the Federal Register for public comment, with further
review of this proposal and possible approval during the March 6-7,
1995, meeting.
The proposed Appendix B reads as follows:
Appendix B. Classification of Etiologic Agents and Oncogenic Viruses on
the Basis of Risk (See Appendix B-VI-A)
Agents evaluated by the Centers for Disease Control (CDC) and the
National Institutes of Health (NIH) and published in the Morbidity and
Mortality Weekly Report, or in a revision of the CDC/NIH ``Biosafety in
Microbiological and Biomedical Research Laboratories'' (BMBL), as agent
summary statements shall automatically be added to this list. Revisions
to lists of agents provided by the Subcommittee on Arbovirus Laboratory
Safety (SALS) as taken from the BMBL (see Appendix B-VI-D) and provided
here in Tables 3-6 shall be incorporated into this list. Appendix B
shall undergo an annual review for the Office of Recombinant DNA
Activities (ORDA) by a special committee of the American Society for
Microbiology (ASM) to ensure that all such updates have been
incorporated. Additions or corrections to this list may also occur
following a review by ORDA, the RAC, and/or by recommendation of the
CDC.
Appendix B-I. Points To Consider in Using Appendix B and in Assessing
the Risk of Handling Microorganisms
Appendix B is not to be used to replace a thorough assessment of
the risk of working with a particular biohazardous agent. However, the
information can be used to establish an initial, qualitative assessment
of the risk of handling an agent. Such information would be appropriate
for initial estimates of the design of facilities needed for the use of
such agents or the requirements for their transport. Much of the
information in the previous version of Appendix B, based upon a 1974
publication of the Centers for Disease Control (see Appendix B-VI-C),
is updated and retained in this revision. Information on agent risk
assessments found in the ``Agent Summary Statements'' of the CDC/NIH
publication ``Biosafety in Microbiological and Biomedical
Laboratories'' (See Appendix B-VI-D), information from the American
Public Health Association publication, ``Control of Communicable
Diseases of Man'' (See Appendix B-VI-B) and input from a special
committee of the American Society for Microbiology provided additional
information for the revised list of four risk groups found in Appendix
B. The definition of each risk group and the relationship of the four
risk groups to four biosafety levels (BL) is found in Tables 1 and 2
from the Laboratory Biosafety Manual of the World Health Organization
(See Appendix B-VI-E). As a general principle, the greater the hazard
posed by the microorganism, the higher the risk group placement. Use of
the term ``risk group'' is recommended by the World Health Organization
and is used here to indicate the result of a qualitative risk
assessment based upon agent characteristics as described below. Risk
Group designations are currently used in Canada for human and animal
pathogens, and in the member nations of the European Union, which list
only human pathogens in the Directive for protection of workers from
exposure to biohazardous agents.
Specific strains of many species may fall into either a more or a
less hazardous risk group depending upon the genetic background and
natural history of the strain. Information on the parent or wild-type
strain is used for the qualitative risk assessment list in Appendix B.
Further information on a specific strain is to be used by the Principal
Investigator or supervisor for a quantitative risk assessment.
In assessing the risk of working with a specific strain, the
following criteria should be considered: any organism directly isolated
from a human or animal should be treated as a potentially pathogenic
organism until proven otherwise; specific strains that are known to be
more hazardous than the parent strain, such as those resistant to a
limited number of drugs used for treatment, may need to be handled at a
higher containment level than the parent strain. On the other hand,
specific strains of Risk Group 2 microorganisms that are known to have
minimal hazard risk to humans may be classified within Risk Group 1 and
handled at BL1. Certain attenuated strains that are commonly used for
live vaccines and specific attenuated strains with an extensive history
of safe laboratory use without harmful effect may be placed in a lower
risk group than the parent organism, as done by the CDC (See Appendices
B-VI-C through -D). Where a strain is attenuated or has lost known
virulence factors (i.e., genes) and is to be used as a product or part
of a product or for prophylactic/therapeutic purposes, then the
containment required by the classification of the parent strain need
not apply when used for such purpose.
Appendix B-I-A. The list of biohazardous agents in Appendix B is
meant to be based on the effect of a biological agent on a healthy
worker. No account is taken of particular effects on those whose
susceptibility may be affected by one or other reasons such as
preexisting disease, medication, compromised immunity, pregnancy or
breast feeding. Additional risk to workers should be considered as a
part of the required (quantitative) risk assessment which takes into
account the potential interactions of the agent-host-activity. Only
agents known to infect humans are meant to be included in Appendix B.
Lists of restricted animal pathogens, included in BMBL and previously
included in Appendix B, should be obtained by contacting the USDA,
Animal and Plant Health Inspection Service (APHIS).
Appendix B-I-B. Genetically modified organisms are not specifically
covered by this list. The determination of the risk of a recombinant
organism is a part of the required quantitative risk assessment of the
specific strain to be carried out by the Principal Investigator/
supervisor.
Appendix B-I-C. For agents where more than one species is known to
be pathogenic for man, this appendix may include the genus name as well
as [[Page 7632]] individual species which are known to be the most
important in terms of human infectivity. When such a genus is listed in
Appendix B, the species and strains known to be non-pathogenic are
meant to be excluded from the list. For parasites, the stages of the
life cycle which are not infectious for humans are excluded.
Appendix B-I-D. Those agents not listed in Risk Groups 2-4 are not
automatically or implicitly classified in Risk Group 1; a risk
assessment must be conducted. The list in Appendix B is meant to serve
as a general guideline for the risk group classification of
microorganisms. Further guidance for microorganisms which are not
specifically listed may be obtained from the Centers for Disease
Control and Prevention, Office of Health and Safety (404-329-3883).
Appendix B-I-E. The list provided in Appendix B reflects the state
of knowledge at the time it was prepared. The nomenclature reflects and
is meant to be in conformity with the latest international agreements
on taxonomy and nomenclature of agents at this time. The list is as
complete as possible but necessarily not exhaustive. Additional
information to be used to update the list in a timely manner shall
include new agent summary statements published by the Centers for
Disease Control as well as taxonomic changes to human pathogens. An
annual review to incorporate the new agents and to correct the taxonomy
has been offered through the ASM.
Appendix B-II. Risk Assessment
Appendix B-II-A. It is the responsibility of the Principal
Investigator/supervisor to assess the risk associated with the handling
of potentially biohazardous microorganisms and to ensure that the
appropriate biosafety practices are employed prior to conducting any
experiments or operations. A rough, qualitative risk assessment is used
for an initial agent classification. However, it is to be followed by a
quantitative risk assessment of the specific strain of the agent, the
immune status of the host relative to the agent in question and
potential agent-host-activity interactions, such as those caused by
aerosol production. For example, although cultures of the organism may
be handled at BSL-2 for Risk Group 2 agents such as the dengue virus,
when used for animal inoculation or transmission work it is handled at
BSL-3. Similarly, such work with monkey pox, VEE or yellow fever
viruses are carried out under BSL-4 containment.
Appendix B-II-B. The quantitative risk assessment described above
is to be used to determine the Biosafety Level (BL), as described in
Appendices G and K, which identifies the appropriate facilities,
equipment, and work practices to be used for specific procedures
carried out by a healthy adult individual (assessed for health status)
with a specific biohazardous agent (assessed for virulence factors
including antibiotic resistance to drugs of treatment). Factors to be
considered in determining the level of containment include agent
factors such as: Virulence, pathogenicity, stability, route of spread,
communicability, the operation(s), quantity, and availability of
vaccine or treatment. The higher risk agents also require more
stringent biosafety practices and facilities as reflected in the
Biosafety Level to which work is to be assigned (See Table 2 for the
relation between risk groups and biosafety level). Although risk
assessment is ultimately a subjective process, the CDC/NIH Guidelines
in BMBL (See Appendix B-VI-D) have provided information about
microorganisms based on the hazard they present and guidance for
defining safe conditions for their use. Further information on specific
biohazardous microorganisms is available in the Agent Summary
Statements of the primary reference (See Appendix B-VI-D), from a
publication of the American Public Health Association ``Control of
Communicable Diseases in Man'' (See Appendix B-VI-B) and from the CDC,
e.g., the Office of Safety and Health and the Special Pathogens Branch.
Changes to the agent which enhance or remove virulence factors should
be considered by the Principal Investigator/supervisor and/or a local
Institutional Biosafety Committee (IBC) which has the authority to
raise or lower the containment level used for that agent. Published
regulations or guidelines from Federal, State or local governments must
also be taken into account.
Appendix B-II-C. When laboratory work is conducted with biological
agents for which epidemiology and etiology are unknown or incompletely
understood, it will be presumed that the work presents a biohazard
similar to related agents until further information can be provided.
This method was used by the Subcommittee on Arbovirus Laboratory Safety
in assessing the risk of work with arboviruses for which risk
information is inadequate or unavailable (See Table C of Appendix B).
It is assumed that information needed for risk evaluation will be
obtained prior to the large-scale use of such an agent.
Appendix B-II-D. Special consideration will be given to large-scale
(greater than 10 liters of culture) and aerosol producing operations
which may pose additional significant risks and thus may require
additional containment (See Appendix K).
Appendix B-III. Risk Groups: Classification of Infectious Substances
and Oncogenic Viruses on the Basis of Risk
The characteristics used for the qualitative risk assessment of
biohazardous agents into the four Risk Groups of human etiologic agents
are defined in Table 1 below, with each higher number representing an
increased hazard. The information and interpretations below are from
the CDC/NIH, BMBL (See Appendix B-VI-D) and the World Health
Organization Laboratory Biosafety Manual (See Appendix B-VI-E).
Table 1.--Classification of Biohazardous Agents by Risk Group (See
Appendix B-VI-E)
Risk Group 1........ (No or very low individual and community risk) An
agent that is unlikely to cause human disease.
Well characterized agents not known to cause
disease in healthy adult humans and of minimal
potential hazard to laboratory personnel and the
environment.
Risk Group 2........ (Moderate individual risk, low community risk)
Agents which can cause human disease but are
unlikely to be a serious hazard to workers, the
community or the environment; laboratory
exposures may cause serious infection but
effective treatment and preventive measures are
available and the risk of spread of infection is
limited.
Risk Group 3........ (High individual risk, low community risk) Agents
which usually cause serious human disease but do
not ordinarily spread from one infected
individual to another. Effective treatment or
preventive measures are available.
Risk Group 4........ (High individual and high community risk) Agents
which can cause serious human disease and can be
readily transmitted from one individual to
another, directly or indirectly. Effective
treatment and preventive measures are not usually
available.
[[Page 7633]]
Table 2.--Relationship of Risk Groups to Biosafety Levels, Practices, and Equipment
(See Appendix B-VI-E)
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Risk
group Biosafety level Examples of laboratories Laboratory practices Safety equipment
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1..... Basic Biosafety Level 1.. Basic Teaching........... GMTa.................... None, open bench work
2..... Basic Biosafety Level 2.. Primary health svcs; GMT plus protective Open bench plus BSCb for
primary level hospital; clothing; biosafety potential aerosols.
diagnostic, teaching and sign.
Public Health.
3..... Containment-Biosafety Special diagnostic....... As level 2 plus special BSC and/or other primary
Level 3. clothing, controlled containment for all
access, directional air activities.
flow.
4..... Maximum Containment- Dangerous pathogens units As level 3 plus airlock Class III BSC or
Biosafety Level 4. entry, shower exit, positive pressure
special waste disposal. suits, double-ended
autoclave filtered air.
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aGMT--good microbiological practices.
bBSC--biological safety cabinet.
Appendix B-III-A. Risk Group 1--Agents
Risk Group 1 agents are usually not placed on a list but are
assumed to include all bacterial, fungal, viral, rickettsial,
chlamydial, and parasitic agents which have been assessed for hazard
and are not included in higher risk groups. Risk Group 1 agents can be
used for undergraduate and secondary educational training and teaching
laboratories and for other facilities in which work is conducted with
defined and characterized strains of viable microorganisms not known to
cause disease in healthy adult humans and of minimal potential hazard
to personnel and the environment under ordinary conditions of use.
These agents can be handled safely in the laboratory without special
apparatus or equipment using techniques generally acceptable for
nonpathogenic materials. Examples of agents in Risk Group 1 are:
Bacillus subtilis, infectious canine hepatitis viruses; influenza
reference strains A/PR/8/34, A/WS/33; agents listed in Appendix C-II of
the NIH Guidelines for Research Involving Recombinant DNA Molecules
(Escherichia coli K12, Saccharomyces cerevisiae, etc.); vectors such as
Baculovirus. It is not appropriate to assume that an unassessed agent
belongs in this risk group. Even vaccine strains which have undergone
multiple in vivo passages would not be considered avirulent based only
on the fact that they are vaccine strains.
Appendix B-III-A-1. Risk Group 1--Low-Risk Oncogenic Viruses (See
Appendix B-VI-G)
Adenovirus7-Simian virus 40 (Ad7-SV40)
Avian leukosis virus
Bovine leukemia virus
Bovine papilloma virus
Chick-embryo-lethal orphan (CELO) virus or fowl adenovirus-1
Dog sarcoma virus
Guinea pig herpes virus
Lucke (Frog) virus
Hamster leukemia virus
Marek's disease virus
Mason-Pfizer monkey virus
Mouse mammary tumor virus
Murine leukemia virus
Murine sarcoma virus
Polyoma virus
Rat leukemia virus
Rous sarcoma virus
Shope fibroma virus
Shope papilloma virus
Simian virus 40 (SV-40)
Appendix B-III-B. Risk Group II--Agents
Agents of moderate potential hazard to healthy human adults and the
environment. Such agents may produce disease of varying degrees of
severity from accidental inoculation, injection or other means of
cutaneous penetration but can usually be adequately and safely
contained by ordinary laboratory techniques. Some agents may cause
disease by contact or respiratory routes, but they are self-limiting
and do not cause a serious illness, e.g. the common cold
(rhinoviruses). Risk Group 2 agents are recommended for use only in
those laboratories where staff are trained to handle microbes which
pose this level of risk. Examples include Streptococcus pneumonia,
Staphylococcus aureus, poliovirus, etc.
Appendix B-III-B-1. Risk Group 2--Bacteria1
\1\When ``spp'' follows the name of a genus, or ``serotype''
follows a species, only those species or serotypes known to be
pathogenic to healthy human adults are meant to be included in this
list.
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Acinetobacter baumannii
Actinobacillus spp.
Actinomyces pyogenes
Aeromonas hydrophila
Amycolata autotrophica
Archanobacterium haemolyticum
Arizona hinshawii--all serotypes
Bacillus anthracis*2
\2\*Agents in Risk Group 2 which require special handling using
BL 3 practices are noted with an asterisk.
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Bartonella henselae, B. quintana, B. vinsonii
Bordetella spp. including B. pertussis*
Borrelia recurrentis, B. burgdorferi
Burkholderia was Pasteurella spp. (except for those listed in Risk
Group 3)
Burkholderia pseudomallei*
Campylobacter coli, C. fetus ssp. fetus, C. jejuni
Chlamydia psittaci*, C. trachomatis*, C. pneumoniae*
Clostridium botulinum*, Cl. chauvoei, Cl. haemolyticum, Cl.
histolyticum, Cl. novyi, Cl. septicum, Cl. tetani
Corynebacterium diphtheriae, C. pseudotuberculosis, C. renale
Dermatophilus congolensis
Edwardsiella tarda
Erysipelothrix rhusiopathiae
Escherichia coli--all enteropathogenic, enterotoxigenic, enteroinvasive
and strains bearing K1 antigen, including E. coli O157:H7
Haemophilus ducreyi, H. influenzae
Helicobacter pylori
Klebsiella spp.
Legionella spp. including L. pneumophila*
Legionella-like organisms
Leptospira interrogans--all serotypes
Listeria spp.
Moraxella spp.
Mycobacterium spp. (except those listed in Risk Group 3) including M.
avium complex, M. asiaticum, M. chelonei, M. fortuitum, M. kansasii, M.
leprae, M. malmoense, M. marinum, M. paratuberculosis, M. scrofulaceum,
M. simiae, M. szulgai, M. ulcerans, M. xenopi [[Page 7634]]
Mycoplasma spp. except M. mycoides and M. agalactiae which are
restricted animal pathogens (See Appendix B-V)
Neisseria gonorrhoea,* N. meningitidis*
Nocardia asteroides, N. brasiliensis, N. otitidiscaviarum, N.
transvalensis
Rhodococcus equi
Salmonella spp. and serotypes including S. arizonae, S. cholerasuis, S.
enteritidis, S. gallinarum-pullorum, S. meleagridis, S. paratyphi, A,
B, C, S. typhi*, S. typhimurium,
Shigella spp.* and serotypes including S. boydii, S. dysenteriae, Type
1, S. flexneri, S. sonnei
Sphaerophorus necrophorus
Staphylococcus aureus
Streptobacillus moniliformis
Streptococcus spp. including Streptococcus pneumoniae, S. pyogenes
Treponema pallidum, T. carateum
Vibrio cholerae, V. parahemolyticus, V. vulnificus
Yersinia enterocolitica, Y. pestis*
Appendix B-III-B-2. Risk Group 2--Fungal Agents3
\3\When ``spp'' follows the name of a genus, or ``serotype''
follows a species, only those species or serotypes known to be
pathogenic to healthy human adults are to be included in this list.
---------------------------------------------------------------------------
Blastomyces dermatitidis
Cladosporium bantianum, C. (Xylohypha) trichoides
Cryptococcus neoformans4
\4\Risk Group 2 agent for which droplets/aerosols are handled in
a Biological Safety Cabinet (BSC).
---------------------------------------------------------------------------
Dactylaria galopava (Ochroconis gallopavum)
Epidermophyton spp.
Exophiala (Wangiella) dermatitidis
Fonsecaea pedrosoi
Microsporum spp.
Paracoccidioides braziliensis
Penicillium marneffei
Sporothrix schenckii
Trichophyton spp.
Appendix B-III-B-3. Risk Group 2--Parasitic Agents
Ancylostoma spp., human hookworms including A. duodenale, A. ceylanicum
Ascaris spp. including Ascaris lumbricoides suum
Babesia spp. including B. divergens, B. microti
Brugia spp. filaria worms including B. malayi, B. timori
Coccidia spp.
Cryptosporidium spp. including C. parvum
Cysticercus cellulosae (hydatid cyst, larva of T. solium)
Echinococcus spp. including E. granulosis, E. multilocularis, E. vogeli
Entamoeba histolytica
Enterobius spp.
Fasciola spp. including F. gigantica, F. hepatica
Giardia spp. including G. lamblia
Heterophyes spp.
Hymenolepis spp. including H. diminuta, H. nana
Isospora spp.
Leishmania spp. including L. braziliensis, L. donovani, L. ethiopia, L.
major, L. mexicana, L. peruvania, L. tropica
Loa loa filaria
Microsporidium spp.
Naegleria fowleri
Necator spp. human hookworm, including N. americanus
Onchoerca spp. filaria including, O. volvulus
Plasmodium spp. including simian species, P. cynomologi, P. falciparum,
P. malariae, P. ovale, P.vivax
Sarcocystis spp. including S. sui hominis
Schistosoma spp. including S. haematobium, S. intercalatum, S.
japonicum, S. mansoni, S. mekongi
Strongyloides spp. including S. stercoralis
Taenia solium
Toxocara spp. including T. canis
Toxoplasma spp. including T. gondii
Trichinella spiralis
Trypanosoma spp. including T. brucei brucei, T. brucei gambiense, T.
brucei rhodesiense, T. cruzi
Wuchereria bancrofti (filaria)
Appendix B-III-B-4. Risk Group 2--Viruses and prions (See Tables 3 and
4)
Adenoviruses-human, all types
Arboviruses (See Table 3)
Arenaviruses (See Table 3)
Bunyamwera virus
Coronaviruses
Coxsackie A and B viruses
Creutzfeldt-Jacob disease agent (prion)
Echoviruses--all types
Encephalomyocarditis virus (EMC)
Encephalomyelitis viruses5* (See Table 3)
\5\*Risk Group 2 Viruses for which droplets/aerosols are handled
with BL 3 practices.
---------------------------------------------------------------------------
Hepatitis A, B*, C*, D, E viruses
Herpesviruses* including Cytomegalovirus, Epstein Barr, Herpes simplex
types 1 and 2 and Herpes zoster, except Herpesvirus simiae (Monkey B
virus) which is in Risk Group 4
Human Immunodeficiency Virus (HIV) all serotypes
Human T-cell lymphotropic viruses* (HTLV) types 1 and 2.
Influenza viruses
Kuru (prion)
Lymphocytic choriomeningitis virus* (except neurotropic strains)
Lymphogranuloma venereum agent
Measles virus
Molluscum contagiosum virus
Mumps virus
Orf virus
Papovaviridae including human papilloma viruses
Parainfluenza virus
Paravaccinia virus
Polioviruses--all types, wild and attenuated
Poxviruses6--all types such as Cowpox**, Monkeypox** or
Vaccinia**, Camelpox, Milker's node virus, Molluscum contagiosum virus,
Orf, Rabbitpox, Tanapox and Yabapox, with the exception of Alastrim,
Smallpox, and Whitepox (See Appendix B VI-H)
\6\All types with double asterisk can be handled at BL2 in a BSC
by immunized personnel.
---------------------------------------------------------------------------
Rabies virus7--all strains, including fixed/attenuated virus,
except Rabies street virus
\7\Rabies virus may be handled at BL 2 by immunized personnel
using a BSC.
---------------------------------------------------------------------------
Reoviruses all types
Respiratory syncytial virus
Rhinoviruses all types
Rubella virus
Simian viruses all types including simian immunodeficiency virus*,
except
Herpesvirus simiae (Monkey B virus) and Marburg virus which are in Risk
Group 4
Transmissible Spongioform Encephalopathies (TME)-prions (Creutzfieldt-
Jacob; Kuru)
Vesicular Stomatitis Virus, lab adapted strains:VSV-Indiana, San Juan
and Glasgow
Appendix B-III-B-5. Risk Group 2--Moderate Risk Oncogenic Viruses (See
Appendix B-VI-G)
Adenovirus
Adenovirus 2--Simian virus 40 (Ad2-SV40)
Epstein-Barr virus (EBV)
Feline leukemia virus (FeLV)
Feline sarcoma virus (FeSV)
Gibbon leukemia virus (GaLV)
Herpesvirus (HV) ateles
Herpesvirus (HV) saimiri
Papovaviridae including human papilloma viruses
Simian sarcoma virus (SSV)-1
Yabapox virus
Appendix B-III-C. Risk Group 3--Agents
Indigenous or exotic agents which may cause serious or potentially
lethal disease as a result of exposure by the inhalation route. Agents
involving special hazards to laboratory personnel or agents derived
from outside the [[Page 7635]] United States which require a permit for
importation, unless they are specified for higher classification.
This risk group includes pathogens which require special conditions
for containment. Agents in this group can be used in laboratories where
staffs have levels of competency equal to or greater than one would
expect in a college department of microbiology, and who have had
special training in handling these or similar pathogens which cause
potentially lethal disease. Workers are to be supervised by competent
scientists trained and experienced in handling these biohazardous
agents/materials. Examples include: Brucella melitensis, Coxiella
burnetii, Mycobacterium tuberculosis, Rickettsia rickettsii, etc.
Appendix B-III-C-1. Risk Group 3--Bacterial Agents, including Chlamydia
and Rickettsia
Bartonella spp.
Brucella spp. including B. abortus, B. canis, B. melitensis (USDA
restricted), B. suis
Burkholderia (Pseudomonas) mallei, B. pseudomallei (see Appendix B-VI-
F)
Coxiella burnetii
Francisella tularensis
Mycobacterium bovis, M. tuberculosis
Pasteurella multocida type B--``buffalo'' and others (see Appendix B-
VI-F)
Rickettsia akari, R. australis, R. canada, R. conorii, R. prowazekii
R. rickettsii, R, siberica, R. tsutsugamushi, R. typhi (R. mooseri)
Yersinia pestis (antibiotic resistant strains)
Appendix B-III-C-2. Risk Group 3--Fungal Agents
Coccidioides immitis (sporulating cultures; contaminated soil)
Histoplasma capsulatum, H. capsulatum var. duboisii
Appendix B-III-C-3. Risk Group 3--Parasitic Agents
None
Appendix B-III-C-4. Risk Group 3--Viral Agents
Arboviruses8 and certain other viruses assigned to Risk Group 3
(see Appendix B-VI-I and Tables 5 and 6).
\8\The 171 arboviruses in Risk Group 3 are found in Appendix B-
VI-I and Tables 5 and 6. Arboviruses indigenous to the United States
are in Risk Group 3 except those listed in Risk Group 2 (Tables 3
and 4). West Nile and Semliki Forest viruses may be classified up or
down depending on the conditions of use and geographical location of
the laboratory.
---------------------------------------------------------------------------
Lymphocytic choriomeningitis virus (LCM) (neurotrophic strains)
Monkey pox virus--when used in vitro (see Appendix B-VI-H)
Rabies Street virus
Appendix B-III-D. Risk Group 4--Agents
Dangerous and exotic agents which pose a high individual risk of
aerosol transmitted laboratory infections which result in a life-
threatening disease, or related agents with unknown means of
transmission. These agents require the most stringent conditions for
their containment because they are extremely hazardous to laboratory
personnel or may cause serious epidemic disease. These agents may only
be used in special facilities where the staff has a level of competency
equal to or greater than one would expect in a college department of
microbiology, and who have had specific and thorough training in
handling dangerous pathogens, including the specific techniques to be
used. Such workers are to be supervised by competent scientists.
Appendix B-III-D-1. Risk Group 4--Bacterial Agents
None
Appendix B-III-D-2. Risk Group 4--Fungal Agents
None
Appendix B-III-D-3. Risk Group 4--Parasitic Agents
None
Appendix B-III-D-4. Risk Group 4--Viral Agents
Absettarov
Central European encephalitis viruses
Crimean hemorrhagic fever (Congo)
Ebola fever virus
Guanarito
Hanzalova
Hemorrhagic fever agents and viruses as yet undefined
Herpesvirus simiae (Monkey B virus)
Hypr
Junin (BL3* if vaccine is used)
Kumlinge
Kyasanur forest disease
Lassa
Machupo
Marburg
Omsk hemorrhagic fever
Russian spring-summer encephalitis
Tick-borne orthomyxoviridae, Dhori & Thogoto
Appendix B-IV. Restricted Plant Pathogens
Non-indigenous pathogens of plants may require special laboratory
design, operation and containment features not generally addressed in
the CDC/NIH guidelines. Information on the importation, possession or
use of these agents is to be obtained from the USDA, APHIS. Guidelines
for handling recombinant plants are in Appendix P.
Appendix B-V. Restricted Animal Pathogens
Non-indigenous pathogens of domestic livestock and poultry may
require special laboratory design, operation, and containment features
not generally addressed in the CDC/NIH guidelines. The importation,
possession or use of these agents is prohibited or restricted by law or
by the U.S. Department of Agriculture regulations or administration
policies. Animal pathogens other than those listed as zoonotic agents
Appendix B may also be subject to USDA regulations. See Appendix Q for
guidelines for recombinant animals.
Appendix B-V-A. Organisms which may not be studied in the United States
except at Specified Facilities
Alastrim (see Appendix B-VI-H)
Small pox (see Appendix B-VI-H)
White pox (see Appendix B-VI-H)
Appendix B-VI. References of Appendix B
Appendix B-VI-A. For the purposes of these Guidelines, the list in
Appendix B has been revised by using the Risk Group classification
recommended by the World Health Organization (See Appendix B-VI-E), and
adding information from agent summary statements of the CDC/NIH
``Biosafety in Microbiological and Biomedical Laboratories'' (See
Appendix B-VI-D), from the APHA, ``Control of Communicable Diseases of
Man'' (See Appendix B-VI-B), and from a special committee of the
American Society for Microbiology. Information in Tables 1 and 2 came
from the WHO reference (See Appendix B-VI-E) while that for Tables 3-6
and for Appendix B-V and B-VI was obtained directly from the CDC on
computer disc. The original reference for this classification was the
publication Classification of Etiologic Agents on the Basis of Hazard,
4th edition, July 1974 (See Appendix B-VI-C). A draft 1982 CDC document
which included a more complete risk assessment of a larger group of
human pathogens was also used (Dr. R. Knudsen, CDC, personal
communication). For the purposes of these NIH Guidelines, these lists
are revised by the NIH. [[Page 7636]]
Appendix B-VI-B. Benenson, Abram S. ed. 1990. Control of Communicable
Diseases in Man. 15th edition. 532 pp. American Public Health Asso.
Washington, D.C.
Appendix B-VI-C. Center for Disease Control, Office of Biosafety. 1974.
Classification of Etiologic Agents on the Basis of Hazard, 4th Edition.
U.S. Department of Health, Education and Welfare, Public Health
Service.
Appendix B-VI-D. Centers for Disease Control and the National
Institutes of Health (CDC/NIH), 1993. Biosafety in Microbiological and
Biomedical Research Laboratories. pp 177. Government Printing Office.
(#017-040-00523-7) Washington, D.C.
Appendix B-VI-E. World Health Organization Laboratory Biosafety
Manual. 2nd Edition. WHO Albany, NY ORDER FROM: WHO Publication Centre,
USA, (Q Corp) 49 Sheridan Avenue, Albany, NY 12210, tel 518-436-9686.
Order # 1152213 (cost $23.40 plus $3.00 handling).
Appendix B-VI-F. A U.S. Department of Agriculture permit, required
for import and interstate transport of pathogens, may be obtained from
the U.S. Department of Agriculture, ATTN: Animal and Plant Health
Inspection Service, Import-Export Products Office, Room 756, Federal
Building, 6505 Belcrest Road, Hyattsville, Maryland 20782. Telephone;
301-436-7830 or 8499; FAX 301-436-8226
Appendix B-VI-G. National Cancer Institute Safety Standards for
Research Involving Oncogenic Viruses, U.S. Department of Health,
Education, and Welfare Publication No. (NIH) 75-790, October 1974.
Appendix B-VI-H. All activities, including storage of variola and
whitepox, are restricted to the single national facility (World Health
Organization Collaborating Center for Smallpox Research, Centers for
Disease Control and Prevention, Atlanta, Georgia).
Appendix B-VI-I. Tables 3-6 (See Appendix B-VI-D)
Appendix B-VI-I-A. Table 3. Arboviruses and Arenaviruses Assigned to
Biosafety Level 2
Acado
Acara
Aguacate
Alfuy
Almpiwar
Amapari
Ananindeua
Anhanga
Anhembi
Anopheles A
Anopheles B
Apeu
Apoi
Aride
Arkonam
Aroa
Aruac
Arumowot
Aura
Avalon
Abras
Abu Hammad
Aabahoyo
Bagaza
Bahig
Bakau
Baku
Bandia
Bangoran
Bangui
Banzi
Barmah Forest
Barur
Batai
Batama
Bauline
Bebaru
Belmont
Benevides
Benfica
Bertioga
Bimiti
Birao
Bluetongue
Boraceia
Botambi
Boteke
Bouboui
Bujaru
Bunyamwera
Bunyip
Burg E Arab
Bushbush
Bussuquara
Buttonwillow
Bwamba
Cacao
Cache Valley
Caimito
California enc.
Calovo
Candiru
Cape Wrath
Capim
Caraparu
Carey Island
Catu
Chaco
Chagres
Chandipura
Changuinola
Charleville
Chenuda
Chilibre
Chobar gorge
Clo Mor
Colorado tick fever
Corriparta
Cotia
Cowbone Ridge
Csiro Village
Cuiaba-D'aguilar
Dakar Bat
Dengue-1
Dengue-2
Dengue-3
Dengue-4
Dera Ghazi Khan
East. equine enc.(d)
Edge Hill
Entebbe Bat
Ep. Hem. Disease
Erve
Eubenangee
Eyach
Flanders
Fort Morgan
Frijoles
Gamboa
Gan Gan
Gomoka
Gossas
Grand Arbaud
Great Island
Guajara
Guama
Guaratuba
Guaroa
Gumbo Limbo
Hart Park
Hazara
Highlands J
Huacho
Hughes
Icoaraci
Ieri
Ilesha
Ilheus
Ingwavuma
Inkoo
Ippy
Irituia
Isfahan
Itaporanga
Itaqui
Jamestown Canyon
Japanaut
Jerry Slough
Johnston Atoll
Joinjakaka
Juan Diaz
Jugra
Jurona
Jutiapa
Kadam
Kaeng Khoi
Kaikalur
Kaisodi
Kamese
Kammavan pettai
Kannaman galam
Kao Shuan
Karimabad
Karshi
Kasba
Kemerovo
Kern Canyon
Ketapang
Keterah [[Page 7637]]
Keuraliba
Keystone
Kismayo
Klamath
Kokobera
Kolongo
Koongol
Kotonkan
Kowanyama
Kunjin
Kununurra
Kwatta
La Crosse
La Joya
Lagos Bat
Landjia
Langat
Lanjan
Las Maloyas
Latino
Le Dantec
Lebombo
Lednice
Lipovnik
Lokern
Lone Star
Lukuni
M'poko
Madrid
Maguari
Mahogany Hammock
Main Drain
Malakal
Manawa
Manzanilla
Mapputta
Maprik
Marco
Marituba
Marrakai
Matariya
Matruh
Matucare
Melao
Mermet
Minatitlan
Minnal
Mirim
Mitchell River
Modoc
Moju
Mono Lake
Mont. myotis leuk.
Moriche
Mosqueiro
Mossuril
Mount Elgon Bat
Murutucu
Mykines
Navarro
Nepuyo
Ngaingan
Nique
Nkolbisson
Nola
Ntaya
Nugget
Nyamanini
Nyando
O'nyong-nyong
Okhotskiy
Okola
Olifantsvlei
Oriboca
Ossa
Pacora
Pacui
Pahayokee
Palyam
Parana
Pata
Pathum Thani
Patois
Phnom-Penh Bat
Pichinde
Pixuna
Pongola
Ponteves
Precarious Point
Pretoria
Prospect Hill
Puchong
Punta Salinas
Punta Toro
Qalyub
Quaranfil
Restan
Rio Bravo
Rio Grande
Ross River
Royal Farm
Sabo
Saboya
Saint Floris
Sakhalin
Salehabad
San angelo
Sandfly f. (Naples)
Sandfly f. (Sicilian)
Sandjimba
Sango
Sathuperi
Sawgrass
Sebokele
Seletar
Sembalam
Serra do Navio
Shamonda
Shark River
Shuni
Silverwater
Simbu
Simian hem. fever
Sindbis
Sixgun City
Snowshoe Hare
Sokuluk
Soldado
Sororoca
Stratford
Sunday Canyon
Tacaiuma
Tacaribe
Taggert
Tahyna
Tamiami
Tanga
Tanjong Rabok
Tataguine
Tehran
Tembe
Tembusu
Tensaw
Tete
Tettnang
Thimiri
Thottapalayam
Tibrogargan
Timbo
Timboteua
Tindholmur
Toscana
Toure
Tribec
Triniti
Trivittatus
Trubanaman
Tsuruse
Turlock
Tyuleniy
Uganda S
Umatilla
Umbre
Una
Upolu
Urucuri
Usutu
Uukuniemi
Vellore
Venkatapuram
Vinces
Virgin River
VS-Indiana
VS-New Jersey
Wad Medani
Wallal
Wanowrie
Warrego
West. equine enc.(d)
Whataroa
Witwatersrand
Wonga
Wongorr
Wyeomyia
Yaquinea Head
Yata
Yogue
Zaliv Terpeniya
Zegla
Zika
Zingilamo
Zirqa
Footnote:
dA vaccine is available and is recommended for all persons
working with this agent.
Appendix B-VI-I-B
Table 4.--Vaccine Strains of Risk Group 3 and 4 Viruses Which May Be
Handled at BL2
------------------------------------------------------------------------
Virus Vaccine strain
------------------------------------------------------------------------
Chikungunya......................... 131/25
Junin............................... Candid #1
[[Page 7638]]
Rift Valley fever................... MP-12
Venezuelan equine encephalomyelitis. TC-83
Yellow fever........................ 17-D
------------------------------------------------------------------------
Appendix B-VI-I-C. Table 5. Arboviruses and Certain Other Viruses
Assigned to Biosafety Level 3 (on the basis of insufficient experience)
Adelaide River
Agua Preta
Alenquer
Almeirim
Altamira
Andasibe
Antequera
Araguari
Aransas Bay
Arbia
Arboledas
Babanki
Batken
Belem
Berrimah
Bimbo
Bobaya
Bobia
Bozo
Buenaventura
Cabassue(c,d)
Cacipacore
Calchaqui
Cananeia
Caninde
Chim
Coastal Plains
Connecticut
Corfou
Dabakala
Douglas
Enseada
Estero Real
Fomede
Forecariah
Fort Sherman
Gabek Forest
Gadgets Gully
Garba
Gordil
Gray Lodge
Gurupi
Iaco
Ibaraki
Ife
Ingangapi
Inini
Issyk-Kul
Itaituba
Itimirim
Itupiranga
Jacareacanga
Jamanxi
Jari
Kedougou
Khasan
Kindia
Kyzylagach
Lake Clarendon
Llano Seco
Macaua
Mapuera
Mboke
Meaban
Mojui Dos Compos
Monte Dourado
Munguba
Naranjal
Nariva
Nasoule
Ndelle
New Minto
Ngari
Ngoupe
Nodamura
Northway
Odrenisrou
Omo
Oriximina
Ouango
Oubangui
Oubi
Ourem
Palestina
Para
Paramushir
Paroo River
Perinet
Petevo
Picola
Playas
Pueblo Viejo
Purus
Radi
Razdan
Resistencia
Rochambeau
Salanga
San Juan
Santa Rosa
Santarem
Saraca
Saumarez Reef
Sedlec
Sena Madureira
Sepik
Shokwe
Slovakia
Somone
Spipur
Tai
Tamdy
Telok Forest
Termeil
Thiafora
Tilligerry
Tinaroo
Tlacotalpan
Tonate(c,d)
Ttinga
Xiburema
Yacaaba
Yaounde
Yoka
Yug Bogkanova
Footnotes:
cSALS recommends that work with this agent should be
conducted only in Biosafety Level 3 facilities which provide for
HEPA filtration of all exhaust air prior to discharge from the
laboratory.
dA vaccine is available and is recommended for all persons
working with this agent.
Appendix B VI-I-D. Table 6. Arboviruses and Certain Other Viruses
Assigned to Biosafety Level 3
Aino
Akabane
Bhanja
Chikungunya(c,d)
Cocal
Dhori
Dugbe
Everglades(c,d)
Flexal
Germiston(c)
Getah
Hantaan
Israel Turkey mening.
Japanese enc.
Junin(c,d)
Kairi
Kimberley
Koutango
Louping Ill(a,c)
Mayaro
Middelburg
Mobala
Mopeia(e)
Mucambo(c,d)
Murray Valley enc.
Nairobi sheep disease(a)
Ndumu
Negishi
Oropouche(c)
Orungo
Peaton
Piry
Powassan
Puumala
Rift Valley fever(a,b,c,d)
Sagiyama
Sal Vieja
San Perlita
Semliki Forest
Seoul
Spondweni
St. Louis enc.
Thogoto
Tocio(c)
Turuna
Venezuelan equine(c,d) encephalitis
Vesicular Stomatitus (alagoas)
Wesselsbron(a,c)
West Nile
Yellow fever(c,d)
Zinga(b)
Footnotes:
aThe importation, possession, or use of this agent is
restricted by USDA regulation or [[Page 7639]] administrative policy
(see Appendix B-VI-D).
bZinga virus is now recognized as being identical to Rift
Valley Fever virus.
cSALS recommends that work with this agent should be
conducted only in Biosafety Level 3 facilities which provide for
HEPA filtration of all exhaust air prior to discharge from the
laboratory.
dA vaccine is available and is recommended for all persons
working with this agent.
eThis virus is presently being registered in the Catalogue
of Arboviruses.
IX. Proposed Amendments to Sections I, III, IV, V, and Appendix M
of the NIH Guidelines Regarding NIH and FDA Consolidated Review of
Human Gene Transfer Protocols
On July 18-19, 1994, the National Task Force on AIDS Drug
Development held an open meeting for the purpose of identifying
barriers to AIDS Drug Discovery that included a proposal to streamline
the dual review process for human gene transfer experiments. Members of
the Task Force recommended a consolidated review process to enhance
interactions between the NIH and the Food and Drug Administration
(FDA). As a result of the Task Force's deliberations, recommendations
were adopted in order to eliminate any unnecessary overlap between the
FDA and NIH review of human gene transfer proposals. Both Drs. Varmus
and Kessler noted that their respective agencies would cooperate fully
to effect the changes necessary to implement these recommendations.
The NIH and FDA proposed that the RAC become advisory to both the
NIH Director and the FDA Commissioner with regard to the review of
human gene transfer protocols. In the interest of maximizing the
resources of both agencies and simplifying the method and period of
review for research protocols involving human gene transfer, the FDA
and NIH should institute an interagency consolidated review process
that incorporates the following principal elements:
(1) All human gene transfer protocols shall be submitted directly
to the FDA. Submission will be in the format required by the FDA and
the same format will be used by the RAC when public review is deemed
necessary.
(2) Upon receipt, FDA review will proceed. The NIH/ORDA staff will
simultaneously evaluate the protocol for possible RAC review.
(3) Factors which may contribute to the need for RAC review
include: (a) new vectors/new gene delivery systems, (b) new diseases,
(c) unique applications of gene transfer, and (d) other issues that
require further public review.
(4) If either the FDA or NIH/ORDA decides that a proposal should be
reviewed by the RAC, the proposal will be forwarded to the RAC primary
reviewers immediately. Whenever possible, Principal Investigators will
be notified within 15 working days following receipt of the submission
whether RAC review will be required. (RAC reviewed applications will be
distributed to RAC members approximately four weeks prior to the next
quarterly RAC meeting.)
(5) Semiannual data reporting procedures will remain the
responsibility of NIH (ORDA). Semiannual data reports will be reviewed
by the RAC in a public forum.
In a letter dated August 2, 1994, Dr. Nelson A. Wivel, Director,
ORDA, NIH, provided the RAC with background information regarding the
National Task Force on AIDS Drug Development meeting, and proposed
amendments to Sections I, III, IV, V, and Appendix M of the NIH
Guidelines, to reflect the proposed consolidated review process. The
revised review process was proposed as follows:
(1) Investigators will be required to submit all human gene
transfer proposals directly to the FDA in the format required by the
FDA; therefore, investigators will no longer be required to provide a
separate submission to NIH/ORDA for RAC review. The FDA Division of
Cellular and Gene Therapies will forward a copy of each submission to
NIH/ORDA. Both the FDA Division of Cellular and Gene Therapies and NIH/
ORDA will simultaneously evaluate each proposal for the necessity for
RAC review. Whenever possible, the investigators will be notified
within 15 working days following receipt of the submission regarding
the necessity for RAC review.
(2) If either the FDA or NIH/ORDA decides that a proposal should
undergo RAC review, the proposal will be forwarded to the RAC primary
reviewers immediately. Any protocol submitted less than 8 weeks before
a RAC meeting will be reviewed at the following quarterly RAC meeting.
(3) The RAC will make recommendations regarding approval/
disapproval of protocols, including any relevant stipulations, to the
NIH Director. The NIH Director will review, approve, and transmit the
RAC's recommendations/stipulations to the FDA Commissioner.
(4) The FDA will consider such recommendations/stipulations and
will be responsible for completion of review. The RAC and NIH/ORDA will
no longer have the responsibility for reviewing material submitted for
Accelerated Review or for the review of minor modifications to human
gene transfer protocols.
These proposed actions were discussed during the September 12-13,
1994, RAC meeting (published for public comments in the Federal
Register, August 23, 1994 (59 FR 43426)). Dr. Philip Noguchi, Director,
Division of Cellular and Gene Therapies, Center for Biologics
Evaluation and Research, FDA, provided additional suggestions regarding
the proposed review process including FDA adoption of the Appendix M,
Points to Consider in the Design and Submission of Protocols for the
Transfer of Recombinant DNA Molecules into the Genome of One or More
Human Subject (Points to Consider), of the NIH Guidelines. The FDA will
require investigators to submit the Points to Consider with their
proposed experiments. A lengthy discussion ensued involving RAC
members' concerns and suggestions regarding the consolidated review
process.
Dr. Noguchi submitted the following compromise proposal regarding
the NIH/FDA consolidated review of human gene transfer experiments:
(1) Appendix M, Points to Consider, will not be deleted from the
NIH Guidelines. The NIH Guidelines will be modified to provide for
submission of Appendix M, Points to Consider, directly to the FDA prior
to IND submission. The FDA will update their guidance documents in a
similar manner. When necessary, the RAC will continue to be responsible
for modifying Appendix M, Points to Consider.
(2) The FDA, NIH/ORDA, and RAC will decide on the necessity for
full RAC review. The submitted Appendix M, Points to Consider, will be
publicly available for all human gene transfer submissions even if RAC
review is not required.
(3) The RAC and FDA will broaden their scope of review for human
gene transfer proposals to jointly and prospectively address global
issues on a regular basis, e.g., ethical consideration in the
implementation of gene therapy patient registry, access for ``orphan''
genetic disease patients to therapies, criteria for prenatal gene
therapy, and transgenic technology for xenotransplantation.
(4) The FDA, NIH/ORDA, and RAC will establish a working group to
enhance data monitoring efforts.
(5) An FDA, NIH/ORDA, and RAC working group will be established to
propose long-term consolidation. The working group will have input from
[[Page 7640]] public, academic, and corporate sources.
The RAC approved a motion made by Dr. Miller and seconded by Dr.
Zallen to accept the following: (1) the FDA proposal submitted by Dr.
Noguchi; (2) adopt the Categories for Accelerated Review that were
approved by the RAC at its March 3-4, 1994, meeting, as guidelines for
proposals that will not require RAC review; (3) establish a working
group to examine the review process for human gene transfer protocols
(in response to Dr. Varmus' request to establish such a group); (3) the
RAC prefers that any stipulation requirements should be satisfactorily
met prior to forwarding its recommendation for approval to the NIH
Director; and (4) accept the proposed amendments to the NIH Guidelines
to reflect this revised consolidated review process (including
acceptance of a revised Appendix M and incorporation of minor editorial
changes).
The motion was approved by a vote of 15 in favor, 0 opposed, and 1
abstention.
On October 26, 1994, NIH/ORDA forwarded these actions to the NIH
Guidelines (incorporating the modifications accepted by the RAC), to
the NIH Director for approval and the FDA Commissioner for concurrence.
FDA legal counsel expressed concern that implementation of the proposed
actions would require amendments to the FDA Investigational New Drug
Application Regulations (21 CFR Part 312) to accommodate the release of
proprietary information. To resolve this concern, a waiver for the
release of information from the FDA to the NIH was proposed. While the
NIH Guidelines could require such a waiver for NIH-funded
investigators, it would be voluntary for others submitting proposed
human gene transfer experiments to the FDA.
The NIH expressed concern that failure to comply with the voluntary
waiver procedures may result in the loss of critical information
necessary to maintain: (1) The human gene therapy database, (2) ``real-
time'' reporting of serious adverse events, (3) comprehensive overview
(by category) by the RAC in a public forum. Public review and access to
submission, review, and follow-up information is critical to the safe
and focussed advancement of human gene therapy research.
As a result of these concerns, NIH and FDA agreed on a compromise
proposal that would accommodate the single submission format proposed
at the July 18-19, 1994, meeting of the National Task Force on AIDS
Drug Development, yet maintain public access to critical information
and ``real-time'' adverse event reporting. The compromise proposal
involves simultaneous submission of a human gene transfer proposal to
both the FDA and the NIH in a single submission format. This format
includes (but is not limited) to the documentation described in
Appendix M-I through M-V, of the Points to Consider. NIH/ORDA and the
FDA will simultaneously evaluate the proposal regarding the necessity
for RAC review.
Section I-A, Purpose, is proposed to read:
Section I-A. Purpose
The purpose of the NIH Guidelines is to specify practices for
constructing and handling: (i) recombinant deoxyribonucleic acid (DNA)
molecules, and (ii) organisms and viruses containing recombinant DNA
molecules.
Section I-A-1. Any recombinant DNA experiment, which according to
the NIH Guidelines requires approval by the NIH, must be submitted to
the NIH or to another Federal agency that has jurisdiction for review
and approval. Once approvals, or other applicable clearances, have been
obtained from a Federal agency other than the NIH (whether the
experiment is referred to that agency by the NIH or sent directly there
by the submitter), the experiment may proceed without the necessity for
NIH review or approval (see exception in Section I-A-1-a).
Section I-A-1-a. In the interest of maximizing the resources of
both the NIH and the Food and Drug Administration (FDA) and simplifying
the method and period for review, research proposals involving the
deliberate transfer of recombinant DNA or DNA or RNA derived from
recombinant DNA into human subjects (human gene transfer) will be
considered through a consolidated review process involving both the FDA
and the NIH. Submission of human gene transfer proposals will be in the
format described in Appendices M-I through M-V of the Points to
Consider. Investigators must simultaneously submit their human gene
transfer proposal to both the FDA and the NIH in a single submission
format. This format includes (but is not limited to) the documentation
described in Appendices M-I through M-V, of the Points to Consider.
NIH/ORDA and the FDA will simultaneously evaluate the proposal
regarding the necessity for RAC review.
Section III beginning paragraphs is proposed to read:
This section describes five categories of experiments involving
recombinant DNA: (i) those that require Institutional Biosafety
Committee approval, RAC review, and NIH Director approval before
initiation (see Section III-A), (ii) those that require NIH/ORDA and
Institutional Biosafety Committee approval before initiation (see
Section III-B); (iii) those that require Institutional Biosafety
Committee approval before initiation (see Section III-C), (iv) those
that require Institutional Biosafety Committee notification
simultaneous with initiation (see Section III-D), and (v) those that
are exempt from the NIH Guidelines (see Section III-E).
Note: If an experiment falls into either Section III-A or
Section III-B and one of the other categories, the rules pertaining
to Section III-A or Section III-B shall be followed. If an
experiment falls into Section III-E and into either Sections III-C
or III-D categories as well, the experiment is considered exempt
from the NIH Guidelines.
Any change in containment level, which is different from those
specified in the NIH Guidelines, may not be initiated without the
express approval of NIH/ORDA (see Minor Actions, Section IV-C-1-b-(2)
and its subsections).
Section III-A is proposed to read:
Section III-A. Experiments that Require Institutional Biosafety
Committee Approval, RAC Review, and NIH Director Approval Before
Initiation (see Section IV-C-1-b-(1)).
Section III-A-1. Major Actions Under the NIH Guidelines
Experiments considered as Major Actions under the NIH Guidelines
cannot be initiated without submission of relevant information on the
proposed experiment to the Office of Recombinant DNA Activities,
National Institutes of Health, Suite 323, 6006 Executive Boulevard, MSC
7052, Bethesda, Maryland 20892-7052, (301) 496-9838, the publication of
the proposal in the Federal Register for 15 days of comment, review by
the RAC, and specific approval by the NIH (see Appendix M for
submission requirements on human gene transfer experiments). The
containment conditions or stipulation requirements for such experiments
will be recommended by the RAC and set by the NIH at the time of
approval. Such experiments require Institutional Biosafety Committee
approval before initiation. Specific experiments already approved are
included in Appendix D which may be obtained from the Office
[[Page 7641]] of Recombinant DNA Activities, National Institutes of
Health, Suite 323, 6006 Executive Boulevard, MSC 7052, Bethesda,
Maryland 20892-7052, (301) 496-9838.
Section III-A-1-a. The deliberate transfer of a drug resistance
trait to microorganisms that are not known to acquire the trait
naturally (see Section V-B), if such acquisition could compromise the
use of the drug to control disease agents in humans, veterinary
medicine, or agriculture, will be reviewed by the RAC.
Section III-A-2. Human Gene Transfer Experiments
Investigators must simultaneously submit their human gene transfer
proposal to both the FDA and the NIH in a single submission format.
This format includes (but is not limited to) the documentation
described in Appendices M-I through M-V, of the Points to Consider. The
NIH/ORDA and the FDA will simultaneously evaluate the proposal
regarding the necessity for RAC review.
Factors that may contribute to the necessity for RAC review
include: (i) New vectors/new gene delivery systems, (ii) new diseases,
(iii) unique applications of gene transfer, and (iv) other issues
considered to require further public discussion. Among the experiments
that may be considered exempt from RAC review are those determined by
the FDA and NIH/ORDA not to represent possible risk to human health or
the environment (see Appendix M-VII, Categories of Human Gene Transfer
Experiments that May Be Exempt from RAC Review). Whenever possible,
investigators will be notified within 15 working days following receipt
of the submission whether RAC review will be required. In the event
that NIH/ORDA and the FDA require RAC review of the submitted proposal,
the documentation described in Appendices M-I through M-V of the Points
to Consider, will be forwarded to the RAC primary reviewers for
evaluation. RAC meetings will be open to the public except where trade
secrets and proprietary information are reviewed. The RAC and FDA
prefer that information provided in response to Appendix M contain no
proprietary data or trade secrets, enabling all aspects of the review
to be open to the public. The RAC will recommend approval or
disapproval of the reviewed proposal to the NIH Director. In the event
that a proposal is contingently approved by the RAC, the RAC prefers
that the conditions be satisfactorily met before the RAC's
recommendation for approval is submitted to the NIH Director. The NIH
Director's decision on the submitted proposal will be transmitted to
the FDA Commissioner and considered as a Major Action by the NIH
Director.
Section III-B is proposed to read:
Section III-B. Experiments That Require NIH/ORDA and Institutional
Biosafety Committee Approval Before Initiation
Section III-B-1. Experiments Involving the Cloning of Toxin Molecules
With LD50 of Less Than 100 Nanograms per Kilogram Body Weight
Deliberate formation of recombinant DNA containing genes for the
biosynthesis of toxin molecules lethal for vertebrates at an LD50
of less than 100 nanograms per kilogram body weight (e.g., microbial
toxins such as the botulinum toxins, tetanus toxin, diphtheria toxin,
and Shigella dysenteriae neurotoxin). Specific approval has been given
for the cloning in Escherichia coli K-12 of DNA containing genes coding
for the biosynthesis of toxic molecules which are lethal to vertebrates
at 100 nanograms to 100 micrograms per kilogram body weight. Specific
experiments already approved under this section may be obtained from
the Office of Recombinant DNA Activities, National Institutes of
Health, Suite 323, 6006 Executive Boulevard, MSC 7052, Bethesda,
Maryland 20892-7052, (301) 496-9838.
Section III-B-1-(a). Experiments in this category cannot be
initiated without submission of relevant information on the proposed
experiment to NIH/ORDA. The containment conditions for such experiments
will be determined by NIH/ORDA in consultation with ad hoc experts.
Such experiments require Institutional Biosafety Committee approval
before initiation (see Section IV-B-2-b-(1)).
Section III-C-7 is proposed to be deleted:
Section III-C-7. Human Gene Transfer Experiments Not Covered by
Sections III-A-2, III-B-2, III-B-3, and Not Considered Exempt Under
Section V-U
Certain experiments involving the transfer of recombinant DNA or
DNA or RNA derived from recombinant DNA into one or more human subjects
that are not covered by Sections III-A-2, III-B-2, III-B-3, and that
are not considered exempt under Section V-U must be registered with
NIH/ORDA. The relevant Institutional Biosafety Committee and
Institutional Review Board must review and approve all experiments in
this category prior to their initiation.
Section IV-B-4-b, Submissions by the Principal Investigator to the
NIH/ORDA, is proposed to read:
Section IV-B-4-b-(3). Petition NIH/ORDA, with concurrence of the
Institutional Biosafety Committee, for approval to conduct experiments
specified in Sections III-A-1 and III-B of the NIH Guidelines;
In Section IV-B-4-e, Responsibilities of the Principal Investigator
During the Conduct of the Research, the following section is added:
Section IV-B-4-e-(5). Comply with semiannual data reporting and
adverse event reporting requirements for NIH and FDA-approved human
gene transfer experiments (see Appendix M-VIII, Reporting
Requirements--Human Gene Transfer Protocols).
Section IV-C-1-b-(1), Major Actions, the first paragraph is
proposed to read:
To execute Major Actions, the NIH Director shall seek the advice of
the RAC and provide an opportunity for public and Federal agency
comment. Specifically, the Notice of Meeting and Proposed Actions shall
be published in the Federal Register at least 15 days before the RAC
meeting. The NIH Director's decision/recommendation (at his/her
discretion) may be published in the Federal Register for 15 days of
comment before final action is taken. The NIH Director's final
decision/recommendation, along with responses to public comments, shall
be published in the Federal Register. The RAC and Institutional
Biosafety Committee Chairs shall be notified of the following
decisions:
Section IV-C-1-b-(1)-(e) is proposed to read:
Section IV-C-1-b-(1)-(e). Recommendations made by the NIH Director
to the FDA Commissioner regarding RAC-reviewed human gene transfer
experiments (see Appendix M-VI-E, RAC Recommendations to the NIH
Director);
Except for renumbering, the rest of the Section IV-C-1-b-(1) would
remain unchanged.
In Section IV-C-1-b-(2), Minor Actions, the following sections are
proposed to be deleted:
Section IV-C-1-b-(2)-(a). Reviewing and approving certain
experiments involving the deliberate transfer of recombinant DNA or DNA
or RNA derived from recombinant DNA into one or more human subjects
that qualify for the Accelerated Review process (see Section III-B-2);
Section IV-C-1-b-(2)-(b). Reviewing and approving minor changes to
human gene transfer protocols under Section III-A-2 and III-B-2;
[[Page 7642]]
The rest of Section IV-C-1-b-(2) would be renumbered.
Section IV-C-3, Office of Recombinant DNA Activities (ORDA), is
proposed to read:
Section IV-C-3. Office of Recombinant DNA Activities (ORDA)
ORDA shall serve as a focal point for information on recombinant
DNA activities and provide advice to all within and outside NIH
including institutions, Biological Safety Officers, Principal
Investigators, Federal agencies, state and local governments, and
institutions in the private sector. ORDA shall carry out such other
functions as may be delegated to it by the NIH Director. ORDA's
responsibilities include, but are not limited to the following:
Section IV-C-3-a. Evaluating human gene transfer protocols for the
necessity for RAC review (see Appendix M-VI-A);
Section IV-C-3-b. Serving as the focal point for data management of
FDA and NIH approved human gene transfer protocols (see Appendix M-
VIII, Reporting Requirements--Human Gene Transfer Protocols);
Section IV-C-3-c. Administering the semiannual data reporting
requirements (and subsequent review) for human gene transfer
experiments, including experiments that are reviewed solely by the FDA
(see Appendix M-VI, Categories of Human Gene Transfer Experiments that
May Be Exempt from RAC Review);
Section IV-C-3-d. Maintaining an inventory of NIH- and FDA-approved
human gene transfer experiments (including subsequent modifications);
Section IV-C-3-e. Reviewing and approving experiments in
conjunction with ad hoc experts involving the cloning of genes encoding
for toxin molecules that are lethal for vertebrates at an LD50 of
less than or equal to 100 nanograms per kilogram body weight in
organisms other than Escherichia coli K-12 (see Section III-B-1 and
Appendices F-I and F-II);
Section IV-C-3-f. Serving as the executive secretary of the RAC;
Section IV-C-3-g. Publishing in the Federal Register:
Section IV-C-3-g-(1). Announcements of RAC meetings and agendas at
least 15 days in advance (Note--If the agenda for a RAC meeting is
modified, ORDA shall make the revised agenda available to anyone upon
request in advance of the meeting);
Section IV-C-3-g-(2). Proposed Major Actions (see Section IV-C-1-b-
(1)) at least 15 days prior to the RAC meeting; and
Section IV-C-3-h. Reviewing and approving the membership of an
institution's Institutional Biosafety Committee, and where it finds the
Institutional Biosafety Committee meets the requirements set forth in
Section IV-B-2 will give its approval to the Institutional Biosafety
Committee membership,
In Section V, Footnotes and References of Sections I through IV,
the following sections are proposed to be deleted:
Section V-U. Human studies in which the induction or enhancement of
an immune response to a vector-encoded microbial immunogen is the major
goal, such an immune response has been demonstrated in model systems,
and the persistence of the vector-encoded immunogen is not expected,
are not covered under Sections III-A-2, III-B-2, or III-B-3. Such
studies may be initiated without RAC review and NIH approval if
approved by another Federal agency.
Section V-V. For recombinant DNA experiments in which the intent is
to modify stably the genome of cells of one or more human subjects (see
Sections III-A-2, III-B-2, and III-B-3).
Section V-W would be renumbered to Section V-U:
Section V-U. In accordance with accepted scientific and regulatory
practices of the discipline of plant pathology, an exotic plant
pathogen (e.g., virus, bacteria, or fungus) is one that is unknown to
occur within the U.S. (see Section V-R). Determination of whether a
pathogen has a potential for serious detrimental impact on managed
(agricultural, forest, grassland) or natural ecosystems should be made
by the Principal Investigator and the Institutional Biosafety
Committee, in consultation with scientists knowledgeable of plant
diseases, crops, and ecosystems in the geographic area of the research.
In Appendix C, Exemptions under Section III-E-6, the following
sections are proposed to read:
Appendix C-I-A. Exceptions
The following categories are not exempt from the NIH Guidelines:
(i) experiments described in Section III-A which require Institutional
Biosafety Committee approval, RAC review, and NIH Director approval
before initiation. * * *
Appendix C-II-A. Exceptions
The following categories are not exempt from the NIH Guidelines:
(i) experiments described in Section III-A which require Institutional
Biosafety Committee approval, RAC review, and NIH Director approval
before initiation. * * *
Appendix C-III-A. Exceptions
The following categories are not exempt from the NIH Guidelines:
(i) experiments described in Section III-A which require Institutional
Biosafety Committee approval, RAC review, and NIH Director approval
before initiation. * * *
Appendix C-IV-A. Exceptions
The following categories are not exempt from the NIH Guidelines:
(i) experiments described in Section III-A which require Institutional
Biosafety Committee approval, RAC review, and NIH Director approval
before initiation. * * *
Appendix C-V-A. Exceptions
The following categories are not exempt from the NIH Guidelines:
(i) experiments described in Section III-A which require Institutional
Biosafety Committee approval, RAC review, and NIH Director approval
before initiation. * * *
Appendix C-VI-A-1. The NIH Director, with advice of the RAC, may revise
the classification for the purposes of these NIH Guidelines (see
Section IV-C-1-b-(2)-(b). * * *
In Appendix F, Containment Conditions for Cloning of Genes Coding
for the Biosynthesis of Molecules Toxic for Vertebrates, the following
sections are proposed to be amended due to reference changes:
Appendix F-I. General Information
. . . The results of such tests shall be forwarded to NIH/ORDA,
which will consult with ad hoc experts, prior to inclusion of the
molecules on the list (see Section IV-C-1-b-(2)-(c)).
Appendix F-III. Cloning of Toxic Molecule Genes in Organisms Other Than
Escherichia coli K-12
Requests involving the cloning of genes coding for toxin molecules
for vertebrates at an LD50 of <100 nanograms="" per="" kilogram="" body="" weight="" in="" host-vector="" systems="" other="" than="" escherichia="" coli="" k-12="" will="" be="" evaluated="" by="" nih/orda="" in="" consultation="" with="" ad="" hoc="" toxin="" experts="" (see="" sections="" iii-b-1="" and="" iv-c-1-b-(2)-(c)).="" in="" appendix="" g,="" physical="" containment,="" the="" following="" section="" is="" proposed="" to="" be="" amended="" due="" to="" a="" reference="" change:="" appendix="" g-ii.="" physical="" containment="" levels="" *="" *="" *="" consideration="" will="" be="" given="" by="" the="" nih="" director,="" with="" the="" advice="" of="" the="" [[page="" 7643]]="" rac,="" to="" other="" combinations="" which="" achieve="" an="" equivalent="" level="" of="" containment="" (see="" section="" iv-c-1-b-(2)-(a).="" in="" appendix="" i,="" biological="" containment,="" the="" following="" section="" is="" proposed="" to="" be="" amended="" due="" to="" a="" reference="" change:="" appendix="" i-ii-a.="" responsibility="" *="" *="" *="" proposed="" host-vector="" systems="" will="" be="" reviewed="" by="" the="" rac="" (see="" section="" iv-c-1-b-(1)-(f).="" *="" *="" *="" minor="" modifications="" to="" existing="" host-="" vector="" systems="" (i.e.,="" those="" that="" are="" of="" minimal="" or="" no="" consequence="" to="" the="" properties="" relevant="" to="" containment),="" may="" be="" certified="" by="" the="" nih="" director="" without="" prior="" rac="" review="" (see="" section="" iv-c-1-b-(2)-(f).="" *="" *="" *="" the="" nih="" director="" may="" rescind="" the="" certification="" of="" a="" host-vector="" system="" (see="" section="" iv-c-1-b-(2)-(g).*="" *="" *="" appendix="" m,="" the="" points="" to="" consider="" in="" the="" design="" and="" submission="" of="" protocols="" for="" the="" transfer="" of="" recombinant="" dna="" molecules="" into="" the="" genome="" of="" one="" or="" more="" human="" subjects="" (points="" to="" consider),="" is="" proposed="" to="" read:="" appendix="" m.="" the="" points="" to="" consider="" in="" the="" design="" and="" submission="" of="" protocols="" for="" the="" transfer="" of="" recombinant="" dna="" molecules="" into="" the="" genome="" of="" one="" or="" more="" human="" subjects="" (points="" to="" consider)="" appendix="" m="" applies="" to="" research="" conducted="" at="" or="" sponsored="" by="" an="" institution="" that="" receives="" any="" support="" for="" recombinant="" dna="" research="" from="" the="" nih.="" researchers="" not="" covered="" by="" the="" nih="" guidelines="" are="" encouraged="" to="" use="" appendix="" m.="" the="" acceptability="" of="" human="" somatic="" cell="" gene="" therapy="" has="" been="" addressed="" in="" several="" public="" documents="" as="" well="" as="" in="" numerous="" academic="" studies.="" in="" november="" 1982,="" the="" president's="" commission="" for="" the="" study="" of="" ethical="" problems="" in="" medicine="" and="" biomedical="" and="" behavioral="" research="" published="" a="" report,="" splicing="" life,="" which="" resulted="" from="" a="" two-year="" process="" of="" public="" deliberation="" and="" hearings.="" upon="" release="" of="" that="" report,="" a="" u.s.="" house="" of="" representatives="" subcommittee="" held="" three="" days="" of="" public="" hearings="" with="" witnesses="" from="" a="" wide="" range="" of="" fields="" from="" the="" biomedical="" and="" social="" sciences="" to="" theology,="" philosophy,="" and="" law.="" in="" december="" 1984,="" the="" office="" of="" technology="" assessment="" released="" a="" background="" paper,="" human="" gene="" therapy,="" which="" concluded:="" civic,="" religious,="" scientific,="" and="" medical="" groups="" have="" all="" accepted,="" in="" principle,="" the="" appropriateness="" of="" gene="" therapy="" of="" somatic="" cells="" in="" humans="" for="" specific="" genetic="" diseases.="" somatic="" cell="" gene="" therapy="" is="" seen="" as="" an="" extension="" of="" present="" methods="" of="" therapy="" that="" might="" be="" preferable="" to="" other="" technologies.="" in="" light="" of="" this="" public="" support,="" the="" recombinant="" dna="" advisory="" committee="" (rac)="" is="" prepared="" to="" consider="" proposals="" for="" somatic="" cell="" gene="" transfer.="" the="" rac="" will="" not="" at="" present="" entertain="" proposals="" for="" germ="" line="" alterations="" but="" will="" consider="" proposals="" involving="" somatic="" cell="" gene="" transfer.="" the="" purpose="" of="" somatic="" cell="" gene="" therapy="" is="" to="" treat="" an="" individual="" patient,="" e.g.,="" by="" inserting="" a="" properly="" functioning="" gene="" into="" the="" subject's="" somatic="" cells.="" germ="" line="" alteration="" involves="" a="" specific="" attempt="" to="" introduce="" genetic="" changes="" into="" the="" germ="" (reproductive)="" cells="" of="" an="" individual,="" with="" the="" aim="" of="" changing="" the="" set="" of="" genes="" passed="" on="" to="" the="" individual's="" offspring.="" in="" the="" interest="" of="" maximizing="" the="" resources="" of="" both="" the="" nih="" and="" the="" food="" and="" drug="" administration="" (fda)="" and="" simplifying="" the="" method="" and="" period="" for="" review,="" research="" proposals="" involving="" the="" deliberate="" transfer="" of="" recombinant="" dna="" or="" dna="" or="" rna="" derived="" from="" recombinant="" dna="" into="" human="" subjects="" (human="" gene="" transfer)="" will="" be="" considered="" through="" a="" consolidated="" review="" process="" involving="" both="" the="" fda="" and="" the="" nih.="" submission="" of="" human="" gene="" transfer="" proposals="" will="" be="" in="" the="" format="" described="" in="" appendices="" m-i="" through="" m-v="" of="" the="" points="" to="" consider.="" investigators="" must="" simultaneously="" submit="" their="" human="" gene="" transfer="" proposal="" to="" both="" the="" fda="" and="" the="" nih="" in="" a="" single="" submission="" format.="" this="" format="" includes="" (but="" is="" not="" limited="" to)="" the="" documentation="" described="" in="" appendices="" m-i="" through="" m-v="" of="" the="" points="" to="" consider.="" nih/="" orda="" and="" the="" fda="" will="" simultaneously="" evaluate="" the="" proposal="" regarding="" the="" necessity="" for="" rac="" review.="" factors="" that="" may="" contribute="" to="" the="" necessity="" for="" rac="" review="" include:="" (i)="" new="" vectors/new="" gene="" delivery="" systems,="" (ii)="" new="" diseases,="" (iii)="" unique="" applications="" of="" gene="" transfer,="" and="" (iv)="" other="" issues="" considered="" to="" require="" further="" public="" discussion.="" among="" the="" experiments="" that="" may="" be="" considered="" exempt="" from="" rac="" review="" are="" those="" determined="" by="" the="" fda="" and="" nih/orda="" not="" to="" represent="" possible="" risk="" to="" human="" health="" or="" the="" environment="" (see="" appendix="" m-vii,="" categories="" of="" human="" gene="" transfer="" experiments="" that="" may="" be="" exempt="" from="" rac="" review).="" whenever="" possible,="" investigators="" will="" be="" notified="" within="" 15="" working="" days="" following="" receipt="" of="" the="" submission="" whether="" rac="" review="" will="" be="" required.="" in="" the="" event="" that="" nih/orda="" and="" the="" fda="" require="" rac="" review="" of="" the="" submitted="" proposal,="" the="" documentation="" described="" in="" appendices="" m-i="" through="" m-v="" of="" the="" points="" to="" consider,="" will="" be="" forwarded="" to="" the="" rac="" primary="" reviewers="" for="" evaluation.="" rac="" meetings="" will="" be="" open="" to="" the="" public="" except="" where="" trade="" secrets="" and="" proprietary="" information="" are="" reviewed.="" the="" rac="" and="" fda="" prefer="" that="" information="" provided="" in="" response="" to="" appendix="" m="" contain="" no="" proprietary="" data="" or="" trade="" secrets,="" enabling="" all="" aspects="" of="" the="" review="" to="" be="" open="" to="" the="" public.="" the="" rac="" will="" recommend="" approval="" or="" disapproval="" of="" the="" reviewed="" proposal="" to="" the="" nih="" director.="" in="" the="" event="" that="" a="" proposal="" is="" contingently="" approved="" by="" the="" rac,="" the="" rac="" prefers="" that="" the="" conditions="" be="" satisfactorily="" met="" before="" the="" rac's="" recommendation="" for="" approval="" is="" submitted="" to="" the="" nih="" director.="" the="" nih="" director's="" decision="" on="" the="" submitted="" proposal="" will="" be="" transmitted="" to="" the="" fda="" commissioner="" and="" considered="" as="" a="" major="" action="" by="" the="" nih="" director.="" public="" review="" of="" human="" gene="" transfer="" proposals="" will="" serve="" to="" inform="" the="" public="" about="" the="" technical="" aspects="" of="" the="" proposals="" as="" well="" as="" the="" meaning="" and="" significance="" of="" the="" research.="" in="" its="" evaluation="" of="" human="" gene="" transfer="" proposals,="" the="" rac,="" nih/="" orda,="" and="" the="" fda="" will="" consider="" whether="" the="" design="" of="" such="" experiments="" offers="" adequate="" assurance="" that="" their="" consequences="" will="" not="" go="" beyond="" their="" purpose,="" which="" is="" the="" same="" as="" the="" traditional="" purpose="" of="" clinical="" investigation,="" namely,="" to="" protect="" the="" health="" and="" well="" being="" of="" human="" subjects="" being="" treated="" while="" at="" the="" same="" time="" gathering="" generalizable="" knowledge.="" two="" possible="" undesirable="" consequences="" of="" the="" transfer="" of="" recombinant="" dna="" would="" be="" unintentional:="" (i)="" vertical="" transmission="" of="" genetic="" changes="" from="" an="" individual="" to="" his/her="" offspring,="" or="" (ii)="" horizontal="" transmission="" of="" viral="" infection="" to="" other="" persons="" with="" whom="" the="" individual="" comes="" in="" contact.="" accordingly,="" appendices="" m-i="" through="" m-="" v="" requests="" information="" that="" will="" enable="" the="" rac,="" nih/orda,="" and="" the="" fda,="" to="" assess="" the="" possibility="" that="" the="" proposed="" experiment(s)="" will="" inadvertently="" affect="" reproductive="" cells="" or="" lead="" to="" infection="" of="" other="" people="" (e.g.,="" medical="" personnel="" or="" relatives).="" in="" recognition="" of="" the="" social="" concern="" that="" surrounds="" the="" subject="" of="" human="" gene="" transfer,="" the="" rac,="" nih/orda,="" and="" the="" fda,="" will="" cooperate="" with="" other="" groups="" in="" assessing="" the="" possible="" long-term="" consequences="" of="" the="" proposal="" and="" related="" laboratory="" and="" animal="" experiments="" in="" order="" to="" define="" appropriate="" human="" applications="" of="" this="" emerging="" technology.="" [[page="" 7644]]="" appendix="" m="" will="" be="" considered="" for="" revisions="" as="" experience="" in="" evaluating="" proposals="" accumulates="" and="" as="" new="" scientific="" developments="" occur.="" this="" review="" will="" be="" carried="" out="" periodically="" as="" needed.="" appendix="" m-i.="" submission="" requirements--human="" gene="" transfer="" proposals="" investigators="" must="" simultaneously="" submit="" the="" following="" material="" to="" both:="" (1)="" the="" office="" of="" recombinant="" dna="" activities="" (orda),="" national="" institutes="" of="" health,="" suite="" 323,="" 6006="" executive="" boulevard,="" msc="" 7052,="" bethesda,="" maryland="" 20892-7052="" (see="" exemption="" in="" appendix="" m-ix-a);="" and="" (2)="" the="" division="" of="" congressional="" and="" public="" affairs,="" document="" control="" center,="" hfm-99,="" center="" for="" biologics="" evaluation="" and="" research,="" 1401="" rockville="" pike,="" rockville,="" maryland="" 20852-1448.="" proposals="" will="" be="" submitted="" in="" the="" following="" order:="" (1)="" scientific="" abstract--1="" page;="" (2)="" non-technical="" abstract--1="" page;="" (3)="" institutional="" biosafety="" committee="" and="" institutional="" review="" board="" approvals="" and="" their="" deliberations="" pertaining="" to="" your="" protocol="" (the="" ibc="" and="" irb="" may,="" at="" their="" discretion,="" condition="" their="" approval="" on="" further="" specific="" deliberation="" by="" the="" rac);="" (4)="" responses="" to="" appendix="" m-ii,="" description="" of="" the="" proposal--5="" pages;="" (5)="" protocol="" (as="" approved="" by="" the="" local="" institutional="" biosafety="" committee="" and="" institutional="" review="" board)--20="" pages;="" (6)="" informed="" consent="" document--approved="" by="" the="" institutional="" review="" board="" (see="" appendix="" m-iii);="" (7)="" appendices="" (including="" tables,="" figures,="" and="" manuscripts);="" (8)="" curricula="" vitae--2="" pages="" for="" each="" key="" professional="" person="" in="" biographical="" sketch="" format;="" and="" (9)="" three="" 3="" 1/2="" inch="" diskettes="" with="" the="" complete="" vector="" nucleotide="" sequence="" in="" ascii="" format.="" appendix="" m-ii.="" description="" of="" the="" proposal="" responses="" to="" this="" appendix="" should="" be="" provided="" in="" the="" form="" of="" either="" written="" answers="" or="" references="" to="" specific="" sections="" of="" the="" protocol="" or="" its="" appendices.="" investigators="" should="" indicate="" the="" points="" that="" are="" not="" applicable="" with="" a="" brief="" explanation.="" investigators="" submitting="" proposals="" that="" employ="" the="" same="" vector="" systems="" may="" refer="" to="" preceding="" documents="" relating="" to="" the="" vector="" sequence="" without="" having="" to="" rewrite="" such="" material.="" appendix="" m-ii-a.="" objectives="" and="" rationale="" of="" the="" proposed="" research="" state="" concisely="" the="" overall="" objectives="" and="" rationale="" of="" the="" proposed="" study.="" provide="" information="" on="" the="" specific="" points="" that="" relate="" to="" whichever="" type="" of="" research="" is="" being="" proposed.="" appendix="" m-ii-a-1.="" use="" of="" recombinant="" dna="" for="" therapeutic="" purposes="" for="" research="" in="" which="" recombinant="" dna="" is="" transferred="" in="" order="" to="" treat="" a="" disease="" or="" disorder="" (e.g.,="" genetic="" diseases,="" cancer,="" and="" metabolic="" diseases),="" the="" following="" questions="" should="" be="" addressed:="" appendix="" m-ii-a-1-a.="" why="" is="" the="" disease="" selected="" for="" treatment="" by="" means="" of="" gene="" therapy="" a="" good="" candidate="" for="" such="" treatment?="" appendix="" m-ii-a-1-b.="" describe="" the="" natural="" history="" and="" range="" of="" expression="" of="" the="" disease="" selected="" for="" treatment.="" what="" objective="" and/or="" quantitative="" measures="" of="" disease="" activity="" are="" available?="" in="" your="" view,="" are="" the="" usual="" effects="" of="" the="" disease="" predictable="" enough="" to="" allow="" for="" meaningful="" assessment="" of="" the="" results="" of="" gene="" therapy?="" appendix="" m-ii-a-1-c.="" is="" the="" protocol="" designed="" to="" prevent="" all="" manifestations="" of="" the="" disease,="" to="" halt="" the="" progression="" of="" the="" disease="" after="" symptoms="" have="" begun="" to="" appear,="" or="" to="" reverse="" manifestations="" of="" the="" disease="" in="" seriously="" ill="" victims?="" appendix="" m-ii-a-1-d.="" what="" alternative="" therapies="" exist?="" in="" what="" groups="" of="" patients="" are="" these="" therapies="" effective?="" what="" are="" their="" relative="" advantages="" and="" disadvantages="" as="" compared="" with="" the="" proposed="" gene="" therapy?="" appendix="" m-ii-a-2.="" transfer="" of="" dna="" for="" other="" purposes="" appendix="" m-ii-a-2-a.="" into="" what="" cells="" will="" the="" recombinant="" dna="" be="" transferred?="" why="" is="" the="" transfer="" of="" recombinant="" dna="" necessary="" for="" the="" proposed="" research?="" what="" questions="" can="" be="" answered="" by="" using="" recombinant="" dna?="" appendix="" m-ii-a-2-b.="" what="" alternative="" methodologies="" exist?="" what="" are="" their="" relative="" advantages="" and="" disadvantages="" as="" compared="" to="" the="" use="" of="" recombinant="" dna?="" appendix="" m-ii-b.="" research="" design,="" anticipated="" risks="" and="" benefits="" appendix="" m-ii-b-1.="" structure="" and="" characteristics="" of="" the="" biological="" system="" provide="" a="" full="" description="" of="" the="" methods="" and="" reagents="" to="" be="" employed="" for="" gene="" delivery="" and="" the="" rationale="" for="" their="" use.="" the="" following="" are="" specific="" points="" to="" be="" addressed:="" appendix="" m-ii-b-1-a.="" what="" is="" the="" structure="" of="" the="" cloned="" dna="" that="" will="" be="" used?="" appendix="" m-ii-b-1-a-(1).="" describe="" the="" gene="" (genomic="" or="" cdna),="" the="" bacterial="" plasmid="" or="" phage="" vector,="" and="" the="" delivery="" vector="" (if="" any).="" provide="" complete="" nucleotide="" sequence="" analysis="" or="" a="" detailed="" restriction="" enzyme="" map="" of="" the="" total="" construct.="" appendix="" m-ii-b-1-a-(2).="" what="" regulatory="" elements="" does="" the="" construct="" contain="" (e.g.,="" promoters,="" enhancers,="" polyadenylation="" sites,="" replication="" origins,="" etc.)?="" from="" what="" source="" are="" these="" elements="" derived?="" summarize="" what="" is="" currently="" known="" about="" the="" regulatory="" character="" of="" each="" element.="" appendix="" m-ii-b-1-a-(3).="" describe="" the="" steps="" used="" to="" derive="" the="" dna="" construct.="" appendix="" m-ii-b-1-b.="" what="" is="" the="" structure="" of="" the="" material="" that="" will="" be="" administered="" to="" the="" patient?="" appendix="" m-ii-b-1-b-(1).="" describe="" the="" preparation,="" structure,="" and="" composition="" of="" the="" materials="" that="" will="" be="" given="" to="" the="" patient="" or="" used="" to="" treat="" the="" patient's="" cells:="" (i)="" if="" dna,="" what="" is="" the="" purity="" (both="" in="" terms="" of="" being="" a="" single="" dna="" species="" and="" in="" terms="" of="" other="" contaminants)?="" what="" tests="" have="" been="" used="" and="" what="" is="" the="" sensitivity="" of="" the="" tests?="" (ii)="" if="" a="" virus,="" how="" is="" it="" prepared="" from="" the="" dna="" construct?="" in="" what="" cell="" is="" the="" virus="" grown="" (any="" special="" features)?="" what="" medium="" and="" serum="" are="" used?="" how="" is="" the="" virus="" purified?="" what="" is="" its="" structure="" and="" purity?="" what="" steps="" are="" being="" taken="" (and="" assays="" used="" with="" their="" sensitivity)="" to="" detect="" and="" eliminate="" any="" contaminating="" materials="" (for="" example,="" vl30="" rna,="" other="" nucleic="" acids,="" or="" proteins)="" or="" contaminating="" viruses="" (both="" replication-competent="" or="" replication-defective)="" or="" other="" organisms="" in="" the="" cells="" or="" serum="" used="" for="" preparation="" of="" the="" virus="" stock="" including="" any="" contaminants="" that="" may="" have="" biological="" effects?="" (iii)="" if="" co-cultivation="" is="" employed,="" what="" kinds="" of="" cells="" are="" being="" used="" for="" co-="" cultivation?="" what="" steps="" are="" being="" taken="" (and="" assays="" used="" with="" their="" sensitivity)="" to="" detect="" and="" eliminate="" any="" contaminating="" materials?="" specifically,="" what="" tests="" are="" being="" conducted="" to="" assess="" the="" material="" to="" be="" returned="" to="" the="" patient="" for="" the="" presence="" of="" live="" or="" killed="" donor="" cells="" or="" other="" non-vector="" materials="" (for="" example,="" vl30="" sequences)="" originating="" from="" those="" cells?="" (iv)="" if="" methods="" other="" than="" those="" covered="" by="" appendices="" m-ii-b-1="" through="" m-ii-b-3="" are="" used="" to="" introduce="" new="" genetic="" information="" into="" target="" cells,="" what="" steps="" are="" being="" taken="" to="" detect="" and="" eliminate="" any="" contaminating="" materials?="" what="" are="" possible="" sources="" of="" contamination?="" what="" is="" the="" sensitivity="" of="" tests="" used="" to="" monitor="" contamination?="" appendix="" m-ii-b-1-b-(2).="" describe="" any="" other="" material="" to="" be="" used="" in="" [[page="" 7645]]="" preparation="" of="" the="" material="" to="" be="" administered="" to="" the="" patient.="" for="" example,="" if="" a="" viral="" vector="" is="" proposed,="" what="" is="" the="" nature="" of="" the="" helper="" virus="" or="" cell="" line?="" if="" carrier="" particles="" are="" to="" be="" used,="" what="" is="" the="" nature="" of="" these?="" appendix="" m-ii-b-2.="" preclinical="" studies,="" including="" risk-assessment="" studies="" provide="" results="" that="" demonstrate="" the="" safety,="" efficacy,="" and="" feasibility="" of="" the="" proposed="" procedures="" using="" animal="" and/or="" cell="" culture="" model="" systems,="" and="" explain="" why="" the="" model(s)="" chosen="" is/are="" most="" appropriate.="" appendix="" m-ii-b-2-a.="" delivery="" system="" appendix="" m-ii-b-2-a-(1).="" what="" cells="" are="" the="" intended="" target="" cells="" of="" recombinant="" dna?="" what="" target="" cells="" are="" to="" be="" treated="" ex="" vivo="" and="" returned="" to="" the="" patient,="" how="" will="" the="" cells="" be="" characterized="" before="" and="" after="" treatment?="" what="" is="" the="" theoretical="" and="" practical="" basis="" for="" assuming="" that="" only="" the="" target="" cells="" will="" incorporate="" the="" dna?="" appendix="" m-ii-b-2-a-(2).="" is="" the="" delivery="" system="" efficient?="" what="" percentage="" of="" the="" target="" cells="" contain="" the="" added="" dna?="" appendix="" m-ii-b-2-a-(3).="" how="" is="" the="" structure="" of="" the="" added="" dna="" sequences="" monitored="" and="" what="" is="" the="" sensitivity="" of="" the="" analysis?="" is="" the="" added="" dna="" extrachromosomal="" or="" integrated?="" is="" the="" added="" dna="" unrearranged?="" appendix="" m-ii-b-2-a-(4).="" how="" many="" copies="" are="" present="" per="" cell?="" how="" stable="" is="" the="" added="" dna="" both="" in="" terms="" of="" its="" continued="" presence="" and="" its="" structural="" stability?="" appendix="" m-ii-b-2-b.="" gene="" transfer="" and="" expression="" appendix="" m-ii-b-2-b-(1).="" what="" animal="" and="" cultured="" cell="" models="" were="" used="" in="" laboratory="" studies="" to="" assess="" the="" in="" vivo="" and="" in="" vitro="" efficacy="" of="" the="" gene="" transfer="" system?="" in="" what="" ways="" are="" these="" models="" similar="" to="" and="" different="" from="" the="" proposed="" human="" treatment?="" appendix="" m-ii-b-2-b-(2).="" what="" is="" the="" minimal="" level="" of="" gene="" transfer="" and/or="" expression="" that="" is="" estimated="" to="" be="" necessary="" for="" the="" gene="" transfer="" protocol="" to="" be="" successful="" in="" humans?="" how="" was="" this="" level="" determined?="" appendix="" m-ii-b-2-b-(3).="" explain="" in="" detail="" all="" results="" from="" animal="" and="" cultured="" cell="" model="" experiments="" which="" assess="" the="" effectiveness="" of="" the="" delivery="" system="" in="" achieving="" the="" minimally="" required="" level="" of="" gene="" transfer="" and="" expression.="" appendix="" m-ii-b-2-b-(4).="" to="" what="" extent="" is="" expression="" only="" from="" the="" desired="" gene="" (and="" not="" from="" the="" surrounding="" dna)?="" to="" what="" extent="" does="" the="" insertion="" modify="" the="" expression="" of="" other="" genes?="" appendix="" m-ii-b-2-b-(5).="" in="" what="" percentage="" of="" cells="" does="" expression="" from="" the="" added="" dna="" occur?="" is="" the="" product="" biologically="" active?="" what="" percentage="" of="" normal="" activity="" results="" from="" the="" inserted="" gene?="" appendix="" m-ii-b-2-b-(6).="" is="" the="" gene="" expressed="" in="" cells="" other="" than="" the="" target="" cells?="" if="" so,="" to="" what="" extent?="" appendix="" m-ii-b-2-c.="" retrovirus="" delivery="" systems="" appendix="" m-ii-b-2-c-(1).="" what="" cell="" types="" have="" been="" infected="" with="" the="" retroviral="" vector="" preparation?="" which="" cells,="" if="" any,="" produce="" infectious="" particles?="" appendix="" m-ii-b-2-c-(2).="" how="" stable="" are="" the="" retroviral="" vector="" and="" the="" resulting="" provirus="" against="" loss,="" rearrangement,="" recombination,="" or="" mutation?="" what="" information="" is="" available="" on="" how="" much="" rearrangement="" or="" recombination="" with="" endogenous="" or="" other="" viral="" sequences="" is="" likely="" to="" occur="" in="" the="" patient's="" cells?="" what="" steps="" have="" been="" taken="" in="" designing="" the="" vector="" to="" minimize="" instability="" or="" variation?="" what="" laboratory="" studies="" have="" been="" performed="" to="" check="" for="" stability,="" and="" what="" is="" the="" sensitivity="" of="" the="" analyses?="" appendix="" m-ii-b-2-c-(3).="" what="" laboratory="" evidence="" is="" available="" concerning="" potential="" harmful="" effects="" of="" the="" transfer="" (e.g.,="" development="" of="" neoplasia,="" harmful="" mutations,="" regeneration="" of="" infectious="" particles,="" or="" immune="" responses)?="" what="" steps="" will="" be="" taken="" in="" designing="" the="" vector="" to="" minimize="" pathogenicity?="" what="" laboratory="" studies="" have="" been="" performed="" to="" check="" for="" pathogenicity,="" and="" what="" is="" the="" sensitivity="" of="" the="" analyses?="" appendix="" m-ii-b-2-c-(4).="" is="" there="" evidence="" from="" animal="" studies="" that="" vector="" dna="" has="" entered="" untreated="" cells,="" particularly="" germ-line="" cells?="" what="" is="" the="" sensitivity="" of="" these="" analyses?="" appendix="" m-ii-b-2-c-(5).="" has="" a="" protocol="" similar="" to="" the="" one="" proposed="" for="" a="" clinical="" trial="" been="" conducted="" in="" non-human="" primates="" and/or="" other="" animals?="" what="" were="" the="" results?="" specifically,="" is="" there="" any="" evidence="" that="" the="" retroviral="" vector="" has="" recombined="" with="" any="" endogenous="" or="" other="" viral="" sequences="" in="" the="" animals?="" appendix="" m-ii-b-2-d.="" non-retrovirus="" delivery/expression="" systems="" if="" a="" non-retroviral="" delivery="" system="" is="" used,="" what="" animal="" studies="" have="" been="" conducted="" to="" determine="" if="" there="" are="" pathological="" or="" other="" undesirable="" consequences="" of="" the="" protocol="" (including="" insertion="" of="" dna="" into="" cells="" other="" than="" those="" treated,="" particularly="" germ-line="" cells)?="" how="" long="" have="" the="" animals="" been="" studied="" after="" treatment?="" what="" safety="" studies="" have="" been="" conducted?="" (include="" data="" about="" the="" level="" of="" sensitivity="" of="" such="" assays.)="" appendix="" m-ii-b-3.="" clinical="" procedures,="" including="" patient="" monitoring="" describe="" the="" treatment="" that="" will="" be="" administered="" to="" patients="" and="" the="" diagnostic="" methods="" that="" will="" be="" used="" to="" monitor="" the="" success="" or="" failure="" of="" the="" treatment.="" if="" previous="" clinical="" studies="" using="" similar="" methods="" have="" been="" performed="" by="" yourself="" or="" others,="" indicate="" their="" relevance="" to="" the="" proposed="" study.="" specifically:="" appendix="" m-ii-b-3-a.="" will="" cells="" (e.g.,="" bone="" marrow="" cells)="" be="" removed="" from="" patients="" and="" treated="" ex="" vivo?="" if="" so,="" describe="" the="" type,="" number,="" and="" intervals="" at="" which="" these="" cells="" will="" be="" removed.="" appendix="" m-ii-b-3-b.="" will="" patients="" be="" treated="" to="" eliminate="" or="" reduce="" the="" number="" of="" cells="" containing="" malfunctioning="" genes="" (e.g.,="" through="" radiation="" or="" chemotherapy)?="" appendix="" m-ii-b-3-c.="" what="" treated="" cells="" (or="" vector/dna="" combination)="" will="" be="" given="" to="" patients?="" how="" will="" the="" treated="" cells="" be="" administered?="" what="" volume="" of="" cells="" will="" be="" used?="" will="" there="" be="" single="" or="" multiple="" treatments?="" if="" so,="" over="" what="" period="" of="" time?="" appendix="" m-ii-b-3-d.="" how="" will="" it="" be="" determined="" that="" new="" gene="" sequences="" have="" been="" inserted="" into="" the="" patient's="" cells="" and="" if="" these="" sequences="" are="" being="" expressed?="" are="" these="" cells="" limited="" to="" the="" intended="" target="" cell="" populations?="" how="" sensitive="" are="" these="" analyses?="" appendix="" m-ii-b-3-e.="" what="" studies="" will="" be="" conducted="" to="" assess="" the="" presence="" and="" effects="" of="" the="" contaminants?="" appendix="" m-ii-b-3-f.="" what="" are="" the="" clinical="" endpoints="" of="" the="" study?="" are="" there="" objectives="" and="" quantitative="" measurements="" to="" assess="" the="" natural="" history="" of="" the="" disease?="" will="" such="" measurements="" be="" used="" in="" patient="" follow-up?="" how="" will="" patients="" be="" monitored="" to="" assess="" specific="" effects="" of="" the="" treatment="" on="" the="" disease?="" what="" is="" the="" sensitivity="" of="" the="" analyses?="" how="" frequently="" will="" follow-up="" studies="" be="" conducted?="" how="" long="" will="" patient="" follow-up="" continue?="" appendix="" m-ii-b-3-g.="" what="" are="" the="" major="" beneficial="" and="" adverse="" effects="" of="" treatment="" that="" you="" anticipate?="" what="" measures="" will="" be="" taken="" in="" an="" attempt="" to="" control="" or="" reverse="" these="" adverse="" effects="" if="" they="" occur?="" compare="" the="" probability="" and="" magnitude="" of="" deleterious="" consequences="" from="" the="" disease="" if="" recombinant="" dna="" transfer="" is="" not="" used.="" [[page="" 7646]]="" appendix="" m-ii-b-3-h.="" if="" a="" treated="" patient="" dies,="" what="" special="" post-="" mortem="" studies="" will="" be="" performed?="" appendix="" m-ii-b-4.="" public="" health="" considerations="" describe="" any="" potential="" benefits="" and="" hazards="" of="" the="" proposed="" therapy="" to="" persons="" other="" than="" the="" patients="" being="" treated.="" specifically:="" appendix="" m-ii-b-4-a.="" on="" what="" basis="" are="" potential="" public="" health="" benefits="" or="" hazards="" postulated?="" appendix="" m-ii-b-4-b.="" is="" there="" a="" significant="" possibility="" that="" the="" added="" dna="" will="" spread="" from="" the="" patient="" to="" other="" persons="" or="" to="" the="" environment?="" appendix="" m-ii-b-4-c.="" what="" precautions="" will="" be="" taken="" against="" such="" spread="" (e.g.,="" patients="" sharing="" a="" room,="" health-care="" workers,="" or="" family="" members)?="" appendix="" m-ii-b-4-d.="" what="" measures="" will="" be="" undertaken="" to="" mitigate="" the="" risks,="" if="" any,="" to="" public="" health?="" appendix="" m-ii-b-4-e.="" in="" light="" of="" possible="" risks="" to="" offspring,="" including="" vertical="" transmission,="" will="" birth="" control="" measures="" be="" recommended="" to="" patients?="" are="" such="" concerns="" applicable="" to="" health="" care="" personnel?="" appendix="" m-ii-b-5.="" qualifications="" of="" investigators="" and="" adequacy="" of="" laboratory="" and="" clinical="" facilities="" indicate="" the="" relevant="" training="" and="" experience="" of="" the="" personnel="" who="" will="" be="" involved="" in="" the="" preclinical="" studies="" and="" clinical="" administration="" of="" recombinant="" dna.="" describe="" the="" laboratory="" and="" clinical="" facilities="" where="" the="" proposed="" study="" will="" be="" performed.="" specifically:="" appendix="" m-ii-b-5-a.="" what="" professional="" personnel="" (medical="" and="" nonmedical)="" will="" be="" involved="" in="" the="" proposed="" study="" and="" what="" is="" their="" relevant="" expertise?="" provide="" a="" two-page="" curriculum="" vitae="" for="" each="" key="" professional="" person="" in="" biographical="" sketch="" format="" (see="" appendix="" m-i,="" submission="" requirements).="" appendix="" m-ii-b-5-b.="" at="" what="" hospital="" or="" clinic="" will="" the="" treatment="" be="" given?="" which="" facilities="" of="" the="" hospital="" or="" clinic="" will="" be="" especially="" important="" for="" the="" proposed="" study?="" will="" patients="" occupy="" regular="" hospital="" beds="" or="" clinical="" research="" center="" beds?="" where="" will="" patients="" reside="" during="" the="" follow-up="" period?="" what="" special="" arrangements="" will="" be="" made="" for="" the="" comfort="" and="" consideration="" of="" the="" patients.="" will="" the="" research="" institution="" designate="" an="" ombudsman,="" patient="" care="" representative,="" or="" other="" individual="" to="" help="" protect="" the="" rights="" and="" welfare="" of="" the="" patient?="" appendix="" m-ii-c.="" selection="" of="" the="" patients="" estimate="" the="" number="" of="" patients="" to="" be="" involved="" in="" the="" proposed="" study.="" describe="" recruitment="" procedures="" and="" patient="" eligibility="" requirements,="" paying="" particular="" attention="" to="" whether="" these="" procedures="" and="" requirements="" are="" fair="" and="" equitable.="" specifically:="" appendix="" m-ii-c-1.="" how="" many="" patients="" do="" you="" plan="" to="" involve="" in="" the="" proposed="" study?="" appendix="" m-ii-c-2.="" how="" many="" eligible="" patients="" do="" you="" anticipate="" being="" able="" to="" identify="" each="" year?="" appendix="" m-ii-c-3.="" what="" recruitment="" procedures="" do="" you="" plan="" to="" use?="" appendix="" m-ii-c-4.="" what="" selection="" criteria="" do="" you="" plan="" to="" employ?="" what="" are="" the="" exclusion="" and="" inclusion="" criteria="" for="" the="" study?="" appendix="" m-ii-c-5.="" how="" will="" patients="" be="" selected="" if="" it="" is="" not="" possible="" to="" include="" all="" who="" desire="" to="" participate?="" appendix="" m-iii.="" informed="" consent="" in="" accordance="" with="" the="" protection="" of="" human="" subjects="" (45="" cfr="" part="" 46),="" investigators="" should="" indicate="" how="" subjects="" will="" be="" informed="" about="" the="" proposed="" study="" and="" the="" manner="" in="" which="" their="" consent="" will="" be="" solicited.="" they="" should="" indicate="" how="" the="" informed="" consent="" document="" makes="" clear="" the="" special="" requirements="" of="" gene="" transfer="" research.="" if="" a="" proposal="" involves="" children,="" special="" attention="" should="" be="" paid="" to="" the="" protection="" of="" human="" subjects="" (45="" cfr="" part="" 46),="" subpart="" d,="" additional="" protections="" for="" children="" involved="" as="" subjects="" in="" research.="" appendix="" m-iii-a.="" communication="" about="" the="" study="" to="" potential="" participants="" appendix="" m-iii-a-1.="" which="" members="" of="" the="" research="" group="" and/or="" institution="" will="" be="" responsible="" for="" contacting="" potential="" participants="" and="" for="" describing="" the="" study="" to="" them?="" what="" procedures="" will="" be="" used="" to="" avoid="" possible="" conflicts="" of="" interest="" if="" the="" investigator="" is="" also="" providing="" medical="" care="" to="" potential="" subjects?="" appendix="" m-iii-a-2.="" how="" will="" the="" major="" points="" covered="" in="" appendix="" m-ii,="" description="" of="" proposal,="" be="" disclosed="" to="" potential="" participants="" and/or="" their="" parents="" or="" guardians="" in="" language="" that="" is="" understandable="" to="" them?="" appendix="" m-iii-a-3.="" what="" is="" the="" length="" of="" time="" that="" potential="" participants="" will="" have="" to="" make="" a="" decision="" about="" their="" participation="" in="" the="" study?="" appendix="" m-iii-a-4.="" if="" the="" study="" involves="" pediatric="" or="" mentally="" handicapped="" subjects,="" how="" will="" the="" assent="" of="" each="" person="" be="" obtained?="" appendix="" m-iii-b.="" informed="" consent="" document="" investigators="" submitting="" human="" gene="" transfer="" proposals="" must="" include="" the="" informed="" consent="" document="" as="" approved="" by="" the="" local="" institutional="" review="" board.="" a="" separate="" informed="" consent="" document="" should="" be="" used="" for="" the="" gene="" transfer="" portion="" of="" a="" research="" project="" when="" gene="" transfer="" is="" used="" as="" an="" adjunct="" in="" the="" study="" of="" another="" technique,="" e.g.,="" when="" a="" gene="" is="" used="" as="" a="" `marker'="" or="" to="" enhance="" the="" power="" of="" immunotherapy="" for="" cancer.="" because="" of="" the="" relative="" novelty="" of="" the="" procedures="" that="" are="" used,="" the="" potentially="" irreversible="" consequences="" of="" the="" procedures="" performed,="" and="" the="" fact="" that="" many="" of="" the="" potential="" risks="" remain="" undefined,="" the="" informed="" consent="" document="" should="" include="" the="" following="" specific="" information="" in="" addition="" to="" any="" requirements="" of="" the="" dhhs="" regulations="" for="" the="" protection="" of="" human="" subjects="" (45="" cfr="" 46).="" indicate="" if="" each="" of="" the="" specified="" items="" appears="" in="" the="" informed="" consent="" document="" or,="" if="" not="" included="" in="" the="" informed="" consent="" document,="" how="" those="" items="" will="" be="" presented="" to="" potential="" subjects.="" include="" an="" explanation="" if="" any="" of="" the="" following="" items="" are="" omitted="" from="" the="" consent="" process="" or="" the="" informed="" consent="" document.="" appendix="" m-iii-b-1.="" general="" requirements="" of="" human="" subjects="" research="" appendix="" m-iii-b-1-a.="" description/purpose="" of="" the="" study="" the="" subjects="" should="" be="" provided="" with="" a="" detailed="" explanation="" in="" non-="" technical="" language="" of="" the="" purpose="" of="" the="" study="" and="" the="" procedures="" associated="" with="" the="" conduct="" of="" the="" proposed="" study,="" including="" a="" description="" of="" the="" gene="" transfer="" component.="" appendix="" m-iii-b-1-b.="" alternatives="" the="" informed="" consent="" document="" should="" indicate="" the="" availability="" of="" therapies="" and="" the="" possibility="" of="" other="" investigational="" interventions="" and="" approaches.="" appendix="" m-iii-b-1-c.="" voluntary="" participation="" the="" subjects="" should="" be="" informed="" that="" participation="" in="" the="" study="" is="" voluntary="" and="" that="" failure="" to="" participate="" in="" the="" study="" or="" withdrawal="" of="" consent="" will="" not="" result="" in="" any="" penalty="" or="" loss="" of="" benefits="" to="" which="" the="" subjects="" are="" otherwise="" entitled.="" appendix="" m-iii-b-1-d.="" benefits="" the="" subjects="" should="" be="" provided="" with="" an="" accurate="" description="" of="" the="" possible="" benefits,="" if="" any,="" of="" participating="" in="" the="" proposed="" study.="" for="" studies="" that="" are="" not="" reasonably="" expected="" to="" provide="" a="" therapeutic="" benefit="" to="" subjects,="" the="" [[page="" 7647]]="" informed="" consent="" document="" should="" clearly="" state="" that="" no="" direct="" clinical="" benefit="" to="" subjects="" is="" expected="" to="" occur="" as="" a="" result="" of="" participation="" in="" the="" study,="" although="" knowledge="" may="" be="" gained="" that="" may="" benefit="" others.="" appendix="" m-iii-b-1-e.="" possible="" risks,="" discomforts,="" and="" side="" effects="" there="" should="" be="" clear="" itemization="" in="" the="" informed="" consent="" document="" of="" types="" of="" adverse="" experiences,="" their="" relative="" severity,="" and="" their="" expected="" frequencies.="" for="" consistency,="" the="" following="" definitions="" are="" suggested:="" side="" effects="" that="" are="" listed="" as="" mild="" should="" be="" ones="" which="" do="" not="" require="" a="" therapeutic="" intervention;="" moderate="" side="" effects="" require="" an="" intervention;="" and="" severe="" side="" effects="" are="" potentially="" fatal="" or="" life-="" threatening,="" disabling,="" or="" require="" prolonged="" hospitalization.="" if="" verbal="" descriptors="" (e.g.,="" ``rare,''="" ``uncommon,''="" or="" ``frequent'')="" are="" used="" to="" express="" quantitative="" information="" regarding="" risk,="" these="" terms="" should="" be="" explained.="" the="" informed="" consent="" document="" should="" provide="" information="" regarding="" the="" approximate="" number="" of="" people="" who="" have="" previously="" received="" the="" genetic="" material="" under="" study.="" it="" is="" necessary="" to="" warn="" potential="" subjects="" that,="" for="" genetic="" materials="" previously="" used="" in="" relatively="" few="" or="" no="" humans,="" unforeseen="" risks="" are="" possible,="" including="" ones="" that="" could="" be="" severe.="" the="" informed="" consent="" document="" should="" indicate="" any="" possible="" adverse="" medical="" consequences="" that="" may="" occur="" if="" the="" subjects="" withdraw="" from="" the="" study="" once="" the="" study="" has="" started.="" appendix="" m-iii-b-1-f.="" costs="" the="" subjects="" should="" be="" provided="" with="" specific="" information="" about="" any="" financial="" costs="" associated="" with="" their="" participation="" in="" the="" protocol="" and="" in="" the="" long-term="" follow-up="" to="" the="" protocol="" that="" are="" not="" covered="" by="" the="" investigators="" or="" the="" institution="" involved.="" subjects="" should="" be="" provided="" an="" explanation="" about="" the="" extent="" to="" which="" they="" will="" be="" responsible="" for="" any="" costs="" for="" medical="" treatment="" required="" as="" a="" result="" of="" research-related="" injury.="" appendix="" m-iii-b-2.="" specific="" requirements="" of="" gene="" transfer="" research="" appendix="" m-iii-b-2-a.="" reproductive="" considerations="" to="" avoid="" the="" possibility="" that="" any="" of="" the="" reagents="" employed="" in="" the="" gene="" transfer="" research="" could="" cause="" harm="" to="" a="" fetus/child,="" subjects="" should="" be="" given="" information="" concerning="" possible="" risks="" and="" the="" need="" for="" contraception="" by="" males="" and="" females="" during="" the="" active="" phase="" of="" the="" study.="" the="" period="" of="" time="" for="" the="" use="" of="" contraception="" should="" be="" specified.="" the="" inclusion="" of="" pregnant="" or="" lactating="" women="" should="" be="" addressed.="" appendix="" m-iii-b-2-b.="" long-term="" follow-up="" to="" permit="" evaluation="" of="" long-term="" safety="" and="" efficacy="" of="" gene="" transfer,="" the="" prospective="" subjects="" should="" be="" informed="" that="" they="" are="" expected="" to="" cooperate="" in="" long-term="" follow-up="" that="" extends="" beyond="" the="" active="" phase="" of="" the="" study.="" the="" informed="" consent="" document="" should="" include="" a="" list="" of="" persons="" who="" can="" be="" contacted="" in="" the="" event="" that="" questions="" arise="" during="" the="" follow-up="" period.="" the="" investigator="" should="" request="" that="" subjects="" continue="" to="" provide="" a="" current="" address="" and="" telephone="" number.="" the="" subjects="" should="" be="" informed="" that="" any="" significant="" findings="" resulting="" from="" the="" study="" will="" be="" made="" known="" in="" a="" timely="" manner="" to="" them="" and/or="" their="" parent="" or="" guardian="" including="" new="" information="" about="" the="" experimental="" procedure,="" the="" harms="" and="" benefits="" experienced="" by="" other="" individuals="" involved="" in="" the="" study,="" and="" any="" long-term="" effects="" that="" have="" been="" observed.="" appendix="" m-iii-b-2-c.="" request="" for="" autopsy="" to="" obtain="" vital="" information="" about="" the="" safety="" and="" efficacy="" of="" gene="" transfer,="" subjects="" should="" be="" informed="" that="" at="" the="" time="" of="" death,="" no="" matter="" what="" the="" cause,="" permission="" for="" an="" autopsy="" will="" be="" requested="" of="" their="" families.="" subjects="" should="" be="" asked="" to="" advise="" their="" families="" of="" the="" request="" and="" of="" its="" scientific="" and="" medical="" importance.="" appendix="" m-iii-b-2-d.="" interest="" of="" the="" media="" and="" others="" in="" the="" research="" to="" alert="" subjects="" that="" others="" may="" have="" an="" interest="" in="" the="" innovative="" character="" of="" the="" protocol="" and="" in="" the="" status="" of="" the="" treated="" subjects,="" the="" subjects="" should="" be="" informed="" of="" the="" following:="" (i)="" that="" the="" institution="" and="" investigators="" will="" make="" efforts="" to="" provide="" protection="" from="" the="" media="" in="" an="" effort="" to="" protect="" the="" participants'="" privacy,="" and="" (ii)="" that="" representatives="" of="" applicable="" federal="" agencies="" (e.g.,="" the="" national="" institutes="" of="" health="" and="" the="" food="" and="" drug="" administration),="" representatives="" of="" collaborating="" institutions,="" vector="" suppliers,="" etc.,="" will="" have="" access="" to="" the="" subjects'="" medical="" records.="" appendix="" m-iv.="" privacy="" and="" confidentiality="" indicate="" what="" measures="" will="" be="" taken="" to="" protect="" the="" privacy="" of="" patients="" and="" their="" families="" as="" well="" as="" to="" maintain="" the="" confidentiality="" of="" research="" data.="" appendix="" m-iv-a.="" what="" provisions="" will="" be="" made="" to="" honor="" the="" wishes="" of="" individual="" patients="" (and="" the="" parents="" or="" guardians="" of="" pediatric="" or="" mentally="" handicapped="" patients)="" as="" to="" whether,="" when,="" or="" how="" the="" identity="" of="" patients="" is="" publicly="" disclosed.="" appendix="" m-iv-b.="" what="" provisions="" will="" be="" made="" to="" maintain="" the="" confidentiality="" of="" research="" data,="" at="" least="" in="" cases="" where="" data="" could="" be="" linked="" to="" individual="" patients?="" appendix="" m-v.="" special="" issues="" although="" the="" following="" issues="" are="" beyond="" the="" normal="" purview="" of="" local="" institutional="" review="" boards,="" investigators="" should="" respond="" to="" the="" following="" questions:="" appendix="" m-v-a.="" what="" steps="" will="" be="" taken,="" consistent="" with="" appendix="" m-iv,="" privacy="" and="" confidentiality,="" to="" ensure="" that="" accurate="" and="" appropriate="" information="" is="" made="" available="" to="" the="" public="" with="" respect="" to="" such="" public="" concerns="" as="" may="" arise="" from="" the="" proposed="" study?="" appendix="" m-v-b.="" do="" you="" or="" your="" funding="" sources="" intend="" to="" protect="" under="" patent="" or="" trade="" secret="" laws="" either="" the="" products="" or="" the="" procedures="" developed="" in="" the="" proposed="" study?="" if="" so,="" what="" steps="" will="" be="" taken="" to="" permit="" as="" full="" communication="" as="" possible="" among="" investigators="" and="" clinicians="" concerning="" research="" methods="" and="" results?="" appendix="" m-vi.="" rac="" review--human="" gene="" transfer="" protocols="" appendix="" m-vi-a.="" categories="" of="" human="" gene="" transfer="" experiments="" that="" require="" rac="" review="" factors="" that="" may="" contribute="" to="" the="" necessity="" for="" rac="" review="" include,="" but="" are="" not="" limited="" to:="" (i)="" new="" vectors/new="" gene="" delivery="" systems,="" (ii)="" new="" diseases,="" (iii)="" unique="" applications="" of="" gene="" transfer,="" and="" (iv)="" other="" issues="" considered="" to="" require="" further="" public="" discussion.="" whenever="" possible,="" investigators="" will="" be="" notified="" within="" 15="" working="" days="" following="" receipt="" of="" the="" submission="" whether="" rac="" review="" will="" be="" required.="" in="" the="" event="" that="" rac="" review="" is="" deemed="" necessary="" by="" the="" nih="" and="" fda,="" the="" proposal="" will="" be="" forwarded="" to="" the="" rac="" primary="" reviewers="" for="" evaluation.="" in="" order="" to="" maintain="" public="" access="" to="" information="" regarding="" human="" gene="" transfer="" protocols,="" nih/orda="" will="" maintain="" the="" documentation="" described="" in="" appendices="" m-i="" through="" m-v="" (including="" protocols="" that="" are="" not="" reviewed="" by="" the="" rac).="" appendix="" m-vi-b.="" rac="" primary="" reviewers'="" written="" comments="" in="" the="" event="" that="" nih/orda="" and/or="" the="" fda="" recommend="" rac="" review="" of="" the="" submitted="" proposal,="" the="" documentation="" described="" in="" appendices="" m-i="" through="" [[page="" 7648]]="" m-v="" will="" be="" forwarded="" to="" the="" rac="" primary="" reviewers="" for="" evaluation.="" the="" rac="" primary="" reviewers="" shall="" provide="" written="" comments="" on="" the="" proposal="" to="" nih/orda.="" the="" rac="" primary="" reviewers'="" comments="" should="" include="" the="" following:="" appendix="" m-vi-b-1.="" emphasize="" the="" issues="" related="" to="" gene="" marking,="" gene="" transfer,="" or="" gene="" therapy.="" appendix="" m-vi-b-2.="" state="" explicitly="" whether="" appendices="" m-i="" through="" m-v="" have="" been="" addressed="" satisfactorily.="" appendix="" m-vi-b-3.="" examine="" the="" scientific="" rationale,="" scientific="" context="" (relative="" to="" other="" proposals="" reviewed="" by="" the="" rac),="" whether="" the="" preliminary="" in="" vitro="" and="" in="" vivo="" data="" were="" obtained="" in="" appropriate="" models="" and="" are="" sufficient,="" and="" whether="" questions="" related="" to="" safety,="" efficacy,="" and="" social/ethical="" context="" have="" been="" resolved.="" appendix="" m-vi-b-4.="" whenever="" possible,="" criticisms="" of="" informed="" consent="" documents="" should="" include="" written="" alternatives="" for="" suggested="" revisions="" for="" the="" rac="" to="" consider.="" appendix="" m-vi-b-5.="" primary="" reviews="" should="" state="" whether="" the="" proposal="" is:="" (i)="" acceptable="" as="" written,="" (ii)="" expected="" to="" be="" acceptable="" with="" specific="" revisions="" or="" after="" satisfactory="" responses="" to="" specific="" questions="" raised="" on="" review,="" or="" (iii)="" unacceptable="" in="" its="" present="" form.="" appendix="" m-vi-c.="" investigator's="" written="" responses="" to="" rac="" primary="" reviewers="" appendix="" m-vi-c-1.="" written="" responses="" (including="" critical="" data="" in="" response="" to="" rac="" primary="" reviewers'="" written="" comments)="" shall="" be="" submitted="" to="" nih/orda="" greater="" than="" or="" equal="" to="" 2="" weeks="" following="" receipt="" of="" the="" review.="" appendix="" m-vi-d.="" oral="" responses="" to="" the="" rac="" investigators="" shall="" limit="" their="" oral="" responses="" to="" the="" rac="" only="" to="" those="" questions="" that="" are="" raised="" during="" the="" meeting.="" investigators="" are="" strongly="" discouraged="" from="" presenting="" critical="" data="" during="" their="" oral="" presentations="" that="" was="" not="" submitted="" greater="" than="" or="" equal="" to="" 2="" weeks="" in="" advance="" of="" the="" rac="" meeting="" at="" which="" it="" is="" reviewed.="" appendix="" m-vi-e.="" rac="" recommendations="" to="" the="" nih="" director="" the="" rac="" will="" recommend="" approval="" or="" disapproval="" of="" the="" reviewed="" proposal="" to="" the="" nih="" director.="" in="" the="" event="" that="" a="" proposal="" is="" contingently="" approved="" by="" the="" rac,="" the="" rac="" prefers="" that="" the="" conditions="" be="" satisfactorily="" met="" before="" the="" rac's="" recommendation="" for="" approval="" is="" submitted="" to="" the="" nih="" director.="" the="" nih="" director's="" decision="" on="" the="" submitted="" proposal="" will="" be="" transmitted="" to="" the="" fda="" commissioner="" and="" considered="" as="" a="" major="" action="" by="" the="" nih="" director.="" appendix="" m-vii.="" categories="" of="" human="" gene="" transfer="" experiments="" that="" may="" be="" exempt="" from="" rac="" review="" a="" proposal="" submitted="" under="" one="" of="" the="" following="" categories="" may="" be="" considered="" exempt="" from="" rac="" review="" unless="" otherwise="" determined="" by="" nih/="" orda="" and="" the="" fda="" on="" a="" case-by-case="" basis="" (see="" appendix="" m-vi-a,="" categories="" of="" human="" gene="" transfer="" experiments="" that="" require="" rac="" review).="" note:="" in="" the="" event="" that="" the="" submitted="" proposal="" is="" determined="" to="" be="" exempt="" from="" rac="" review,="" the="" documentation="" described="" in="" appendices="" m-i="" through="" m-v="" will="" be="" maintained="" by="" nih/orda="" for="" compliance="" with="" semiannual="" data="" reporting="" and="" adverse="" event="" reporting="" requirements="" (see="" appendix="" m-viii,="" reporting="" requirements--human="" gene="" transfer="" protocols).="" any="" subsequent="" modifications="" to="" proposals="" that="" were="" not="" reviewed="" by="" the="" rac="" must="" be="" submitted="" to="" nih/orda="" in="" order="" to="" facilitate="" data="" reporting="" requirements.="" appendix="" m-vii-a.="" vaccines="" this="" category="" includes="" recombinant="" dna="" vaccines="" not="" otherwise="" exempt="" from="" rac="" review="" (see="" appendix="" m-ix-a="" for="" exempt="" vaccines).="" appendix="" m-vii-b.="" lethally="" irradiated="" tumor="" cells/no="" replication-="" competent="" virus="" this="" category="" includes="" experiments="" involving="" lethally="" irradiated="" tumor="" cells="" and:="" (1)="" vector="" constructs="" that="" have="" previously="" been="" approved="" by="" the="" rac="" (or="" with="" the="" incorporation="" of="" minor="" modifications),="" or="" (2)="" a="" different="" tumor="" cell="" target.="" appendix="" m-vii-c.="" new="" site/original="" investigator="" this="" category="" includes="" the="" following:="" (1)="" initiation="" of="" a="" protocol="" at="" an="" additional="" site="" other="" than="" the="" site="" that="" was="" originally="" approved="" by="" the="" rac,="" and="" (2)="" the="" investigator="" at="" the="" new="" site="" is="" the="" same="" as="" the="" investigator="" approved="" for="" the="" original="" study.="" appendix="" m-vii-d.="" new="" site/new="" investigator="" this="" category="" includes="" the="" following:="" (1)="" initiation="" of="" a="" protocol="" at="" an="" additional="" site="" other="" than="" the="" site="" that="" was="" originally="" approved="" by="" the="" rac,="" and="" (2)="" the="" investigator="" at="" the="" new="" site="" is="" different="" than="" the="" investigator="" approved="" for="" the="" original="" site.="" appendix="" m-vii-e.="" ``umbrella''="" protocols="" this="" category="" includes="" initiation="" of="" a="" rac-approved="" protocol="" at="" more="" than="" one="" additional="" site="" (the="" principal="" investigator="" may="" be="" the="" same="" or="" different="" than="" the="" principal="" investigator="" approved="" for="" the="" original="" site).="" appendix="" m-vii-f.="" modifications="" related="" to="" gene="" transfer="" this="" category="" includes="" experiments="" involving="" a="" modification="" to="" the="" clinical="" protocol="" that="" is="" not="" related="" to="" the="" gene="" transfer="" portion="" of="" study.="" appendix="" m-vii-g.="" gene="" marking="" protocols="" this="" category="" includes="" human="" gene="" marking="" experiments="" involving="" vector="" constructs="" that="" have="" previously="" been="" approved="" by="" the="" rac="" and:="" (1)="" minor="" modifications="" to="" the="" vector="" constructs,="" or="" (2)="" a="" different="" tumor="" cell="" target.="" appendix="" m-viii.="" reporting="" requirements--human="" gene="" transfer="" protocols="" appendix="" m-viii-a.="" semiannual="" data="" reporting="" investigators="" who="" have="" received="" approval="" from="" the="" fda="" to="" initiate="" a="" human="" gene="" transfer="" protocol="" (whether="" or="" not="" it="" has="" been="" reviewed="" by="" the="" rac)="" shall="" be="" required="" to="" comply="" with="" the="" semiannual="" data="" reporting="" requirements.="" semi-annual="" data="" report="" forms="" will="" be="" forwarded="" by="" nih/="" orda="" to="" investigators.="" data="" submitted="" in="" these="" reports="" will="" be="" evaluated="" by="" the="" rac,="" nih/orda,="" and="" the="" fda="" and="" reviewed="" by="" the="" rac="" at="" its="" next="" regularly="" scheduled="" meeting.="" appendix="" m-viii-b.="" adverse="" event="" reporting="" investigators="" who="" have="" received="" approval="" from="" the="" fda="" to="" initiate="" a="" human="" gene="" transfer="" protocol="" (whether="" or="" not="" it="" has="" been="" reviewed="" by="" the="" rac)="" must="" report="" any="" serious="" adverse="" event="" immediately="" to="" the="" local="" irb,="" ibc,="" nih="" office="" for="" protection="" from="" research="" risks,="" fda,="" and="" nih/="" orda,="" followed="" by="" the="" submission="" of="" a="" written="" report="" filed="" with="" each="" group.="" reports="" submitted="" to="" nih/orda="" shall="" be="" sent="" to="" the="" office="" of="" recombinant="" dna="" activities,="" national="" institutes="" of="" health,="" 6006="" executive="" boulevard,="" suite="" 323,="" bethesda,="" maryland="" 20892-7052,="" (301)="" 496-9838.="" appendix="" m-ix.="" footnotes="" of="" appendix="" m="" appendix="" m-ix-a.="" human="" studies="" in="" which="" the="" induction="" or="" enhancement="" of="" an="" immune="" response="" to="" a="" vector-encoded="" microbial="" immunogen="" is="" the="" major="" goal,="" such="" an="" immune="" response="" has="" been="" demonstrated="" in="" model="" systems,="" and="" the="" persistence="" of="" the="" vector-="" encoded="" immunogen="" is="" not="" [[page="" 7649]]="" expected,="" may="" be="" initiated="" without="" rac="" review="" if="" approved="" by="" another="" federal="" agency.="" x.="" discussion="" on="" adenoviral="" vector="" toxicology="" on="" january="" 19,="" 1995,="" dr.="" philip="" noguchi,="" food="" and="" drug="" administration,="" rockville,="" maryland,="" requested="" the="" recombinant="" dna="" advisory="" committee="" discuss="" adenoviral="" vector="" toxicology.="" in="" his="" letter,="" he="" states:="" ``the="" rac="" has="" correctly="" identified="" an="" emerging="" issue="" in="" terms="" of="" preclinical="" toxicities="" of="" adenoviral="" vectors="" given="" parenterally.="" from="" the="" fda's="" point="" of="" view,="" the="" area="" of="" biotoxicology="" is="" an="" evolving="" one="" that="" has="" been="" one="" of="" fda's="" main="" tools="" for="" determining="" dosing="" in="" gene="" therapy="" clinical="" trials.="" for="" gene="" therapies,="" most="" preclinical="" toxicology="" studies="" to="" date="" with="" retroviral="" and="" adenoviral="" vectors="" have="" not="" revealed="" toxicities="" of="" the="" magnitude="" seen="" recently.="" while="" the="" newest="" results="" are="" indeed="" significant,="" from="" the="" fda's="" point="" of="" view,="" animal="" toxicity="" is="" the="" primary="" means="" of="" estimating="" safe="" starting="" doses="" in="" human="" trials.="" thus,="" lack="" of="" overt="" or="" major="" preclinical="" toxicity="" is="" not="" comforting,="" but="" instead="" raises="" the="" specter="" of="" unanticipated="" adverse="" events="" in="" humans.="" the="" unexpected="" adverse="" event="" in="" a="" cystic="" fibrosis="" patient="" given="" an="" adenoviral="" vector="" is="" a="" case="" in="" point.="" the="" fda="" would="" like="" to="" have="" one="" of="" its="" toxicologists="" present="" a="" fifteen="" minute="" overview="" of="" our="" current="" philosophy="" and="" testing="" requirements.="" this="" would="" be="" followed="" by="" a="" short="" presentation="" by="" a="" patient="" who="" will="" give="" a="" perspective="" on="" safety="" concerns="" in="" the="" real="" world="" of="" cancer="" therapy.''="" xi.="" discussion="" on="" adenoviral="" vector="" toxicology="" on="" january="" 19,="" 1995,="" dr.="" philip="" noguchi,="" food="" and="" drug="" administration,="" rockville,="" maryland,="" requested="" the="" recombinant="" dna="" advisory="" committee="" to="" discuss="" transgenic="" xenotransplantation.="" in="" his="" letter,="" he="" states:="" ``millions="" of="" americans="" suffer="" tissue="" loss="" or="" end-stage="" organ="" failure,="" leading="" to="" over="" eight="" million="" surgical="" procedures="" annually.="" current="" therapies="" include="" organ="" transplantation,="" surgical="" reconstruction="" using="" human="" tissues,="" and="" use="" of="" mechanical="" devices="" such="" as="" kidney="" dialysis="" machines.="" these="" treatments="" have="" significantly="" reduced="" the="" morbidity="" and="" mortality="" associated="" with="" tissue="" loss="" and="" end-stage="" organ="" failure.="" transplantation="" as="" curative="" or="" live-saving="" therapy,="" however,="" is="" greatly="" hampered="" by="" a="" critical="" donor="" shortage.="" for="" example,="" over="" 40,000="" patients="" die="" from="" liver="" failure="" annually="" yet="" only="" 4,000="" donors="" are="" available="" annually="" to="" address="" this="" need="" for="" lifesaving="" organs.="" the="" number="" of="" patients="" who="" die="" while="" on="" waiting="" lists="" for="" organ="" transplantation="" is="" increasing="" while="" the="" availability="" of="" donor="" organs="" is="" decreasing.="" novel="" combination="" products="" used="" as="" bridging="" mechanisms="" may="" extend="" patients'="" lives="" and="" increase="" the="" number="" of="" patients="" on="" organ="" transplant="" waiting="" lists.="" the="" unmet="" demand="" for="" clinically="" needed="" human="" tissues="" coupled="" with="" the="" scientific="" and="" biotechnological="" progress="" during="" the="" past="" decade="" have="" also="" provided="" the="" impetus="" for="" new="" therapies="" involving="" xenogeneic="" cells,="" tissues,="" and="" organs.="" ``the="" fda="" has="" become="" aware="" through="" the="" press="" and="" personal="" contacts="" that="" some="" institutional="" review="" boards="" are="" reviewing="" proposals="" for="" xenotransplantation.="" although="" it="" appears="" that="" most="" of="" the="" current="" proposed="" protocols="" seek="" to="" use="" nonhuman="" primate="" donors="" with="" conventional="" patient="" immunosuppression,="" a="" growing="" number="" of="" academic="" and="" commercial="" groups="" are="" exploring="" the="" use="" of="" transgenic="" animals="" in="" which="" human="" genes="" are="" introduced="" into="" the="" animal="" in="" an="" attempt="" to="" lower="" or="" mask="" immunogenicity.="" this="" latter="" category="" is="" a="" form="" of="" human="" gene="" transfer,="" since="" the="" transplanted="" transgenic="" organs="" contain="" human="" genes="" and/or="" human="" gene="" products.="" the="" rac="" review="" process="" has="" served="" society="" well="" in="" the="" measured="" public="" introduction="" of="" gene="" therapies="" into="" clinical="" experimentation.="" we="" suggest="" that="" this="" exciting="" new="" area,="" in="" which="" genetic="" engineering="" is="" further="" extended="" to="" the="" manipulation="" and="" construction="" of="" new="" therapeutic="" entities,="" would="" likewise="" benefit="" from="" regular="" scientific,="" legal="" and="" ethical="" review="" in="" a="" public="" forum.="" ``some="" issues="" for="" public="" discussion="" might="" include:="" (1)="" preclinical:="" what="" kind="" of="" animal="" model="" testing="" would="" be="" needed="" before="" initiation="" of="" transgenic="" xenotransplantation?="" what="" would="" be="" the="" most="" appropriate="" animal="" model?="" what="" degree="" of="" scientific="" rationale="" is="" necessary?="" (2)="" recipient="" issues:="" should="" categories="" of="" patients="" be="" defined="" for="" first="" experimentation?="" those="" who="" are="" acutely="" dying="" with="" no="" immediate="" human="" organ="" available?="" those="" whose="" priority="" is="" so="" low="" that="" the="" patient="" would="" die="" before="" receiving="" an="" organ?="" what="" kinds="" of="" patient="" screening="" and="" follow-up="" would="" be="" needed?="" (3)="" hazards:="" what="" type="" of="" donor="" screening="" should="" be="" conducted?="" what="" new="" hazards="" might="" be="" created="" with="" transgenic="" transplantation,="" i.e.,="" activation="" of="" a="" latent="" human="" virus="" in="" the="" animal="" organ?="" how="" could="" these="" concerns="" be="" addressed,="" i.e.="" specific="" scientific="" studies?="" (4)="" informed="" consent="" and="" study="" results:="" what="" new="" elements="" of="" informed="" consent="" would="" be="" required?="" how="" can="" the="" field="" be="" monitored="" for="" success="" and="" failure?="" should="" the="" local="" irbs="" take="" the="" lead="" in="" primary="" monitoring="" of="" patient="" safety?="" would="" the="" data="" monitoring="" efforts="" used="" for="" gene="" therapies="" be="" useful="" in="" this="" new="" field?="" ``obviously,="" we="" do="" not="" expect="" that="" definitive="" answers="" to="" these="" questions="" and="" issues="" would="" be="" forthcoming="" at="" the="" meeting,="" but="" we="" would="" like="" to="" broach="" the="" subject="" so="" that="" future="" discussions="" can="" be="" planned.="" we="" suggest="" that="" the="" rac="" might="" wish="" to="" augment="" its="" current="" panel="" with="" one="" or="" more="" ad="" hoc="" consultants="" with="" specific="" expertise="" in="" transplantation.''="" omb's="" ``mandatory="" information="" requirements="" for="" federal="" assistance="" program="" announcements''="" (45="" fr="" 39592,="" june="" 11,="" 1980)="" requires="" a="" statement="" concerning="" the="" official="" government="" programs="" contained="" in="" the="" catalog="" of="" federal="" domestic="" assistance.="" normally,="" nih="" lists="" in="" its="" announcements="" the="" number="" and="" title="" of="" affected="" individual="" programs="" for="" the="" guidance="" of="" the="" public.="" because="" the="" guidance="" in="" this="" notice="" covers="" not="" only="" virtually="" every="" nih="" program="" but="" also="" essentially="" every="" federal="" research="" program="" in="" which="" dna="" recombinant="" molecule="" techniques="" could="" be="" used,="" it="" has="" been="" determined="" not="" to="" be="" cost="" effective="" or="" in="" the="" public="" interest="" to="" attempt="" to="" list="" these="" programs.="" such="" a="" list="" would="" likely="" require="" several="" additional="" pages.="" in="" addition,="" nih="" could="" not="" be="" certain="" that="" every="" federal="" program="" would="" be="" included="" as="" many="" federal="" agencies,="" as="" well="" as="" private="" organizations,="" both="" national="" and="" international,="" have="" elected="" to="" follow="" the="" nih="" guidelines.="" in="" lieu="" of="" the="" individual="" program="" listing,="" nih="" invites="" readers="" to="" direct="" questions="" to="" the="" information="" address="" above="" about="" whether="" individual="" programs="" listed="" in="" the="" catalog="" of="" federal="" domestic="" assistance="" are="" affected.="" suzanne="" medgyesi-mitschang,="" acting="" deputy="" director="" for="" science="" policy="" and="" technology="" transfer.="" [fr="" doc.="" 95-2870="" filed="" 2-7-95;="" 8:45="" am]="" billing="" code="" 4140-01-p="">