Recombinant DNA Research: Proposed Actions Under the Guidelines

Federal RegisterFeb 8, 1995

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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

----------------------------------------------------------------------------------------------------------------

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).

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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

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.

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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.

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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-

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,

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

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