[Federal Register Volume 62, Number 31 (Friday, February 14, 1997)]
[Notices]
[Pages 7108-7123]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-3735]


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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.

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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, amended 59 FR 40170, 60 FR 20726, 61 FR 1482, 61 FR 10004, 62 FR 
4782). Interested parties are invited to submit comments concerning 
these proposals. There proposals will be considered by the Recombinant 
DNA Advisory Committee (RAC) at its meeting on March 6-7, 1997. After 
consideration of these proposals and comments by the RAC, the NIH 
Director will issue decisions in accordance with the NIH Guidelines.

Dates: Interested parties are invited to submit comments concerning 
this proposal. Comments received by February 27, 1997, will be 
reproduced and distributed to the RAC for consideration at its March 6-
7, 1997, meeting. After consideration of this proposal and comments by 
the RAC, the NIH Director will issue decisions in accordance with the 
NIH Guidelines.

Addresses: Written comments and recommendations should be submitted to 
Debra Knorr, Office of Recombinant DNA Activities, National Institutes 
of Health, MSC 7010, 6000 Executive Boulevard, Suite 302, Bethesda, 
Maryland 20892-7010, or by FAX to 301-496-9839.
    All comments received in 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, National Institutes of Health, MSC 7010, 6000 Executive 
Boulevard, Suite 302, Bethesda, Maryland 20892-7010, Phone 301-496-
9838, FAX 301-496-9839.

Supplementary Information: The NIH will consider the following actions 
under the NIH Guidelines for Research Involving Recombinant DNA 
Molecules:

I. Amendment to the Overall Procedures for Human Gene Transfer 
Protocols

I-A. Notice of Intent

    On July 8, 1996, the NIH Director published a Notice of Intent to 
Propose Amendments to the NIH Guidelines for Research Involving 
Recombinant DNA Molecules Regarding Enhanced Oversight of Recombinant 
DNA Activities (61 FR 35774). This Notice of Intent proposed 
modifications in NIH oversight of human gene transfer research. 
Specifically, it was proposed that the RAC would be terminated and that 
all approval responsibilities for recombinant DNA experiments involving 
human gene transfer would be relinquished to the Food and Drug 
Administration (FDA), which retains statutory authority for such 
approval. Under this revised oversight structure, a newly created ORDA 
Advisory Committee (OAC) would preserve continued public accountability 
for recombinant DNA research. To ensure quality and efficiency of 
public discussion of the scientific merit and the ethical issues 
relevant to gene therapy clinical trials, it was proposed that the NIH 
Director implement a regular series of Gene Therapy Policy Conferences 
(GTPC). Finally, the proposal assured the continuation of the publicly 
available comprehensive NIH database of clinical trials with human gene 
transfer, including reporting of adverse events.
    In response to the Notice of Intent, the NIH received 71 written 
comments (90 signatures) reflecting a broad spectrum of public opinion 
on the proposed changes. Comments were received from a variety of 
stakeholders, including individuals representing academia,

[[Page 7109]]

industry, patient advocacy organizations, consumer advocacy 
organizations, professional scientific societies, ethicists, other 
Federal agencies, NIH-funded investigators, past and present RAC 
members, and private citizens. Careful consideration was given to each 
of the written comments that were submitted.

I-B. Proposed Actions--November 1996

    On November 22, 1996, the NIH Director published Notice of Proposed 
Actions Under the NIH Guidelines for Research Involving Recombinant DNA 
Molecules (61 FR 59725). The Notice of Proposed Actions was in response 
to public opinion and in keeping with the NIH Director's intent to 
increase the usefulness and productivity of public discussion of gene 
therapy.
    In the Proposed Actions, the NIH Director proposed to: (1) Retain 
the RAC, while modifying its roles and responsibilities relevant to 
human gene therapy research, (2) continue RAC discussion of novel human 
gene transfer experiments without RAC approval of individual human gene 
transfer experiments; (3) reduce the membership of RAC from 25 members 
to 15 members; (4) regularly convene GTPC; and (5) maintain public 
access to human gene transfer clinical trial information. The following 
summarizes the roles and responsibilities of the NIH Director, the RAC, 
the ORDA, and the local institutions under the Notice of Proposed 
Actions.
I-B-1. Proposed Roles and Responsibilities in Accordance with the NIH 
Guidelines
I-B-1-a. The NIH Director
    The roles and responsibilities of the NIH Director remain unchanged 
except for relinquishing approval of human gene transfer experiments, 
and establishing and convening Gene Therapy Policy Conferences. The NIH 
Director is responsible for establishing the NIH Guidelines, overseeing 
their implementation, and their final interpretation; promulgating 
requirements as necessary to implement the NIH Guidelines; establishing 
and maintaining the RAC; establishing and maintaining ORDA; conducting 
and supporting training programs in laboratory safety for Institutional 
Biosafety Committee members, Biological Safety Officers and other 
institutional experts (if applicable), Principal Investigators, and 
laboratory staff; and establishing and convening Gene Therapy Policy 
Conferences.
I-B-1-b. The Recombinant DNA Advisory Committee
    The RAC will remain a chartered public advisory committee to the 
NIH Director regarding recombinant DNA research conducted in compliance 
with the NIH Guidelines. The RAC will conduct quarterly meetings. RAC 
members will continue to be appointed by the DHHS Secretary or his/her 
designee for 4-year terms. RAC membership will be reduced from 25 to 15 
members. At least eight of these members shall be knowledgeable in the 
fields of molecular genetics, molecular biology, recombinant DNA 
research, or other related fields and at least four of these members 
shall be persons knowledgeable in applicable law, standards of 
professional conduct and practice, public attitudes, the environment, 
public health, occupational health, or related fields. Representatives 
of Federal agencies shall continue to serve as non-voting members.
    The RAC will be responsible for: (1) Identifying novel human gene 
transfer experiments deserving of public discussion by the full RAC and 
transmitting comments/recommendations about specific human gene 
transfer experiments or categories of human gene transfer experiments 
to the NIH Director. (2) Identifying novel ethical issues relevant to 
specific human applications of gene transfer and recommending 
appropriate modifications to the Points to Consider that will provide 
guidance in the preparation of relevant Informed Consent documents. (3) 
Identifying novel scientific and safety issues relevant to specific 
human applications of gene transfer and recommending appropriate 
modifications to the Points to Consider that will provide guidance in 
the design and submission of human gene transfer clinical trials. (4) 
Publicly reviewing human gene transfer clinical trial data captured by 
NIH/ORDA in accordance with the annual data reporting requirements. (5) 
Identifying broad scientific and ethical/social issues relevant to gene 
therapy research as potential Gene Therapy Policy Conference topics.
    The RAC will advise the NIH Director on the following actions: (1) 
Adopting changes in the NIH Guidelines. (2) Assigning containment 
levels, changing containment levels, and approving experiments 
considered as Major Actions under the NIH Guidelines, i.e., the 
deliberate transfer of a drug resistance trait to microorganisms that 
are not known to acquire the trait naturally, if such acquisition could 
compromise the use of the drug to control disease agents in humans, 
veterinary medicine, or agriculture. (3) Promulgating and amending 
lists of classes of recombinant DNA molecules to be exempt from the NIH 
Guidelines because they consist entirely of DNA segments from species 
that exchange DNA by known physiological processes or otherwise do not 
present a significant risk to health or the environment. (4) Certifying 
new host-vector systems.
I-B-1-c. Gene Therapy Policy Conferences (GTPCs)
    In order to enhance the depth and value of public discussion 
relevant to scientific, safety, and ethical/societal implications of 
gene therapy research, the NIH Director will convene GTPC at regular 
intervals. As appropriate, the NIH Director may convene GTPC 
immediately following scheduled RAC meetings. GTPC will be administered 
by the NIH/ORDA. Conference participation will not involve a standing 
committee membership but rather will offer the unique advantage of 
assembling numerous participants who possess significant scientific, 
ethical, and legal expertise and/or interest that is directly 
applicable to a specific gene therapy research issue. At least one 
member of the RAC will serve as Co-chair of each GTPC and report the 
findings of the GTPC to the full committee at its next scheduled 
meeting. The RAC representative for each GTPC will be chosen based on 
the participant's area of expertise relative to the specific gene 
therapy research issue to be discussed. GTPC will have representation 
from other Federal agencies, including the FDA. GTPCs will focus on 
broad over-arching policy and scientific issues related to gene therapy 
research. Proposals for GTPC topics may be submitted by members of the 
RAC, representatives of academia, industry, patient and consumer 
advocacy organizations, other Federal agencies, professional scientific 
societies, and the general public. GTPC topics will not be limited to 
discussion of human applications of gene therapy research, i.e., they 
may include basic research on the use of novel gene delivery vehicles, 
or novel applications of gene transfer. The findings of the GTPC will 
be transmitted to the NIH Director and will be made publicly available. 
The NIH Director anticipates that this public policy forum will serve 
as a model for interagency communication and collaboration, 
concentrated expert discussion of novel scientific issues and their 
potential societal implications, and enhanced opportunity for public 
discussion of the

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potential impact of such applications on human health and the 
environment.
I-B-1-d. The Office of Recombinant DNA Activities (ORDA)
    ORDA is an organizational unit of the NIH Office of Science Policy 
within the Office of the Director. 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's 
responsibilities include (but are not limited to) the following: (1) 
Serving as the focal point for public access to summary information 
pertaining to human gene transfer experiments. (2) Serving as the focal 
point for data management of human gene transfer experiments. (3) 
Administering the annual data reporting requirements (and subsequent 
review) for human gene transfer experiments. (4) Transmitting comments/
recommendations arising from public RAC discussion of a novel human 
gene transfer experiment to the NIH Director. RAC recommendations shall 
be forwarded to the Principal Investigator, sponsoring institution, and 
other Department of Health and Human Services (DHHS) components, as 
appropriate. (5) Collaborating with Principal Investigators, 
Institutional Biosafety Committees, Institutional Review Boards, and 
other DHHS components, to ensure human gene transfer experiment 
registration compliance. (6) Administering Gene Therapy Policy 
Conferences as deemed appropriate by the NIH Director. (7) 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. (8) 
Serving as the executive secretary of the RAC. (9) Publishing in the 
Federal Register the announcements of RAC meetings and tentative 
agendas at least 15 days in advance, announcements of Gene Therapy 
Policy Conferences and tentative agendas at least 15 days in advance, 
proposed Major Actions at least 15 days prior to the RAC meeting; and 
(10) Reviewing and approving the membership of an institution's 
Institutional Biosafety Committee.
I-B-1-e. Local Institutions
    The Notice of Proposed Actions would change the roles and 
responsibilities of local institutions, Institutional Biosafety 
Committees, Biosafety Officers, Principal Investigators, Animal 
Facility Directors, Greenhouse Supervisors, and Human Gene Therapy 
experts relevant to recombinant DNA research conducted in compliance 
with the NIH Guidelines. These changes now include the following 
requirements: (1) When the institution conducts recombinant DNA 
research that requires Institutional Biosafety Committee approval, the 
institution shall appoint at least one individual with expertise in 
plant, plant pathogen, or plant pest containment principles (who is 
also a member of the Institutional Biosafety Committee); (2) when the 
institution conducts recombinant DNA research that requires 
Institutional Biosafety Committee approval, the institution shall 
appoint at least one individual with expertise in animal containment 
principles (who is also a member of the Institutional Biosafety 
Committee); and (3) when the institution participates in or sponsors 
recombinant DNA research involving human subjects, the institution must 
ensure that: (a) The Institutional Biosafety Committee has adequate 
expertise and training (using ad hoc consultants as deemed necessary) 
and (b) all aspects of Appendix M, Points to Consider in the Design and 
Submission of Protocols for the Transfer of Recombinant DNA Molecules 
into One or More Human Subjects (Points to Consider), have been 
appropriately addressed by the Principal Investigator prior to 
submission to NIH/ORDA.

I-C. Recombinant DNA Advisory Committee Meeting--December 1996

    During the December 9, 1996, Recombinant DNA Advisory Committee 
meeting, the following motions were made:
I-C-1. Future RAC Membership--Committee Motion 1
    A motion was made to invite former RAC members back to serve as ad 
hoc consultants in order to ensure institutional continuity of the RAC. 
The motion passed by a vote of 15 in favor, 0 opposed, and no 
abstentions.
I-C-2. Triggering Mechanism for RAC Discussion--Committee Motion 2
    A motion was made that: (1) The capacity for principal 
investigators and institutional representatives to request public RAC 
discussion of an individual gene transfer protocol should be deleted. 
(2) A decision by the RAC to require full review of an individual 
protocol should not have to be approved by the NIH Director. (3) The 
NIH Director or an appropriate FDA representative may also request RAC 
review of an individual protocol. (4) Rather than a majority vote, RAC 
recommendations for full review of an individual protocol should be 
changed to a minimum of three members. (5) The decision regarding 
necessity for RAC discussion should be made within 15 working days. The 
motion passed by a vote of 16 in favor, 0 opposed, and no abstentions.
I-C-3. Feedback Mechanism--Committee Motion 3
    A motion was made to request FDA to report back to the RAC how the 
RAC recommendations on an individual protocol were implemented. The RAC 
should require investigators to provide additional information if the 
FDA information is not adequate. The motion failed by a vote of 3 in 
favor, 7 opposed, and 4 abstentions.
I-C-4. Feedback Mechanism--Committee Motion 4
    A motion was made to require investigators to report back to the 
RAC in writing in a timely fashion. The report should include a 
statement of how the investigators have responded to RAC's 
recommendations and any modifications to the protocol following FDA 
review. The motion passed by a vote of 12 in favor, 1 opposed, and 1 
abstention.
I-C-5. Relationship of the RAC and GTPC--Committee Motion 5
    A motion was made that the RAC, with the NIH Director's approval, 
should have the primary responsibility for: (1) Planning the GTPC 
agendas, and (2) summarizing GTPC recommendations in the form of a 
report back to the NIH Director. The close GTPC/RAC relationship should 
not preclude other parties from suggesting GTPC topics and GTPC should 
be convened in consultation with FDA. The motion passed by a vote of 13 
in favor, 0 opposed, and 2 abstentions.
I-C-6. Proposed Actions Concepts--Committee Motion 6
    A motion was made to accept the overall concepts put forward in the 
Proposed Actions as published in the November 22, 1996, Federal 
Register (61 FR 59725). Specifically: (1) Retain the RAC, while 
modifying its roles and responsibilities relevant to human gene therapy 
research, (2) continue RAC discussion of novel human gene transfer 
experiments without RAC approval of individual human gene transfer 
experiments; (3) reduce the membership of RAC from 25 members to 15 
members; (4) regularly convene GTPC; and (5) maintain public access to 
human

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gene transfer clinical trial information. The members of the RAC noted 
that several minor modifications still remained unresolved, 
particularly with regard to the future discussion of gene therapy 
protocols and defining the role of the RAC relative to the GTPCs. The 
RAC recommended that final action on the Proposed Actions should be 
postponed to the March 6-7, 1997, RAC meeting, in order to more fully 
address these unresolved issues. The motion passed by a vote of 12 in 
favor, 0 opposed, and 2 abstentions.

II. Meetings Between the NIH and FDA Regarding Simultaneous Submission 
to Human Gene Transfer Protocols to the NIH and the FDA

    In a letter dated November 20, 1996, Dr. Andra Miller, Cytokine and 
Gene Therapy Branch, Center of Biologics Evaluation and Research, FDA, 
requested that the NIH Guidelines should be amended regarding 
procedures for simultaneous submission of Appendix M material to the 
RAC and FDA. In her November 20, 1996, letter, Dr. Miller states:
    `` * * * (1) Remove the requirement for submission of Appendix M to 
the FDA. The FDA does not accept Appendix M in place of an IND 
submission. The FDA is not proposed to be and need not be included in 
the decision making process to identify protocols to undergo full RAC 
review. Therefore, there is no reason for sponsors to submit Appendix M 
materials to the FDA.
    ``(2) Explore the feasibility of a unified format for submission of 
protocols to the RAC and FDA. This would relieve the sponsor of the 
burden of preparing duplicative submission to satisfy each agency.
    ``(3) Establish a mechanism for FDA staff to bring general issues 
of novelty and concern to the RAC for discussion. This will provide a 
mechanism for public input toward the resolution of issues we all must 
consider and provide direction for policy development and growth in the 
field of gene therapy.''
    On January 27, 1997, NIH and FDA staff met to consider amendments 
to the NIH Guidelines that incorporate the recommendations of both the 
NIH and the FDA with regard to simultaneous submission of human gene 
transfer protocols. The recommendations of NIH and FDA staff are 
incorporated below in the Proposed Actions Regarding the Overall 
Procedures for Human Gene Transfer Protocol.

III. Proposed Actions Regarding the Overall Procedures for Human Gene 
Transfer Protocols

    The NIH will consider the following proposed actions under the NIH 
Guidelines for Research Involving Recombinant DNA Molecules:

[Note: Editorial changes and updating of references have been 
incorporated to clarify the document.]

III-A. Proposed Amendments to Section I, Scope of the NIH Guidelines

    Section I is proposed to be amended to read:
Section I. Scope of the NIH Guidelines
Section I-A. Purpose
    [This section remains unchanged.]
    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 regarding 
requirement for human gene transfer protocol registration.)
    Section I-A-1-a. Experiments involving the deliberate transfer of 
recombinant DNA or DNA or RNA derived from recombinant DNA into human 
subjects (human gene transfer) cannot be initiated without simultaneous 
submission to both NIH/ORDA and the FDA of such information on the 
proposed experiment as is prescribed by those agencies. Submission of 
human gene transfer protocols to the NIH will be in the format 
described in Appendix M-I, Submission Requirements--Human Gene Transfer 
Experiments, of the NIH Guidelines. Submission to NIH shall be for 
registration purposes and will ensure continued public access to 
relevant human gene transfer information conducted in compliance with 
the NIH Guidelines. Submission of human gene transfer protocols to the 
FDA will be in the format described in 21 CFR, Chapter I, Subchapter D, 
Part 312, Subpart B, Section 23, IND Content and Format.
    If a determination is made that an experiment will undergo full RAC 
discussion, NIH/ORDA will immediately notify the Principal 
Investigator. RAC members may forward requests for additional 
information relevant to a specific protocol through NIH/ORDA to the 
Principal Investigator. In making a determination whether an experiment 
is novel, and thus deserving of full RAC discussion, reviewers will 
examine the scientific rational, scientific content (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 
contest have been resolved. RAC's recommendation(s) on a specific human 
gene transfer experiment will be forwarded to the NIH Director, the 
Principal Investigator, the sponsoring institution, and to other 
Department of Health and Human Services (DHHS) components, as 
appropriate.
Section I-B. Definition of Recombinant DNA Molecules
    [This section remains unchanged.]
Section I-C. General Applicability
    Section I-C-1. The NIH Guidelines are applicable to:
    Section I-C-1-a. All recombinant DNA research within the United 
States (U.S.) or its territories that is within the category of 
research described in either Section I-C-1-a-(1) or Section I-C-1-a-
(2).
    Section I-C-1-a-(1). Research that is conducted at or sponsored by 
an institution that receives any support for recombinant DNA research 
from the NIH, including research performed directly by the NIH. An 
individual who receives support for research involving recombinant DNA 
must be associated with or sponsored by an institution that assumes the 
responsibilities assigned in the NIH Guidelines.
    Section I-C-1-a-(2). Research that involves testing in humans of 
materials containing recombinant DNA developed with NIH funds, if the 
institution that developed those materials sponsors or participates in 
those projects. Participation includes research collaboration or 
contractual agreements, not mere provision of research materials.
    Section I-C-1-b. All recombinant DNA research performed abroad that 
is within the category of research described in either Section I-C-1-b-
(1) or Section I-C-1-b-(2).
    Section I-C-1-b-(1). Research supported by NIH funds.
    Section I-C-1-b-(2). Research that involves testing in humans of 
materials containing recombinant DNA developed with NIH funds, if the 
institution that developed those materials sponsors or participates in 
those projects. Participation includes research

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collaboration or contractual agreements, not mere provision of research 
materials.
    Section I-C-1-b-(3). If the host country has established rules for 
the conduct of recombinant DNA research, then the research must be in 
compliance with those rules. If the host country does not have such 
rules, the proposed research must be reviewed and approved by an NIH-
approved Institutional Biosafety Committee or equivalent review body 
and accepted in writing by an appropriate national governmental 
authority of the host country. The safety practices that are employed 
abroad must be reasonably consistent with the NIH Guidelines.
Section I-D. Compliance With the NIH Guidelines
    As a condition for NIH funding of recombinant DNA research, 
institutions shall ensure that such research conducted at or sponsored 
by the institution, irrespective of the source of funding, shall comply 
with the NIH Guidelines.
    Information concerning noncompliance with the NIH Guidelines may be 
brought forward by any person. It should be delivered to both NIH/ORDA 
and the relevant institution. The institution, generally through the 
Institutional Biosafety Committee, shall take appropriate action. The 
institution shall forward a complete report of the incident 
recommending any further action to the Office of Recombinant DNA 
Activities, National Institutes of Health/MSC 7010, 6000 Executive 
Boulevard, Suite 302, Bethesda, Maryland 20892-7010, (301) 496-9838.
    In cases where NIH proposes to suspend, limit, or terminate 
financial assistance because of noncompliance with the NIH Guidelines, 
applicable DHHS and Public Health Service procedures shall govern.
    The policies on compliance are as follows:
    Section I-D-1. All NIH-funded projects involving recombinant DNA 
techniques must comply with the NIH Guidelines. Non-compliance may 
result in: (i) Suspension, limitation, or termination of financial 
assistance for the noncompliant NIH-funded research project and of NIH 
funds for other recombinant DNA research at the institution, or (ii) a 
requirement for prior NIH approval of any or all recombinant DNA 
projects at the institution.
    Section I-D-2. All non-NIH funded projects involving recombinant 
DNA techniques conducted at or sponsored by an institution that 
receives NIH funds for projects involving such techniques must comply 
with the NIH Guidelines. Noncompliance may result in: (i) Suspension, 
limitation, or termination of NIH funds for recombinant DNA research at 
the institution, or (ii) a requirement for prior NIH approval of any or 
all recombinant DNA projects at the institution.

[The remainder of Section I is proposed to be renumbered to reflect 
above changes.]

III-B. Proposed Amendments to Section II, Safety Considerations

    The second paragraph of Section II-A-3 is proposed to be amended to 
read:
Section II-A-3. Comprehensive Risk Assessment
    * * * A final assessment of risk based on these considerations is 
then used to set the appropriate containment conditions for the 
experiment (see Section II-B, Containment). The containment level 
required may be equivalent to the Risk Group classification of the 
agent or it may be raised or lowered as a result of the above 
considerations. The Institutional Biosafety Committee must approve the 
risk assessment and the biosafety containment level for recombinant DNA 
experiments described in Sections III-A, Experiments that Require 
Institutional Biosafety Committee Approval, RAC Review, and NIH 
Director Approval Before Initiation, III-B, Experiments that Require 
NIH/ORDA and Institutional Biosafety Committee Approval Before 
Initiation, III-C, Experiments that Require Institutional Biosafety 
Committee and Institutional Review Board Approvals and NIH/ORDA 
Registration Before Initiation, and III-D, Experiments that Require 
Institutional Biosafety Committee Approval Before Initiation * * *

III-C. Proposed Amendments to Section III, Experiments Covered by the 
NIH Guidelines

    Section III is proposed to be amended to read:
Section III. Experiments Covered by the NIH Guidelines
    This section describes six categories of experiments involving 
recombinant DNA: (i) Those that require Institutional Biosafety 
Committee (IBC) 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 and Institutional Review Board approvals and NIH/ORDA 
registration before initiation (see Section III-C), (iv) those that 
require Institutional Biosafety Committee approval before initiation 
(see Section III-D), (v) those that require Institutional Biosafety 
Committee notification simultaneous with initiation (see Section III-
E), and (vi) those that are exempt from the NIH Guidelines (see Section 
III-F).

    Note: If an experiment falls into Sections III-A, III-B, or III-
C and one of the other sections, the rules pertaining to Sections 
III-A, III-B, or III-C shall be followed. If an experiment falls 
into Section III-F and into either Sections III-D or III-E 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 Section IV-C-1-b-(2) and its 
subsections, Minor Actions).
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), Major Actions)
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/MSC 7010, 6000 Executive Boulevard, Suite 
302, Bethesda, Maryland 20892-7010, (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. 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, Major 
Actions Taken under the NIH Guidelines, which may be obtained from the 
Office of Recombinant DNA Activities, National Institutes of Health/MSC 
7010, 6000 Executive Boulevard, Suite 302, Bethesda, Maryland 20892-
7010, (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, Footnotes and References of Sections I-IV), 
if such acquisition could compromise the use of the drug to

[[Page 7113]]

control disease agents in humans, veterinary medicine, or agriculture, 
will be reviewed by the RAC.
Section III-B. Experiments That Require NIH/ORDA and Institutional 
Biosafety Committee Approval Before Initiation
    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), Institutional Biosafety Committee).
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/MSC 7010, 6000 Executive Boulevard, Suite 302, Bethesda, 
Maryland 20892-7010, (301) 496-9838.
Section III-C. Experiments That Require Institutional Biosafety 
Committee and Institutional Review Board Approvals and NIH/ORDA 
Registration Before Initiation
Section III-C-1. Experiments Involving the Deliberate Transfer of 
Recombinant DNA or DNA or RNA Derived From Recombinant DNA Into Human 
Subjects
    Experiments involving the deliberate transfer of recombinant DNA or 
DNA or RNA derived from recombinant DNA into human subjects (human gene 
transfer) cannot be initiated without simultaneous submission of 
relevant information on the proposed experiment to both NIH/ORDA and 
the FDA. Submission to NIH/ORDA shall be for registration purposes and 
will ensure continued public access to relevant human gene transfer 
information conducted in compliance with the NIH Guidelines. Submission 
of human gene transfer protocols to the NIH will be in the format 
described in Appendix M-I, Submission Requirements--Human Gene Transfer 
Experiments, of the NIH Guidelines. Submission of human gene transfer 
protocols to the FDA will be in the format described in 21 CFR, Chapter 
I, Subchapter D, Part 312, Subpart B, Section 23, IND Content and 
Format. Prior to submission of a human gene transfer experiment to NIH/
ORDA, the Principal Investigator must obtain Institutional Biosafety 
Committee (IBC) approval from each institution that will handle 
recombinant DNA material that is to be administered to human subjects 
and Institutional Review Board approval from each institution in which 
human subjects will undergo gene transfer. Specifically: (1) Any 
institution involved in the production of the vectors for human 
application, (2) any institution at which there is ex vivo transduction 
of the recombinant DNA material into target cells for human 
application, and (3) any institution at which the recombinant DNA 
material will be directly administered to human subjects. These local 
committee approvals and relevant protocol documentation shall be 
submitted to NIH/ORDA for registration purposes and determination 
regarding the necessity of full RAC review and approval/disapproval.
    The RAC prefers that submission to NIH/ORDA in accordance with 
Appendix M-I, Submission Requirements--Human Gene Transfer Experiments, 
of the NIH Guidelines, contain no proprietary data or trade secrets, 
enabling all aspects of the review to be open to the public. Following 
receipt by NIH/ORDA, relevant information shall be entered into the NIH 
human gene transfer database for registration purposes. Summary 
information pertaining to the human gene transfer protocol will be 
forwarded to RAC members. The NIH/ORDA summary information shall 
include comparisons to previously registered protocols. Specific items 
of similarity to previous experiments include (but are not limited to): 
(i) Gene delivery vehicle, (ii) functional gene, (iii) marker gene, 
(iv) packaging cell (if applicable), (v) disease application, (vi) 
route of administration, and (vii) patient selection criteria.
    RAC members shall notify NIH/ORDA within 15 working days if the 
protocol has been determined to represent novel characteristics 
requiring further public discussion.
    Full RAC review of an individual human gene transfer experiment can 
be initiated by the NIH Director or recommended to the NIH Director by: 
(i) Three or more RAC members, or (ii) other Federal agencies. An 
individual human gene transfer experiment that is recommended for full 
RAC review should represent novel characteristics deserving of public 
discussion. RAC recommendations on a specific human gene transfer 
experiment shall be forwarded to the NIH Director, the Principal 
Investigator, the sponsoring institution, and other Department of 
Health and Human Services (DHHS) components, as appropriate.

    Note: For specific directives concerning the use of retroviral 
vectors for gene delivery, consult Appendix B-V-1, Murine Retroviral 
Vectors.
Section III-D. Experiments That Require Institutional Biosafety 
Committee Approval Before Initiation
[This section remains unchanged except for renumbering and reference 
changes due to renumbering.]
Section III-E. Experiments That Require Institutional Biosafety 
Committee Notice Simultaneous With Initiation
[This section remains unchanged except for renumbering and reference 
changes due to renumbering.]
Section III-F. Exempt Experiments
[This section remains unchanged except for renumbering and reference 
changes due to renumbering.]

III-D. Proposed Amendments to Section IV, Roles and Responsibilities

    Section IV is proposed to be amended to read:
SECTION IV. ROLES AND RESPONSIBILITIES
Section IV-A. Policy
    The safe conduct of experiments involving recombinant DNA depends 
on the individual conducting such activities. The NIH Guidelines cannot 
anticipate every possible situation. Motivation and good judgment are 
the key essentials to protection of health and the environment. The NIH 
Guidelines are intended to assist the institution, Institutional 
Biosafety Committee, Biological Safety Officer, and Principal 
Investigator in determining safeguards that should be implemented. The 
NIH Guidelines will never be complete or final since all conceivable 
experiments involving recombinant DNA cannot be foreseen. Therefore, it 
is the responsibility of the institution and those associated with it 
to adhere to the intent of the NIH Guidelines as well as to their 
specifics. Each institution (and the Institutional

[[Page 7114]]

Biosafety Committee acting on its behalf) is responsible for ensuring 
that all recombinant DNA research conducted at or sponsored by that 
institution is conducted in compliance with the NIH Guidelines. General 
recognition of institutional authority and responsibility properly 
establishes accountability for safe conduct of the research at the 
local level. The following roles and responsibilities constitute an 
administrative framework in which safety is an essential and integral 
part of research involving recombinant DNA molecules. Further 
clarifications and interpretations of roles and responsibilities will 
be issued by the NIH as necessary.
Section IV-B. Responsibilities of the Institution
Section IV-B-1. General Information
    Each institution conducting or sponsoring recombinant DNA research 
which is covered by the NIH Guidelines is responsible for ensuring that 
the research is conducted in full conformity with the provisions of the 
NIH Guidelines. In order to fulfill this responsibility, the 
institution shall:
    Section IV-B-1-a. Establish and implement policies that provide for 
the safe conduct of recombinant DNA research and that ensure compliance 
with the NIH Guidelines. As part of its general responsibilities for 
implementing the NIH Guidelines, the institution may establish 
additional procedures, as deemed necessary, to govern the institution 
and its components in the discharge of its responsibilities under the 
NIH Guidelines. Such procedures may include: (i) statements formulated 
by the institution for the general implementation of the NIH 
Guidelines, and (ii) any additional precautionary steps the institution 
deems appropriate.
    Section IV-B-1-b. Establish an Institutional Biosafety Committee 
that meets the requirements set forth in Section IV-B-2-a and carries 
out the functions detailed in Section IV-B-2-b.
    Section IV-B-1-c. Appoint a Biological Safety Officer (who is also 
a member of the Institutional Biosafety Committee) if the institution: 
(i) Conducts recombinant DNA research at Biosafety Level (BL) 3 or BL4, 
or (ii) engages in large scale (greater than 10 liters) research. The 
Biological Safety Officer carries out the duties specified in Section 
IV-B-3.
    Section IV-B-1-d. Appoint at least one individual with expertise in 
plant, plant pathogen, or plant pest containment principles (who is 
also a member of the Institutional Biosafety Committee) if the 
institution conducts recombinant DNA research that requires 
Institutional Biosafety Committee approval in accordance with Appendix 
P, Physical and Biological Containment for Recombinant DNA Research 
Involving Plants.
    Section IV-B-1-e. Appoint at least one individual with expertise in 
animal containment principles (who is also a member of the 
Institutional Biosafety Committee) if the institution conducts 
recombinant DNA research that requires Institutional Biosafety 
Committee approval in accordance with Appendix Q, Physical and 
Biological Containment for Recombinant DNA Research Involving Animals.
    Section IV-B-1-f. When the institution participates in or sponsors 
recombinant DNA research involving human subjects, the institution must 
ensure that: (i) The Institutional Biosafety Committee has adequate 
expertise and training (using ad hoc consultants as deemed necessary) 
and (ii) all aspects of Appendix M, Points to Consider in the Design 
and Submission of Protocols for the Transfer of Recombinant DNA 
Molecules into One or More Human Subjects (Points to Consider), have 
been appropriately addressed by the Principal Investigator prior to 
submission to NIH/ORDA. Institutional Biosafety Committee approval must 
be obtained from each institution that will handle recombinant DNA 
material that is to be administered to human subjects.
    Section IV-B-1-g. Assist and ensure compliance with the NIH 
Guidelines by Principal Investigators conducting research at the 
institution as specified in Section IV-B-4.
    Section IV-B-1-h. Ensure appropriate training for the Institutional 
Biosafety Committee Chair and members, Biological Safety Officer and 
other containment experts (when applicable), Principal Investigators, 
and laboratory staff regarding laboratory safety and implementation of 
the NIH Guidelines. The Institutional Biosafety Committee Chair is 
responsible for ensuring that Institutional Biosafety Committee members 
are appropriately trained. The Principal Investigator is responsible 
for ensuring that laboratory staff are appropriately trained. The 
institution is responsible for ensuring that the Principal Investigator 
has sufficient training; however, this responsibility may be delegated 
to the Institutional Biosafety Committee.
    Section IV-B-1-i. Determine the necessity for health surveillance 
of personnel involved in connection with individual recombinant DNA 
projects; and if appropriate, conduct a health surveillance program for 
such projects. The institution shall establish and maintain a health 
surveillance program for personnel engaged in large scale research or 
production activities involving viable organisms containing recombinant 
DNA molecules which require BL3 containment at the laboratory scale. 
The institution shall establish and maintain a health surveillance 
program for personnel engaged in animal research involving viable 
recombinant DNA-containing microorganisms that require BL3 or greater 
containment in the laboratory. The Laboratory Safety Monograph 
discusses various components of such a program (e.g., records of agents 
handled, active investigation of relevant illnesses, and the 
maintenance of serial serum samples for monitoring serologic changes 
that may result from the employees' work experience). Certain medical 
conditions may place a laboratory worker at increased risk in any 
endeavor where infectious agents are handled. Examples cited in the 
Laboratory Safety Monograph include gastrointestinal disorders and 
treatment with steroids, immunosuppressive drugs, or antibiotics. 
Workers with such disorders or treatment should be evaluated to 
determine whether they should be engaged in research with potentially 
hazardous organisms during their treatment or illness. Copies of the 
Laboratory Safety Monograph are available from the Office of 
Recombinant DNA Activities, National Institutes of Health/MSC 7010, 
6000 Executive Boulevard, Suite 302, Bethesda, Maryland 20892-7010, 
(301) 496-9838.
    Section IV-B-1-j. Report any significant problems, violations of 
the NIH Guidelines, or any significant research-related accidents and 
illnesses to NIH/ORDA within thirty days, unless the institution 
determines that a report has already been filed by the Principal 
Investigator or Institutional Biosafety Committee. Reports shall be 
sent to the Office of Recombinant DNA Activities, National Institutes 
of Health/MSC 7010, 6000 Executive Boulevard, Suite 302, Bethesda, 
Maryland 20892-7010, (301) 496-9838.
Section IV-B-2. Institutional Biosafety Committee (IBC)
    The institution shall establish an Institutional Biosafety 
Committee whose responsibilities need not be restricted to recombinant 
DNA. The Institutional Biosafety Committee shall meet the following 
requirements:

[[Page 7115]]

Section IV-B-2-a. Membership and Procedures
    Section IV-B-2-a-(1). The Institutional Biosafety Committee must be 
comprised of no fewer than five members so selected that they 
collectively have experience and expertise in recombinant DNA 
technology and the capability to assess the safety of recombinant DNA 
research and to identify any potential risk to public health or the 
environment. At least two members shall not be affiliated with the 
institution (apart from their membership on the Institutional Biosafety 
Committee) and who represent the interest of the surrounding community 
with respect to health and protection of the environment (e.g., 
officials of state or local public health or environmental protection 
agencies, members of other local governmental bodies, or persons active 
in medical, occupational health, or environmental concerns in the 
community). The Institutional Biosafety Committee shall include at 
least one individual with expertise in plant, plant pathogen, or plant 
pest containment principles when experiments utilizing Appendix P, 
Physical and Biological Containment for Recombinant DNA Research 
Involving Plants, require prior approval by the Institutional Biosafety 
Committee. The Institutional Biosafety Committee shall include at least 
one scientist with expertise in animal containment principles when 
experiments utilizing Appendix Q, Physical and Biological Containment 
for Recombinant DNA Research Involving Animals, require Institutional 
Biosafety Committee prior approval. When the institution conducts 
recombinant DNA research at BL3, BL4, or Large Scale (greater than 10 
liters), a Biological Safety Officer is mandatory and shall be a member 
of the Institutional Biosafety Committee (see Section IV-B-3, 
Biological Safety Officer). When the institution participates in or 
sponsors recombinant DNA research involving human subjects, the 
institution must ensure that: (i) The Institutional Biosafety Committee 
has adequate expertise and training (using ad hoc consultants as deemed 
necessary) and (ii) all aspects of Appendix M, Points to Consider in 
the Design and Submission of Protocols for the Transfer of Recombinant 
DNA Molecules into One or More Human Subjects (Points to Consider), 
have been appropriately addressed by the Principal Investigator prior 
to submission to NIH/ORDA. Institutional Biosafety Committee approval 
must be obtained from each institution that will handle recombinant DNA 
material that is to be administered to human subjects.

    Note: Individuals, corporations, and institutions not otherwise 
covered by the NIH Guidelines, are encouraged to adhere to the 
standards and procedures set forth in Sections I through IV (see 
Section IV-E, Voluntary Compliance. The policy and procedures for 
establishing an Institutional Biosafety Committee under Voluntary 
Compliance, are specified in Section IV-E-2, Institutional Biosafety 
Committee Approval).

    Section IV-B-2-a-(2). In order to ensure the competence necessary 
to review and approve recombinant DNA activities, it is recommended 
that the Institutional Biosafety Committee: (i) Include persons with 
expertise in recombinant DNA technology, biological safety, and 
physical containment; (ii) include or have available as consultants 
persons knowledgeable in institutional commitments and policies, 
applicable law, standards of professional conduct and practice, 
community attitudes, and the environment, and (iii) include at least 
one member representing the laboratory technical staff.
    Section IV-B-2-a-(3). The institution shall file an annual report 
with NIH/ORDA which includes: (i) A roster of all Institutional 
Biosafety Committee members clearly indicating the Chair, contact 
person, Biological Safety Officer (if applicable), plant expert (if 
applicable), and animal expert (if applicable); and (ii) biographical 
sketches of all Institutional Biosafety Committee members (including 
community members).
    Section IV-B-2-a-(4). No member of an Institutional Biosafety 
Committee may be involved (except to provide information requested by 
the Institutional Biosafety Committee) in the review or approval of a 
project in which he/she has been or expects to be engaged or has a 
direct financial interest.
    Section IV-B-2-a-(5). The institution, that is ultimately 
responsible for the effectiveness of the Institutional Biosafety 
Committee, may establish procedures that the Institutional Biosafety 
Committee shall follow in its initial and continuing review and 
approval of applications, proposals, and activities.
    Section IV-B-2-a-(6). When possible and consistent with protection 
of privacy and proprietary interests, the institution is encouraged to 
open its Institutional Biosafety Committee meetings to the public.
    Section IV-B-2-a-(7). Upon request, the institution shall make 
available to the public all Institutional Biosafety Committee meeting 
minutes and any documents submitted to or received from funding 
agencies which the latter are required to make available to the public. 
If public comments are made on Institutional Biosafety Committee 
actions, the institution shall forward both the public comments and the 
Institutional Biosafety Committee's response to the Office of 
Recombinant DNA Activities, National Institutes of Health/MSC 7010, 
6000 Executive Boulevard, Suite 302, Bethesda, Maryland 20892-7010, 
(301) 496-9838.
Section IV-B-2-b. Functions
    On behalf of the institution, the Institutional Biosafety Committee 
is responsible for:
    Section IV-B-2-b-(1). Reviewing recombinant DNA research conducted 
at or sponsored by the institution for compliance with the NIH 
Guidelines as specified in Section III, Experiments Covered by the NIH 
Guidelines, and approving those research projects that are found to 
conform with the NIH Guidelines. This review shall include: (i) 
Independent assessment of the containment levels required by the NIH 
Guidelines for the proposed research; (ii) assessment of the 
facilities, procedures, practices, and training and expertise of 
personnel involved in recombinant DNA research; and (iii) ensuring 
compliance with all surveillance, data reporting, and adverse event 
reporting requirements required by the NIH Guidelines.
    Section IV-B-2-b-(2). Notifying the Principal Investigator of the 
results of the Institutional Biosafety Committee's review and approval.
    Section IV-B-2-b-(3). Lowering containment levels for certain 
experiments as specified in Section III-C-2-a, Experiments in which DNA 
from Human or Animal Pathogens (Risk Group 2, Risk Group 3, Risk Group 
4, or Restricted Agents is Cloned into Nonpathogenic Prokaryotic or 
Lower Eukaryotic Host-Vector Systems.
    Section IV-B-2-b-(4). Setting containment levels as specified in 
Sections III-C-4-b, Experiments Involving Whole Animals, and III-C-5, 
Experiments Involving Whole Plants.
    Section IV-B-2-b-(5). Periodically reviewing recombinant DNA 
research conducted at the institution to ensure compliance with the NIH 
Guidelines.
    Section IV-B-2-b-(6). Adopting emergency plans covering accidental 
spills and personnel contamination resulting from recombinant DNA 
research.

    Note: The Laboratory Safety Monograph describes basic elements 
for developing specific procedures dealing with major spills of 
potentially hazardous materials in the

[[Page 7116]]

laboratory, including information and references about 
decontamination and emergency plans. The NIH and the Centers for 
Disease Control and Prevention are available to provide consultation 
and direct assistance, if necessary, as posted in the Laboratory 
Safety Monograph. The institution shall cooperate with the state and 
local public health departments by reporting any significant 
research-related illness or accident that may be hazardous to the 
public health.

    Section IV-B-2-b-(7). Reporting any significant problems with or 
violations of the NIH Guidelines and any significant research-related 
accidents or illnesses to the appropriate institutional official and 
NIH/ORDA within 30 days, unless the Institutional Biosafety Committee 
determines that a report has already been filed by the Principal 
Investigator. Reports to NIH/ORDA shall be sent to the Office of 
Recombinant DNA Activities, National Institutes of Health/MSC 7010, 
6000 Executive Boulevard, Suite 302, Bethesda, Maryland 20892-7010, 
(301) 496-9838.
    Section IV-B-2-b-(8). The Institutional Biosafety Committee may not 
authorize initiation of experiments which are not explicitly covered by 
the NIH Guidelines until NIH (with the advice of the RAC when required) 
establishes the containment requirement.
    Section IV-B-2-b-(9). Performing such other functions as may be 
delegated to the Institutional Biosafety Committee under Section IV-B-
2, Institutional Biosafety Committee.
Section IV-B-3. Biological Safety Officer (BSO)
    Section IV-B-3-a. The institution shall appoint a Biological Safety 
Officer if it engages in large scale research or production activities 
involving viable organisms containing recombinant DNA molecules.
    Section IV-B-3-b. The institution shall appoint a Biological Safety 
Officer if it engages in recombinant DNA research at BL3 or BL4. The 
Biological Safety Officer shall be a member of the Institutional 
Biosafety Committee.
    Section IV-B-3-c. The Biological Safety Officer's duties include, 
but are not limited to:
    Section IV-B-3-c-(1). Periodic inspections to ensure that 
laboratory standards are rigorously followed;
    Section IV-B-3-c-(2). Reporting to the Institutional Biosafety 
Committee and the institution any significant problems, violations of 
the NIH Guidelines, and any significant research-related accidents or 
illnesses of which the Biological Safety Officer becomes aware unless 
the Biological Safety Officer determines that a report has already been 
filed by the Principal Investigator;
    Section IV-B-3-c-(3). Developing emergency plans for handling 
accidental spills and personnel contamination and investigating 
laboratory accidents involving recombinant DNA research;
    Section IV-B-3-c-(4). Providing advice on laboratory security;
    Section IV-B-3-c-(5). Providing technical advice to Principal 
Investigators and the Institutional Biosafety Committee on research 
safety procedures.

    Note: See the Laboratory Safety Monograph for additional 
information on the duties of the Biological Safety Officer.
Section IV-B-4. Plant, Plant Pathogen, or Plant Pest Containment Expert
    When the institution conducts recombinant DNA research that 
requires Institutional Biosafety Committee approval in accordance with 
Appendix P, Physical and Biological Containment for Recombinant DNA 
Research Involving Plants, the institution shall appoint at least one 
individual with expertise in plant, plant pathogen, or plant pest 
containment principles (who is also a member of the Institutional 
Biosafety Committee).
Section IV-B-5. Animal Containment Expert
    When the institution conducts recombinant DNA research that 
requires Institutional Biosafety Committee approval in accordance with 
Appendix Q, Physical and Biological Containment for Recombinant DNA 
Research Involving Animals, the institution shall appoint at least one 
individual with expertise in animal containment principles (who is also 
a member of the Institutional Biosafety Committee).
Section IV-B-6. Human Gene Therapy Expert
    When the institution participates in or sponsors recombinant DNA 
research involving human subjects, the institution must ensure that: 
(i) The Institutional Biosafety Committee has adequate expertise and 
training (using ad hoc consultants as deemed necessary) and (ii) all 
aspects of Appendix M, Points to Consider in the Design and Submission 
of Protocols for the Transfer of Recombinant DNA Molecules into One or 
More Human Subjects (Points to Consider), have been appropriately 
addressed by the Principal Investigator prior to submission to NIH/
ORDA. Institutional Biosafety Committee approval must be obtained from 
each institution that will handle recombinant DNA material that is to 
be administered to human subjects.
Section IV-B-7. Principal Investigator (PI)
    On behalf of the institution, the Principal Investigator is 
responsible for full compliance with the NIH Guidelines in the conduct 
of recombinant DNA research.
Section IV-B-7-a. General Responsibilities
    As part of this general responsibility, the Principal Investigator 
shall:
    Section IV-B-7-a-(1). Initiate or modify no recombinant DNA 
research which requires Institutional Biosafety Committee approval 
prior to initiation (see Sections III-A, III-B, III-C, and III-D, 
Experiments Covered by the NIH Guidelines) until that research or the 
proposed modification thereof has been approved by the Institutional 
Biosafety Committee and has met all other requirements of the NIH 
Guidelines;
    Section IV-B-7-a-(2). Determine whether experiments are covered by 
Section III-D, Experiments that Require Institutional Biosafety 
Committee Notice Simultaneous with Initiation, and that the appropriate 
procedures are followed;
    Section IV-B-7-a-(3). Report any significant problems, violations 
of the NIH Guidelines, or any significant research-related accidents 
and illnesses to the Biological Safety Officer (where applicable), 
Greenhouse/Animal Facility Director (where applicable), Institutional 
Biosafety Committee, NIH/ORDA, and other appropriate authorities (if 
applicable) within 30 days. Reports to NIH/ORDA shall be sent to the 
Office of Recombinant DNA Activities, National Institutes of Health/MSC 
7010, 6000 Executive Boulevard, Suite 302, Bethesda, Maryland 20892-
7010, (301) 496-9838;
    Section IV-B-7-a-(4). Report any new information bearing on the NIH 
Guidelines to the Institutional Biosafety Committee and to NIH/ORDA 
(reports to NIH/ORDA shall be sent to the Office of Recombinant DNA 
Activities, National Institutes of Health/MSC 7010, 6000 Executive 
Boulevard, Suite 302, Bethesda, Maryland 20892-7010, (301) 496-9838);
    Section IV-B-7-a-(5). Be adequately trained in good microbiological 
techniques;
    Section IV-B-7-a-(6). Adhere to Institutional Biosafety Committee-
approved emergency plans for handling accidental spills and personnel 
contamination; and
    Section IV-B-7-a-(7). Comply with shipping requirements for 
recombinant DNA molecules (see Appendix H, Shipment, for shipping 
requirements

[[Page 7117]]

and the Laboratory Safety Monograph for technical recommendations).
Section IV-B-7-b. Submissions by the Principal Investigator to the NIH/
ORDA
    The Principal Investigator shall:
    Section IV-B-7-b-(1). Submit information to NIH/ORDA for 
certification of new host-vector systems;
    Section IV-B-7-b-(2). Petition NIH/ORDA, with notice to the 
Institutional Biosafety Committee, for proposed exemptions to the NIH 
Guidelines;
    Section IV-B-7-b-(3). Petition NIH/ORDA, with concurrence of the 
Institutional Biosafety Committee, for approval to conduct experiments 
specified in Sections III-A-1, Major Actions Under the NIH Guidelines, 
and III-B, Experiments that Require NIH/ORDA and Institutional 
Biosafety Committee Approval Before Initiation;
    Section IV-B-7-b-(4). Petition NIH/ORDA for determination of 
containment for experiments requiring case-by-case review; and
    Section IV-B-7-b-(5). Petition NIH/ORDA for determination of 
containment for experiments not covered by the NIH Guidelines.
    Section IV-B-7-b-(6). Ensure that all aspects of Appendix M, Points 
to Consider in the Design and Submission of Protocols for the Transfer 
of Recombinant DNA Molecules into One or More Human Subjects, have been 
appropriately addressed prior to submission of human gene therapy 
experiments to NIH/ORDA.
Section IV-B-7-c. Submissions by the Principal Investigator to the 
Institutional Biosafety Committee
    The Principal Investigator shall:
    Section IV-B-7-c-(1). Make an initial determination of the required 
levels of physical and biological containment in accordance with the 
NIH Guidelines;
    Section IV-B-7-c-(2). Select appropriate microbiological practices 
and laboratory techniques to be used for the research;
    Section IV-B-7-c-(3). Submit the initial research protocol and any 
subsequent changes (e.g., changes in the source of DNA or host-vector 
system), if covered under Sections III-A, III-B, III-C, or III-D 
(Experiments Covered by the NIH Guidelines), to the Institutional 
Biosafety Committee for review and approval or disapproval; and
    Section IV-B-7-c-(4). Remain in communication with the 
Institutional Biosafety Committee throughout the conduct of the 
project.
Section IV-B-7-d. Responsibilities of the Principal Investigator Prior 
to Initiating Research
    The Principal Investigator shall:
    Section IV-B-7-d-(1). Make available to all laboratory staff the 
protocols that describe the potential biohazards and the precautions to 
be taken;
    Section IV-B-7-d-(2). Instruct and train laboratory staff in: (i) 
The practices and techniques required to ensure safety, and (ii) the 
procedures for dealing with accidents; and
    Section IV-B-7-d-(3). Inform the laboratory staff of the reasons 
and provisions for any precautionary medical practices advised or 
requested (e.g., vaccinations or serum collection).
Section IV-B-7-e. Responsibilities of the Principal Investigator During 
the Conduct of the Research
    The Principal Investigator shall:
    Section IV-B-7-e-(1). Supervise the safety performance of the 
laboratory staff to ensure that the required safety practices and 
techniques are employed;
    Section IV-B-7-e-(2). Investigate and report any significant 
problems pertaining to the operation and implementation of containment 
practices and procedures in writing to the Biological Safety Officer 
(where applicable), Greenhouse/Animal Facility Director (where 
applicable), the Institutional Biosafety Committee, NIH/ORDA, and other 
appropriate authorities (if applicable) (reports to the NIH/ORDA shall 
be sent to the Office of Recombinant DNA Activities, National 
Institutes of Health/MSC 7010, 6000 Executive Boulevard, Suite 302, 
Bethesda, Maryland 20892-7010, (301) 496-9838);
    Section IV-B-7-e-(3). Correct work errors and conditions that may 
result in the release of recombinant DNA materials; and
    Section IV-B-7-e-(4). Ensure the integrity of the physical 
containment (e.g., biological safety cabinets) and the biological 
containment (e.g., purity and genotypic and phenotypic 
characteristics).
    Section IV-B-7-e-(5). Comply with annual data reporting and adverse 
event reporting requirements for human gene transfer experiments (see 
Appendix M-VII, Reporting Requirements--Human Gene Transfer Protocols).
Section IV-C. Responsibilities of the National Institutes of Health 
(NIH)
Section IV-C-1. NIH Director
    The NIH Director is responsible for: (i) Establishing the NIH 
Guidelines, (ii) overseeing their implementation, and (iii) their final 
interpretation. The NIH Director has responsibilities under the NIH 
Guidelines that involve ORDA and the RAC. ORDA's responsibilities under 
the NIH Guidelines are administrative. Advice from the RAC is primarily 
scientific, technical, and ethical. In certain circumstances, there is 
specific opportunity for public comment with published response prior 
to final action.
Section IV-C-1-a. General Responsibilities
    The NIH Director is responsible for:
    Section IV-C-1-a-(1). Promulgating requirements as necessary to 
implement the NIH Guidelines;
    Section IV-C-1-a-(2). Establishing and maintaining the RAC to carry 
out the responsibilities set forth in Section IV-C-2, Recombinant DNA 
Advisory Committee (RAC membership is specified in its charter and in 
Section IV-C-2);
    Section IV-C-1-a-(3). Establishing and maintaining NIH/ORDA to 
carry out the responsibilities defined in Section IV-C-3, Office of 
Recombinant DNA Activities;
    Section IV-C-1-a-(4). Conducting and supporting training programs 
in laboratory safety for Institutional Biosafety Committee members, 
Biological Safety Officers and other institutional experts (if 
applicable), Principal Investigators, and laboratory staff.
    Section IV-C-1-a-(5). Establishing and convening Gene Therapy 
Policy Conferences as described in Appendix M, Points to Consider in 
the Design and Submission of Protocols for the Transfer of Recombinant 
DNA Molecules into One or More Human Subjects.
Section IV-C-1-b. Specific Responsibilities
    In carrying out the responsibilities set forth in this section, the 
NIH Director, or a designee shall weigh each proposed action through 
appropriate analysis and consultation to determine whether it complies 
with the NIH Guidelines and presents no significant risk to health or 
the environment.
Section IV-C-1-b-(1). Major Actions
    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

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shall be notified of the following decisions:
    Section IV-C-1-b-(1)-(a). Changing containment levels for types of 
experiments that are specified in the NIH Guidelines when a Major 
Action is involved;
    Section IV-C-1-b-(1)-(b). Assigning containment levels for types of 
experiments that are not explicitly considered in the NIH Guidelines 
when a Major Action is involved;
    Section IV-C-1-b-(1)-(c). Promulgating and amending a list of 
classes of recombinant DNA molecules to be exempt from the NIH 
Guidelines because they consist entirely of DNA segments from species 
that exchange DNA by known physiological processes or otherwise do not 
present a significant risk to health or the environment;
    Section IV-C-1-b-(1)-(d). Permitting experiments specified by 
Section III-A, Experiments that Require Institutional Biosafety 
Committee Approval, RAC Review, and NIH Director Approval Before 
Initiation;
    Section IV-C-1-b-(1)-(e). Certifying new host-vector systems with 
the exception of minor modifications of already certified systems (the 
standards and procedures for certification are described in Appendix I-
II, Certification of Host-Vector Systems). Minor modifications 
constitute (e.g., those of minimal or no consequence to the properties 
relevant to containment); and
    Section IV-C-1-b-(1)-(f). Adopting other changes in the NIH 
Guidelines.
Section IV-C-1-b-(2). Minor Actions
    NIH/ORDA shall carry out certain functions as delegated to it by 
the NIH Director (see Section IV-C-3, Office of Recombinant DNA 
Activities). Minor Actions (as determined by NIH/ORDA in consultation 
with the RAC Chair and one or more RAC members, as necessary) will be 
transmitted to the RAC and Institutional Biosafety Committee Chairs:
    Section IV-C-1-b-(2)-(a). Changing containment levels for 
experiments that are specified in Section III, Experiments Covered by 
the NIH Guidelines (except when a Major Action is involved);
    Section IV-C-1-b-(2)-(b). Assigning containment levels for 
experiments not explicitly considered in the NIH Guidelines;
    Section IV-C-1-b-(2)-(c). Revising the Classification of Etiologic 
Agents for the purpose of these NIH Guidelines (see Section V-A, 
Footnotes and References of Sections I-IV).
    Section IV-C-1-b-(2)-(d). Interpreting the NIH Guidelines for 
experiments to which the NIH Guidelines do not specifically assign 
containment levels;
    Section IV-C-1-b-(2)-(e). Setting containment under Sections III-C-
1-d, Experiments Using Risk Group 2, Risk Group 3, Risk Group 4, or 
Restricted Agents as Host-Vector Systems, and III-C-2-b, Experiments in 
which DNA from Risk Group 2, Risk Group 3, Risk Group 4, or Restricted 
Agents is Cloned into Nonpathogenic Prokaryotic or Lower Eukaryotic 
Host-Vector Systems;
    Section IV-C-1-b-(2)-(f). Approving minor modifications of already 
certified host-vector systems (the standards and procedures for such 
modifications are described in Appendix I-II, Certification of Host-
Vector Systems);
    Section IV-C-1-b-(2)-(g). Decertifying already certified host-
vector systems;
    Section IV-C-1-b-(2)-(h). Adding new entries to the list of 
molecules toxic for vertebrates (see Appendix F, Containment Conditions 
for Cloning of Genes Coding for the Biosynthesis of Molecules Toxic for 
Vertebrates); and
    Section IV-C-1-b-(2)-(i). Determining appropriate containment 
conditions for experiments according to case precedents developed under 
Section IV-C-1-b-(2)-(c).
Section IV-C-2. Recombinant DNA Advisory Committee (RAC)
    The RAC is responsible for carrying out specified functions cited 
below as well as others assigned under its charter or by the DHHS 
Secretary and the NIH Director. The RAC consists of 15 voting members 
including the Chair, appointed by the DHHS Secretary or his/her 
designee, at least 8 of whom are selected from authorities 
knowledgeable in the fields of molecular genetics, molecular biology, 
recombinant DNA research, or other scientific fields. At least 4 
members of the RAC shall be persons knowledgeable in applicable law, 
standards of professional conduct and practice, public attitudes, the 
environment, public health, occupational health, or related fields. 
Representatives from Federal agencies shall serve as non-voting 
members. Nominations for the RAC may be submitted to the Office of 
Recombinant DNA Activities, National Institutes of Health/MSC 7010, 
6000 Executive Boulevard, Suite 302, Bethesda, Maryland 20892-7010, 
(301) 496-9838.
    All meetings of the RAC shall be announced in the Federal Register, 
including tentative agenda items, 15 days before the meeting. Final 
agendas, if modified, shall be available at least 72 hours before the 
meeting. No item defined as a Major Action under Section IV-C-1-b-(1) 
may be added to an agenda following Federal Register publication.
    The RAC shall be responsible for:
    Section IV-C-2-a. Advising the NIH Director on the following 
actions: (1) Adopting changes in the NIH Guidelines. (2) Assigning 
containment levels, changing containment levels, and approving 
experiments considered as Major Actions under the NIH Guidelines, i.e., 
the deliberate transfer of a drug resistance trait to microorganisms 
that are not known to acquire the trait naturally, if such acquisition 
could compromise the use of the drug to control disease agents in 
humans, veterinary medicine, or agriculture. (3) Promulgating and 
amending lists of classes of recombinant DNA molecules to be exempt 
from the NIH Guidelines because they consist entirely of DNA segments 
from species that exchange DNA by known physiological processes or 
otherwise do not present a significant risk to health or the 
environment. (4) Certifying new host-vector systems.
    Section IV-C-2-b. Identifying novel human gene transfer experiments 
deserving of public discussion by the full RAC;
    Section IV-C-2-c. Transmitting specific comments/recommendations 
about: (i) a specific human gene transfer experiment, or (ii) a 
category of human gene transfer experiments, to the NIH Director;
    Section IV-C-2-d. Publicly reviewing human gene transfer clinical 
trial data and relevant information evaluated and summarized by NIH/
ORDA in accordance with the annual data reporting requirements; and
    Section IV-C-2-e. Identifying broad scientific and ethical/social 
issues relevant to gene therapy research as potential Gene Therapy 
Policy Conference topics.
    Section IV-C-2-f. Identifying novel ethical issues relevant to 
specific human applications of gene transfer and recommending 
appropriate modifications to the Points to Consider that will provide 
guidance in the preparation of relevant Informed Consent documents;
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:

[[Page 7119]]

    Section IV-C-3-a. Serving as the focal point for public access to 
summary information pertaining to human gene transfer experiments;
    Section IV-C-3-b. Serving as the focal point for data management of 
human gene transfer experiments;
    Section IV-C-3-c. Administering the annual data reporting 
requirements (and subsequent review) for human gene transfer 
experiments (see Appendix M-VII, Reporting Requirements--Human Gene 
Transfer Protocols);
    Section IV-C-3-d. Transmitting comments/recommendations arising 
from public RAC discussion of a novel human gene transfer experiment to 
the NIH Director. RAC recommendations shall be forwarded to the 
Principal Investigator, the sponsoring institution, and other 
Department of Health and Human Services (DHHS) components, as 
appropriate.
    Section IV-C-3-e. Collaborating with Principal Investigators, 
Institutional Biosafety Committees, Institutional Review Boards, and 
other DHHS components (including the FDA and Office for Protection from 
Research Risks); to ensure human gene transfer experiment registration 
compliance in accordance with Appendix M-I, Submission Requirements, 
Human Gene Transfer Experiments of the NIH Guidelines.
    Section IV-C-3-f. Administering Gene Therapy Policy Conferences as 
deemed appropriate by the NIH Director.
    Section IV-C-3-g. 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, 
Experiments Involving the Cloning of Toxin Molecules with LD50 of 
Less than 100 Nanograms Per Kilogram Body Weight, Appendix F-I, 
Containment Conditions for Cloning of Genes Coding for the Biosynthesis 
of Molecules Toxic for Vertebrates--General Information, and Appendix 
F-II, Cloning of Toxin Molecules Genes in Escherichia coli K-12);
    Section IV-C-3-h. Serving as the executive secretary of the RAC;
    Section IV-C-3-i. Publishing in the Federal Register:
    Section IV-C-3-i-(1). Announcements of RAC meetings and tentative 
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-i-(2). Announcements of Gene Therapy Policy 
Conferences and tentative agendas at least 15 days in advance;
    Section IV-C-3-i-(3). Proposed Major Actions (see Section IV-C-1-b-
(1), Major Actions) at least 15 days prior to the RAC meeting; and
    Section IV-C-3-j. 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, Institutional Biosafety Committee (IBC), giving its 
approval to the Institutional Biosafety Committee membership.
Section IV-C-4. Other NIH Components
    Other NIH components shall be responsible for certifying maximum 
containment (BL4) facilities, inspecting them periodically, and 
inspecting other recombinant DNA facilities as deemed necessary.
Section IV-D. Voluntary Compliance
Section IV-D-1. Basic Policy--Voluntary Compliance
    Individuals, corporations, and institutions not otherwise covered 
by the NIH Guidelines are encouraged to follow the standards and 
procedures set forth in Sections I through IV. In order to simplify 
discussion, references hereafter to `institutions' are intended to 
encompass corporations and individuals who have no organizational 
affiliation. For purposes of complying with the NIH Guidelines, an 
individual intending to carry out research involving recombinant DNA is 
encouraged to affiliate with an institution that has an Institutional 
Biosafety Committee approved under the NIH Guidelines.
    Since commercial organizations have special concerns, such as 
protection of proprietary data, some modifications and explanations of 
the procedures are provided in Sections IV-E-2 through IV-E-5-b, 
Voluntary Compliance, in order to address these concerns.
Section IV-D-2. Institutional Biosafety Committee Approval--Voluntary 
Compliance
    It should be emphasized that employment of an Institutional 
Biosafety Committee member solely for purposes of membership on the 
Institutional Biosafety Committee does not itself make the member an 
institutionally affiliated member. Except for the unaffiliated members, 
a member of an Institutional Biosafety Committee for an institution not 
otherwise covered by the NIH Guidelines may participate in the review 
and approval of a project in which the member has a direct financial 
interest so long as the member has not been, and does not expect to be, 
engaged in the project. Section IV-B-2-a-(4), Institutional Biosafety 
Committee, is modified to that extent for purposes of these 
institutions.
Section IV-D-3. Certification of Host-Vector Systems--Voluntary 
Compliance
    A host-vector system may be proposed for certification by the NIH 
Director in accordance with the procedures set forth in Appendix I-II, 
Certification of Host-Vector Systems. In order to ensure protection for 
proprietary data, any public notice regarding a host-vector system 
which is designated by the institution as proprietary under Section IV-
D, Voluntary Compliance, will be issued only after consultation with 
the institution as to the content of the notice.
Section IV-D-4. Requests for Exemptions and Approvals--Voluntary 
Compliance
    Requests for exemptions or other approvals as required by the NIH 
Guidelines should be submitted based on the procedures set forth in 
Sections I through IV. In order to ensure protection for proprietary 
data, any public notice regarding a request for an exemption or other 
approval which is designated by the institution as proprietary under 
Section IV-E-5-a, Voluntary Compliance, will be issued only after 
consultation with the institution as to the content of the notice.
Section IV-D-5. Protection of Proprietary Data--Voluntary Compliance
Section IV-D-5-a. General
    In general, the Freedom of Information Act requires Federal 
agencies to make their records available to the public upon request. 
However, this requirement does not apply to, among other things, 
``trade secrets and commercial or financial information that is 
obtained from a person and that is privileged or confidential.'' Under 
18 U.S.C. 1905, it is a criminal offense for an officer or employee of 
the U.S. or any Federal department or agency to publish, divulge, 
disclose, or make known ``in any manner or to any extent not authorized 
by law any information coming to him in the course of his employment or 
official duties or by reason of any examination or investigation made 
by, or return, report or record made to or filed with, such department 
or agency or officer or employee thereof, which information

[[Page 7120]]

concerns or relates to the trade secrets, (or) processes * * * of any 
person, firm, partnership, corporation, or association.'' This 
provision applies to all employees of the Federal Government, including 
special Government employees. Members of the RAC are ``special 
Government employees.''
    In submitting to NIH for purposes of voluntary compliance with the 
NIH Guidelines, an institution may designate those items of information 
which the institution believes constitute trade secrets, privileged, 
confidential, commercial, or financial information. If NIH receives a 
request under the Freedom of Information Act for information so 
designated, NIH will promptly contact the institution to secure its 
views as to whether the information (or some portion) should be 
released. If the NIH decides to release this information (or some 
portion) in response to a Freedom of Information request or otherwise, 
the institution will be advised and the actual release will be delayed 
in accordance with 45 Code of Federal Regulations, section 5.65 (d) and 
(e).
Section IV-D-5-b. Presubmission Review
    Any institution not otherwise covered by the NIH Guidelines, which 
is considering submission of data or information voluntarily to NIH, 
may request presubmission review of the records involved to determine 
if NIH will make all or part of the records available upon request 
under the Freedom of Information Act.
    A request for presubmission review should be submitted to NIH/ORDA 
along with the records involved to the Office of Recombinant DNA 
Activities, National Institutes of Health/MSC 7010, 6000 Executive 
Boulevard, Suite 302, Bethesda, Maryland 20892-7010, (301) 496-9838. 
These records shall be clearly marked as being the property of the 
institution on loan to NIH solely for the purpose of making a 
determination under the Freedom on Information Act. NIH/ORDA will seek 
a determination from the responsible official under DHHS regulations 
(45 Code of Federal Regulations, Part 5) as to whether the records 
involved, (or some portion) will be made available to members of the 
public under the Freedom of Information Act. Pending such a 
determination, the records will be kept separate from NIH/ORDA files, 
will be considered records of the institution and not NIH/ORDA, and 
will not be received as part of NIH/ORDA files. No copies will be made 
of such records.
    NIH/ORDA will inform the institution of the DHHS Freedom of 
Information Officer's determination and follow the institution's 
instructions as to whether some or all of the records involved are to 
be returned to the institution or to become a part of NIH/ORDA files. 
If the institution instructs NIH/ORDA to return the records, no copies 
or summaries of the records will be made or retained by DHHS, NIH, or 
ORDA. The DHHS Freedom of Information Officer's determination will 
represent that official's judgment at the time of the determination as 
to whether the records involved (or some portion) would be exempt from 
disclosure under the Freedom on Information Act if at the time of the 
determination the records were in NIH/ORDA files and a request was 
received for such files under the Freedom of Information Act.

V-E. Proposed Amendments to Appendix A, Exemptions Under Section III-E-
5--Sublists of Natural Exchanges

    Appendix A, first paragraph, is proposed to be amended to reflect 
renumbering of a previous section.

IV-F. Proposed Amendments to Appendix C, Exemptions Under Section III-
E-6

    Appendix C is proposed to be amended to reflect renumbering of a 
previous section.

IV-G. Proposed Amendments to Appendix I, Biological Containment

    After the first paragraph in Section I-II-A, Responsibility, the 
following Note is proposed to be added:

    Note. A host-vector system may be proposed for certification by 
the NIH Director in accordance with the procedures set forth in 
Appendix I-II, Certification of Host-Vector Systems. In order to 
ensure protection for proprietary data, any public notice regarding 
a host-vector system which is designated by the institution as 
proprietary under Section IV-D, Voluntary Compliance, will be issued 
only after consultation with the institution as to the content of 
the notice (see Section IV-D-3, Certification of Host-Vector 
Systems--Voluntary Compliance).

III-H. Proposed Amendments to Appendix M, Points to Consider in the 
Design and Submission of Protocols for the Transfer of Recombinant DNA 
Molecules into One or More Human Subjects

    Appendix M is proposed to be amended to read:

Appendix M. The Points To Consider in the Design and Submission of 
Protocols for the Transfer of Recombinant DNA Molecules into 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 (see Section I-C, General Applicability).
    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

[[Page 7121]]

(human gene transfer) will be considered through a consolidated review 
process involving both the NIH/ORDA and the FDA. Investigators shall 
simultaneously submit their relevant information on the proposed human 
gene transfer experiments to both the NIH/ORDA and the FDA. Submission 
of human gene transfer protocols to the NIH will be in the format 
described in Appendix M-I, Submission Requirements--Human Gene Transfer 
Experiments, of the NIH Guidelines. Submission to NIH shall be for 
registration purposes and will ensure continued public access to 
relevant human gene transfer information conducted in compliance with 
the NIH Guidelines. Submission of human gene transfer protocols to the 
FDA will be in the format described in 21 CFR, Chapter I, Subchapter D, 
Part 312, Subpart B, Section 23, IND Content and Format.
    Factors that may contribute to public discussion of a human gene 
transfer experiment by the RAC 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 discussion are those determined not to represent possible risk to 
human health or the environment. Full RAC review of an individual human 
gene transfer experiment can be initiated by the NIH Director or 
recommended to the NIH Director by: (i) three or more RAC members, or 
(ii) other Federal agencies. An individual human gene transfer 
experiment that is recommended for full RAC review should represent 
novel characteristics deserving of public discussion. If the Director, 
NIH, determines that an experiment will undergo full RAC discussion, 
NIH/ORDA will immediately notify the Principal Investigator. RAC 
members may forward individual requests for additional information 
relevant to a specific protocol through NIH/ORDA to the Principal 
Investigator. In making a determination whether an experiment is novel, 
and thus deserving of full RAC discussion, reviewers will 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. RAC recommendations on a specific human gene transfer 
experiment shall be forwarded to the NIH Director, the Principal 
Investigator, the sponsoring institution, and other Department of 
Health and Human Services (DHHS) components, as appropriate. Relevant 
documentation will be included in the material for the RAC meeting at 
which the experiment is scheduled to be discussed. RAC meetings will be 
open to the public except where trade secrets and proprietary 
information are reviewed (see Section IV-D-5, Protection of Proprietary 
Data). The RAC prefers 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.

    Note: Any application submitted to NIH/ORDA should not be 
designated as ``confidential'' in its entirety. In the event that a 
sponsor determines that specific responses to one or more of the 
items described in Appendix M should be considered as proprietary or 
trade secret, each item should be clearly identified as such. The 
cover letter (attached to the submitted material) should: (1) 
Clearly indicate that select portions of the application contain 
information considered as proprietary or trade secret, (2) a brief 
explanation as to the reason that each of these items is determined 
proprietary or trade secret.

    Public discussion of human gene transfer experiments (and access to 
relevant information) shall serve to inform the public about the 
technical aspects of the proposals, the meaning and significance of the 
research, significant safety issues, and ethical/societal implications 
of the research. RAC discussion is intended to ensure safe and ethical 
conduct of gene therapy experiments and facilitate public understanding 
of this novel area of biomedical research.
    RAC recommendations on a specific human gene transfer experiment 
shall be forwarded to the NIH Director, the Principal Investigator, the 
sponsoring institution, and other Department of Health and Human 
Services (DHHS) components, as appropriate. In its evaluation of human 
gene transfer proposals, the RAC 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 request 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 order to enhance the depth and value of public discussion 
relevant to scientific, safety, and ethical/societal implications of 
gene therapy research, the NIH Director will convene GTPC at regular 
intervals. As appropriate, the NIH Director will convene GTPC 
immediately following scheduled RAC meetings. GTPC will be administered 
by the NIH/ORDA. Conference participation will not involve a standing 
committee membership but rather will offer the unique advantage of 
assembling numerous participants who possess significant scientific, 
ethical, and legal expertise and/or interest that is directly 
applicable to a specific gene therapy research issue. At least one 
member of the RAC will serve as Co-chair of each GTPC and report the 
findings of the GTPC to the full committee at its next scheduled 
meeting. The RAC representative for each GTPC will be chosen based on 
the participant's area of expertise relative to the specific gene 
therapy research issue to be discussed. GTPC will have representation 
from other Federal agencies, including the FDA. GTPCs will focus on 
broad over-arching policy and scientific issues related to gene therapy 
research. Proposals for GTPC topics may be submitted by members of the 
RAC, representatives of academia, industry, patient and consumer 
advocacy organizations, other Federal agencies, professional scientific 
societies, and the general public. GTPC topics will not be limited to 
discussion of human applications of gene therapy research, i.e., they 
may include basic research on the use of novel gene delivery vehicles, 
or novel applications of gene transfer. The findings of the GTPC will 
be transmitted to the NIH Director and will be made publicly available. 
The NIH Director anticipates that this public policy forum will serve 
as a model for interagency communication and collaboration, 
concentrated expert discussion of novel scientific issues and their 
potential societal implications, and enhanced opportunity for public 
discussion of specific issues and potential impact of such applications 
on human health and the environment.
    Appendix M will be considered for revisions as experience in 
evaluating proposals accumulates and as new

[[Page 7122]]

scientific developments occur. This review will be carried out 
periodically as needed.

Appendix M-I. Submission Requirements--Human Gene Transfer Experiments

    Investigators must submit the following material to the Office of 
Recombinant DNA Activities, National Institutes of Health/MSC 7010, 
6000 Executive Boulevard, Suite 302, Bethesda, Maryland 20892-7010, 
(301) 496-9838 (see exemption in Appendix M-VIII-A, Footnotes of 
Appendix M). Proposals to the NIH will be submitted in the following 
order: (1) Scientific abstract; (2) non-technical abstract; (3) 
Institutional Biosafety Committee and Institutional Review Board 
approvals and their deliberations pertaining to your protocol; (4) 
Responses to Appendix M-II through M-V, Description of the Proposal, 
Informed Consent, Privacy and Confidentiality, and Special Issues; (5) 
clinical protocol (as approved by the local Institutional Biosafety 
Committee and Institutional Review Board); (6) Informed Consent 
document--approved by the Institutional Review Board (see Appendix M-
III, Informed Consent); (7) appendices (including tables, figures, and 
manuscripts); (8) curricula vitae--2 pages for each key professional 
person in biographical sketch format; and (9) two 3\1/2\-inch diskettes 
with the complete vector nucleotide sequence in ASCII format. 
Investigators must submit their human gene transfer protocols to the 
FDA in the format described in 21 CFR, Chapter I, Subchapter D, Part 
312, Subpart B, Section 23, IND Content and Format. Submissions should 
be sent to 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.

Appendix M-II. Description of the Proposal

    [This section remains unchanged.]

Appendix M-III. Informed Consent

    [This section remains unchanged.]

Appendix M-IV. Privacy and Confidentiality

    [This section remains unchanged.]

Appendix M-V. Special Issues

    [This section remains unchanged.]

Appendix M-VI. RAC Review--Human Gene Transfer Experiments

    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). The RAC prefers that information provided in 
response to Appendix M, Points to Consider, contain no proprietary data 
or trade secrets, enabling all aspects of the discussion to be open to 
the public.

Appendix M-VI-A. RAC Members' Written Comments

    Following receipt by NIH/ORDA, summary information on each human 
gene transfer protocol will be forwarded to RAC members. Each RAC 
member shall notify NIH/ORDA within 15 working days regarding the 
necessity for full RAC discussion. Full RAC review of an individual 
human gene transfer experiment can be initiated by the NIH Director or 
recommended to the NIH Director by: (i) Three or more RAC members, or 
(ii) other Federal agencies. An individual human gene transfer 
experiment that is recommended for full RAC review should represent 
novel characteristics deserving of public discussion. If the Director, 
NIH, determines that an experiment will undergo full RAC discussion, 
NIH/ORDA will immediately notify the Principal Investigator. RAC 
members may forward individual requests for additional information 
relevant to a specific protocol through NIH/ORDA to the Principal 
Investigator. In making a determination whether an experiment is novel, 
and thus deserving of full RAC discussion, reviewers will 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. RAC recommendations on a specific human gene transfer 
experiment shall be forwarded to the NIH Director, the Principal 
Investigator, the sponsoring institution, and other Department of 
Health and Human Services (DHHS) components, as appropriate.

Appendix M-VII. Reporting Requirements--Human Gene Transfer Protocols

Appendix M-VII-A. Annual Data Reporting
    Investigators shall comply with the annual data reporting 
requirements. Annual Data Report forms will be forwarded by NIH/ORDA to 
investigators. Data submitted in these reports will be evaluated by the 
RAC and NIH/ORDA, and reviewed at a future RAC meeting.
Appendix M-VII-B. Adverse Event Reporting
    Investigators who have received approval from the FDA to initiate a 
human gene transfer protocol must report any serious adverse event 
immediately to the local Institutional Review Board, Institutional 
Biosafety Committee, Office for Protection from Research Risks (if 
applicable), NIH/ORDA, and FDA, 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/MSC 7010, 6000 Executive Boulevard, Suite 302, Bethesda, 
Maryland 20892-7010, (301) 496-9838.

Appendix M-VIII. Footnotes of Appendix M

    Appendix M-VIII-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 expected, are exempt from Appendix M-I, 
Submission Requirements, and Appendix M-VIII, Reporting Requirements-
Human Gene Transfer Experiments.''

IV. Addition to Appendix D of the NIH Guidelines Regarding a Human Gene 
Transfer Protocol/Dr. Crystal

    In a letter dated January 8, 1997, Dr. Ronald Crystal of New York-
Hospital-Cornell Medical Center, New York, New York, submitted a human 
gene transfer protocol entitled: Immune Response to Intradermal 
Administration of an Adenovirus Type 5 Gene Transfer Vector (ADGVCD.10) 
in Normal Individuals (NIH Protocol #9701-171) to the RAC for 
evaluation regarding the necessity for RAC review and approval.

V. Amendments to Appendix B of the NIH Guidelines Regarding 
Classification of Human Etiologic Agents on the Basis of Hazard

    In a letter dated January 21, 1997, Dr. Diane Fleming, Chair of the 
Subcommittee on Laboratory Safety, American Society for Microbiology, 
Washington, D.C., requested the following addition of certain select 
agents not previously listed. The letter reads:
    * * * Select agents were identified by the Centers for Disease 
Control and Prevention as being subject to special

[[Page 7123]]

site registration and handling requirements under 42 CFR Part 72. Only 
three of the special agents are not listed in Appendix B, but they 
could now be added as follows:
    Appendix B-III-D. Risk Group 3 viruses. Add
    Arenaviruses: Flexal
    Justification: Flexal is already covered by `other viruses listed 
in the reference source' but now that it is on the list of select 
agents, it should be listed here as well.
    Appendix B-IV-D. Risk Group 4 viruses. Add
    Arenaviruses: Sabia
    Paramyxoviruses: Equine morbilli virus
    Justification: As Chairman of the Subcommittee on Arboviral 
Laboratory Safety (SALS), Dr. Michael P. Kiley told me that both Sabia 
and equine morbilli virus are to be handled under Biosafety Level 4 
containment. (Dr. Michael P. Kiley, of the Federal Laboratories for 
Health Canada and Agriculture and Agri-Food, Winnipeg, Manitoba, 
Canada, January 21, 1997, personal communication regarding the 
classification of Sabia and equine morbilli virus).
    * * * Recommendations for corrections and changes to errors in 
Appendix B which may not require RAC review:
    * * * Appendix B-II-A, pg 1487
    Acinetobacter baumannii formerly Acinetobacter calcoaceticus var 
anitratus is known as the Acinetobacter calcoaceticus-baumannii 
complex. We can add var. anitratus to the A. calcoaceticus.
    * * * Appendix II-B-IV-D. Remove erroneous reference to 
Togaviruses, Group A now associated with the Arenaviruses.
* * * * *
    OMB's ``Mandatory Information Requirements for Federal Assistance 
Program Announcements'' (45 FR 39592) 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 to be not 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.

    Dated: February 10, 1997.
Lana Skirboll,
Associate Director for Science Policy, National Institutes of Health
[FR Doc. 97-3735 Filed 2-13-97; 8:45 am]
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