[Federal Register Volume 62, Number 211 (Friday, October 31, 1997)]
[Notices]
[Pages 59032-59046]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-28921]



[[Page 59031]]

_______________________________________________________________________

Part II





Department of Health and Human Services





_______________________________________________________________________



National Institutes of Health



_______________________________________________________________________



Recombinant DNA Research: Actions Under the Guidelines; Notice

Federal Register / Vol. 62, No. 211 / Friday, October 31, 1997 / 
Notices

[[Page 59032]]



DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Recombinant DNA Research: Actions Under the Guidelines

AGENCY: Notice of Actions Under the NIH Guidelines for Research 
Involving Recombinant DNA Molecules (NIH Guidelines) (59 FR 34496, 
amended 59 FR 40170, 60 FR 20726, 61 FR 1482, 61 FR 10004, 62 FR 4782).

FOR FURTHER INFORMATION CONTACT: Additional information can be obtained 
from Debra Knorr, Acting Director, Office of Recombinant DNA Activities 
(ORDA), Office of Science Policy, National Institutes of Health, MSC 
7010, 6000 Executive Boulevard, Suite 302, Bethesda, Maryland 20892-
7010, Phone 301-496-9838, FAX 301-496-9839. ORDA's web site is located 
at http://www.nih.gov/od/orda for further information about the office.

SUPPLEMENTARY INFORMATION: Today's actions are being promulgated under 
the NIH Guidelines for Research Involving Recombinant DNA Molecules. 
These Proposed Actions were published for comment in the Federal 
Register of July 8, 1996 (61 FR 7108), and August 20, 1997 (62 FR 
44387). The Proposed Actions were reviewed and recommended for approval 
by the NIH Recombinant DNA Advisory Committee (RAC) at its meetings on 
December 9, 1996, March 6-7, 1997, and September 12, 1997.

I. Background Information and Decisions on Actions Under the NIH 
Guidelines

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

I-A-1. Notice of Intent--July 1996

    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 the NIH oversight of human gene transfer research. 
Specifically, it was proposed that 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 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 (GTPCs). 
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, 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, 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 was submitted.

I-B. Proposed Actions--November 1996

    On November 22, 1996, the NIH Director published the Notice of 
Proposed Actions Under the NIH Guidelines for Research Involving 
Recombinant DNA Molecules (61 FR 59725). These Proposed Actions were 
prepared in response to public opinion and in keeping with the NIH 
Director's intent to increase the usefulness and productivity of public 
discussion of human gene transfer research.
    In the Proposed Actions, the NIH Director proposed to: (1) Retain 
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) regularly convene GTPCs; and (4) maintain 
public access to human gene transfer clinical trial information. The 
following summarizes the roles and responsibilities of the NIH 
Director, RAC, ORDA, and 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. NIH Director

    The roles and responsibilities of the NIH Director in accordance 
with the NIH Guidelines remain unchanged except for the following: (1) 
Approval of human gene transfer experiments by the NIH Director will be 
relinquished to FDA which already holds statutory authority for such 
approval under 21 CFR, Chapter I, Subchapter D. (2) GTPCs will be 
established and regularly convened by the NIH Director.

I-B-1-b. Recombinant DNA Advisory Committee (RAC)

    The roles and responsibilities of RAC related to human gene 
transfer research remain the same except for the following: (1) RAC 
will identify novel human gene transfer experiments deserving of public 
discussion by the full RAC and will transmit its comments/
recommendations on specific human gene transfer experiments or 
categories of human gene transfer experiments to the NIH Director, the 
principal Investigator, the sponsoring institution, and other 
Department of Health and Human Services (DHHS) components, as 
appropriate. (2) Novel scientific, safety, social, and ethical issues 
relevant to specific human applications of gene transfer will be 
identified by RAC, which will recommend to the NIH Director appropriate 
modifications to 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) that will provide guidance in 
the design and submission of human gene transfer clinical trials. (3) 
RAC will publicly review human gene transfer clinical trial data 
submitted to NIH/ORDA in accordance with the annual data reporting 
requirements contained in Appendix M-VII-B of the NIH Guidelines. (4) 
Broad scientific,safety, social, and ethical issues relevant to human 
gene transfer research will be identified by RAC and submitted to the 
NIH Director as recommendations for consideration as potential GTPC 
topics.

I-B-1-c. Gene Therapy Policy Conferences (GTPCs)

    In order to enhance the depth and value of public discussion 
relevant to scientific, safety, social, and ethical implications of 
gene therapy research, the NIH Director will convene GTPCs at regular 
intervals. As appropriate, the NIH Director may convene a GTPC in 
conjunction with a regularly scheduled RAC meeting. GTPCs will be 
administered by 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, safety, social, and ethical expertise and/or interest that 
is directly applicable to a specific gene therapy research issue. At

[[Page 59033]]

least one member of RAC will serve as Co-chair of each GTPC and report 
the findings of each GTPC to RAC 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. GTPCs will have representation from other Federal 
agencies, including FDA and the Office for Protection from Research 
Risks (OPRR). GTPCs will focus on broad overarching policy and 
scientific issues related to gene therapy research. Proposals for GTPC 
topics may be submitted by members of 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 human gene 
transfer. GTPC findings 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 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. The roles and responsibilities of 
NIH/ORDA remain unchanged except for the following: (1) Serving as the 
focal point for public access to summary information pertaining to 
human gene transfer experiments. (2) Transmitting to the NIH Director 
comments/recommendations arising from public RAC discussion of a novel 
human gene transfer experiment. RAC recommendations shall be forwarded 
to the Principal Investigator(s), the sponsoring institution, and other 
DHHS components, as appropriate. (3) Collaborating with Principal 
Investigators, IBCs, Institutional Review Boards (IRBs), and other DHHS 
components, to ensure human gene transfer experiment registration 
compliance. (4) Administering GTPCs as deemed appropriate by the NIH 
Director. (5) Publishing announcements of GTPCs and tentative agendas 
in the Federal Register at least 15 days in advance.

I-B-1-e. Institutional Biosafety Committees (IBCs)

    The roles and responsibilities of IBCs related to human gene 
transfer experiments remain unchanged, except when the institution 
participates in or sponsors recombinant DNA research involving human 
subjects, the institution must ensure that: (a) The IBC has adequate 
expertise and training (using ad hoc consultants as deemed necessary), 
and (b) all aspects of Appendix M, Points to Consider, have been 
appropriately addressed by the Principal Investigator prior to 
submission to NIH/ORDA.

I-C. Proposed Actions--December 1996 RAC Meeting

    On November 22, 1996, the NIH Director published a Notice of 
Proposed Actions Under the NIH Guidelines for Research Involving 
Recombinant DNA Molecules (61 FR 59725). The Notice of Proposed Actions 
was prepared in response to public opinion and in keeping with the NIH 
Director's intent to increase the usefulness and productivity of public 
discussion of human gene transfer research. As a result of its December 
9, 1996, deliberations of the Proposed Actions under the NIH 
Guidelines, RAC proposed the following modifications to the November 
22, 1996, Notice of Intent:

I-C-1. Triggering Mechanism for RAC Discussion

    A motion was made that: (1) The capacity for Principal 
Investigators and institutional representatives to request RAC 
discussion of an individual human gene transfer protocol should be 
deleted. (2) The NIH Director or an appropriate FDA representative may 
request RAC review of an individual protocol. (3) Rather than a 
majority vote, RAC recommendations for full review of an individual 
protocol should be changed to a minimum of three members. (4) 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-2. Reporting Requirements

    A motion was made to request that FDA report back to the RAC on how 
RAC recommendations on an individual protocol were implemented. RAC 
should require investigator to provide additional information if FDA is 
unable to provide the necessary information. The motion failed by a 
vote of 3 in favor, 7 opposed, and 4 abstentions.
    Another motion was made to require investigators to submit a 
written report to the RAC that includes the following information: (1) 
How the investigator(s) responded to RAC's recommendations on the 
protocol (if applicable), and (2) any modifications to the protocol as 
required by FDA. The motion passed by a vote of 12 in favor, 1 opposed, 
and 1 abstention.

I-C-3. Relationship of RAC and GTPCs

    A motion was made that the RAC, with the NIH Director's approval, 
should have the primary responsibility for: (1) planning GTPC agendas, 
and (2) summarizing GTPC recommendations in the form of a report back 
to the NIH Director. The close GTP/RAC relationship should not preclude 
other parties from suggesting GTPC topics and GTPCs should be convened 
in consultation with FDA and OPRR. The motion passed by a vote of 13 in 
favor, 0 opposed, and 2 abstentions.

I-C-4. Proposed Actions--Structural Changes

    A motion was made to accept the overall structural changes put 
forward in the Proposed Actions as published in the November 22, 1996, 
Federal Register (61 FR 59725). However, RAC recommended that 
promulgation of the final actions should be postponed to the March 6-7, 
1997, RAC meeting, in order to more fully address these unresolved 
issues. The structural changes endorsed by RAC were as follows: (1) 
Retain 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) regularly convene GTPCs; and (4) maintain 
public access to human gene transfer clinical trial information. RAC 
members noted that several minor modification still remained 
unresolved, particularly with regard to the format for future 
discussion of gene therapy protocols and defining the role of RAC 
relative to GTPCs. The motion passed by a vote of 12 in favor, 0 
opposed, and 2 abstentions.

I-D. Proposed Action--March 1997

    On February 14, 1997, the NIH Director published a revised Notice 
of Proposed Actions Under the NIH Guidelines for Research Involving 
Recombinant DNA Molecules (62 FR 7108). 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 
discussing of

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human gene transfer research. During its March 6-7, 1997, meeting, RAC 
recommended the following changes to the February 14, 1997, Proposed 
Actions under the NIH Guidelines.

I-D-1. Relationship of RAC and GTPCs

    A motion was made to include the following modifications will 
regard to the role of RAC relative to GTPCs: (1) One member of RAC will 
co-chair each GTPC. (2) GTPCs will be held in conjunction with RAC 
meetings when appropriate (preferably on the first day). (3) All RAC 
members will be invited to attend GTPCs. The motion passed by a vote of 
8 in favor, 0 opposed, and no abstentions.

I-D-2. IBC Approval Requirements

    A motion was made to modify IBC approval requirements for human 
gene transfer protocols under Section III-C-a of the NIH Guidelines. 
Specifically, RAC proposed that IBC approval must be obtained from each 
institution at which recombinant DNS material will be administered to 
human subjects (as opposed to each institution involved in the 
production of vectors for human application and each institution at 
which there is ex vivo transduction of recombinant DNA material into 
target cells for human application). The motion passed by a vote of 6 
in favor, 0 opposed, and 2 abstentions.

I-D-3. NIH Human Gene Therapy Database

    A motion was made to identify the objectives of the human gene 
transfer database. As a result of RAC's deliberation on this issue, the 
following five objectives were identified: (1) Maintain and 
institutional memory, (2) provide administrative details of protocol 
registration, (3) provide annual status reports of protocols, (4) 
facilitate risk assessment of individual applications of human gene 
transfer, and (5) enhance public awareness of relevant scientific, 
safety, social, and ethical issues. The motion passed by a vote of 7 in 
favor, 0 opposed, and 1 abstention.

I-E. Requirement for Submission of Appendix M to 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 RAC 
and FDA. In her November 20, 1996, letter, Dr. Miller states:

``(1) Remove the requirement for submission of Appendix M to FDA. 
FDA does not accept Appendix M in place of an IND submission. FDA is 
not proposed to be and need not be included in the decisionmaking 
process to identify protocols to undergo full RAC review. Therefore, 
there is no reason for sponsors to submit Appendix M materials to 
FDA.
    ``(2) Explore the feasibility of a unified format for submission 
of protocols to 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 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 NIH 
and FDA with regard to simultaneous submission of human gene transfer 
protocols.
    During its December 9, 1996, and March 6-7, 1997, meetings, RAC 
discussed the proposed changes to the NIH Guidelines submitted by Dr. 
Miller. The consensus of RAC was that the requirement for submission of 
responses to Appendix M to FDA should be removed since FDA does not 
accept responses to Appendix M in place of an Investigational New Drug 
(IND) application. However, RAC stated that all human gene transfer 
protocols should include discussion of issues raised in Appendix M-II 
through M-V of the NIH Guidelines in the clinical protocols. The 
proposed action was published in the Federal Register of August 20, 
1997, for public comment. No comment was received from the public with 
regard to the proposed action.
    During the September 12, 1997, RAC meeting, RAC approved the 
amendments to the NIH Guidelines to eliminate the requirement for 
submission of responses to Appendix M of the NIH Guidelines to FDA. The 
motion passed by a vote of 12 in favor, 0 opposed, and 0 abstentions.

I-F. Environmental Assessment--October 1997

    As a prerequisite to amending the NIH Guidelines for the purpose of 
relinquishing the requirement for NIH Director approval of individual 
human gene transfer experiments, NIH prepared an Environmental 
Assessment for the Proposed Actions in accordance with requirements of 
the National Environmental Protection Act of 1969, 42 U.S.C. This 
Environmental Assessment that was completed in October 1997 included a 
finding of no significant impact on the environment. Copies of the 
Environmental Assessment 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.
    These actions under the NIH Guidelines are detailed in Section II--
Summary of Actions. I accept these recommendations, and the NIH 
Guidelines will be amended accordingly.

II. Summary of Actions

    NIH will take the following action under the NIH Guidelines for 
Research Involving Recombinant DNA Molecules:

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

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

    Section I is 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 NIH, must be submitted to 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 NIH (whether the experiment 
is referred to that agency by 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 FDA of such information on the proposed 
experiment as is prescribed by those agencies. Submission of human gene 
transfer protocols to NIH shall 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

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Guidelines. Investigational New Drug (IND) applications shall be 
submitted to FDA 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 deserving of full RAC discussion, reviewers will examine 
the scientific rational, scientific content (relative to other 
proposals reviewed by RAC), whether the preliminary in vitro and in 
vivo safety data were obtained in appropriate models and are 
sufficient, and whether questions related to relevant social and 
ethical issues 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 
other 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 NIH, including research performed directly by 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 collaboration or 
contractual agreements, not mere provisions 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.''

[Previously numbered Section I-D, General Definitions, will be 
renumbered to Section I-E.]

II-B. Amendments to Section II, Safety Considerations

    The second paragraph of Section II-A-3 is 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 * * *''

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

    Section III is amended to read:

``SECTION III. EXPERIMENTS COVERED BY THE NIH GUIDELINES

    ``This section describes six categories of experiments involving 
recombinant

[[Page 59036]]

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 II-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 II-A, II-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 
RAC, and specific approval by NIH. The containment conditions or 
stipulation requirements for such experiments will be recommended by 
RAC and set by 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 control 
disease agents in humans, veterinary medicine, or agriculture, will be 
reviewed by 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 LD<INF>50</INF> 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 
LD<INF>50</INF> of less than 100 nanograms per kilogram body weight 
(e.g., microbial toxins such as the botulinum toxins, tetanus toxin, 
diphteria 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 10892-7010, (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 One or 
More Human Subjects

    ``Research proposals involving the deliberate transfer of 
recombinant DNA, or DNA or RNA derived from recombinant DNA, into human 
subjects (human gene transfer) will be considered through a review 
process involving both NIH/ORDA and RAC. Investigators shall submit 
relevant information on the proposed human gene transfer experiments to 
NIH/ORDA. Submission of human gene transfer protocols to NIH will be in 
the format described in Appendix M-I, Submission Requirements--Human 
Gene Transfer Experiments. Submission to NIH/ORDA shall be for 
registration purposes and will ensure continued public access to 
relevant human gene transfer information in compliance with the NIH 
Guidelines. Investigational New Drug (IND) applications should be 
submitted to FDA in the format described in 21 CFR, chapter I, 
subchapter D, part 312, subpart B, section 23, IND content and Format.
    ``Institutional Biosafety Committee approval must be obtained from 
each institution at which recombinant DNA material will be administered 
to human subjects (as opposed to each institution invovled in the 
production of vectors for human application and each institution at 
which there is ex vivo transduction of recombinant DNA material into 
target cells for human application).
    ``RAC prefers that submission to NIH/ORDA in accordance with 
Appendix M-I, Submission Requirements--Human Gene Transfer Experiments, 
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. 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.

[[Page 59037]]

    ``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 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.''

[Previously numbered Section III-C, Experiments that Require 
Institutional Biosafety Committee Approval Before Initiation, will be 
renumbered to Section III-D. References in this section will be changed 
due to renumbering.]
[Previously numbered Section III-D, Experiments that Require 
Institutional Biosafety Committee Notice Simultaneous with Initiation, 
will be renumbered to Section III-E. References in this section will be 
changed due to renumbering.]
[Previously numbered Section III-E, Exempt Experiments, will be 
renumbered to Section III-F. References in this section will be changed 
due to renumbering.]

II-D. Amendments to Section IV, Roles and Responsibilities

    Section IV is 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 the 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 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 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 
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 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. Ensure that when the institution participates 
in or sponsors recombinant DNA research involving human subjects: (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 Subject (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 at which recombinant DNA material will be administered 
to human subjects (as opposed to each institution involved in the 
production of vectors for human application and each institution at 
which there is ex vivo transduction of recombinant DNA material into 
target cells for human application).
    ``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

[[Page 59038]]

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:

``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 and 
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 at which 
recombinant DNA material will be administered to human subjects (as 
opposed to each institution involved in the production of vectors for 
human application and each institution at which there is ex vivo 
transduction of recombinant DNA material into target cells from human 
application).

    ``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-D-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), plan expert (if 
applicable), animal expert (if applicable), human gene therapy 
expertise or ad hoc consultant (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

[[Page 59039]]

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-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 Eurkaryotic 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 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 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 a 
member of the Institutional Biosafety Committee).

``Section IV-B-6. Human Gene Therapy Expertise

    ``When the institution participates in or sponsors recombinant DNA 
research

[[Page 59040]]

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.

``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 ensure 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 and the Laboratory Safety Monograph for technical 
recommendations).

``Section IV-B-7-b. Submissions by the Principal Investigator to 
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), Institutional Biosafety Committee, NIH/ORDA, and other 
appropriate authorities (if applicable) (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-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 reporting requirements for 
human gene

[[Page 59041]]

transfer experiments conducted in compliance with the NIH Guidelines 
(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 RAC. ORDA's responsibilities under the 
NIH Guidelines are administrative. Advice from 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 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 L, Gene Therapy Policy 
Conferences.

``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 RAC and provide an opportunity for public and Federal agency 
comment. Specifically, the Notice of Meeting and Proposed Actions shall 
be published in the Federal Register at least 15 days before the RAC 
meeting. The NIH Director's decision/recommendation (at his/her 
discretion) may be published in the Federal Register for 15 days of 
comment before final action is taken. The NIH Director's final 
decision/recommendation, along with responses to public comments, shall 
be published in the Federal Register. The RAC and Institutional 
Biosafety Committee Chairs shall be notified of the following 
decisions:
    ``Section IV-C-1-b-(1)-(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 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)

    ``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. 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 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.

[[Page 59042]]

Nominations for RAC members 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 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.
    ``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 to the NIH Director specific 
comments/recommendations about: (i) A specific human gene transfer 
experiment, or (ii) a category of human gene transfer experiments;
    ``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;
    ``Section IV-C-2-e. Identifying broad scientific, safety, social, 
and ethical issues relevant to gene therapy research as potential Gene 
Therapy Policy Conference topics;
    ``Section IV-C-2-f. Identifying novel social and 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; and
    ``Section IV-C-2-g. 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.

``Section IV-C-3. Office of Recombinant DNA Activities (ORDA)

    ``ORDA shall serve as a focal point for information on recombinant 
DNA activities and provide advice to all within and outside NIH 
including institutions, Biological Safety Officers, Principal 
Investigators, Federal agencies, state and local governments, and 
institutions in the private sector. ORDA shall carry out such other 
functions as may be delegated to it by the NIH Director. ORDA's 
responsibilities include (but are not limited to) the following:
    ``Section IV-C-3-a. 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 DHHS 
components, as appropriate.
    ``Section IV-C-3-e. Collaborating with Principal Investigators, 
Institutional Biosafety Committees, Institutional Review Boards, and 
other DHHS components (including 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 (see Appendix L, Gene Therapy 
Policy Conference).
    ``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 
LD<INF>50</INF> of less than or equal to 100 nanagrams 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 
LD<INF>50</INF> of Less than 100 Nanograms Per Kilogram Body Weight, 
Appendix F, Containment Conditions for Cloning of Genes Coding for the 
Biosynthesis of Molecules Toxic for Verebrates);
    ``Section IV-C-3-h. Serving as the executive secretary of 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, and 
individual intending to carry out research involving recombinant DNA is 
encouraged to

[[Page 59043]]

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 Section IV-D-2 through IV-D-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-D-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-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 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 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 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, Sec. 5.65 (d) and (e).

``Section IV-D-5-b. Pre-submission Review

    ``Any institution not otherwise covered by the NIH Guidelines, 
which is considering submission of data or information voluntarily to 
NIH, may request pre-submission 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 pre-submission 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 CFR 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 of 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.''

II-E. Amendments to Appendix A, Exemptions Under Section III-E-5--Sub-
lists of Natural Exchanges

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

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

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

II-G. Amendments to Appendix I, Biological Containment

    After the first paragraph in Section I-II-A, Responsibility, the 
following Note is 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

[[Page 59044]]

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 as to the content of the notice (see Section 
IV-D-3, Certification of Host-Vector Systems-Voluntary 
Compliance).''

II-H. Addition of Appendix L, Gene Therapy Policy Conferences, to the 
NIH Guidelines

    Appendix L is to read:

``Appendix L. Gene Therapy Policy Conferences (GTPCs)

    ``In order to enhance the depth and value of public discussion 
relevant to scientific, safety, social, and ethical implications of 
gene therapy research, the NIH Director will convene GTPCs at regular 
intervals. As appropriate, the NIH Director may convene a GTPC in 
conjunction with a RAC meeting. GTPCs will be administered by 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 RAC will 
serve as Co-chair of each GTPC and report the findings of each GTPC to 
RAC 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. All RAC 
members will be invited to attend GTPCs. GTPCs will have representation 
from other Federal agencies, including FDA and OPRR. GTPCs will focus 
on broad overarching policy and scientific issues related to gene 
therapy research. Proposals for GTPC topics may be submitted by members 
of 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 human gene transfer. The RAC, with the 
Director's approval, will have the primary responsibility for planning 
GTPC agendas. GTPC findings 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.''

II-I. 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 amended to read:

``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)

    ``Appendix M applies to research conducted at or sponsored by an 
institution that receives any support for recombinant DNA research from 
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 that 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, RAC is prepared 
to consider proposals for somatic cell gene transfer.
    ``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.
    ``Research proposals involving the deliberate transfer of 
recombinant DNA, or DNA or RNA derived from recombinant DNA, into human 
subjects (human gene transfer) will be considered through a review 
process involving both NIH/ORDA and RAC. Investigators shall submit 
their relevant information on the proposed human gene transfer 
experiments to NIH/ORDA. Submission of human gene transfer protocols to 
NIH will be in the format described in Appendix M-I, Submission 
Requirements--Human Gene Transfer Experiments. Submission to NIH shall 
be for registration purposes and will ensure continue public access to 
relevant human gene transfer information conducted in compliance with 
the NIH Guidelines. Investigational New Drug (IND) applications should 
be submitted to FDA in the format described in 21 CFR, Chapter I, 
Subchapter D, Part 312, Subpart B, Section 23, IND Content and Format.
    ``Institutional Biosafety Committee approval must be obtained from 
each institution at which recombinant DNA material will be administered 
to human subjects (as opposed to each institution involved in the 
production of vectors for human application and each institution at 
which there is ex vivo transduction of recombinant DNA material into 
target cells for human application).
    ``Factors that may contribute to public discussion of a human gene 
transfer experiment by 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 discussions, 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

[[Page 59045]]

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 RAC), 
whether the preliminary in vitro and in vivo safety data were obtained 
in appropriate models and are sufficient, and whether questions related 
to relevant social and ethical issues 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 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). 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 shall 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) shall: (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, meaning and significance of the 
research, and significant safety, social, and ethical 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.
    In its evaluation of human gene transfer proposals, 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 RAC and NIH/ORDA 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).
    ``Appendix M will be considered for revisions as experience in 
evaluating proposals accumulates and as new scientific developments 
occur. This review will be carried out periodically as needed.

``Appendix M-I. Submission Requirements--Human Gene Transfer 
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 shall be submitted to NIH/ORDA 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 
(Institutional Biosafety Committee approval must be obtained from each 
institution at which recombinant DNA material will be administered to 
human subjects (as opposed to each institution involved in the 
production of vectors for human application and each institution at 
which there is ex vivo transduction of recombinant DNA material into 
target cells for human application)); (4) Responses to Appendix M-II 
through M-V, Description of the Proposal, Informed Consent, Privacy and 
Confidentiality, and Special Issues (the pertinent responses can be 
provided in the protocol or as an appendix to the protocol); (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); and (8) curricula vitae--2 pages for each key 
professional person in biographical sketch format. Investigational New 
Drug (IND) applications shall be submitted to FDA in the format 
described in 21 CFR, chapter I, subchapter D, part 312, subpart B, 
section 23, IND Content and Format. Submissions to FDA 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 RAC). 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

[[Page 59046]]

discussion, reviewers shall examine the scientific rationale, 
scientific context (relative to other proposals reviewed by RAC), 
whether the preliminary in vitro and in vitro safety data were obtained 
in appropriate models and are sufficient, and whether questions related 
to relevant social and ethical issues have been resolved. RAC 
recommendations on a specific human gene transfer experiment shall be 
forwarded to the NIH Director, the Principal Investigator, the 
sponsoring insititution, and other DHHS components, as appropriate.

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

``Appendix M-VII-A. Investigational New Drug Application Reporting

    ``Upon receipt of notification of permission to proceed with an 
Investigational New Drug application for a human gene transfer 
protocol, the Principal Investigator(s) shall submit a written report 
that includes the following information: (1) How the investigator(s) 
responded to RAC's recommendations on the protocol (if applicable), and 
(2) any modifications to the protocol as required by FDA.

``Appendix M-VII-B. Annual Data Reporting and Gene Therapy Database

    ``Investigators shall comply with 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 RAC 
and NIH/ORDA, and reviewed at a future RAC meeting. Information 
obtained through annual data reporting will be included in a human gene 
transfer database that will be administered by NIH/ORDA. The purpose of 
this human gene transfer database is to: (1) Maintain an institutional 
memory, (2) provide administrative details of protocol registration, 
(3) provide annual status reports of protocols, (4) facilitate risk 
assessment of individual applications of human gene transfer, and (5) 
enhance public awareness of relevant scientific, safety, social, and 
ethical issues.

``Appendix M-VII-C. Adverse Event Reporting

    ``Investigators who have received approval for FDA to initiate a 
human gene transfer protocol must report any serious adverse event 
immediately to the local Institutional Review Board, Institutional 
Boisafety 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 VIII. Footnotes of Appendix M

    ``Appendix VIII-A. Human studies in which induction or enhancement 
of an immune response to a vector-encoded microbialimmunogen 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-VII, Reporting Requirements--Human Gene Transfer 
Experiments.''
    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 virtually every NIH 
and Federal research program in which recombinant DNA molecule 
techniques could be used, it has been determined not to be cost 
effective or in the public interst 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.

    Effective Date: October 22, 1997.
Harold Varmus,
Director, National Institutes of Health.
[FR Doc. 97-28921 Filed 10-30-97; 8:45 am]
BILLING CODE 4140-01-M