[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
[[Page 59034]]
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 LD50 of Less Than 100 Nanograms per Kilogram Body
Weight
``Deliberate formation of recombinant DNA containing genes for the
biosynthesis of toxin molecules lethal for vertebrates at an
LD50 of less than 100 nanograms per kilogram body weight
(e.g., microbial toxins such as the botulinum toxins, tetanus toxin,
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
LD50 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
LD50 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
