[Federal Register Volume 62, Number 31 (Friday, February 14, 1997)]
[Notices]
[Pages 7108-7123]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-3735]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
Recombinant DNA Research: Proposed Actions Under the Guidelines
Agency: National Institutes of Health (NIH), PHS, DHHS.
Action: Notice of Proposed Actions Under the NIH Guidelines for
Research Involving Recombinant DNA Molecules.
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SUMMARY: This notice sets forth proposed actions to be taken under the
NIH Guidelines for Research Involving Recombinant DNA Molecules (59 FR
34496, amended 59 FR 40170, 60 FR 20726, 61 FR 1482, 61 FR 10004, 62 FR
4782). Interested parties are invited to submit comments concerning
these proposals. There proposals will be considered by the Recombinant
DNA Advisory Committee (RAC) at its meeting on March 6-7, 1997. After
consideration of these proposals and comments by the RAC, the NIH
Director will issue decisions in accordance with the NIH Guidelines.
Dates: Interested parties are invited to submit comments concerning
this proposal. Comments received by February 27, 1997, will be
reproduced and distributed to the RAC for consideration at its March 6-
7, 1997, meeting. After consideration of this proposal and comments by
the RAC, the NIH Director will issue decisions in accordance with the
NIH Guidelines.
Addresses: Written comments and recommendations should be submitted to
Debra Knorr, Office of Recombinant DNA Activities, National Institutes
of Health, MSC 7010, 6000 Executive Boulevard, Suite 302, Bethesda,
Maryland 20892-7010, or by FAX to 301-496-9839.
All comments received in response to this notice will be considered
and will be available for public inspection in the above office on
weekdays between the hours of 8:30 a.m. and 5 p.m.
For Further Information Contact: Background documentation and
additional information can be obtained from the Office of Recombinant
DNA Activities, National Institutes of Health, MSC 7010, 6000 Executive
Boulevard, Suite 302, Bethesda, Maryland 20892-7010, Phone 301-496-
9838, FAX 301-496-9839.
Supplementary Information: The NIH will consider the following actions
under the NIH Guidelines for Research Involving Recombinant DNA
Molecules:
I. Amendment to the Overall Procedures for Human Gene Transfer
Protocols
I-A. Notice of Intent
On July 8, 1996, the NIH Director published a Notice of Intent to
Propose Amendments to the NIH Guidelines for Research Involving
Recombinant DNA Molecules Regarding Enhanced Oversight of Recombinant
DNA Activities (61 FR 35774). This Notice of Intent proposed
modifications in NIH oversight of human gene transfer research.
Specifically, it was proposed that the RAC would be terminated and that
all approval responsibilities for recombinant DNA experiments involving
human gene transfer would be relinquished to the Food and Drug
Administration (FDA), which retains statutory authority for such
approval. Under this revised oversight structure, a newly created ORDA
Advisory Committee (OAC) would preserve continued public accountability
for recombinant DNA research. To ensure quality and efficiency of
public discussion of the scientific merit and the ethical issues
relevant to gene therapy clinical trials, it was proposed that the NIH
Director implement a regular series of Gene Therapy Policy Conferences
(GTPC). Finally, the proposal assured the continuation of the publicly
available comprehensive NIH database of clinical trials with human gene
transfer, including reporting of adverse events.
In response to the Notice of Intent, the NIH received 71 written
comments (90 signatures) reflecting a broad spectrum of public opinion
on the proposed changes. Comments were received from a variety of
stakeholders, including individuals representing academia,
[[Page 7109]]
industry, patient advocacy organizations, consumer advocacy
organizations, professional scientific societies, ethicists, other
Federal agencies, NIH-funded investigators, past and present RAC
members, and private citizens. Careful consideration was given to each
of the written comments that were submitted.
I-B. Proposed Actions--November 1996
On November 22, 1996, the NIH Director published Notice of Proposed
Actions Under the NIH Guidelines for Research Involving Recombinant DNA
Molecules (61 FR 59725). The Notice of Proposed Actions was in response
to public opinion and in keeping with the NIH Director's intent to
increase the usefulness and productivity of public discussion of gene
therapy.
In the Proposed Actions, the NIH Director proposed to: (1) Retain
the RAC, while modifying its roles and responsibilities relevant to
human gene therapy research, (2) continue RAC discussion of novel human
gene transfer experiments without RAC approval of individual human gene
transfer experiments; (3) reduce the membership of RAC from 25 members
to 15 members; (4) regularly convene GTPC; and (5) maintain public
access to human gene transfer clinical trial information. The following
summarizes the roles and responsibilities of the NIH Director, the RAC,
the ORDA, and the local institutions under the Notice of Proposed
Actions.
I-B-1. Proposed Roles and Responsibilities in Accordance with the NIH
Guidelines
I-B-1-a. The NIH Director
The roles and responsibilities of the NIH Director remain unchanged
except for relinquishing approval of human gene transfer experiments,
and establishing and convening Gene Therapy Policy Conferences. The NIH
Director is responsible for establishing the NIH Guidelines, overseeing
their implementation, and their final interpretation; promulgating
requirements as necessary to implement the NIH Guidelines; establishing
and maintaining the RAC; establishing and maintaining ORDA; conducting
and supporting training programs in laboratory safety for Institutional
Biosafety Committee members, Biological Safety Officers and other
institutional experts (if applicable), Principal Investigators, and
laboratory staff; and establishing and convening Gene Therapy Policy
Conferences.
I-B-1-b. The Recombinant DNA Advisory Committee
The RAC will remain a chartered public advisory committee to the
NIH Director regarding recombinant DNA research conducted in compliance
with the NIH Guidelines. The RAC will conduct quarterly meetings. RAC
members will continue to be appointed by the DHHS Secretary or his/her
designee for 4-year terms. RAC membership will be reduced from 25 to 15
members. At least eight of these members shall be knowledgeable in the
fields of molecular genetics, molecular biology, recombinant DNA
research, or other related fields and at least four of these members
shall be persons knowledgeable in applicable law, standards of
professional conduct and practice, public attitudes, the environment,
public health, occupational health, or related fields. Representatives
of Federal agencies shall continue to serve as non-voting members.
The RAC will be responsible for: (1) Identifying novel human gene
transfer experiments deserving of public discussion by the full RAC and
transmitting comments/recommendations about specific human gene
transfer experiments or categories of human gene transfer experiments
to the NIH Director. (2) Identifying novel ethical issues relevant to
specific human applications of gene transfer and recommending
appropriate modifications to the Points to Consider that will provide
guidance in the preparation of relevant Informed Consent documents. (3)
Identifying novel scientific and safety issues relevant to specific
human applications of gene transfer and recommending appropriate
modifications to the Points to Consider that will provide guidance in
the design and submission of human gene transfer clinical trials. (4)
Publicly reviewing human gene transfer clinical trial data captured by
NIH/ORDA in accordance with the annual data reporting requirements. (5)
Identifying broad scientific and ethical/social issues relevant to gene
therapy research as potential Gene Therapy Policy Conference topics.
The RAC will advise the NIH Director on the following actions: (1)
Adopting changes in the NIH Guidelines. (2) Assigning containment
levels, changing containment levels, and approving experiments
considered as Major Actions under the NIH Guidelines, i.e., the
deliberate transfer of a drug resistance trait to microorganisms that
are not known to acquire the trait naturally, if such acquisition could
compromise the use of the drug to control disease agents in humans,
veterinary medicine, or agriculture. (3) Promulgating and amending
lists of classes of recombinant DNA molecules to be exempt from the NIH
Guidelines because they consist entirely of DNA segments from species
that exchange DNA by known physiological processes or otherwise do not
present a significant risk to health or the environment. (4) Certifying
new host-vector systems.
I-B-1-c. Gene Therapy Policy Conferences (GTPCs)
In order to enhance the depth and value of public discussion
relevant to scientific, safety, and ethical/societal implications of
gene therapy research, the NIH Director will convene GTPC at regular
intervals. As appropriate, the NIH Director may convene GTPC
immediately following scheduled RAC meetings. GTPC will be administered
by the NIH/ORDA. Conference participation will not involve a standing
committee membership but rather will offer the unique advantage of
assembling numerous participants who possess significant scientific,
ethical, and legal expertise and/or interest that is directly
applicable to a specific gene therapy research issue. At least one
member of the RAC will serve as Co-chair of each GTPC and report the
findings of the GTPC to the full committee at its next scheduled
meeting. The RAC representative for each GTPC will be chosen based on
the participant's area of expertise relative to the specific gene
therapy research issue to be discussed. GTPC will have representation
from other Federal agencies, including the FDA. GTPCs will focus on
broad over-arching policy and scientific issues related to gene therapy
research. Proposals for GTPC topics may be submitted by members of the
RAC, representatives of academia, industry, patient and consumer
advocacy organizations, other Federal agencies, professional scientific
societies, and the general public. GTPC topics will not be limited to
discussion of human applications of gene therapy research, i.e., they
may include basic research on the use of novel gene delivery vehicles,
or novel applications of gene transfer. The findings of the GTPC will
be transmitted to the NIH Director and will be made publicly available.
The NIH Director anticipates that this public policy forum will serve
as a model for interagency communication and collaboration,
concentrated expert discussion of novel scientific issues and their
potential societal implications, and enhanced opportunity for public
discussion of the
[[Page 7110]]
potential impact of such applications on human health and the
environment.
I-B-1-d. The Office of Recombinant DNA Activities (ORDA)
ORDA is an organizational unit of the NIH Office of Science Policy
within the Office of the Director. ORDA shall serve as a focal point
for information on recombinant DNA activities and provide advice to all
within and outside NIH including institutions, Biological Safety
Officers, Principal Investigators, Federal agencies, state and local
governments, and institutions in the private sector. ORDA's
responsibilities include (but are not limited to) the following: (1)
Serving as the focal point for public access to summary information
pertaining to human gene transfer experiments. (2) Serving as the focal
point for data management of human gene transfer experiments. (3)
Administering the annual data reporting requirements (and subsequent
review) for human gene transfer experiments. (4) Transmitting comments/
recommendations arising from public RAC discussion of a novel human
gene transfer experiment to the NIH Director. RAC recommendations shall
be forwarded to the Principal Investigator, sponsoring institution, and
other Department of Health and Human Services (DHHS) components, as
appropriate. (5) Collaborating with Principal Investigators,
Institutional Biosafety Committees, Institutional Review Boards, and
other DHHS components, to ensure human gene transfer experiment
registration compliance. (6) Administering Gene Therapy Policy
Conferences as deemed appropriate by the NIH Director. (7) Reviewing
and approving experiments in conjunction with ad hoc experts involving
the cloning of genes encoding for toxin molecules that are lethal for
vertebrates at an LD50 of less than or equal to 100 nanograms per
kilogram body weight in organisms other than Escherichia coli K-12. (8)
Serving as the executive secretary of the RAC. (9) Publishing in the
Federal Register the announcements of RAC meetings and tentative
agendas at least 15 days in advance, announcements of Gene Therapy
Policy Conferences and tentative agendas at least 15 days in advance,
proposed Major Actions at least 15 days prior to the RAC meeting; and
(10) Reviewing and approving the membership of an institution's
Institutional Biosafety Committee.
I-B-1-e. Local Institutions
The Notice of Proposed Actions would change the roles and
responsibilities of local institutions, Institutional Biosafety
Committees, Biosafety Officers, Principal Investigators, Animal
Facility Directors, Greenhouse Supervisors, and Human Gene Therapy
experts relevant to recombinant DNA research conducted in compliance
with the NIH Guidelines. These changes now include the following
requirements: (1) When the institution conducts recombinant DNA
research that requires Institutional Biosafety Committee approval, the
institution shall appoint at least one individual with expertise in
plant, plant pathogen, or plant pest containment principles (who is
also a member of the Institutional Biosafety Committee); (2) when the
institution conducts recombinant DNA research that requires
Institutional Biosafety Committee approval, the institution shall
appoint at least one individual with expertise in animal containment
principles (who is also a member of the Institutional Biosafety
Committee); and (3) when the institution participates in or sponsors
recombinant DNA research involving human subjects, the institution must
ensure that: (a) The Institutional Biosafety Committee has adequate
expertise and training (using ad hoc consultants as deemed necessary)
and (b) all aspects of Appendix M, Points to Consider in the Design and
Submission of Protocols for the Transfer of Recombinant DNA Molecules
into One or More Human Subjects (Points to Consider), have been
appropriately addressed by the Principal Investigator prior to
submission to NIH/ORDA.
I-C. Recombinant DNA Advisory Committee Meeting--December 1996
During the December 9, 1996, Recombinant DNA Advisory Committee
meeting, the following motions were made:
I-C-1. Future RAC Membership--Committee Motion 1
A motion was made to invite former RAC members back to serve as ad
hoc consultants in order to ensure institutional continuity of the RAC.
The motion passed by a vote of 15 in favor, 0 opposed, and no
abstentions.
I-C-2. Triggering Mechanism for RAC Discussion--Committee Motion 2
A motion was made that: (1) The capacity for principal
investigators and institutional representatives to request public RAC
discussion of an individual gene transfer protocol should be deleted.
(2) A decision by the RAC to require full review of an individual
protocol should not have to be approved by the NIH Director. (3) The
NIH Director or an appropriate FDA representative may also request RAC
review of an individual protocol. (4) Rather than a majority vote, RAC
recommendations for full review of an individual protocol should be
changed to a minimum of three members. (5) The decision regarding
necessity for RAC discussion should be made within 15 working days. The
motion passed by a vote of 16 in favor, 0 opposed, and no abstentions.
I-C-3. Feedback Mechanism--Committee Motion 3
A motion was made to request FDA to report back to the RAC how the
RAC recommendations on an individual protocol were implemented. The RAC
should require investigators to provide additional information if the
FDA information is not adequate. The motion failed by a vote of 3 in
favor, 7 opposed, and 4 abstentions.
I-C-4. Feedback Mechanism--Committee Motion 4
A motion was made to require investigators to report back to the
RAC in writing in a timely fashion. The report should include a
statement of how the investigators have responded to RAC's
recommendations and any modifications to the protocol following FDA
review. The motion passed by a vote of 12 in favor, 1 opposed, and 1
abstention.
I-C-5. Relationship of the RAC and GTPC--Committee Motion 5
A motion was made that the RAC, with the NIH Director's approval,
should have the primary responsibility for: (1) Planning the GTPC
agendas, and (2) summarizing GTPC recommendations in the form of a
report back to the NIH Director. The close GTPC/RAC relationship should
not preclude other parties from suggesting GTPC topics and GTPC should
be convened in consultation with FDA. The motion passed by a vote of 13
in favor, 0 opposed, and 2 abstentions.
I-C-6. Proposed Actions Concepts--Committee Motion 6
A motion was made to accept the overall concepts put forward in the
Proposed Actions as published in the November 22, 1996, Federal
Register (61 FR 59725). Specifically: (1) Retain the RAC, while
modifying its roles and responsibilities relevant to human gene therapy
research, (2) continue RAC discussion of novel human gene transfer
experiments without RAC approval of individual human gene transfer
experiments; (3) reduce the membership of RAC from 25 members to 15
members; (4) regularly convene GTPC; and (5) maintain public access to
human
[[Page 7111]]
gene transfer clinical trial information. The members of the RAC noted
that several minor modifications still remained unresolved,
particularly with regard to the future discussion of gene therapy
protocols and defining the role of the RAC relative to the GTPCs. The
RAC recommended that final action on the Proposed Actions should be
postponed to the March 6-7, 1997, RAC meeting, in order to more fully
address these unresolved issues. The motion passed by a vote of 12 in
favor, 0 opposed, and 2 abstentions.
II. Meetings Between the NIH and FDA Regarding Simultaneous Submission
to Human Gene Transfer Protocols to the NIH and the FDA
In a letter dated November 20, 1996, Dr. Andra Miller, Cytokine and
Gene Therapy Branch, Center of Biologics Evaluation and Research, FDA,
requested that the NIH Guidelines should be amended regarding
procedures for simultaneous submission of Appendix M material to the
RAC and FDA. In her November 20, 1996, letter, Dr. Miller states:
`` * * * (1) Remove the requirement for submission of Appendix M to
the FDA. The FDA does not accept Appendix M in place of an IND
submission. The FDA is not proposed to be and need not be included in
the decision making process to identify protocols to undergo full RAC
review. Therefore, there is no reason for sponsors to submit Appendix M
materials to the FDA.
``(2) Explore the feasibility of a unified format for submission of
protocols to the RAC and FDA. This would relieve the sponsor of the
burden of preparing duplicative submission to satisfy each agency.
``(3) Establish a mechanism for FDA staff to bring general issues
of novelty and concern to the RAC for discussion. This will provide a
mechanism for public input toward the resolution of issues we all must
consider and provide direction for policy development and growth in the
field of gene therapy.''
On January 27, 1997, NIH and FDA staff met to consider amendments
to the NIH Guidelines that incorporate the recommendations of both the
NIH and the FDA with regard to simultaneous submission of human gene
transfer protocols. The recommendations of NIH and FDA staff are
incorporated below in the Proposed Actions Regarding the Overall
Procedures for Human Gene Transfer Protocol.
III. Proposed Actions Regarding the Overall Procedures for Human Gene
Transfer Protocols
The NIH will consider the following proposed actions under the NIH
Guidelines for Research Involving Recombinant DNA Molecules:
[Note: Editorial changes and updating of references have been
incorporated to clarify the document.]
III-A. Proposed Amendments to Section I, Scope of the NIH Guidelines
Section I is proposed to be amended to read:
Section I. Scope of the NIH Guidelines
Section I-A. Purpose
[This section remains unchanged.]
Section I-A-1. Any recombinant DNA experiment, which according to
the NIH Guidelines requires approval by the NIH, must be submitted to
the NIH or to another Federal agency that has jurisdiction for review
and approval. Once approvals, or other applicable clearances, have been
obtained from a Federal agency other than the NIH (whether the
experiment is referred to that agency by the NIH or sent directly there
by the submitter), the experiment may proceed without the necessity for
NIH review or approval. (See exception in Section I-A-1-a regarding
requirement for human gene transfer protocol registration.)
Section I-A-1-a. Experiments involving the deliberate transfer of
recombinant DNA or DNA or RNA derived from recombinant DNA into human
subjects (human gene transfer) cannot be initiated without simultaneous
submission to both NIH/ORDA and the FDA of such information on the
proposed experiment as is prescribed by those agencies. Submission of
human gene transfer protocols to the NIH will be in the format
described in Appendix M-I, Submission Requirements--Human Gene Transfer
Experiments, of the NIH Guidelines. Submission to NIH shall be for
registration purposes and will ensure continued public access to
relevant human gene transfer information conducted in compliance with
the NIH Guidelines. Submission of human gene transfer protocols to the
FDA will be in the format described in 21 CFR, Chapter I, Subchapter D,
Part 312, Subpart B, Section 23, IND Content and Format.
If a determination is made that an experiment will undergo full RAC
discussion, NIH/ORDA will immediately notify the Principal
Investigator. RAC members may forward requests for additional
information relevant to a specific protocol through NIH/ORDA to the
Principal Investigator. In making a determination whether an experiment
is novel, and thus deserving of full RAC discussion, reviewers will
examine the scientific rational, scientific content (relative to other
proposals reviewed by the RAC), whether the preliminary in vitro and in
vivo data were obtained in appropriate models and are sufficient, and
whether questions related to safety, efficacy, and social/ethical
contest have been resolved. RAC's recommendation(s) on a specific human
gene transfer experiment will be forwarded to the NIH Director, the
Principal Investigator, the sponsoring institution, and to other
Department of Health and Human Services (DHHS) components, as
appropriate.
Section I-B. Definition of Recombinant DNA Molecules
[This section remains unchanged.]
Section I-C. General Applicability
Section I-C-1. The NIH Guidelines are applicable to:
Section I-C-1-a. All recombinant DNA research within the United
States (U.S.) or its territories that is within the category of
research described in either Section I-C-1-a-(1) or Section I-C-1-a-
(2).
Section I-C-1-a-(1). Research that is conducted at or sponsored by
an institution that receives any support for recombinant DNA research
from the NIH, including research performed directly by the NIH. An
individual who receives support for research involving recombinant DNA
must be associated with or sponsored by an institution that assumes the
responsibilities assigned in the NIH Guidelines.
Section I-C-1-a-(2). Research that involves testing in humans of
materials containing recombinant DNA developed with NIH funds, if the
institution that developed those materials sponsors or participates in
those projects. Participation includes research collaboration or
contractual agreements, not mere provision of research materials.
Section I-C-1-b. All recombinant DNA research performed abroad that
is within the category of research described in either Section I-C-1-b-
(1) or Section I-C-1-b-(2).
Section I-C-1-b-(1). Research supported by NIH funds.
Section I-C-1-b-(2). Research that involves testing in humans of
materials containing recombinant DNA developed with NIH funds, if the
institution that developed those materials sponsors or participates in
those projects. Participation includes research
[[Page 7112]]
collaboration or contractual agreements, not mere provision of research
materials.
Section I-C-1-b-(3). If the host country has established rules for
the conduct of recombinant DNA research, then the research must be in
compliance with those rules. If the host country does not have such
rules, the proposed research must be reviewed and approved by an NIH-
approved Institutional Biosafety Committee or equivalent review body
and accepted in writing by an appropriate national governmental
authority of the host country. The safety practices that are employed
abroad must be reasonably consistent with the NIH Guidelines.
Section I-D. Compliance With the NIH Guidelines
As a condition for NIH funding of recombinant DNA research,
institutions shall ensure that such research conducted at or sponsored
by the institution, irrespective of the source of funding, shall comply
with the NIH Guidelines.
Information concerning noncompliance with the NIH Guidelines may be
brought forward by any person. It should be delivered to both NIH/ORDA
and the relevant institution. The institution, generally through the
Institutional Biosafety Committee, shall take appropriate action. The
institution shall forward a complete report of the incident
recommending any further action to the Office of Recombinant DNA
Activities, National Institutes of Health/MSC 7010, 6000 Executive
Boulevard, Suite 302, Bethesda, Maryland 20892-7010, (301) 496-9838.
In cases where NIH proposes to suspend, limit, or terminate
financial assistance because of noncompliance with the NIH Guidelines,
applicable DHHS and Public Health Service procedures shall govern.
The policies on compliance are as follows:
Section I-D-1. All NIH-funded projects involving recombinant DNA
techniques must comply with the NIH Guidelines. Non-compliance may
result in: (i) Suspension, limitation, or termination of financial
assistance for the noncompliant NIH-funded research project and of NIH
funds for other recombinant DNA research at the institution, or (ii) a
requirement for prior NIH approval of any or all recombinant DNA
projects at the institution.
Section I-D-2. All non-NIH funded projects involving recombinant
DNA techniques conducted at or sponsored by an institution that
receives NIH funds for projects involving such techniques must comply
with the NIH Guidelines. Noncompliance may result in: (i) Suspension,
limitation, or termination of NIH funds for recombinant DNA research at
the institution, or (ii) a requirement for prior NIH approval of any or
all recombinant DNA projects at the institution.
[The remainder of Section I is proposed to be renumbered to reflect
above changes.]
III-B. Proposed Amendments to Section II, Safety Considerations
The second paragraph of Section II-A-3 is proposed to be amended to
read:
Section II-A-3. Comprehensive Risk Assessment
* * * A final assessment of risk based on these considerations is
then used to set the appropriate containment conditions for the
experiment (see Section II-B, Containment). The containment level
required may be equivalent to the Risk Group classification of the
agent or it may be raised or lowered as a result of the above
considerations. The Institutional Biosafety Committee must approve the
risk assessment and the biosafety containment level for recombinant DNA
experiments described in Sections III-A, Experiments that Require
Institutional Biosafety Committee Approval, RAC Review, and NIH
Director Approval Before Initiation, III-B, Experiments that Require
NIH/ORDA and Institutional Biosafety Committee Approval Before
Initiation, III-C, Experiments that Require Institutional Biosafety
Committee and Institutional Review Board Approvals and NIH/ORDA
Registration Before Initiation, and III-D, Experiments that Require
Institutional Biosafety Committee Approval Before Initiation * * *
III-C. Proposed Amendments to Section III, Experiments Covered by the
NIH Guidelines
Section III is proposed to be amended to read:
Section III. Experiments Covered by the NIH Guidelines
This section describes six categories of experiments involving
recombinant DNA: (i) Those that require Institutional Biosafety
Committee (IBC) approval, RAC review, and NIH Director approval before
initiation (see Section III-A), (ii) those that require NIH/ORDA and
Institutional Biosafety Committee approval before initiation (see
Section III-B), (iii) those that require Institutional Biosafety
Committee and Institutional Review Board approvals and NIH/ORDA
registration before initiation (see Section III-C), (iv) those that
require Institutional Biosafety Committee approval before initiation
(see Section III-D), (v) those that require Institutional Biosafety
Committee notification simultaneous with initiation (see Section III-
E), and (vi) those that are exempt from the NIH Guidelines (see Section
III-F).
Note: If an experiment falls into Sections III-A, III-B, or III-
C and one of the other sections, the rules pertaining to Sections
III-A, III-B, or III-C shall be followed. If an experiment falls
into Section III-F and into either Sections III-D or III-E as well,
the experiment is considered exempt from the NIH Guidelines.
Any change in containment level, which is different from those
specified in the NIH Guidelines, may not be initiated without the
express approval of NIH/ORDA (see Section IV-C-1-b-(2) and its
subsections, Minor Actions).
Section III-A. Experiments That Require Institutional Biosafety
Committee Approval, RAC Review, and NIH Director Approval Before
Initiation
(See Section IV-C-1-b-(1), Major Actions)
Section III-A-1. Major Actions Under the NIH Guidelines
Experiments considered as Major Actions under the NIH Guidelines
cannot be initiated without submission of relevant information on the
proposed experiment to the Office of Recombinant DNA Activities,
National Institutes of Health/MSC 7010, 6000 Executive Boulevard, Suite
302, Bethesda, Maryland 20892-7010, (301) 496-9838, the publication of
the proposal in the Federal Register for 15 days of comment, review by
the RAC, and specific approval by the NIH. The containment conditions
or stipulation requirements for such experiments will be recommended by
the RAC and set by the NIH at the time of approval. Such experiments
require Institutional Biosafety Committee approval before initiation.
Specific experiments already approved are included in Appendix D, Major
Actions Taken under the NIH Guidelines, which may be obtained from the
Office of Recombinant DNA Activities, National Institutes of Health/MSC
7010, 6000 Executive Boulevard, Suite 302, Bethesda, Maryland 20892-
7010, (301) 496-9838.
Section III-A-1-a. The deliberate transfer of a drug resistance
trait to microorganisms that are not known to acquire the trait
naturally (see Section V-B, Footnotes and References of Sections I-IV),
if such acquisition could compromise the use of the drug to
[[Page 7113]]
control disease agents in humans, veterinary medicine, or agriculture,
will be reviewed by the RAC.
Section III-B. Experiments That Require NIH/ORDA and Institutional
Biosafety Committee Approval Before Initiation
Experiments in this category cannot be initiated without submission
of relevant information on the proposed experiment to NIH/ORDA. The
containment conditions for such experiments will be determined by NIH/
ORDA in consultation with ad hoc experts. Such experiments require
Institutional Biosafety Committee approval before initiation (see
Section IV-B-2-b-(1), Institutional Biosafety Committee).
Section III-B-1. Experiments Involving the Cloning of Toxin Molecules
With LD50 of Less Than 100 Nanograms per Kilogram Body Weight
Deliberate formation of recombinant DNA containing genes for the
biosynthesis of toxin molecules lethal for vertebrates at an LD50
of less than 100 nanograms per kilogram body weight (e.g., microbial
toxins such as the botulinum toxins, tetanus toxin, diphtheria toxin,
and Shigella dysenteriae neurotoxin). Specific approval has been given
for the cloning in Escherichia coli K-12 of DNA containing genes coding
for the biosynthesis of toxic molecules which are lethal to vertebrates
at 100 nanograms to 100 micrograms per kilogram body weight. Specific
experiments already approved under this section may be obtained from
the Office of Recombinant DNA Activities, National Institutes of
Health/MSC 7010, 6000 Executive Boulevard, Suite 302, Bethesda,
Maryland 20892-7010, (301) 496-9838.
Section III-C. Experiments That Require Institutional Biosafety
Committee and Institutional Review Board Approvals and NIH/ORDA
Registration Before Initiation
Section III-C-1. Experiments Involving the Deliberate Transfer of
Recombinant DNA or DNA or RNA Derived From Recombinant DNA Into Human
Subjects
Experiments involving the deliberate transfer of recombinant DNA or
DNA or RNA derived from recombinant DNA into human subjects (human gene
transfer) cannot be initiated without simultaneous submission of
relevant information on the proposed experiment to both NIH/ORDA and
the FDA. Submission to NIH/ORDA shall be for registration purposes and
will ensure continued public access to relevant human gene transfer
information conducted in compliance with the NIH Guidelines. Submission
of human gene transfer protocols to the NIH will be in the format
described in Appendix M-I, Submission Requirements--Human Gene Transfer
Experiments, of the NIH Guidelines. Submission of human gene transfer
protocols to the FDA will be in the format described in 21 CFR, Chapter
I, Subchapter D, Part 312, Subpart B, Section 23, IND Content and
Format. Prior to submission of a human gene transfer experiment to NIH/
ORDA, the Principal Investigator must obtain Institutional Biosafety
Committee (IBC) approval from each institution that will handle
recombinant DNA material that is to be administered to human subjects
and Institutional Review Board approval from each institution in which
human subjects will undergo gene transfer. Specifically: (1) Any
institution involved in the production of the vectors for human
application, (2) any institution at which there is ex vivo transduction
of the recombinant DNA material into target cells for human
application, and (3) any institution at which the recombinant DNA
material will be directly administered to human subjects. These local
committee approvals and relevant protocol documentation shall be
submitted to NIH/ORDA for registration purposes and determination
regarding the necessity of full RAC review and approval/disapproval.
The RAC prefers that submission to NIH/ORDA in accordance with
Appendix M-I, Submission Requirements--Human Gene Transfer Experiments,
of the NIH Guidelines, contain no proprietary data or trade secrets,
enabling all aspects of the review to be open to the public. Following
receipt by NIH/ORDA, relevant information shall be entered into the NIH
human gene transfer database for registration purposes. Summary
information pertaining to the human gene transfer protocol will be
forwarded to RAC members. The NIH/ORDA summary information shall
include comparisons to previously registered protocols. Specific items
of similarity to previous experiments include (but are not limited to):
(i) Gene delivery vehicle, (ii) functional gene, (iii) marker gene,
(iv) packaging cell (if applicable), (v) disease application, (vi)
route of administration, and (vii) patient selection criteria.
RAC members shall notify NIH/ORDA within 15 working days if the
protocol has been determined to represent novel characteristics
requiring further public discussion.
Full RAC review of an individual human gene transfer experiment can
be initiated by the NIH Director or recommended to the NIH Director by:
(i) Three or more RAC members, or (ii) other Federal agencies. An
individual human gene transfer experiment that is recommended for full
RAC review should represent novel characteristics deserving of public
discussion. RAC recommendations on a specific human gene transfer
experiment shall be forwarded to the NIH Director, the Principal
Investigator, the sponsoring institution, and other Department of
Health and Human Services (DHHS) components, as appropriate.
Note: For specific directives concerning the use of retroviral
vectors for gene delivery, consult Appendix B-V-1, Murine Retroviral
Vectors.
Section III-D. Experiments That Require Institutional Biosafety
Committee Approval Before Initiation
[This section remains unchanged except for renumbering and reference
changes due to renumbering.]
Section III-E. Experiments That Require Institutional Biosafety
Committee Notice Simultaneous With Initiation
[This section remains unchanged except for renumbering and reference
changes due to renumbering.]
Section III-F. Exempt Experiments
[This section remains unchanged except for renumbering and reference
changes due to renumbering.]
III-D. Proposed Amendments to Section IV, Roles and Responsibilities
Section IV is proposed to be amended to read:
SECTION IV. ROLES AND RESPONSIBILITIES
Section IV-A. Policy
The safe conduct of experiments involving recombinant DNA depends
on the individual conducting such activities. The NIH Guidelines cannot
anticipate every possible situation. Motivation and good judgment are
the key essentials to protection of health and the environment. The NIH
Guidelines are intended to assist the institution, Institutional
Biosafety Committee, Biological Safety Officer, and Principal
Investigator in determining safeguards that should be implemented. The
NIH Guidelines will never be complete or final since all conceivable
experiments involving recombinant DNA cannot be foreseen. Therefore, it
is the responsibility of the institution and those associated with it
to adhere to the intent of the NIH Guidelines as well as to their
specifics. Each institution (and the Institutional
[[Page 7114]]
Biosafety Committee acting on its behalf) is responsible for ensuring
that all recombinant DNA research conducted at or sponsored by that
institution is conducted in compliance with the NIH Guidelines. General
recognition of institutional authority and responsibility properly
establishes accountability for safe conduct of the research at the
local level. The following roles and responsibilities constitute an
administrative framework in which safety is an essential and integral
part of research involving recombinant DNA molecules. Further
clarifications and interpretations of roles and responsibilities will
be issued by the NIH as necessary.
Section IV-B. Responsibilities of the Institution
Section IV-B-1. General Information
Each institution conducting or sponsoring recombinant DNA research
which is covered by the NIH Guidelines is responsible for ensuring that
the research is conducted in full conformity with the provisions of the
NIH Guidelines. In order to fulfill this responsibility, the
institution shall:
Section IV-B-1-a. Establish and implement policies that provide for
the safe conduct of recombinant DNA research and that ensure compliance
with the NIH Guidelines. As part of its general responsibilities for
implementing the NIH Guidelines, the institution may establish
additional procedures, as deemed necessary, to govern the institution
and its components in the discharge of its responsibilities under the
NIH Guidelines. Such procedures may include: (i) statements formulated
by the institution for the general implementation of the NIH
Guidelines, and (ii) any additional precautionary steps the institution
deems appropriate.
Section IV-B-1-b. Establish an Institutional Biosafety Committee
that meets the requirements set forth in Section IV-B-2-a and carries
out the functions detailed in Section IV-B-2-b.
Section IV-B-1-c. Appoint a Biological Safety Officer (who is also
a member of the Institutional Biosafety Committee) if the institution:
(i) Conducts recombinant DNA research at Biosafety Level (BL) 3 or BL4,
or (ii) engages in large scale (greater than 10 liters) research. The
Biological Safety Officer carries out the duties specified in Section
IV-B-3.
Section IV-B-1-d. Appoint at least one individual with expertise in
plant, plant pathogen, or plant pest containment principles (who is
also a member of the Institutional Biosafety Committee) if the
institution conducts recombinant DNA research that requires
Institutional Biosafety Committee approval in accordance with Appendix
P, Physical and Biological Containment for Recombinant DNA Research
Involving Plants.
Section IV-B-1-e. Appoint at least one individual with expertise in
animal containment principles (who is also a member of the
Institutional Biosafety Committee) if the institution conducts
recombinant DNA research that requires Institutional Biosafety
Committee approval in accordance with Appendix Q, Physical and
Biological Containment for Recombinant DNA Research Involving Animals.
Section IV-B-1-f. When the institution participates in or sponsors
recombinant DNA research involving human subjects, the institution must
ensure that: (i) The Institutional Biosafety Committee has adequate
expertise and training (using ad hoc consultants as deemed necessary)
and (ii) all aspects of Appendix M, Points to Consider in the Design
and Submission of Protocols for the Transfer of Recombinant DNA
Molecules into One or More Human Subjects (Points to Consider), have
been appropriately addressed by the Principal Investigator prior to
submission to NIH/ORDA. Institutional Biosafety Committee approval must
be obtained from each institution that will handle recombinant DNA
material that is to be administered to human subjects.
Section IV-B-1-g. Assist and ensure compliance with the NIH
Guidelines by Principal Investigators conducting research at the
institution as specified in Section IV-B-4.
Section IV-B-1-h. Ensure appropriate training for the Institutional
Biosafety Committee Chair and members, Biological Safety Officer and
other containment experts (when applicable), Principal Investigators,
and laboratory staff regarding laboratory safety and implementation of
the NIH Guidelines. The Institutional Biosafety Committee Chair is
responsible for ensuring that Institutional Biosafety Committee members
are appropriately trained. The Principal Investigator is responsible
for ensuring that laboratory staff are appropriately trained. The
institution is responsible for ensuring that the Principal Investigator
has sufficient training; however, this responsibility may be delegated
to the Institutional Biosafety Committee.
Section IV-B-1-i. Determine the necessity for health surveillance
of personnel involved in connection with individual recombinant DNA
projects; and if appropriate, conduct a health surveillance program for
such projects. The institution shall establish and maintain a health
surveillance program for personnel engaged in large scale research or
production activities involving viable organisms containing recombinant
DNA molecules which require BL3 containment at the laboratory scale.
The institution shall establish and maintain a health surveillance
program for personnel engaged in animal research involving viable
recombinant DNA-containing microorganisms that require BL3 or greater
containment in the laboratory. The Laboratory Safety Monograph
discusses various components of such a program (e.g., records of agents
handled, active investigation of relevant illnesses, and the
maintenance of serial serum samples for monitoring serologic changes
that may result from the employees' work experience). Certain medical
conditions may place a laboratory worker at increased risk in any
endeavor where infectious agents are handled. Examples cited in the
Laboratory Safety Monograph include gastrointestinal disorders and
treatment with steroids, immunosuppressive drugs, or antibiotics.
Workers with such disorders or treatment should be evaluated to
determine whether they should be engaged in research with potentially
hazardous organisms during their treatment or illness. Copies of the
Laboratory Safety Monograph are available from the Office of
Recombinant DNA Activities, National Institutes of Health/MSC 7010,
6000 Executive Boulevard, Suite 302, Bethesda, Maryland 20892-7010,
(301) 496-9838.
Section IV-B-1-j. Report any significant problems, violations of
the NIH Guidelines, or any significant research-related accidents and
illnesses to NIH/ORDA within thirty days, unless the institution
determines that a report has already been filed by the Principal
Investigator or Institutional Biosafety Committee. Reports shall be
sent to the Office of Recombinant DNA Activities, National Institutes
of Health/MSC 7010, 6000 Executive Boulevard, Suite 302, Bethesda,
Maryland 20892-7010, (301) 496-9838.
Section IV-B-2. Institutional Biosafety Committee (IBC)
The institution shall establish an Institutional Biosafety
Committee whose responsibilities need not be restricted to recombinant
DNA. The Institutional Biosafety Committee shall meet the following
requirements:
[[Page 7115]]
Section IV-B-2-a. Membership and Procedures
Section IV-B-2-a-(1). The Institutional Biosafety Committee must be
comprised of no fewer than five members so selected that they
collectively have experience and expertise in recombinant DNA
technology and the capability to assess the safety of recombinant DNA
research and to identify any potential risk to public health or the
environment. At least two members shall not be affiliated with the
institution (apart from their membership on the Institutional Biosafety
Committee) and who represent the interest of the surrounding community
with respect to health and protection of the environment (e.g.,
officials of state or local public health or environmental protection
agencies, members of other local governmental bodies, or persons active
in medical, occupational health, or environmental concerns in the
community). The Institutional Biosafety Committee shall include at
least one individual with expertise in plant, plant pathogen, or plant
pest containment principles when experiments utilizing Appendix P,
Physical and Biological Containment for Recombinant DNA Research
Involving Plants, require prior approval by the Institutional Biosafety
Committee. The Institutional Biosafety Committee shall include at least
one scientist with expertise in animal containment principles when
experiments utilizing Appendix Q, Physical and Biological Containment
for Recombinant DNA Research Involving Animals, require Institutional
Biosafety Committee prior approval. When the institution conducts
recombinant DNA research at BL3, BL4, or Large Scale (greater than 10
liters), a Biological Safety Officer is mandatory and shall be a member
of the Institutional Biosafety Committee (see Section IV-B-3,
Biological Safety Officer). When the institution participates in or
sponsors recombinant DNA research involving human subjects, the
institution must ensure that: (i) The Institutional Biosafety Committee
has adequate expertise and training (using ad hoc consultants as deemed
necessary) and (ii) all aspects of Appendix M, Points to Consider in
the Design and Submission of Protocols for the Transfer of Recombinant
DNA Molecules into One or More Human Subjects (Points to Consider),
have been appropriately addressed by the Principal Investigator prior
to submission to NIH/ORDA. Institutional Biosafety Committee approval
must be obtained from each institution that will handle recombinant DNA
material that is to be administered to human subjects.
Note: Individuals, corporations, and institutions not otherwise
covered by the NIH Guidelines, are encouraged to adhere to the
standards and procedures set forth in Sections I through IV (see
Section IV-E, Voluntary Compliance. The policy and procedures for
establishing an Institutional Biosafety Committee under Voluntary
Compliance, are specified in Section IV-E-2, Institutional Biosafety
Committee Approval).
Section IV-B-2-a-(2). In order to ensure the competence necessary
to review and approve recombinant DNA activities, it is recommended
that the Institutional Biosafety Committee: (i) Include persons with
expertise in recombinant DNA technology, biological safety, and
physical containment; (ii) include or have available as consultants
persons knowledgeable in institutional commitments and policies,
applicable law, standards of professional conduct and practice,
community attitudes, and the environment, and (iii) include at least
one member representing the laboratory technical staff.
Section IV-B-2-a-(3). The institution shall file an annual report
with NIH/ORDA which includes: (i) A roster of all Institutional
Biosafety Committee members clearly indicating the Chair, contact
person, Biological Safety Officer (if applicable), plant expert (if
applicable), and animal expert (if applicable); and (ii) biographical
sketches of all Institutional Biosafety Committee members (including
community members).
Section IV-B-2-a-(4). No member of an Institutional Biosafety
Committee may be involved (except to provide information requested by
the Institutional Biosafety Committee) in the review or approval of a
project in which he/she has been or expects to be engaged or has a
direct financial interest.
Section IV-B-2-a-(5). The institution, that is ultimately
responsible for the effectiveness of the Institutional Biosafety
Committee, may establish procedures that the Institutional Biosafety
Committee shall follow in its initial and continuing review and
approval of applications, proposals, and activities.
Section IV-B-2-a-(6). When possible and consistent with protection
of privacy and proprietary interests, the institution is encouraged to
open its Institutional Biosafety Committee meetings to the public.
Section IV-B-2-a-(7). Upon request, the institution shall make
available to the public all Institutional Biosafety Committee meeting
minutes and any documents submitted to or received from funding
agencies which the latter are required to make available to the public.
If public comments are made on Institutional Biosafety Committee
actions, the institution shall forward both the public comments and the
Institutional Biosafety Committee's response to the Office of
Recombinant DNA Activities, National Institutes of Health/MSC 7010,
6000 Executive Boulevard, Suite 302, Bethesda, Maryland 20892-7010,
(301) 496-9838.
Section IV-B-2-b. Functions
On behalf of the institution, the Institutional Biosafety Committee
is responsible for:
Section IV-B-2-b-(1). Reviewing recombinant DNA research conducted
at or sponsored by the institution for compliance with the NIH
Guidelines as specified in Section III, Experiments Covered by the NIH
Guidelines, and approving those research projects that are found to
conform with the NIH Guidelines. This review shall include: (i)
Independent assessment of the containment levels required by the NIH
Guidelines for the proposed research; (ii) assessment of the
facilities, procedures, practices, and training and expertise of
personnel involved in recombinant DNA research; and (iii) ensuring
compliance with all surveillance, data reporting, and adverse event
reporting requirements required by the NIH Guidelines.
Section IV-B-2-b-(2). Notifying the Principal Investigator of the
results of the Institutional Biosafety Committee's review and approval.
Section IV-B-2-b-(3). Lowering containment levels for certain
experiments as specified in Section III-C-2-a, Experiments in which DNA
from Human or Animal Pathogens (Risk Group 2, Risk Group 3, Risk Group
4, or Restricted Agents is Cloned into Nonpathogenic Prokaryotic or
Lower Eukaryotic Host-Vector Systems.
Section IV-B-2-b-(4). Setting containment levels as specified in
Sections III-C-4-b, Experiments Involving Whole Animals, and III-C-5,
Experiments Involving Whole Plants.
Section IV-B-2-b-(5). Periodically reviewing recombinant DNA
research conducted at the institution to ensure compliance with the NIH
Guidelines.
Section IV-B-2-b-(6). Adopting emergency plans covering accidental
spills and personnel contamination resulting from recombinant DNA
research.
Note: The Laboratory Safety Monograph describes basic elements
for developing specific procedures dealing with major spills of
potentially hazardous materials in the
[[Page 7116]]
laboratory, including information and references about
decontamination and emergency plans. The NIH and the Centers for
Disease Control and Prevention are available to provide consultation
and direct assistance, if necessary, as posted in the Laboratory
Safety Monograph. The institution shall cooperate with the state and
local public health departments by reporting any significant
research-related illness or accident that may be hazardous to the
public health.
Section IV-B-2-b-(7). Reporting any significant problems with or
violations of the NIH Guidelines and any significant research-related
accidents or illnesses to the appropriate institutional official and
NIH/ORDA within 30 days, unless the Institutional Biosafety Committee
determines that a report has already been filed by the Principal
Investigator. Reports to NIH/ORDA shall be sent to the Office of
Recombinant DNA Activities, National Institutes of Health/MSC 7010,
6000 Executive Boulevard, Suite 302, Bethesda, Maryland 20892-7010,
(301) 496-9838.
Section IV-B-2-b-(8). The Institutional Biosafety Committee may not
authorize initiation of experiments which are not explicitly covered by
the NIH Guidelines until NIH (with the advice of the RAC when required)
establishes the containment requirement.
Section IV-B-2-b-(9). Performing such other functions as may be
delegated to the Institutional Biosafety Committee under Section IV-B-
2, Institutional Biosafety Committee.
Section IV-B-3. Biological Safety Officer (BSO)
Section IV-B-3-a. The institution shall appoint a Biological Safety
Officer if it engages in large scale research or production activities
involving viable organisms containing recombinant DNA molecules.
Section IV-B-3-b. The institution shall appoint a Biological Safety
Officer if it engages in recombinant DNA research at BL3 or BL4. The
Biological Safety Officer shall be a member of the Institutional
Biosafety Committee.
Section IV-B-3-c. The Biological Safety Officer's duties include,
but are not limited to:
Section IV-B-3-c-(1). Periodic inspections to ensure that
laboratory standards are rigorously followed;
Section IV-B-3-c-(2). Reporting to the Institutional Biosafety
Committee and the institution any significant problems, violations of
the NIH Guidelines, and any significant research-related accidents or
illnesses of which the Biological Safety Officer becomes aware unless
the Biological Safety Officer determines that a report has already been
filed by the Principal Investigator;
Section IV-B-3-c-(3). Developing emergency plans for handling
accidental spills and personnel contamination and investigating
laboratory accidents involving recombinant DNA research;
Section IV-B-3-c-(4). Providing advice on laboratory security;
Section IV-B-3-c-(5). Providing technical advice to Principal
Investigators and the Institutional Biosafety Committee on research
safety procedures.
Note: See the Laboratory Safety Monograph for additional
information on the duties of the Biological Safety Officer.
Section IV-B-4. Plant, Plant Pathogen, or Plant Pest Containment Expert
When the institution conducts recombinant DNA research that
requires Institutional Biosafety Committee approval in accordance with
Appendix P, Physical and Biological Containment for Recombinant DNA
Research Involving Plants, the institution shall appoint at least one
individual with expertise in plant, plant pathogen, or plant pest
containment principles (who is also a member of the Institutional
Biosafety Committee).
Section IV-B-5. Animal Containment Expert
When the institution conducts recombinant DNA research that
requires Institutional Biosafety Committee approval in accordance with
Appendix Q, Physical and Biological Containment for Recombinant DNA
Research Involving Animals, the institution shall appoint at least one
individual with expertise in animal containment principles (who is also
a member of the Institutional Biosafety Committee).
Section IV-B-6. Human Gene Therapy Expert
When the institution participates in or sponsors recombinant DNA
research involving human subjects, the institution must ensure that:
(i) The Institutional Biosafety Committee has adequate expertise and
training (using ad hoc consultants as deemed necessary) and (ii) all
aspects of Appendix M, Points to Consider in the Design and Submission
of Protocols for the Transfer of Recombinant DNA Molecules into One or
More Human Subjects (Points to Consider), have been appropriately
addressed by the Principal Investigator prior to submission to NIH/
ORDA. Institutional Biosafety Committee approval must be obtained from
each institution that will handle recombinant DNA material that is to
be administered to human subjects.
Section IV-B-7. Principal Investigator (PI)
On behalf of the institution, the Principal Investigator is
responsible for full compliance with the NIH Guidelines in the conduct
of recombinant DNA research.
Section IV-B-7-a. General Responsibilities
As part of this general responsibility, the Principal Investigator
shall:
Section IV-B-7-a-(1). Initiate or modify no recombinant DNA
research which requires Institutional Biosafety Committee approval
prior to initiation (see Sections III-A, III-B, III-C, and III-D,
Experiments Covered by the NIH Guidelines) until that research or the
proposed modification thereof has been approved by the Institutional
Biosafety Committee and has met all other requirements of the NIH
Guidelines;
Section IV-B-7-a-(2). Determine whether experiments are covered by
Section III-D, Experiments that Require Institutional Biosafety
Committee Notice Simultaneous with Initiation, and that the appropriate
procedures are followed;
Section IV-B-7-a-(3). Report any significant problems, violations
of the NIH Guidelines, or any significant research-related accidents
and illnesses to the Biological Safety Officer (where applicable),
Greenhouse/Animal Facility Director (where applicable), Institutional
Biosafety Committee, NIH/ORDA, and other appropriate authorities (if
applicable) within 30 days. Reports to NIH/ORDA shall be sent to the
Office of Recombinant DNA Activities, National Institutes of Health/MSC
7010, 6000 Executive Boulevard, Suite 302, Bethesda, Maryland 20892-
7010, (301) 496-9838;
Section IV-B-7-a-(4). Report any new information bearing on the NIH
Guidelines to the Institutional Biosafety Committee and to NIH/ORDA
(reports to NIH/ORDA shall be sent to the Office of Recombinant DNA
Activities, National Institutes of Health/MSC 7010, 6000 Executive
Boulevard, Suite 302, Bethesda, Maryland 20892-7010, (301) 496-9838);
Section IV-B-7-a-(5). Be adequately trained in good microbiological
techniques;
Section IV-B-7-a-(6). Adhere to Institutional Biosafety Committee-
approved emergency plans for handling accidental spills and personnel
contamination; and
Section IV-B-7-a-(7). Comply with shipping requirements for
recombinant DNA molecules (see Appendix H, Shipment, for shipping
requirements
[[Page 7117]]
and the Laboratory Safety Monograph for technical recommendations).
Section IV-B-7-b. Submissions by the Principal Investigator to the NIH/
ORDA
The Principal Investigator shall:
Section IV-B-7-b-(1). Submit information to NIH/ORDA for
certification of new host-vector systems;
Section IV-B-7-b-(2). Petition NIH/ORDA, with notice to the
Institutional Biosafety Committee, for proposed exemptions to the NIH
Guidelines;
Section IV-B-7-b-(3). Petition NIH/ORDA, with concurrence of the
Institutional Biosafety Committee, for approval to conduct experiments
specified in Sections III-A-1, Major Actions Under the NIH Guidelines,
and III-B, Experiments that Require NIH/ORDA and Institutional
Biosafety Committee Approval Before Initiation;
Section IV-B-7-b-(4). Petition NIH/ORDA for determination of
containment for experiments requiring case-by-case review; and
Section IV-B-7-b-(5). Petition NIH/ORDA for determination of
containment for experiments not covered by the NIH Guidelines.
Section IV-B-7-b-(6). Ensure that all aspects of Appendix M, Points
to Consider in the Design and Submission of Protocols for the Transfer
of Recombinant DNA Molecules into One or More Human Subjects, have been
appropriately addressed prior to submission of human gene therapy
experiments to NIH/ORDA.
Section IV-B-7-c. Submissions by the Principal Investigator to the
Institutional Biosafety Committee
The Principal Investigator shall:
Section IV-B-7-c-(1). Make an initial determination of the required
levels of physical and biological containment in accordance with the
NIH Guidelines;
Section IV-B-7-c-(2). Select appropriate microbiological practices
and laboratory techniques to be used for the research;
Section IV-B-7-c-(3). Submit the initial research protocol and any
subsequent changes (e.g., changes in the source of DNA or host-vector
system), if covered under Sections III-A, III-B, III-C, or III-D
(Experiments Covered by the NIH Guidelines), to the Institutional
Biosafety Committee for review and approval or disapproval; and
Section IV-B-7-c-(4). Remain in communication with the
Institutional Biosafety Committee throughout the conduct of the
project.
Section IV-B-7-d. Responsibilities of the Principal Investigator Prior
to Initiating Research
The Principal Investigator shall:
Section IV-B-7-d-(1). Make available to all laboratory staff the
protocols that describe the potential biohazards and the precautions to
be taken;
Section IV-B-7-d-(2). Instruct and train laboratory staff in: (i)
The practices and techniques required to ensure safety, and (ii) the
procedures for dealing with accidents; and
Section IV-B-7-d-(3). Inform the laboratory staff of the reasons
and provisions for any precautionary medical practices advised or
requested (e.g., vaccinations or serum collection).
Section IV-B-7-e. Responsibilities of the Principal Investigator During
the Conduct of the Research
The Principal Investigator shall:
Section IV-B-7-e-(1). Supervise the safety performance of the
laboratory staff to ensure that the required safety practices and
techniques are employed;
Section IV-B-7-e-(2). Investigate and report any significant
problems pertaining to the operation and implementation of containment
practices and procedures in writing to the Biological Safety Officer
(where applicable), Greenhouse/Animal Facility Director (where
applicable), the Institutional Biosafety Committee, NIH/ORDA, and other
appropriate authorities (if applicable) (reports to the NIH/ORDA shall
be sent to the Office of Recombinant DNA Activities, National
Institutes of Health/MSC 7010, 6000 Executive Boulevard, Suite 302,
Bethesda, Maryland 20892-7010, (301) 496-9838);
Section IV-B-7-e-(3). Correct work errors and conditions that may
result in the release of recombinant DNA materials; and
Section IV-B-7-e-(4). Ensure the integrity of the physical
containment (e.g., biological safety cabinets) and the biological
containment (e.g., purity and genotypic and phenotypic
characteristics).
Section IV-B-7-e-(5). Comply with annual data reporting and adverse
event reporting requirements for human gene transfer experiments (see
Appendix M-VII, Reporting Requirements--Human Gene Transfer Protocols).
Section IV-C. Responsibilities of the National Institutes of Health
(NIH)
Section IV-C-1. NIH Director
The NIH Director is responsible for: (i) Establishing the NIH
Guidelines, (ii) overseeing their implementation, and (iii) their final
interpretation. The NIH Director has responsibilities under the NIH
Guidelines that involve ORDA and the RAC. ORDA's responsibilities under
the NIH Guidelines are administrative. Advice from the RAC is primarily
scientific, technical, and ethical. In certain circumstances, there is
specific opportunity for public comment with published response prior
to final action.
Section IV-C-1-a. General Responsibilities
The NIH Director is responsible for:
Section IV-C-1-a-(1). Promulgating requirements as necessary to
implement the NIH Guidelines;
Section IV-C-1-a-(2). Establishing and maintaining the RAC to carry
out the responsibilities set forth in Section IV-C-2, Recombinant DNA
Advisory Committee (RAC membership is specified in its charter and in
Section IV-C-2);
Section IV-C-1-a-(3). Establishing and maintaining NIH/ORDA to
carry out the responsibilities defined in Section IV-C-3, Office of
Recombinant DNA Activities;
Section IV-C-1-a-(4). Conducting and supporting training programs
in laboratory safety for Institutional Biosafety Committee members,
Biological Safety Officers and other institutional experts (if
applicable), Principal Investigators, and laboratory staff.
Section IV-C-1-a-(5). Establishing and convening Gene Therapy
Policy Conferences as described in Appendix M, Points to Consider in
the Design and Submission of Protocols for the Transfer of Recombinant
DNA Molecules into One or More Human Subjects.
Section IV-C-1-b. Specific Responsibilities
In carrying out the responsibilities set forth in this section, the
NIH Director, or a designee shall weigh each proposed action through
appropriate analysis and consultation to determine whether it complies
with the NIH Guidelines and presents no significant risk to health or
the environment.
Section IV-C-1-b-(1). Major Actions
To execute Major Actions, the NIH Director shall seek the advice of
the RAC and provide an opportunity for public and Federal agency
comment. Specifically, the Notice of Meeting and Proposed Actions shall
be published in the Federal Register at least 15 days before the RAC
meeting. The NIH Director's decision/recommendation (at his/her
discretion) may be published in the Federal Register for 15 days of
comment before final action is taken. The NIH Director's final
decision/recommendation, along with responses to public comments, shall
be published in the Federal Register. The RAC and Institutional
Biosafety Committee Chairs
[[Page 7118]]
shall be notified of the following decisions:
Section IV-C-1-b-(1)-(a). Changing containment levels for types of
experiments that are specified in the NIH Guidelines when a Major
Action is involved;
Section IV-C-1-b-(1)-(b). Assigning containment levels for types of
experiments that are not explicitly considered in the NIH Guidelines
when a Major Action is involved;
Section IV-C-1-b-(1)-(c). Promulgating and amending a list of
classes of recombinant DNA molecules to be exempt from the NIH
Guidelines because they consist entirely of DNA segments from species
that exchange DNA by known physiological processes or otherwise do not
present a significant risk to health or the environment;
Section IV-C-1-b-(1)-(d). Permitting experiments specified by
Section III-A, Experiments that Require Institutional Biosafety
Committee Approval, RAC Review, and NIH Director Approval Before
Initiation;
Section IV-C-1-b-(1)-(e). Certifying new host-vector systems with
the exception of minor modifications of already certified systems (the
standards and procedures for certification are described in Appendix I-
II, Certification of Host-Vector Systems). Minor modifications
constitute (e.g., those of minimal or no consequence to the properties
relevant to containment); and
Section IV-C-1-b-(1)-(f). Adopting other changes in the NIH
Guidelines.
Section IV-C-1-b-(2). Minor Actions
NIH/ORDA shall carry out certain functions as delegated to it by
the NIH Director (see Section IV-C-3, Office of Recombinant DNA
Activities). Minor Actions (as determined by NIH/ORDA in consultation
with the RAC Chair and one or more RAC members, as necessary) will be
transmitted to the RAC and Institutional Biosafety Committee Chairs:
Section IV-C-1-b-(2)-(a). Changing containment levels for
experiments that are specified in Section III, Experiments Covered by
the NIH Guidelines (except when a Major Action is involved);
Section IV-C-1-b-(2)-(b). Assigning containment levels for
experiments not explicitly considered in the NIH Guidelines;
Section IV-C-1-b-(2)-(c). Revising the Classification of Etiologic
Agents for the purpose of these NIH Guidelines (see Section V-A,
Footnotes and References of Sections I-IV).
Section IV-C-1-b-(2)-(d). Interpreting the NIH Guidelines for
experiments to which the NIH Guidelines do not specifically assign
containment levels;
Section IV-C-1-b-(2)-(e). Setting containment under Sections III-C-
1-d, Experiments Using Risk Group 2, Risk Group 3, Risk Group 4, or
Restricted Agents as Host-Vector Systems, and III-C-2-b, Experiments in
which DNA from Risk Group 2, Risk Group 3, Risk Group 4, or Restricted
Agents is Cloned into Nonpathogenic Prokaryotic or Lower Eukaryotic
Host-Vector Systems;
Section IV-C-1-b-(2)-(f). Approving minor modifications of already
certified host-vector systems (the standards and procedures for such
modifications are described in Appendix I-II, Certification of Host-
Vector Systems);
Section IV-C-1-b-(2)-(g). Decertifying already certified host-
vector systems;
Section IV-C-1-b-(2)-(h). Adding new entries to the list of
molecules toxic for vertebrates (see Appendix F, Containment Conditions
for Cloning of Genes Coding for the Biosynthesis of Molecules Toxic for
Vertebrates); and
Section IV-C-1-b-(2)-(i). Determining appropriate containment
conditions for experiments according to case precedents developed under
Section IV-C-1-b-(2)-(c).
Section IV-C-2. Recombinant DNA Advisory Committee (RAC)
The RAC is responsible for carrying out specified functions cited
below as well as others assigned under its charter or by the DHHS
Secretary and the NIH Director. The RAC consists of 15 voting members
including the Chair, appointed by the DHHS Secretary or his/her
designee, at least 8 of whom are selected from authorities
knowledgeable in the fields of molecular genetics, molecular biology,
recombinant DNA research, or other scientific fields. At least 4
members of the RAC shall be persons knowledgeable in applicable law,
standards of professional conduct and practice, public attitudes, the
environment, public health, occupational health, or related fields.
Representatives from Federal agencies shall serve as non-voting
members. Nominations for the RAC may be submitted to the Office of
Recombinant DNA Activities, National Institutes of Health/MSC 7010,
6000 Executive Boulevard, Suite 302, Bethesda, Maryland 20892-7010,
(301) 496-9838.
All meetings of the RAC shall be announced in the Federal Register,
including tentative agenda items, 15 days before the meeting. Final
agendas, if modified, shall be available at least 72 hours before the
meeting. No item defined as a Major Action under Section IV-C-1-b-(1)
may be added to an agenda following Federal Register publication.
The RAC shall be responsible for:
Section IV-C-2-a. Advising the NIH Director on the following
actions: (1) Adopting changes in the NIH Guidelines. (2) Assigning
containment levels, changing containment levels, and approving
experiments considered as Major Actions under the NIH Guidelines, i.e.,
the deliberate transfer of a drug resistance trait to microorganisms
that are not known to acquire the trait naturally, if such acquisition
could compromise the use of the drug to control disease agents in
humans, veterinary medicine, or agriculture. (3) Promulgating and
amending lists of classes of recombinant DNA molecules to be exempt
from the NIH Guidelines because they consist entirely of DNA segments
from species that exchange DNA by known physiological processes or
otherwise do not present a significant risk to health or the
environment. (4) Certifying new host-vector systems.
Section IV-C-2-b. Identifying novel human gene transfer experiments
deserving of public discussion by the full RAC;
Section IV-C-2-c. Transmitting specific comments/recommendations
about: (i) a specific human gene transfer experiment, or (ii) a
category of human gene transfer experiments, to the NIH Director;
Section IV-C-2-d. Publicly reviewing human gene transfer clinical
trial data and relevant information evaluated and summarized by NIH/
ORDA in accordance with the annual data reporting requirements; and
Section IV-C-2-e. Identifying broad scientific and ethical/social
issues relevant to gene therapy research as potential Gene Therapy
Policy Conference topics.
Section IV-C-2-f. Identifying novel ethical issues relevant to
specific human applications of gene transfer and recommending
appropriate modifications to the Points to Consider that will provide
guidance in the preparation of relevant Informed Consent documents;
Section IV-C-3. Office of Recombinant DNA Activities (ORDA)
ORDA shall serve as a focal point for information on recombinant
DNA activities and provide advice to all within and outside NIH
including institutions, Biological Safety Officers, Principal
Investigators, Federal agencies, state and local governments, and
institutions in the private sector. ORDA shall carry out such other
functions as may be delegated to it by the NIH Director. ORDA's
responsibilities include (but are not limited to) the following:
[[Page 7119]]
Section IV-C-3-a. Serving as the focal point for public access to
summary information pertaining to human gene transfer experiments;
Section IV-C-3-b. Serving as the focal point for data management of
human gene transfer experiments;
Section IV-C-3-c. Administering the annual data reporting
requirements (and subsequent review) for human gene transfer
experiments (see Appendix M-VII, Reporting Requirements--Human Gene
Transfer Protocols);
Section IV-C-3-d. Transmitting comments/recommendations arising
from public RAC discussion of a novel human gene transfer experiment to
the NIH Director. RAC recommendations shall be forwarded to the
Principal Investigator, the sponsoring institution, and other
Department of Health and Human Services (DHHS) components, as
appropriate.
Section IV-C-3-e. Collaborating with Principal Investigators,
Institutional Biosafety Committees, Institutional Review Boards, and
other DHHS components (including the FDA and Office for Protection from
Research Risks); to ensure human gene transfer experiment registration
compliance in accordance with Appendix M-I, Submission Requirements,
Human Gene Transfer Experiments of the NIH Guidelines.
Section IV-C-3-f. Administering Gene Therapy Policy Conferences as
deemed appropriate by the NIH Director.
Section IV-C-3-g. Reviewing and approving experiments in
conjunction with ad hoc experts involving the cloning of genes encoding
for toxin molecules that are lethal for vertebrates at an LD50 of
less than or equal to 100 nanograms per kilogram body weight in
organisms other than Escherichia coli K-12 (see Section III-B-1,
Experiments Involving the Cloning of Toxin Molecules with LD50 of
Less than 100 Nanograms Per Kilogram Body Weight, Appendix F-I,
Containment Conditions for Cloning of Genes Coding for the Biosynthesis
of Molecules Toxic for Vertebrates--General Information, and Appendix
F-II, Cloning of Toxin Molecules Genes in Escherichia coli K-12);
Section IV-C-3-h. Serving as the executive secretary of the RAC;
Section IV-C-3-i. Publishing in the Federal Register:
Section IV-C-3-i-(1). Announcements of RAC meetings and tentative
agendas at least 15 days in advance (Note--If the agenda for a RAC
meeting is modified, ORDA shall make the revised agenda available to
anyone upon request in advance of the meeting);
Section IV-C-3-i-(2). Announcements of Gene Therapy Policy
Conferences and tentative agendas at least 15 days in advance;
Section IV-C-3-i-(3). Proposed Major Actions (see Section IV-C-1-b-
(1), Major Actions) at least 15 days prior to the RAC meeting; and
Section IV-C-3-j. Reviewing and approving the membership of an
institution's Institutional Biosafety Committee, and where it finds the
Institutional Biosafety Committee meets the requirements set forth in
Section IV-B-2, Institutional Biosafety Committee (IBC), giving its
approval to the Institutional Biosafety Committee membership.
Section IV-C-4. Other NIH Components
Other NIH components shall be responsible for certifying maximum
containment (BL4) facilities, inspecting them periodically, and
inspecting other recombinant DNA facilities as deemed necessary.
Section IV-D. Voluntary Compliance
Section IV-D-1. Basic Policy--Voluntary Compliance
Individuals, corporations, and institutions not otherwise covered
by the NIH Guidelines are encouraged to follow the standards and
procedures set forth in Sections I through IV. In order to simplify
discussion, references hereafter to `institutions' are intended to
encompass corporations and individuals who have no organizational
affiliation. For purposes of complying with the NIH Guidelines, an
individual intending to carry out research involving recombinant DNA is
encouraged to affiliate with an institution that has an Institutional
Biosafety Committee approved under the NIH Guidelines.
Since commercial organizations have special concerns, such as
protection of proprietary data, some modifications and explanations of
the procedures are provided in Sections IV-E-2 through IV-E-5-b,
Voluntary Compliance, in order to address these concerns.
Section IV-D-2. Institutional Biosafety Committee Approval--Voluntary
Compliance
It should be emphasized that employment of an Institutional
Biosafety Committee member solely for purposes of membership on the
Institutional Biosafety Committee does not itself make the member an
institutionally affiliated member. Except for the unaffiliated members,
a member of an Institutional Biosafety Committee for an institution not
otherwise covered by the NIH Guidelines may participate in the review
and approval of a project in which the member has a direct financial
interest so long as the member has not been, and does not expect to be,
engaged in the project. Section IV-B-2-a-(4), Institutional Biosafety
Committee, is modified to that extent for purposes of these
institutions.
Section IV-D-3. Certification of Host-Vector Systems--Voluntary
Compliance
A host-vector system may be proposed for certification by the NIH
Director in accordance with the procedures set forth in Appendix I-II,
Certification of Host-Vector Systems. In order to ensure protection for
proprietary data, any public notice regarding a host-vector system
which is designated by the institution as proprietary under Section IV-
D, Voluntary Compliance, will be issued only after consultation with
the institution as to the content of the notice.
Section IV-D-4. Requests for Exemptions and Approvals--Voluntary
Compliance
Requests for exemptions or other approvals as required by the NIH
Guidelines should be submitted based on the procedures set forth in
Sections I through IV. In order to ensure protection for proprietary
data, any public notice regarding a request for an exemption or other
approval which is designated by the institution as proprietary under
Section IV-E-5-a, Voluntary Compliance, will be issued only after
consultation with the institution as to the content of the notice.
Section IV-D-5. Protection of Proprietary Data--Voluntary Compliance
Section IV-D-5-a. General
In general, the Freedom of Information Act requires Federal
agencies to make their records available to the public upon request.
However, this requirement does not apply to, among other things,
``trade secrets and commercial or financial information that is
obtained from a person and that is privileged or confidential.'' Under
18 U.S.C. 1905, it is a criminal offense for an officer or employee of
the U.S. or any Federal department or agency to publish, divulge,
disclose, or make known ``in any manner or to any extent not authorized
by law any information coming to him in the course of his employment or
official duties or by reason of any examination or investigation made
by, or return, report or record made to or filed with, such department
or agency or officer or employee thereof, which information
[[Page 7120]]
concerns or relates to the trade secrets, (or) processes * * * of any
person, firm, partnership, corporation, or association.'' This
provision applies to all employees of the Federal Government, including
special Government employees. Members of the RAC are ``special
Government employees.''
In submitting to NIH for purposes of voluntary compliance with the
NIH Guidelines, an institution may designate those items of information
which the institution believes constitute trade secrets, privileged,
confidential, commercial, or financial information. If NIH receives a
request under the Freedom of Information Act for information so
designated, NIH will promptly contact the institution to secure its
views as to whether the information (or some portion) should be
released. If the NIH decides to release this information (or some
portion) in response to a Freedom of Information request or otherwise,
the institution will be advised and the actual release will be delayed
in accordance with 45 Code of Federal Regulations, section 5.65 (d) and
(e).
Section IV-D-5-b. Presubmission Review
Any institution not otherwise covered by the NIH Guidelines, which
is considering submission of data or information voluntarily to NIH,
may request presubmission review of the records involved to determine
if NIH will make all or part of the records available upon request
under the Freedom of Information Act.
A request for presubmission review should be submitted to NIH/ORDA
along with the records involved to the Office of Recombinant DNA
Activities, National Institutes of Health/MSC 7010, 6000 Executive
Boulevard, Suite 302, Bethesda, Maryland 20892-7010, (301) 496-9838.
These records shall be clearly marked as being the property of the
institution on loan to NIH solely for the purpose of making a
determination under the Freedom on Information Act. NIH/ORDA will seek
a determination from the responsible official under DHHS regulations
(45 Code of Federal Regulations, Part 5) as to whether the records
involved, (or some portion) will be made available to members of the
public under the Freedom of Information Act. Pending such a
determination, the records will be kept separate from NIH/ORDA files,
will be considered records of the institution and not NIH/ORDA, and
will not be received as part of NIH/ORDA files. No copies will be made
of such records.
NIH/ORDA will inform the institution of the DHHS Freedom of
Information Officer's determination and follow the institution's
instructions as to whether some or all of the records involved are to
be returned to the institution or to become a part of NIH/ORDA files.
If the institution instructs NIH/ORDA to return the records, no copies
or summaries of the records will be made or retained by DHHS, NIH, or
ORDA. The DHHS Freedom of Information Officer's determination will
represent that official's judgment at the time of the determination as
to whether the records involved (or some portion) would be exempt from
disclosure under the Freedom on Information Act if at the time of the
determination the records were in NIH/ORDA files and a request was
received for such files under the Freedom of Information Act.
V-E. Proposed Amendments to Appendix A, Exemptions Under Section III-E-
5--Sublists of Natural Exchanges
Appendix A, first paragraph, is proposed to be amended to reflect
renumbering of a previous section.
IV-F. Proposed Amendments to Appendix C, Exemptions Under Section III-
E-6
Appendix C is proposed to be amended to reflect renumbering of a
previous section.
IV-G. Proposed Amendments to Appendix I, Biological Containment
After the first paragraph in Section I-II-A, Responsibility, the
following Note is proposed to be added:
Note. A host-vector system may be proposed for certification by
the NIH Director in accordance with the procedures set forth in
Appendix I-II, Certification of Host-Vector Systems. In order to
ensure protection for proprietary data, any public notice regarding
a host-vector system which is designated by the institution as
proprietary under Section IV-D, Voluntary Compliance, will be issued
only after consultation with the institution as to the content of
the notice (see Section IV-D-3, Certification of Host-Vector
Systems--Voluntary Compliance).
III-H. Proposed Amendments to Appendix M, Points to Consider in the
Design and Submission of Protocols for the Transfer of Recombinant DNA
Molecules into One or More Human Subjects
Appendix M is proposed to be amended to read:
Appendix M. The Points To Consider in the Design and Submission of
Protocols for the Transfer of Recombinant DNA Molecules into One or
More Human Subjects (Points To Consider)
Appendix M applies to research conducted at or sponsored by an
institution that receives any support for recombinant DNA research from
the NIH. Researchers not covered by the NIH Guidelines are encouraged
to use Appendix M (see Section I-C, General Applicability).
The acceptability of human somatic cell gene therapy has been
addressed in several public documents as well as in numerous academic
studies. In November 1982, the President's Commission for the Study of
Ethical Problems in Medicine and Biomedical and Behavioral Research
published a report, Splicing Life, which resulted from a two-year
process of public deliberation and hearings. Upon release of that
report, a U.S. House of Representatives subcommittee held three days of
public hearings with witnesses from a wide range of fields from the
biomedical and social sciences to theology, philosophy, and law. In
December 1984, the Office of Technology Assessment released a
background paper, Human Gene Therapy, which concluded: civic,
religious, scientific, and medical groups have all accepted, in
principle, the appropriateness of gene therapy of somatic cells in
humans for specific genetic diseases. Somatic cell gene therapy is seen
as an extension of present methods of therapy that might be preferable
to other technologies. In light of this public support, the Recombinant
DNA Advisory Committee (RAC) is prepared to consider proposals for
somatic cell gene transfer.
The RAC will not at present entertain proposals for germ line
alterations but will consider proposals involving somatic cell gene
transfer. The purpose of somatic cell gene therapy is to treat an
individual patient, e.g., by inserting a properly functioning gene into
the subject's somatic cells. Germ line alteration involves a specific
attempt to introduce genetic changes into the germ (reproductive) cells
of an individual, with the aim of changing the set of genes passed on
to the individual's offspring.
In the interest of maximizing the resources of both the NIH and the
Food and Drug Administration (FDA) and simplifying the method and
period for review, research proposals involving the deliberate transfer
of recombinant DNA or DNA or RNA derived from recombinant DNA into
human subjects
[[Page 7121]]
(human gene transfer) will be considered through a consolidated review
process involving both the NIH/ORDA and the FDA. Investigators shall
simultaneously submit their relevant information on the proposed human
gene transfer experiments to both the NIH/ORDA and the FDA. Submission
of human gene transfer protocols to the NIH will be in the format
described in Appendix M-I, Submission Requirements--Human Gene Transfer
Experiments, of the NIH Guidelines. Submission to NIH shall be for
registration purposes and will ensure continued public access to
relevant human gene transfer information conducted in compliance with
the NIH Guidelines. Submission of human gene transfer protocols to the
FDA will be in the format described in 21 CFR, Chapter I, Subchapter D,
Part 312, Subpart B, Section 23, IND Content and Format.
Factors that may contribute to public discussion of a human gene
transfer experiment by the RAC include: (i) New vectors/new gene
delivery systems, (ii) new diseases, (iii) unique applications of gene
transfer, and (iv) other issues considered to require further public
discussion. Among the experiments that may be considered exempt from
RAC discussion are those determined not to represent possible risk to
human health or the environment. Full RAC review of an individual human
gene transfer experiment can be initiated by the NIH Director or
recommended to the NIH Director by: (i) three or more RAC members, or
(ii) other Federal agencies. An individual human gene transfer
experiment that is recommended for full RAC review should represent
novel characteristics deserving of public discussion. If the Director,
NIH, determines that an experiment will undergo full RAC discussion,
NIH/ORDA will immediately notify the Principal Investigator. RAC
members may forward individual requests for additional information
relevant to a specific protocol through NIH/ORDA to the Principal
Investigator. In making a determination whether an experiment is novel,
and thus deserving of full RAC discussion, reviewers will examine the
scientific rationale, scientific context (relative to other proposals
reviewed by the RAC), whether the preliminary in vitro and in vivo data
were obtained in appropriate models and are sufficient, and whether
questions related to safety, efficacy, and social/ethical context have
been resolved. RAC recommendations on a specific human gene transfer
experiment shall be forwarded to the NIH Director, the Principal
Investigator, the sponsoring institution, and other Department of
Health and Human Services (DHHS) components, as appropriate. Relevant
documentation will be included in the material for the RAC meeting at
which the experiment is scheduled to be discussed. RAC meetings will be
open to the public except where trade secrets and proprietary
information are reviewed (see Section IV-D-5, Protection of Proprietary
Data). The RAC prefers that information provided in response to
Appendix M contain no proprietary data or trade secrets, enabling all
aspects of the review to be open to the public.
Note: Any application submitted to NIH/ORDA should not be
designated as ``confidential'' in its entirety. In the event that a
sponsor determines that specific responses to one or more of the
items described in Appendix M should be considered as proprietary or
trade secret, each item should be clearly identified as such. The
cover letter (attached to the submitted material) should: (1)
Clearly indicate that select portions of the application contain
information considered as proprietary or trade secret, (2) a brief
explanation as to the reason that each of these items is determined
proprietary or trade secret.
Public discussion of human gene transfer experiments (and access to
relevant information) shall serve to inform the public about the
technical aspects of the proposals, the meaning and significance of the
research, significant safety issues, and ethical/societal implications
of the research. RAC discussion is intended to ensure safe and ethical
conduct of gene therapy experiments and facilitate public understanding
of this novel area of biomedical research.
RAC recommendations on a specific human gene transfer experiment
shall be forwarded to the NIH Director, the Principal Investigator, the
sponsoring institution, and other Department of Health and Human
Services (DHHS) components, as appropriate. In its evaluation of human
gene transfer proposals, the RAC will consider whether the design of
such experiments offers adequate assurance that their consequences will
not go beyond their purpose, which is the same as the traditional
purpose of clinical investigation, namely, to protect the health and
well being of human subjects being treated while at the same time
gathering generalizable knowledge. Two possible undesirable
consequences of the transfer of recombinant DNA would be unintentional:
(i) Vertical transmission of genetic changes from an individual to his/
her offspring, or (ii) horizontal transmission of viral infection to
other persons with whom the individual comes in contact. Accordingly,
Appendices M-I through M-V request information that will enable the
RAC, NIH/ORDA, and the FDA, to assess the possibility that the proposed
experiment(s) will inadvertently affect reproductive cells or lead to
infection of other people (e.g., medical personnel or relatives).
In order to enhance the depth and value of public discussion
relevant to scientific, safety, and ethical/societal implications of
gene therapy research, the NIH Director will convene GTPC at regular
intervals. As appropriate, the NIH Director will convene GTPC
immediately following scheduled RAC meetings. GTPC will be administered
by the NIH/ORDA. Conference participation will not involve a standing
committee membership but rather will offer the unique advantage of
assembling numerous participants who possess significant scientific,
ethical, and legal expertise and/or interest that is directly
applicable to a specific gene therapy research issue. At least one
member of the RAC will serve as Co-chair of each GTPC and report the
findings of the GTPC to the full committee at its next scheduled
meeting. The RAC representative for each GTPC will be chosen based on
the participant's area of expertise relative to the specific gene
therapy research issue to be discussed. GTPC will have representation
from other Federal agencies, including the FDA. GTPCs will focus on
broad over-arching policy and scientific issues related to gene therapy
research. Proposals for GTPC topics may be submitted by members of the
RAC, representatives of academia, industry, patient and consumer
advocacy organizations, other Federal agencies, professional scientific
societies, and the general public. GTPC topics will not be limited to
discussion of human applications of gene therapy research, i.e., they
may include basic research on the use of novel gene delivery vehicles,
or novel applications of gene transfer. The findings of the GTPC will
be transmitted to the NIH Director and will be made publicly available.
The NIH Director anticipates that this public policy forum will serve
as a model for interagency communication and collaboration,
concentrated expert discussion of novel scientific issues and their
potential societal implications, and enhanced opportunity for public
discussion of specific issues and potential impact of such applications
on human health and the environment.
Appendix M will be considered for revisions as experience in
evaluating proposals accumulates and as new
[[Page 7122]]
scientific developments occur. This review will be carried out
periodically as needed.
Appendix M-I. Submission Requirements--Human Gene Transfer Experiments
Investigators must submit the following material to the Office of
Recombinant DNA Activities, National Institutes of Health/MSC 7010,
6000 Executive Boulevard, Suite 302, Bethesda, Maryland 20892-7010,
(301) 496-9838 (see exemption in Appendix M-VIII-A, Footnotes of
Appendix M). Proposals to the NIH will be submitted in the following
order: (1) Scientific abstract; (2) non-technical abstract; (3)
Institutional Biosafety Committee and Institutional Review Board
approvals and their deliberations pertaining to your protocol; (4)
Responses to Appendix M-II through M-V, Description of the Proposal,
Informed Consent, Privacy and Confidentiality, and Special Issues; (5)
clinical protocol (as approved by the local Institutional Biosafety
Committee and Institutional Review Board); (6) Informed Consent
document--approved by the Institutional Review Board (see Appendix M-
III, Informed Consent); (7) appendices (including tables, figures, and
manuscripts); (8) curricula vitae--2 pages for each key professional
person in biographical sketch format; and (9) two 3\1/2\-inch diskettes
with the complete vector nucleotide sequence in ASCII format.
Investigators must submit their human gene transfer protocols to the
FDA in the format described in 21 CFR, Chapter I, Subchapter D, Part
312, Subpart B, Section 23, IND Content and Format. Submissions should
be sent to the Division of Congressional and Public Affairs, Document
Control Center, HFM-99, Center for Biologics Evaluation and Research,
1401 Rockville Pike, Rockville, Maryland 20852-1448.
Appendix M-II. Description of the Proposal
[This section remains unchanged.]
Appendix M-III. Informed Consent
[This section remains unchanged.]
Appendix M-IV. Privacy and Confidentiality
[This section remains unchanged.]
Appendix M-V. Special Issues
[This section remains unchanged.]
Appendix M-VI. RAC Review--Human Gene Transfer Experiments
In order to maintain public access to information regarding human
gene transfer protocols, NIH/ORDA will maintain the documentation
described in Appendices M-I through M-V (including protocols that are
not reviewed by the RAC). The RAC prefers that information provided in
response to Appendix M, Points to Consider, contain no proprietary data
or trade secrets, enabling all aspects of the discussion to be open to
the public.
Appendix M-VI-A. RAC Members' Written Comments
Following receipt by NIH/ORDA, summary information on each human
gene transfer protocol will be forwarded to RAC members. Each RAC
member shall notify NIH/ORDA within 15 working days regarding the
necessity for full RAC discussion. Full RAC review of an individual
human gene transfer experiment can be initiated by the NIH Director or
recommended to the NIH Director by: (i) Three or more RAC members, or
(ii) other Federal agencies. An individual human gene transfer
experiment that is recommended for full RAC review should represent
novel characteristics deserving of public discussion. If the Director,
NIH, determines that an experiment will undergo full RAC discussion,
NIH/ORDA will immediately notify the Principal Investigator. RAC
members may forward individual requests for additional information
relevant to a specific protocol through NIH/ORDA to the Principal
Investigator. In making a determination whether an experiment is novel,
and thus deserving of full RAC discussion, reviewers will examine the
scientific rationale, scientific context (relative to other proposals
reviewed by the RAC), whether the preliminary in vitro and in vivo data
were obtained in appropriate models and are sufficient, and whether
questions related to safety, efficacy, and social/ethical context have
been resolved. RAC recommendations on a specific human gene transfer
experiment shall be forwarded to the NIH Director, the Principal
Investigator, the sponsoring institution, and other Department of
Health and Human Services (DHHS) components, as appropriate.
Appendix M-VII. Reporting Requirements--Human Gene Transfer Protocols
Appendix M-VII-A. Annual Data Reporting
Investigators shall comply with the annual data reporting
requirements. Annual Data Report forms will be forwarded by NIH/ORDA to
investigators. Data submitted in these reports will be evaluated by the
RAC and NIH/ORDA, and reviewed at a future RAC meeting.
Appendix M-VII-B. Adverse Event Reporting
Investigators who have received approval from the FDA to initiate a
human gene transfer protocol must report any serious adverse event
immediately to the local Institutional Review Board, Institutional
Biosafety Committee, Office for Protection from Research Risks (if
applicable), NIH/ORDA, and FDA, followed by the submission of a written
report filed with each group. Reports submitted to NIH/ORDA shall be
sent to the Office of Recombinant DNA Activities, National Institutes
of Health/MSC 7010, 6000 Executive Boulevard, Suite 302, Bethesda,
Maryland 20892-7010, (301) 496-9838.
Appendix M-VIII. Footnotes of Appendix M
Appendix M-VIII-A. Human studies in which the induction or
enhancement of an immune response to a vector-encoded microbial
immunogen is the major goal, such an immune response has been
demonstrated in model systems, and the persistence of the vector-
encoded immunogen is not expected, are exempt from Appendix M-I,
Submission Requirements, and Appendix M-VIII, Reporting Requirements-
Human Gene Transfer Experiments.''
IV. Addition to Appendix D of the NIH Guidelines Regarding a Human Gene
Transfer Protocol/Dr. Crystal
In a letter dated January 8, 1997, Dr. Ronald Crystal of New York-
Hospital-Cornell Medical Center, New York, New York, submitted a human
gene transfer protocol entitled: Immune Response to Intradermal
Administration of an Adenovirus Type 5 Gene Transfer Vector (ADGVCD.10)
in Normal Individuals (NIH Protocol #9701-171) to the RAC for
evaluation regarding the necessity for RAC review and approval.
V. Amendments to Appendix B of the NIH Guidelines Regarding
Classification of Human Etiologic Agents on the Basis of Hazard
In a letter dated January 21, 1997, Dr. Diane Fleming, Chair of the
Subcommittee on Laboratory Safety, American Society for Microbiology,
Washington, D.C., requested the following addition of certain select
agents not previously listed. The letter reads:
* * * Select agents were identified by the Centers for Disease
Control and Prevention as being subject to special
[[Page 7123]]
site registration and handling requirements under 42 CFR Part 72. Only
three of the special agents are not listed in Appendix B, but they
could now be added as follows:
Appendix B-III-D. Risk Group 3 viruses. Add
Arenaviruses: Flexal
Justification: Flexal is already covered by `other viruses listed
in the reference source' but now that it is on the list of select
agents, it should be listed here as well.
Appendix B-IV-D. Risk Group 4 viruses. Add
Arenaviruses: Sabia
Paramyxoviruses: Equine morbilli virus
Justification: As Chairman of the Subcommittee on Arboviral
Laboratory Safety (SALS), Dr. Michael P. Kiley told me that both Sabia
and equine morbilli virus are to be handled under Biosafety Level 4
containment. (Dr. Michael P. Kiley, of the Federal Laboratories for
Health Canada and Agriculture and Agri-Food, Winnipeg, Manitoba,
Canada, January 21, 1997, personal communication regarding the
classification of Sabia and equine morbilli virus).
* * * Recommendations for corrections and changes to errors in
Appendix B which may not require RAC review:
* * * Appendix B-II-A, pg 1487
Acinetobacter baumannii formerly Acinetobacter calcoaceticus var
anitratus is known as the Acinetobacter calcoaceticus-baumannii
complex. We can add var. anitratus to the A. calcoaceticus.
* * * Appendix II-B-IV-D. Remove erroneous reference to
Togaviruses, Group A now associated with the Arenaviruses.
* * * * *
OMB's ``Mandatory Information Requirements for Federal Assistance
Program Announcements'' (45 FR 39592) requires a statement concerning
the official government programs contained in the Catalog of Federal
Domestic Assistance. Normally NIH lists in its announcements the number
and title of affected individual programs for the guidance of the
public. Because the guidance in this notice covers not only virtually
every NIH program but also essentially every Federal research program
in which DNA recombinant molecule techniques could be used, it has been
determined to be not cost effective or in the public interest to
attempt to list these programs. Such a list would likely require
several additional pages. In addition, NIH could not be certain that
every Federal program would be included as many Federal agencies, as
well as private organizations, both national and international, have
elected to follow the NIH Guidelines. In lieu of the individual program
listing, NIH invites readers to direct questions to the information
address above about whether individual programs listed in the Catalog
of Federal Domestic Assistance are affected.
Dated: February 10, 1997.
Lana Skirboll,
Associate Director for Science Policy, National Institutes of Health
[FR Doc. 97-3735 Filed 2-13-97; 8:45 am]
BILLING CODE 4140-01-P
