[Federal Register Volume 61, Number 227 (Friday, November 22, 1996)]
[Notices]
[Pages 59726-59742]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-29891]
[[Page 59725]]
_______________________________________________________________________
Part III
Department of Health and Human Services
_______________________________________________________________________
National Institutes of Health
_______________________________________________________________________
Recombinant DNA Research: Proposed Actions Under the Guidelines; Notice
Federal Register / Vol. 61, No. 227 / Friday, November 22, 1996 /
Notices
[[Page 59726]]
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: On July 8, 1996, the NIH published a Notice of Intent to
modify NIH's oversight of gene therapy. Specifically, the NIH proposed
to: (1) Terminate the NIH Recombinant DNA Advisory Committee (RAC); (2)
relinquish all approval responsibilities for recombinant DNA
experiments involving human gene transfer to the Food and Drug
Administration (FDA), which holds statutory authority for such
approval; (3) establish the Office of Recombinant DNA Activities
Advisory Committee (OAC); (4) limit the membership of OAC to 6-10
individuals, as compared to the 25 members appointed to the RAC; (5)
regularly convene Gene Therapy Policy Conferences; and (6) continue the
publicly available, comprehensive NIH database of human gene transfer
clinical trials, including adverse events.
The NIH received 71 written comments in response to the Notice of
Intent, reflecting a broad range of opinions. After careful
consideration of these comments, the NIH Director revised the proposal
put forward in the July 8, Notice of Intent. This revised proposal,
described herein as the Notice of Proposed Actions, reflects both
public opinion and the NIH Director's intent to increase the
effectiveness and efficiency of public discussion of gene therapy.
Specifically, because of the historical importance of the RAC as a
public platform for discussion of the science, as well as the safe and
ethical conduct of gene therapy research, the NIH Director proposes 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 Gene
Therapy Policy Conferences; and (5) maintain public access to human
gene transfer clinical trial information.
This notice sets forth proposed actions to be taken by the
Director, National Institutes of Health (NIH), regarding enhanced
mechanisms for scientific and ethical/societal oversight of human gene
transfer research, under the NIH Guidelines for Research Involving
Recombinant DNA Molecules (NIH Guidelines) (59 FR 34496, amended 59 FR
40170, amended 60 FR 20726, amended 61 FR 1482, amended 61 FR 10004).
These proposed actions reflect a revision of the proposal set forth in
the July 8, 1996, Federal Register Notice of Intent. It is important to
note that the proposal outlined in the July 8, 1996, Notice of Intent
and the revised proposed actions described herein are applicable only
to recombinant DNA experiments involving human subjects. NIH oversight
of recombinant DNA research conducted in compliance with the NIH
Guidelines (with the exception of human gene transfer research) remains
unchanged.
DATES: Interested parties are invited to submit comments concerning
this proposal. Comments received by December 2, 1996, will be
reproduced and distributed to the Recombinant DNA Advisory Committee
for consideration at its December 9, 1996, meeting. After consideration
of this proposal and comments by the Recombinant DNA Advisory
Committee, the Director of the National Institutes of Health will issue
decisions in accordance with the NIH Guidelines.
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 5:00 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: In l990, the NIH reviewed and approved its
first gene therapy experiment. In the ensuing six years, knowledge
about and experience with somatic cell human gene therapy has grown
substantially. As the field has matured, the NIH has sought to preserve
both the effectiveness and efficiency of its oversight of human gene
therapy research by periodically modifying the functions of the
Recombinant DNA Advisory Committee (RAC).
When the NIH first published the Points to Consider in the Design
and Submission of Protocols for the Transfer of Recombinant DNA Into
the Genome of Human Subjects (Points to Consider) in the Federal
Register in 1990, each human gene therapy experiment was reviewed by
both the Human Gene Therapy Subcommittee (HGTS) and the RAC, and then
approved by the NIH Director. In 1992, when the HGTS was merged with
its parent committee (the Recombinant DNA Advisory Committee), the NIH
adopted a semiannual reporting process for human gene transfer
experiments. One year later, the NIH established an expedited review
process for single patient protocols by allowing written RAC review of
such protocols between the committee's quarterly meetings. In the
following year, the NIH adopted an accelerated review process for
certain categories of clinical trials that had been routinely reviewed
by the RAC and determined not to represent any significant risk to
human health and the environment. Under this mechanism, such protocols
were subject to written review by several RAC members outside of the
committee's quarterly meetings and NIH Office of Recombinant DNA
Activities (ORDA) approval. In l995, another change relevant to RAC
review occurred when the RAC approved consolidated review, in which all
protocols determined not to represent a novel gene therapy delivery
strategy or target disease were exempted from RAC review and approval
and were approved solely by the Food and Drug Administration (FDA).
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 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
[[Page 59727]]
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. 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.
I. Revised Proposal in Response to Public Comment
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, 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.
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, the NIH Director has revised the proposal
set forth in the July 8, 1996, Notice of Intent. In this amended
proposal, the NIH Director proposes to retain the RAC, while modifying
its responsibilities relevant to human gene therapy research. In doing
so, the NIH Director acknowledges the public's view that the RAC has
historical importance as a societal platform for discussion of the
science, as well as the safe and ethical conduct of gene therapy
research. The NIH Director recognizes that this tradition is lacking in
OAC and, therefore, decided to retain the RAC instead of replacing it
with OAC. The NIH Director's intent to increase the effectiveness and
efficiency of the RAC will be achieved by the continuing discussion of
novel human gene transfer experiments without RAC approval of
individual human gene transfer experiments. The membership of the RAC
will be reduced from 25 to 15 individuals to increase efficiency while
ensuring sufficient representation from scientific, ethical, and legal
communities. In order to stimulate public discussion of the safety,
scientific merit, and ethical nature of present and future
opportunities in gene therapy research, the NIH Director proposes to
regularly convene Gene Therapy Policy Conferences (GTPCs). Finally,
recognizing the importance of public access to human gene transfer
clinical trial information, the NIH will continue to maintain the gene
therapy clinical trial database.
II. Analysis of Written Comments in Response to the Notice of
Intent
The following analysis compares and contrasts, point by point, the
proposal set forth in the July 8, 1996, Notice of Intent, the public
response to each point, and the new proposal described herein as the
Notice of Proposed Actions.
II-A. Notice of Intent
Terminate the RAC and establish the Office of Recombinant DNA
Activities Advisory Committee (OAC).
Notice of Proposed Actions
Retain the RAC, while modifying its roles and responsibilities
relevant to human gene therapy research.
Of the 71 comments submitted in response to the Notice of Intent,
10 did not specifically address NIH's proposal to terminate the RAC. Of
the 61 responses which did address the proposal to terminate the RAC,
20 expressed support and 41 expressed opposition. Supporting and
opposing comments were submitted by representatives of: Academia (5
supported, 15 opposed), industry (8 supported, 4 opposed), private
citizens (4 supported, 6 opposed), current and previous RAC members (3
supported, 10 opposed), professional scientific societies (1 supported,
2 opposed), the ethics community (1 supported, 5 opposed), consumer
advocacy organizations (0 supported, 4 opposed), patient advocacy
organizations (0 supported, 6 opposed), and professional scientific
societies (0 supported, 2 opposed).
Comments in support of termination of the RAC reflected an interest
in making substantive changes in the role of the RAC. Most of these
comments supported the proposed restructuring of the functions of the
RAC and did not specifically endorse termination of RAC. Opposing
comments focused on the historical importance of retaining the RAC as
an internationally recognized forum for public discussion of the
science, safety, and ethics of human gene therapy research. These
authors articulated the critical role that the RAC plays in maintaining
public confidence in human gene therapy research.
The importance of the continuation of the RAC, per se, was
underscored by comments which specifically addressed the establishment
of the OAC. Of the 53 comments which addressed this issue, 12 expressed
support and 41 expressed opposition. The majority of comments submitted
in opposition to the OAC stated that the proposed functions of the OAC
could be accomplished by the RAC, or by a restructured version of the
RAC. Several authors emphasized that, absent the historic credibility
of the RAC, the OAC might suffer from an inability to attract and
motivate the type of expertise and judgement needed for this important
public forum.
II-B. Notice of Intent
Relinquish all approval responsibilities for recombinant DNA
experiments involving human gene transfer to the Food and Drug
Administration (FDA) which holds statutory authority for such approval.
Notice of Proposed Actions
Relinquish all approval responsibilities of the RAC to the Food and
Drug Administration (FDA) which holds statutory authority for such
approval, while maintaining RAC discussion of novel human gene transfer
experiments.
Of the 71 comments submitted in response to the Notice of Intent,
24 respondents did not specifically address the proposal to eliminate
RAC approval of human gene transfer experiments; 23 respondents were in
support and 24 respondents were opposed to abolishing protocol
approval. Supporting and opposing comments were submitted by
representatives of academia (7 supported, 7 opposed), industry (11
supported, 0 opposed), private citizens (2 supported, 7 opposed),
previous or current RAC members (4 supported, 5 opposed), professional
scientific societies (4 supported, 1 opposed), the ethics community (2
supported, 4 opposed), patient advocacy organizations (0 supported, 2
opposed), and consumer advocacy organizations (0 supported, 4 opposed).
In discussing the responses to the proposal to eliminate RAC
approval of human gene therapy protocols, it is important to note that
the NIH Director's interest in relinquishing RAC approval recognizes
FDA authority to approve human gene therapy research under its
Investigational New Drug regulations. This proposal eliminates
duplication of this effort by the NIH, which does not have such
regulatory authority.
Respondents supporting elimination of RAC approval felt that the
current status of human gene transfer research is such that NIH
approval is no longer warranted and that it is appropriate that the FDA
exclusively manage the approval process. This point of view was
supported by authors who suggested that the efficient use of Federal
resources is optimized by
[[Page 59728]]
eliminating duplicate approval by the NIH. Opposing points of view
emphasized that the FDA does not routinely take moral and ethical
considerations into account in their review and approval process. Other
comments opposed to exclusive FDA approval expressed concern that
without NIH authority to approve individual human gene transfer
experiments, the FDA could ignore any recommendations coming from the
NIH.
After careful consideration of these letters, the NIH Director
proposes to retain this element of the Notice of Intent, i.e.,
eliminate NIH approval of individual protocols. Under this new proposal
the RAC will continue to emphasize the ethical, social, and scientific
issues arising from the public review and discussion of individual
novel protocols. The NIH Director recognizes that opinions on the
proposed elimination of NIH approval of human gene transfer experiments
were diverse. The majority of comments submitted in opposition to this
issue emphasized the critical role of the RAC in providing a forum for
the public discussion of ethical issues relevant to human gene therapy
research. The NIH Director maintains that the elimination of RAC
approval will not hamper critical public discussion, nor will it result
in any untoward effects on human health or the environment. NIH's
mission is to sponsor and conduct medical research of the highest
scientific merit to improve the health of the nation and the world.
Many of the submitted comments confirmed the NIH Director's concern
that NIH approval on the grounds of safety is often perceived as a
scientific endorsement of early-phase clinical trials, some of which
have inadequate study design and insufficient preclinical foundations.
II-C. Notice of Intent
Limit the membership of OAC to 6-10 individuals, as compared to the
25 members appointed to the RAC; membership would represent the
scientific, ethical and public advocacy communities.
Notice of Proposed Actions
Reduce the membership of RAC from 25 members to 15 members
representing the scientific, ethical, and public advocacy communities.
Of the 71 comments submitted in response to the Notice of Intent,
only 6 comments submitted specifically addressed the composition of
OAC; 2 expressed support and 4 expressed opposition. Supporting and
opposing comments were submitted by representatives of academia (1
supported, 0 opposed), current RAC members (1 supported, 2 opposed) and
private citizens (0 supported, 2 opposed). Although the vast majority
of responses to the Notice of Intent did not address the proposed
reduction in the size of the committee membership, those who were
opposed expressed concern that a standing committee membership of 6-10
individuals could not adequately represent the four fields of expertise
required under the committee charter. Other suggested that a minimum of
12-15 members would be sufficient.
In order to facilitate efficient review and discussion and in
response to comments questioning the extent of the reduction, the NIH
Director proposes to reduce the current RAC membership from 25 to 15
members, including the Chair. The appointment of the 15 member RAC will
adhere to the RAC Charter such that they will be appointed by the DHHS
Secretary or his/her designee. 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.
II-D. Notice of Intent
Convene regular Gene Therapy Policy Conferences.
Notice of Proposed Actions
Convene regular Gene Therapy Policy Conferences.
Of the 71 comments submitted in response to the Notice of Intent,
33 specifically addressed NIH's proposal to convene GTPCs. These
responses were equally divided, with 16 expressing support and 17
expressing opposition. Supporting and opposing comments were submitted
by representatives of academia (3 supported, 5 opposed), industry (7
supported, 3 opposed), private citizens (4 supported, 1 opposed),
current or previous RAC members (2 supported, 7 opposed), professional
scientific societies (0 supported, 2 opposed), consumer advocacy
organizations (0 supported, 2 opposed), patient advocacy organizations
(0 supported, 1 opposed), and the ethics community (0 supported, 4
opposed).
Opposing comments did not question the concept of holding GTPCs,
but rather suggested that the roles and responsibilities of the GTPCs
could be accomplished through the RAC. Supporting comments were
enthusiastic about a separate forum for public discussion of human gene
therapy issues which would expand its discussions beyond individual
protocols. Some responses put forth suggestions for future GTPCs,
including discussion of controversial issues that arise as a
consequence of human gene transfer clinical trials such as reproductive
decisions, susceptibility to workplace dangers, and privacy questions.
It was also suggested that GTPC topics should be actively solicited
from industry and academia to facilitate development of new
technologies.
After careful consideration of the comments submitted with regard
to the proposed establishment of GTPCs, the NIH Director proposes to
retain this element of the Notice of Intent and to establish GTPCs.
However, it is important to note several clarifications of the previous
proposal. GTPCs will focus on broad over-arching policy and scientific
issues related to gene therapy research. The RAC will advise the NIH
Director on GTPC topics. GTPC topics submitted by a member of the RAC,
representatives of academia, industry, patient and consumer advocacy
organizations, other Federal agencies, professional scientific
societies, and the general public will be considered by the NIH
Director. 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. A member of the RAC will co-chair each
GTPC. This member will be selected by the RAC. All RAC members will be
encouraged to attend these meetings. The NIH Director anticipates that
GTPCs will serve as a model for interagency communication and
collaboration, concentrated expert discussion of novel scientific
issues, and enhanced opportunity for public understanding of specific
gene therapy issues including ethical, legal, and social concerns.
II-E. Notice of Intent
Ensure public access to human gene transfer experiments information
by maintaining the publicly available, comprehensive NIH database of
human gene transfer clinical trials, including adverse events.
Notice of Proposed Actions
Ensure public access to human gene transfer experiments information
by maintaining the publicly available, comprehensive NIH database of
human
[[Page 59729]]
gene transfer clinical trials, including adverse events.
Of the 71 comments submitted in response to the Notice of Intent,
25 comments specifically addressed NIH's proposal to maintain its human
gene transfer database; 20 expressed support and 5 expressed
opposition. Supporting and opposing comments were submitted by
representatives of academia (8 supported, 1 opposed), industry (4
supported, 2 opposed), private citizens (1 supported, 0 opposed),
current or previous RAC members (5 supported, 2 opposed), the ethics
community (1 supported, 0 opposed), and the European community (France)
(1 supported, 0 opposed).
The overwhelming majority of comments expressed strong support for
the NIH Director's proposal to maintain the human gene transfer
database. Supporting comments emphasized the importance of maintaining
public understanding of human gene therapy research. The majority of
comments argued that the human gene transfer database is a vital tool
for ensuring public confidence in this novel area of research. Many
comments underscored the importance of capturing positive as well as
negative data derived from gene therapy clinical trials. Other
commentors felt that public access to such information avoids
unnecessary duplication of effort and clearly identifies gaps in
knowledge that are worthy of further preclinical and clinical
investigation.
In response to these comments, the NIH Director will maintain
public accountability for human gene therapy research through the
publicly available, comprehensive database for human gene transfer
clinical trials. Information entered into the database will be derived
from the documentation submitted to NIH/ORDA in compliance with: (i)
Appendix M-I, Submission Requirements--Human Gene Transfer Experiments
and (ii) Appendix M-VII--Reporting Requirements--Human Gene Transfer
Experiments, of 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) of the NIH Guidelines. In
compliance with the NIH Guidelines, investigators will continue to be
required to register human gene transfer experiments with NIH/ORDA to
ensure continued public access to protocol information, ongoing data
(including adverse and significant clinical events), and long-term
follow-up data.
III. Proposed Roles and Responsibilities in Accordance With the NIH
Guidelines
III-A. The NIH Director
The roles and responsibilities of the NIH Director remain unchanged
except for relinquishing approval of human gene transfer experiments.
The NIH Director is responsible for: (1) Establishing the NIH
Guidelines and overseeing their implementation. (2) Promulgating
requirements as necessary to implement the NIH Guidelines. (3)
Establishing and maintaining the RAC. (4) Establishing and maintaining
ORDA.
III-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.
III-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 Gene Therapy
Policy Conferences (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 also 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
[[Page 59730]]
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
communications 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.
III-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 the safe conduct of recombinant DNA
research. (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) Reviewing and approving the
membership of Institutional Biosafety Committees. (10) Changing
containment levels for experiments that are specified in Section III,
Experiments Covered by the NIH Guidelines (except when a Major Action
is involved). (11) Assigning containment levels for experiments not
explicitly considered in the NIH Guidelines. (12) Interpreting the NIH
Guidelines for experiments to which the NIH Guidelines do not
specifically assign containment levels. (13) Approving minor
modifications and decertifying host-vector systems. (14) Preparing
minutes of RAC meetings and gene therapy policy conferences.
III-E. Local Institutions
The roles and responsibilities of local institutions, Institutional
Biosafety Committees, Biosafety Officers, Principal Investigators,
Animal Facility Directors, and Greenhouse Supervisors relevant to
recombinant DNA research conducted in compliance with the NIH
Guidelines, remains unchanged.
IV. Proposed Actions
The NIH will consider the following actions under the NIH
Guidelines for Research Involving Recombinant DNA Molecules:
[Note: Editorial changes and updating of references are proposed
to clarify the document in addition to the Proposed Actions
regarding the Notice of Intent.]
IV-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. In the interest of maximizing the resources of
both the NIH and the Food and Drug Administration (FDA) and simplifying
the method and period for review, research proposals involving the
deliberate transfer of recombinant DNA or DNA or RNA derived from
recombinant DNA into human subjects (human gene transfer) will be
considered through a consolidated submission process involving both the
NIH and the FDA. An investigator shall simultaneously submit a human
gene transfer experiment to both the NIH and the FDA in a single
submission format. This format shall include (but is not limited to)
the documentation described in Appendices M-I through M-V, of 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). Submission to the NIH Office of Recombinant DNA
Activities (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. The RAC will receive
periodic updates regarding recent submissions to NIH/ORDA. 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 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 will be
forwarded to the NIH Director, the Principal Investigator, the
sponsoring institution, and, as appropriate, to other Department of
Health and Human Services (DHHS) components.
``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
[[Page 59731]]
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 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. The policies on noncompliance 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.
``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 remainder of Section I is proposed to be renumbered to reflect
above changes.]
IV-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 * * *.''
IV-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
expressed 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
[[Page 59732]]
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 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
``Experiments in this category cannot be initiated without
simultaneous submission of relevant information on the proposed
experiment to both NIH/ORDA and the FDA in a single submission format.
This format shall include (but is not limited to) the documentation
described in Appendices M-I through M-V, of 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).
Prior to initiation of a human gene transfer experiment, the Principal
Investigator must obtain both Institutional Biosafety Committee and
Institutional Review Board approvals. 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 discussion. 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 review to be open to the public.
Full RAC review of an individual human gene transfer experiment can be
recommended by: (i) A majority of the RAC, (ii) other Federal agencies,
(iii) the Principal Investigator, or (iv) the sponsoring institution.
An individual human gene transfer experiment that is recommended for
full RAC review should represent novel characteristics deserving of
public discussion. Recommendations for full RAC review of individual
human gene transfer experiments will be transmitted to the NIH
Director, who will determine whether an individual human gene transfer
experiment shall be discussed by the full RAC and determine the
priority of the discussions if more than one experiment is awaiting
discussion. RAC recommendations on a specific human gene transfer
experiment shall be forwarded to the NIH Director, the Principal
Investigator, the sponsoring institution, and, as appropriate, other
Department of Health and Human Services (DHHS) components.
``Institutional Biosafety Committee approval must be obtained from
any institution responsible for constructing or handling the
recombinant DNA material to be used in the experiments. 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.
``Section III-C-1. Experiments Involving the Deliberate Transfer of
Recombinant DNA or DNA or RNA Derived From Recombinant DNA Into Human
Subjects
``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. 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 recommended by: (i) a majority of
the RAC, (ii) other Federal agencies, (iii) the Principal Investigator,
or (iv) the sponsoring institution. An individual human gene transfer
experiment that is recommended for full RAC review should represent
novel characteristics deserving of public discussion. Recommendations
for full RAC review of individual human gene transfer experiments will
be transmitted to the NIH Director, who will determine whether an
individual human gene transfer experiment shall be discussed by the
full RAC and determine the priority of the discussions if more than one
experiment is awaiting discussion.
[[Page 59733]]
If a determination is made that an experiment shall undergo discussion
by the full RAC, 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. Relevant documentation will be included
in the material for the RAC meeting at which the experiment is
scheduled to be discussed. RAC recommendations on a specific human gene
transfer experiment shall be forwarded to the NIH Director, the
Principal Investigator, the sponsoring institution, and, as
appropriate, other Department of Health and Human Services (DHHS)
components.
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.]
IV-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 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. 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-g. 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.
``Note: 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-h. Determine the necessity for health surveillance
of personnel involved in connection with individual recombinant DNA
projects;
[[Page 59734]]
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-i. Report any significant problems, violations of
the NIH Guidelines, or any significant research-related accidents and
illnesses to NIH/ORDA within thirty days, unless the institution
determines that a report has already been filed by the Principal
Investigator or Institutional Biosafety Committee. Reports shall be
sent to the Office of Recombinant DNA Activities, National Institutes
of Health/MSC 7010, 6000 Executive Boulevard, Suite 302, Bethesda,
Maryland 20892-7010, (301) 496-9838.
``Section IV-B-2. Institutional Biosafety Committee (IBC)
``The institution shall establish an Institutional Biosafety
Committee whose responsibilities need not be restricted to recombinant
DNA. The Institutional Biosafety Committee shall meet the following
requirements:
``Section IV-B-2-a. Membership and Procedures
``Section IV-B-2-a-(1). The Institutional Biosafety Committee must
be comprised of no fewer than five members so selected that they
collectively have experience and expertise in recombinant DNA
technology and the capability to assess the safety of recombinant DNA
research and to identify any potential risk to public health or the
environment. At least two members shall not be affiliated with the
institution (apart from their membership on the Institutional Biosafety
Committee) and who represent the interest of the surrounding community
with respect to health and protection of the environment (e.g.,
officials of state or local public health or environmental protection
agencies, members of other local governmental bodies, or persons active
in medical, occupational health, or environmental concerns in the
community). The Institutional Biosafety Committee shall include at
least one individual with expertise in plant, plant pathogen, or plant
pest containment principles when experiments utilizing Appendix P,
Physical and Biological Containment for Recombinant DNA Research
Involving Plants, require prior approval by the Institutional Biosafety
Committee. The Institutional Biosafety Committee shall include at least
one scientist with expertise in animal containment principles when
experiments utilizing Appendix Q, Physical and Biological Containment
for Recombinant DNA Research Involving Animals, require Institutional
Biosafety Committee prior approval. When the institution conducts
recombinant DNA research at BL3, BL4, or Large Scale (greater than 10
liters), a Biological Safety Officer is mandatory and shall be a member
of the Institutional Biosafety Committee (see Section IV-B-3,
Biological Safety Officer).
``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.
``Note: 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 will be administered
to human subjects.
``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
[[Page 59735]]
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 (Class 2, Class 3, Class 4, or Class 5
Agents is Cloned into Nonpathogenic Prokaryotic or Low er 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 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 be 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 Expertise
``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.
[[Page 59736]]
``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 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
[[Page 59737]]
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 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 containment 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 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 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
[[Page 59738]]
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 actions listed
in Sections IV-C-1-b, NIH Director--Specific Responsibility;
``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-3. Office of Recombinant DNA Activities (ORDA)
``ORDA shall serve as a focal point for information on recombinant
DNA activities and provide advice to all within and outside NIH
including institutions, Biological Safety Officers, Principal
Investigators, Federal agencies, state and local governments, and
institutions in the private sector. ORDA shall carry out such other
functions as may be delegated to it by the NIH Director. ORDA's
responsibilities include (but are not limited to) the following:
``Section IV-C-3-a. Serving as the focal point for public access to
summary information pertaining to human gene transfer experiments;
``Section IV-C-3-b. Serving as the focal point for data management
of human gene transfer experiments;
``Section IV-C-3-c. Administering the annual data reporting
requirements (and subsequent review) for human gene transfer
experiments (see Appendix M-VII, Reporting Requirements--Human Gene
Transfer Protocols);
``Section IV-C-3-d. Transmitting comments/recommendations arising
from public RAC discussion of a novel human gene transfer experiment to
the NIH Director. RAC recommendations shall be forwarded to the
Principal Investigator, the sponsoring institution, and, as
appropriate, other Department of Health and Human Services (DHHS)
components.
``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;
``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 do so by following 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
[[Page 59739]]
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 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.''
IV-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).''
IV-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
[[Page 59740]]
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 (human gene transfer) will be considered through a
consolidated review process involving both the NIH and the FDA.
Investigators shall simultaneously submit their human gene transfer
proposal to both the NIH and the FDA. Submissions shall include (but
are not limited to) the documentation described in Appendices M-I
through M-V of the Points to Consider.
``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 recommended by: (i) A majority of the
RAC, (ii) other Federal agencies, (iii) the Principal Investigator, or
(iv) the sponsoring institution. An individual human gene transfer
experiment that is recommended for full RAC review should represent
novel characteristics deserving of public discussion. Recommendations
for full RAC review of individual human gene transfer experiments will
be transmitted to the NIH Director. The NIH Director will determine
whether an individual human gene transfer experiment shall be discussed
by the full RAC and will determine the priority of the discussions if
more that one experiment is awaiting discussion. 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, as appropriate, other Department of Health
and Human Services (DHHS) components. 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 requests 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 recognition of the social concern that surrounds the subject
of human gene transfer, the RAC, NIH/ORDA, and the FDA, will cooperate
with other groups in assessing the possible long-term consequences of
the proposal and related laboratory and animal experiments in order to
define appropriate human applications of this emerging technology.
``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 Gene Therapy
Policy Conferences (GTPC) as deemed appropriate. GTPC will be
administered by the NIH/ORDA. These conferences 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. GTPC
topics for discussion may be submitted by a member of the RAC, other
Federal agencies, Principal Investigators, industry representatives,
patient advocacy groups, or individuals who represent the general
public interest through NIH/ORDA to the NIH Director. GTPC topics may
include areas such as basic research on the use of novel gene delivery
vehicles, novel applications of gene transfer, and relevant ethical/
societal implications of a particular application of gene transfer
technology. 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 communications and collaboration, concentrated expert
discussion of novel scientific issues and their potential societal
implications, and enhanced opportunity for public discussion of
specific issues and
[[Page 59741]]
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 scientific developments
occur. This review will be carried out periodically as needed.
``Appendix M-I. Submission Requirements--Human Gene Transfer
Experiments
``Investigators must simultaneously submit the following material
to both: (1) 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); and (2) 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. Proposals 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.
``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 recommended by: (i) A majority of
the RAC, (ii) other Federal agencies, (iii) the Principal Investigator,
or (iv) the sponsoring institution. 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, as appropriate, other
Department of Health and Human Services (DHHS) components.
``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.''
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
[[Page 59742]]
the Catalog of Federal Domestic Assistance are affected.
Dated: November 15, 1996.
Harold Varmus,
Director National Institutes of Health.
[FR Doc. 96-29891 Filed 11-21-96; 8:45 am]
BILLING CODE 4140-01-P