[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]]

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Part III





Department of Health and Human Services





_______________________________________________________________________



National Institutes of Health



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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

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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