[Federal Register Volume 59, Number 162 (Tuesday, August 23, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-20826]


[[Page Unknown]]

[Federal Register: August 23, 1994]


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Recombinant DNA Research: Proposed Actions Under the Guidelines 
AGENCY: National Institutes of Health, PHS, DHHS.

ACTION: Notice of Proposed Actions Under the NIH Guidelines for 
Research Involving Recombinant DNA Molecules (59 FR 34496).

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SUMMARY: This notice sets forth proposed actions to be taken under the 
National Institutes of Health (NIH) Guidelines for Research Involving 
Recombinant DNA Molecules (59 FR 34496). Interested parties are invited 
to submit comments concerning these proposals. These proposals will be 
considered by the Recombinant DNA Advisory Committee at its meeting on 
September 12-13, 1994. After consideration of these proposals 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.

DATES: Comments received by September 5, 1994, will be reproduced and 
distributed to the Recombinant DNA Advisory Committee for consideration 
at its September 12-13, 1994, meeting.

ADDRESSES: Written comments and recommendations should be submitted to 
Dr. Nelson A. Wivel, Director, Office of Recombinant DNA Activities 
(ORDA), Building 31, Room 4B11, National Institutes of Health, 
Bethesda, Maryland 20892, or sent by FAX to 301-496-9839.
    All comments received in timely response to this notice will be 
considered and will be available for public inspection in the above 
office on weekdays between the hours of 8:30 a.m. and 5 p.m.

FOR FURTHER INFORMATION CONTACT: Background documentation and 
additional information can be obtained from the Office of Recombinant 
DNA Activities, Building 31, Room 4B11, National Institutes of Health, 
Bethesda, Maryland 20892, (301) 496-9838.

SUPPLEMENTARY INFORMATION: The NIH will consider the following actions 
under the NIH Guidelines for Research Involving Recombinant DNA 
Molecules:

I. Addition to Appendix D of the NIH Guidelines Regarding a Human 
Gene Transfer Protocol/Dr. Crystal

    In a letter dated July 18, 1994, Dr. Ronald Crystal of the New York 
Hospital-Cornell Medical Center, New York, New York, submitted a human 
gene transfer protocol entitled: Evaluation of Repeat Administration of 
a Replication Deficient, Recombinant Adenovirus Containing the Normal 
Cystic Fibrosis Transmembrane Conductance Regulator cDNA to the Airways 
of Individuals w/Cystic Fibrosis to the Recombinant DNA Advisory 
Committee for formal review and approval.

II. Addition to Appendix D of the NIH Guidelines Regarding a Human 
Gene Transfer Protocol/Drs. Isner and Walsh

    In a letter dated July 5, 1994, Drs. Jeffrey M. Isner and Kenneth 
Walsh of the St. Elizabeth's Medical Center, Tufts University, Boston, 
Massachusetts, submitted a human gene transfer protocol entitled: 
Arterial Gene Transfer for Therapeutic Angiogenesis in Patients with 
Peripheral Artery Disease to the Recombinant DNA Advisory Committee for 
formal review and approval.

III. Addition to Appendix D of the NIH Guidelines Regarding a Human 
Gene Transfer Protocol/Dr. Gluckman

    In a letter dated July 15, 1994, Dr. Jack L. Gluckman of the 
University of Cincinnati Medical Center, Cincinnati, Ohio, submitted a 
human gene transfer protocol entitled: Intratumoral Injection of Herpes 
Simplex Thymidine Kinase Vector Producer Cells (PA317/G1Tk1SvNa.7) and 
Intravenous Ganciclovir for the Treatment of Locally Recurrent or 
Persistent Head and Neck Cancer to the Recombinant DNA Advisory 
Committee for formal review and approval.

IV. Addition to Appendix D of the NIH Guidelines Regarding a Human 
Gene Transfer Protocol/Dr. Flotte

    In a letter dated July 14, 1994, Dr. Terence R. Flotte of Johns 
Hopkins Children's Center, Baltimore, Maryland, submitted a human gene 
transfer protocol entitled: A Phase I Study of an Adeno-associated 
Virus-CFTR Gene vector in Adult CF Patients with Mild Lung Disease to 
the Recombinant DNA Advisory Committee for formal review and approval.

V. Addition to Appendix D of the NIH Guidelines Regarding a Human 
Gene Transfer Protocol/Dr. Lyerly

    In a letter received on July 18, 1994, Dr. H. Kim Lyerly of Duke 
University Medical Center, Durham, North Carolina, submitted a human 
gene transfer protocol entitled: A Pilot Study of Autologous Human 
Interleukin-2 Gene Modified Tumor Cells in Patients with Refractory or 
Recurrent Metastatic Breast Cancer to the Recombinant DNA Advisory 
Committee for formal review and approval.

VI. Addition to Appendix D of the NIH Guidelines Regarding a Human 
Gene Transfer Protocol/Dr. Whitley

    In a letter dated July 15, 1994, Dr. Chester B. Whitley of the 
University of Minnesota, Minneapolis, Minnesota, submitted a human gene 
transfer protocol entitled: Retroviral-Mediated Transfer of the 
Iduronate-2-Sulfatase Gene Into Lymphocytes for Treatment of Mild 
Hunter Syndrome (Mucopolysaccharidosis Type II) to the Recombinant DNA 
Advisory Committee for formal review and approval.

VII. Addition to Appendix D of the NIH Guidelines Regarding a Human 
Gene Transfer Protocol/Drs. Holt and Arteaga

    In a letter dated July 15, 1994, Drs. Jeffrey Holt and Carlos B. 
Arteaga of Vanderbilt University, Nashville, Tennessee, submitted a 
human gene transfer protocol entitled: Gene Therapy for the Treatment 
of Metastatic Breast Cancer by In Vivo Infection with Breast-Targeted 
Retroviral Vectors Expressing Antisense c-fos or Antisense c-myc RNA to 
the Recombinant DNA Advisory Committee for formal review and approval.

VIII. Addition to Appendix D of the NIH Guidelines Regarding a 
Human Gene Transfer Protocol/Drs. Eck, Alavi

    In a letter dated July 15, 1994, Drs. Stephen L. Eck and Jane B. 
Alavi of the University of Pennsylvania Medical Center, Philadelphia, 
Pennsylvania, submitted a human gene transfer protocol entitled: 
Treatment of Advanced CNS Malignancy w/the Recombinant Adenovirus 
H5.020RSVTK: A Phase I Trial to the Recombinant DNA Advisory Committee 
for formal review and approval.

IX. Addition to Appendix D of the NIH Guidelines Regarding a Human 
Gene Transfer Protocol/Dr. Albelda

    In a letter received on July 18, 1994, Dr. Steven M. Albelda of the 
University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, 
submitted a human gene transfer protocol entitled: Treatment of 
Advanced Mesothelioma with the Recombinant Adenovirus H5.010RSVTK: A 
Phase I Trial to the Recombinant DNA Advisory Committee for formal 
review and approval.

X. Amendments to Sections I, III, IV, V, and Appendix M of the NIH 
Guidelines Regarding Consolidated Review of Human Gene Transfer 
Protocols

    On July 18-19, 1994, the National Task Force on AIDS Drug 
Development held an open meeting for the purpose of identifying 
barriers to AIDS Drug Discovery that included a proposal to streamline 
the dual review process for human gene transfer experiments. Members of 
the Task Force recommended a consolidated review process to enhance 
interactions between the NIH and the FDA. As a result of the Task 
Force's deliberations, recommendations were adopted in order to 
eliminate any unnecessary overlap between the FDA and NIH review of 
human gene transfer proposals. Both Drs. Varmus and Kessler noted that 
their respective agencies would cooperate fully to effect the changes 
necessary to implement these recommendations. The recommendations were:
    ``The NIH and FDA recommend that the RAC become advisory to both 
the NIH Director and the FDA with regard to the review of human gene 
transfer protocols. In the interest of maximizing the resources of both 
agencies and in simplifying the method and period for review of 
research protocols involving human gene transfer, it is planned that 
the FDA and NIH institute a new consolidated review process that 
incorporates the following principal elements:
    (1) All gene transfer protocols shall be submitted directly to the 
FDA. Submission will be in the format required by the FDA and the same 
format will be used by the RAC when public review is deemed necessary.
    (2) Upon receipt, FDA review will proceed. The NIH Office of 
Recombinant DNA Activities (ORDA) staff will simultaneously evaluate 
the protocol for possible RAC review.
    (3) Factors which may contribute to the need for RAC review 
include: (1) novel approaches, (2) new diseases, (3) unique 
applications of gene transfer, and (4) other issues that require 
further public review.
    (4) Whenever possible, principal investigators will be notified 
within 15 working days following receipt of the submission whether RAC 
review will be required. (RAC reviewed applications will be forwarded 
to reviewers 8 weeks prior to the next quarterly RAC meeting.)
    (5) Semi-annual data reporting procedures will remain the 
responsibility of NIH (ORDA). Semi-annual data reports will be reviewed 
by the RAC in a public forum.''
    Investigators will no longer be required to provide a separate 
submission to NIH/ORDA for RAC review. The FDA Division of Cellular and 
Gene Therapies will forward a copy of each submission to NIH/ORDA. Any 
protocol submitted < 8 weeks before a RAC meeting will be reviewed at 
the following quarterly RAC meeting.
    The RAC will make recommendations regarding approval/disapproval of 
protocols, including any relevant stipulations, to the NIH Director. 
The NIH Director will transmit the RAC's recommendations/stipulations 
to the FDA Commissioner.
    The FDA will consider such recommendations/stipulations and will be 
responsible for completion of review. The RAC and NIH/ORDA will no 
longer have the responsibility for reviewing material submitted in 
response to stipulation requirements or for the review of minor 
modifications to human gene transfer protocols.
    The following proposed amendments to the NIH Guidelines reflect the 
new streamlined review process.

Section I (Scope of the NIH Guidelines) currently reads:

    ``Section I. Scope of the NIH Guidelines
    ``Section I-A. Purpose
    ``The purpose of the NIH Guidelines is to specify practices for 
constructing and handling: (i) recombinant deoxyribonucleic acid (DNA) 
molecules, and (ii) organisms and viruses containing recombinant DNA 
molecules.
    ``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 approval, or other applicable clearances, has 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 Sections I-A-2 and I-A-3).
    ``Section I-A-2. Certain experiments that involve the deliberate 
transfer of recombinant DNA or DNA or RNA derived from recombinant DNA 
into one or more human subjects (see Section V-U) shall be considered 
Major Actions (see Section IV-C-1-b-(1)), and shall require RAC review 
and NIH Director approval, if determined by NIH/ORDA in consultation 
with the RAC Chair and/or one or more RAC members, as necessary, to: 
(i) represent novel characteristics (e.g., target disease or vector), 
(ii) represent an uncertain degree of risk to human health or the 
environment, or (iii) contain information determined to require further 
public review (see Section III-A-2).
    ``Section I-A-3. Experiments involving the transfer of recombinant 
DNA to one or more human subjects that are not considered under Section 
III-A-2 may qualify for Accelerated Review (see Section III-B-2 and 
Appendix M-V) and will be considered as Minor Actions (see Section IV-
C-1-b-(2)-(a)). Actions that qualify for Accelerated Review will be 
reviewed and approved by NIH/ORDA in consultation with the RAC Chair 
and/or one or more RAC members, as necessary.
    ``Certain experiments involving the transfer of recombinant DNA or 
DNA or RNA derived from recombinant DNA into one or more human subjects 
(see Section V-U) may be considered exempt from RAC and/or NIH/ORDA 
review and/or NIH Director approval and only require registration with 
NIH/ORDA (see Section III-C-7).''

Section I-A is proposed to read:

    ``Section I. Scope of the NIH Guidelines
    ``Section I-A. Purpose
    ``The purpose of the NIH Guidelines is to specify practices for 
constructing and handling: (i) recombinant deoxyribonucleic acid (DNA) 
molecules, and (ii) organisms and viruses containing recombinant DNA 
molecules.
    ``Section I-A-1. If a recombinant DNA experiment requiring NIH 
approval is also subject to review and approval by another Federal 
agency, the proposed experiment must be submitted to the other Federal 
agency. Once approval, or other applicable clearances, has been 
obtained from a Federal agency other than the NIH, the experiment may 
proceed without the necessity for NIH review or approval, except as 
provided in Section I-A-1-a.
    ``Section I-A-1-a. Experiments involving the deliberate transfer of 
recombinant DNA or DNA or RNA derived from recombinant DNA into one or 
more human subjects shall be submitted directly to the Food and Drug 
Administration (FDA). Such proposals shall be submitted to the Director 
of the Division of Cellular and Gene Therapies, Office of Therapeutics 
Research and Review, Center for Biologics Evaluation and Research, Food 
and Drug Administration, 1401 Rockville Pike, HFM-515, Rockville, 
Maryland 20852-1448, (301) 496-4709. Upon receipt, FDA will transmit 
all human gene transfer protocols to the NIH Office of Recombinant DNA 
Activities (ORDA). Simultaneously with the FDA review, NIH/ORDA will 
evaluate the protocol for possible RAC review. Whenever possible, 
Principal Investigators will be notified within 15 working days 
following receipt of the submission whether RAC review will be 
required. RAC reviewed applications will be forwarded to reviewers 8 
weeks prior to the next quarterly RAC meeting. Factors that may 
contribute to the need for RAC review include: (i) novel approaches, 
(ii) new diseases, (iii) unique applications of gene transfer, and (iv) 
other issues that may require further public review. The RAC's 
recommendations, including specific requirements and stipulations, will 
be forwarded to the NIH Director. The NIH Director's final 
recommendation will be forwarded to the FDA Commissioner.''

Section III (Experiments Covered by the NIH Guidelines), paragraph 1, 
currently reads:

    ``This section describes five categories of experiments involving 
recombinant DNA: (i) those that require RAC review and NIH and 
Institutional Biosafety Committee approval before initiation. . . .''

Section III, paragraph 1, is proposed to read:

    ``This section describes five categories of experiments involving 
recombinant DNA: (i) those that require Institutional Biosafety 
Committee approval, RAC review, and NIH Director consideration before 
initiation. . . .''

Section III-A currently reads:

    ``Section III-A. Experiments that Require Institutional Biosafety 
Committee Approval, RAC Review, and NIH Approval Before Initiation
    ``Experiments in this category are considered Major Actions (see 
Section IV-C-1-b-(1)) cannot be initiated without submission of 
relevant information on the proposed experiment to the Office of 
Recombinant DNA Activities, National Institutes of Health, Building 31, 
Room 4B11, Bethesda, Maryland 20892, (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 (not applicable for Expedited 
Review single patient human gene transfer experiments considered under 
Appendix M-VI). The containment conditions 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 which may be obtained from the Office of Recombinant DNA 
Activities, National Institutes of Health, Building 31, Room 4B11, 
Bethesda, Maryland 20892, (301) 496-9838.
    ``Section III-A-1. Deliberate transfer of a drug resistance trait 
to microorganisms that are not known to acquire the trait naturally 
(see Section V-B), if such acquisition could compromise the use of the 
drug to control disease agents in humans, veterinary medicine, or 
agriculture.
    ``Section III-A-2. Certain experiments involving the deliberate 
transfer of recombinant DNA or DNA or RNA derived from recombinant DNA 
into one or more human subjects (see Section V-U) shall be considered 
Major Actions (see Section IV-C-1-b-(1) and Appendix M-III), and shall 
require RAC review and NIH Director approval, if determined by NIH/
ORDA, in consultation with the RAC Chair and one or more RAC members, 
as necessary, to: (i) represent novel characteristics (e.g., target 
disease or vector), (ii) represent an uncertain degree of risk to human 
health or the environment, or (iii) contain information determined to 
require further public review. The requirement for RAC review shall not 
be considered to preempt any other required review or approval of 
experiments with one or more human subjects. Relevant Institutional 
Biosafety Committee and Institutional Review Board reviews and 
approvals of the proposal should be completed before submission to NIH. 
Certain experiments involving deliberate transfer of recombinant DNA or 
DNA or RNA derived from recombinant DNA into one or more human subjects 
may qualify for the Accelerated Review process (see Section III-B-2). 
Certain categories of experiments involving the deliberate transfer of 
recombinant DNA or DNA or RNA derived from recombinant DNA into one or 
more human subjects and that are not covered by Section V-U, may be 
considered exempt from RAC and/or NIH/ORDA review and/or NIH Director 
approval and only require registration with NIH/ORDA (see Section III-
C-7).''

Section III-A is proposed to read:

    ``Section III-A. Experiments that Require Institutional Biosafety 
Committee Approval, RAC Review, and NIH Director Consideration Before 
Initiation (see Section IV-C-1-b-(1)).
    ``Section III-A-1. Major Actions
    ``Experiments described in Sections III-A-1-a and III-A-2 cannot be 
initiated without submission of relevant information on the proposed 
experiment to the Office of Recombinant DNA Activities, National 
Institutes of Health, Suite 323, 6006 Executive Boulevard, MSC 7052, 
Bethesda, Maryland 20892-7052, (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 for 
such experiments will be recommended by the RAC and, except as provided 
in Section III-A-2, will be 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 which may be obtained from the Office of Recombinant DNA 
Activities, National Institutes of Health, Suite 323, 6006 Executive 
Boulevard, MSC 7052, Bethesda, Maryland 20892-7052, (301) 496-9838.
    ``Section III-A-1. Deliberate transfer of a drug resistance trait 
to microorganisms that are not known to acquire the trait naturally 
(see Section V-B), if such acquisition could compromise the use of the 
drug to control disease agents in humans, veterinary medicine, or 
agriculture.
    ``Section III-A-2. Major Actions Involving Human Gene Transfer 
Experiments
    ``Experiments involving the deliberate transfer of recombinant DNA 
or DNA or RNA derived from recombinant DNA into one or more human 
subjects under Section I-A-1, and that are determined appropriate for 
RAC review and NIH Director consideration shall be considered as a 
Major Action, except that the NIH Director will make a recommendation 
to the FDA Commissioner who will make the final decision on the 
proposed experiment.''
    Sections III-B-2 and -3 is proposed to be deleted:

``Section III-B-2. Accelerated Review of Human Gene Transfer 
Experiments

    ``As determined by NIH/ORDA, in consultation with the RAC Chair and 
one or more RAC members, as necessary, certain categories of human gene 
transfer experiments may be considered as Minor Actions and qualify for 
Accelerated Review and approval (see Section IV-C-1-b-(2)-(a), Appendix 
M-III-A, and Appendix M-V). The RAC Chair will present a report of all 
NIH/ORDA approved human gene transfer protocols at the next regularly 
scheduled RAC meeting. If NIH/ORDA determines that an experiment does 
not qualify for the Accelerated Review process, the Principal 
Investigator must submit the proposal for full RAC review  8 
weeks prior to the next scheduled RAC meeting (See Section III-A-2).

``Section III-B-3. Minor Modifications to Human Gene Transfer 
Experiments

    ``A minor modification in a human gene transfer protocol is a 
modification that does not significantly alter the basic design of the 
protocol and that does not increase risk to human subjects or the 
environment. After approval has been obtained by the relevant 
Institutional Biosafety Committee and Institutional Review Board, NIH/
ORDA will consider the change in consultation with the RAC Chair and 
one or more RAC members, as necessary. Submit minor modifications to 
the Office of Recombinant DNA Activities, National Institutes of 
Health, Building 31, Room 4B11, Bethesda, Maryland 20892, (301) 496-
9838. The RAC Chair will provide a report on any such approvals at the 
next regularly scheduled RAC meeting.''
    Section III-C-7 (Experiments that Require Institutional Biosafety 
Committee Approval Before Initiation/Human Gene Transfer Experiments 
Not Covered by Sections III-A-2, III-B-2, III-B-3, and Not Considered 
Exempt Under Section V-U) is proposed to be deleted:
    ``Section III-C-7. Human Gene Transfer Experiments Not Covered by 
Sections III-A-2, III-B-2, III-B-3, and Not Considered Exempt Under 
Section V-U
    ``Certain experiments involving the transfer of recombinant DNA or 
DNA or RNA derived from recombinant DNA into one or more human subjects 
that are not covered by Sections III-A-2, III-B-2, III-B-3, and that 
are not considered exempt under Section V-U must be registered with 
NIH/ORDA. The relevant Institutional Biosafety Committee and 
Institutional Review Board must review and approve all experiments in 
this category prior to their initiation.''
    Section IV-B-4-e-(5) (Roles and Responsibilities/Responsibilities 
of the Principal Investigator During the Conduct of Research) is 
proposed to be inserted:
    ``Section IV-B-4-e-(5). Comply with semi-annual data reporting and 
adverse event reporting requirements for FDA-approved human gene 
transfer experiments (see Appendix M-I-C).''
    Section IV-C-1-b-(1) (Responsibilities of the National Institutes 
of Health/Specific Responsibilities) currently reads:
    ``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 to the NIH Guidelines shall be 
published in the Federal Register at least 15 days before the RAC 
meeting (not applicable for Expedited Review single patient human gene 
transfer experiments considered under Appendix M-VI). The NIH 
Director's decision, 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, 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) is proposed to read:
    ``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)-(d) currently reads:
    ``Section IV-C-1-b-(1)-(d). Permitting experiments specified by 
Section III-A;''
    Section IV-C-1-b-(1)-(d) is proposed to read:
    ``Section IV-C-1-b-(1)-(d). Permitting experiments specified by 
Section III-A-1;''
    Section IV-C-1-b-(1)-(e) is proposed to be included:
    ``Section IV-C-1-b-(1)-(e). Recommendations made by the NIH 
Director to the FDA Commissioner regarding RAC-reviewed human gene 
transfer experiments (see Appendix M-I-B);''
    Renumber remaining sections in IV-C-1-b-(1).
    Sections IV-C-1-b-(2)-a and -(b) (Responsibilities of the National 
Institutes of Health/Minor Actions) is proposed to be deleted:
    ``Section IV-C-1-b-(2)-(a). Reviewing and approving certain 
experiments involving the deliberate transfer of recombinant DNA or DNA 
or RNA derived from recombinant DNA into one or more human subjects 
that qualify for the Accelerated Review process (see Section III-B-2);
    ``Section IV-C-1-b-(2)-(b). Reviewing and approving minor changes 
to human gene transfer protocols under Section III-A-2 and III-B-2;''
    Renumber remaining sections in IV-C-1-b-(2).
    Section IV-C-3 (Responsibilities of the National Institutes of 
Health/Office of Recombinant DNA Activities) currently reads:
    ``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, including 
those authorities described in Section IV-C-1-b-(2). ORDA's 
responsibilities include, but are not limited to the following:
    ``Section IV-C-3-a. 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 
100 nanograms per kilogram body weight in organisms other 
than Escherichia coli K-12 (see Section III-B-1 and Appendices F-I and 
F-II);
    ``Section IV-C-3-b. Reviewing and approving certain experiments 
involving the deliberate transfer of recombinant DNA or DNA or RNA 
derived from recombinant DNA into one or more human subjects, in 
consultation with the RAC Chair and one or more RAC members, as 
necessary, that qualify for the Accelerated Review process (see Section 
III-B-2);
    ``Section IV-C-3-c. Reviewing and approving minor changes to human 
gene transfer protocols approved under Sections III-A-2 and III-B-2, in 
consultation with the RAC Chair and one or more RAC members, as 
necessary;
    ``Section IV-C-3-d. 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 will give its approval to the Institutional Biosafety 
Committee membership;
    ``Section IV-C-3-e. Publishing in the Federal Register:
    ``Section IV-C-3-e-(1). Announcements of RAC meetings and 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 at least 72 hours in advance of the meeting);
    ``Section IV-C-3-e-(2). Proposed Major Actions to the NIH 
Guidelines (see Section IV-C-1-b-(1)) at least 15 days prior to the RAC 
meeting;
    ``Section IV-C-3-f. Serve as the focal point for data management of 
NIH-approved human gene transfer protocols approved under Sections III-
A-2 and III-B-2 and registered with NIH/ORDA as required under Section 
III-C-7;
    ``Section IV-C-3-g. Serve as the executive secretary of the RAC; 
and
    ``Section IV-C-3-h. Maintain a list of Major and Minor Actions 
approved under Section III-A-2 and III-B-3 and a list of experiments 
registered with NIH/ORDA as described in Section III-C-7.''
    Section IV-C-3 is proposed to read:
    ``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. 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 
100 nanograms per kilogram body weight in organisms other 
than Escherichia coli K-12 (see Section III-B-1 and Appendices F-I and 
F-II);
    ``Section IV-C-3-b. Evaluating human gene transfer protocols 
(transmitted by the FDA) for the necessity for RAC review (see Appendix 
M-I-A).
    ``Section IV-C-3-c. 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 will give its approval to the Institutional Biosafety 
Committee membership;
    ``Section IV-C-3-d. Publishing in the Federal Register:
    ``Section IV-C-3-d-(1). Announcements of RAC meetings and 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 at least 72 hours in advance of the meeting);
    ``Section IV-C-3-d-(2). Proposed Major Actions (see Section IV-C-1-
b-(1)) at least 15 days prior to the RAC meeting;
    ``Section IV-C-3-e. Serve as the focal point for data management of 
FDA-approved human gene transfer protocols (see Appendix M-I-C-2);
    ``Section IV-C-3-f. Serve as the executive secretary of the RAC; 
and
    ``Section IV-C-3-g. Maintain a list of Major Actions recommended 
for approval by the NIH Director to the FDA Commissioner, under Section 
III-A-2.''
    Section V-U and V-V (Footnotes and References of Sections I-IV) is 
proposed to be deleted:
    ``Section V-U. 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 not covered under Sections III-A-2, III-B-2, or III-B-3. 
Such studies may be initiated without RAC review and NIH approval if 
approved by another Federal agency.
    ``Section V-V. For recombinant DNA experiments in which the intent 
is to modify stably the genome of cells of one or more human subjects 
(see Sections III-A-2, III-B-2, and III-B-3).''
    Renumber Section V-W to Section V-U.
    Appendix M is revised to read as follows:
    ``Appendix M. Human Gene Transfer Experiments
    ``Appendix M-I. Human Gene Transfer Experiments--Submission 
Requirements
    ``Appendix M-I-A. Human Gene Transfer Experiments--Submission to 
the FDA
    ``In the interest of maximizing the resources of both the NIH and 
the FDA and in simplifying the method and period for review, research 
protocols involving the deliberate transfer of recombinant DNA or DNA 
or RNA derived from recombinant DNA into human subjects will be 
submitted directly to the FDA and considered through a consolidated 
review process involving both the FDA and the NIH. Submission will be 
in the format required by the FDA and the same format will be used by 
the RAC when public review is deemed necessary. Upon receipt, FDA will 
transmit all human gene transfer protocols to the NIH/ORDA. FDA and 
NIH/ORDA will simultaneously evaluate the protocol for possible RAC 
review. Protocols shall be submitted to the Director of the Division of 
Cellular and Gene Therapies, Office of Therapeutics Research and 
Review, Center for Biologics Evaluation and Research, Food and Drug 
Administration, 1401 Rockville Pike, HFM-515, Rockville, Maryland 
20852-1448, (301) 496-4709.
    ``Appendix M-I-B. Human Gene Transfer Experiments Requiring RAC 
Review and NIH Director Consideration
    ``Appendix M-I-B-1. Factors that may contribute to the need for RAC 
review include: (i) novel approaches, (ii) new diseases, (iii) unique 
applications of gene transfer, and (iv) other issues that require 
further public review. Whenever possible, Principal Investigators will 
be notified within 15 working days following receipt of the submission 
whether RAC review will be required (RAC reviewed applications will be 
forwarded to RAC primary reviewers 8 weeks prior to the next quarterly 
RAC meeting).
    ``Appendix M-I-B-2. Written comments submitted by the RAC primary 
reviewers shall be submitted to NIH/ORDA4 weeks before the 
RAC meeting at which the protocol will be reviewed.
    ``Appendix M-I-B-3. Written responses (including critical data in 
response to the primary reviewers' comments) shall be submitted by the 
Principal Investigator to NIH/ORDA 2 weeks before the RAC 
meeting at which the protocol will be reviewed.
    ``Appendix M-I-B-4. Principal Investigators will limit their oral 
responses to the RAC only to those questions that are raised during the 
meeting. Oral presentations of previously submitted material and/or 
critical data that was not submitted 2 weeks prior to the 
RAC meeting are prohibited.
    ``Appendix M-I-B-5. The RAC primary reviewers' comments should 
include the following:
    ``Appendix M-I-B-5-a. Emphasize the issues related to gene marking, 
gene transfer, or gene therapy.
    ``Appendix M-I-B-5-b. Examine the scientific rationale, scientific 
context (relative to other proposals reviewed by the RAC), whether 
preliminary in vitro or in vivo data were obtained in appropriate 
models and are sufficient, and whether questions related to safety, 
efficacy, and social/ethical considerations have been resolved.
    ``Appendix M-I-B-5-c. RAC primary reviews should state whether the 
proposal is: (i) acceptable as written, (ii) expected to be acceptable 
with specific revisions or after satisfactory responses to specific 
questions raised on review, or (iii) unacceptable in its present form.
    ``Appendix M-I-B-6. Following public review, the RAC's 
recommendations regarding the proposal will be transmitted to the NIH 
Director for consideration.
    ``Appendix M-I-B-7. The NIH Director's recommendation regarding the 
proposal will be transmitted to the FDA Commissioner.
    ``Appendix M-I-C. Human Gene Transfer Experiments--NIH and FDA 
Reporting Requirements
    ``Appendix M-I-C-1. Adverse Event Reporting
    ``Principal 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, the 
NIH Office for Protection from Research Risks, Director of the Division 
of Cellular and Gene Therapies/FDA, and NIH/ORDA 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, 6006 Executive Boulevard, Suite 323, 
Bethesda, Maryland 20892-7052, (301) 496-9838.
     ``Appendix M-I-C-2. Semi-Annual Data Reporting
    ``Principal Investigators who have received approval from the FDA 
to initiate a human gene transfer protocol shall be required to comply 
with semi-annual data reporting requirements. Semi-annual Data 
Reporting forms will be forwarded by NIH/ORDA to the Principal 
Investigators. Data submitted in these reports will be evaluated by 
NIH/ORDA and reviewed by the RAC at its next regularly scheduled 
meeting.''
    OMB's ``Mandatory Information Requirements for Federal Assistance 
Program Announcements'' (45 FR 39592, June 11, 1980) 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 not to be cost effective or in the public 
interest to attempt to list these programs. Such a list would likely 
require several additional pages. In addition, NIH could not be certain 
that every Federal program would be included as many Federal agencies, 
as well as private organizations, both national and international, have 
elected to follow the NIH Guidelines. In lieu of the individual program 
listing, NIH invites readers to direct questions to the information 
address above about whether individual programs listed in the Catalog 
of Federal Domestic Assistance are affected.

    Dated: August 10, 1994.
John K. Uzzell,
Acting Deputy Director for Science Policy and Technology Transfer.
[FR Doc. 94-20826 Filed 8-22-94; 8:45 am]
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