[Federal Register Volume 64, Number 154 (Wednesday, August 11, 1999)]
[Notices]
[Pages 43884-43892]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-20646]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Office of Recombinant DNA Activities; Recombinant DNA Research: 
Proposed Actions Under the NIH Guidelines

AGENCY: National Institutes of Health (NIH), PHS, DHHS.

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

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SUMMARY: This notice sets forth proposed actions to the NIH Guidelines 
for Research Involving Recombinant DNA Molecules (NIH Guidelines) (59 
FR 34496, amended 59 FR 40170, 60 FR 20726, 61 FR 1482, 61 FR 10004, 62 
FR 4782, 62 FR 53335, 62 FR 56196, 62 FR 59032, 63 FR 8052, 63 FR 
26018, 64 FR 25361). These proposed actions will be considered by the 
Recombinant DNA Advisory Committee (RAC) during its September 2-3, 
1999, meeting. Public comments and any recommendations made by the RAC 
on these proposed actions will be considered by the NIH Director. 
Decisions regarding these proposed actions will be issued in accordance 
with the NIH Guidelines, as deemed appropriate by the NIH Director.

DATES: Interested parties are invited to submit comments concerning the 
proposed actions. Comments received by August 25, 1999, will be 
reproduced and distributed to the RAC for consideration at its 
September 2-3, 1999, meeting. After consideration of this proposal and 
comments by the RAC, the NIH Director will issue decisions in 
accordance with the NIH Guidelines.

PUBLIC COMMENTS: Interested parties are invited to comment on these 
proposed actions. Written comments should be submitted to: Debra Knorr, 
RAC Executive Secretary, 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. Written 
comments received by August 25, 1999, will be reproduced and 
distributed to the committee members for their consideration during the 
September 2-3, 1999, RAC meeting. All comments received in response to 
this notice will be considered by the RAC 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.

CONTACT INFORMATION: For further information regarding these proposed 
actions please contact: The Office of Recombinant DNA Activities 
(ORDA), National Institutes of Health, MSC 7010, 6000 Executive 
Boulevard, Suite 302, Bethesda, Maryland 20892-7010, Phone: 301-496-
9838, Facsimile: 301-496-9839. Additional information is also available 
at ORDA's web site:
http://www.nih.gov/od/orda.

SUPPLEMENTARY INFORMATION: The NIH has continually refined its 
oversight of human gene transfer research as the field has developed. 
In December 1996, the RAC review process was modified to consist of a 
rapid initial analysis of each human gene transfer experiment to 
determine which protocols present significant novel scientific, safety, 
ethical, legal and/or social issues and therefore warrant further RAC 
review and public discussion. In October 1997, the NIH Guidelines were 
amended to eliminate the requirement for approval by the RAC of 
individual protocols. The objectives of both of these actions were to 
streamline the review process and ensure that the roles and 
responsibilities of the NIH complement, rather than duplicate, those of 
other Federal agencies while preserving public confidence in the field.
    At present, human gene transfer protocols must be approved by the 
local Institutional Biosafety Committee (IBC) and the local 
Institutional Review Board (IRB) prior to submission to the NIH Office 
of Recombinant DNA Activities (ORDA) for RAC review. Within 15 days of 
receipt of the complete submission to ORDA, investigators are informed 
of the RAC's decision as to whether a given protocol is novel and 
therefore warrants further review and public discussion. To provide 
adequate time for additional analysis of the protocol and public notice 
of the upcoming RAC review and discussion, a protocol must be received 
by ORDA at least eight weeks prior to

[[Page 43885]]

a RAC meeting. Over the past two years, approximately 10% of protocols 
were determined by the RAC to warrant further analysis and public 
discussion because they presented novel safety and/or ethical issues. 
Examples of novel characteristics included new disease indications, 
vulnerable patient populations, and new classes of viral vectors.
    In an effort to optimize further and streamline this process, the 
NIH is proposing to modify further the requirements for protocol 
submission for RAC review. Specifically, clinical trial proposals may 
be submitted for RAC review before having been approved by the local 
IBC and IRB; however, clinical trial investigations may not be 
initiated until the RAC review process has been completed, IBC and IRB 
approvals have been obtained, and applicable regulatory 
authorization(s) have been obtained.
    The above changes will allow investigators to receive RAC input at 
an earlier stage of protocol development and allow multiple levels of 
protocol review to occur simultaneously. This proposed action is 
intended to reduce the delays in initiating clinical trials that may 
result from the multiple, sequential reviews currently conducted by the 
local institutional review bodies and federal government agencies. The 
NIH is interested in exploring strategies to expedite further the 
process of public discussion by the RAC of novel protocols.
    Other changes to the NIH Guidelines are presented in these Proposed 
Actions in order to clarify the process and requirements for protocol 
submission, review, and reporting. These Proposed Actions will preserve 
RAC's critical role in the review and public discussion of novel human 
gene transfer experiments in advance of clinical application.

I. Proposed Actions

    I-A. Proposed Amendments to Section I, Scope of the NIH Guidelines; 
Section III, Experiments Covered by the NIH Guidelines; Section IV, 
Roles and Responsibilities; 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); of the 
NIH Guidelines Regarding Human Gene Transfer Experiments.
    Section I-A-1-a, Scope of the NIH Guidelines, currently reads:
    ``Experiments involving the deliberate transfer of recombinant DNA 
or DNA or RNA derived from recombinant DNA into human subjects (human 
gene transfer) cannot be initiated without simultaneous submission to 
both NIH/ORDA and FDA of such information on the proposed experiment as 
is prescribed by those agencies. Submission of human gene transfer 
protocols to NIH shall be in the format described in Appendix M-I, 
Submission Requirements--Human Gene Transfer Experiments, of the NIH 
Guidelines. Submission to NIH shall be for registration purposes and 
will ensure continued public access to relevant human gene transfer 
information conducted in compliance with the NIH Guidelines. 
Investigational New Drug (IND) applications shall be submitted to FDA 
in the format described in 21 CFR, Chapter I, Subchapter D, Part 312, 
Subpart B, Section 23, IND Content and Format.
    ``If a determination is made that an experiment will undergo full 
RAC discussion, NIH/ORDA will immediately notify the Principal 
Investigator. RAC members may forward requests for additional 
information relevant to a specific protocol through NIH/ORDA to the 
Principal Investigator. In making a determination whether an experiment 
is novel and deserving of full RAC discussion, reviewers will examine 
the scientific rational, scientific content (relative to other 
proposals reviewed by RAC), whether the preliminary in vitro and in 
vivo safety data were obtained in appropriate models and are 
sufficient, and whether questions related to relevant social and 
ethical issues have been resolved. RAC's recommendation(s) on a 
specific human gene transfer experiment will be forwarded to the NIH 
Director, the Principal Investigator, the sponsoring institution, and 
other DHHS components, as appropriate.''
    Section I-A-1-a is proposed to be amended to read:
    ``Experiments involving the deliberate transfer of recombinant DNA 
or DNA or RNA derived from recombinant DNA into human subjects (human 
gene transfer) cannot be initiated without submission to NIH/ORDA and 
completion of the RAC review process. The RAC review process shall 
include an initial determination as to whether the submission has novel 
characteristics warranting full RAC review and public discussion. 
During the initial determination, RAC members shall notify NIH/ORDA of 
their recommendations regarding the necessity for full RAC review and 
public discussion. At any time during the review process, individual 
RAC members may contact NIH/ORDA to request additional information 
deemed important to the decision-making process. NIH/ORDA will 
immediately notify the Principal Investigator(s) of RAC requests for 
additional information. The initial RAC review shall be completed and 
NIH/ORDA will notify the Principal Investigator of the results of this 
review within 15 working days of receipt of a complete submission. RAC 
review at a public meeting of an individual human gene transfer 
experiment can be: (1) initiated by the NIH Director, or (2) 
recommended to NIH/ORDA by: (a) three or more RAC members, or (b) other 
Federal agencies. An individual human gene transfer experiment that is 
recommended for full RAC review should have novel characteristics 
deserving of public discussion. Following that review and discussion, 
RAC recommendations on a specific human gene transfer experiment shall 
be forwarded to the NIH Director, the Principal Investigator, the 
sponsoring institution, and/or other DHHS components, as appropriate. 
Submission of human gene transfer protocols to NIH shall be in the 
format described in Appendix M-I, Submission Requirements--Human Gene 
Transfer Experiments, of the NIH Guidelines.'' Investigational New Drug 
(IND) applications shall be submitted to FDA in the format described in 
21 CFR, Chapter I, Subchapter D, Part 312, Subpart B, Section 23, IND 
Content and Format.
    Section III, Experiments Covered by the NIH Guidelines, preamble, 
first paragraph, currently reads:
    ``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).''
    Section III, Experiments Covered by the NIH Guidelines, preamble, 
first paragraph, is proposed to be amended to read:
    ``This section describes six categories of experiments involving 
recombinant DNA: (i) those that require Institutional Biosafety 
Committee (IBC) approval,

[[Page 43886]]

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 completion of the RAC review process 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).''
    Section III-C, Experiments that Require Institutional Biosafety 
Committee and Institutional Review Board Approvals and NIH/ORDA 
Registration Before Initiation, currently reads:
    ``Section III-C, Experiments that Require Institutional Biosafety 
Committee and Institutional Review Board Approvals and NIH/ORDA 
Registration Before Initiation.
    ``Section III-C-1, Experiments Involving the Deliberate Transfer of 
Recombinant DNA or DNA or RNA Derived from Recombinant DNA into One or 
More Human Subjects.
    ``Research proposals involving the deliberate transfer of 
recombinant DNA, or DNA or RNA derived from recombinant DNA, into human 
subjects (human gene transfer) will be considered through a review 
process involving both NIH/ORDA and RAC. Investigators shall submit 
relevant information on the proposed human gene transfer experiments to 
NIH/ORDA. Submission of human gene transfer protocols to NIH will be in 
the format described in Appendix M-I, Submission Requirements--Human 
Gene Transfer Experiments. Submission to NIH/ORDA shall be for 
registration purposes and will ensure continued public access to 
relevant human gene transfer information in compliance with the NIH 
Guidelines. Investigational New Drug (IND) applications should be 
submitted to FDA in the format described in 21 CFR, Chapter I, 
Subchapter D, Part 312, Subpart B, Section 23, IND Content and Format.
    ``Institutional Biosafety Committee approval must be obtained from 
each institution at which recombinant DNA material will be administered 
to human subjects (as opposed to each institution involved in the 
production of vectors for human application and each institution at 
which there is ex vivo transduction of recombinant DNA material into 
target cells for human application).
    ``RAC prefers that submission to NIH/ORDA in accordance with 
Appendix M-I, Submission Requirements--Human Gene Transfer Experiments, 
contain no proprietary data or trade secrets, enabling all aspects of 
the review to be open to the public. Following receipt by NIH/ORDA, 
relevant information shall be entered into the NIH human gene transfer 
database for registration purposes. Summary information pertaining to 
the human gene transfer protocol will be forwarded to RAC members. NIH/
ORDA summary information shall include comparisons to previously 
registered protocols. Specific items of similarity to previous 
experiments include (but are not limited to): (i) Gene delivery 
vehicle, (ii) functional gene, (iii) marker gene, (iv) packaging cell 
(if applicable), (v) disease application, (vi) route of administration, 
and (vii) patient selection criteria.
    ``RAC members shall notify NIH/ORDA within 15 working days if the 
protocol has been determined to represent novel characteristics 
requiring further public discussion.
    ``Full RAC review of an individual human gene transfer experiment 
can be initiated by the NIH Director or recommended to the NIH Director 
by: (i) Three or more RAC members, or (ii) other Federal agencies. An 
individual human gene transfer experiment that is recommended for full 
RAC review should represent novel characteristics deserving of public 
discussion. RAC recommendations on a specific human gene transfer 
experiment shall be forwarded to the NIH Director, the Principal 
Investigator, the sponsoring institution, and other DHHS components, as 
appropriate.

    ``Note: For specific directives concerning the use of retroviral 
vectors for gene delivery, consult Appendix B-V-1, Murine Retroviral 
Vectors.''

    Section III-C-1 is proposed to be amended to read:
    ``Section III-C, Experiments that Require Institutional Biosafety 
Committee and Institutional Review Board Approvals and RAC Review 
Before Initiation.
    ``Section III-C-1. Experiments Involving the Deliberate Transfer of 
Recombinant DNA or DNA or RNA Derived from Recombinant DNA into One or 
More Human Subjects.
    ``Investigators shall not initiate any human gene transfer 
experiments until the RAC review process has been completed as 
described in the NIH Guidelines (see 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)); 
Institutional Biosafety Committee approvals have been obtained from 
each institution at which recombinant DNA material will be administered 
to human subjects (rather than from each site involved in manufacturing 
gene transfer products); Institutional Review Board approval(s) have 
been obtained; and applicable regulatory authorization(s) have been 
obtained.
    ``Submission to NIH/ORDA shall be in accordance with Appendix M-I, 
Submission, Review, and Reporting Requirements--Human Gene Transfer 
Experiments, and should contain no proprietary data or trade secrets, 
enabling all aspects of the review to be open to the public. Following 
receipt by NIH/ORDA, relevant information shall be entered into the NIH 
human gene transfer database. Summary information pertaining to the 
human gene transfer protocol will be forwarded to RAC members. NIH/ORDA 
summary information shall include comparisons to previously registered 
protocols. Specific items of similarity to previous experiments include 
(but are not limited to): (i) Gene delivery vehicle, (ii) functional 
gene, (iii) marker gene, (iv) packaging cell (if applicable), (v) 
disease application, (vi) route of administration, and (vii) patient 
selection criteria.
    ``The RAC review process shall include an initial determination as 
to whether the submission has novel characteristics warranting full RAC 
review and public discussion. During the initial determination, RAC 
members shall notify NIH/ORDA of their recommendations regarding the 
necessity for full RAC review and public discussion. At any time during 
the review process, individual RAC members may contact NIH/ORDA to 
request additional information deemed important to the decision-making 
process. NIH/ORDA will immediately notify the Principal Investigator(s) 
of RAC requests for additional information. The initial RAC review 
shall be completed and NIH/ORDA will notify the Principal Investigator 
of the results of this review within 15 working days of receipt of a 
complete submission. RAC review at a public meeting of an individual 
human gene transfer experiment can be: (1) Initiated by the NIH 
Director, or (2) recommended to NIH/ORDA by: (a) Three or more RAC 
members, or (b) other Federal agencies. An individual human gene 
transfer experiment that is recommended for full RAC review should have 
novel characteristics

[[Page 43887]]

deserving of public discussion. Following that review and discussion, 
RAC recommendations on a specific human gene transfer experiment shall 
be forwarded to the NIH Director, the Principal Investigator, the 
sponsoring institution, and/or other DHHS components, as appropriate.
    ``Investigational New Drug (IND) applications should be submitted 
to FDA in the format described in 21 CFR, Chapter I, Subchapter D, Part 
312, Subpart B, Section 23, IND Content and Format.

    ``Note: For specific directives concerning the use of retroviral 
vectors for gene delivery, consult Appendix B-V-1, Murine Retroviral 
Vectors.''

    ``Section IV-B-1-f, under Roles and Responsibilities, of the 
Institution currently reads in part:
    ``* * * and (ii) all aspects of Appendix M, Points to Consider in 
the Design and Submission of Protocols for the Transfer of Recombinant 
DNA Molecules into One or More Human Subjects (Points to Consider), 
have been appropriately addressed by the Principal Investigator prior 
to submission to NIH/ORDA. Institutional Biosafety Committee approval 
must be obtained from each institution at which recombinant DNA 
material will be administered to human subjects (as opposed to each 
institution involved in the production of vectors for human application 
and each institution at which there is ex vivo transduction of 
recombinant DNA material into target cells for human application).''
    ``Section IV-B-1-f is proposed to be amended to read in part:
    ``* * * 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 the initiation of any human gene transfer experiments. Institutional 
Biosafety Committee approval must be obtained from each institution at 
which recombinant DNA material will be administered to human subjects 
(rather than from each site involved in manufacturing gene transfer 
products).''
    ``Section IV-B-2-a-(1) under Roles and Responsibilities, 
Institutional Biosafety Committee (IBC), Membership and Procedures, 
currently reads in part:
    ``* * * and (ii) all aspects of Appendix M, Points to Consider in 
the Design and Submission of Protocols for the Transfer of Recombinant 
DNA Molecules into One or More Human Subjects (Points to Consider), 
have been appropriately addressed by the Principal Investigator prior 
to submission to NIH/ORDA. Institutional Biosafety Committee approval 
must be obtained from each institution at which recombinant DNA 
material will be administered to human subjects (as opposed to each 
institution involved in the production of vectors for human application 
and each institution at which there is ex vivo transduction of 
recombinant DNA material into target cells for human application).''
    ``Section IV-B-2-a-(1) is proposed to be amended to read:
    ``* * * 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 the initiation of any human gene transfer experiments. Institutional 
Biosafety Committee approval must be obtained from each institution at 
which recombinant DNA material will be administered to human subjects 
(rather than from each site involved in manufacturing gene transfer 
products).''
    ``Section IV-B-6 under Roles and Responsibilities, Institutional 
Biosafety Committee (IBC), Human Gene Therapy Expertise, currently 
reads in part:
    ``* * * and (ii) all aspects of Appendix M, Points to Consider in 
the Design and Submission of Protocols for the Transfer of Recombinant 
DNA Molecules into One or More Human Subjects (Points to Consider), 
have been appropriately addressed by the Principal Investigator prior 
to submission to NIH/ORDA.''
    ``Section IV-B-6 is proposed to be amended to read:
    ``* * * 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 the initiation of human gene transfer experiments.''
    ``Section IV-B-7-b-(6) under Roles and Responsibilities, Principal 
Investigator, currently reads:
    ``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 (Points to Consider), have 
been appropriately addressed prior to submission of human gene therapy 
experiments to NIH/ORDA.''
    ``Section IV-B-7-b-(6) is proposed to be amended to read:
    ``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 (Points to Consider), have 
been appropriately addressed prior to submission of human gene transfer 
experiments to NIH/ORDA, and provide a letter signed by the Principal 
Investigator(s) (PI) on institutional letterhead acknowledging that the 
documentation being submitted to NIH/ORDA complies with the 
requirements set forth in Appendix M, Points to Consider; that an exact 
duplicate of this submission has been sent to the Institutional 
Biosafety Committee; and that the proposed study will not be initiated 
until: (1) The RAC review process has been completed, (2) final 
approval(s) have been obtained from the IBC(s) at each clinical trial 
site(s), (3) final approval(s) have been obtained from the IRB(s), and 
(4) applicable regulatory authorization(s) have been obtained.''
    ``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), preamble, paragraphs 4 
through 7 are proposed to be deleted from the preamble and incorporated 
with modification into a reorganized Appendix M-I, Submission, Review, 
and Reporting Requirements--Human Gene Transfer Experiments.
    ``Research proposals involving the deliberate transfer of 
recombinant DNA, or DNA or RNA derived from recombinant DNA, into human 
subjects (human gene transfer) will be considered through a review 
process involving both NIH/ORDA and the RAC. Investigators shall submit 
their relevant information on the proposed human gene transfer 
experiments to NIH/ORDA. Submission of human gene transfer protocols to 
NIH will be in the format described in Appendix M-I, Submission 
Requirements--Human Gene Transfer Experiments. Submission to NIH shall 
be for registration purposes and will ensure continued public access to 
relevant human gene transfer information conducted in compliance with 
the NIH Guidelines. Investigational New Drug (IND) applications should 
be submitted to FDA in the format described in 21 CFR, Chapter I, 
Subchapter D, Part 312, Subpart B, Section 23, IND Content and Format.
    ``Institutional Biosafety Committee approval must be obtained from 
each institution at which recombinant DNA material will be administered 
to human subjects (as opposed to each institution

[[Page 43888]]

involved in the production of vectors for human application and each 
institution at which there is ex vivo transduction of recombinant DNA 
material into target cells for human application).
    ``Factors that may contribute to public discussion of a human gene 
transfer experiment by RAC include: (i) New vectors/new gene delivery 
systems, (ii) new diseases, (iii) unique applications of gene transfer, 
and (iv) other issues considered to require further public discussion. 
Among the experiments that may be considered exempt from RAC discussion 
are those determined not to represent possible risk to human health or 
the environment. Full RAC review of an individual human gene transfer 
experiment can be initiated by the NIH Director or recommended to the 
NIH Director by: (i) Three or more RAC members, or (ii) other Federal 
agencies. An individual human gene transfer experiment that is 
recommended for full RAC review should represent novel characteristics 
deserving of public discussion. If the Director, NIH, determines that 
an experiment will undergo full RAC 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 RAC), 
whether the preliminary in vitro and in vivo safety data were obtained 
in appropriate models and are sufficient, and whether questions related 
to relevant social and ethical issues have been resolved. RAC 
recommendations on a specific human gene transfer experiment shall be 
forwarded to the NIH Director, the Principal Investigator, the 
sponsoring institution, and other DHHS components, as appropriate. 
Relevant documentation will be included in the material for the RAC 
meeting at which the experiment is scheduled to be discussed. RAC 
meetings will be open to the public except where trade secrets and 
proprietary information are reviewed (see Section IV-D-5, Protection of 
Proprietary Data). RAC prefers that information provided in response to 
Appendix M contain no proprietary data or trade secrets, enabling all 
aspects of the review to be open to the public.
    ``Note: Any application submitted to NIH/ORDA shall not be 
designated as `confidential' in its entirety. In the event that a 
sponsor determines that specific responses to one or more of the items 
described in Appendix M should be considered as proprietary or trade 
secret, each item should be clearly identified as such. The cover 
letter (attached to the submitted material) shall: (1) Clearly indicate 
that select portions of the application contain information considered 
as proprietary or trade secret, (2) a brief explanation as to the 
reason that each of these items is determined proprietary or trade 
secret.''
    Appendix M, Points to Consider, Preamble, paragraphs 8 and 9, 
currently reads:
    ``Public discussion of human gene transfer experiments (and access 
to relevant information) shall serve to inform the public about the 
technical aspects of the proposals, meaning and significance of the 
research, and significant safety, social, and ethical implications of 
the research. RAC discussion is intended to ensure the safe and ethical 
conduct of gene therapy experiments and facilitate public understanding 
of this novel area of biomedical research.''
    ``In its evaluation of human gene transfer proposals, RAC will 
consider whether the design of such experiments offers adequate 
assurance that their consequences will not go beyond their purpose, 
which is the same as the traditional purpose of clinical investigation, 
namely, to protect the health and well being of human subjects being 
treated while at the same time gathering generalizable knowledge. Two 
possible undesirable consequences of the transfer of recombinant DNA 
would be unintentional: (i) Vertical transmission of genetic changes 
from an individual to his/her offspring, or (ii) horizontal 
transmission of viral infection to other persons with whom the 
individual comes in contact. Accordingly, Appendices M-I through M-V 
request information that will enable RAC and NIH/ORDA to assess the 
possibility that the proposed experiment(s) will inadvertently affect 
reproductive cells or lead to infection of other people (e.g., medical 
personnel or relatives).''
    Appendix M, Points to Consider, Preamble, paragraphs 8 and 9, are 
proposed to be amended to read:
    ``Research proposals involving the deliberate transfer of 
recombinant DNA, or DNA or RNA derived from recombinant DNA, into human 
subjects (human gene transfer) will be considered through a review 
process involving NIH/ORDA and the RAC (described below in Appendix M-
I). In its evaluation of human gene transfer proposals, RAC will 
consider whether the design of such experiments offers adequate 
assurance that their consequences will not go beyond their purpose, 
which is the same as the traditional purpose of clinical investigation, 
namely, to protect the health and well being of human subjects being 
treated while at the same time gathering generalizable knowledge. Two 
possible undesirable consequences of the transfer of recombinant DNA 
would be unintentional: (i) Vertical transmission of genetic changes 
from an individual to his/her offspring, or (ii) horizontal 
transmission of viral infection to other persons with whom the 
individual comes in contact. Accordingly, Appendices M-I through M-V 
request information that will enable RAC and NIH 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 its evaluation of human gene transfer proposals, RAC will also 
consider whether a proposed human gene transfer experiment presents 
novel characteristics warranting further review by the full RAC and 
public discussion (as discussed in Appendix M-I below). Public 
discussion of human gene transfer experiments (and access to relevant 
information) shall serve to inform the public about the technical 
aspects of the proposals, meaning and significance of the research, and 
significant safety, social, and ethical implications of the research. 
The process of RAC review and public discussion is intended to foster 
the safe and ethical conduct of human gene transfer experiments and 
facilitate public understanding of this novel area of biomedical 
research.''
    Appendix M-I, currently entitled Submission Requirements--Human 
Gene Transfer Experiments, currently reads:
    ``Appendix M-I, Submission Requirements--Human Gene Transfer 
Experiments.
    ``Investigators must submit the following material (see exemption 
in Appendix M-VIII-A, Footnotes of Appendix M) to 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. Investigators may submit this 
material electronically and can obtain specific instructions from the 
ORDA home page (http://www.nih.gov/od/orda) regarding electronic 
submission requirements. For all submissions, whether printed or 
electronic, ORDA will confirm receipt within three working days after 
receiving the submission. Investigators

[[Page 43889]]

should contact ORDA if they do not receive this confirmation.
    ``Proposals in printed form and/or in an electronic version shall 
be submitted to NIH/ORDA in the following order: (1) Scientific 
abstract; (2) non-technical abstract; (3) Responses to Appendix 
M-II through M-V, Description of the Proposal, Informed Consent, 
Privacy and Confidentiality, and Special Issues (the pertinent 
responses can be provided in the protocol or as an appendix to the 
protocol); (4) clinical protocol as approved by the local Institutional 
Biosafety Committee and Institutional Review Board; (5) Informed 
Consent document as approved by the Institutional Review Board (see 
Appendix M-III, Informed Consent); (6) appendices (including tables, 
figures, and manuscripts); (7) curricula vitae--no more than two pages 
for each key professional person in biographical sketch format; and (8) 
all submissions must include Institutional Biosafety Committee (IBC) 
and Institutional Review Board (IRB) approvals and their deliberations 
pertaining to your protocol. IBC approval must be obtained from each 
institution at which recombinant DNA material will be administered to 
human subjects (as opposed to each institution involved in the 
production of vectors for human application and each institution at 
which there is ex vivo transduction of recombinant DNA material into 
target cells for human application). Because these written IBC and IRB 
approvals require appropriate signatures, investigators cannot submit 
them electronically. Investigators should submit these signed approvals 
either by mail or by facsimile transmission.
    ``Investigational New Drug (IND) applications shall be submitted to 
the FDA in the format described in 21 CFR, Chapter I, Subchapter D, 
Part 312, Subpart B, Section 23, IND Content and Format. Submissions to 
the FDA should be sent to the Division of Congressional and Public 
Affairs, Document Control Center, HFM-99, Center for Biologics 
Evaluation and Research, 1401 Rockville Pike, Rockville, Maryland 
20852-1448.
    ``Note: NIH/ORDA will accept submission material at any time. 
However, if a protocol is submitted less than eight weeks before a 
scheduled RAC meeting and subsequently is recommended for public 
discussion by the full RAC, the public discussion of that protocol will 
be deferred until the next scheduled RAC meeting. This eight-week 
period is needed to ensure adequate time for review by the committee 
members.''
    Appendix M-VI, RAC Review--Human Gene Transfer Experiments, 
currently reads (and is proposed to be incorporated in Appendix M-I):
    ``Appendix M-VI, RAC Review--Human Gene Transfer Experiments.
    ``In order to maintain public access to information regarding human 
gene transfer protocols, NIH/ORDA will maintain the documentation 
described in Appendices M-I through M-V (including protocols that are 
not reviewed by RAC). RAC prefers that information provided in response 
to Appendix M, Points to Consider, contain no proprietary data or trade 
secrets, enabling all aspects of the discussion to be open to the 
public.
    ``Appendix M-VI-A, RAC Members' Written Comments.
    ``Following receipt by NIH/ORDA, summary information on each human 
gene transfer protocol will be forwarded to RAC members. Each RAC 
member shall notify NIH/ORDA within 15 working days regarding the 
necessity for full RAC discussion. Full RAC review of an individual 
human gene transfer experiment can be initiated by the NIH Director or 
recommended to the NIH Director by: (i) Three or more RAC members, or 
(ii) other Federal agencies. An individual human gene transfer 
experiment that is recommended for full RAC review should represent 
novel characteristics deserving of public discussion. If the Director, 
NIH, determines that an experiment will undergo full RAC discussion, 
NIH/ORDA will immediately notify the Principal Investigator. RAC 
members may forward individual requests for additional information 
relevant to a specific protocol through NIH/ORDA to the Principal 
Investigator. In making a determination whether an experiment is novel, 
and thus deserving of full RAC discussion, reviewers shall examine the 
scientific rationale, scientific context (relative to other proposals 
reviewed by RAC), whether the preliminary in vitro and in vivo safety 
data were obtained in appropriate models and are sufficient, and 
whether questions related to relevant social and ethical issues have 
been resolved. RAC recommendations on a specific human gene transfer 
experiment shall be forwarded to the NIH Director, the Principal 
Investigator, the sponsoring institution, and other DHHS components, as 
appropriate.''
    Appendix M-VII, Reporting Requirements--Human Gene Transfer 
Protocols currently reads (and is proposed to be incorporated in 
Appendix M-I):
    ``Appendix M-VII, Reporting Requirements--Human Gene Transfer 
Protocols.
    ``Appendix M-VII-A, Investigational New Drug Application Reporting.
    ``Upon receipt of notification of permission to proceed with an 
Investigational New Drug application for a human gene transfer 
protocol, the Principal Investigator(s) shall submit a written report 
that includes the following information: (1) How the investigator(s) 
responded to RAC's recommendations on the protocol (if applicable), and 
(2) any modifications to the protocol as required by FDA.
    ``Appendix M-VII-B, Annual Data Reporting and Gene Therapy 
Database.
    ``Investigators shall comply with annual data reporting 
requirements. Annual Data Report forms will be forwarded by NIH/ORDA to 
investigators. Data submitted in these reports will be evaluated by RAC 
and NIH/ORDA, and reviewed at a future RAC meeting. Information 
obtained through annual data reporting will be included in a human gene 
transfer database that will be administered by NIH/ORDA. The purpose of 
this human gene transfer database is to: (1) Maintain an institutional 
memory, (2) provide administrative details of protocol registration, 
(3) provide annual status reports of protocols, (4) facilitate risk 
assessment of individual applications of human gene transfer, and (5) 
enhance public awareness of relevant scientific, safety, social, and 
ethical issues.
    ``Appendix M-VII-C, Adverse Event Reporting.
    ``Investigators who have received approval from 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, is proposed to be 
renumbered to Appendix M-VII.
    Appendix M-I is proposed to be amended to read:
    ``Appendix M-I. Submission, Review, and Reporting Requirements--
Human Gene Transfer Experiments.
    ``Appendix M-I-A. Submission Requirements.
    ``Investigators must submit the following material (see exemption 
in Appendix M-VI-A, Footnotes of Appendix M) to the Office of

[[Page 43890]]

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. Investigators may submit this 
material electronically. ORDA will confirm receipt within three working 
days after receiving the submission. Investigators should contact ORDA 
if they do not receive this confirmation. Additional information 
regarding RAC activities is located on the ORDA home page (http://
www.nih.gov/od/orda).
    ``Proposals in printed form and/or in an electronic version shall 
be submitted to NIH/ORDA in the following order: (1) Cover letter on 
institutional letterhead that has been signed by the Principal 
Investigator(s) at the proposed clinical trial site(s). The cover 
letter must acknowledge that the documentation submitted to NIH/ORDA 
complies with the requirements set forth in Appendix M-I of the NIH 
Guidelines and that an exact duplicate of this documentation has been 
submitted to the IBC at the proposed clinical trial site(s). The cover 
letter must acknowledge that the proposed study will not be initiated 
until: (a) The RAC review process has been completed; (b) final 
approval(s) have been obtained from the IBC(s) at each clinical trial 
site(s); (c) final approval(s) have been obtained from the IRB(s); and 
(d) all applicable regulatory authorization(s) have been obtained. (2) 
Scientific abstract. (3) Non-technical abstract. (4) The proposed 
clinical protocol, including tables, figures, and relevant manuscripts. 
(5) Responses to Appendix M-II through M-V, Description of the 
Proposal, Informed Consent, Privacy and Confidentiality, and Special 
Issues. Responses to Appendices M-II through M-V may be provided either 
as an appendix to the clinical protocol or within the clinical 
protocol. If responses to Appendices M-II through M-V are included 
within the clinical protocol, each response must be accompanied by its 
corresponding reference to Appendix M-II through M-V. (6) Proposed 
Informed Consent document (see Appendix M-III, Informed Consent). (7) 
Curricula vitae of the principal investigator(s) at the proposed 
clinical trial site(s) (no more than two pages for each key 
professional person in biographical sketch format).
    ``Note: NIH/ORDA will accept submission material at any time. 
However, if a protocol is submitted less than eight weeks before a 
scheduled RAC meeting and subsequently is recommended for public 
discussion by the full RAC, the public discussion of that protocol will 
be deferred until the next scheduled RAC meeting. This eight-week 
period is needed to ensure adequate time for review by the committee 
members as well as public notice and comment.
    ``Investigational New Drug (IND) applications shall be submitted to 
the FDA in the format described in 21 CFR, Chapter I, Subchapter D, 
Part 312, Subpart B, Section 23, IND Content and Format. Submissions to 
the FDA should be sent to the Division of Congressional and Public 
Affairs, Document Control Center, HFM-99, Center for Biologics 
Evaluation and Research, 1401 Rockville Pike, Rockville, Maryland 
20852-1448.
    ``Appendix M-I-B. RAC Review Requirements.
    ``Appendix M-I-B-1. Initial RAC Review
    ``Human gene transfer experiments submitted to NIH/ORDA must meet 
the requirements set forth in Appendix M-I, Submission, Review, and 
Reporting Requirements--Human Gene Transfer Experiments, and should not 
contain proprietary data or trade secrets, enabling all aspects of the 
review to be open to the public. Investigators shall not initiate the 
proposed study prior to completion of the RAC review process.
    ``The RAC review process shall include an initial determination as 
to whether the submission has novel characteristics warranting full RAC 
review and public discussion. During the initial determination, RAC 
members shall notify NIH/ORDA of their recommendations regarding the 
necessity for full RAC review and public discussion. At any time during 
the review process, individual RAC members may contact NIH/ORDA to 
request additional information deemed important to the decision-making 
process. NIH/ORDA will immediately notify the Principal Investigator(s) 
of RAC requests for additional information. The initial RAC review 
shall be completed and NIH/ORDA will notify the Principal Investigator 
of the results of this review within 15 working days of receipt of a 
complete submission. RAC review at a public meeting of an individual 
human gene transfer experiment can be: (1) Initiated by the NIH 
Director, or (2) recommended to NIH/ORDA by: (a) Three or more RAC 
members, or (b) other Federal agencies. An individual human gene 
transfer experiment that is recommended for full RAC review should have 
novel characteristics deserving of public discussion. Following that 
review and discussion, RAC recommendations on a specific human gene 
transfer experiment shall be forwarded to the NIH Director, the 
Principal Investigator, the sponsoring institution, and/or other DHHS 
components, as appropriate.
    ``An individual human gene transfer experiment that is recommended 
for full RAC review should represent novel characteristics deserving of 
public discussion. In making a determination whether an experiment is 
novel, reviewers shall examine the scientific rationale, scientific 
context (relative to other proposals reviewed by RAC). Factors that may 
warrant 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.
    ``Appendix M-I-B-2. Full RAC Review and Public Discussion
    ``RAC meetings will be open to the public except where trade 
secrets and proprietary information are reviewed. Relevant 
documentation will be included in the material for the RAC meeting at 
which the experiment is scheduled to be discussed. Following RAC review 
and public discussion, RAC recommendations on a specific human gene 
transfer experiment shall be forwarded to the NIH Director, the 
Principal Investigator, the sponsoring institution, and/or other DHHS 
components, as appropriate.

    ``Note: To enable all aspects of the review process to be open to 
the public, information provided in response to Appendix M should not 
contain proprietary data or trade secrets and any application submitted 
to NIH/ORDA shall not be designated as `confidential' in its entirety. 
In the event that an investigator determines that specific responses to 
one or more of the items described in Appendix M should be considered 
as proprietary or trade secret, each item should be clearly identified 
as such. The cover letter (attached to the submitted material) shall: 
(1) Clearly indicate the information that is considered as proprietary 
or trade secret, (2) an explanation as to the reason that each of these 
items is determined proprietary or trade secret.
    ``Appendix M-I-C. Reporting Requirements.
    ``Appendix M-I-C-1. Initiation of the Clinical Investigation.
    ``The Principal Investigator(s) shall submit the following to NIH/
ORDA within 15 working days of initiation of a human gene transfer 
experiment: (1) A copy of the Informed Consent document approved by the 
IRB, (2) a copy of the protocol approved by the IBC and IRB, and (3) a 
copy of the final IBC

[[Page 43891]]

approval(s) at the clinical trial site(s); (4) a copy of the final IRB 
approval(s); (5) a brief written report that includes the following 
information: (a) how the investigator(s) responded to RAC's 
recommendations on the protocol (if applicable), and (b) any 
modifications to the protocol as required by FDA.
    ``Appendix M-I-C-2. Annual Reporting.
    ``Investigators shall comply with annual data reporting 
requirements. Annual data report forms will be forwarded by NIH/ORDA to 
investigators. Information submitted in these annual reports will be 
evaluated by NIH/ORDA and the RAC, and possibly considered at a future 
RAC meeting. Information obtained through the annual data reporting 
process will be included in the NIH/ORDA clinical trials database to: 
(1) Provide clinical trial information; (2) provide administrative 
details of protocol registration; (3) provide annual status reports of 
protocols; (4) facilitate risk assessment of individual applications of 
human gene transfer; and (5) enhance public awareness of relevant 
scientific, safety, social, and ethical issues.
    ``Appendix M-I-C-3. Serious Adverse Event Reporting.
    ``Investigators who have received authorization from 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-III-B currently reads in part:
    ``Investigators submitting human gene transfer proposals must 
include the Informed Consent document as approved by the local 
Institutional Review Board. A separate. * * *''
    Appendix M-III-B is proposed to read:
    ``Investigators submitting human gene transfer proposals must 
include a copy of the proposed Informed Consent document. A separate * 
* *''

II. 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 (Points to Consider), 
of the NIH Guidelines, Regarding Prenatal Gene Transfer Research

    II-A. Background Information.
    On July 31, 1998, Dr. W. French Anderson, University of Southern 
California, Los Angeles, California, and Dr. Esmail Zanjani, Veterans 
Hospital, Reno, Nevada, submitted the following two ``pre-protocols'' 
for in utero gene transfer entitled: (1) In Utero Gene Transfer for the 
Treatment of ADA-Deficient SCID and (2) In Utero Gene Transfer for the 
Treatment of a-Thalassemia. These two ``pre-protocols'' provided the 
catalyst for the RAC recommendation to the NIH Director made at its 
September 1998 meeting that a Gene Therapy Policy Conference (GTPC) 
should be held on the topic of prenatal gene transfer. On January 7-8, 
1999, NIH convened the GTPC entitled: Prenatal Gene Transfer: 
Scientific, Medical, and Ethical Issues. This meeting provided a public 
forum for the presentation and discussion of relevant scientific data 
and policy issues by members of the scientific, biomedical, ethical, 
and legal communities and the public. The anticipated outcome of the 
GTPC is two-fold: (1) Development of a policy paper that will highlight 
the conclusions of the working groups and conference participants, and 
(2) a comprehensive list of issues that should be further deliberated 
by the RAC at subsequent meetings. To achieve this goal, RAC members 
and ad hoc experts were assigned to one or more of the following 
working groups based on their individual areas of expertise: Working 
Group I--Preclinical Research Issues; Working Group II--Clinical 
Research Issues; and Working Group III--Ethical, Legal, and Societal 
Issues.
    At the March 11-12, 1999, RAC meeting, the RAC discussed three 
working group reports and issued a consensus statement that reads:
    The RAC continues to explore the issues raised by the potential of 
in utero gene transfer research. However, at present, the members 
unanimously agree that it is premature to undertake any human in utero 
gene transfer experiment.
    Rationale: Significant additional preclinical and clinical studies 
addressing vector transduction efficacy, biodistribution, and toxicity 
are required before a human in utero gene transfer protocol should 
proceed. In addition, a more thorough understanding of the ontogeny of 
human organ systems, such as the immune and nervous systems, is needed 
to better define the potential efficacy and risks of human in utero 
gene transfer. Prerequisites for considering any specific human in 
utero gene transfer procedure include an understanding of the 
pathophysiology of the candidate disease and a demonstrable advantage 
to the in utero approach. Once the above criteria are met, the 
committee would be willing to consider well rationalized in utero gene 
transfer protocols.''
    Appendix M, Points to Consider, Preamble, to include a new 
paragraph after paragraph 3, is proposed to read:
    The RAC continues to explore the issues raised by the potential of 
in utero gene transfer research. However, at present, the RAC concludes 
that it is premature to undertake any human in utero gene transfer 
experiment. Significant additional preclinical and clinical studies 
addressing vector transduction efficacy, biodistribution, and toxicity 
are required before a human in utero gene transfer protocol should 
proceed. In addition, a more thorough understanding of the ontogeny of 
human organ systems, such as the immune and nervous systems, is needed 
to better define the potential efficacy and risks of human in utero 
gene transfer. Prerequisites for considering any specific human in 
utero gene transfer procedure include an understanding of the 
pathophysiology of the candidate disease and a demonstrable advantage 
to the in utero approach. Once the above criteria are met, the RAC 
would be willing to consider well rationalized in utero gene transfer 
protocols.''

III. Discussion of Three Novel Human Gene Transfer Protocols

    During the September 2-3, 1999, RAC meeting, three novel human gene 
transfer protocols will be discussed: (1) Limb girdle muscular 
dystrophy using adeno-associated viral vector delivery of sarcoglycan 
genes, (2) hemophilia A using systemic retroviral vector delivery of a 
gene encoding factor VIII, and (3) gyrate atrophy using retroviral 
vector delivery of a gene encoding ornithine aminotransferase.

IV. Discussion on Expediting RAC Public Review Process of Human 
Gene Transfer Experiments

    The NIH is interested in exploring strategies to expedite further 
the process of public discussion by the RAC of novel protocols.
    OMB's ``Mandatory Information Requirements for Federal Assistance

[[Page 43892]]

Program Announcements'' (45 FR 39592) requires a statement concerning 
the official government programs contained in the Catalog of Federal 
Domestic Assistance. Normally NIH lists in its announcements the number 
and title of affected individual programs for the guidance of the 
public. Because the guidance in this notice covers not only virtually 
every NIH program but also essentially every Federal research program 
in which DNA recombinant molecule techniques could be used, it has been 
determined to be not cost effective or in the public interest to 
attempt to list these programs. Such a list would likely require 
several additional pages. In addition, NIH could not be certain that 
every Federal program would be included as many Federal agencies, as 
well as private organizations, both national and international, have 
elected to follow the NIH Guidelines. In lieu of the individual program 
listing, NIH invites readers to direct questions to the information 
address above about whether individual programs listed in the Catalog 
of Federal Domestic Assistance are affected.

    Dated: August 5, 1999.
Lana R. Skirboll,
Associate Director for Science Policy, National Institutes of Health.
[FR Doc. 99-20646 Filed 8-10-99; 8:45 am]
BILLING CODE 4140-01-P