[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