[Federal Register Volume 62, Number 161 (Wednesday, August 20, 1997)]
[Notices]
[Pages 44387-44390]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-22030]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
Recombinant DNA Research: Proposed Actions Under the Guidelines
AGENCY: National Institutes of Health (NIH), PHS, DHHS.
ACTION: Notice of Proposed Actions Under the NIH Guidelines for
Research Involving Recombinant DNA Molecules (NIH Guidelines).
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SUMMARY: This notice sets forth proposed actions to be taken under the
NIH Guidelines for Research Involving Recombinant DNA Molecules (59 FR
34496, amended 59 FR 40170, 60 FR 20726, 61 FR 1482, 61 FR 10004, 62 FR
4782). Interested parties are invited to submit comments concerning
these proposals. These proposals will be considered by the Recombinant
DNA Advisory Committee (RAC) at its meeting on September 12, 1997.
After consideration of these proposals and comments by the RAC, the NIH
Director will issue decisions in accordance with the NIH Guidelines.
DATES: Interested parties are invited to submit comments concerning
this proposal. Comments received by September 5, 1997, will be
reproduced and distributed to the RAC for consideration at its
September 12, 1997, meeting. After consideration of this proposal and
comments by the RAC, the NIH Director will issue decisions in
accordance with the NIH Guidelines.
ADDRESSES: Written comments and recommendations should be submitted to
Debra Knorr, Office of Recombinant DNA Activities, National Institutes
of Health, MSC 7010, 6000 Executive Boulevard, Suite 302, Bethesda,
Maryland 20892-7010, Phone 301-496-9838, FAX 301-496-9839.
All comments received in response to this notice will be considered
and will be available for public inspection in the above office on
weekdays between the hours of 8:30 a.m. and 5:00 p.m.
FOR FURTHER INFORMATION CONTACT: Background documentation and
additional information can be obtained from the Office of Recombinant
DNA Activities, National Institutes of Health, MSC 7010, 6000 Executive
Boulevard, Suite 302, Bethesda, Maryland 20892-7010, Phone 301-496-
9838, FAX 301-496-9839. The Office of Recombinant DNA Activities web
site is located at Http://www.nih.gov/od/orda for further information
about the office.
SUPPLEMENTARY INFORMATION: The NIH will consider the following actions
under the NIH Guidelines for Research Involving Recombinant DNA
Molecules (NIH Guidelines):
A. Amendment to the Submission Requirements--Human Gene Transfer
Experiments Under Appendix M of the NIH Guidelines
During the June 12-13, 1997, RAC meeting, the following motions
were approved by the Committee:
(1) A motion was made to eliminate the point-by-point responses to
Appendix M-II, Description of the Proposal; however, the questions
raised in Appendix M-II must be addressed in the clinical protocol. The
motion passed by a vote of 8 in favor, 0 opposed, and 1 abstention.
(2) A motion was made that the RAC should not review any gene
transfer protocol until the investigator has provided ORDA with
evidence of protocol submission to the Institutional Biosafety
Committee (IBC). IBC notification is needed in order to avoid the
circumstances in which the RAC might review a protocol that has not
been submitted to the IBC. The motion passed by a vote of 8 in favor, 1
opposed, and no abstentions.
(3) A motion was made to delete prior IBC and Institutional Review
Board (IRB) approvals, responses to Appendix M-II through M-V, and
vector sequence diskettes from Appendix M-I, Submission Requirements--
Human Gene Transfer Experiments. The RAC accepted the submission
requirements as follows:
``Appendix M-I, Submission Requirements--Human Gene Transfer
Experiments''
``Investigators must submit the following material 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 (see exemption in Appendix M-IX-A, Footnotes of Appendix
M). Proposals will be submitted in the following order: (1) Scientific
abstract; (2) non-technical abstract; (3) protocol (including
discussion of issues in Appendix M-II through M-V); (4) Informed
Consent document prepared for IRB submission (see Appendix M-III,
Informed Consent); (5) letter stating that submission has been made to
the IBC; (6) appendices (including tables, figures, and manuscripts);
and (7) curricula vitae for each key professional person in
biographical sketch format.''
The motion passed by a vote of 7 in favor, 0 opposed, and 1
abstention.
B. Amendment to Institutional Biosafety Committee (IBC) Approvals of
Experiments Involving Transgenic Rodents Under Section III of the NIH
Guidelines
Section III-C-4, Experiments Involving Whole Animals, of the NIH
Guidelines stipulates that all transgenic animal experiments are
subject to IBC approval before initiation. In correspondence dated
April 22, 1997, Dr. George Gutman, an IBC representative of the
University of California, Irvine, California, inquired whether
experiments involving the production or use of transgenic mice under
Biosafety Level 1 containment could be initiated simultaneously with
IBC notification. Current requirements under the NIH Guidelines require
that IBC approval be obtained prior to initiation of such experiments.
The RAC discussed this issue during its June 1997 meeting, recommending
that this requirement be changed to initiation simultaneous with IBC
notification. The RAC agreed that the requirement of IBC approval prior
to initiation is unnecessary and recommended that the NIH Guidelines
should be amended such that: (1) The generation of transgenic rodents
at the Biosafety Level 1 containment (not all animals) can be initiated
simultaneous with IBC notification, and (2) the purchase and use of
transgenic rodents should be exempt from the NIH Guidelines.
A motion was made that these proposed changes to the NIH Guidelines
should be published in the Federal Register for consideration at the
September 12, 1997, RAC meeting. The proposed action would allow: (1)
The generation of transgenic rodents that require Biosafety Level 1
containment to be included under Section III-D, Experiments that
Require IBC Notice Simultaneous with Initiation; and (2) the purchase
and use of transgenic rodents should be exempt from the NIH Guidelines.
The motion passed by a vote of 9 in favor, 0 opposed, and no
abstentions.
C. The Dissociation of Simultaneous Submission of Responses to Appendix
M of the NIH Guidelines to NIH/ORDA and the Food and Drug
Administration (FDA)
In a letter dated November 20, 1996, Dr. Andra Miller, Food and
Drug Administration, requested that the NIH Guidelines should be
amended
[[Page 44388]]
regarding procedures for simultaneous submission of Appendix M material
to the RAC and FDA. In her November 20, 1996, letter, Dr. Miller
states:
``* * * To remove the requirement for submission of Appendix M to
the FDA. The FDA does not accept Appendix M in place of an IND
submission. The FDA is not proposed to be and need not be included in
the decision making process to identify protocols to undergo full RAC
review. Therefore, there is no reason for sponsors to submit Appendix M
materials to the FDA.''
During its December 9, 1996, and March 6-7, 1997, meetings, the RAC
discussed this issue. The consensus of the RAC was that the requirement
for submission of responses of Appendix M to the FDA should be removed,
since FDA does not accept responses to Appendix M in place of an
Investigational New Drug (IND) application. However, the RAC stated
that all human gene transfer protocols should include discussion of
issues raised in Appendix M-II through M-V of the NIH Guidelines in the
clinical protocols.
The NIH will consider the following proposed actions under the NIH
Guidelines:
A. Proposed Amendments to Section I-A. Purpose
Section I-A-1-a is proposed to be amended to read:
``Section I-A-1-a''
``Section I-A-1-a. Experiments involving the deliberate transfer of
recombinant DNA or DNA or RNA derived from recombinant DNA into human
subjects (human gene transfer) cannot be initiated without submission
to NIH/ORDA of such information on the proposed experiment as is
prescribed by this agency. Submission of human gene transfer protocols
to the NIH will 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, a determination
regarding the necessity for full RAC discussion, and to ensure
continued public access to relevant human gene transfer information
conducted in compliance with the NIH Guidelines.''
B. Proposed Amendments to Section III-A. Experiments That Require
Institutional Biosafety Committee Approval, RAC Review, and NIH
Director Approval Before Initiation (See Section IV-C-1-b-(1), Major
Actions)
Section III-A-2 is proposed to be amended to read:
``Section III-A-2. Human Gene Transfer Experiments''
``Investigators must submit their human gene transfer proposal to
the NIH in a single submission format. This format includes (but is not
limited to) the documentation described in Appendix M-I, Submission
Requirements--Human Gene Transfer Experiments. The NIH/ORDA in
consultation with the RAC, will evaluate the proposal regarding the
necessity for RAC review.
``Factors that may contribute to the necessity for RAC review
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 review are those determined by
the RAC and the NIH/ORDA not to represent possible risk to human health
or the environment (see Appendix M-VII, Categories of Human Gene
Transfer Experiments that May Be Exempt from RAC Review). Whenever
possible, investigators will be notified within 15 working days
following receipt of the submission whether RAC review will be
required. In the event that the RAC requires review of the submitted
proposal, all documentation described in Appendix M-I, Submission
Requirements--Human Gene Transfer Experiments, will be forwarded to the
RAC primary reviewers for evaluation. RAC meetings will be open to the
public except where trade secrets and proprietary information are
reviewed. The RAC prefers that information provided in the submission
documentation contain no proprietary data or trade secrets, enabling
all aspects of the review to be open to the public. The RAC will
recommend approval or disapproval of the reviewed proposal to the NIH
Director. In the event that a proposal is contingently approved by the
RAC, the RAC conditions must be satisfactorily met before the RAC's
recommendation for approval is submitted to the NIH Director. The NIH
Director's decision on the submitted proposal will be considered as a
Major Action by the NIH Director.
``Note: For specific directives concerning the use of retroviral
vectors for gene delivery, consult Appendix B-V-1, Murine Retroviral
Vectors.''
C. Proposed Amendments to Section III-C-4. Experiments Involving Whole
Animals
(Section III-C are experiments that require Institutional Biosafety
Committee approval before initiation.)
Section III-C-4-c is proposed to be amended to read:
``Section III-C-4-c. Exceptions under Section III-C-4.
``Section III-C-4-c-(1). Experiments involving the generation of
transgenic rodents that require BL1 containment are described under
Section III-D-3, Experiments Involving Transgenic Rodents.
``Section III-C-4-c-(2). The purchase and use of transgenic rodents
is exempt from the NIH Guidelines under Section III-E, Exempt
Experiments (see Appendix C-VI, The Purchase and Use of Transgenic
Rodents).''
D. Proposed Amendments to Section III-D. Experiments That Require
Institutional Biosafety Committee Notice Simultaneous With Initiation
Section III-D-3 is proposed to be amended to read:
``Section III-D-3. Experiments Involving Transgenic Rodent''
``This section covers experiments involving the generation of
rodents in which the animal's genome has been altered by stable
introduction of recombinant DNA, or DNA derived therefrom, into the
germ-line (transgenic rodents). Only experiments that require BL1
containment are covered under this section; experiments that require
BL2. BL3, or BL4 containment are covered under Section III-C-4,
Experiments Involving Whole Animals.''
E. Section IV-C-1-b-(1)-(e). Responsibilities of the NIH Director
Section IV-C-1-b-(1)-(e) is proposed to be deleted.
``Section IV-C-1-b-(1)-(e). Recommendations made by the NIH
Director to the FDA Commissioner regarding RAC reviewed human gene
transfer experiments (see Appendix M-III-E, RAC Recommendations to the
NIH Director;''
(The rest of Section IV-C-b-(1) will be renumbered.)
F. Proposed Amendments to Appendix C, Exemptions Under Section III-
E-6
A new section, Appendix C-VI, is proposed to read:
[[Page 44389]]
``Appendix C-VI. The Purchase and Use of Transgenic Rodents''
``The purchase and use of transgenic rodents for experiments that
require BL1 containment are exempt from the NIH Guidelines.''
(The old Appendix C-VI, Footnotes and References of Appendix C,
will be renumbered to Appendix C-VII through Appendix C-VII-E.)
G. Proposed Amendments to Appendix M, The Points to Consider in the
Design and Submission of Protocols for the Transfer of Recombinant DNA
Molecules Into the Genome of One or More Human Subjects (Points to
Consider)
The preamble of Appendix M is proposed to be amended to read:
``Appendix M applies to research conducted at or sponsored by an
institution that receives any support for recombinant DNA research from
the NIH. Researchers not covered by the NIH Guidelines are encouraged
to use Appendix M.
``The acceptability of human somatic cell gene therapy has been
addressed in several public documents as well as in numerous academic
studies. In November 1982, the President's Commission for the Study of
Ethical Problems in Medicine and Biomedical and Behavioral Research
published a report, Splicing Life, which resulted from a two-year
process of public deliberation and hearings. Upon release of that
report, a U.S. House of Representatives subcommittee held three days of
public hearings with witnesses from a wide range of fields from the
biomedical and social sciences to theology, philosophy, and law. In
December 1984, the Office of Technology Assessment released a
background paper, Human Gene Therapy, which concluded: civic,
religious, scientific, and medical groups have all accepted, in
principle, the appropriateness of gene therapy of somatic cells in
humans for specific genetic diseases. Somatic cell gene therapy is seen
as an extension of present methods of therapy that might be preferable
to other technologies. In light of this public support, the Recombinant
DNA Advisory Committee (RAC) is prepared to consider proposals for
somatic cell gene transfer.
``The RAC will not at present entertain proposals for germ line
alterations but will consider proposals involving somatic cell gene
transfer. The purpose of somatic cell gene therapy is to treat an
individual patient, e.g., by inserting a properly functioning gene into
the subject's somatic cells. Germ line alteration involves a specific
attempt to introduce genetic changes into the germ (reproductive) cells
of an individual, with the aim of changing the set of genes passed on
to the individual's offspring.
``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 the NIH/ORDA and the RAC. Public review of human
gene transfer protocols will serve to inform the public about the
technical aspects of the proposals as well as the meaning and
significance of the research. Investigators must submit human gene
transfer protocols to the NIH/ORDA in the format described in Appendix
M-I. Submission Requirements--Human Gene Transfer Experiments. NIH/ORDA
and the RAC will evaluate the proposal regarding the necessity for RAC
review.
``Factors that may contribute to the necessity for RAC review
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 review are those determined by
the RAC and the NIH/ORDA not to represent possible risk to human health
or the environment (see Appendix M-VII, Categories of Human Gene
Transfer Experiments that May Be Exempt from RAC Review). Whenever
possible, investigators will be notified within 15 working days
following receipt of the submission whether RAC review will be
required. In the event that NIH/ORDA and the RAC require RAC review of
the submitted proposal, the documentation described in Appendix M-I.
Submission Requirements--Human Gene Transfer Experiments, will be
forwarded to the RAC primary reviewers for evaluation. RAC meetings
will be open to the public except where trade secrets and proprietary
information are reviewed. The RAC prefers that information provided in
the submission documentation contains no proprietary data or trade
secrets, enabling all aspects of the review to be open to the public.
The RAC will recommend approval or disapproval of the reviewed proposal
to the NIH Director. In the event that a proposal is contingently
approved by the RAC, the RAC conditions must be satisfactorily met
before the RAC's recommendation for approval is submitted to the NIH
Director. The NIH Director's decision on the submitted proposal will be
considered as a Major Action by the NIH Director.
``Public review of human gene transfer proposals will serve to
inform the public about the technical aspects of the proposals as well
as the meaning and significance of the research.
``In its evaluation of human gene transfer proposals, the RAC and
NIH/ORDA will consider whether the design of such experiments offers
adequate assurance that their consequences will not go beyond their
purpose, which is the same as the traditional purpose of clinical
investigation, namely, to protect the health and well being of human
subjects being treated while at the same time gathering generalizable
knowledge. Two possible undesirable consequences of the transfer of
recombinant DNA would be unintentional: (i) Vertical transmission of
genetic changes from an individual to his/her offspring, or (ii)
horizontal transmission of viral infection to other persons with whom
the individual comes in contact. Accordingly, Appendices M-I through M-
V requests information that will enable the RAC 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).
``In recognition of the social concern that surrounds the subject
of human gene transfer, the RAC and NIH/ORDA will cooperate with other
groups in assessing the possible long-term consequences of the proposal
and related laboratory and animal experiments in order to define
appropriate human applications of this emerging technology.
``Appendix M will be considered for revisions as experience in
evaluating proposals accumulates and as new scientific developments
occur. This review will be carried out periodically as needed.''
Appendix M-I is proposed to be amended to read:
``Appendix M-I. Submission Requirements--Human Gene Transfer
Proposals''
``Investigators must submit the following material 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 (see exemption in Appendix M-IX-A, Footnotes of Appendix
M). Proposals will be submitted in the following order: (1) Scientific
abstract; (2) non-technical abstract; (3) clinical protocol (including
discussion of all issues raised in Appendix M-II through
[[Page 44390]]
M-V); (4) Informed Consent document prepared for IRB submission (see
Appendix M-III, Informed Consent); (5) letter stating that submission
has been made to the IBC; (6) appendices (including tables, figures,
and manuscripts); and (7) curricula vitae for each key professional
person in biographical sketch format.
``Note: Final IBC and IRB approvals should be submitted to NIH/
ORDA upon receipt of the following: (1) NIH notification of
exemption from full RAC discussion, or (2) subsequent to full RAC
discussion (if applicable). Human gene transfer protocols shall not
be initiated prior to submission of final IBC and IRB approvals to
the NIH/ORDA.''
Appendix M-VI-A is proposed to be amended to read:
``Appendix M-VI-A. Categories of Human Gene Transfer Experiments That
Require RAC Review''
``Factors that may contribute to the necessity for RAC review
include, but are not limited to: (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.
Whenever possible, investigators will be notified within 15 working
days following receipt of the submission whether RAC review will be
required. In the event that RAC review is deemed necessary by the NIH
and the RAC, the proposal will be forwarded to the RAC primary
reviewers for evaluation. In order to maintain public access to
information regarding human gene transfer protocols, NIH/ORDA will
maintain the documentation described in Appendix M-I (including
protocols that are not reviewed by the RAC).''
Appendix M-VI-B is proposed to be amended to read:
``Appendix M-VI-B. RAC Primary Reviewers' Written Comments''
``In the event that NIH/ORDA or the RAC recommends RAC review of
the submitted proposal, the documentation described in Appendix M-I
will be forwarded to the RAC primary reviewers for evaluation.''
Appendix M-VI-E is proposed to be amended to read:
``Appendix M-VI-E. RAC Recommendations to the NIH Director''
``The RAC will recommend approval or disapproval of the reviewed
proposal to the NIH Director. In the event that a proposal is
contingently approved by the RAC, the RAC prefers that the conditions
be satisfactorily met before the RAC's recommendation for approval is
submitted to the NIH Director. The NIH Director's decision on the
submitted proposal will be considered as a Major Action by the NIH
Director.''
Appendix M-VII is proposed to be amended to read:
``Appendix M-VII. Categories of Human Gene Transfer Experiments That
May Be Exempt from RAC Review''
``A proposal submitted under one of the following categories may be
considered exempt from RAC review unless otherwise determined by NIH/
ORDA and the RAC on a case-by-case basis (see Appendix M-VI-A,
Categories of Human Gene Transfer Experiments that Require RAC Review).
Note: For proposals that are exempt from RAC review, the
documentation described in Appendix M-I will be maintained by NIH/
ORDA for compliance with annual data reporting and adverse event
reporting requirements (see Appendix M-VIII, Reporting
Requirements--Human Gene Transfer Protocols). Any subsequent
modifications to proposals that were not reviewed by the RAC must be
submitted to NIH/ORDA in order to facilitate data reporting
requirements.''
OMB's ``Mandatory Information Requirements for Federal Assistance
Program Announcements'' (45 FR 39592) requires a statement concerning
the official government programs contained in the Catalog of Federal
Domestic Assistance. Normally NIH lists in its announcements the number
and title of affected individual programs for the guidance of the
public. Because the guidance in this notice covers not only virtually
every NIH program but also essentially every Federal research program
in which DNA recombinant molecule techniques could be used, it has been
determined to be not cost effective or in the public interest to
attempt to list these programs. Such a list would likely require
several additional pages. In addition, NIH could not be certain that
every Federal program would be included as many Federal agencies, as
well as private organizations, both national and international, have
elected to follow the NIH Guidelines. In lieu of the individual program
listing, NIH invites readers to direct questions to the information
address above about whether individual programs listed in the Catalog
of Federal Domestic Assistance are affected.
Dated: August 4, 1997.
Lana R. Skirboll,
Associate Director for Science Policy, National Institutes of Health.
[FR Doc. 97-22030 Filed 8-19-97; 8:45 am]
BILLING CODE 4140-01-P
