[Federal Register Volume 60, Number 220 (Wednesday, November 15, 1995)]
[Notices]
[Pages 57528-57531]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-28245]
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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 (59 FR 34496, amended 59
FR 40170, amended 60 FR 20726).
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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, amended 60 FR 20726). Interested parties
are invited to submit comments concerning these proposals. The
proposals will be considered by the Recombinant DNA Advisory Committee
at its meeting on December 4-5, 1995. After consideration of these
proposals and comments by the Recombinant DNA Advisory Committee, the
Director of the National Institutes of Health will issue decisions in
accordance with the NIH Guidelines.
DATES: Comments received by November 27, 1995, will be reproduced and
distributed to the Recombinant DNA Advisory Committee for consideration
at its December 4-5, 1995, meeting.
ADDRESSES: Written comments and recommendations should be submitted to
Dr. Nelson A. Wivel, Director, Office of Recombinant DNA Activities,
National Institutes of Health, MSC 7010, 6000 Executive Boulevard,
Suite 302, Bethesda, Maryland 20892-7010, or sent by FAX to 301-496-
9839.
All comments received in timely response to this notice will be
considered and will be available for public inspection in the above
office on weekdays between the hours of 8:30 a.m. and 5 p.m.
FOR FURTHER INFORMATION CONTACT:
Background documentation and additional information can be obtained
from the Office of Recombinant DNA Activities, National Institutes of
Health, MSC 7010, 6000 Executive Boulevard, Suite 302, Bethesda,
Maryland 20892-7010, Phone 301-496-9838, FAX to 301-496-9839.
SUPPLEMENTARY INFORMATION: The NIH will consider the following actions
under the NIH Guidelines for Research Involving Recombinant DNA
Molecules:
I. Addition to Appendix D of the NIH Guidelines Regarding a Human Gene
Transfer Protocol/Drs. Black and Fakhrai
In a letter dated January 6, 1995, Drs. Keith L. Black and Habib
Fakhrai of the University of California, Los Angeles, California,
submitted a human gene transfer protocol entitled: A Study of the
Safety of Injecting Cancer Patients with Genetically Modified Tumor
Cells; Injection of Glioblastoma Patients with Irradiated Autologous
Glioma Tumor Cells Genetically Modified to Express a TGF-2
Antisense mRNA Alone or in Combination with Increasing Doses of Tumor
Cells Which Have Been Genetically Modified to Secrete Interleukin-2
(IL-2): A Phase I Study to the Recombinant DNA Advisory Committee for
formal review and approval during the March 6-7, 1995, meeting.
During the March 6-7, 1995, Recombinant DNA Advisory Committee
meeting, a motion was made and seconded to defer the protocol submitted
by Drs. Black and Fakhrai based on the lack of sufficient preclinical
data. The investigators and the primary reviewers were to agree on a
mutually acceptable experimental design to address the scientific
questions posed by the Recombinant DNA Advisory Committee members. Once
these studies have been conducted, the investigators are required to
submit this data to the full Recombinant DNA Advisory Committee for
review and approval. The protocol was deferred by a vote of 16 in
favor, 0 opposed, and no abstentions.
On August 9, 1995, Dr. Fakhrai submitted an experimental design
that was reviewed by a Recombinant DNA Advisory Committee primary
reviewer.
[[Page 57529]]
The experimental design was found to be mutually acceptable.
On October 10, 1995, Dr. Fakhrai submitted a revised protocol
entitled: A Phase I Study of the Safety of Injecting Malignant Glioma
Patients with Irradiated TGF-2 Antisense Gene Modified
Autologous Tumor Cells to the Recombinant DNA Advisory Committee for
formal review and approval during the December 4-5, 1995, meeting.
II. Addition to Appendix D of the NIH Guidelines Regarding a Human Gene
Transfer Protocol/Drs. Hortobagyi, Lopez-Berestein, Hung
In a letter dated July 11, 1995, Drs. Gabriel Hortobagyi, Gabriel
Lopez-Berestein, and Mien-Chie Hung of the University of Texas, MD
Anderson Cancer Center, Houston, Texas, submitted a human gene transfer
protocol entitled: Phase I Study of E1A Gener Therapy for Patients with
Metastatic Breast or Ovarian Cancer that Overexpress HER-2/neu to the
Recombinant DNA Advisory Committee for formal review and approval
during the September 11-12, 1995, meeting.
During the September 11-12, 1995, Recombinant DNA Advisory
Committee meeting, a motion was made and seconded to disapprove the
protocol submitted by Drs. Hortobagyi. The motion to disapprove the
protocol (absence of relevant scientific data supporting the proposed
study) failed by a vote of 4 in favor, 9 opposed, and 2 abstentions.
Another motion was made and seconded to accept the protocol contingent
on review and approval by a subcommittee of the Recombinant DNA
Advisory Committee of a revised experimental design and additional
preclinical data derived from additional experiments. A friendly
amendment was made and accepted that the protocol be deferred pending
review and approval by the full Recombinant DNA Advisory Committee of
the revised experimental design and subsequent data derived from these
experiments. The amended motion to defer was contingent on full
Recombinant DNA Advisory Committee review of: (1) a revised
experimental design (particularly relating to specific anatomical
sites), (2) quantitative assessment of ex vivo transduction rate, (3)
data demonstrating the level of sensitivity of in vitro assays, and (4)
a revised Informed Consent document. The motion passed by a vote of 13
in favor, 1 opposed, and 1 abstention.
On October 9, 1995, Dr. Hortobagyi submitted a revised protocol to
the Recombinant DNA Advisory Committee for formal review and approval
during the December 4-5, meeting.
III. Addition to Appendix D of the NIH Guidelines Regarding a Human
Gene Transfer Protocol/Dr. Batshaw
In a letter dated October 9, 1995, Dr. Mark Batshaw, Institute for
Human Gene Therapy, University of Pennsylvania Medical Center,
Philadelphia, Pennsylvania, submitted a human gene transfer protocol
entitled: A Phase I Study of Adenoviral Vector Mediated Gene Transfer
to Liver in Adults with Partial Ornithine Transcarbamylase Deficiency
to the Recombinant DNA Advisory Committee for formal review and
approval during the December 4-5, meeting.
IV. Proposed Amendments to the NIH Guidelines Regarding Semiannual/
Annual Data Reporting
In a letter dated June 16, 1995, Dr. Gary Nabel outlined the
redundant and onerous reporting requirements of multiple Federal
agencies and local institutions. At a minimum, amending the NIH
Guidelines to accommodate annual data reporting requirements rather
than semiannual reporting requirements should greatly reduce the burden
currently placed on principal investigators of human gene transfer
protocols.
In a letter dated August 16, Ms. Debra Knorr, NIH Office of
Recombinant DNA Activities, submitted to the Recombinant DNA Advisory
Committee the intent to submit proposed amendments to the NIH
Guidelines regarding annual data reporting. During the September 12,
1995, Recombinant DNA Advisory Committee meeting, Dr. LeRoy Walters,
Chair, invited members of the Recombinant DNA Advisory Committee and
the public to provide comments on the proposed amendments. No comments
on the proposed amendments have been submitted to the Office of
Recombinant DNA Activities to date.
The proposed amendments read as follows:
``Section IV-B-4-e-(5) currently reads:
``Section IV-B-4-e-(5). Comply with semiannual data reporting and
adverse event reporting requirements for NIH and FDA-approved human
gene transfer experiments (see Appendix M-VIII, Reporting
Requirements--Human Gene Transfer Protocols).''
Section IV-B-4-e-(5) is amended to read:
``Section IV-B-4-e-(5). Comply with annual data reporting and
adverse event reporting requirements for NIH and FDA-approved human
gene transfer experiments (see Appendix M-VIII, Reporting
Requirements--Human Gene Transfer Protocols).''
Section IV-C-3-c currently reads:
``Section IV-C-3-c. Administering the semiannual data reporting
requirements (and subsequent review) for human gene transfer
experiments, including experiments that are reviewed solely by the FDA
(see Appendix M-VI, Categories of Human Gene Transfer Experiments that
May Be Exempt from RAC Review);''
Section IV-C-3-c is amended to read.
``Section IV-C-3-c. Administering the annual data reporting
requirements (and subsequent review) for human gene transfer
experiments, including experiments that are reviewed solely by the FDA
(see Appendix M-VI, Categories of Human Gene Transfer Experiments that
May Be Exempt from RAC Review);''
Appendix M-VII currently reads:
``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 FDA on a case-by-case basis (see Appendix M-VI-A,
Categories of Human Gene Transfer Experiments that Require RAC Review).
``Note: In the event that the submitted proposal is determined to
be exempt from RAC review, the documentation described in Appendices M-
I through M-V will be maintained by NIH/ORDA for compliance with
semiannual 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.''
Appendix M-VII is 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 FDA on a case-by-case basis (see Appendix M-VI-A,
Categories of Human Gene Transfer Experiments that Require RAC Review).
``Note: In the event that the submitted proposal is determined to
be exempt from RAC Review, the documentation described in Appendices M-
I through M-V 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
[[Page 57530]]
reviewed by the RAC must be submitted to NIH/ORDA in order to
facilitate data reporting requirements.''
Appendix M-VIII-A currently reads:
``Appendix M-VIII-A. Semiannual Data Reporting
``Investigators who have received approval from the FDA to initiate
a human gene transfer protocol (whether or not it has been reviewed by
the RAC) shall be required to comply with the semiannual data reporting
requirements. Semiannual Data Report forms will be forwarded by NIH/
ORDA to investigators. Data submitted in these reports will be
evaluated by the RAC, NIH/ORDA, and the FDA and reviewed by the RAC at
its next regularly scheduled meeting.''
Appendix M-VIII-A is amended to read:
``Appendix M-VIII-A. Annual Data Reporting
``Investigators who have received approval from the FDA to initiate
a human gene transfer protocol (whether or not it has been reviewed by
the RAC) shall be required to comply with the annual data reporting
requirements. Annual Data Report forms will be forwarded by NIH/ORDA to
investigators. Data submitted in these reports will be evaluated by the
RAC, NIH/ORDA, and the FDA and reviewed by the RAC at its next
regularly scheduled meeting.''
V. Presentation on Ethical Issues Associated With In Utero Gene
Therapy/Dr. Fletcher
Dr. John C. Fletcher, Kornfeld Professor and Director of the Center
for Biomedical Ethics, University of Virginia, Charlottesville,
Virginia, will be giving a presentation concerning the ethical issues
associated with the proposed use of in utero gene therapy.
VI. Proposed Discussion Regarding NIH Purview of Human Gene Transfer
Experiments
In a letter dated November 2, 1995, Ms. Debra Knorr proposed a
discussion regarding NIH purview of human gene transfer experiments for
the December 4-5, 1995, Recombinant DNA Advisory Committee meeting.
Analysis of human gene transfer oversight will be discussed in the
context of the following:
1. The September 8, 1995, recommendations of the NIH RAC Ad Hoc
Review Committee--Inder Verma, Ph.D., Chair;
2. Data Management--maintaining public accountability relevant to
human gene transfer experiments; and
3. Factors to consider in implementation of streamlined review
procedures.
The NIH Director defined a number of issues relevant to the
development of the field of human gene therapy, including the quality
of science, the fiscal resource being devoted to the field, the role of
industry in the development of clinical trials, and the disparity
between scientific accomplishments and the public perceptions of human
gene therapy. As a result, Dr. Varmus established two separate ad hoc
advisory committees to evaluate the field of human gene therapy
research.
The Ad Hoc RAC Review Committee, chaired by Inder Verma, Ph.D., was
charged with providing a comprehensive assessment of past and current
RAC activities in an effort to develop recommendations regarding the
future role of the RAC relevant to human gene transfer experiments. The
September 8, 1995, Ad Hoc RAC Review Committee recommendations are
included as follows:
``Dr. Harold Varmus, Director, National Institutes of Health,
appointed an ad hoc review committee to review the activities of the
NIH Recombinant DNA Advisory Committee (RAC). The Director asked the
committee to provide recommendations about the changing role of the
RAC, the ways it may need to modify its operations, and how it should
function to coordinate and facilitate productive gene therapy research.
``The committee finds that:
``1. Gene therapy represents a special development in medical
research because of its potential for modification of the human genome
and for the creation and dissemination of novel transmissible
pathogenic vectors. In addition, there is the possibility of
controversial extensions of this work, such as modification of the
germline or the use of gene transfer for enhancement purposes. Thus
gene therapy differs in major ways from other clinical technologies in
use or under development and is, therefore, deserving of continued
public scrutiny.
``2. The RAC has served--and continues to serve--several important
purposes for the scientific community, patients, and the general
public. In particular, by focusing its attention on the emerging field
of gene therapy research and helping to set appropriate scientific
safety and informed consent guidelines for investigators. As a public
forum of discussion, RAC has provided an enormous service not only to
the general public, researchers at academic and similar institutions
and within the biotechnology industry, but also to officials at the
Food and Drug Administration (FDA). In addition, RAC continues to be a
credible forum for airing a wide range of public concerns about this
emerging field of medical research.
``Based on these findings, the committee recommends that:
``1. To avoid duplication of effort and unnecessary delay, RAC
should no longer carry out case by case review of every clinical gene
transfer protocol. This function is carried out by the FDA, which is
required by statute to review all such protocols before approval.
``2. Review of protocols by the RAC in an open public forum should
continue in several areas of concern in which a particular protocol or
new technology represents a significant degree of departure from
familiar practices. Such departures include, but are not limited to,
the use of novel vectors, particularly in cases in which modified human
pathogens (such as herpes viruses or lentiviruses) are being evaluated;
gene transfer in utero, potential germ line modification, and other
similar manipulations; and gene transfer in normal volunteers. In
addition, review of protocols by the RAC is warranted in other
situations which could lead to the formulation of significant new
policy.
``3. The RAC should define the criteria and work out procedures for
identifying specific protocols requiring public review.
``4. The RAC should continue to provide advice on policy matters
revolving around gene therapy and other recombinant DNA issues to the
NIH Director, individual members of the research community,
institutional review boards, and the public. Moreover, that critical
function should be extended, enabling RAC explicitly to provide advice
and recommendations on policy matters to FDA. However, the committee
recommended against reconstituting RAC or a comparable advisory body
within the FDA, pointing out that several important policy functions of
RAC are outside the mission of that agency.
``5. A mechanism should be devised to enable ORDA, NIH and the RAC
to continue to be provided with the data needed for monitoring clinical
gene transfer protocols. Hence, the committee recommends that the NIH
Director urge the FDA Commissioner to exempt the broad area of gene
therapy from many of the proprietary restraints reserved for ordinary
therapeutic drug products and biologics that come under FDA review.
Such a broad exemption, similar to the one now in place for products
being developed for the treatment of individuals infected with HIV,
would greatly expedite efforts to monitor and evaluate gene transfer
protocols and,
[[Page 57531]]
ultimately, would accelerate progress in the clinical application of
gene therapy.''
The Panel to Assess NIH Investment in Gene Therapy Research,
chaired by Stuart J. Orkin, M.D. and Arno G. Motulsky, M.D., is charged
with evaluating the current status of NIH-funded (directly and
indirectly) gene therapy clinical trials and developing recommendations
regarding future NIH investment in gene therapy research. The panel is
currently preparing its recommendations which will be presented at the
December 1995 Director's Advisory Committee meeting.
NIH invites written comments from industry, patient advocacy
groups, other Federal agencies, and other interested parties.
OMB's ``Mandatory Information Requirements for Federal Assistance
Program Announcements'' (45 FR 39592, June 11, 1980) requires a
statement concerning the official government programs contained in the
Catalog of Federal Domestic Assistance. Normally, NIH lists in its
announcements the number and title of affected individual programs for
the guidance of the public. Because the guidance in this notice covers
not only virtually every NIH program but also essentially every Federal
research program in which DNA recombinant molecule techniques could be
used, it has been determined not to be cost effective or in the public
interest to attempt to list these programs. Such a list would likely
require several additional pages. In addition, NIH could not be certain
that every Federal program would be included as many Federal agencies,
as well as private organizations, both national and international, have
elected to follow the NIH Guidelines. In lieu of the individual program
listing, NIH invites readers to direct questions to the information
address above whether individual programs listed in the Catalog of
Federal Domestic Assistance are affected.
Effective Date: November 8, 1995.
Lana Skirboll,
Associate Director for Science Policy.
[FR Doc. 95-28245 Filed 11-14-95; 8:45 am]
BILLING CODE 4140-01-M
