[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