[Federal Register Volume 64, Number 31 (Wednesday, February 17, 1999)]
[Notices]
[Pages 7964-7966]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-3851]


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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.

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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, 62 FR 53335, 62 FR 56196, 62 FR 59032, 63 FR 8052, 63 FR 26018). 
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 March 11-12, 1999. 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 February 24, 1999, will be 
reproduced and distributed to the RAC for consideration at its March 
11-12, 1999, 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, or by FAX to 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' 
(ORDA) 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:

I. Amendment to Appendix B-I. Risk Group 1 (RG1) Agents

    On December 11, 1998, ORDA received a facsimile from Dr. Margarita 
C. Curras-Collazo, University of California at Riverside, Riverside, 
California, requesting under Section IV-C-1-(2), Minor Actions, of the 
NIH Guidelines, to lower the containment level (from Biological Level 
(BL) 2 to 1) for recombinant adeno-associated vectors (AAV) produced in 
the absence of helper viruses. Subsequent to this request, ORDA 
received a telephone call from Ms. Brenda Wong, Biological Safety 
Officer, University of California at San Diego, La Jolla, California, 
asking that this determination be reconsidered due to the potential of 
insertional metagenesis of recombinant AAV. ORDA has solicited the 
opinion of three experts in the AAV field, in addition to the opinion 
of the RAC Chair.
    It is the opinion of the RAC Chair and the three experts that BL1 
is appropriate for recombinant AAV vectors produced

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in the absence of helper viruses; therefore, an amendment to the NIH 
Guidelines is appropriate. Part of the rationale for this decision is 
based on the fact that experiments involving certain recombinant 
retroviral vectors, which insert randomly into the genome and could 
potentially cause insertional mutagenesis, are designated as BL1.
    Currently the affected section of the NIH Guidelines states in 
part: ``RG1 agents are not associated with disease in healthy adult 
humans. Examples of RG1 agents include asporogenic Bacillus subtilis or 
Bacillus licheniformis (see Appendix C-IV-A, Bacillus subtilis or 
Bacillus licheniformis Host-Vector Systems, Exceptions), Escherichia 
coli-K12 (see Appendix C-II-A, Escherichia coli-K12 Host Vector 
Systems, Exceptions), and adeno-associated virus types 1 through 4.''
    At the March 11-12, 1999, meeting, the RAC will consider an 
amendment to Appendix B-1, of the NIH Guidelines. The new section, 
Appendix B-1, is proposed to read:

    RG1 agents are not associated with disease in healthy adult 
humans. Examples of RG1 agents include asporogenic Bacillus subtilis 
or Bacillus licheniformis (see Appendix C-IV-A, Bacillus subtilis or 
Bacillus licheniformis Host-Vector Systems, Exceptions), Escherichia 
coli K-12 (see Appendix C-II-A, Escherichia coli K-12 Host Vector 
Systems, Exceptions), adeno-associated virus types 1 through 4, and 
recombinant AAV constructs, in which the transgene does not encode 
either a tumor suppressor or a toxin molecule and are produced in 
the absence of a helper virus.

II. Addition to Appendix D of the NIH Guidelines Regarding the 
Introduction of a Gene Coding for Ampicillin Resistance into 
Chlamydia trachomatis/Dr. Stothard

    In a facsimile dated January 27, 1999, Dr. Diane Stothard of 
Indiana University, Indianapolis, Indiana, is requesting permission to 
conduct experiments which involve the introduction of a gene coding for 
ampicillin resistance into Chlamydia trachomatis, a Risk Group 2 agent. 
According to Section III-A-1-a of the NIH Guidelines, experiments that 
involve the transfer of a drug resistance trait to a microorganism that 
is not known to acquire the trait naturally shall be reviewed by the 
RAC. Ampicillin type drugs are one of the few accepted treatments for 
pregnant women.
    At the March 11-12, 1999, meeting, the RAC will consider a proposed 
addition to Appendix D, of the NIH Guidelines, to allow the 
introduction of gene coding for ampicillin resistance into Chlamydia 
trachomatis, a Risk Group 2 agent.

III. Discussion Regarding Prenatal Gene Transfer Research

    On January 7-8, 1999, the NIH held a Gene Therapy Policy Conference 
entitled: Prenatal Gene Transfer: Scientific, Medical, and Ethical 
Issues. This conference was not an endorsement by the NIH of prenatal 
gene transfer research. Rather, this conference was an initial step in 
an ongoing process of active public deliberation among scientists, 
clinicians, families, policy makers, individuals, and groups of 
concerned citizens to gather expert views and solicit public opinion 
regarding the substantive public policy issues raised by prenatal gene 
transfer research. It is anticipated that continued deliberation of 
this issues will ultimately lead to the development of NIH and FDA 
policy in this arena. The conference participants concluded, ``At 
present, there is insufficient preclinical data to support the 
initiation of clinical trials involving prenatal gene transfer.'' A 
substantial number of critical scientific, safety, ethical, legal, and 
social issues must be addressed before clinical trials proceed in this 
arena. These issues include (but are not limited to): (1) Efficiency of 
gene transfer to target cells; (2) specificity of delivery to target 
cells; (3) level, duration, and regulation of gene expression; (4) 
appropriate disease candidates; (5) fetal immune response to transgene 
products and/or vectors; (6) emergence of fetal immune tolerance; (7) 
effects of gene transfer on pre- and post-natal development; (8) 
possibility of generation and activation of transmissible vector or 
virus; (9) possibility of initiating oncogenic or degenerative 
processes; (10) limitations related to the accuracy of disease 
diagnosis; (11) implications of diagnostic limitations on the design 
and conduct of clinical trials; (12) elements of optimal clinical trial 
design and analysis; (13) definition of clinical endpoints for the 
analysis of clinical outcomes; (14) potential risk to the fetus and 
acceptable level of risk to the fetus in human experimentation; (15) 
potential risk to the pregnant woman; (16) inclusion and exclusion 
criteria for the pregnant woman; (17) inclusion criteria for the fetus; 
(18) pre- and post-pregnancy monitoring of the pregnant woman; (19) 
pre- and post-partum monitoring of the fetus/child; (20) detection and 
assessment of inadvertent germ-line transmission; (21) ethical issues 
specific to the fetus; (22) ethical issues specific to the pregnant 
woman; (23) patient recruitment/enrollment processes; (24) informed 
consent issues; (25) societal issues; and (26) legal issues.
    The RAC will continue to deliberate these issues during the March 
11-12, 1999, meeting and at its future meetings.

IV. Presentation on Gonadal Biodistribution of Gene Transfer 
Vectors and the Potential Risk of Inadvertent Germ-line 
Transmission

    Representatives of the Food and Drug Administration (FDA) and other 
invited speakers will present an overview of preclinical data related 
to gonadal biodistribution of gene transfer vectors and the attendant 
ethical and safety issues related to preclinical assessment of vector 
biodistribution and potential risk of inadvertent germ-line 
transmission to the RAC during the March 11-12, 1999, meeting. This 
discussion serves as a follow-up to the December 15, 1997, and March 9, 
1998, discussions between the FDA and the RAC at which FDA 
representatives informed the RAC of several preclinical studies 
demonstrating that DNA homologous to gene transfer vectors has been 
found in gonadal tissue subsequent to vector administration to extra 
gonadal sites.
    On December 15, 1997, Drs. Steven Bauer and Anne Pilaro, Center for 
Biologics Evaluation and Research, FDA, presented an overview related 
to the FDA's observation that preclinical animal studies designed to 
assess vector biodistribution have demonstrated unexpected persistence 
of vector nucleic acid sequences in gonadal tissue. Specifically: (1) 
Nucleic acid persistence in gonadal tissues is evidenced by positive 
polymerase chain reaction (PCR) signals in DNA extracted from whole 
gonads, and (2) evidence of nucleic acid persistence in gonadal tissues 
has been observed with multiple classes of vectors, formulations, and 
routes of administration. The FDA became aware of these data as part of 
its review of Investigational New Drug (IND) applications.
    Representatives of the FDA noted that the following issues must be 
resolved before the implications of these observations can be 
determined: (1) The source of the gonadal PCR signal has not been 
determined, i.e., germ cells, blood cells, or stroma. Current PCR 
methods for detecting vector sequences are highly sensitive (capable of 
detecting one vector copy per microgram of cellular DNA); however, 
there is a high incidence of false positives and negatives. (2) There 
are limited data about whether these vector sequences are episomal or 
integrated. (3) It is unknown whether the presence of

[[Page 7966]]

vector nucleic acid sequences in gonadal tissue is associated with any 
developmental effects. FDA representatives welcomed the opportunity to 
present this information to the RAC and the public as a timely and 
appropriate mechanism for increasing public awareness of these findings 
and to stimulate continued public discussion of the implications of 
these observations.
    Under the limits of confidentiality, the FDA could not discuss 
further specifics of the observations; therefore, the RAC recommended 
that ORDA should send a letter to all principal investigators of 
clinical gene therapy trials and all IBCs requesting submission of all 
available data related to persistence of nucleic acid vectors in 
gonadal tissue. The RAC requested this information as part of its role 
and responsibility to ensure public awareness of recombinant DNA issues 
within the context of the NIH Guidelines. The NIH Guidelines are 
applicable to all research that is conducted at, or sponsored by, an 
institution that receives any support for recombinant DNA research from 
the NIH. ORDA received approximately 80 responses to this request.
    During its March 9, 1998, meeting, the RAC discussed these 
responses. Four responses indicated that vector sequences were detected 
in either the ovaries or testes in preclinical animal studies; however, 
the number of responses received was not representative of the number 
of clinical trials currently registered with ORDA. RAC members 
expressed concern about the quantity and quality of responses to the 
ORDA letter. These concerns included whether the information collected 
thus far was subject to quality control and if researchers took any 
precautions to prevent contamination of the analyzed tissue. Of 
additional concern was the fact that many clinical investigators were 
not conducting appropriate assays to determine the presence of nucleic 
acid vectors in gonadal tissue.
    Based on the limited information available to the RAC at that time, 
the committee acknowledged its responsibility to raise a cautionary 
note regarding the possibility that such evidence suggests inadvertent 
germ-line alteration. The RAC discussed the complexities involved in 
designing appropriate testing procedures. The RAC concluded that there 
is a need to initiate well-designed studies to adequately evaluate the 
implications of finding vector sequences in gonadal tissue.

V. Discussion on Gene Transfer Vector Containment

    The NIH Office of Recombinant DNA Activities (ORDA) has received 
numerous inquiries from research investigators and Institutional 
Biosafety Committee (IBC) representatives regarding the appropriate 
containment practices and procedures for the generation and use of 
multiple classes of gene transfer vectors. During the March 11-12, 
1999, meeting, the RAC will initiate a discussion regarding a 
reexamination of the proper containment level for a wide variety of 
vectors employed in gene transfer research. In addition, several new 
methodologies, such as the use of chimeric nucleic acids, that are 
currently not covered by the NIH Guidelines will be addressed to aid in 
laying the groundwork for a redefinition of the term ``recombinant 
DNA.'' The RAC will discuss the need to update the NIH Guidelines 
regarding appropriate containment practices and procedures for gene 
transfer vectors in a variety of settings, i.e., laboratories, animals, 
and human subjects.
    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: February 3, 1999.
Lana Skirboll,
Associate Director for Science Policy, National Institutes of Health.
[FR Doc. 99-3851 Filed 2-16-99; 8:45 am]
BILLING CODE 4140-01-P