[Federal Register Volume 63, Number 31 (Tuesday, February 17, 1998)]
[Notices]
[Pages 8052-8055]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-3879]



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Part VI





Department of Health and Human Services





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National Institutes of Health



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Recombinant DNA Research: Actions Under the Guidelines; Notice

  Federal Register / Vol. 63, No. 31 / Tuesday, February 17, 1998 / 
Notices  

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Recombinant DNA Research: Actions Under the Guidelines

AGENCY: National Institutes of Health (NIH), PHS, DHHS.

ACTION: Notice of Actions Under the NIH Guidelines for Research 
Involving Recombinant DNA Molecules (NIH Guidelines).

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SUMMARY: This notice sets forth actions to be taken by the Director, 
National Institutes of Health (NIH), 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).

FOR FURTHER INFORMATION CONTACT:  Background documentation and 
additional information can be obtained from 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, FAX 301-496-9839. The ORDA web site is located at http://
www.nih.gov/od/orda/ for further information about the office.

SUPPLEMENTARY INFORMATION: Today's actions are being promulgated under 
the NIH Guidelines for Research Involving Recombinant DNA Molecules 
(NIH Guidelines). The proposed actions were published for comment in 
the Federal Register on October 16, 1997 (62 FR 53908) and November 19, 
1997 (62 FR 61862), and reviewed by the NIH Recombinant DNA Advisory 
Committee (RAC) at its meeting on December 16, 1997.

I. Amendments to Institutional Biosafety Committee (IBC) Approvals of 
Experiments Involving Transgenic Rodents Under Section III of the NIH 
Guidelines

I-A. Background Information and Decisions on Actions Under the NIH 
Guidelines

    Section III-D-4, Experiments Involving Whole Animals, of the NIH 
Guidelines requires that all transgenic animal experiments obtain IBC 
approval before initiation. In a correspondence dated April 22, 1997, 
Dr. George Gutman, an IBC representative of the University of 
California, Irvine, California, inquired whether experiments involving 
production or use of transgenic mice under Biosafety Level 1 
containment could be initiated simultaneous with IBC notification.
    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 
for IBC approval prior to initiation is unnecessary and recommended 
that the NIH Guidelines should be amended so that: (1) The generation 
of transgenic rodents under 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-
E, 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.
    On September 10, 1997, a letter was received from the American 
Biological Safety Association requesting that the public comment period 
for the proposed actions under the NIH Guidelines published in the 
Federal Register on August 20, 1997 (62 FR 44387) be extended for an 
additional 60 days.
    At its September 12, 1997 meeting, the RAC was scheduled to vote on 
the issues surrounding the amendments to IBC approvals of experiments 
involving transgenic rodents. Considering the American Biological 
Safety Association's request to extend the public comment period, the 
RAC decided to modify the language of the proposed actions and publish 
the revised version in the Federal Register for additional public 
comment as requested by the American Biological Safety Association. The 
RAC accepted the proposed actions with the deletion of two words ``and 
use'' from the language, ``the purchase and use of transgenic rodent * 
* *'' A motion was made by the RAC to accept the amendments to the NIH 
Guidelines with regard to: (1) The generation of transgenic rodents 
under Biosafety Level 1 containment (not all animals) can be initiated 
simultaneously with IBC notification, and (2) the purchase of 
transgenic rodents should be exempt from the NIH Guidelines. The motion 
passed by a vote of 11 in favor, 0 opposed, and no abstentions.
    The proposed actions were published in the Federal Register on 
October 16, 1997 (62 FR 53908). On December 2, 1997, a letter was 
received from C. Geoffrey Davis, Ph.D., Vice President, Research, 
Abgenix, Inc., Freemont, California, requesting to add two words, ``or 
transfer,'' to the language of the proposed action published in the 
Federal Register regarding the purchase or transfer of transgenic 
rodents to be exempt from the NIH Guidelines. In a letter dated 
December 5, 1997, Richard C. Knudsen, President, American Biological 
Safety Association, endorsed the proposed action and requested 
insertion of a statement, ``(See Appendix G-III-M, Footnotes and 
References of Appendix G),'' to aid individuals in determining the 
suitability of Biosafety Level 1 containment for their constructs. 
Appendix C-VI, The Purchase of Transgenic Rodents, is proposed to read:
    ``The purchase of transgenic rodents for experiments that require 
BL1 containment (See Appendix G-III-M, Footnotes and References of 
Appendix G) are exempt from the NIH Guidelines.''
    During the December 16, 1997, RAC meeting, the RAC accepted the 
proposed actions with the amendments requested by Abgenix, Inc. and 
American Biological Safety Association. The motion passed by a vote of 
13 in favor, 0 opposed, and no abstentions.
    The actions are detailed in Section I-B--Summary of Actions. I 
accept the RAC recommendations, and the NIH Guidelines will be amended 
accordingly.

I-B. Summary of Actions

I-B-1. Amendments to Section III-D-4. Experiments Involving Whole 
Animals
[Section III-D are experiments that require Institutional Biosafety 
Committee approval before initiation.]
    Section III-D-4-c is added to read:
    Section III-D-4-c. Exceptions under Section III-D-4.
    Section III-D-4-c-(1). Experiments involving the generation of 
transgenic rodents that require BL1 containment are described under 
Section III-E-3, Experiments Involving Transgenic Rodents.
    Section III-D-4-c-(2). The purchase or transfer of transgenic 
rodents is exempt from the NIH Guidelines under Section III-F, Exempt 
Experiments (see Appendix C-VI, The Purchase or Transfer of Transgenic 
Rodents).''

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I-B-2. Amendments to Section III-E. Experiments that Require 
Institutional Biosafety Committee Notice Simultaneous with Initiation
    Section III-E-3 is added to read:
    Section III-E-3. Experiments Involving Transgenic Rodents.
    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-D-4, Experiments Involving 
Whole Animals.''
    I-B-3. Amendments to Appendix C, Exemptions Under Section III-F-6.
    A new section, Appendix C-VI, is added to read:
    Appendix C-VI. The Purchase or Transfer of Transgenic Rodents.
    The purchase or transfer of transgenic rodents for experiments that 
require BL1 containment (See Appendix G-III-M, Footnotes and References 
of Appendix G) are exempt from the NIH Guidelines.''

[Appendix C-VI, Footnotes and References of Appendix C, will be 
renumbered to Appendix C-VII through Appendix C-VII-E.]

II. Amendment to Appendix K, Physical Containment for Large Scale Uses 
of Organisms Containing Recombinant DNA Molecules, of the NIH 
Guidelines

II-A. Background Information and Decisions on Actions Under the NIH 
Guidelines

    In a letter dated November 5, 1997, Gerard J. McGarrity, Ph.D., 
Senior Vice President for Development, Genetic Therapy, Inc., 
Gaithersburg, Maryland, requested amendments to Appendix K, Physical 
Containment for Large Scale Uses of Organisms Containing Recombinant 
DNA Molecules, of the NIH Guidelines to clarify the containment 
requirements for large scale production of viral vectors for gene 
therapy. The letter states that:
    The purpose of this correspondence is to point out a section of 
Appendix K of the NIH Guidelines (January 1997) that requires 
clarification for large scale production of viral vectors for gene 
therapy.
    ``Appendix K specifies containment guidelines for research or 
production material that exceed 10 liters in volume. Each of the large 
scale (LS) biosafety levels (BL): Good Large Scale Production (GLSP), 
BL1/LS (Appendix K-III-C), BL2/LS (Appendix K-IV-C) and BL3/LS 
(Appendix K-V-C) specify the requirements that:
    `Culture fluids (except as allowed by Appendix K-III-D, K-IV-D, K-
V-D) shall not be removed from a closed system or other primary 
containment equipment unless the viable organisms containing 
recombinant DNA molecules have been inactivated by a validated 
inactivation procedure.'
    ``Related language addresses the primary containment equipment:
    `A closed system or other primary containment equipment that has 
contained viable organisms containing recombinant DNA molecules shall 
not be opened for maintenance or other purposes unless it has been 
sterilized by a validated sterilization procedure.' (Sections K-III-F, 
K-IV-F and K-V-F)
    ``As its title (Physical Containment for Large Scale Uses of 
Organisms Containing Recombinant DNA Molecules) indicates, Appendix K 
was written to deal with prokaryotic and eukaryotic cells that 
elaborate proteins expressed by recombinant DNA molecules. It was not 
intended for the production of viral vectors used in gene therapy. In 
fact, adherence to sections K-III-C, K-IV-C, or K-V-C is incompatible 
with the production and harvest of viral vectors in volumes larger than 
10 liters as active viral vectors must be removed from the equipment. 
Clearly, this was not the purpose of Appendix K.
    ``Several possible solutions exist. First, Section III-D-6 of the 
Guidelines, ``Experiments Involving More Than 10 Liters Of Culture,' 
states:
    `The appropriate containment will be decided by the Institutional 
Biosafety Committee. Where appropriate, Appendix K, Physical 
Containment for Large Scale Uses of Organisms Containing Recombinant 
DNA Molecules, shall be used.'
    ``We interpret this to mean that for production of viral vectors, 
the IBC has the authority to establish the specifics of large scale 
containment, using the principles described in Appendix K. For 
harvesting of supernatant fluids that contain the viral vector product, 
the IBC can establish practices and facilities which are consistent 
with the objectives and spirit of the NIH Guidelines.
    ``In this regard, Genetic Therapy, Inc., has adhered to Section 
III-D-6 in the establishment of facilities and practices for large 
scale production of retroviral vectors to the extent that Sections can 
be applied to viral vectors. These have included the practices for the 
appropriate large scale biosafety level except for the requirement to 
inactivate the culture fluids and to sterilize the primary containment 
equipment prior to opening the primary containment equipment and 
removing the culture fluids. These practices have been approved by our 
IBC.
    ``A second possible solution is to limit volumes to less than 10 
liters. However, this will be impractical for commercial purposes. 
Third, the Guidelines can be modified to address the requirements for 
large scale production of viral vectors for gene therapy.
    ``For the longer term, we believe it is most appropriate to revise 
the relevant portions of Appendix K to enable application of large 
scale to viral vectors. We request that RAC address this issue and 
propose the following language be added to the end of Sections K-III-C, 
K-IV-C and K-V-C of Appendix K:
    `Culture fluids that contain viable organisms or viral vectors 
intended as final product may be removed from the primary containment 
equipment by way of closed systems for sample analysis, further 
processing or final fill.'
    ``We propose the following language be added to the end of the 
first sentence of Sections K-III-F, K-IV-F and K-V-F:
    `. . . except when the culture fluids contain viable organisms or 
vectors intended as final product as described in Section K-III-C (or 
K-IV-C or K-V-C respectively) above.'
    ``We believe these additions maintain the original concept of 
Appendix K while addressing the needs of specific product types.''
    During the December 16, 1997, RAC meeting, the RAC deliberated and 
accepted Dr. McGarrity's request. A motion was made to accept the 
language of the proposed action published in the Federal Register on 
November 19, 1997 (62 FR 61862) for the amendments to Appendix K. The 
amendments will allow production and harvest of biologically active 
viral vectors in volumes larger than 10 liters. The motion passed by a 
vote of 13 in favor, 0 opposed, and no abstentions.
    The actions are detailed in Section II-B--Summary of Actions. I 
accept the RAC recommendations, and the NIH Guidelines will be amended 
accordingly.

II-B. Summary of Actions

    Appendix K-III-C is amended to read:
    ``Appendix K-III. Biosafety Level 1 (BL1)--Large Scale.
    ``Appendix K-III-C. Culture fluids (except as allowed in Appendix 
K-III-D) shall not be removed from a closed system or other primary 
containment equipment unless the viable organisms containing 
recombinant DNA molecules have been inactivated by a validated

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inactivation procedure. A validated inactivation procedure is one which 
has been demonstrated to be effective using the organism that will 
serve as the host for propagating the recombinant DNA molecules. 
Culture fluids that contain viable organisms or viral vectors intended 
as final product may be removed from the primary containment equipment 
by way of closed systems for sample analysis, further processing or 
final fill.''
    Appendix K-III-F is amended to read:
    ``Appendix K-III-F. A closed system or other primary containment 
equipment that has contained viable organisms containing recombinant 
DNA molecules shall not be opened for maintenance or other purposes 
unless it has been sterilized by a validated sterilization procedure 
except when the culture fluids contain viable organisms or vectors 
intended as final product as described in Section K-III-C above. A 
validated sterilization procedure is one which has been demonstrated to 
be effective using the organism that will serve as the host for 
propagating the recombinant DNA molecules.''
    Appendix K-IV-C is amended to read:
    ``Appendix K-IV. Biosafety Level 2 (BL2)--Large Scale.
    ``Appendix K-IV-C. Culture fluids (except as allowed in Appendix K-
IV-D) shall not be removed from a closed system or other primary 
containment equipment unless the viable organisms containing 
recombinant DNA molecules have been inactivated by a validated 
inactivation procedure. A validated inactivation procedure is one which 
has been demonstrated to be effective using the organism that will 
serve as the host for propagating the recombinant DNA molecules. 
Culture fluids that contain viable organisms or viral vectors intended 
as final product may be removed from the primary containment equipment 
by way of closed systems for sample analysis, further processing or 
final fill.''
    Appendix K-IV-F is amended to read:
    ``Appendix K-IV-F. A closed system or other primary containment 
equipment that has contained viable organisms containing recombinant 
DNA molecules shall not be opened for maintenance or other purposes 
unless it has been sterilized by a validated sterilization procedure 
except when the culture fluids contain viable organisms or vectors 
intended as final product as described in Section K-IV-C above. A 
validated sterilization procedure is one which has been demonstrated to 
be effective using the organisms that will serve as the host for 
propagating the recombinant DNA molecules.''
    Appendix K-V-C is amended to read:
    ``Appendix K-V. Biosafety Level 3 (BL3)--Large Scale.
    ``Appendix K-V-C. Culture fluids (except as allowed in Appendix K-
V-D) shall not be removed from a closed system or other primary 
containment equipment unless the viable organisms containing 
recombinant DNA molecules have been inactivated by a validated 
inactivation procedure. A validated inactivation procedure is one which 
has been demonstrated to be effective using the organisms that will 
serve as the host for propagating the recombinant DNA molecules. 
Culture fluids that contain viable organisms or viral vectors intended 
as final product may be removed from the primary containment equipment 
by way of closed systems for sample analysis, further processing or 
final fill.''
    Appendix K-V-F is amended to read:
    ``Appendix K-V-F. A closed system or other primary containment 
equipment that has contained viable organisms containing recombinant 
DNA molecules shall not be opened for maintenance or other purposes 
unless it has been sterilized by a validated sterilization procedure 
except when the culture fluids contain viable organisms or vectors 
intended as final product as described in Section K-V-C above. A 
validated sterilization procedure is one which has been demonstrated to 
be effective using the organisms that will serve as the host for 
propagating the recombinant DNA molecules.''

III. Amendment to Appendix M-I, Submission Requirements--Human Gene 
Transfer Experiments, Regarding Deadline Submission for RAC Review

III-A. Background Information and Decisions on Actions Under the NIH 
Guidelines

    On November 12, 1997, Dr. Scott McIvor, a member of the Recombinant 
DNA Advisory Committee (RAC), requested a proposed action regarding the 
deadline for submission of human gene transfer protocols that will 
require public discussion at regularly scheduled RAC meetings.
    To give the RAC sufficient time to review protocols, and to allow 
the investigators to respond to comments of the primary reviewer, an 
action is proposed to amend the NIH Guidelines, Appendix M-I, 
Submission Requirements--Human Gene Transfer Experiments, to include a 
submission deadline. Submission material will be accepted by NIH/ORDA 
at any time. However, if a protocol is recommended for full RAC review, 
the submission material must be received in NIH/ORDA a minimum of eight 
weeks prior to the next scheduled RAC meeting.
    During the December 16, 1997, RAC meeting, a motion was made to 
accept the proposed action regarding deadline submission for RAC 
review, which was published in the Federal Register on November 19, 
1997 (62 FR 61862). A note to Appendix M-I, Submission Requirements--
Human Gene Transfer Experiments, was amended to read:

    ``Note: Submission material will be accepted by NIH/ORDA at any 
time. However, if a protocol is recommended for full RAC review, the 
submission material must be received in NIH/ORDA a minimum of eight 
weeks prior to the next scheduled RAC meeting.''

    The motion passed by a vote of 6 in favor, 0 opposed, and 2 
abstentions. To clarify the meaning of this note, NIH/ORDA later 
modified the amended note to Appendix M-I to read:

    ``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.''

III-B. Summary of Actions

    Appendix M-I. Submission Requirements--Human Gene Transfer 
Experiments, is amended to read:
    ``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-VIII-A, Footnotes of 
Appendix M). Proposals shall be submitted to NIH/ORDA in the following 
order: (1) Scientific abstract; (2) non-technical abstract; (3) 
Institutional Biosafety Committee and Institutional Review Board 
approvals and their deliberations pertaining to your protocol 
(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)); (4) Responses to Appendix M-II 
through M-V, Description of the Proposal, Informed Consent, Privacy and

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Confidentiality, and Special Issues (the pertinent responses can be 
provided in the protocol or as an appendix to the protocol); (5) 
clinical protocol (as approved by the local Institutional Biosafety 
Committee and Institutional Review Board); (6) Informed Consent 
document--approved by the Institutional Review Board (see Appendix M-
III, Informed Consent); (7) appendices (including tables, figures, and 
manuscripts); and (8) curricula vitae--2 pages for each key 
professional person in biographical sketch format. 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. Submissions to 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.''

    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 virtually every 
NIH and 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 about whether 
individual programs listed in the Catalog of Federal Domestic 
Assistance are affected.

    Dated: February 4, 1998.
Harold Varmus,
Director, National Institutes of Health.
[FR Doc. 98-3879 Filed 2-13-98; 8:45 am]
BILLING CODE 4140-01-P