[Federal Register Volume 62, Number 223 (Wednesday, November 19, 1997)]
[Notices]
[Pages 61862-61864]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-30321]



[[Page 61861]]

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Part II





Department of Health and Human Services





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National Institutes of Health



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Recombinant DNA Research: Proposed Actions Under the Guidelines; Notice

   Federal Register / Vol. 62, No. 223 / Wednesday, November 19, 1997 / 
Notices  

[[Page 61862]]



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, 62 FR 53335, 62 FR 56196, 62 FR 59032). 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 December 15-16, 1997, along with the proposed actions 
published in the Federal Register on October 16, 1997 (62 FR 53908). 
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 the 
proposed actions. Comments received by December 8, 1997, will be 
reproduced and distributed to the RAC for consideration at its December 
15-16, 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.

I. Proposed Actions Regarding Amendments to the NIH Guidelines

    The NIH will consider the following actions under the NIH 
Guidelines for Research Involving Recombinant DNA Molecules (NIH 
Guidelines):

I-A. Amendment to Appendix M-I, Submission Requirements--Human Gene 
Transfer Experiments, Under the NIH Guidelines Regarding Deadline for 
Submission for RAC Review

    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 the RAC meetings.
    To give the RAC sufficient time to review the protocols and the 
investigators to respond to primary reviewer's written comments, 
Appendix M-I, Submission Requirements--Human Gene Transfer Experiments, 
of the NIH Guidelines, is proposed to be amended to include a statement 
regarding the 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.
    Appendix M-I is proposed 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 (Instutitional 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 
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: 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.''

I-B. Amendment to Appendix K, Physical Containment for Large Scale Uses 
of Organisms Containing Recombinant DNA Molecules, of 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 of 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

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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. If 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 Section 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.''

    Appendix K-III-C is proposed to read:

``Appendix K-III. Biosafety Level (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 
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 proposed 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 purpose 
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 proposed 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 proposed 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 proposed 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 proposed 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.''

I-C. Amendment to Section III-D-6, Experiments Involving More Than 10 
Liters of Culture, of the NIH Guidelines

    In a letter dated November 6, 1997, Richard A. Knazek, Medical 
Officer, Clinical Research, National Center for Research Resources, 
NIH, requested an amendment to Section III-D-6, Experiments Involving 
More Than 10 Liters of Culture, of the NIH Guidelines. Dr. Knazek 
proposed an addition of a statement, ``When more than 10 Liters of 
culture media is to be produced within a GMP-accredited facility for 
subsequent clinical use, the level of appropriate containment shall be 
determined by the Institutional Biosafety Committee (IBC) affiliated 
with the institution where the investigator will perform the clinical 
manipulation of the vector.'' Dr. Knazek stated the rationale of his 
request as follows:

    ``The purpose of this amendment is to prevent an additional 
layer of bureaucracy from impeding the implementation of an 
appropriately reviewed and approved gene therapy protocol.
    ``The risks due to exposure to a gene vector will be greatest at 
the time when the final media product is either incubated with the 
target cells (ex vivo transduction) and/or

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infused into the recipient (in vivo transduction). The IBC at that 
clinical institution bears the responsibility of being knowledgeable 
about attendant risks to the investigator, laboratory and medical 
personnel, patient and the environment.
    ``While being produced within a qualified GMP facility, the 
vector is, by definition, both protected from the environment and 
prevented from escaping into the environment.
    ``Clearly, the vector and its proposed use must be scrutinized 
by an IBC. However, the IBC review of the vector and its protocol is 
most appropriately performed at the clinical site rather than at the 
GMP facility. Review by more than one IBC would be redundant.''

    Section III-D-6 is proposed to read:

``Section III-D. Experiments That Require Institutional Biosafety 
Committee Approval Before Initiation

    ``Section III-D-6. Experiments Involving More than 10 Liters of 
Culture. 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. Appendix K describes 
containment conditions Good Large Scale Practice through BL3-Large 
Scale. When more than 10 Liters of culture media is to be produced 
within a GMP-accredited facility for subsequent clinical use, the 
level of appropriate containment shall be determined by the IBC 
affiliated with the institution where the investigator will perform 
the clinical manipulation of the vector.''

    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: November 12, 1997.
Lana R. Skirboll,
Associate Director for Science Policy, National Institutes of Health.
[FR Doc. 97-30321 Filed 11-18-97; 8:45 am]
BILLING CODE 4140-01-M