[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
_______________________________________________________________________
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
