[Federal Register Volume 59, Number 162 (Tuesday, August 23, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-20826]
[[Page Unknown]]
[Federal Register: August 23, 1994]
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Recombinant DNA Research: Proposed Actions Under the Guidelines
AGENCY: National Institutes of Health, PHS, DHHS.
ACTION: Notice of Proposed Actions Under the NIH Guidelines for
Research Involving Recombinant DNA Molecules (59 FR 34496).
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SUMMARY: This notice sets forth proposed actions to be taken under the
National Institutes of Health (NIH) Guidelines for Research Involving
Recombinant DNA Molecules (59 FR 34496). Interested parties are invited
to submit comments concerning these proposals. These proposals will be
considered by the Recombinant DNA Advisory Committee at its meeting on
September 12-13, 1994. 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 September 5, 1994, will be reproduced and
distributed to the Recombinant DNA Advisory Committee for consideration
at its September 12-13, 1994, meeting.
ADDRESSES: Written comments and recommendations should be submitted to
Dr. Nelson A. Wivel, Director, Office of Recombinant DNA Activities
(ORDA), Building 31, Room 4B11, National Institutes of Health,
Bethesda, Maryland 20892, 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, Building 31, Room 4B11, National Institutes of Health,
Bethesda, Maryland 20892, (301) 496-9838.
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/Dr. Crystal
In a letter dated July 18, 1994, Dr. Ronald Crystal of the New York
Hospital-Cornell Medical Center, New York, New York, submitted a human
gene transfer protocol entitled: Evaluation of Repeat Administration of
a Replication Deficient, Recombinant Adenovirus Containing the Normal
Cystic Fibrosis Transmembrane Conductance Regulator cDNA to the Airways
of Individuals w/Cystic Fibrosis to the Recombinant DNA Advisory
Committee for formal review and approval.
II. Addition to Appendix D of the NIH Guidelines Regarding a Human
Gene Transfer Protocol/Drs. Isner and Walsh
In a letter dated July 5, 1994, Drs. Jeffrey M. Isner and Kenneth
Walsh of the St. Elizabeth's Medical Center, Tufts University, Boston,
Massachusetts, submitted a human gene transfer protocol entitled:
Arterial Gene Transfer for Therapeutic Angiogenesis in Patients with
Peripheral Artery Disease to the Recombinant DNA Advisory Committee for
formal review and approval.
III. Addition to Appendix D of the NIH Guidelines Regarding a Human
Gene Transfer Protocol/Dr. Gluckman
In a letter dated July 15, 1994, Dr. Jack L. Gluckman of the
University of Cincinnati Medical Center, Cincinnati, Ohio, submitted a
human gene transfer protocol entitled: Intratumoral Injection of Herpes
Simplex Thymidine Kinase Vector Producer Cells (PA317/G1Tk1SvNa.7) and
Intravenous Ganciclovir for the Treatment of Locally Recurrent or
Persistent Head and Neck Cancer to the Recombinant DNA Advisory
Committee for formal review and approval.
IV. Addition to Appendix D of the NIH Guidelines Regarding a Human
Gene Transfer Protocol/Dr. Flotte
In a letter dated July 14, 1994, Dr. Terence R. Flotte of Johns
Hopkins Children's Center, Baltimore, Maryland, submitted a human gene
transfer protocol entitled: A Phase I Study of an Adeno-associated
Virus-CFTR Gene vector in Adult CF Patients with Mild Lung Disease to
the Recombinant DNA Advisory Committee for formal review and approval.
V. Addition to Appendix D of the NIH Guidelines Regarding a Human
Gene Transfer Protocol/Dr. Lyerly
In a letter received on July 18, 1994, Dr. H. Kim Lyerly of Duke
University Medical Center, Durham, North Carolina, submitted a human
gene transfer protocol entitled: A Pilot Study of Autologous Human
Interleukin-2 Gene Modified Tumor Cells in Patients with Refractory or
Recurrent Metastatic Breast Cancer to the Recombinant DNA Advisory
Committee for formal review and approval.
VI. Addition to Appendix D of the NIH Guidelines Regarding a Human
Gene Transfer Protocol/Dr. Whitley
In a letter dated July 15, 1994, Dr. Chester B. Whitley of the
University of Minnesota, Minneapolis, Minnesota, submitted a human gene
transfer protocol entitled: Retroviral-Mediated Transfer of the
Iduronate-2-Sulfatase Gene Into Lymphocytes for Treatment of Mild
Hunter Syndrome (Mucopolysaccharidosis Type II) to the Recombinant DNA
Advisory Committee for formal review and approval.
VII. Addition to Appendix D of the NIH Guidelines Regarding a Human
Gene Transfer Protocol/Drs. Holt and Arteaga
In a letter dated July 15, 1994, Drs. Jeffrey Holt and Carlos B.
Arteaga of Vanderbilt University, Nashville, Tennessee, submitted a
human gene transfer protocol entitled: Gene Therapy for the Treatment
of Metastatic Breast Cancer by In Vivo Infection with Breast-Targeted
Retroviral Vectors Expressing Antisense c-fos or Antisense c-myc RNA to
the Recombinant DNA Advisory Committee for formal review and approval.
VIII. Addition to Appendix D of the NIH Guidelines Regarding a
Human Gene Transfer Protocol/Drs. Eck, Alavi
In a letter dated July 15, 1994, Drs. Stephen L. Eck and Jane B.
Alavi of the University of Pennsylvania Medical Center, Philadelphia,
Pennsylvania, submitted a human gene transfer protocol entitled:
Treatment of Advanced CNS Malignancy w/the Recombinant Adenovirus
H5.020RSVTK: A Phase I Trial to the Recombinant DNA Advisory Committee
for formal review and approval.
IX. Addition to Appendix D of the NIH Guidelines Regarding a Human
Gene Transfer Protocol/Dr. Albelda
In a letter received on July 18, 1994, Dr. Steven M. Albelda of the
University of Pennsylvania Medical Center, Philadelphia, Pennsylvania,
submitted a human gene transfer protocol entitled: Treatment of
Advanced Mesothelioma with the Recombinant Adenovirus H5.010RSVTK: A
Phase I Trial to the Recombinant DNA Advisory Committee for formal
review and approval.
X. Amendments to Sections I, III, IV, V, and Appendix M of the NIH
Guidelines Regarding Consolidated Review of Human Gene Transfer
Protocols
On July 18-19, 1994, the National Task Force on AIDS Drug
Development held an open meeting for the purpose of identifying
barriers to AIDS Drug Discovery that included a proposal to streamline
the dual review process for human gene transfer experiments. Members of
the Task Force recommended a consolidated review process to enhance
interactions between the NIH and the FDA. As a result of the Task
Force's deliberations, recommendations were adopted in order to
eliminate any unnecessary overlap between the FDA and NIH review of
human gene transfer proposals. Both Drs. Varmus and Kessler noted that
their respective agencies would cooperate fully to effect the changes
necessary to implement these recommendations. The recommendations were:
``The NIH and FDA recommend that the RAC become advisory to both
the NIH Director and the FDA with regard to the review of human gene
transfer protocols. In the interest of maximizing the resources of both
agencies and in simplifying the method and period for review of
research protocols involving human gene transfer, it is planned that
the FDA and NIH institute a new consolidated review process that
incorporates the following principal elements:
(1) All gene transfer protocols shall be submitted directly to the
FDA. Submission will be in the format required by the FDA and the same
format will be used by the RAC when public review is deemed necessary.
(2) Upon receipt, FDA review will proceed. The NIH Office of
Recombinant DNA Activities (ORDA) staff will simultaneously evaluate
the protocol for possible RAC review.
(3) Factors which may contribute to the need for RAC review
include: (1) novel approaches, (2) new diseases, (3) unique
applications of gene transfer, and (4) other issues that require
further public review.
(4) Whenever possible, principal investigators will be notified
within 15 working days following receipt of the submission whether RAC
review will be required. (RAC reviewed applications will be forwarded
to reviewers 8 weeks prior to the next quarterly RAC meeting.)
(5) Semi-annual data reporting procedures will remain the
responsibility of NIH (ORDA). Semi-annual data reports will be reviewed
by the RAC in a public forum.''
Investigators will no longer be required to provide a separate
submission to NIH/ORDA for RAC review. The FDA Division of Cellular and
Gene Therapies will forward a copy of each submission to NIH/ORDA. Any
protocol submitted < 8="" weeks="" before="" a="" rac="" meeting="" will="" be="" reviewed="" at="" the="" following="" quarterly="" rac="" meeting.="" the="" rac="" will="" make="" recommendations="" regarding="" approval/disapproval="" of="" protocols,="" including="" any="" relevant="" stipulations,="" to="" the="" nih="" director.="" the="" nih="" director="" will="" transmit="" the="" rac's="" recommendations/stipulations="" to="" the="" fda="" commissioner.="" the="" fda="" will="" consider="" such="" recommendations/stipulations="" and="" will="" be="" responsible="" for="" completion="" of="" review.="" the="" rac="" and="" nih/orda="" will="" no="" longer="" have="" the="" responsibility="" for="" reviewing="" material="" submitted="" in="" response="" to="" stipulation="" requirements="" or="" for="" the="" review="" of="" minor="" modifications="" to="" human="" gene="" transfer="" protocols.="" the="" following="" proposed="" amendments="" to="" the="" nih="" guidelines="" reflect="" the="" new="" streamlined="" review="" process.="" section="" i="" (scope="" of="" the="" nih="" guidelines)="" currently="" reads:="" ``section="" i.="" scope="" of="" the="" nih="" guidelines="" ``section="" i-a.="" purpose="" ``the="" purpose="" of="" the="" nih="" guidelines="" is="" to="" specify="" practices="" for="" constructing="" and="" handling:="" (i)="" recombinant="" deoxyribonucleic="" acid="" (dna)="" molecules,="" and="" (ii)="" organisms="" and="" viruses="" containing="" recombinant="" dna="" molecules.="" ``section="" i-a-1.="" any="" recombinant="" dna="" experiment,="" which="" according="" to="" the="" nih="" guidelines="" requires="" approval="" by="" the="" nih,="" must="" be="" submitted="" to="" the="" nih="" or="" to="" another="" federal="" agency="" that="" has="" jurisdiction="" for="" review="" and="" approval.="" once="" approval,="" or="" other="" applicable="" clearances,="" has="" been="" obtained="" from="" a="" federal="" agency="" other="" than="" the="" nih="" (whether="" the="" experiment="" is="" referred="" to="" that="" agency="" by="" the="" nih="" or="" sent="" directly="" there="" by="" the="" submitter),="" the="" experiment="" may="" proceed="" without="" the="" necessity="" for="" nih="" review="" or="" approval="" (see="" exception="" in="" sections="" i-a-2="" and="" i-a-3).="" ``section="" i-a-2.="" certain="" experiments="" that="" involve="" the="" deliberate="" transfer="" of="" recombinant="" dna="" or="" dna="" or="" rna="" derived="" from="" recombinant="" dna="" into="" one="" or="" more="" human="" subjects="" (see="" section="" v-u)="" shall="" be="" considered="" major="" actions="" (see="" section="" iv-c-1-b-(1)),="" and="" shall="" require="" rac="" review="" and="" nih="" director="" approval,="" if="" determined="" by="" nih/orda="" in="" consultation="" with="" the="" rac="" chair="" and/or="" one="" or="" more="" rac="" members,="" as="" necessary,="" to:="" (i)="" represent="" novel="" characteristics="" (e.g.,="" target="" disease="" or="" vector),="" (ii)="" represent="" an="" uncertain="" degree="" of="" risk="" to="" human="" health="" or="" the="" environment,="" or="" (iii)="" contain="" information="" determined="" to="" require="" further="" public="" review="" (see="" section="" iii-a-2).="" ``section="" i-a-3.="" experiments="" involving="" the="" transfer="" of="" recombinant="" dna="" to="" one="" or="" more="" human="" subjects="" that="" are="" not="" considered="" under="" section="" iii-a-2="" may="" qualify="" for="" accelerated="" review="" (see="" section="" iii-b-2="" and="" appendix="" m-v)="" and="" will="" be="" considered="" as="" minor="" actions="" (see="" section="" iv-="" c-1-b-(2)-(a)).="" actions="" that="" qualify="" for="" accelerated="" review="" will="" be="" reviewed="" and="" approved="" by="" nih/orda="" in="" consultation="" with="" the="" rac="" chair="" and/or="" one="" or="" more="" rac="" members,="" as="" necessary.="" ``certain="" experiments="" involving="" the="" transfer="" of="" recombinant="" dna="" or="" dna="" or="" rna="" derived="" from="" recombinant="" dna="" into="" one="" or="" more="" human="" subjects="" (see="" section="" v-u)="" may="" be="" considered="" exempt="" from="" rac="" and/or="" nih/orda="" review="" and/or="" nih="" director="" approval="" and="" only="" require="" registration="" with="" nih/orda="" (see="" section="" iii-c-7).''="" section="" i-a="" is="" proposed="" to="" read:="" ``section="" i.="" scope="" of="" the="" nih="" guidelines="" ``section="" i-a.="" purpose="" ``the="" purpose="" of="" the="" nih="" guidelines="" is="" to="" specify="" practices="" for="" constructing="" and="" handling:="" (i)="" recombinant="" deoxyribonucleic="" acid="" (dna)="" molecules,="" and="" (ii)="" organisms="" and="" viruses="" containing="" recombinant="" dna="" molecules.="" ``section="" i-a-1.="" if="" a="" recombinant="" dna="" experiment="" requiring="" nih="" approval="" is="" also="" subject="" to="" review="" and="" approval="" by="" another="" federal="" agency,="" the="" proposed="" experiment="" must="" be="" submitted="" to="" the="" other="" federal="" agency.="" once="" approval,="" or="" other="" applicable="" clearances,="" has="" been="" obtained="" from="" a="" federal="" agency="" other="" than="" the="" nih,="" the="" experiment="" may="" proceed="" without="" the="" necessity="" for="" nih="" review="" or="" approval,="" except="" as="" provided="" in="" section="" i-a-1-a.="" ``section="" i-a-1-a.="" experiments="" involving="" the="" deliberate="" transfer="" of="" recombinant="" dna="" or="" dna="" or="" rna="" derived="" from="" recombinant="" dna="" into="" one="" or="" more="" human="" subjects="" shall="" be="" submitted="" directly="" to="" the="" food="" and="" drug="" administration="" (fda).="" such="" proposals="" shall="" be="" submitted="" to="" the="" director="" of="" the="" division="" of="" cellular="" and="" gene="" therapies,="" office="" of="" therapeutics="" research="" and="" review,="" center="" for="" biologics="" evaluation="" and="" research,="" food="" and="" drug="" administration,="" 1401="" rockville="" pike,="" hfm-515,="" rockville,="" maryland="" 20852-1448,="" (301)="" 496-4709.="" upon="" receipt,="" fda="" will="" transmit="" all="" human="" gene="" transfer="" protocols="" to="" the="" nih="" office="" of="" recombinant="" dna="" activities="" (orda).="" simultaneously="" with="" the="" fda="" review,="" nih/orda="" will="" evaluate="" the="" protocol="" for="" possible="" rac="" review.="" whenever="" possible,="" principal="" investigators="" will="" be="" notified="" within="" 15="" working="" days="" following="" receipt="" of="" the="" submission="" whether="" rac="" review="" will="" be="" required.="" rac="" reviewed="" applications="" will="" be="" forwarded="" to="" reviewers="" 8="" weeks="" prior="" to="" the="" next="" quarterly="" rac="" meeting.="" factors="" that="" may="" contribute="" to="" the="" need="" for="" rac="" review="" include:="" (i)="" novel="" approaches,="" (ii)="" new="" diseases,="" (iii)="" unique="" applications="" of="" gene="" transfer,="" and="" (iv)="" other="" issues="" that="" may="" require="" further="" public="" review.="" the="" rac's="" recommendations,="" including="" specific="" requirements="" and="" stipulations,="" will="" be="" forwarded="" to="" the="" nih="" director.="" the="" nih="" director's="" final="" recommendation="" will="" be="" forwarded="" to="" the="" fda="" commissioner.''="" section="" iii="" (experiments="" covered="" by="" the="" nih="" guidelines),="" paragraph="" 1,="" currently="" reads:="" ``this="" section="" describes="" five="" categories="" of="" experiments="" involving="" recombinant="" dna:="" (i)="" those="" that="" require="" rac="" review="" and="" nih="" and="" institutional="" biosafety="" committee="" approval="" before="" initiation.="" .="" .="" .''="" section="" iii,="" paragraph="" 1,="" is="" proposed="" to="" read:="" ``this="" section="" describes="" five="" categories="" of="" experiments="" involving="" recombinant="" dna:="" (i)="" those="" that="" require="" institutional="" biosafety="" committee="" approval,="" rac="" review,="" and="" nih="" director="" consideration="" before="" initiation.="" .="" .="" .''="" section="" iii-a="" currently="" reads:="" ``section="" iii-a.="" experiments="" that="" require="" institutional="" biosafety="" committee="" approval,="" rac="" review,="" and="" nih="" approval="" before="" initiation="" ``experiments="" in="" this="" category="" are="" considered="" major="" actions="" (see="" section="" iv-c-1-b-(1))="" cannot="" be="" initiated="" without="" submission="" of="" relevant="" information="" on="" the="" proposed="" experiment="" to="" the="" office="" of="" recombinant="" dna="" activities,="" national="" institutes="" of="" health,="" building="" 31,="" room="" 4b11,="" bethesda,="" maryland="" 20892,="" (301)="" 496-9838,="" the="" publication="" of="" the="" proposal="" in="" the="" federal="" register="" for="" 15="" days="" of="" comment,="" review="" by="" the="" rac,="" and="" specific="" approval="" by="" the="" nih="" (not="" applicable="" for="" expedited="" review="" single="" patient="" human="" gene="" transfer="" experiments="" considered="" under="" appendix="" m-vi).="" the="" containment="" conditions="" for="" such="" experiments="" will="" be="" recommended="" by="" the="" rac="" and="" set="" by="" the="" nih="" at="" the="" time="" of="" approval.="" such="" experiments="" require="" institutional="" biosafety="" committee="" approval="" before="" initiation.="" specific="" experiments="" already="" approved="" are="" included="" in="" appendix="" d="" which="" may="" be="" obtained="" from="" the="" office="" of="" recombinant="" dna="" activities,="" national="" institutes="" of="" health,="" building="" 31,="" room="" 4b11,="" bethesda,="" maryland="" 20892,="" (301)="" 496-9838.="" ``section="" iii-a-1.="" deliberate="" transfer="" of="" a="" drug="" resistance="" trait="" to="" microorganisms="" that="" are="" not="" known="" to="" acquire="" the="" trait="" naturally="" (see="" section="" v-b),="" if="" such="" acquisition="" could="" compromise="" the="" use="" of="" the="" drug="" to="" control="" disease="" agents="" in="" humans,="" veterinary="" medicine,="" or="" agriculture.="" ``section="" iii-a-2.="" certain="" experiments="" involving="" the="" deliberate="" transfer="" of="" recombinant="" dna="" or="" dna="" or="" rna="" derived="" from="" recombinant="" dna="" into="" one="" or="" more="" human="" subjects="" (see="" section="" v-u)="" shall="" be="" considered="" major="" actions="" (see="" section="" iv-c-1-b-(1)="" and="" appendix="" m-iii),="" and="" shall="" require="" rac="" review="" and="" nih="" director="" approval,="" if="" determined="" by="" nih/="" orda,="" in="" consultation="" with="" the="" rac="" chair="" and="" one="" or="" more="" rac="" members,="" as="" necessary,="" to:="" (i)="" represent="" novel="" characteristics="" (e.g.,="" target="" disease="" or="" vector),="" (ii)="" represent="" an="" uncertain="" degree="" of="" risk="" to="" human="" health="" or="" the="" environment,="" or="" (iii)="" contain="" information="" determined="" to="" require="" further="" public="" review.="" the="" requirement="" for="" rac="" review="" shall="" not="" be="" considered="" to="" preempt="" any="" other="" required="" review="" or="" approval="" of="" experiments="" with="" one="" or="" more="" human="" subjects.="" relevant="" institutional="" biosafety="" committee="" and="" institutional="" review="" board="" reviews="" and="" approvals="" of="" the="" proposal="" should="" be="" completed="" before="" submission="" to="" nih.="" certain="" experiments="" involving="" deliberate="" transfer="" of="" recombinant="" dna="" or="" dna="" or="" rna="" derived="" from="" recombinant="" dna="" into="" one="" or="" more="" human="" subjects="" may="" qualify="" for="" the="" accelerated="" review="" process="" (see="" section="" iii-b-2).="" certain="" categories="" of="" experiments="" involving="" the="" deliberate="" transfer="" of="" recombinant="" dna="" or="" dna="" or="" rna="" derived="" from="" recombinant="" dna="" into="" one="" or="" more="" human="" subjects="" and="" that="" are="" not="" covered="" by="" section="" v-u,="" may="" be="" considered="" exempt="" from="" rac="" and/or="" nih/orda="" review="" and/or="" nih="" director="" approval="" and="" only="" require="" registration="" with="" nih/orda="" (see="" section="" iii-="" c-7).''="" section="" iii-a="" is="" proposed="" to="" read:="" ``section="" iii-a.="" experiments="" that="" require="" institutional="" biosafety="" committee="" approval,="" rac="" review,="" and="" nih="" director="" consideration="" before="" initiation="" (see="" section="" iv-c-1-b-(1)).="" ``section="" iii-a-1.="" major="" actions="" ``experiments="" described="" in="" sections="" iii-a-1-a="" and="" iii-a-2="" cannot="" be="" initiated="" without="" submission="" of="" relevant="" information="" on="" the="" proposed="" experiment="" to="" the="" office="" of="" recombinant="" dna="" activities,="" national="" institutes="" of="" health,="" suite="" 323,="" 6006="" executive="" boulevard,="" msc="" 7052,="" bethesda,="" maryland="" 20892-7052,="" (301)="" 496-9838,="" the="" publication="" of="" the="" proposal="" in="" the="" federal="" register="" for="" 15="" days="" of="" comment,="" review="" by="" the="" rac,="" and="" specific="" approval="" by="" the="" nih.="" the="" containment="" conditions="" for="" such="" experiments="" will="" be="" recommended="" by="" the="" rac="" and,="" except="" as="" provided="" in="" section="" iii-a-2,="" will="" be="" set="" by="" the="" nih="" at="" the="" time="" of="" approval.="" such="" experiments="" require="" institutional="" biosafety="" committee="" approval="" before="" initiation.="" specific="" experiments="" already="" approved="" are="" included="" in="" appendix="" d="" which="" may="" be="" obtained="" from="" the="" office="" of="" recombinant="" dna="" activities,="" national="" institutes="" of="" health,="" suite="" 323,="" 6006="" executive="" boulevard,="" msc="" 7052,="" bethesda,="" maryland="" 20892-7052,="" (301)="" 496-9838.="" ``section="" iii-a-1.="" deliberate="" transfer="" of="" a="" drug="" resistance="" trait="" to="" microorganisms="" that="" are="" not="" known="" to="" acquire="" the="" trait="" naturally="" (see="" section="" v-b),="" if="" such="" acquisition="" could="" compromise="" the="" use="" of="" the="" drug="" to="" control="" disease="" agents="" in="" humans,="" veterinary="" medicine,="" or="" agriculture.="" ``section="" iii-a-2.="" major="" actions="" involving="" human="" gene="" transfer="" experiments="" ``experiments="" involving="" the="" deliberate="" transfer="" of="" recombinant="" dna="" or="" dna="" or="" rna="" derived="" from="" recombinant="" dna="" into="" one="" or="" more="" human="" subjects="" under="" section="" i-a-1,="" and="" that="" are="" determined="" appropriate="" for="" rac="" review="" and="" nih="" director="" consideration="" shall="" be="" considered="" as="" a="" major="" action,="" except="" that="" the="" nih="" director="" will="" make="" a="" recommendation="" to="" the="" fda="" commissioner="" who="" will="" make="" the="" final="" decision="" on="" the="" proposed="" experiment.''="" sections="" iii-b-2="" and="" -3="" is="" proposed="" to="" be="" deleted:="" ``section="" iii-b-2.="" accelerated="" review="" of="" human="" gene="" transfer="" experiments="" ``as="" determined="" by="" nih/orda,="" in="" consultation="" with="" the="" rac="" chair="" and="" one="" or="" more="" rac="" members,="" as="" necessary,="" certain="" categories="" of="" human="" gene="" transfer="" experiments="" may="" be="" considered="" as="" minor="" actions="" and="" qualify="" for="" accelerated="" review="" and="" approval="" (see="" section="" iv-c-1-b-(2)-(a),="" appendix="" m-iii-a,="" and="" appendix="" m-v).="" the="" rac="" chair="" will="" present="" a="" report="" of="" all="" nih/orda="" approved="" human="" gene="" transfer="" protocols="" at="" the="" next="" regularly="" scheduled="" rac="" meeting.="" if="" nih/orda="" determines="" that="" an="" experiment="" does="" not="" qualify="" for="" the="" accelerated="" review="" process,="" the="" principal="" investigator="" must="" submit="" the="" proposal="" for="" full="" rac="" review=""> 8
weeks prior to the next scheduled RAC meeting (See Section III-A-2).
``Section III-B-3. Minor Modifications to Human Gene Transfer
Experiments
``A minor modification in a human gene transfer protocol is a
modification that does not significantly alter the basic design of the
protocol and that does not increase risk to human subjects or the
environment. After approval has been obtained by the relevant
Institutional Biosafety Committee and Institutional Review Board, NIH/
ORDA will consider the change in consultation with the RAC Chair and
one or more RAC members, as necessary. Submit minor modifications to
the Office of Recombinant DNA Activities, National Institutes of
Health, Building 31, Room 4B11, Bethesda, Maryland 20892, (301) 496-
9838. The RAC Chair will provide a report on any such approvals at the
next regularly scheduled RAC meeting.''
Section III-C-7 (Experiments that Require Institutional Biosafety
Committee Approval Before Initiation/Human Gene Transfer Experiments
Not Covered by Sections III-A-2, III-B-2, III-B-3, and Not Considered
Exempt Under Section V-U) is proposed to be deleted:
``Section III-C-7. Human Gene Transfer Experiments Not Covered by
Sections III-A-2, III-B-2, III-B-3, and Not Considered Exempt Under
Section V-U
``Certain experiments involving the transfer of recombinant DNA or
DNA or RNA derived from recombinant DNA into one or more human subjects
that are not covered by Sections III-A-2, III-B-2, III-B-3, and that
are not considered exempt under Section V-U must be registered with
NIH/ORDA. The relevant Institutional Biosafety Committee and
Institutional Review Board must review and approve all experiments in
this category prior to their initiation.''
Section IV-B-4-e-(5) (Roles and Responsibilities/Responsibilities
of the Principal Investigator During the Conduct of Research) is
proposed to be inserted:
``Section IV-B-4-e-(5). Comply with semi-annual data reporting and
adverse event reporting requirements for FDA-approved human gene
transfer experiments (see Appendix M-I-C).''
Section IV-C-1-b-(1) (Responsibilities of the National Institutes
of Health/Specific Responsibilities) currently reads:
``Section IV-C-1-b-(1). Major Actions. To execute Major Actions,
the NIH Director shall seek the advice of the RAC and provide an
opportunity for public and Federal agency comment. Specifically, the
Notice of Meeting and Proposed Actions to the NIH Guidelines shall be
published in the Federal Register at least 15 days before the RAC
meeting (not applicable for Expedited Review single patient human gene
transfer experiments considered under Appendix M-VI). The NIH
Director's decision, at his/her discretion, may be published in the
Federal Register for 15 days of comment before final action is taken.
The NIH Director's final decision, along with responses to public
comments, shall be published in the Federal Register. The RAC and
Institutional Biosafety Committee Chairs shall be notified of the
following decisions:''
Section IV-C-1-b-(1) is proposed to read:
``Section IV-C-1-b-(1). Major Actions. To execute Major Actions,
the NIH Director shall seek the advice of the RAC and provide an
opportunity for public and Federal agency comment. Specifically, the
Notice of Meeting and Proposed Actions shall be published in the
Federal Register at least 15 days before the RAC meeting. The NIH
Director's decision/recommendation, at his/her discretion, may be
published in the Federal Register for 15 days of comment before final
action is taken. The NIH Director's final decision/recommendation,
along with responses to public comments, shall be published in the
Federal Register. The RAC and Institutional Biosafety Committee Chairs
shall be notified of the following decisions:''
Section IV-C-1-b-(1)-(d) currently reads:
``Section IV-C-1-b-(1)-(d). Permitting experiments specified by
Section III-A;''
Section IV-C-1-b-(1)-(d) is proposed to read:
``Section IV-C-1-b-(1)-(d). Permitting experiments specified by
Section III-A-1;''
Section IV-C-1-b-(1)-(e) is proposed to be included:
``Section IV-C-1-b-(1)-(e). Recommendations made by the NIH
Director to the FDA Commissioner regarding RAC-reviewed human gene
transfer experiments (see Appendix M-I-B);''
Renumber remaining sections in IV-C-1-b-(1).
Sections IV-C-1-b-(2)-a and -(b) (Responsibilities of the National
Institutes of Health/Minor Actions) is proposed to be deleted:
``Section IV-C-1-b-(2)-(a). Reviewing and approving certain
experiments involving the deliberate transfer of recombinant DNA or DNA
or RNA derived from recombinant DNA into one or more human subjects
that qualify for the Accelerated Review process (see Section III-B-2);
``Section IV-C-1-b-(2)-(b). Reviewing and approving minor changes
to human gene transfer protocols under Section III-A-2 and III-B-2;''
Renumber remaining sections in IV-C-1-b-(2).
Section IV-C-3 (Responsibilities of the National Institutes of
Health/Office of Recombinant DNA Activities) currently reads:
``Section IV-C-3. Office of Recombinant DNA Activities (ORDA)
``ORDA shall serve as a focal point for information on recombinant
DNA activities and provide advice to all within and outside NIH
including institutions, Biological Safety Officers, Principal
Investigators, Federal agencies, state and local governments, and
institutions in the private sector. ORDA shall carry out such other
functions as may be delegated to it by the NIH Director, including
those authorities described in Section IV-C-1-b-(2). ORDA's
responsibilities include, but are not limited to the following:
``Section IV-C-3-a. Reviewing and approving experiments in
conjunction with ad hoc experts involving the cloning of genes encoding
for toxin molecules that are lethal for vertebrates at an LD50
100 nanograms per kilogram body weight in organisms other
than Escherichia coli K-12 (see Section III-B-1 and Appendices F-I and
F-II);
``Section IV-C-3-b. Reviewing and approving certain experiments
involving the deliberate transfer of recombinant DNA or DNA or RNA
derived from recombinant DNA into one or more human subjects, in
consultation with the RAC Chair and one or more RAC members, as
necessary, that qualify for the Accelerated Review process (see Section
III-B-2);
``Section IV-C-3-c. Reviewing and approving minor changes to human
gene transfer protocols approved under Sections III-A-2 and III-B-2, in
consultation with the RAC Chair and one or more RAC members, as
necessary;
``Section IV-C-3-d. Reviewing and approving the membership of an
institution's Institutional Biosafety Committee, and where it finds the
Institutional Biosafety Committee meets the requirements set forth in
Section IV-B-2 will give its approval to the Institutional Biosafety
Committee membership;
``Section IV-C-3-e. Publishing in the Federal Register:
``Section IV-C-3-e-(1). Announcements of RAC meetings and agendas
at least 15 days in advance (NOTE--If the agenda for a RAC meeting is
modified, ORDA shall make the revised agenda available to anyone upon
request at least 72 hours in advance of the meeting);
``Section IV-C-3-e-(2). Proposed Major Actions to the NIH
Guidelines (see Section IV-C-1-b-(1)) at least 15 days prior to the RAC
meeting;
``Section IV-C-3-f. Serve as the focal point for data management of
NIH-approved human gene transfer protocols approved under Sections III-
A-2 and III-B-2 and registered with NIH/ORDA as required under Section
III-C-7;
``Section IV-C-3-g. Serve as the executive secretary of the RAC;
and
``Section IV-C-3-h. Maintain a list of Major and Minor Actions
approved under Section III-A-2 and III-B-3 and a list of experiments
registered with NIH/ORDA as described in Section III-C-7.''
Section IV-C-3 is proposed to read:
``Section IV-C-3. Office of Recombinant DNA Activities (ORDA)
``ORDA shall serve as a focal point for information on recombinant
DNA activities and provide advice to all within and outside NIH
including institutions, Biological Safety Officers, Principal
Investigators, Federal agencies, state and local governments, and
institutions in the private sector. ORDA shall carry out such other
functions as may be delegated to it by the NIH Director. ORDA's
responsibilities include, but are not limited to the following:
``Section IV-C-3-a. Reviewing and approving experiments in
conjunction with ad hoc experts involving the cloning of genes encoding
for toxin molecules that are lethal for vertebrates at an LD50
100 nanograms per kilogram body weight in organisms other
than Escherichia coli K-12 (see Section III-B-1 and Appendices F-I and
F-II);
``Section IV-C-3-b. Evaluating human gene transfer protocols
(transmitted by the FDA) for the necessity for RAC review (see Appendix
M-I-A).
``Section IV-C-3-c. Reviewing and approving the membership of an
institution's Institutional Biosafety Committee, and where it finds the
Institutional Biosafety Committee meets the requirements set forth in
Section IV-B-2 will give its approval to the Institutional Biosafety
Committee membership;
``Section IV-C-3-d. Publishing in the Federal Register:
``Section IV-C-3-d-(1). Announcements of RAC meetings and agendas
at least 15 days in advance (NOTE--If the agenda for a RAC meeting is
modified, ORDA shall make the revised agenda available to anyone upon
request at least 72 hours in advance of the meeting);
``Section IV-C-3-d-(2). Proposed Major Actions (see Section IV-C-1-
b-(1)) at least 15 days prior to the RAC meeting;
``Section IV-C-3-e. Serve as the focal point for data management of
FDA-approved human gene transfer protocols (see Appendix M-I-C-2);
``Section IV-C-3-f. Serve as the executive secretary of the RAC;
and
``Section IV-C-3-g. Maintain a list of Major Actions recommended
for approval by the NIH Director to the FDA Commissioner, under Section
III-A-2.''
Section V-U and V-V (Footnotes and References of Sections I-IV) is
proposed to be deleted:
``Section V-U. Human studies in which the induction or enhancement
of an immune response to a vector-encoded microbial immunogen is the
major goal, such an immune response has been demonstrated in model
systems, and the persistence of the vector-encoded immunogen is not
expected, are not covered under Sections III-A-2, III-B-2, or III-B-3.
Such studies may be initiated without RAC review and NIH approval if
approved by another Federal agency.
``Section V-V. For recombinant DNA experiments in which the intent
is to modify stably the genome of cells of one or more human subjects
(see Sections III-A-2, III-B-2, and III-B-3).''
Renumber Section V-W to Section V-U.
Appendix M is revised to read as follows:
``Appendix M. Human Gene Transfer Experiments
``Appendix M-I. Human Gene Transfer Experiments--Submission
Requirements
``Appendix M-I-A. Human Gene Transfer Experiments--Submission to
the FDA
``In the interest of maximizing the resources of both the NIH and
the FDA and in simplifying the method and period for review, research
protocols involving the deliberate transfer of recombinant DNA or DNA
or RNA derived from recombinant DNA into human subjects will be
submitted directly to the FDA and considered through a consolidated
review process involving both the FDA and the NIH. Submission will be
in the format required by the FDA and the same format will be used by
the RAC when public review is deemed necessary. Upon receipt, FDA will
transmit all human gene transfer protocols to the NIH/ORDA. FDA and
NIH/ORDA will simultaneously evaluate the protocol for possible RAC
review. Protocols shall be submitted to the Director of the Division of
Cellular and Gene Therapies, Office of Therapeutics Research and
Review, Center for Biologics Evaluation and Research, Food and Drug
Administration, 1401 Rockville Pike, HFM-515, Rockville, Maryland
20852-1448, (301) 496-4709.
``Appendix M-I-B. Human Gene Transfer Experiments Requiring RAC
Review and NIH Director Consideration
``Appendix M-I-B-1. Factors that may contribute to the need for RAC
review include: (i) novel approaches, (ii) new diseases, (iii) unique
applications of gene transfer, and (iv) other issues that require
further public review. Whenever possible, Principal Investigators will
be notified within 15 working days following receipt of the submission
whether RAC review will be required (RAC reviewed applications will be
forwarded to RAC primary reviewers 8 weeks prior to the next quarterly
RAC meeting).
``Appendix M-I-B-2. Written comments submitted by the RAC primary
reviewers shall be submitted to NIH/ORDA4 weeks before the
RAC meeting at which the protocol will be reviewed.
``Appendix M-I-B-3. Written responses (including critical data in
response to the primary reviewers' comments) shall be submitted by the
Principal Investigator to NIH/ORDA 2 weeks before the RAC
meeting at which the protocol will be reviewed.
``Appendix M-I-B-4. Principal Investigators will limit their oral
responses to the RAC only to those questions that are raised during the
meeting. Oral presentations of previously submitted material and/or
critical data that was not submitted 2 weeks prior to the
RAC meeting are prohibited.
``Appendix M-I-B-5. The RAC primary reviewers' comments should
include the following:
``Appendix M-I-B-5-a. Emphasize the issues related to gene marking,
gene transfer, or gene therapy.
``Appendix M-I-B-5-b. Examine the scientific rationale, scientific
context (relative to other proposals reviewed by the RAC), whether
preliminary in vitro or in vivo data were obtained in appropriate
models and are sufficient, and whether questions related to safety,
efficacy, and social/ethical considerations have been resolved.
``Appendix M-I-B-5-c. RAC primary reviews should state whether the
proposal is: (i) acceptable as written, (ii) expected to be acceptable
with specific revisions or after satisfactory responses to specific
questions raised on review, or (iii) unacceptable in its present form.
``Appendix M-I-B-6. Following public review, the RAC's
recommendations regarding the proposal will be transmitted to the NIH
Director for consideration.
``Appendix M-I-B-7. The NIH Director's recommendation regarding the
proposal will be transmitted to the FDA Commissioner.
``Appendix M-I-C. Human Gene Transfer Experiments--NIH and FDA
Reporting Requirements
``Appendix M-I-C-1. Adverse Event Reporting
``Principal Investigators who have received approval from the FDA
to initiate a human gene transfer protocol must report any serious
adverse event immediately to the local Institutional Review Board, the
NIH Office for Protection from Research Risks, Director of the Division
of Cellular and Gene Therapies/FDA, and NIH/ORDA followed by the
submission of a written report filed with each group. Reports submitted
to NIH/ORDA shall be sent to the Office of Recombinant DNA Activities,
National Institutes of Health, 6006 Executive Boulevard, Suite 323,
Bethesda, Maryland 20892-7052, (301) 496-9838.
``Appendix M-I-C-2. Semi-Annual Data Reporting
``Principal Investigators who have received approval from the FDA
to initiate a human gene transfer protocol shall be required to comply
with semi-annual data reporting requirements. Semi-annual Data
Reporting forms will be forwarded by NIH/ORDA to the Principal
Investigators. Data submitted in these reports will be evaluated by
NIH/ORDA and reviewed by the RAC at its next regularly scheduled
meeting.''
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 about whether individual programs listed in the Catalog
of Federal Domestic Assistance are affected.
Dated: August 10, 1994.
John K. Uzzell,
Acting Deputy Director for Science Policy and Technology Transfer.
[FR Doc. 94-20826 Filed 8-22-94; 8:45 am]
BILLING CODE 4140-01-P
