34476 
Federal Register / V'ol. 59, No. 127 / Tuesday, July 3, 1994 / Notices 
Any change in containment level, 
utiicti is different from those .specified 
in the ,N1H Guidelines, may not be 
initiated without the express approval 
of NIH/ORDA (see Minor Actions. 
Section IV-C-l-b-(2) and its 
siiiisecfions). 
Section Ill-A. Experiments That Require 
Institutional Bio.safety Committee 
Approval. RAC Review, and NIH 
.Approval Before Initiation 
Experiments in this category are 
considered Major Actions (see Section 
IV-C-l-b-(l)) and 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, reviewed by the RAC, and 
specific approval by the NIH (not 
applicable for Elxpedited 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. Sucli 
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-l-b-(l) and 
Appendix M-IIT), 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 hinnan health or the 
environment, or (ili) 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-B. Experiments That Require 
NIH/ORDA and Institutional Biosafety 
Committee Approval Before Initiation 
Section III-B- 1 . Experiments Involving 
the Cloning of Toxin Molecules with 
LD 50 of Less Than 100 Nanograms per 
Kilogram Body Weight 
Deliberate formation of recombinant 
DNA containing genes for the 
biosynthesis of toxin molecules lethal 
for vertebrates at an LD 50 of less than 
100 nanograms per kilogram body 
weight (e.g., microbial toxins such as 
the botulinum toxins, tetanus toxin, 
diphtheria toxin, and Shigella 
dysenteriae neurotoxin). Specific 
approval has been given for tlie cloning 
in Escherichia coli K-12 of DNA 
containing genes coding for the 
biosynthesis of toxic molecules which 
are lethal to vertebrates at 100 
nanograms to 100 micrograms per 
kilogram body weight Specific 
experinnents already approved under 
this section 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-B-l-(a). Experiments in 
this category carmot be initiated without 
submission of relevant information on 
the proposed experiment to NIH/ORDA. 
The containinent conditions for such 
experiments will be determined by NIH/ 
OI^A in consultation with ad hoc 
experts. Such experiments require 
Institutional Biosafety Committee 
approval before initiation (see Section 
IV- B-2-MD). 
Section IIl-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-l-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 w'eeks prior to the next scheduled 
R.AC meeting (See Section III-A-2). 
Section IIl-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. Experiments That Require 
Institutional Biosafety Committee 
Approval Before Initiation 
Prior to the initiation of an 
experiment that falls into this category, 
the Principal Investigator must submit a 
registration document to the 
Institutional Biosafety Committee which 
contains the following information: (i) 
The source(s) of DNA; (ii) the nature of 
the inserted DNA sequences: (iii) the 
host(s) and vector(s) to be used; (iv) if 
an attempt will be made to obtain 
expression of a foreign gene, and if so, 
indicate the protein that will be 
produced; and (v) the containment 
conditions that will be implemented as 
specified in the NIH Guidelines. For 
experiments in this category, the 
registration document shall be dated, 
signed by the Principal Investigator, and 
filed with the Institutional Biosafety 
Committee. The Institutional Biosafety 
Committee shall review and approve all 
Recombinant DNA Research, Volume 19 
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