Federal Register / Vol. 59, No, 127 / Tuesday, July 5, 1994 / Notices 
34199 
describe higher levels of containment 
for research with certain transgenic 
animals involving agents which pose 
recognized hazard. 
In constructing the NIH Guidelines, it 
was necessary to define boundary 
conditions for the different levels of 
physical and biological containment 
and for the classes of experiments to 
which they apply. These definitions do 
not take into account all existing and 
anticipated information on special 
procedures that will allow particular 
experiments to be conduct^ under 
different conditions than indicated here 
without affecting risk. Individual 
investigators and Institutional Biosafety 
Committees are urged to devise simple 
and more effective containment 
procedures and to submit recommended 
changes in the NIH Guidelines to permit 
the use of these procedures. 
Section III. Experiments Covered by the 
NIH Guidelines 
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 
(see section Dl-A), (il) those that require 
NIH/ORDA and Institutional Biosafety 
Committee approval before initiation 
(see section ni-B); (iii) those that 
require Institutional Biosafety 
Committee approval before initiation 
(see section III-C), (iv) those that require 
Institutional Biosafety Committee 
notification simultaneous with 
initiation (see section III-D), and (v) 
those that are exempt from the NIH 
Guidelines (see section 111-E). 
Note: If an experiment falls into either 
section IIl-A or section Ul-B and one of the 
other categories, the rules pertaining to 
section Ill-A or section Ill-B shall be 
followed. If an experiment falls into section 
III- E and into either sections III-C or III-D 
categories as well, the experiment is 
considered exempt from the NIH Guidelines. 
Any change in containment level, 
which is different from those specified 
in the NIH Guidelines, may not be 
initiated without the express approval 
of NIH/ORDA (see Minor Actions, 
section IV-C-l-b-(2) and its 
subsections). 
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-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, review'ed by the RAC, and 
specific approval by the NIH (not 
applicable for Expedited Review single 
patient human gene transfer 
experiments considered under 
Appendix M-Vl). 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 A^ctivities, 
National Institutes of Health, Building 
31, room 4B11, Bethesda, Maryland 
20892, (301) 496-9838. 
Section ID-A-l. 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 lIl-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 rV-C-l-b-(l) 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 Conunittee 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 fi-om 
recombinant DNA into one or more 
human subjects may qualify for the 
Accelerateo Review process (see section 
IlI-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-IJ, 
may be considered exempt from RAC 
and/or NIH/ORDA re\dew and/or Nil i 
Director approval and only require 
registration witli NIH/ORDA (see 
section lIl-C-7). 
Section Ill-B. Experiments That Reqri.'e 
NIH/ORDA and Institutional Biosafetv 
Committee Approval Before Initiation 
Section Ill-B-1. Experiments Involvii-q 
the Ooning of Toxin Molecules with 
LDso of Less than 100 Nonograms per 
Kilogram Body Weight 
Deliberate formation of recombinant 
DNA containing genes for the 
biosynthesis of toxin mpler.ules lethal 
for vertebrates at an LDso 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 the 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 
experiments already approved under 
this section may be obtained fi-om the 
Office of Recombinant DNA Activities. 
NaUoiral Institutes of Health, Building 
31, room 4B11, Bethesda. Maryland 
20892, (301) 496-9838. 
Section IU-B-l-(a). Experiments in 
this category caimot be initiated without 
submission of relevant information on 
the proposed experiment to NIH/ORDA. 
The containment 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-b-(l)) 
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 
quahfy for Accelerated Review and 
approval (see section lV-C-l-b-(2)-(a), 
Apjmndix 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 schedule^' 
RAC meeting (See section liI-A-2). 
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Recombinant DNA Research, Volume 19 
