NOTICES 
60099 
the Guidelines now specify that an in- 
stitution need not register with NIH 
its projects funded by another Federal 
agency when that agency maintains a 
registry and provides the NIH with es- 
sential information. The institution 
will register projects directly with NIH 
if the supporting Federal agency does 
not choose to maintain its own regis- 
try. 
At a meeting held with the DHEW 
Committee, representatives of the 
Pharmaceutical Manufacturers Associ- 
ation urged greater protection for pro- 
prietary and patent information under 
the Guidelines. The proposed revised 
Guidelines offered a system of volun- 
tary registration and certification for 
the private sector which was not avail- 
able under the 1976 Guidelines. In ad- 
dition, a representative from the Com- 
merce Department also urged expan- 
sion of the Guidelines to protect pro- 
prietary and patent information. On 
the other hand, environmental inter- 
est groups have expressed concern 
that there be maximum disclosure of 
information. Because of the complex- 
ity of the issue, and the general per- 
ception that NIH does not have the 
powers to completely protect propri- 
etary rights and trade secrets, this 
aspect of the Guidelines will be han- 
dled separately after their issuance. 
The Food and Drug Administration is 
now considering issuing regulations 
that would require drug companies to 
comply with the NIH Guidelines. 
Compliance. Several of the commen- 
tators and witnesses at the September 
15 hearing recommended stronger lan- 
guage in the Guidelines concerning 
compliance with the Guideline provi- 
sions. The proposed revision stated 
that noncompliance may result in sus- 
pension, limitation, or termination of 
financial assistance. Several commen- 
tators urged that the language be 
made mandatory. Others suggested 
that possible violations be ranked, 
with definite penalties set in each 
case, including criminal penalties. Still 
others urged invocation of Section 361 
of the PHS Act to ensure compliance 
through regulation. 
Many of these issues were raised at 
the December hearing of the Direc- 
tor’s Advisory Committee and in corre- 
spondence on the Guidelines as pro- 
posed by the RAC. In response to the 
suggestions, a section on compliance 
was included in the proposed revision. 
However, as I noted in my Decision ac- 
companying that publication, NIH has 
no authority to impose fines in the ab- 
sence of new legislation. I also noted 
that appropriate HEW procedures will 
be followed should suspension or ter- 
mination of a grant be necessary. In 
light of the lack of statutory authori- 
ty, penalties for negligence and crimi- 
nal penalties should not be specified. 
It has been suggested that NIH might 
seek reimbursement for any funds ex- 
pended upon activities not conducted 
in accordance with contractual assur- 
ances. This recommendation differs 
from current HEW grant policy and 
will require much more consideration. 
On the basis of DHEW Committee 
discussion, a new provision will allow 
NIH to require prior approval of any 
and all recombinant DNA research 
projects if the institution fails to 
compy with the Guidelines. 
Invocation of Section 361 of the 
Public Health Act has been carefully 
considered by the Interagency Com- 
mittee and the Department over the 
past two years. The most recent ex- 
pression of interest in this authority 
was in a letter six Senators requesting 
Secretary Calif ano to consider invok- 
ing Section 361 to regulate recombin- 
ant DNA research. The letter and the 
Secretary’s response are included in 
Appendix III to this Decision. Briefly, 
the Secretary said that the Depart- 
ment does not intend to evoke existing 
statutory authorities to regulate re- 
combinant DNA activities at this time. 
He went on to quote the Interagency 
Committee’s report of March 15, 1977, 
dealing with elements for legislation, 
including the determination that Sec- 
tion 361 would require a reasonable 
basis for concluding that recombinant 
DNA research may cause human dis- 
ease. Such a conclusion is tenuous at 
best and would at present be an inap- 
propriate basis for invoking the regu- 
lation. The Secretary, however, noted 
in his letter that if the Department 
had to act speedily, Section 361 is 
available and would be used. In the 
Secretary’s view, only legislation 
would justify establishing regulations. 
V. Footnotes and References 
In reply to correspondents’ suggestions 
and NIH review, minor changes have been 
made in Footnotes 3 and 5; and five new 
footnotes— 2A, 19A, 33A, 33B, and 37A— 
have been added. 
A correspondent recommended that text 
be added to Footnote 2 to discuss the basis 
for allowing cloning of genetic information 
from Vesicular stomatitis virus and moder- 
ate-risk oncogenic viruses. Since Footnote 2 
already refers the reader to the July 28, 
1978, Decision document, where this is dis- 
cussed in detail, no further discussion in 
Footnote 2 seems necessary. 
Appendix A 
(Director’s Decision concerning Appendix 
A of the Guidelines) 
There were many comments concerning 
the list of exchangers in Appendix A to be 
exempted from the Guidelines under Ex- 
emption I-E-4. 
Some correspondents recommended addi- 
tions to the list, including Caulobacter cres- 
centus, Agrobacterium, Proteus, and Xanth- 
omonas. 
On the other hand, some correspondents 
felt that there was insufficient documenta- 
tion for the entries on the list and that the 
list should be by species, not genus. 
One correspondent recommended citing 
Bergey's Manual of Determinative Bacteri- 
ology. Another wrote. "It is also question- 
able why one should list Escherichia coli ex- 
changers and not others in nature such as 
the organisms that exchange with Bacillus 
subtilis, with Haemophilus influenzae, with 
Neisseria gonorrhoeae, etc." 
In response to the many comments re- 
ceived, the list of organisms to be exempt 
from the Guidelines under Exemption I-E-4 
has been carefully reconsidered. The discus- 
sion below attempts to make more explicit 
the considerations used in constructing this 
list. In addition, the criteria for Inclusion on 
the list have been tightened, reducing the 
list considerably and thus exempting fewer 
experiments from the Guidelines. Refer- 
ences supporting the entries to the list are 
given below (refs. 1-22). The final list (Ap- 
pendix A) closely resembles the “first list” 
described in Appendix D to the July 28, 
1978, Environmental Impact Assessment. 
It should be emphasized that the evolu- 
tion of this list will continue as more experi- 
ments are done and as we gain more knowl- 
edge in this rapidly advancing field. In addi- 
tion, other organisms recommended by 
some of the commentators ( Bacillus or Hae- 
mophilus species, for instance) are currently 
being considered by the RAC for future in- 
clusion under this exemption. 
As noted in Appendix D to the July 23, 
1978, Environmental Impact Assessment: 
"The natural transfer of genes between bac- 
teria occurs by transduction (bacterial virus- 
mediated). transformation (uptake of isolat- 
ed DNA by a bacterial cell), or conjugation 
(plasmid-mediated transfer of genes be- 
tween bacteria requiring cell-to-cell con- 
tact). A reasonable generalization is that 
virtually all closely related species of bacte- 
ria can exchange genes by transduction and 
transformation, the former limited by the 
relatively narrow host-range of transducing 
bacteriophage and the latter by the require- 
ment. in the case of chromosomal DNA, for 
homology of DNA in most recombination 
events. Conjugal mating with exchange of 
DNA can occur between virtually all Gram- 
negative bacteria, including naturally occur- 
ring soil and intestinal species, when medi- 
ated by a plasmid of broad host-range (for 
example, the Inc P-1 group plasmids). Re- 
cently, conjugal mating has also been shown 
to occur between strains of certain species 
of Streptococcus, a Gram-positive organism 
(for example, Streptococcus faecalis). To 
date, however, conjugal mating has not 
been demonstrated between Gram-negative 
and Gram-positive bacteria. 
“The relatedness of different microbial 
species can be estimated by determining the 
extent of DNA homology between them or 
by studying the properties of different mi- 
croorganisms in genetic crosses. As a general 
rule, organisms that show considerable ho- 
mology of their nucleotide sequences under 
a standard set of experimental conditions 
have the capacity to mutually integrate 
chromosomal genes. For example, in the 
case of the Enterobacteriaceae family of 
bacteria (includes Escherichia coli K-12), 
there is both extensive DNA-DNA homology 
(1) and chromosomal gene exchange (2) 
with a reasonable correlation between the 
degree of DNA-DNA homology and the ca- 
pacity to mutually integrate chromosomal 
genes. 
“Genetic relatedness, as indicated by a 
high level of DNA-DNA homology between 
different microorganisms, is not, however. 
FEDERAL REGISTER, VOL. 43, NO. 247— FRIDAY, DECEMBER 22, 1978 
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