6706 
Federal Register / VoL 59, No. 29 / Friday, February 11, 1994 / Notices 
Guidelines are encouraged to use the Points 
to Consider. Experiments in which 
recombinant DNA is introduced into one or 
more human subjects with the intent of 
stably modifying the subject’s genome are 
covered by Sections 111— A-3 and III— B— 2 of 
the NIH Guidelines (see Footnote 21 of the 
NIH Guidelines). Elxpieriments in which 
recombinant DNA is introduced into one or 
more human subjects with no risk of stably 
modifying the subject’s genome are covered 
under Section IU-C-6 of the NIH Guidelines 
(see Footnote 21 of the NIH Guidelines). 
Sections III— A— 3, III— B— 2, and UI-C-6 of the 
NIH Guidelines apply both to recombinant 
DNA and to DNA or RNA derived from 
recombinant DNA." 
(Amended] ‘This document is intended to 
provide guidance in preparing proposals for 
NIH consideration under Sections UI-A— 3 
and in-B— 2 of the NIH Guidelines. Section 
III-A-3 addresses Major Actions to the NIH 
Guidelines involving the transfer of 
recombinant DNA into one or more human 
subjects that have been 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 (tii), contain information 
determined to require frirther public review. 
Proposals considered under Section 111— A-3 
of the NIH Guidelines will be reviewed by 
the RAC and approved by the NIH Director. 
RAC review of experiments considered under 
Section IIl-A-3 of the NIH Guidelines will 
follow publication of a precis of the proposal 
in the Federal Register and an opportunity 
for public comment Section III— ^2 
addresses Minor Actions to the NIH 
Guidelines involving die transfer of 
recombinant DNA into one more human 
subjects that have been determined by NIH 
(ORDA), in consultation with the RAC C2iaLr 
and one or more RAC members, as necessary, 
to qualify for the accelerated review process. 
Proposals considered under Sections lII-A-3 
and in-B-2 will be on a case-by-case basis. 
A list of actions to the NIH Guidelines 
approved under Sections IU-A-3 and LII-B- 
2 involving the transfer of recombinant DNA 
Into one or more human subjects is available 
from the Office of Recombinant DNA 
Activities. Building 31, Room 4B11, National 
Institutes of Health, Bethesda, Maryland, 
20892. The list of actions to the NIH 
Guidelines involving the transfer of 
recombinant DNA into one or more human 
subjects does not include experiments 
considered to be exempt from RAC and NIH 
(ORDA) review under Section IIl-C-6 of the 
NIH Guidelines.” 
(No changes] "In general, it is expected 
that the transfer of recombinant DNA into 
one or more human subjects will not present 
a risk to public health or to the environment 
as the recombinant DNA is expected to be 
confined to human subjects. Nevertheless, 
Part I-B— 4-b specifically asks the researchers 
to address this p>oint” 
(No changes] "This document will be 
considered for revision as experience in 
evaluating proposals accumulates and as new 
scientific developments occur. ’This review 
will be carried out periodically as needed." 
[Amended] "A proposal involving the 
transfer of recombinant DNA into one or 
more human subjects will be considered by 
the RAC and/or NIH (ORDA) only after the 
protocol has been approved by the local 
institutional Biosafety Committee (IBC) and 
the local Institutional Review Board (IRB) in 
accordance with DHHS Federal Regulations 
for the Protection of Human Subjects (45 
Code of Federal Regulations, port 46). (If a 
proposal involves children, special attention 
should be paid to subpait D of these DHHS 
regulations.) The IRB and IBC may, at their 
discretion, condition their approval on 
further specific deliberation by the RAC and/ 
or NIH (ORDA). Consideration of human 
gene transfer proposals by the RAC and/or 
NIH (ORDA) may proceed simultaiveously 
wHh review by other involved federal 
agencies (See Part VI-A) provided that NIH 
(ORDA) is notified of the simultaneous 
review. Meetings of the full RAC will be open 
to the public except where trade secrets or 
proprietary information would be disclosed. 
The committee prefers that proposals 
submitted for RAC review contain no 
proprietary Infiormation or trade secrets, 
enabling all aspects of the review to be open 
to the public. The public review of these 
protocols will serve to inform the public not 
only on the technical aspects of the proposals 
but also on the meaning and significance of 
the research." 
(No changes] "The clinical application of 
recombinant DNA techniques raises two 
general kinds of questions; (i) The questions 
usually discussed by IRBs in their review of 
any proposed research involving one or more 
human subjects; and (ii) broader issues. The 
first type of question is addressed principally 
in Part III of this document. Several broader 
issues are discussed later in this Introduction 
and in part fl below." 
(Amended] “Following this Introduction, 
this document is divided into four parts. Part 
1 requests a description of the protocol with 
special attention to the sbort-tenn risks and 
benefits of the proposed research to the 
patient and to other people, the selection of 
patients, informed consent, and privacy and 
confidentiality. In part II. investigators are 
requested to address special issues pertaining 
to the free flow of Information about the 
clinical trials. These issues lie outside the 
usual purview of IRBs and reflect general 
public concerns about biomedical research. 
Part III summarizes other requested 
documentation that will assist the RAC and/ 
or NIH (ORDA) in its review of the proposals. 
Part IV specifies reporting requirements." 
(Amended) "The RAC will not at present 
entertain proposals for germ-line alterations 
but will consider for approval protocols 
involving somatic cell gene transfer. The 
purpose of somatic cell gene therapy is to 
treat an individual patient, e.g., by inserting 
a projperly functioning gene into a patient's 
somatic cells. In germ line alterations, a 
spedfic attempt is made to introduce genetic 
changes into the germ (reproductive) cells of 
an individual, with the aim of changing the 
set of genes passed on to the individual’s 
offspring." 
(No changes] "The acceptability of human 
somatic cell gene therapy has been addressed 
in several public documents as well as in 
numerous academic studies. The 1962 report 
of the President's Commission for the Study 
of Etlucal Problems in Medicine and 
Biomedical and Behavioral Research. 
Splicing Life, resulted from a two-year 
process of public deliberations and hearings. 
Upon release of that repwrl. a U.S. House of 
Representatives subcommittee held three 
days of public hearings with witnesses from 
a wide range of fields from the biomedical 
and social sciences to theology, philosophy, 
and law. In December 1984. t^ Office of 
Technology Assessment released a 
background paper. Human Gene Therapy, 
which concluded: civic, religious, scientific, 
and medical groups have all acxrepted, in 
principle, the appropriateness of gene 
therapy of somatic cells in humans for 
specif genetic diseases. Somatic cell gene 
therapy is seen as an extansioa of present 
method of therapy that might be preferable 
to other technologies. In li^t of this public 
support, the RAC is prepaid to consider 
proposals for somatic c^l gene therapy.” 
(Amended] "In its evaluation of proposals 
involving the transfer of recombinant DMA 
into one or more human subjects, the RAC 
%vill consider whether the d^ign of such 
experiments offers adequate assurance that 
their consequences will not go beyond their 
purpose, which is the same as the traditional 
purpose of clinical investigations, namely, to 
protect the health and well-being of the 
individual subjectfs) being treat^ wtiile at 
the same time gathering generalizable 
knowledge. Two possible undesirable 
consequences of ffie transfer of recombinant 
L^A would be unintentional: (!) Vertical 
transmission of genetic changes from an 
individual to his of her offspring, or (ii) 
horizontal transmission of viral infection to 
other persons with whom the individual 
comes in contact Accordingly, this 
document requests information that will 
enable the RAC and/or NIH (ORDA) to assess 
the possibility that the proposed exp>eriments 
will inadvertently affect reproductive cells or 
lead to infection of other p>eople (e.g., 
personnel or relatives). 
(Amended) "In recognition of the social 
concern that surrounds the subject of gene 
transfer, the RAC and NIH (ORDA) will 
cooperate with other groups in assessing the 
possible long-term consequences of the 
transfer of recombinant DNA Into one or 
more human subjects and related laboratory 
and animal experiments in order to define 
appropriate human applications of this 
emerging technology." 
(No changes] "Responses to the questions 
raised in these Points to Consider should be 
provided in the form of either written 
answers or references to specific sections of 
the protocol or its appendices." 
(No changes] “Investigators should 
indicate points which are not applicable with 
a brief explanation. Investigators submitting 
proposals that employ essentially the same 
vector systems (or with minor variatioosh 
and/or that are based on the same predioical 
testing as proposals previously reviewed by 
the RAC. may refer to preceding documents 
without having to rewrite such material." 
(No Changes — Part I- A through l-C.| 
(Proposed Changes — Parts I-D and I-E. See 
agenda item XII proposed amendments.) 
[ 6 ] 
Recombinant DNA Research, Volume 19 
