Federal Register / Voi. 59^,. No. 127 t Tuesday, Juty 5, 199^4 t Notices 
34529 
no risk. iQ public health or to the 
environment is expected. Nevertheless, 
Appendix M— l-B—4-b specifically asks 
the researchers to address this pomU 
This appendix will be consicered for 
revision as experience in evaluating 
proposals accumulates and as new 
scientific developments occur. This 
review will be carried out periodically 
as needed. 
A proposal involving the transfer of 
recombinant DNA or DMA or RNA 
derived from 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 and Institutional 
Review Board in accordance with DHHS 
Regulations tor the Federal Regulations 
for the Protection of Human Subjects (45 
Code of Federal Regulations, Part 46). If 
a proposal involves children, special 
attention should be paid to subpart D of 
these DHHS regulations. The 
Institutional Review Board and 
fnstitutionaf Biosafety Committee 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 sirauhaneously 
with review by other involved Federal 
agencies (see Appendix M-VIT-A) 
provided that NIH/ORDA is notified of 
the simultaneous review. Meetings of 
the full RAC and its subcommittee will 
be open to the pubfic except where 
trade secrets or proprietary information 
would be disclosed. The committee 
prefers that proposals submitted for 
RAC review contairr no proprietary 
informatkm or trade secrets, enabling all 
aspects of the review to be open to the 
public. Poblic review of these protocols 
will serve to inform the public about the 
technica'l aspects of the proposals as 
well as the meaning an<l significance of 
the research. 
The clinical application of 
recombinant DNA techniques raises two 
general kinds of questions: (i) the 
questions usually discussed by 
Institutional Review Boards in their 
review of any proposed research 
involviag one or more human subjects; 
and (n) broader issues. The first type of 
question is addressed principally in 
Appendix M- 1 of this document. Several 
broader issues are discussed throughout 
Appendix M. 
Appendix M.T requests a description 
of the protocol with apeciai attention to 
the short-term risks and benefits of the 
proposed research to the patient and to 
other people, the selection ol patients, 
informed consent, privacy, ami 
confidentiality. Appendix M-II 
addresses special issues pertaining to 
the free flow of information about the 
clinical trials. These issues tie outside 
the usual purview of Institutional' 
Review Boards and reflect general 
public concerns about biomedical 
research. Appendix M-IIl summarizes 
guidelines for submission of human 
gene transfer protocols for RAC review. 
Appendix M-IV specifies reporting 
requirements. Appendix M-V describes 
the procedures for Accelerated; Review 
of human gene transfer experiments. 
Appendix M-VI describes the 
procedures to be followed for Expedited 
Review of single patient human gene 
transfer experiments. Appendix M-VII 
contains the footnotes to Appendix M. 
The RAC will not at present entertain 
proposals for germ-line alterations but 
wiE consider for approval protocols 
involving somatic cell gene transfer. The 
purpose of somatic ceU gene therapy is 
to treat an individual patient, eg., by 
inserting a properly functioning gene 
into a patient’s somatic cells. In germ- 
line alteratrons, a specific attempt is 
made to Introduce genetic changes into 
the germ CreprodncUve) cells of an. 
individual, with the aim of changing the 
set of genes passed on to the 
individual’s offering. 
The acceptability of human somatic 
cell gene therapy has been addressed in 
several public documents as well as in 
numerous academic studies. In 
November 19S2, the President’s 
Commission for the Study of Ethical 
Problems in Medicine and Biomedical 
and Behavioral Research published a 
report. Splicing Life, which resulted 
from a two-year process of pubh'c 
deliberations and hearing. Upon release 
of that report, a U.S. House of 
Representatives subcommittee held 
three days of public hearings with 
witnesses from a wide range of fields 
firom the biomedical and social' sciences 
to theology, philosophy, and law. hr 
December 1964, the Office of 
Technology Assessment released a 
background paper, Huma.n Gene 
Therapy, which conchidedr civic, 
religious, scientific, and medical grouprs 
have all accepted, in principle, the 
appropriateness of gene therapy of 
somatic cells in humans for specific 
genetic diseases. Somatic cell gene 
therapy is seen as an extension of 
present methods of therapy that might 
bo preferable to other technologies. In 
liglit of this, public support, the RAC is 
prepared to consider proposals for 
somatic cell gene therapy. 
In its cvahiation of prop<»sals 
iirvobring the transfer of njcombinant 
DNA or DNA or RNA derived from 
recombinant DNA intoone ormore 
human subjects, the RAC will consider 
whether the design of such' experiments 
offers adequate assuraTioe that their 
consequences wiE not go beyond their 
purpose, which is the same as the 
traditional purpose of clinical 
investigations, namely, fo protect the 
health and well-being of one or more 
human subjects being treated while at 
the same time gathering generaFizable 
knowledge. Two possible undesirable 
consequences of the transfer of 
recombinant DNA would be 
unintentional: (i)' vertical transmission 
of genetic changes fi-om- an individual to 
his/her offspring, or (TfJ horrzcoital 
transmission of viral mfection to other 
persons with whom the individual 
comes in contact. Accorcffngly, this 
docmnent requests information that will 
enable the RAC and/or NER/ORDA to 
assess the possibility that the proposed 
experiments will inadvertently affect 
reproductive cells or lead to infection of 
other people (e.g., medical personnel or 
relatives). 
In recognition of the social concern 
that surrounds the subject of gpne 
transfer, the RAC and NIH/ORDA wilt 
cooperate with other groups in assessing 
the possible long-temi consequences of 
the transfer of recombinant DNA or 
DNA or RNA derived froia recombinant 
DNA into one or mote human subjects 
and related laboratory and animal 
experiments in oidec to define 
appropriate human applications of this 
emerging technology. 
Responses to Appendix M should be 
provided in the form of eiithsi written 
answers or references to specific 
sections of the protocol or its 
appendices. Principar Investigators 
should mdicate poinis whidi are not 
applicable with a brief expfonation. 
Principal Investigatots submitting 
proposals that employ essentially the 
same vector systems (or with minor 
variations), and/or that are based on the 
same preclinical testing as proposals 
previoosly reviewed by the RAC, may 
rcler to preceding documents without 
having to rewrite such material. 
Appendix M-I. Description of Proposal 
Appendix M-1— A. Objectives and 
Rationale of the Proposed Research 
State concisely the overall objectives 
and rationale of the proposed study. 
Provide information on the specific 
points that relate to whichever type of 
research is being proposed. 
Appendix M-f-A-1. Use of 
Rocoinhinant DN!A for Therapeutjc 
Purposes. For research in which 
recorabiiiant DNA is transferred in order 
to treat a disease or disorder (e.g., 
genetic diseases, cancer, and metabolic 
[ 730 ] 
Recombinant DNA Research, Volume 19 
