33464 
Federal Register / Vol. 50, No. 160 / Monday, August 19, 1985 / Notices 
is notified of the simultaneous review. 
Meetings of the committee will be open 
to the public except where trade secrets 
or proprietary information will be 
disclosed. The committee would prefer 
that the first proposal submitted for 
RAC review contain no proprietary 
information 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. 
(5) The clinical application of 
recombinant DNA techniques to human 
gene therapy raises two general kinds of 
questions: (1) The questions usually 
discussed by IRBs in their review of any 
proposed research involving human 
subjects: and (2) broader social issues. 
The first type of question is addressed 
principally in Part I of this document. 
Several of the broader social issues 
surrounding human gene therapy are 
discussed later in this Introduction and 
in Part II below. 
(6) Following the Introduction, this 
document is divided into four parts. Part 
I deals with the short-term risks and 
benefits of the proposed research to the 
patient 3 to other people, as well as with 
issues of fairness in 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 clinical trials of 
gene therapy. 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 its working group in 
their review of gene therapy proposals. 
Part IV specifies reporting requirements; 
/ (7) A distinction should be drawn 
between making genetic changes in 
somatic cells and in germ line cells. The 
purpose of somatic cell gene therapy is 
to treat an individual patient, e.g., by 
inserting a properly functioning gene 
into a patient’s bone marrow cells in 
vitro and then reintroducing the cells 
into the patient’s body. In germ line 
alterations, a specific 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. 
The RAC and its working group will not 
clinical trials of human somatic-cell gene therapy. 
For general information on FDA's policies and 
regulatory requirements, please see the Federal 
Register, Volume 49. pages 5087S-80, 1984. 
s The term "patient" and its variants are used in 
the text as a shorthand designation for "patient- 
subject." 
at present entertain proposals for germ 
line alterations but will consider for 
approval protocols involving somatic- 
cell gene therapy. 
(8) The acceptability of human 
somatic-cell gene therapy has been 
addressed in several recent documents 
as well as in numerous academic 
studies. The November 1982 report of 
the President’s Commission for the 
Study of Ethical Problems in Medicine 
and Biomedical and Behavioral 
Research, Splicing Life, resulted from a 
tw'o-year process of public deliberations 
and hearings; upon release of that 
report, a House 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, the Office of 
Technology Assessment released a 
background paper, Human Gene 
Therapy, which brought these earlier 
documents up-to-date. As the latter 
report concluded: 
Civic, religious, scientific, and medical 
groups 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 be preferable to other technologies. 
(9) Concurring with this judgment, the 
RAC and its working group are prepared 
to consider for approval somatic-cell 
therapy protocols, provided that the 
design of such experiments offers 
adequate assurance that their 
consequences will not go beyond their 
purpose, which is the same as the 
traditional purpose of all clinical 
investigations, namely, to benefit the 
health and well-being of the individual 
being treated while at the same time 
gathering generalizable knowledge. 
(10) The two possible undesirable 
consequences of somatic-cell therapy 
would be unintentional (1) vertical 
transmission of genetic changes from an 
individual to his or her offspring or (2) 
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 its working group to assess the 
likelihood that the proposed somatic-cell 
gene therapy will inadvertently affect 
reproductive cells or lead to infection of 
other people (e.g., treatment personnel' 
or relatives). 
(11) In recognition of the social 
concern that surrounds the general 
discussion of human gene therapy, the 
working group will continue to consider 
the possible long-range effects of 
applying knowledge gained from these 
and related experiments. While research 
in molecular biology could lead to the 
development of techniques for germ line 
intervention or for the use of genetic 
means to enhance human capabilities 
rather than to correct defects in patients, 
the working group does not believe that 
these effects will follow immediately or 
inevitably from experiments with 
somatic-cell gene therapy. The working 
group will cooperate with other groups 
in assessing the possible long-term 
consequences of somatic-cell gene 
therapy and related laboratory and 
animal experiments in order to define 
appropriate human applications of this 
emerging technology. 
(12) 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. 
I. Description of Proposal 
A. Objectives and Rationale of the 
Proposed Research 
State concisely the overall objectives 
and rationale of the proposed study. 
Please provide information on the 
following specific points: 
1. Why is the disease selected for 
treatment by means of gene therapy a 
good candidate for such treatment? 
2. Describe the natural history and 
range of expression of the disease 
selected for treatment. In your view, are 
the usual effects of the disease 
predictable enough to allow for 
meaningful assessment of the results of 
gene therapy? 
3. Is the protocol designed to prevent 
all manifestations of the disease, to halt 
the progression of the disear e after 
symptoms have begun to appear, or to 
reverse manifestations of the disease in 
seriously ill victims? 
4. What alternative therapies exist? In 
what groups of patients are these 
therapies effective? What are their 
relative advantages and disadvantages 
as compared with the proposed gene 
therapy? 
B. Research Design, Anticipated Risks 
and Benefits 
1. Structure and Characteristics of the 
Biological System 
Provide a full description of the 
methods and reagents to be employed 
for gene delivery and the rationale for 
their use. The following are specific 
points to be addressed: 
a. What is the structure of the cloned 
DNA that will be used? 
(1) Describe the gene (genomic or 
cDNA), the bacterial plasmid or phage 
[326] 
