2942 
Federal Register / Vol. 50. No. 14 / Tuesday. January 22. 1985 / Notices 
Points To Consider in the Design and 
Submission of Human Somatic-Cell Gene 
Therapy Protocols 
l forking Group on Human Gene Therapy 
AY H Recombinant DXA Advisory Committee 
Outline 
Introduction 
I. Description of Proposal 
A. Objectives and ra’ionale of the 
proposed research 
B. Reseach design, anticipated risks and 
benefits 
1. Structure and characteristics of the 
biological system 
2. Preclinical studies, including risk 
assessment studies 
3. Clinical procedures, including patient 
monitoring 
4. Public-health considerations 
5. Qualifications of investigators, 
adequacy of laboratory and clinical 
facilities 
C. Selection of subjects 
D. Informed consent 
E. Privacy and confidentiality 
II. Social Issues 
A. Provision of accurate information to the 
public 
B. Timely communication of reseach 
methods and results to investigators and 
clinicians 
C. Other concerns of society 
III. Requested documentation 
A. Original protocol 
B. IRB and IBC minutes and 
recommendations 
C. One-page abstract of gene therapy 
protocol 
D. Curricula vitae for professional 
personnel 
E. Responses to the questions raised in 
these "Points to Consider" 
F. Indication of other federal agencies to 
which the protocol is being submitted 
C. Other pertinent material 
Points to Consider in the Design and 
Submission of Human Somatic-Cell 
Gene Therapy Protocols 
Introduction 
Experiments in which recombinant 
DNA 1 is introduced into cells of a 
human subject with the intent of stably 
modifying the subject’s genome are 
covered by Section III-A-4 of the 
National Institutes of Health (NIH) 
Guidelines for Research Involving 
Recombinant DNA Molecules (49 FR 
46266). Section III— A — 4 requires such 
experiments to oe reviewed by the NIH 
Recombinant DNA Advisory Committee 
(RAC) and approved by the NIH. RAC 
consideration of each proposal will 
follow publication of a precis of the 
proposal in the Federal Register, an 
‘ Experiments using retroviruses (RNA) as vectors 
are also covered by the NIH Guidelines for 
Research Involving Recombinant DNA Molecules 
and hence by this document. Section III-A-4 applies 
to both recombinant DNA and DNA derived from 
recombinant DNA. 
opportunity for public comment, and 
review of the proposal by a working 
group of the RAC. RAC 
recommendations on each proposal will 
be forwarded to the NIH Director for a 
decision, which will then be published 
in the Federal Register. In accordance 
with Section IV-C-l-B of the NIH 
Guidelines, the NIH Director may 
approve proposals only if he finds that 
they present “no significant risk to 
health or the environment." 
In general, it is expected that somatic- 
cell gene therapy protocols will not 
present a risk to the environment as the 
recombinant DNA is expected to be 
confined to the human subject. 
Nevertheless, item I-B— 4-b of the 
“Points to Consider" document asks the 
researchers to address specifically this 
point. 
This document is intended to provide 
guidance in preparing proposals for NIH 
consideration under Section III-A-4. Not 
every point mentioned in the document 
will necessarily require attention in 
every proposal. It is expected that the 
document will be considered for 
revision at least annually as experience 
in evaluating proposals accumulates. 
A proposal will be considered by the 
RAC only after the protocol has been 
approved by the local Institutional 
Biosafety Committee (IBC) and by the 
Ideal Institutional Review Board (IRB) in 
accordance with Department of Health 
and Human Service regulations for the 
protection of human subjects (45 CFR. 
Part 46). If a proposal involves children, 
special attention should be paid to 
Subpart D of these regulations. The IRB 
and IBC. may at their discretion, 
condition their approval on further 
specific deliberation by the RAC and its 
working group. Consideraion of gene 
therapy proposals by the RAC may 
proceed simultaneously with review by 
any other involved federal agencies 
(e.g.. the Food and Drug Administration) 
provided that the RAC is notified of the 
simultaneous review. The committee 
expects that the first proposals 
submitted for RAC review will contain 
no proprietary information on trade 
secrets; therefore, the review will be 
open to the public. The public review of 
these protocols will serve to educate the 
public not only on the technical aspects 
of the proposals but also on the meaning 
and significance of the research. 
The clinical application of 
recombinant DNA techniques to human 
gene therapy raises two general kinds of 
questions. Part I of this document deals 
with the short-term risks and benefits of 
the proposed research to the patient 5 
and to other people as well as with 
issues of equity in the selection of 
subjects, informed consent, and privacy 
and confidentiality. In Part II, 
investigators are requested to address 
broader ethical and social issues 
pertaining to the research and its longer- 
term implications. These broader 
questions go beyond the usual purview 
of IRBs and reflect the kinds of public 
concerns discussed by a recent 
presidential commission in its report 
entitled Splicing Life: The Social and 
Ethical Issues of Genetic Engineering 
with Human Beings. Responses to the 
questions raised in these “Points to 
Consider" should be in the form of 
either written answers or references to 
specific sections of the protocol or other 
documentation which accompanies the 
proposal. In addition. Part III of the 
"Points to Consider’-’ summarizes other 
documentation that will assist the RAC 
and its working group in their review of 
gene therapy proposals. 
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 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 disease 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: 
*The term “patient" and its variants are used in 
the text as a shorthand designation for “patient- 
subject." 
[292] 
