John C. Fletcher 
Assuming that sufficient animal and technical data will exist to 
consider a transition to human studies, the following problems of 
moral choice will be presented to members of IRBs by prospective 
protocols in gene therapy: 
(1) the degree of sufficiency that ought to be demonstrated in safety studies 
in animals to warrant transition to human studies; 
(2) the relation of risks to benefits of the proposed study for the subjects in 
light of the existing alternatives for therapy; 
(3) the criteria for selection of subjects who can most benefit from the re- 
search with the least risk of harm; 
(4) the informed consent of parents, and the assent (if possible) of children; 
and, 
(5) whether special protections need to be added for vulnerable subjects, 
such as children who may be cognitively or mentally impaired. 
The moral choice about transition from animal to human studies is 
imbedded in technical information, but the principles of beneficience 
and nonmaleficence are relevant for the interpretation of data. Thus, 
every rational step in animal studies should be undertaken to reduce 
the risk of harm to patients. Depending on the efficacy of demon- 
strations in mice, the requisite primate studies may be ranked as 
(a) imperative prior to the human trial or (b) imperative but accept- 
able to perform concurrently with the first trial in humans. The latter 
alternative clearly requires results in the mouse that exceed current 
expectations. 
The principle of beneficence is also relevant to the timing of a 
human trial. Beneficence requires a duty to relieve suffering. Physi- 
cians and parents may be convinced that not to try the experiment 
will add to the danger and burden of suffering of the children. An 
IRB may be in doubt because animal studies have raised questions 
that need further answers. At some point the IRB and investigator 
need to reach agreement on the limits of requisite animal experi- 
ments, so that potential therapy, however small the likely benefit, 
will not be unduly delayed. 
The other problems of moral choice, with the exception of the 
last, are not unfamiliar to participants in research review. A large 
body of experience in research ethics (Levine, 1981) supports an 
expectation that such decisions can be made well. Further review at 
the national level will provide reassurance to physician-investigators, 
parents, and society that everything that could have been done by 
way of expert review had been done. 
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