June 1, 1990, Human Gene Therapy Subcommittee Minutes 
greater than minimal risk, but presenting the prospect of direct benefit to the individual 
subjects." This may have been referred as "minimal risk" in a communication which he 
sent to Dr. Childress, but wanted to underline the wording used by the IRB. 
Dr. Walters then asked Dr. Neiman to present a secondary review of the protocol. Dr. 
Neiman prefaced his comments by saying his thinking has evolved since writing his 
review, based on receiving comments from the investigators as well as reading the 
materials recently received. He said that Dr. Parkman had covered many of the 
concerns he had with the protocol. Dr. Neiman said he would not go over the entire 
protocol again, but merely focus on some specific points of emphasis. 
Dr. Neiman said that the first area he wished to discuss was patient selection. Since 
there are varying sets of diagnoses and phenotypes in terms of ADA deficiency, a 
decision tree needs to be better defined. He said the criteria for bone marrow 
transplantation have been evolving. It often takes time for people to decide when 
transplantation is appropriate. Further, the introduction of PEG-ADA therapy is new 
and evolving. Finally, there is a problem with dealing with small numbers of patients in 
trying to define the role of gene therapy in dealing with this disease. 
Dr. Neiman said a general recommendation is that there be a method in place for 
getting state-of-the-science opinions on a given area when the subcommittee is asked to 
judge a protocol. He suggested a small group of experts be assembled which could 
provide independent interpretations of the science being proposed. 
Dr. Neiman said he would like to hear from the investigators as to the therapeutic goals 
of the procedure. If correction of clinical assays is a goal, he wanted to know the clinical 
significance of the assays. He said that a more precise definition of therapeutic goals 
was necessary. 
Dr. Neiman said his second area of concern was safety. Here he focused on 
oncogenesis. In animals, insertion of retroviral promoters and enhancers can turn on 
gene function at insertion sites and is known to stimulate the development of neoplasias. 
This could result in unknown but potentially lethal risks to the subjects. This should be 
outlined as a risk in the informed consent for the protocol. Animal models could be 
profitably used as screens for multiple insertion studies to provide additional safety data. 
Dr. Neiman said that the last area he wished to discuss was efficacy in view of the 
absence of an animal model. The parameters of cell expansion and character of the 
infused cell population in terms of functional subsets and differing immunologic 
responses should be characterized. Rules should be established, giving a high probability 
of therapeutic success prior to using this therapy in humans where there are other 
modalities of therapy currently available in the form of bone marrow transplantation and 
PEG-ADA therapy. 
Recombinant DNA Research, Volume 14 
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