11 
Dr. Varmus said tests could be constructed which might suggest limits, but he did 
not knew if the sensitivity of the tests would be high. 
Dr. nottesman suggested the working group ask the investigator to discuss the 
potential consequences of retroviral integration. Dr. Grobstein said in human 
gene therapy a higher degree of uncertainty or risk might be acceptable than 
would be acceptable wdth other therapies, but the working group would like to 
ascertain whether the investigator has considered this outcome. 
Dr. Walters called the attention of the working group to Section I-A-2-c, 
Clinical and public-health considerations . 
Drs. Anderson and Varmus suggested that Item I-A-2-c-( 1 ) , which addresses 
the methodology of gene transfer, be included in Section I-A-2-b. Section 
I-A-2-c should ask how success would be judged and validated. Drs. Anderson 
and Varmus suggested the investigator should be asked in Section I-A-2-c to 
state the significance of issues addressed in Sections I-A-2-a and I-A-2-b . 
Dr. Anderson suggested in vitro tissue culture studies with the patient's cells 
might in some cases be required before the vector is introduced into the 
patient. Dr. Varmus said specifically requiring such information may burden 
investigators. Dr. Murray felt those investigators who will be bringing the 
first human gene therapy proposals to the RAC for review are including these 
tests as part of the protocols. 
Dr. Gorovitz said there is a difference between asking an investigator if data 
fran cultured cell testing exist and requiring that such data be generated 
before approval to proceed is given. He preferred the working group ask 
investigators whether such information exists; if available, such data should 
be part of the review. If such information is not available, approval could be 
given and cultured cell testing might be required as part of the experimental 
protocol . 
Dr. Mahoney said specifying an information requirement for data generated with 
the patient's cells in culture may be short-sighted; he could envisage cases 
in which information generated fran targeted organs might be more pertinent. 
Dr. Gorovitz agreed that data generated from the patient's cells in culture 
might be important in one case but irrelevant in another; he suggested the 
draft document state this informational requirement in general terms in the 
preamble . 
Dr. Motulsky asked if the working group or RAC would make site visits. 
Dr. Gartland said RAC to date has not made a site visit; however, the possibility 
of a site visit should not be ruled out. Dr. Gottesman said in most cases 
investigators appear before RAC when their proposals are reviewed. This system 
has worked well. 
Mr. Capron suggested Section I-A-2-c of the document should underscore both the 
investigator's role and the IRB's repons ibility to monitor the experiments. He 
suggested a footnote be added to the working group document indicating the IRB 
[ 99 ] 
