Recombinant DMA Advisoiy Committee - 2/4/91 
and increasing the dose twice as fast, will affect the ability to determine what the real 
maximum entry dose level should be. Dr. Rosenberg said this was a good point but 
noted that toxic effects of TNF would be expected to be seen hours after infusion, 
although some might take longer because of slower clearance from the liver. The 
patients were being closely monitored as far as central venous oxygen saturation, 
systemic vascular resistance, and cardiac output, and to date no changes in any 
parameter have been noted. To date, the patients had been treated on an out-patient 
basis because of the lack of any signs of deleterious effects. However, when the doses 
are escalated to higher levels he anticipated they would need to remain hospitalized. 
Dr. McGarrity asked the committee members how long they thought that it would be 
necessary to continue to receive these interim reports from the investigators on approved 
protocols. He also asked whether there needed to be some clarification as to what is a 
"minor" modification or change so that neither the investigators nor the committee are 
put in the position of being surprised by something in the future. 
Dr. Walters said the issue of how long interim reports should continue had not been 
discussed by the HGTS. He noted that the HGTS did receive correspondence between 
the FDA and Dr. Rosenberg relative to the changes that had been made to the protocol. 
Dr. McGarrity asked where the delays had come in the final approvals necessary to 
begin the THF-^l protocol, and whether they were due to technical difficulties with the 
FDA, or internal NIH delay. Much mention had been made of delays, and he thought it 
was good for the committee to be aware of the situation in this case. Dr. Rosenberg 
said the FDA approved the protocol on January 8, 1991. Dr. McGarrity noted that this 
was considerably longer than the 30 days in which the FDA is required to act on a 
submission. Dr. Rosenberg said they did respond within 30 days but their response 
asked for more data on potential toxicities and changes in doses. Negotiations between 
the investigators and the FDA resulted in the protocol not being approved by the FDA 
until January 8, 1991. 
Dr. McGarrity thanked Dr. Rosenberg for his update on the TNFjjl protocol and noted 
for the record that a written update was also submitted on the neomycin-resistant TIL 
protocol. 
Dr. Walters said for the first few human gene therapy protocols, it may be worthwhile to 
continue to get updates at each meeting of the RAC, primarily on issues of safety. It will 
be much longer before any efficacy data will be available. However, since this research 
is so novel, these reports may help the RAC and HGTS in their ability to monitor these 
protocols. 
Dr. McGarrity thanked all the investigators and wished them continued success in their 
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Recombinant DNA Research, Volume 14 
