Recombinant DNA Advisory Committee - 12/2-3/93 
a minor modification to change the site of production of the clinical grade retroviral 
preparations from Genetic Therapy, Inc., to Microbiological Associates, Inc. After 
reviewing the submitted data, all three primary reviewers, Drs. Miller, Hirano, and 
Geiduschek, recommended disapproval. On September 22, 1993, and October 7, 1993, 
Dr. Roth submitted additional data. The three primary RAC reviewers subsequently 
recommended disapproval of this additional data submitted in response to the stipulation 
requirements, although the minor modification was approved. On November 11, 1993, 
Dr. Roth submitted additional data and made a request for a compassionate plea 
exemption. The request for compassionate plea exemption was denied by ORDA on 
November 16, 1993, based on the "Procedures to be Followed for Expedited Review" (58 
FR 2174). Drs. Miller, Geiduschek, and Hirano did not accept the additional data as 
fulfilling the stipulation requirement. Dr. Miller suggested that the full RAC should 
discuss whether Dr. Roth's data adequately meets the stipulation requirements for 
approval. Upon request by Dr. Walters (Chair), Dr. Roth provided a written statement 
on December 1, 1993, providing his rationale that the stipulation requirements were 
adequately addressed. 
Dr. Miller explained that there are concerns regarding safety and efficacy issues since 
this gene transfer protocol introduces oncogenes (which promote cancer development) 
and tumor suppressor genes (which retard tumor growth). The first stipulation was to 
provide data demonstrating lack of generation of transforming virus in 100 ml of the 
clinical grade retrovirus supernatants. Subsequent discussion between the primary 
reviewers and the investigator resulted in a modification of this stipulation. The revised 
stipulation is: "assay a single patient dose for the presence of transforming virus, i.e., 10 
ml of supernatant at a vector titer of 1 x 10 7 cfu/ml (total of 10 8 cfu)." The data 
provided by the investigator in response to this stipulation was found to be inadequate 
due to lack of proper control experiments and the low level of sensitivity of the assay. 
The second stipulation involves the provision of data documenting the "bystander effect" 
claimed by the investigators, i.e., the ability of gene-modified tumor cells to suppress the 
growth of unmodified tumor cells. This "bystander effect" is crucial for efficacy of the 
present approach to suppress tumor growth, since only a small faction of tumor cells will 
be transduced by the vectors. Although there was an initial misunderstanding by the 
investigators with regard to this stipulation. Dr. Miller stated that he held extensive 
telephone conversations with Dr. Roth, in which the stipulation was explained and the 
investigator stated that he understood the necessary requirements. Dr. Miller noted that 
his comments with regard to this stipulation were outlined extensively in his review of 
this protocol. Data has never been submitted in response to this second stipulation. The 
third stipulation involves demonstration that there are no rearrangements in the vector 
structure during vector production from the producer cells. Dr. Miller stated that the 
new vector LNp53B, employs a bidirectional SV40 polyadenylation site that promotes 
rearrangement and may result in vectors with unknown activity. Northern and Southern 
blot analyses of the vector structure, and transcription in producer cells would 
demonstrate that there is no such rearrangement. The investigators have not provided 
satisfactory data in response to this third stipulation. The fourth stipulation involves 
minor changes in the Informed Consent document. An amended document was 
submitted by the investigators and adequately meets this stipulation. 
Recombinant DNA Research, Volume 18 
[551] 
