Recombinant DNA Advisory Committee- 9/12-13/94 
several specific questions regarding the present protocol, and most of them were 
satisfactorily answered by the investigator. (1) Since the critical target cells within the 
lung itself are unknown, will a 5-10% overall transduction efficiency of epithelial cells 
necessarily translate into the same transduction rate in the critical target cells of the lung? 
Dr. D. Ginsburg was not totally convinced that this issue was sufficiently addressed in the 
published results of the previous study. (2) Have the levels of expression with the new 
vector (Ad GN CFTR.10) been compared to results with the previous work? What is the 
data demonstrating the superiority of the CMV promoter in the new vector? (3) Can the 
investigators provide data to validate quantitative PCR assays of the transduction rate in 
the lung? This is the measurement used for a primary biologic parameter of efficacy, and 
there are technical difficulties in performing this assay. (4) The investigator claimed that 
the vector doses given in the cotton rat experiments were 100-fold greater than the highest 
dose to be administered to humans in this study. Dr. D. Ginsburg was not comfortable 
with the calculation of the relative dose. The calculation was based on the body weight 
difference but this is not a systemic therapy but topical application to the pulmonary 
epithelium. The basis of this calculation may not be valid for estimating toxicity in 
humans. (5) The investigator has reported an adverse reaction in one patient in his 
previous trial. This adverse reaction was not adequately described in the published paper. 
Even a minor respiratory infection is potentially much more serious in a CF patient. Any 
inflammatory reaction might have more serious sequelae in patients with compromised 
lung function than in normal individuals. (6) Since there are large number of eligible 
patients with this common disease, why not exclude all minors from the study? The 
investigator responded in writing that there is no added risk to the minors. 
In summary, Dr. D. Ginsburg said this is a relatively small change from the previously 
approved protocol. Dr. D. Ginsburg was satisfied with the responses to most of his 
questions. He pointed out two outstanding issues that need further responses from the 
investigator, i.e., the issue of relative dosage between the rat and humans, and the issue of 
greater risk to a patient with compromised lung function. 
Dr. Walters noted Dr. Crystal’s paper has been published in Nature Genetics, Volume 8, 
pp. 42-51, 1994. 
Review-Dr. DeLeon 
Dr. DeLeon found the proposal to be well presented and most of her comments were 
mentioned in Dr. D. Ginsburg’s review. She still had some concern about the statistics. 
With a population of 26 patients, 2 in each cohort, and 14 of them being used repeatedly 
in both Part A and Part C of the study, Dr. DeLeon said that better statistical methods 
could be applied. She would like the investigators to elaborate on this point. She had 
questions about the use of quantitative PCR. If it is not going to be used, the protocol 
should be revised to reflect this change. Most of the issues raised regarding the Informed 
Consent document have been answered by the investigator. Dr. DeLeon would favor 
approval of the protocol. 
Review-Dr. Zallen 
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Recombinant DNA Research, Volume 20 
