21738 
Federal Register / Vol. 58, No. 77 / Friday, April 23, 1993 / Notices 
Health, Bethesda. Maryland, submitted 
a human gene therapy protocol to the 
RAC for formal review and approval. 
The original title of this protocol was: 
Gene Therapy of the Respiratory 
Manifestations of Cystic Fibrosis using a 
Replication Deficient, Recombinant 
Adenovirus to Transfer the Normal 
Human Cystic Fibrosis Transmembrane 
Conductance Regulator cDNA to the 
Airway Epithelium. This request was 
published for comment in the Federal 
Register on November 2, 1992 (57 FR 
49584). 
The protocol was reviewed during the 
RAC meeting on December 3-4. 1992. 
By a vote of 17 in favor, 0 opposed, and 
no abstentions, the RAC recommended 
approval of the protocol with the 
following modifications: (1) The patient 
eligibility criterion requiring that 
patients are documented to be sterile 
will be replaced with a statement 
suggesting that all patients should 
exercise appropriate birth control 
methods. (2) include the statement. 
“There may be no long term benefit to 
patients from this procedure” irt the 
Informed Consent Document, and (3) 
revise the title of the protocol to read as 
follows: A Phase I Study, in Cystic 
Fibrosis (CF) Patients, of the Safety, 
Toxicity, and Biological Efficacy of a 
Single Administration of a Replication 
Deficient, Recombinant Adenovirus 
Carrying the cDNA of the Normal 
Human Cystic Fibrosis Transmembrane 
Conductance Regulator (CFTRJ Gene in 
the Lung, and (4) demonstrate that there 
is loss than one replication-competent 
adenovirus particle per 20 milliliters of 
supernatant (standard dosage). 
On February 4, 1993, Dr. Crystal 
submitted the modified sections of the 
protocol to ORDA except for the data 
requested in modification number (4). 
Dr. Crystal stated that a lot release, has 
been established for each preparation. 
Lot release forms with the relevant data 
will be forwarded to ORDA and FDA 
simultaneously. Approval from these 
agencies must be obtained before the 
clinical experiment can proceed. This 
information was reviewed by the RAC 
Executive Secretary, and it was 
determined that it meets the request of 
the RAC. The following section may be 
added to Appendix D: 
"Appendix D-XXXXI 
“Dr. Ronald G. Crystal, National 
Institutes of Health, Bethesda, 
Maryland, may conduct experiments on 
10 cystic fibrosis (CF) patients £ 21 
years of age. Patients will receive an 
initial administration of the replication- 
deficient type 5 adenovirus vector, 
AdCl- I K, to their left nares. If no 
toxicity is observed from intranasal 
administration, patients will receive a 
single administration of AdCFTR to the 
respiratory epithelium of their left large 
bronchi. Five groups of patients (2 
patients per group) will be studied 
based on increased dosage 
administration of AdCFTR This study 
will determine the: (1) in vivo safety and 
efficacy of the administration of 
AdCFTR into the respiratory 
epithelium; (2) efficacy of the correction 
of the biologic abnormalities of CF in 
the respiratory epithelium; (3) duration 
of the biologic correction; (4) efficacy of 
the correction of the abnormal electrical 
potential difference of the airway 
epithelial sheet; (5) clinical parameters 
relevant to the disease process; and (6) 
if humoral-immunity develops against 
AdCFTR sufficient to prevent repeat 
administration." 
I accept this recommendation, and 
Apoendix XXXXI of the NTH Guidelines 
will be added accordingly. 
C. Addition of Appendix D-XXXXII of 
the NJH Guidelines 
In a letter dated December 7, 1992. Dr. 
Kenneth Culver. Iowa Methodist 
Medical Center. Des Moines. Iowa, and 
Dr. John C. Van Gilder, University of 
Iowa. Iowa City, Iowa, indicated the 
intention to submit a human gene 
therapy protocol to the RAC for formal 
review and approval. The title of this 
protocol is: Gene Therapy for the 
Treatment of Malignant Brain Tumors 
with In Vivo Tumor Transduction with 
the Herpes Simplex Thymidine Kinase 
Gene/Ganciclovir System. This request 
was published for comment in the 
Federal Register'on February 12, 1993 
(58 FR 8500). 
The protocol was reviewed during the 
RAC meeting on March 1-2, 1993. By a 
vote of 19 in favor, 0 opposed, and no 
abstentions, the RAC recommended 
approval of the protocol with the 
following modifications: (1) Patient 
eligibility will be limited to those 
patients who have measurable residual 
tumor immediately following the post- 
operative procedure as demonstrated by 
imaging studies, i.e., MRI or CT scans. 
(2) Patient enrollment in the protocol 
will be limited to 15 patients. If a 
positive response is observed in any of 
the first 15 patients, the investigators 
may submit a request to treat an 
additional 15 patients. The total number 
of patients treated will be divided 
between Iowa Methodist Medical Center 
and the University of Iowa. (3) 
Following 3 injections of herpes 
simplex thymidine kinase (HS-tk) 
vector-producing cells (VPC), patients 
will be eligible for additional treatments 
only if they have demonstrated stable 
disease for a minimum of 6 months. The 
following section may be added to 
Appendix D: 
"Appendix D-XXXXH 
"Dr. Kenneth Culver, Iowa Methodist 
Medical Center, Des Moines, Iowa, and 
Dr. John Van Gilder, University of Iowa, 
Iowa City. Iowa, may conduct 
experiments on 15 patients £18 years of 
age with recurrent malignant primary 
brain tumors or lung, melanoma, renal 
cell carcinoma, or breast carcinoma, 
brain metastases who have failed 
standard therapy for their disease. 
Patient eligibility will be limited to 
those patients who have measurable 
residual tumor immediately following 
the post-operative procedure as 
demonstrated by imaging studies. The 
number of patients treated will be 
equally divided between the Iowa 
Methodist Medical Center and the 
University of Iowa. If a positive 
response is observed in any of the first 
15 patients, the investigators may 
submit a request to treat an additional 
15 patients. 
"Following surgical debulking, 
patients will receive a maximum of 3 
interlesional injections of the GlTkSvNa 
vector-producing cell line (VPC) to 
induce regression of residual tumor 
cells by ganciclovir (GCV) therapy. 
Patients who demonstrate stable disease 
for a minimum of 6 months following 
this treatment will be eligible for 
additional VPC injections and 
subsequent GCV therapy." 
I accept this recommendation, and 
Appendix D-XXXXH of the NBi 
Guidelines will be added accordingly. 
D. Addition of Appendix D-XXXX1II of 
the NTH Guidelines 
In a letter dated December 31, 1992, 
Drs. Malcolm Brenner, Robert Krance, 
Helen E. Heslop, Victor Santana, and 
James Ihle of the St. Jude Children's 
Research Hospital, Memphis, 
Tennessee, submitted a human gene 
transfer protocol to the RAC for formal 
review and approval. The title of this 
protocol is: Assessment of the Efficacy 
of Purging by Using Gene-Marked 
Autologous Marrow Transplantation for 
Children with Acute Myelogenous 
Leukemia in First Complete Remission. 
This request was published for 
comment in the Federal Register on 
February 12, 1993 (58 FR 8500). 
The protocol was reviewed during the 
RAC meeting on March 1—2, 1993. By a 
vote of 17 in favor, 0 opposed, and no 
abstentions, the RAC recommended 
approval of the protocol. The following 
section may be added to Appendix D: 
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Recombinant DNA Research, Volume 17 
