Recombinant DNA Advisory Committee - 12/1-2/94 
"Sentinel" mouse studies were conducted to address the potential risks of aerosol administration. "Sentinel" 
mice were placed in the cage with vector-treated mice. Low level adenovirus sequences were detected in the 
"sentinel mice" by PCR. The investigators assume that these adenovirus sequences were acquired by direct 
contact. Dr. Straus suggested that this experiment should be revised so that these two groups do not have any 
physical contact but share the same air space. Such studies would have to be conducted before approval could 
be recommended. 
Review-Mr. Capron 
Mr. Capron stated that the original Informed Consent documents were verbose and difficult to follow. The 
revised Informed Consent documents are improved over the original version. Since the proposed study 
involves 2 separate institutions, the language in these 2 documents differs significantly, particularly with regard 
to the provision of medical care in the event of research-related injury. The New England Medical Center 
Informed Consent document indicates the provision of medical care for injury "directly caused by Genzyme 
material." Such a statement falsely suggests that no other compensation would be available, e.g., in the case of 
negligence. The Massachusetts General Hospital Informed Consent document indicates that medical care will 
be provided at no cost but does not address other forms of compensation. Mr. Capron noted that the 
investigator’s name was omitted as the contact person in case of injury from the Massachusetts General 
Hospital document. With the exception of these specific issues, Mr. Capron stated that the revised Informed 
Consent documents are acceptable. 
Other Comments 
Dr. Zallen noted that the investigators have not provided proper responses to several specific questions asked 
in the recently revised Points to Consider (Appendix M-I-D). Considering the risk/benefit ratio of CF gene 
therapy, Dr. Zallen questioned whether the ratio is appropriate to treat CF individuals with very mild 
symptoms as proposed in this study. 
Dr. Zallen expressed concern that the investigators stated in their written responses that a single day of patient 
isolation should be sufficient based on data indicating that adenovirus cannot be cultured 24 hours following 
nasal administration (Protocol #9212-036). Dr. Parkman commented that the proposed change should be 
considered in determining the isolation period. The first several subjects entered on the study should be 
monitored for virus shedding before being released. Dr. Parkman asked the investigators to comment on the 
proposed period of time that will be allowed for decontamination of the facility prior to release of the treated 
subject. Dr. Straus noted that similar precautions have been recommended for other RAC-approved 
protocols. Data must be obtained regarding persistence of the vector in the environment. Dr. Samulski 
recommended that an infectious particle assay would provide a more accurate assessment of environmental 
persistence rather than PCR analysis. 
Investigator Response-Drs. Dorkln and Lapey 
Dr. Dorkin described the containment equipment proposed to protect health care workers. The proposed 
system involves 3 levels of containment. The first containment level is provided by the nebulizer unit. The 
vector will be delivered by intermittent nebulization activated by inspiration. Subjects will wear nose clips and 
protective clothing and exhale through a High Efficiency Particulate Air (HEP A) filter with an 99.999% 
efficiency. The system will approximate a closed system as long as the patient is breathing through the 
mouthpiece. Nebulization is limited to 2 seconds during inspiration. The second level of containment is 
provided by the "Demistifier 2000" canopy. Nebulization of the vector will occur within this canopy in which 
air is drawn upward from the bottom of the canopy and out through the filter at a rate of between 4 and 6 air 
exchanges per minute. The third level of containment is provided by the negative pressure room which 
exceeds 12 air exchanges per hour. Health care providers will be required to wear similar protective clothing 
such as the HEPA-filter masks. Dr. Dorkin said that the recommended techniques developed by Dr. Sawyer 
will be used to sample both the inside and outside air. The subject will undergo nebulization of the vector for 
30 minutes. Following the nebulization procedure, the subject will be required to remain within the canopy for 
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