Federal Register / Vol. 59, No. 127 / Tuesday, July 5, 1994 / Notices 
34531 
preparation? Which cells, if any. 
produce infectious particles? 
Appendix M-I-B-2-c-(2). How stable 
are the retroviral vector and the 
resulting provirus against loss, 
rearrangement, recombination, or 
mutation? What information is available 
on how' much rearrangement of 
recombination with endogenous or 
other viral sequences is likely to occur 
in the patient’s cells? What steps have 
been t^en in designing the vector to 
minimize instability or variation? What 
laboratory studies have been performed 
to check for stability, and what is the 
sensitivity of the analyses? 
Appendix M-l-B-2-c-(3). What 
laboratory evidence is available 
concerning potential harmful effects of 
the transfer (e.g., development of 
neoplasia, harmful mutations, 
regeneration of infectious particles, or 
immune responses)? What steps will be 
taken in designing the vector to 
minimize pathogenicity? What 
laboratory studies have been performed 
to check for pathogenicity, and what is 
the sensitivity of the analyses? 
Appendix M-l-B-2-c-{4). Is there 
evidence from animal studies that 
vector DNA has entered untreated cells, 
particularly germ-line cells? What is the 
sensitivity of the analyses? 
Appendix M-l-B-2-c-{5). Has a 
protocol similar to the one proposed for 
a clinical trial been conducted in non- 
humah primates and/or other animals? 
What were the results? Sprecifically, is 
there any evidence that the retroviral 
vector has recombined with any 
endogenous or other viral sequences in 
the animals? 
Appendix M~I-B-2-d. Non- Retrovirus 
Delivery/Expression Systems. If a non- 
retroviral delivery system is used, what 
animal studies have been conducted to 
determine if there are pathological or 
other undesirable consequences of the 
protocol (including insertion of DNA 
into cells other than those treated, 
particularly germ-line cells)? How long 
have the animals been studied aher 
treatment? What safety studies have 
been conducted? (Include data about the 
level of sensitivity of such assays.) 
Appendix M-I-B-3. Clinical 
Procedures, Including Patient 
Monitoring. Describe the treatment that 
will be administered to patients and the 
diagnostic methods that wall be used to 
monitor the success or failure of the 
treatment. If previous clinical studies 
using similar methods have been 
performed by yourself or others, 
indicate their relevance to the proposed 
study. Specincally: 
Appendix M-I-B-3-a. Will cells (e g., 
bone marrow cells) be removed from 
patients and treated ex vivo? If so. 
describe the type, number, cind intervals 
at which these cells will be removed. 
Appendix M-I-B-3-b. Will patients 
be treated to eliminate or reduce the 
number of cells containing 
malfunctioning genes (e.g., through 
radiation or chemotherapy)? 
Appendix M-I-B-3-c. What treated 
cells (or vector/DNA combination) will 
be given to patients? How will the 
treated cells be administered? What 
volume of cells will be used? Will there 
be single or multiple treatments? If so, 
over what period of time? 
Appendix M-I-B-3-d. How will it be 
determined that new gene sequences 
have been inserted into the patient's 
cells and if these sequences are being 
expressed? Are these cells limited to the 
intended target cell populations? How 
sensitive are these analyses? 
Appendix M-I-B-3-e. What studies 
will be conducted to assess the presence 
and effects of the contaminants? 
Appendix M-I-B-3-f. What are the 
clinical endpoints of the study? Are 
there objections and quantitative 
measurements to assess the natural 
history of the disease? Will such 
measurements be used in patient follow- 
up? How will patients be monitored to 
assess specific effects of the treatm^it 
on the disease? What is the sensitivity 
of the analyses? How frequently will 
follow-up studies be conducted? How 
long will patient follow-up continue? 
Appendix M-I-B-3-g, What are the 
major beneficial and adverse effects of 
treatment that you anticipate? What 
measures will be taken in an attempt to 
control or reverse these adverse effects 
if they occur? Compare the probability 
and magnitude of deleterious 
consequences from the disease if 
recombinant DNA transfer is not used. 
Appendix M-I-B-3-h. If a treated 
patient dies, what special post-mortem 
studies will be performed? 
Appendix M-I-B-4. Public Health 
Considerations. Describe any potential 
beneGts and hazards of the proposed 
therapy to persons other than the 
patients being treated. SpeciGcally; 
Appendix M-I-B— 4-a. On what basis 
are potential public health beneGts or 
hazards postulated? 
Appendix M-I-B— 4-b. Is there a 
significant possibility that the added 
DNA will spread from the patient to 
other persons or to the environment? 
Appendix M-I-B— 4-c. What 
precautions will be taken against such 
spread (e.g., patients sharing a room, 
health-care workers, or family 
members)? 
Appendix M-I-B-4-d. What 
measures will bo undertaken to mitigate 
the risks, if any, to public health? 
Appendix M-I-B— 4 e . In light of 
possible risks to offspring, including 
vertical transmission, will birth control 
measures be recommended to patients? 
Are such concerns applicable to health 
care personnel? 
Appendix .M-l-B-5. Qualifications of 
Investigators and Adequacy of 
Laboratory and Clinical Facilities. 
Indicate the relevant training and 
experience of the personnel who will be 
involved in the preclinical studies and 
clinical administration of recombinant 
DNA. Describe the laboratory and 
clinical facilities where the proposed 
study will be performed. SpeciGcally: 
Appendix M-l-B-5-a. VVhat 
professional personnel (medical and 
nonmedical) will be involved in the 
proposed study and what is their 
relevant expertise? Provide a two-page 
curriculum vitae for each key 
professional person in biographical 
sketch format (see Appendix M-III-E). 
Appendix M-I-B-5-b. At what 
hospital or clinic will the treatment be 
given? Which facilities of the hospital or 
clinic will be especially important for 
the proposed study? Will patients 
occupy regular hospital beds or clinical 
research center beds? Where will 
patients reside during the follow-up 
period? \yhat special arrangements will 
be made for the comfort and 
consideration of the patients. Will the 
research institution designate an 
ombudsman, patient care representative, 
or other individual to help protect the 
rights and welfare of the patient? 
Appendix M-I-C. Selection of the 
Patients 
Estimate the number of patients to he 
involved in the proposed study. 
Describe recruitment procedures and 
patieiit eligibility requirements, paying 
paiticujar attention to whether these 
procedures and requirements are fair 
and equitable. SpeciGcally: 
Appendix M-I-C-1. How many 
patients do you plan to involve in the 
proposed study? 
Appendix M-I-C-2. How many 
eligible patients do you anticipate being 
able to identify each year? 
Appendix M-l-C-3. What 
recruitment procedures do you plan lo 
use? 
Appendix M-I-C-4. What selection 
criteria do ybu plan to employ? What 
are the exclusion and inclusion criteria 
fo/ the study? 
Appendix M-l-C-5. How will 
patients be selected if it is not possible 
to include all who desire to participate? 
Appendix M-l-D. Informed Consent 
Indicate how patients will be 
informed about the proposed study and 
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Recombinant DNA Research, Volume 19 
