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Federal Register / VoL 55. No. 41 / Thursday. March 1. 1990 / Notices 
(3) Explain in detail all results from animal 
and cultured cell model experiments which 
assess the efiectiveness of the delivery 
> system (parl2.a. abovej in achieving the 
' minimaUyrequired level of gene transfer and 
-expression (Zb.(2) above). 
(4) To what extent is expression only from 
the desired gene (and not from the 
surrounding DNA)? To what extent does the 
insertion modify the expression of other 
genes? 
(5) In what percentage of cells does 
expression from the added DNA occur? Is the 
product biologically active? What percentage 
of normal activity results from the inserted 
gene? 
(6) Is the gene expressed in cells other than 
the target cells? If so. to what extent? 
c. Laboratory studies pertaining to the - 
safety of the delivery/expression system. 
(1) If a retroviral system is used: 
(a) What cell types have been infected with 
the retroviral vector preparation? Which 
cells, if any. produce infectious particles? 
(b) How stable are die retroviral vector and 
the resulting provirus against loss, 
rearrangement recombination, or mutation? 
What information ia 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 taken in designing the vector to 
minimiTj» instability or varianon? What 
laboratory studies have been performed to 
check for stability, and what is the sensitivity 
of the analyses? 
(c) What laboratory evidence is available 
concerning potential harmful effects of the 
transfer, e.g, development of neoplasia, 
harmful mutations, regeneration of infections 
particles, or immune resoonses? What steps 
have been taken in de. cning the vector to 
minimize pathogenicity 1 What laboratory 
studies have been performed to check for 
pathogenicity, and what is the sensitivity of - 
the analyses? 
(d) Is there evidence &om animal studies 
that vector DNA has entered untreated cells, 
particularly germ line cells? I^'hat is the , 
• sensitivity of the analyses? • 
(e) Has a protocol similar to (he one 
proposed for a clinical trial been carried out 
in non-human primates and/or other 
animals? What were the results? Spedfically. 
is there any evidence that the retroviral 
vector has recombined with any endogenoos 
or other viral sequences in the animals? 
(2) If a non-retroviral delivery system is 
used; What animal studies have been done 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 after treatment? What tests have 
been used and what is their sensitivity? 
3. Ginical procedures. Including patient 
monitoring 
t^Describe the treatment that will be - 
administered to patients and the diagnostic 
methods that will be used to monitor the 
: auccess 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. 
a. Will cells (e.g, bone marrow cells) be 
removed from patients and treated ex vivo? If 
so. what kinds of cells will be removed fr-om 
the patients, how many, how often, and at 
what intervals? 
b. Will patients be treated to eliminate or 
reduce the number of cells containing 
malfunctioning genes (e.g.. through radiation 
or chemotherapy]? 
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 sa over what 
period of time? 
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? 
e. Wbat studies will he done to assess the 
presence and effects of the contaminants? 
L What are the clinical endpoints of the 
study? Are there objective and quantitative 
measurements to assess the natural history of 
the disease? Will such measurements be used 
in following patients? How will patients be 
.monitored to assess specific effects of the 
treatment on the disease? Wbat is the 
sensitivity of the analyses? How frequently 
-%vill follow-up studies be done? How long will 
patient follow-up continue? 
g. What are the major beneficial and 
adverse effects of treatment that you 
anticipate? What measures wiiltw taken in 
an attempt to control or reverse these 
adverse effects if they occur? Compare the 
probability and magnitude of potential 
adverse effects on patients with the 
probability and magnitude of deleterious 
consequences from the disease if 
recombinant DNA transfer is not used. 
h. If a treated patient dies, what special 
post mortem studies will be {>erfonned7 
■4. Public health considerations ' 
Describe any potential benefits and 
hazards of the proposed therapy to persons 
other than the patients being treated 
Spedfically: 
a. On what basis are potential public 
health benefits or hazards postulated? 
b. Is there a significant possibility that the 
added DNA will spread from the patient to 
other persons or to the envirorunent? 
c. What precautions Vvill be taken against 
such spread (e.g.. to patients sharing a room, 
health-care workers, or family members]? 
d. Wbat measures will be undertaken to 
mitigate the risks, if any, to public health? 
e. In light of possible risks to offspring, 
including vertical transmission, will birth 
control measures be recommended to the 
patients? Are such concerns applicable to 
health care personnel? 
5. Qualificatloos of investigators, 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. 
In addition, please describe the laboratory 
and clinical fadlities where the proposed 
study will be performed. 
a. Wbat professional personnel (medical 
and nonmedical] will be involved in the 
proposed study and what ia their relevant 
expertise? Please provide curricula vitae of 
key professional penonnel (see section III-E). 
L At what hospital or dinic will the 
treatment be given? Which facilities of the 
hospital or dinic 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? What spedal 
arrangements will be made for the comfort 
and consideration of the patients? Will the 
researxdi institution designate an 
ombudsman, patient care representative, or 
other individual to help protect the rights and 
welfare of the patient? 
C Selection of patients 
Estimate the number of patients to be 
involved in the proposed study. Describe 
recruitment procedures and patient eligibility 
requirements. pa}ring particular attention to 
whether these procedures and requirements 
are fair and equitable. 
1. How many patients do you plan to 
involve in the proposed study? 
2. How many eligible patients do you 
antidpate being able to identify eac^ year? 
.. 3. What recruitment procedures do you 
plan to use? 
4. What selection criteria do you plan to 
employ? Wbat are the exdusion and 
indusion criteria for the study? 
5. How will patients be selected ifit is not 
possible to include all who desire to 
partidpate? 
D. Informed consent 
Indicate how patients will be informed 
about the proposed study and how their 
consent will be solidted. The consent 
procedure should adhere to the requirements 
of DHHS regulations for the protection of 
human subjects (45 CFR. part 46). If the study 
involves pediatric or mentally handicapped 
patients, describe procedures for seeking the 
permission of parents or guardians and. 
where applicable, the assent of each patient 
Areas of special concern highlighted below 
indude potential adverse effects, finandal 
costs, privacy, long-term follow-up, and post 
mortem examination. 
1. How will the major points covered in 
sections I-’A through 1-C of this document be 
diadosed to potential partidpants in this 
study and/or parents or guardians in 
language that is understandable to them? 
2. How will the innovative character and 
the theoretically possible adverse effects of 
the experiment be discussed with patients 
and/or parents or guardians? How will the 
potential adverse effects be compared with 
the consequences of the disease? 
3. What explanation of the financial cosU 
of the experiment, follow-up care, and any 
available alternatives will be provided to 
patients and/or parents or guardians? 
4. How will patients and/or their parents or 
guardians be informed that the umovative 
'* character of the experiment may lead to great 
intere‘.t by the media in the research and in 
treated patients? 
5. How will patients and/or their parents or 
guardians be informed; 
a. About the irreversible consequences oi 
some of the procedures performed? 
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Recombinant DNA Research, Volume 14 
