Federal Register / Vol. 57, No. 212 / Monday. November 2, 1992 / Notices 
Vivo Safety and Efficacy in Nasal 
Epithelium. 
IV. Addition to Appendix D of the NIH 
Guidelines Regarding a Human Gene 
Therapy Protocol/Dr. Wilson 
In a letter dated October 8. 1992, Dr. 
lames M. Wilson, University of 
Michigan Medical Center, Ann Arbor, 
Michigan, submitted a human gene 
therapy protocol to the Recombinant 
DNA Advisory Committee for formal 
review and approval. The title of this 
protocol is: Gene Therapy of Cystic 
Fibrosis Lung Diseases Using El Deleted 
Adenoviruses: A Phase I Trial. 
V. Amendment to the Points To 
Consider in the Design and Submission 
of Protocols for the Transfer of 
Recombinant DNA Into the Genome of 
Human Subjects Regarding Reporting 
Requirements for Human Gene 
Transfer/Gene Therapy Protocols 
The Points to Consider (March 1, 1990, 
55 FR 7447) states under Part IV — 
Reporting Requirements that: 
"B. Reports regarding the general 
progress of patients should be filed with 
both your locals IRB and ORDA within 
six-months of the commencement of the 
experiment and at six-month intervals 
thereafter. These twice-yearly reports 
should continue for a sufficient period of 
time to allow observation of all major 
effects. In the event of a patient’s death, 
a summary of thp special post-mortem 
studies and statement of the cause of 
death should be submitted to the IRB 
and ORDA, if available.” 
Dr. Brigid Leventhal, Chair of Working 
Group on Data Management, will 
provide a summary of the reports 
submitted to ORDA by the principal 
investigators of NIH/RAC approved 
protocols, and make recommendations 
regarding actions to be taken in the 
event of non-reporting. 
VI. Amendment to the Points To 
Consider Regarding the Separation of 
Gene Marking Information Consent 
Document From the Therapeutic 
Informed Consent Documents 
During the September 14-15, 1992, 
RAC meeting, Dr. Leonard Post 
requested that when a gene transfer 
protocol is submitted as an addition to a 
therapeutical protocol, the principal 
investigator should submit two separate 
informed consent documents, one for the 
gene marking portion and one for the 
therapeutic portion of the protocol. In 
the Points to Consider, Part I-D — 
Informed Consent (March 1. 1990, 55 FR 
7446), a new sentence would be added 
to the introductory paragraph: 
“When gene transfer is a procedure 
separate from the therapeutic protocol, 
an informed consent document should 
be submitted for both the gene marking 
and therapeutic procedures." 
VII. Discussion Regarding Costs 
Associated With Treatment for 
Research-Related Injuries 
The issue of payment for costs 
associated with research-related injury 
is becoming a matter of increased 
concern for some members of the RAC. 
During the Human Gene Therapy 
Subcommittee meeting on November 21- 
22, 1991, Ms. Abbey S. Meyers and Dr. 
Doris T. Zallen released a statement 
that any requirement that a patient/ 
subject pay all costs associated with 
treatment for research-related injuries 
unacceptable. Recombinant DNA 
research applied to humans (e.g., gene 
therapy, gene transfer, gene marking) is 
a new area of investigation. The likely 
consequences of the research are not yet 
known. It is unfair to expect individuals, 
their families, or their insurers to absorb 
unpredictable and potentially significant 
costs arising out of their participation as 
research subjects — especially in 
experiments from which they, 
themselves can derive no benefit. At a 
m in im um, research sponsors or their 
institutions should be responsible for 
such costs. Ms. Meyers and Dr. Zallen 
stated that it would be appropriate for 
the National Institutes of Health to 
establish uniform standards for payment 
of medically-related costs for injuries 
arising out of non-therapeutic 
biomedical research on humans. 
During the September 14-15, 1992, 
RAC meeting, Dr. Charles McCarthy, 
Kennedy Institute of Ethics, Georgetown 
University, made a presentation on 
Financial Obligation of Research 
Institutions to Patients Who Participate 
in Clinical Research Protocols. This 
presentation was presented in the 
context of the Cede of Federal 
Regulations (45 CFR 46) relating to the 
part protection of human subjects. Dr. 
Zallen suggested that the RAC forward 
a letter to thlTDirector, NIH. The RAC 
will consider uniformed standards for 
the payment of medically related costs 
for injury arising out of non-therapeutic 
biomedical research. 
VIII. Amendment to the Points To 
Consider Regarding Safety of Delivery / 
Expression Systems and Report on 
Murine Replication-Competent 
Retrovirus (RCR) Assays 
During the September 14-15, 1992, 
RAC meeting, there was a discussion 
regarding requirements for the assays of 
replication-competent retrovirus in 
vector supernatants. In the Points To 
Consider (March 1, 1990, 55 FR 7445), it 
states: 
i l 
49585 
"I. Description of Proposal * * *. 
"B. Research design, anticipated risks, ! 
and benefits * * *. 
"2. Preclinical studies, including risk 
assessment studies * * *. 
"c. Laboratory studies pertaining to 
the safety of the delivery/expression | 
system. 
“(1) If a retroviral system is used: 
* • * 
“(b) 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 
taken in designing the vector to 
minimize instability or variation? Whal 
laboratory studies have been performed 
to check for stability, and what is the 
sensitivity of the analyses? * * *. 
"(e) Has a protocol similar to the one 
proposed for a clinical trial been carried 
out in non-human primates and/or other 
animals? What were the results? 
Specifically, is there any evidence that 
the retroviral vector has recombined 
with any endogenous or other viral 
sequences in the animals?" 
The recommended assays for 
detecting the presence of adventitious 
agents, including replication-competent 
retroviruses (RTR) has evolved as the 
RAC has gained experience in the 
review and approval of human gene 
transfer/therapy protocols. As the 
number of protocols has increased, so 
have the requirements for minimal 
detectable levels of these agents in 
vector supernatant preparations. The 
Points To Consider require the 
investigator to provide evidence that 
vector constructs are stable in vitro and 
in vivo. 
Since it is very important that 
retroviral vectors be free of RCR, it is 
important to quantitate the relative 
safety margin afforded by the assay 
systems used. To confirm that this 
safety margin is adequate, the RAC will 
discuss specific assay requirements and 
minimal levels of detection for possible 
inclusion in the Points To Consider. 
Drs. W. French Anderson, National 
Institutes of Health, Bethesda, 
Maryland; Gerard J. McGarrity, Genetic 
Therapy, Inc., Gaithersburg, Maryland; 
and Robert Moen, Genetic Therapy, Inc., 
Gaithersburg, Maryland, submitted a 
Report on Murine Replication — 
Competent Retrovirus (RCR) Assays. 
OMB's "Mandatory Information . 
Requirements for Federal Assistance 
Program Announcements" (45 FR 39592, 
June 11, 1980) requires a statement 
concerning the official government 
Recombinant DNA Research, Volume 16 
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