/ VoL 56. No. 13a / Tliursdfly, July 16, 1991 / Notices 
33176 Federal Register 
I Appendix K—DefinHions to Accompany 
'! Containment Grid and Proposed 
; ! Modiftcadon of Appendix K - 
\ Accidental relea s e T he timatentioaal 
I discfaarse of a mkxobiological agent (Le.. 
I . microorganiam or virus} or eukaryotic cell 
: I due to a faOore in the containment system. 
Biological barrier^i-An tny>ediment 
(natural o ccur r iug or introdaced} to the 
infectivity and/or survival of a 
, microbiological agent or eukaryotic cell once 
I it has been released into the environment 
Closed gytem-^ system. Vrhich by its 
design and proper operation, prevents release 
of a microbialogical agent or etdcaiyotic cell 
I contained therein. ^ ’ 
Cbntouuneaf— The confinement of a 
. microbiologicai agent or eukaryotic cell that 
:{ is being caltiired, stored, manipulated. 
' transported or destroyed in or^ to prevent 
I or Ih^ its c ontact with people and/or the 
I enviromnent Methods used to adiieve this 
I include: physical and biological barriers and 
! inactivation using physical or (dieniical 
j means. . ■ ■ . 
! de minimis release — A release of viable 
microbiological agents or edcaiyotic c«»ll« 
that does not result in the establishment of 
disease in healdiy people, plants or animals 
or In uncontrolled proliferation of any 
microbiological agents or eukaryotic cpH*. 
Disinfection — A process v^ch viable 
I microbiological agents or eukaryotic cells are 
\ reduced to a level tmlikely to produce disease 
i| in healthy people, plants or animals. 
Good Large Scale Practice (GLSP) 
I Organism — For an organism to qualify for 
CLSP consideration, it must meet the 
following cxiteiia: (Reference: Organization 
for Economic Cooperation and Development 
Recombinant DMA Safety Considerations. 
1387. pp. M-3S). 
a. The host organism should be non- 
I pathogenic, sho^d not contain adventitious 
j agents and should have an extended history 
I of safe large-scale use or have built-in 
environmental limitations that permit 
optimum growth in the large-scale setting but 
limited survival without adverse 
consequences in the enviroomenL 
b. The recombinant DNA-engineered 
organism should be non-pathogenic, should 
be ae safe in the large-scale setting as the 
host organism, and without adverse 
consequences in the environmenL 
c. The vector/iiuert should be well 
characterized and fiee fiom known harmful 
sequences; should be limited in size as much 
as possible to the DNA required to perform 
the intended function: should not increase the 
stability of the construct in the environment 
unless that is a requirement of the intended 
function; should be poorly mobilizable; and 
should not transfer any resistance markers to 
tnicroorganisms not known to acquire them 
naturally if such acquisition could 
compromise the use of a drug to control 
disease agents In human or veterinary 
medicine or agriculture. 
InacUvation — ^Any process that destroys 
the ability of a specific microbiological agent 
or eukaryotic cell to self-replicate. 
Incidental release — The discharge of a 
microbiological agent or eukaryotic cell from 
a contaiiunent system that is expected when 
the system is appropriately designed and 
properly operated and maintained. 
Minimaadon — The design and operation 
of containment systems in order that any 
inc ident al release la a <fe minimis release. 
Pathogen — Any microbiological agent or 
eukaryotic cell containing sufficient genetic 
information, which upon expression of such 
information, b capable of producing disease 
in healthy people, plants or animals. 
Physa'al barrier— t^jaipmeai, facilities and 
devices (e.g., fermentors. hactoiies. filters, 
thermal oxidizers) designed to adiieve 
containmenL 
Release— The discharge of a 
microbiological agent or eukaryotic cdl from 
a containment system. Diachaiges can be 
inddental or acddentaL Incidental releases 
are de minimis to natnre; accidental releases 
may be de minimis to nature. ' - 
I accept the recommended in 
appendix K and the NIH Guidelines are 
amended accordin^y. 
B. Addition of Appendix D-XVn to the 
“NJH Guidelines ** Regarding Human 
Gene Transfer Protocol/Dr. Brenner 
In a letter received on October 5, 1990. 
Or. Malcolm IC Brenner of SL Jude 
Children’s Research Hospital of 
Memphis, Tennessee, inthcated his 
intention to submit a human gene 
transfer protocol to the Human Gene 
Therapy Subcppimittee and the 
Recombinant DNA Advisory Committee 
for formal review and approval The title 
of the protocol is; 
** Autologous Bone Marrow Transplant 
for Children with Acute Myelogenous 
Leukemia (AML) in First Complete 
Remission: Use of Marker Genes to 
Investigate the Biology of Marrow 
Reconstitution and the Mechanism of 
Relapse." 
This request was published for 
comment in the Federal Ref^ter on 
November 13. 1990 (55 FR 47399). 
The protocol was reviewed by the 
Human Gene Therapy Subcommittee 
during its November 30, 1990. meeting. 
The subcommittee recommended 
provisional approval pending receipt of 
the following additiotial information. 
The consent form should include 
statements about patient confidentiality. 
There should be additional information 
in the consent form about long-term 
patient reevaluation. There should be 
more specific detail about the 
transduction protocol and more detail 
about the molecular identification of 
blast colonies. An assent form should be 
developed for use with patients over the 
age of seven. 
The Human Gene Therapy 
Subcommittee forwarded ffie protocol to 
the Recombinant DNA Advisory 
Committee for consideration during its 
February 4, 1991. meeting. 
This request was published for 
comment in the Federal Register on 
December 27. 1990 (55 FR 53258). 
At the meeting of February 4 . 1991, the 
Recombinant DNA Advisory Committee 
considered the recommendations of the 
Human Gene Therapy Subcommittee 
and confirmed tiiat the requested 
revisions in the consent form were 
made, that the assent form was added, 
and that sufficient detail about 
methodology of the transduction 
procedure was provided. The RAC, by a 
vote of 16 in favor, none opposed, and 
no abstentions, approved the protocol. 
I accept this recommendation and 
appendix D-XVn of the NIH Guidelines 
wdl be added accordin^y. 
C Addition of Appendix D-XVUI to the 
"NIH Guidelines" Regarding Human 
Gene Tranter Prvtocols/Dr. Brenner 
In a letter dated February 22. 1991. Dr. 
Malcolm K. Brenner of SL Jude - 
Children’s Research Hospital of 
Memphis. Tennessee, indicated his 
intention to submit two human gene 
transfer protocols to the Human Gene • 
Therapy Subcommittee end the 
Recombinant DNA Advisory Committee 
for formal review and approval 
’Ihe first protocol is entitled: **A Phase 
I/n Trial of High-^ose Carboplatin and 
^poside with Autologous Marrow 
Support for Treatment of Stage D 
Neuroblastoma in First Remission: Use 
of Marker Genes to Investigate the 
Biology of Marrow Reconstitution'aDd 
the Mechanism of Relapse." 
The second protocol is entitled: “A 
Phase n Trial of Hi^dDose Carboplatin 
and Etoposlde with Autologous Marrow 
Support for Treatment of Relapse/ 
Rebractory Neuroblastoma Without 
Apparent Bone Marrow Involvement: 
Use of Marker Genes to Investigate the 
Biology of Marrow Reconstitution and 
the Mechanism of Relapse." 
These protocols were reviewed during 
the Human Gene Therapy Subcommittee 
meeting on November ^ 1990. The 
protocols were deferred with a request 
for additional data and further 
cf ’ eration at the next meeting on 
Ap. J.1991. 
This request was published for 
comment in the Federal Register on 
March 7. 1991 (56 FR 9707). 
On April S. 1991, the Human Gene 
Therapy Subcommittee gave provisional 
approval to both protocols with the 
stipulation that reviewers further 
evaluate Dr. Brenner’s procedures for in 
vitro bone marrow assays to detect 
residual tumor. Second, a provision for 
early termination of the protocol needs 
to be developed if the relapse rate in tlie 
patient population exceeds the 
statistical predictions. 
The Human Gene Therapy 
Subcommittee forwarded these 
Recombinant DNA Research, Volume 14 
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