Questions for the
Committee:
1. The Code of Federal Regulations (CFR) Part 312.42 defines the bases for FDA to place a study on clinical hold. CFR 312.42(b)(iv) (“insufficient information”) was cited previously as a basis for placing INDs on clinical hold in response to the development of leukemia in subjects of X-SCID clinical trials. However, we note CFR 312.42(b)(i) that states FDA may place a study on hold if it finds that “Human subjects are or would be exposed to an unreasonable and significant risk of illness or injury”. With this requirement in mind, please discuss the current incidence of leukemia (3/12) and death of one subject from leukemia reported in the clinical trial in France relative to the potential benefit of retroviral vector-mediated gene transfer in X-SCID. Consider in your discussion:
a. The risk/benefit issues for gene therapy vs. haploidentical bone marrow transplantation.
b. The incidence of leukemia associated with retroviral vector administration that would make clinical trials of this therapy unacceptable in X-SCID. Would this advice differ if a subject in another clinical trial develops leukemia? Would another subject death due to leukemia influence your recommendations?
2. Please comment on what changes, if any, would reduce the risk to subjects in clinical trials using retroviral vector-mediated gene transfer in X-SCID. Please consider the following:
a. Limit the dose based on total vector copy number in the transduced cells.
b. Limit the dose based on total number of transduced cells.
c. Alteration of retroviral vector design.
3. Please discuss the impact, if any, of the SAEs in X-SCID, combined with the development of myeloid sarcoma in the single monkey administered hematopoietic stem cells after ex vivo transduction with a retroviral vector, on the use of retroviral vectors in other clinical indications. Please comment specifically on the risk/benefit considerations:
a. In ADA-SCID relative to X-SCID.
b. In other clinical indications.
4. Given the increased efficiency of lentiviral vectors to transduce cells, often resulting in multiple vector copies per cell (up to 10 have been reported), please discuss whether restrictions on vector copy number per cell are warranted for the use of lentiviral vectors in ex vivo transduction clinical protocols, and if so, what limit would you advise?
Table of Contents
Questions for the
Committee………………………………………………………Tab 1
Briefing Document for
Topic II, CTGTAC Meeting #38...………………..Tab 2
Briefing Document and Meeting Summary for
October, 2002 Meeting
#33 of BRMAC…………………………………………Tab 3
Briefing Document and Meeting Summary for
February, 2003, Meeting #34 of BRMAC……………………………………….Tab 4
Press Release from
AFSSAPS……………………………………………………….Tab 5
Tables
1-4………………………………………………………………………………….Tab 6
Slides from Dr. Rebecca H. Buckley’s presentation
at the October 10,
2002, Meeting #33 of BRMAC………………………….Tab 7
Reprints of Selected
Publications…………………………………………………Tab 8
Appendix 3. Press Release from AFSSAPS
agence française de securite sanitaire
des produits de sante |
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Appendix 4.
Table 1. Comparison of X-SCID Retroviral
Vector-Mediated Gene Transfer
Characteristic |
Fischer [1] |
Thrasher [2] |
Weinberg* |
Malech* |
Cell Source |
Bone Marrow |
Bone Marrow |
Bone Marrow |
Bone Marrow |
CD34+ Selection |
Miltenyi Biotec |
CliniMACS |
Isolex 300 I |
Isolex 300I |
Media |
X-Vivo-10 |
X-Vivo-10 |
X-vivo-15 |
X-Vivo 10 |
Serum/Other |
4% FCS |
1% HSA |
None |
1% HSA |
Cytokines (Source): 1. Flt-3 ligand 2. IL-3 3. TPO 4. MGDF 5. SCF 6. IL-6 |
300 ng/ml (Immunex) 60 ng/ml (Novartis) ----------- 100 ng/ml (Amgen) 300 ng/ml (Amgen) ------------ |
300 ng/ml (R&D) 20 ng/ml (R&D) 100 ng/ml (R&D) ------------ 300 ng/ml (R&D) ------------
|
300 ng/ml (Immunex) ------------ 50 ng/ml (R&D) -----------
50 ng/ml (R&D) ------------ |
50 ng/ml (R&D) 5 ng/ml (R&D) 50 ng/ml (R&D) -------------- 50 ng/ml (R&D) 25 ng/ml (R&D) |
Hrs Prestim. |
24 |
40 |
40 |
18 |
Transduction 1. Fibronectin 2. Exposures 3. Time |
Yes Three 72 hours |
Yes Three 56 hours |
Yes Three 72 hours |
Yes Four 78 hours |
Vector Backbone (LTR) |
MFG (MoMLV LTR) |
MFG (MoMLV LTR) |
MND (MPSV LTR) |
MFG (MoMLV LTR) |
Vector Envelope (Packaging Line) |
A-MuLV (Psi-CRIP) |
GaLV (PG-13) |
GaLV (PG-13) |
GaLV (PG13) |
10Hacein-Bey-Abina, S., et al., Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. New England Journal of Medicine, 2002. 346(16): p. 1185-1193.
11Gaspar, H.B., et al., Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet, 2004. 364(9452): p. 2181-7.
* Details provided with kind permission from Drs. Weinberg and Podsakoff of The Saban Research Institute of Childrens Hospital Los Angeles, and Dr. Malech of NIH/NIAID.
Table 2.
Clinical Summary of X-SCID Trials
Investigator |
Previous BMT? |
Previous infectious or other complications |
Max Dose
transplantedgamma-c+ cells/kg |
Longest time from
treatment to last follow-up |
Fischer [1] |
No |
Yes (except 1) |
20 x 106 |
5 years |
Thrasher [2] |
No |
Yes |
9.62 x 106 |
29 months |
Weinberg# |
Previous BMT not excluded. |
Yes |
NA |
NA |
Malech* |
Yes, haploidentical with low or no evidence of engraftment |
Yes |
32 x 106 |
9 months |
10 Hacein-Bey-Abina, S., et al., Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. New England Journal of Medicine, 2002. 346(16): p. 1185-1193.
11 Gaspar, H.B., et al., Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet, 2004. 364(9452): p. 2181-7.
* Details provided with kind permission from Dr. Malech of NIH/NIAID.
# Details provided with kind permission from Drs. Weinberg and Podsakoff of The Saban Research Institute of Children’s Hospital Los Angeles; no subjects treated to date.
Table 3. Comparison of ADA-SCID Retroviral Vector-Mediated
Gene Transfer
Characteristic |
Bordignon[3] |
Kohn* |
Cell Source |
Bone Marrow |
Bone marrow |
CD34+ Selection |
CliniMACS |
Isolex300I |
Media |
X-Vivo10 |
X-Vivo15 |
Serum/Other |
4% FCS |
None |
Cytokines (Source): 1. Flt-3 ligand 2. IL-3 3. TPO 4. MGDF 5. SCF |
300 ng/ml (Immunex) 60 ng/ml (Novartis) 100 ng/ml (Glaxo SmithKline) ------------- 300 ng/ml (Amgen) |
300 ng/ml (Immunex) --------------- --------------- 50 ng/ml (Amgen) 50 ng/ml (Amgen) |
Hrs Prestim. |
24 hours |
40 hours |
Transduction 1. Fibronectin 2. Exposures 3. Time |
Yes Three 72 hours |
Yes Three 72 hours |
Vector Backbone (LTR) |
LXSN (MoMLV LTR) |
MND (MPSV LTR) GCSAP (MPSV LTR) |
Vector Envelope (Packaging Line) |
A-MuLV (GP+Am12) |
GALV (PG13) |
9 Aiuti, A., et al., Gene therapy for adenosine deaminase deficiency. Curr Opin Allergy
Clin Immunol, 2003. 3(6): p. 461-6.
*Details
provided with kind permission from Drs. Kohn and Podsakoff of The Saban
Research Institute of Children’s Hospital Los Angeles. Conditions reflect methods used since 2001,
not previously.
Table 4. Clinical Summary of ADA-SCID Trials
Investigator |
Previous BMT/ Conditioning |
Previous infectious or other complications |
Max Dose
transplantedADA+ cells/kg |
Longest time from
treatment |
Bordignon[3] |
1 of 2 subjects Busulfan conditioning |
Yes |
2.15 x 106 |
Approx 3.5 years |
Kohn* |
1 of 4 subjects No conditioning |
No |
6.67 x 106 |
Approx 40 months |
9 Aiuti, A., et al., Gene therapy for adenosine deaminase deficiency. Curr Opin Allergy Clin Immunol, 2003. 3(6): p. 461-6.
*Details provided with kind permission from Drs. Kohn and Podsakoff of The Saban Research Institute of Children’s Hospital Los Angeles. Conditions reflect methods used since 2001, not previously.
1. Hacein-Bey-Abina, S., et al., Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. New England Journal of Medicine, 2002. 346(16): p. 1185-1193.
2. Gaspar, H.B., et al., Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet, 2004. 364(9452): p. 2181-7.
3. Aiuti, A., et al., Gene therapy for adenosine deaminase deficiency. Curr Opin Allergy Clin Immunol, 2003. 3(6): p. 461-6.