Page 60 - 2014 Printable Abstract Book
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/radiological (R/N) event, even though no RCTs of medical countermeasures have been or will be
completed for individuals with ARS. A strong recommendation was made by an international panel of
subject matter experts convened in Geneva, Switzerland to administer G-CSF or GM-CSF to manage HS
with an ANC of <500 cells/mm^3 in a hypothetical scenario involving hospitalization of 100-200 persons
(Dainiak N et al. Disaster Med Public Health Prep, 2011; 5: 202-212). A joint meeting of the FDA’s medical
Imaging Drugs Advisory Committee and Oncologic Drugs Advisory Committee on May 3, 2013
recommended that leukocyte growth factors (G-CSF, GM-CSF, Peg-G-CSF and Tbo-G-CSF) be added to FDA
approved uses for these agents in an R/N incident. Here, we discuss the rationale, quality of published
evidence, review process and other considerations (i.e., high-quality studies in experimental animals and
prior publications of opinions of other expert groups) for these recommendations. The impact of
cytokines on survival, duration of neutropenia and frequency of febrile episodes will be reviewed. A
summary of 5 R/N incidents (20 cases) will be presented where cytokines were used that formed the basis
of the Geneva recommendations. These recommendations will be re-examined in
light of results obtained in 9 additional incidents (23 cases), including Fleurus, Belgium (1 case), Dakar,
Senegal (1 case), Nueva Aldea, Chile (1 case), Samut Prakarn, Thailand (9 cases), Meet Halfa, Egypt (5
cases), Nesvizh, Belarus (1 case), San Salvador, El Salvador (3 cases), Yanango, Peru (1 case) and Soreq,
Israel (1 case). Outstanding issues to be discussed include optimal timing of cytokine administration, long-
term impact on hematopoiesis and extrapolation of results from clinical populations to general and special
populations.
(S1302) Animal-Based Scientific Evidence Supporting FDA Approval for Use of G-CSF to Treat Radiation
2
1
1
1
Casualties. Ann Farese ; K. G. Hankey ; B. Katz ; and T. J. MacVittie, Radiation Oncology, University of
1
2
Maryland, Baltimore, MD and Division of Biostatistics, Indiana University, Indianapolis, IN
The lack of US Food and Drug Administration (FDA)-approved treatment(s) for the subsyndromes [e.g.,
hematopoietic (H) and gastrointestinal (GI)] within the Acute Radiation Syndrome (ARS) is a paramount
concern of government and medical personnel. The FDA-“Animal Rule” was developed as a means to
evaluate the efficacy of drugs or biologics where it would be unethical to perform the required trials in
humans. This “rule” provided a means to provide the necessary data for FDA-review, approval and
eventual licensure for use in the treatment of humans experiencing ARS following radiation exposure. To
this end, we have developed a well-characterized, nonhuman primate (NHP) (rhesus macaque) research
platform to identify and evaluate medical countermeasures (MCM) to treat the general population
exposed to potentially lethal doses of radiation in the event of a terrorist attack. The dose response
relationship (DRR) and slope using 6 MV LINAC, total-body irradiation (TBI) and medical management
predicted the LD50/60 for the H-ARS to be 7.50 Gy. The efficacy studies for Neupogen® (filgrastim) and
Neulasta® (pegfilgrastim) were designed to show a significant improvement in survival as the primary
clinically relevant parameter. Each study was randomized, blinded, and powered to show a 30% difference
in 60-day survival using a chi square test at a 5% significance level (one-tailed Neupogen; two-tailed
Neulasta). Both studies were performed in the model described above under Good Laboratory Practice
(GLP)-compliant protocols. The improvement in survival was highly significant in both studies. Neupogen
was administered subcutaneously (SC), daily, at 10 μg/kg until the ANC ≥ 1000/μL for 3 consecutive days
post-TBI. There was a 38% increase in survival in the Neupogen-treated animals vs the control cohort (79%
survival following Neupogen vs 41% survival in controls; P = 0.004). A final report for this study was
58 | P a g e
completed for individuals with ARS. A strong recommendation was made by an international panel of
subject matter experts convened in Geneva, Switzerland to administer G-CSF or GM-CSF to manage HS
with an ANC of <500 cells/mm^3 in a hypothetical scenario involving hospitalization of 100-200 persons
(Dainiak N et al. Disaster Med Public Health Prep, 2011; 5: 202-212). A joint meeting of the FDA’s medical
Imaging Drugs Advisory Committee and Oncologic Drugs Advisory Committee on May 3, 2013
recommended that leukocyte growth factors (G-CSF, GM-CSF, Peg-G-CSF and Tbo-G-CSF) be added to FDA
approved uses for these agents in an R/N incident. Here, we discuss the rationale, quality of published
evidence, review process and other considerations (i.e., high-quality studies in experimental animals and
prior publications of opinions of other expert groups) for these recommendations. The impact of
cytokines on survival, duration of neutropenia and frequency of febrile episodes will be reviewed. A
summary of 5 R/N incidents (20 cases) will be presented where cytokines were used that formed the basis
of the Geneva recommendations. These recommendations will be re-examined in
light of results obtained in 9 additional incidents (23 cases), including Fleurus, Belgium (1 case), Dakar,
Senegal (1 case), Nueva Aldea, Chile (1 case), Samut Prakarn, Thailand (9 cases), Meet Halfa, Egypt (5
cases), Nesvizh, Belarus (1 case), San Salvador, El Salvador (3 cases), Yanango, Peru (1 case) and Soreq,
Israel (1 case). Outstanding issues to be discussed include optimal timing of cytokine administration, long-
term impact on hematopoiesis and extrapolation of results from clinical populations to general and special
populations.
(S1302) Animal-Based Scientific Evidence Supporting FDA Approval for Use of G-CSF to Treat Radiation
2
1
1
1
Casualties. Ann Farese ; K. G. Hankey ; B. Katz ; and T. J. MacVittie, Radiation Oncology, University of
1
2
Maryland, Baltimore, MD and Division of Biostatistics, Indiana University, Indianapolis, IN
The lack of US Food and Drug Administration (FDA)-approved treatment(s) for the subsyndromes [e.g.,
hematopoietic (H) and gastrointestinal (GI)] within the Acute Radiation Syndrome (ARS) is a paramount
concern of government and medical personnel. The FDA-“Animal Rule” was developed as a means to
evaluate the efficacy of drugs or biologics where it would be unethical to perform the required trials in
humans. This “rule” provided a means to provide the necessary data for FDA-review, approval and
eventual licensure for use in the treatment of humans experiencing ARS following radiation exposure. To
this end, we have developed a well-characterized, nonhuman primate (NHP) (rhesus macaque) research
platform to identify and evaluate medical countermeasures (MCM) to treat the general population
exposed to potentially lethal doses of radiation in the event of a terrorist attack. The dose response
relationship (DRR) and slope using 6 MV LINAC, total-body irradiation (TBI) and medical management
predicted the LD50/60 for the H-ARS to be 7.50 Gy. The efficacy studies for Neupogen® (filgrastim) and
Neulasta® (pegfilgrastim) were designed to show a significant improvement in survival as the primary
clinically relevant parameter. Each study was randomized, blinded, and powered to show a 30% difference
in 60-day survival using a chi square test at a 5% significance level (one-tailed Neupogen; two-tailed
Neulasta). Both studies were performed in the model described above under Good Laboratory Practice
(GLP)-compliant protocols. The improvement in survival was highly significant in both studies. Neupogen
was administered subcutaneously (SC), daily, at 10 μg/kg until the ANC ≥ 1000/μL for 3 consecutive days
post-TBI. There was a 38% increase in survival in the Neupogen-treated animals vs the control cohort (79%
survival following Neupogen vs 41% survival in controls; P = 0.004). A final report for this study was
58 | P a g e
