Cell Therapy Liaison Meeting January 27, 2006 Industry

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Cell Therapy Liaison MeetingJanuary 27,
2006Industry Outline of Issues and Data

• Susan L. Stramer, PhD
• American Red Cross
• representing multiple contributing Blood and HPC
  Centers

Updated March 20, 2006
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Issue and Goals

• Mini-pool (MP) NAT for HIV-1 and HCV of HPC
  donation samples is not currently acceptable
  testing must be performed by individual donation
  (ID) NAT (AABB/ISCT teleconference Nov 9, 2005)
• Upon communication of this information from AABB
  (AABB Pulse Points, Nov 29, 2005), blood centers
  converted from MP to ID NAT with the goal of
  qualification of MP NAT for HPC donations in the
  future
• Multiple communications within organizations to
  ensure compliance e.g., ARC, Dec 7, 2005 AATB,
  Nov 17, 2005

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Issues and Goals

• Specimens from other living donors (except whole
  blood, blood components or source plasma) and
  from cadaveric donors should be tested using the
  individual donor testing method only
• (GP insert, version IN0076-01 REV A)
• Definition of a blood component product
  containing a part of human blood separated by
  physical or mechanical means (21 CFR 1271.3(i))
• Interpretation was that donations from HPC donors
  (peripheral blood stem cells, maternal cord
  blood, bone marrow) meet this criteria

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Issues and Goals

• Analysis in support of MP NAT prospectively/retros
  pectively by comparing frequency of infectious
  disease markers in HPC donations to those of
  donations of whole blood (autologous and
  allogeneic FT/RPT donations i.e., those already
  approved for MP NAT)
• Data to be shared with FDA but will be submitted
  to manufacturers so that their package inserts
  may be modified to include a claim for MP NAT of
  HPC donations (assuming the data support such a
  modification)

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Points to Consider

• NAT clinical trials, and prospective use of the
  licensed assays, have included samples from the
  following donations in context of MP NAT
  allogeneic FT/RPT, autologous, pheresis, HPCs
• All samples from heart-beating donors meeting the
  sample suitability criteria of the clinical
  protocols/licensed inserts were considered
  suitable for pooling and testing
• Only donations of organ and tissue donors have
  been tested by ID NAT due to sample suitability
  issues testing frequently occurs in separate
  laboratories to segregate from samples tested by
  MP NAT
• Hemodilution/hemolysis (not included in this
  presentation)
• At request of FDA, separate analysis was
  performed post-licensure to include volunteer
  source pheresis insert modified based on
  analyzed data

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Points to Consider-False Positivity

• Impact of ID NAT on lost donors/products
• MP involves two rounds of testing in contrast to
  ID NAT
• False positive rates since FDA licensure
• 140,000-1100,000 (0.001-0.0025) for MP NAT by
  site
• 1555-12150 for ID NAT by lot (0.08-0.18 mean
  0.13)
• 32-180X (80X mean) higher reactive rate for ID
  NAT
• Decrease in specificity of 99
• Additional loss of 130 donors/donations for every
  100,000 tested
• Result is the loss of valuable, sometimes
  irreplaceable donors/donations

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Points to Consider-Cost

• Impact of ID NAT on cost
• Additional 3-5 per donation for ID vs MP NAT
• Current price approx 10.00 per MP NAT
  additional 300,000-500,000 for every 100,000
  donations for ID NAT
• One manufacturer (GP/Chiron) has agreed not to
  increase pricing until March 2006 then price
  will increase

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Points to Consider-Logistics

• Impact of ID NAT on logistics
• Up to 8000 samples/day arrive in a consolidated
  testing lab
• No automated systems to sort samples performed
  manually based on visual examination of each tube
  and sorting based on WBN codes on tube labels
• Procedures/processes developed to identify and
  test HPC donations by ID NAT
• Error prone what is impact of an HPC
  inadvertently tested by MP NAT?
• Increase in staff needed for sorting/testing/QC
• Cost not captured in this presentation

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Analysis Goals

• To determine the infectious disease marker
  prevalence/incidence rates for donations of
  Hematopoietic Progenitor Cells (HPC) donors to
  qualify these donations for MP NAT by
  demonstrating equivalence to blood donation types
  already included in the intended use statements
  for licensed NAT assays, and prove that the risks
  associated with MP NAT as compared to ID NAT for
  HPC donations are no greater than the difference
  between MP and ID NAT for donations of whole blood

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Analysis Methods

• Prevalence of HIV, HCV and HBV determined by
  antibody or antigen confirmed positive rates
  (using specific confirmatory tests or NAT, or
  repeat reactivity if none of the above exist,
  such as anti-HBc)
• Incidence of each agent (including WNV) will be
  determined by NAT yield (antibody/antigen
  negative)
• Included in the analysis are the test results for
  samples of donations of HPC donors collected from
  geographically distinct US collection facilities
  from the time of NAT licensure to the end of 2005
• Results from screening ARC whole blood donations
  from a similar period of time serve as the control

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Analysis Methods

• Spreadsheet distributed through AABB and ABC to
  collecting and testing sites (Nov 30, 2005)
• Requested results for all infectious disease
  testing including anti-HIV-1/2, HIV-1 NAT,
  anti-HCV, HCV NAT, HBsAg, anti-HBc, HBV NAT and
  WNV, as available
• FDA licensed tests or testing using approved
  investigational protocols/reagents
• Break out requested by HPC type
• Peripheral blood stem cells (PS)
• Bone marrow (B)
• Maternal cord blood (C)

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Analysis Methods

• Data submitted to ARC to prepare a consolidated
  line listing and to perform analysis vs a control
  population already approved for MP NAT
• ARC donor population autologous and allogeneic
  donations from 4/1/04-3/31/05
• 6.55 million allogeneic and 1.066 million
  autologous donations
• Data included in the analysis represent all
  donations that meet the licensed/investigational
  package insert sample suitability requirements

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Data Collection from HPC Sites

• Data received from 10 organizations, many with
  multiple organizations represented
• e.g., NMDP has 72 submitting centers with 34
  different testing sites
• 171,619 HPC submitted data points having both NAT
  and serology results (next slide)
• 139,654 HPC samples associated with a donation
  (removal of 31,965 unknown types not associated
  with a donation)

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Donations Analyzed-update 3/20/06
Site Samples Submitted Results with NAT Results with NAT and Serology
BSL 71,006 57,697 57,682
ARC 31,781 29,184 14,917
Bergen 181 181 181
PSBC 2291 2113 2113
Bonfils 2789 804 803
NMDP 54,257 45,865 45,806
StemCyte 15,441 15,441 15,441
CHOC 2030 2030 2030
FBS 10,283 10,283 10,269
CIRBC 23,258 22,377 22,377
TOTAL 213,268 185,975 171,619
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Submissions from All Submitting Sites Combined
by HPC Donation Type Complete Data for
N139,654 (3/20/06)
HPC Type Frequency Percent
Unknown 4354 3.1
Bone marrow 7144 5.1
Bone marrow/PS 676 0.5
Cord blood 114,070 81.7
PS 13,410 9.6
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Frequencies of Marker Positives in Whole Blood
DonationsARC 4/1/04-3/31/056.55 million
Allogeneic and 1.066 million Autologous Donations
Combined Donations per 10,000 Allogeneic Donations per 10,000 Autologous Donations per 10,000
Anti-HIV Total 0.305 0.263 2.908
Anti-HIV FT 1.142 1.025 3.957
Anti-HIV RPT 0.121 0.100 2.048
Anti-HIV Range 0.100-3.957 0.100-3.957 0.100-3.957
HIV NAT Total 0.0075 0.0076 0
HIV NAT FT 0.0167 0.0174 0
HIV NAT RPT 0.0055 0.0056 0
HIV NAT Range 0-0.0174 0-0.0174 0-0.0174
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Frequencies of Marker Positives in Whole Blood
DonationsARC 4/1/04-3/31/056.55 million
Allogeneic and 1.066 million Autologous Donations
Combined Donations per 10,000 Allogeneic Donations per 10,000 Autologous Donations per 10,000
Anti-HCV Total 5.103 3.483 104.67
Anti-HCV FT 22.33 18.31 118.71
Anti-HCV RPT 1.320 0.324 93.17
Anti-HCV Range 0.324-118.71 0.324-118.71 0.324-118.71
HCV NAT Total 0.042 0.040 0.188
HCV NAT FT 0.117 0.104 0.417
HCV NAT RPT 0.026 0.026 0
HCV NAT Range 0-0.417 0-0.417 0-0.417
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Frequencies of Marker Positives in Whole Blood
DonationsARC 4/1/04-3/31/056.55 million
Allogeneic and 1.066 million Autologous Donations
Combined Donations per 10,000 Allogeneic Donations per 10,000 Autologous Donations per 10,000
Anti-HBc Total 35.61 29.66 401.34
Anti-HBc FT 121.32 107.96 441.74
Anti-HBc RPT 16.79 12.98 368.25
Anti-HBc Range 12.98-441.74 12.98-441.74 12.98-441.74
HBsAg Total 1.492 1.287 14.16
HBsAg FT 6.954 6.497 17.91
HBsAg RPT 0.304 0.176 12.12
HBsAg Range 0.176-17.91 0.176-17.91 0.176-17.91
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Frequencies of Marker Positives in Whole Blood
DonationsARC 4/1/04-3/31/056.55 million
Allogeneic and 1.066 million Autologous Donations
Combined Donations per 10,000 Allogeneic Donations per 10,000 Autologous Donations per 10,000
WNV Total 0.122 0.117 0.375
WNV FT 0.133 0.113 0.624
WNV RPT 0.119 0.118 0.171
WNV Range 0.113-0.624 0.113-0.624 0.113-0.624
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Frequencies of Marker Positives in HPC
DonationsAll Submitting Sites Date of
Licensure-12/31/05139,654 HPC Donations vs
Control Donations
Anti-HIV per 10,000 donations HIV-1 NAT per 10,000 donations
HPC Total 0.36 0
Bone Marrow/PS 0.00 0
Cord Blood only 0.18 0
PS only 2.24 0
Unknown 0 0
HPC Range 0-2.24 NA
Control Range 0.10-3.96 0-0.017
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Frequencies of Marker Positives in HPC
DonationsAll Submitting Sites Date of
Licensure-12/31/05139,654 HPC Donations vs
Control Donations
Anti-HCV per 10,000 donations HCV NAT per 10,000 donations
HPC Total 15.40 0.93
Bone Marrow/PS 33.24 1.28
Cord Blood only 14.11 0.96
PS only 20.89 0
Unknown 0 2.30
HPC Range 0-33.24 0-2.30
Control Range 0.32-118.71 0-0.417
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Frequencies of Marker Positives in HPC
DonationsAll Submitting Sites Date of
Licensure-12/31/05109,286 HPC Donations vs
Control Donations
Anti-HBc per 10,000 donations HBsAg per 10,000 donations HBV NAT per 10,000 donations
HPC Total 274.42 25.44 0
Bone Marrow/PS 132.97 9.01 0
Cord Blood only 301.44 28.88 0
PS only 100.0 1.59 0
Unknown 87.30 2.30 0
HPC Range 87.30-301.44 1.59-28.88 0
Control Range 12.98-441.74 0.176-17.91 na
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Frequencies of Marker Positives in HPC
DonationsAll Submitting Sites Date of
Licensure-12/31/0538,052 HPC Donations vs
Control Donations
WNV NAT per 10,000 donations
HPC Total 0.79
Bone Marrow /PS 0
Cord Blood only 0
PS only 1.89
Unknown 5.51
HPC Range 0-5.51
Control Range 0.113-0.624
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Comparisons by MarkerHPC vs Control Sample Sets
Analyzing Controls as Combined, Allogeneic and
Autologous

• HIV
• Antibody gt only significant difference observed
  was autologous gt HPCs
• 2.91 autologous vs 0.36 HPCs/10,000 donations
• NAT gt no HIV yield samples
• HCV
• Antibody gt significant differences observed
  where autologous gt all others
• 105 autologous vs 15.40 HPCs/10,000 donations
• NAT gt no significant differences between
  autologous and HPC donations
• Confirmatory data lacking for five of thirteen
  HCV NAT yield HPC donations

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Comparisons by MarkerHPC vs Control Sample Sets
Analyzing Controls as Combined, Allogeneic and
Autologous

• HBV
• Antibody gt significant differences where
  autologous highest
• 30 allogeneic, 36 combined, 274 HPCs vs 401
  autologous/10,000 donations
• HBsAg gt significant differences where HPC
  highest
• 1.29 allogeneic, 1.49 combined, 14.16 autologous
  vs 25.44 HPCs/10,000 donations
• Impact of Ortho 3 false positivity unknown
• 70 (196/278) of HPC positives Ortho 3 confirmed
• NAT gt no yield samples
• WNV
• NAT gt no significant differences between any
  groups
• Confirmatory data lacking for two of three WNV
  NAT yield HPC donations

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Comparison of Prevalence Rates/10,000 donations
Combined Whole Blood Autologous Whole Blood Combined HPCs
Anti-HIV 0.30 2.91 0.36
Anti-HCV 5.10 104.7 15.40
Anti-HBc 35.61 401.3 274.4
HBsAg 1.49 14.16 25.44,
plt0.05 for one or multiple comparisons Ortho
System 3
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Summary and Conclusions

• Overall comparison of prevalence rates shows no
  difference between control groups and HPC
  donations
• 3 of 4 cases autologous higher, 1 case of 4, HPC
  higher where Ortho 3 used only for HPC group
• No significant differences in incidence (as
  determined by NAT yield) observed between control
  groups and HPC donations
• With HPC NAT-reactives mostly unconfirmed
• No additional risk of MP NAT for HPC donations as
  compared to the control groups for which MP NAT
  occurs

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Next Steps

• Share presentation with test kit manufacturers
• Prepare line listings by submitting site/donation
  type, including analysis versus control
  population and provide to the NAT test kit
  manufacturers for labeling modifications to allow
  MP NAT of HPC donations
• Next series of slides highlight the individual
  manufacturers data (3/20/06)