Vaccinia Immune Globulins: Characteristics, Supply, Clinical Use and Licensure

1
Vaccinia Immune Globulins Characteristics,
Supply, Clinical Use and Licensure

• May 8, 2002
• Dorothy Scott, M.D.
• Laboratory of Plasma Derivatives
• Division of Hematology, OBRR, CBER, FDA

2
Vaccinia Immune Globulin Issues

• 1. Current Products VIG and VIGIV
• Supply Potency - Licensing
• Anti-vaccinia antibody activity in
• licensed IGIV products

3
Estimated VIG Product Needs CDC 5/2002

• Depends upon scenario
• mass vaccination (no contraindications)
• 70,620 doses (includes pregnant women)
• 30,032 (not including pregnant women)
• Selective vaccination pre-event
  (contraindications adhered to HIV testing done
  pregnancy testing) assume 80 non-pregnancy
  contraindications detected
• 6,006 doses
• Selective vaccination post-event (smallpox
  contacts deferral secondary contacts with
  contraindications)
• Estimate depends upon exposures

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Estimated VIG Needs CDC 5/2002

• Uncertainties
• Prophylaxis (pregnancy, eczema,
  immunocompromised)
• Complication rates in elderly
• Dose that will de facto be used
• Real scenario

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Range of VIG Needs

• CDC estimate 21 - 247 VIG-treatable
  complications/million vaccinees
• 6,000 70,600 doses VIG
• (presuming 100 mg/kg X 1 dose, and 70 kg
  patients 1 dose 7 grams)

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Vaccinia Immune Globulins- current availability

• VIG
• I.m. preparation
• Available from CDC under IND
• Source plasma from vaccinated military recruits
• Manufactured 1994 (Baxter)
• VIGIV Product 1
• I.v. preparation
• IND studies under way
• Same Source plasma as VIG
• VIGIV Product 2
• I.v. preparation
• IND development under way

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VIG Products Current and Near-Future
Availability

• Scenario
• Selective vaccination pre-event
  (contraindications adhered to HIV testing done
  pregnancy testing) 6,006 doses 24 - gt100
• mass vaccination (no contraindications)
• 70,620 doses ( pregnant women) 2.1- 10.5
• 30,032 (not pregnant women) 4.8 - 25
• Selective vaccination post-event (smallpox
  contacts deferral secondary contacts with
  contraindications)
• Range depends upon exposures

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Comparison of VIG and VIGIV (Product 1)
HPLC (CBER, FDA) PRN titers (2 Collaborating
Laboratories) Lethality Prevention in SCID Mice
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Characterization of VIG/VIGIV Preparations HPLC
1/10/02
Monomer Dimer Aggregates Fragments VIG 4
81 14 5 0 VIG -20 79 14 7
0 VIGIV 1 92 6 2 0.0
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Anti-vaccinia Titers by PRN 50 Neutralization
(µg/ml)
Lab 1 Lab 2 Lab 2 VIG 17 58 28 V
IGIV 18 5.5 32 16 Ratio 1.0 1.8 1.7 VIG/
VIGIV
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SCID mouse Model
SCID B and T cell deficiency Macrophages,
APC, NK cells, complement activity unaffected G
reatly increased susceptibility to murine
pathogens More severe immunodeficiency than
nudes Vaccinia infection in SCID mice- onset
clinical symptoms 2 weeks Mean Mortality (FDA
Expts.) 27 4 days (literature 29 6
days) Vaccinia (WR) IGIV, 1h at RT
Inject I.p.
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In vivo Vaccinia Neutralization by VIG Products
VIG 5
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Summary SCID Experiments VIG vs. VIGIV (product
1)
Mouse Survival VIG VIG VIGIV 16.5 mg 5
mg 5 mg 3/12 0/12 17/18 Surviving mice
pox-free (55- 117 days after challenge)
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VIG vs. VIGIV

• VIG expected to lose potency over time
• In vitro tests (current standard) no
  conclusively demonstrated difference (low n)
• VIGIV(1) more activity in SCID neutralization
  model
• More relevant in vivo studies desirable
• Additional research may clarify whether
  prioritization VIG products should be considered.

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Additional Considerations Potency of VIG
products

• NO known protective titer for treatment of
  vaccinia complications
• Best guess VIG 0.1 mg/kg (Baxter dose when
  licensed)
• NO standard for comparison until 5/2002 (prior
  standard degraded)
• CBER interim standard in progress sent to
  testing laboratories (to obtain call D. Scott at
  301-496-4396)
• NO validated potency tests
• SOPs
• Relationship between in vitro tests and clinical
  efficacy not assured

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Current Thinking Clinical Trials for Licensure
of VIGIV (1)

• Licensure based upon PK equivalence and safety
  data. PK not inferior (gt 0.8) to VIG given I.m.
• Human surrogate markers (e.g. influence VIGIV on
  vaccine take, lesion size) not required
  pre-approval yet to be validated
• Accelerated Approval designation desirable (21
  CFR 601.40 601.46)
• expedited availability of licensed product
• Phase IV commitments to human surrogate marker
  validation/efficacy

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Current Thinking Clinical Trials for Licensure
of VIGIV (2)

• New product indications limited to treatment of
  VIG-treatable vaccinia vaccine complications
  labeling specific to data provided by
  manufacturer of each product

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Current Thinking Clinical Trials for Licensure
of VIGIV (3)

• Animal model studies encouraged
• Human surrogate efficacy studies encouraged
• Licensure requirements may change as result of
  animal/human studies
• Manufacturers of approved products may have to
  update data in accordance with new CBER standards

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Additional VIG Product Supplies Current Efforts

• FDA
• - Streamlining regulatory aspects of development
  (e.g. current thinking on requirements for
  licensure)
• IND involvement facilitating access to products
  proactively rapid IND review
• CDC currently contracting for adequate VIGIV
  supply IND development

20
Does commercial IGIV contain anti-vaccinia
antibodies?If so, do licensed products have
similar anti-vaccinia activity?

• Vaccinations in U.S. stopped
• 1971 routine use (mortality concerns)
• 1976 healthcare workers
• 1982 travelers
• 1994 military
• Long-term antibody production possible in some
  donors after decades prevalence unknown (up to
  10 years after 1 dose 30 years after 3 doses)

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IGIV Bank to Vaccinia Testing Laboratories for
Neutralization Titers

• Laboratory 1
• Plaque reduction neutralization
• Vero cells, Dryvax
• Laboratory 2
• Plaque reduction neutralization
• Vero cells, NYCBOH strain
• Laboratory 3
• ?-Galactosidase vaccinia strain
• HeLa cells, vSC56 vaccinia

7 Products 5 Lots Each
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IGIV Product
23
IGIV Product
24
IGIV Product
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Summary Anti-vaccinia antibodies in licensed IGIV

• IGIVs can neutralize vaccinia in vitro (?-gal
  and plaque reduction assays) At best 5-8 fold
  LESS potent than VIGIV (1)
• IGIVs have neutralization activity against
  vaccinia in vivo (preliminary data), in presence
  or absence of excipients
• Two products (C and D) have consistently best
  titers in 3/3 laboratories one product (E) has
  lowest titers in 3/3 laboratories
• Manufacturing method and/or donors may account
  for differences

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Amount of IGIV Required to Fill VIG/VIGIV
Shortfall

• Product C or D IGIV potency 8 fold less than
  VIG/VIGIV
• Dose of VIG/VIGIV for 70 Kg patient 7g
• Dose of IGIV 7 x 8 56g/person
• 10,000 complications x 56g/person 560 kg IGIV
• 1 lot of Product C 20 Kg 28 lots needed per
  10,000 complications
• 1 average lot of Product C sufficient for 357
  treatments
• IGIV distribution in U.S. 22,000 kg in 2001
  product C D, 4,700 kg/year (84,000 doses)

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Caveats/Plans

• No current evidence suggesting equivalent
  activity in vivo of anti-vaccinia antibodies in
  IGIV and VIG products
• Antibody subclasses, affinities may be different
• How can this best be ascertained
• Animal studies
• Human studies
• IGIV supply issues (feasibility)
• Not assured that all C and D lots high titer
• DHHS is discussing possibility of high-titer IGIV
  lot reserve.