Phillip L' Gomez III, Ph'D', M'B'A'

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Product Development Moving from the Bench to
the Clinic Introduction to the Principles and
Practice of Clinical Research
Phillip L. Gomez III, Ph.D., M.B.A. Director,
Vaccine Production
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Product Development

• Product Development
• Role of Private Sector in Product Development
• Product Resource Allocation
• Costs of Product Development
• Path from Bench to Clinic example
• Conclusions

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Product Development

• Product Development
• Role of Private Sector in Product Development
• Product Resource Allocation
• Costs of Product Development
• Path from Bench to Clinic example
• Conclusions

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Product Development
1967. Dr. Hunein Maassab of the University of
Michigan develops a live, cold-adapted flu virus
for use in a vaccine.
2003. FluMist is available for use for the first
time to health adults and children ages 5 through
49.
Source NIAID Website
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Product Development
Phase 4 Inspection Safety Efficacy Lot Release

Clinical Investigational Plan

BLA Data to support approval Inspection
IND
Phase 1 Safety Immuno-
genicity
Phase 2 Immunogenicity Safety Dose Ranging
Phase 3 Efficacy Safety Immuno-genicity
BLA Supplement Post-approval Changes New
Indications Dosing Manufacture Equip./Facilities
IND Investigational New Drug Application
BLABiologics License Application
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Product Development

• Product Development
• Role of Private Sector in Product Development
• Product Resource Allocation
• Costs of Product Development
• Path from Bench to Clinic example
• Conclusions

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Role of Private Sector in Product Development
NIH Budget FY200 17.8B
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Product Development

• Product Development
• Role of Private Sector in Product Development
• Product Resource Allocation
• Costs of Product Development
• Path from Bench to Clinic example
• Conclusions

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Product Development

• The Selection of a Product for Development is
  based on
• Financial value of the product if successful
  (future revenue - cost of development)
• Probability of success (scientific, legal,
  engineering, business)

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Industrial Model

• Develop comprehensive product development plans
  including development costs and future revenue
  from sales
• Discount cash flows back to present time to
  calculate Net Present Value (NPV) of project
• Assign probability of success for each step in
  product development
• Value project NPVProbability of Success

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Product Development

• Product Development
• Role of Private Sector in Product Development
• Product Resource Allocation
• Costs of Product Development
• Path from Bench to Clinic example
• Conclusions

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Drug Development Costs

• Data difficult to obtain
• Measurement of total cost
• Out of pocket expenses
• Risk adjusted cost of capital
• Basic Research Costs are Not Included

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Drug Development Costs
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Probability of Success
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Probability of Success
Struck, Nature Biotechnology, Vol. 14 May 1996
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Product Development

• Product Development
• Role of Private Sector in Product Development
• Product Resource Allocation
• Costs of Product Development
• Path from Bench to Clinic example
• Conclusions

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Vaccine Development
Development of Vaccine Research Center HIV
Candidate Vaccines for the Developing World July
31, 2001
New HIV Vaccine Holds Promise of Global
Effectiveness November 13, 2002
NIAID Launches First Phase II Trial of a
Global HIV/AIDS Vaccine October 11, 2005
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Product Development

• Why so long and expensive???
• Process
• Facility
• Toxicology
• (Clinical Trials)

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Product Development

• Manufacture of materials for clinical trials
• Produced according to current Good Manufacturing
  Practices described by FDA
• Philosophy of cGMP
• Document/approve exactly what youre going to do
• Document/approve exactly what you did
• Review all work to ensure that what you did is
  exactly what you said you would do
• Paramount concern is safety of clinical subject

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Process

• Consistency
• Scalable
• Safety
• Raw materials
• Cell lines
• Excipients
• Analytical methods

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Facility - Vaccine Pilot Plant Characteristics

• Multi-Product (Prokaryotic or Eukaryotic)
• (most process equipment portable for
  flexibility)
• Four Independent Production Suites (trains)
• (defined by maximum reactor size 2 x 100L
  400L, 2,000L)
• Aseptic Filling Suite
• (lt 5,000 or lt 50,000 units)
• GMP Warehouse
• (including storage and distribution of clinical
  trial materials)
• Quality Control and Assay Development

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Lobby
Support
Support
QC Lab
Future Expansion
Dispensary
Filling Suite
Warehouse
Warehouse
Maintenance
Waste Stage
Offices
Process Utilities
Building Utilities
Waste Staging
Cylinder/Solvent Staging
Shipping Receiving
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Vaccine Pilot Plant - March 2005

• FDA Type C Meeting 3/04
• Shell completed 9/04
• Gilbane Initiated Interior work 9/04
• Construction 70 Complete 3/05

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Return Corridor

• Wide corridors for flexible equipment entry
• Unidirectional material/personnel flow
• 4000 gallons of epoxy flooring

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100 L Fermentation/Cell Culture Room

• Open design for flexibility
• Disposable fluid path buffer/media handling

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2000 L Bioreactor

• All bioreactors dual-use (prokaryotic/eukaryotic
  )
• First application of dual use submitted to FDA
• Total of 11 Bioreactors (15-2000L)

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Utility Panel

• Flexible delivery of 19 utility systems
• Approximately 9 miles of pipe
• Over 180 miles of cable

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Air-handling in Interstitial Space

• 16 separate air handling units and 2 make up air
  units
• Compliance with US/EU/ISO cGMP design standards
• 384 tons of steel

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Filling Transfer Isolator

• Aseptic filling in barrier/isolator
• Full sterilization with VHP
• Minimizes potential for sterility breach of
  product

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Collaborations/contractors NatureTech, GE
BioSciences
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Pre-clinical Safety Studies to support Phase 1

• To recommend an initial safe starting dose dose
  regimen in human subjects
• To identify potential target organs for toxicity
  related to the product
• To identify appropriate serological and
  immunological parameters for monitoring safety
  efficacy in human subjects
• To identify potential at risk populations for
  administration of the product
• To help determine an acceptable risk/benefit
  ratio for human subjects
• To help elucidate the mechanism of action of the
  product

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Pre-Clinical Safety Testing (GLP)

• Repeat Dose Safety Testing
• Biodistribution protocols
• All potential routes tested Toxicity
• Single-dose
• 24, 60 day timepoints
• Time 6-12 months

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DNA/rAd Pre-Clinical Safety Evaluation
One additional dose beyond that to be given in
the clinic on an accelerated schedule DNA
plasmid inoculated by Biojector adenovectors by
needlesyringe
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Pre-Clinical Biodistribution Studies

• GLP
• Single Administration of Ebola DNA
• Sacrifice at 8, 30, 60 days (rabbits)
• Draft FDA Draft Guidance lt30 copies/µg genomic
  DNA

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Pre-Clinical DNA Biodistribution Studies
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Probability of Success
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Speed to the Clinic
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Product Development

• Product Development
• Role of Private Sector in Product Development
• Product Resource Allocation
• Costs of Product Development
• Path from Bench to Clinic example
• Conclusions

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Conclusions

• Product Development is multi-disciplinary
• Industry estimates drug development cost at
  approximately 8-10 years and 800 million (year
  2000 dollars)
• Economics drive the selection of drug candidates
• FDA establishes strict rules for the manufacture
  (cGMP), testing (GLP) and clinical evaluation
  (GCP) of new drug products

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Vaccine Research Center
National Institutes of Health
1-866-833-LIFE www.vrc.nih.gov VRCforLIFE_at_mail.nih
.gov