Points to Consider in Preclinical Development

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Points to Consider in Preclinical Development

• Pacific BioLabs, Hercules, CA

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Presentation Outline

• Preclinical Development Info Statistics
• Reasons For Drug Failure
• More Constraints
• Drug Development Stages
• Regulatory Terms
• Preclinical Studies
• Timing of Studies
• What testing is needed?

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Presentation Outline

• Savings Opportunities
• Benefits of Outsourcing
• Outsourcing Considerations

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Preclinical Development Opportunity

• Preclinical toxicology is a major strategic
  opportunity in drug development for cost savings
  and is critical for long-term effectiveness.
  Through good preclinical work, drug developers
  can avoid clinical trials that won't succeed.
• Begin with the end in mind.

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RD Expenditures

• Pharmaceutical companies continually face
  increasing challenges in drug development from
  shorter product life cycles, global competition,
  and increased consumer demand.

PhRMA Annual Survey, 2001
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Time and Financial Constraints

• The drug development process is time-consuming
  and expensive
• RD is time consumingIt takes 10 to 15 years to
  bring a new drug to market.
• From 5,000 to 10,000 compounds must be screened
  to yield 1 potentially successful drug.
• 10 or 15 to 30 billion is spent for preclinical
  studies today.
• 15 will be spent on preclinical studies in the
  next three to five years.

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Time to market has been compressed
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Drug R.O.I.
Only 3 out of 10 marketed drugs produce revenues
that match or exceed average RD costs
After-Tax RD Costs
Source Grabowski, H. and Vernon, J. return to
RD on New Drug Introductions in the 1980s,
Journal of Health Economics, Vol 13, 1994
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Drug Development Stages

• Discovery
• Product Selection
• Preclinical
• Clinical
• Phase I
• Phase II
• Phase III

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Cost Per Stage

• Discovery - .5M
• Product Selection - .5M
• Preclinical - 1- 1.5M
• Clinical
• Phase I - 5-10M
• Phase II - 10-20M
• Phase III - 30-50M
• Product Launch - 5-10M

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Reasons For Drug Failure
80 can be detected in preclinical phase
80
Source 198 NCEs in clinical development by large
UK companies, 19641985.
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More Constraints

• ADME/TOX Problems Eliminate Many Drug Candidates
• 40 of drug candidates (new chemical entities)
  are rejected because of poor pharmacokinetics
  (Absorption, Distribution, Metabolism,
  ExcretionADME).
• 11 of drug candidates are eliminated because of
  toxicology.
• Some approved drugs are taken off of the market
  because of toxicity not detected during
  preclinical or clinical screening.

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Regulatory Terms

• Good Manufacturing Practice (GMP)
• U.S. biopharmaceuticals must be manufactured
  under GMP. Code of Federal Regulations, Title 21
  (CFR Title 21) Parts 210, 211, and 600. GMP also
  relate to process validation, equipment
  qualification, quality assurance, quality
  control, and documentation.
• Good Laboratory Practice (GLP)
• Preclinical development is conducted per GLP as
  detailed in 21 CFR Part 58. The GLP is an
  enforced code of practice intended to reduce
  accidents affecting research projects or
  manufactured products. Enforced by the FDA, the
  GLPs require documentation of all actions
  surrounding the product, from cataloging raw
  materials and tracking samples to reporting tests
  performed and explaining problems and deviations.
  All activity is recorded, trained staff uses only
  established procedures, and records and samples
  are maintained.

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Preclinical Studies

• ADME/PK
• Objective To study the effects of test materials
  with respect to absorption, distribution,
  metabolism, and excretion
• Duration hours to days
• Animals Required typically 2 species (rodent and
  non-rodent)
• Safety Pharmacology
• Objective To investigate undesirable
  pharmacological effects of the test material
• Duration Usually single dose
• Animals Required 2 species (rodent and
  non-rodent)
• Core battery Cardiovascular, Respiratory, CNS
• Telemetry

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Preclinical Studies

• Acute Toxicity
• Objective To determine Maximum Tolerated Dose
  (MTD) and No Observable Effect Level (NOEL)
• Duration Typically 14 days after single dose
• Animals Required 2 species (rodent and
  non-rodent)
• Parameters
• Mortality ? Clinical pathology ? Gross necropsy
• ? Weight change ? Clinical observations
• Points to consider
• Dose selection for repeat dose studies
• Choice of Species (Fialuridine)

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Preclinical Studies

• Sub Acute Toxicity
• Objective To determine toxicity after repeated
  administration of the test material
• Duration 14 28 days
• Animals Required 2 species (rodent and
  non-rodent)
• Parameters
• Mortality ? Clinical pathology ? Urinalysis
• Histology ? Weight change ? Clinical obs
• Points to consider
• Dosing regimen similar to clinical
• Recovery period
• Duration of clinical trials (Phase I, II, III)
• Toxicokinetics
• Immunotoxicity

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Preclinical Studies

• Subchronic/Chronic Toxicity
• Objective In support of products used to treat
  chronic conditions
• Duration 30 days to 2 years
• Animals Required 2 species (rodent and
  non-rodent)
• Parameters
• Mortality ? Clinical pathology
• Clinical obs ? Behavioral Assessment
• Histology ? Weight change
• Points to consider
• Clinical Trials (EU)

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Preclinical Studies

• Carcinogenicity
• Objective To evaluate the tumorigenic potential
  in animals and risk to humans
• Duration 12 months
• Species Mouse or Rat
• Parameters
• Tumor development ? Clinical pathology
• Clinical observations and assessment
• Points to consider
• Considerations from
• Pharmacology, Pharmacokinetic or Toxicology
  (mechanistic in vitro and in vivo) data
• Structure-activity relationships
• Compound accumulation over long-term use
• Continuous use in humans for 6 months

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Timing of Studies
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Timing of Studies
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Timing of Studies
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Timing of Studies
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What testing is needed?

• Consider the following in better designing
  preclinical trials to increase the drug
  development success rate

• Use preclinical data to increase the overall
  strategic success in
• Picking the right compound
• Picking the right formulation
• Picking the right delivery method
• Avoid compounds likely to cause problems in
  clinical trials.
• Use parallel optimization Integration of
  analysis of binding qualities and ADME/Tox
  properties.

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Savings Opportunities

• Development of computational modeling
• Running experiments in parallel rather than
  sequentially, greatly increasing efficiency and
  reducing the elapsed time for RD.
• Screening multiple compounds (from high
  throughput screening) in one experiment.
• Outsourcing

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Benefits of Outsourcing

• Outsourcing is becoming a major trend in
  preclinical development and is projected to
  increase from the current 20-25 to 30-50 of RD
  expenditures in the next few years.
• Why outsource?
• Capacity issues (large pharma)
• High cost of an animal facility
• Preserved RD focus
• Wider range of available technical expertise
• Regulatory compliance
• Flexibility

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Outsourcing Considerations

• When planning and designing the individual
  studies to be outsourced, consider
• When and where (vendor) to outsource
• ICH Guidelines and Specific Considerations for
  Preclinical Safety Evaluation of
  Biotechnology-Derived Pharmaceuticals
• Planning the protocol
• Species
• Doses
• Lowlowest efficacious dose
• Highhighest anticipated exposure (safety
  margin?)
• 1x, 5x, 10x mg/kg
• Rationale

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Considerations (Cont)

• Data and report format
• Report deadline
• Technical and administrative issues
• Identify primary administrative and technical
  contacts in both the sponsor company and contract
  facility.
• Specify timelines and responsibilities
• Consider GLP requirements

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Outsourcing Relationships

• Establish initial goals and objectives that are
  SMART and routinely review these
• Continually track and measure performance and
  provide feedback
• Ensure that the relationship is win-win
• Have high level involvement
• Define a communications and conflict
  resolution/escalation process.
• Have a quarterly or yearly review process in
  place

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Pacific BioLabs

• Pacific BioLabs is a contract research
  organization (CRO), located in SF Bay Area
  -Hercules, California
• An independent laboratory offering
• cGMP and GLP testing services
• Areas of service
• Preclinical Toxicology
• Pharmacology
• Biocompatibility
• Microbiology
• Sterility

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Pacific BioLabs (PBL)
We are an ISO 90012000 certified laboratory,
with an outstanding track record in regulatory
compliance and client service. Our
AAALAC-accredited animal facilities meet the
highest USDA and NIH standards.
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NVP Experience

• gt 20 years experience in animal testing
• Product development experience
• Small Molecules - Peptides
• Conjugates - Antibodies
• Proteins - Nucleic Acids
• Work with leading large and start-up
  pharmaceutical and biotech companies
• Highly qualified technical staff.

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Questions ?
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Pacific BioLabs551 Linus Pauling DriveHercules,
CA 94547510-964-9000510-964-0551
Faxwww.pacificbiolabs.com
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Appendix
35
Number of New Drug Approvals
EMEA established
Source www.phrma.org
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Preclinical Studies

• Irritation and Sensitization
• Objective To determine the potential of test
  material to cause irritation and/or sensitization
• Duration Hours to weeks (depends upon test)
• Animals Required 2 species (mice and guinea
  pigs)
• Parameters observable effects (pruritis,
  erythema, edema, etc)

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Preclinical Studies

• Immunotoxicity
• Objective To determine the potential of a test
  material to induce an immune response
• Duration Hours to weeks (depends upon test)
• Animals Required 2 species (mice and guinea
  pigs)
• Parameters observable effects (pruritis,
  erythema, edema, etc)

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Preclinical Studies

• Reprotoxicity/Genotoxicity/Mutagenicity
• Objective To determine the potential of a test
  to cause one of the above issues
• Duration Weeks to years (depends upon test)
• Animals Required in-vivo and in-vitro tests
• Parameters many

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Technical Points to Consider

• Formulations
• Side effects
• Toxicity problems
• Dosage
• Route of administration
• Bioanalytical support
• API formulationanalytical characterization
  preferred
• Stability
• API assay
• Impurities
• Diluents, inert ingredients
• Dose solution analysis
• Homogeneity
• API level all dose groups