Points to Consider

in Preclinical
Development

Pacific BioLabs, Hercules, CA

 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?
 Presentation Outline
 Savings Opportunities
 Benefits of Outsourcing
 Outsourcing Considerations
 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.

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

R&D Expenditures

35000
30000
25000 Domestic US
20000 R&D
$M
15000 R&D Abroad
10000
5000
0

PhRMA Annual Survey, 2001

 Time and Financial Constraints
The drug development process is time-
consuming and expensive:
 R&D is time consuming—It 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.
 Time to market has been
compressed
Phase I Phase II Phase III Pre-Reg
Development time (months) *

120
100
80
60
40
20
0
86-90 91-95 96-01
 Drug R.O.I.
Only 3 out of 10 marketed drugs produce revenues
that match or exceed average R&D costs

After Tax Present Value in 1990 $M

1200
1000
800
600
400
After-Tax R&D Costs
200
0
1 2 3 4 5 6 7 8 9 10
1980-84 Pharmaceuticals

Source: Grabowski, H. and Vernon, J. “return to R&D on New Drug

Introductions in the 1980s,” Journal of Health Economics, Vol 13, 1994
Drug Development Stages
 Discovery
 Product Selection
 Preclinical
 Clinical

– Phase I
– Phase II
– Phase III
 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
Reasons For Drug Failure
5%
10%
5%

11%

39% 80% can be

80% detected in
preclinical
phase
30%
Pharmacokinetics Lack of efficacy
Animal toxicity Commercial reasons
Adverse effects in man Miscellaneous

Source: 198 NCEs in clinical development by large UK companies, 1964–1985.

 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, Excretion—ADME).
– 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.
 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.
 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
 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)
 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
 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)
 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 +
 Timing of Studies

Preclinical Duration Time Clinical Study

Study Supported
Safety pharmacology 1-3 weeks, depending Before Phase I. Phase I/II
on kinetic data Information
should be
Toxicokinetic, 14 days available by the
pharmacokinetic time early Phase
studies I trials are
completed.
Single dose acute A few hours to
toxicity or dose several weeks
escalation study depending on
in two species sample and test
type
Local tolerance
studies using
relevant route of
administration
 Timing of Studies

Preclinical Duration Time Clinical Study

Study Supported
Repeated dose Should equal or exceed Before Phase I Phase I/II:
toxicity studies in the duration of Phase I/II 2 weeks to12 months
one rodent and one studies: (minimum 2
non-rodent weeks, maximum 12
months; generally 1-3
months for biotech- Before Phase
derived products) III
 Timing of Studies
Preclinical Duration Time Clinical Study
Study Supported
Genotoxicity Variable Complete before start Phase I/II
of Phase II and all Pediatric clinical trials
pediatric clinical trials

Reproductive toxicity Variable Not required * Phase I/II (males, and

studies females not of child-
Complete all female bearing potential)
reproductive toxicity
and genotoxicity
Phase I/II (pregnant
studies before Phase females and females of
I/II studies. Pre- and childbearing potential)
postnatal development
study before marketing
approval.. Pediatric clinical trials

Complete before
pediatric studies
 Timing of Studies

Preclinical Duration Time Clinical Study

Study Supported
Carcinogenicity Variable Before long-term Pediatric clinical trials
studies pediatric trials. Not
usually needed
unless there is cause
for concern.
 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.
 Savings Opportunities
 Development of computational modeling
 Running experiments in parallel rather
than sequentially, greatly increasing
efficiency and reducing the elapsed time
for R&D.
 Screening multiple compounds (from
high throughput screening) in one
experiment.
 Outsourcing
 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 R&D
expenditures in the next few years.
Why outsource?
– Capacity issues (large pharma)
– High cost of an animal facility
– Preserved R&D focus
– Wider range of available technical expertise
– Regulatory compliance
– Flexibility
 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
– Low—lowest efficacious dose
– High—highest anticipated exposure (+safety
margin?)
– 1x, 5x, 10x mg/kg
– Rationale
 Considerations (Con’t)
 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
 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;
 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
 Pacific BioLabs (PBL)

We are an ISO 9001:2000 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.
 NVP Experience
 > 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.
Questions ?
Pacific BioLabs
551 Linus Pauling Drive
Hercules, CA 94547
510-964-9000
510-964-0551 Fax
www.pacificbiolabs.com
Appendix
Number of New Drug Approvals

60

50

40
# of Drugs

30 USA
EU
20

10

0
90 91 92 93 94 95 96 97 98 99 '00

Source: www.phrma.org EMEA established

 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)
 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)
 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
 Technical Points to Consider
 Formulations
 Side effects
 Toxicity problems
 Dosage
 Route of administration
 Bioanalytical support
 API formulation—analytical characterization preferred
– Stability
– API assay
– Impurities
– Diluents, inert ingredients
 Dose solution analysis
– Homogeneity
– API level all dose groups