peclinical development2003
TRANSCRIPT
Points to Consider Points to Consider in Preclinical in Preclinical DevelopmentDevelopment
Pacific BioLabs, Hercules, CAPacific BioLabs, Hercules, CA
Presentation OutlinePresentation 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 OutlinePresentation Outline Savings Opportunities
Benefits of Outsourcing
Outsourcing Considerations
Preclinical Development Preclinical Development OpportunityOpportunity
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 ExpendituresR&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
05000
100001500020000250003000035000
$M
Domestic USR&D
R&D Abroad
PhRMA Annual Survey, 2001
Time and Financial ConstraintsTime 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 Time to market has been compressedcompressed
0
20
40
60
80
100
120
86-90 91-95 96-01
Dev
elo
pm
ent
tim
e (m
on
ths)
*
Phase I Phase II Phase III Pre-Reg
Drug R.O.I.Drug R.O.I.
0
200
400
600
800
1000
1200
1 2 3 4 5 6 7 8 9 101980-84 Pharmaceuticals
After Tax Present Value in 1990 $M
After-Tax R&D Costs
Only 3 out of 10 marketed drugs produce revenues that match or exceed average R&D costs
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 StagesDrug Development Stages Discovery Product Selection PreclinicalPreclinical Clinical
– Phase I– Phase II– Phase III
Cost Per StageCost 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 FailureReasons For Drug Failure
39%
30%
11%
5%5%
10%
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.
80%
80% can be detected in preclinical phase
More ConstraintsMore ConstraintsADME/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 TermsRegulatory 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 StudiesPreclinical StudiesADME/PKADME/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 PharmacologySafety 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 StudiesPreclinical StudiesAcute ToxicityAcute 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 StudiesPreclinical StudiesSub Acute ToxicitySub 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 StudiesPreclinical StudiesSubchronic/Chronic ToxicitySubchronic/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 StudiesPreclinical StudiesCarcinogenicityCarcinogenicity
• 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 StudiesTiming of Studies
Preclinical Study
Duration Time Clinical Study Supported
Safety pharmacology 1-3 weeks, depending on kinetic data
Before Phase I. Information should be available by the time early Phase I trials are completed.
Phase I/II
Toxicokinetic, pharmacokinetic studies
14 days
Single dose acute toxicity or dose escalation study in two species
A few hours to several weeks depending on sample and test type
Local tolerance studies using relevant route of administration
Timing of StudiesTiming of Studies
Preclinical Study
Duration Time Clinical Study Supported
Repeated dose toxicity studies in one rodent and one non-rodent
Should equal or exceed the duration of Phase I/II studies: (minimum 2 weeks, maximum 12 months; generally 1-3 months for biotech-derived products)
Before Phase I
Before Phase III
Phase I/II: 2 weeks to12 months
Timing of StudiesTiming of StudiesPreclinical
StudyDuration Time Clinical Study
SupportedGenotoxicity Variable Complete before start
of Phase II and all pediatric clinical trials
Phase I/II
Pediatric clinical trials
Reproductive toxicity studies
Variable Not required *
Complete all female reproductive toxicity and genotoxicity studies before Phase I/II studies. Pre- and postnatal development study before marketing approval..
Complete before pediatric studies
Phase I/II (males, and females not of child-bearing potential)
Phase I/II (pregnant females and females of childbearing potential)
Pediatric clinical trials
Timing of StudiesTiming of Studies
Preclinical Study
Duration Time Clinical Study Supported
Carcinogenicity studies
Variable Before long-term pediatric trials. Not usually needed unless there is cause for concern.
Pediatric clinical trials
What testing is needed?What testing is needed?
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.
Consider the following in better designing preclinical trials to increase the drug development success rate:
Savings OpportunitiesSavings 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 OutsourcingBenefits of OutsourcingOutsourcing 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 ConsiderationsOutsourcing ConsiderationsWhen 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)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: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 BioLabsPacific 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)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 ExperienceNVP 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 ?Questions ?
Pacific BioLabsPacific BioLabs551 Linus Pauling Drive551 Linus Pauling Drive
Hercules, CA 94547Hercules, CA 94547510-964-9000510-964-9000
510-964-0551 Fax510-964-0551 Faxwww.pacificbiolabs.comwww.pacificbiolabs.com
AppendixAppendix
Number of New Drug ApprovalsNumber of New Drug Approvals
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rug
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90 91 92 93 94 95 96 97 98 99 '00
USA
EU
Source: www.phrma.org EMEA established
Preclinical StudiesPreclinical StudiesIrritation and SensitizationIrritation 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 StudiesPreclinical StudiesImmunotoxicityImmunotoxicity
– 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 StudiesPreclinical StudiesReprotoxicity/Genotoxicity/MutagenicityReprotoxicity/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 ConsiderTechnical 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