Peclinical development2003

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

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86-90 91-95 96-01

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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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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