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    Dr. Charlene ChenDr. Charlene Chen

    Charlene@mail.dcb.org.twCharlene@mail.dcb.org.tw02-2695-6933 x 3116

    Nonclinical Safety EvaluationNonclinical Safety Evaluation

    in Drug Developmentin Drug Development

    DiscoveryStage

    DevelopmentStage

    IND NDATargetIdentification& Validation

    LeadIdentification

    &Optimization

    PreclinicalDevelopment

    ClinicalDevelopment

    PostApproval

    Phases of Drug DevelopmentPhases of Drug Development

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    New Drug Discovery ProcessNew Drug Discovery Process

    Phases of Drug DevelopmentPhases of Drug Development

    Acute and Sub-chronic Toxicity Chronic Toxicity Carcinogenicity

    NonNonNon---clinicalclinicalclinical

    Efficacy

    Metabolism

    Safety in

    Animals

    22 5 yrs5 yrs

    10 Evaluated10 Evaluated

    Phase IPhase IPhase I

    Safety

    PK-PD

    20-80 Health

    Volunteers

    Up to 1 yrUp to 1 yr

    5 Enter5 Enter

    Phase IIPhase IIPhase II

    Efficacy

    Safety in100-300Patients

    Up to 2 yrsUp to 2 yrs

    3 Enter3 Enter

    Phase IIIPhase IIIPhase III

    ConfirmatoryEfficacy

    SafetyLong-term

    1000-3000Patients

    33 5 yrs5 yrs

    2 Enter2 Enter

    RegulatoryRegulatoryRegulatory

    ApprovedApprovedApproved

    NDA

    Up to 2.5 yrsUp to 2.5 yrs

    1 Enter1 Enter

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    The Discovery Testing Scheme

    Reasons for Attrition (1991 to 2000)

    Nature Review/ Drug Discovery 3:711-715

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    Different Area of ToxicologyDifferent Area of Toxicology

    Mechanistic ToxicologyMechanistic Toxicology

    RegulatoryRegulatory

    ToxicologyToxicology

    DescriptiveDescriptive

    ToxicologyToxicology

    RiskRisk

    AssessmentAssessment

    Guideline and RegulationGuideline and Regulation

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    OECD GuidelinesOECD GuidelinesDuration Guideline No. Title

    Acute 401 Acute Oral Toxicity

    402 Acute Dermal Toxicity

    403 Acute Inhalation Toxicity

    420 Acute Oral Toxicity - Fixed Dose Method

    423 Acute Oral Toxicity - Acute Toxic Class Method

    425 Acute Oral Toxicity - Up-and-Down Procedure

    Subacute 407 Repeat Dose 28-day Oral Toxicity Study in Rodents

    410 Repeat Dose Dermal Toxicity - 21/28-Day Study

    412 Repeat Dose Inhalation Toxicity - 28/14-Day

    Subchronic 408 Subchronic Oral Toxicity - Rodent: 90-Day

    409 Subchronic Oral Toxicity - Non-Rodent: 90-Day

    411 Subchronic Dermal Toxicity: 90-Day

    413 Subchronic Inhalation Toxicity: 90-Day

    Chronic 451 Carcinogenicity Studies

    452 Chronic Toxicity

    453 Combined Chronic Toxicity/Carcinogenicity Studies

    http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances

    PharmaceuticalsPharmaceuticalsGuideline : ICH

    S9: Non-clinical Evaluation for Anticancer Pharmaceuticals (2010)S9: Anticancer Safety

    S8: Immunotoxicity Studies (2006)S8: Immunotoxicology

    S7B: QT Prolongation (2005)S7A: Safety Pharmacology (2001)S7: Pharmacology

    S6 (R1): Safety Studies for Biotechnology Derived

    Products (2009)

    S6: Safety Studies for

    Biotechnology Derived Products

    (1997)

    S6: Biotech Safety

    S5B: Male Fertility (1996)S5A: Toxicity to Reproduction

    (1994)

    S5: Reprotoxicology

    S4: Repeat Dose Toxicity in Non-Rodents (1999)S4: Repeat Dose Toxicity inRodents (1999)S4: Toxicity

    S3B: Pharmacokinetics

    (1995)

    S3A: Toxicokinetics (1995)S3: Kinetics

    S2 (R1): Genotox testing and

    Data Interpretation (2008)

    S2B: Standard Battery of

    Tests (1997)

    S2A: Specific Aspects of

    Regulatory Tests (1996)

    S2: Genotoxicity

    S1C: Dose Selection (2008)S1B: Testing for

    Carcinogenicity (1998)

    S1A: Need for Carcinogenicity

    Studies (1996)

    S1: Carcinogenicity

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    ICH GUIDELINEICH GUIDELINEDuration of Repeated Dose Toxicity Studies to Support Phase I and II

    Trials in EU and Phase I , II and III Trials in the US and Japan

    Chronic6 Months> 6 Months

    6 Months6 MonthsUp to 6 Months

    3 Months3 MonthsUp to 3 Months

    1 Months1 MonthsUp to 1 Months

    2 Weeks2-4 WeeksUp to 2 Weeks

    2 Weeks2-4 WeeksSingle Dose

    Non-rodentsRodents

    Minimum Duration of RepeatedDose Toxicity Studies

    Duration of ClinicalTrials

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    www.doh.gov.tw

    1.

    (Acute toxicity test)

    2. (Subacute toxicity test)

    3.

    (Chronic test)

    4. (Reproductive test)

    5.

    (Drug dependence)

    6. (Antigenicity test)

    7.

    (Mutagenicity test)

    8.

    (Carcinogenicity test)

    9. (Local irritation)

    www.doh.gov.tw

    * * *1.

    (Acute Toxicity Study)

    2. (Subacute Toxicity Study)

    3. (Genotoxicity Study) 4.

    (Chronic Toxicity Study)

    5. ( Teratology Study)

    6.

    (Reproductive test)

    7.

    (Carcinogenicity Study)

    *

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    Cosmetic

    FoodApplied to body

    for cleansing,beautifying, or

    altering appearance

    Ingested to affectstructure or

    function of body

    Ingested tosupplement

    diet

    Consumed forits taste, aroma,or nutritive value

    Regulatory Approaches forRegulatory Approaches for

    a Botanical Producta Botanical Product

    Is it intendedfor use as a drugunder 21 U.S.C.321(g)?

    Drug

    Dietarysupplement YesNo

    Used to diagnose,

    cure, mitigate,treator prevent disease

    What isthe intendeduse?

    BotanicalProduct

    Herbal MedicineHerbal Medicine

    Follow same regulation for chemical drugs

    Mixture of multiple ingredients or plants

    EMEA: Guidance on non-clinical testing of

    herbal drug preparations with long-termmarketing experience

    USFDA: Guidance for Industry: Botanicaldrug products, 2004

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    Genetic ToxicologyGenetic Toxicology

    Genetic Toxicity StudiesGenetic Toxicity Studies

    Purpose: Access the likelihood that the drug compound ismutagenic or carcinogenic.

    AMES test: Detect genetic changesconduct in bacteria

    DNA damage: Micronucleus ( in vitroand in vivo)CHO cell and mouse peripheral blood cell

    Chromosomal damage: Chromosomal aberration

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    Test System: Salmonella typhimurium

    TA97 or TA1537, TA98, TA100, TA102, and TA1535

    Principles:

    Histidine- Histidine+

    Metabolic Activation:

    Aroclor 1254-induced rat liver homogenate

    -- S9 mixture

    SalmonellaReverse Gene Mutation

    (Ames Test)(SOP: DCB-DV-TE00201)

    Chromosome Aberration Assay

    Test system: CHO, V79 cells or Human peripheralblood lymphocytes

    Max. conc.: >50% cytotoxicity or solubility limit , 5mg/ml or 10 mM

    Conc. levels: 3 conc. ; positive and negativecontrols with duplicate cultures

    TA treatment: 3h S9 and 20h (or 24h, 48 h) S9,cell harvest at 20h (or 24 h, 48 h)

    Analysis: code slides, score 200 metaphasesper conc.

    (SOP: DCB-DV-TE00217)

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    Micronucleus Assay

    (Mouse Peripheral Blood)

    Test system: BALB/c or ICR mice

    Dose levels: 3 doses ; positive and vehiclecontrols, 5 mice/group

    Drug treatment: gavage or i.p. injection; single ormultiple administration

    Blood collection: 48 and 72h for single dose;

    36-48 h after the final dose for themultiple dose study

    Analysis: score 2000 reticulocytes per animal

    (SOP: DCB-DV-TE00227)

    (SOP: DCB-DV-TE00258)

    Animal StudiesAnimal Studies

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    Test SystemTest System IACUC-approved protocol

    Health screening prior to study startRodents: SPF

    Dogs: standard vaccinations

    Quarantine: veterinary approval to release prior tostudy initiation

    Acclimation

    Rodents: usually 7 days

    Dogs: at least 14 days

    Acute ToxicityAcute Toxicity

    One or more doses administered over a period of up to24 hours

    Goal: Determine toxic dose levels and observeclinical indications of toxicity.

    Purpose: Help to determine doses for repeated dosestudies in animals and Phase I studies inhuman

    Contents: Clinical observation (1, 2, 3, 4 hours after dosingthen daily)Body weightGross necropsy

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    Acute ToxicityAcute Toxicity

    151413121110987654321Study Day

    Weighing

    Clinical Observation

    Gross Necropsy

    Weighing

    General: 4 groups (3 dose 1 control)Limit Test: 2 groups (1 dose 1 control)

    6 /group (3/ 3)

    10 /group (5/ 5)

    Weighing

    Dosing

    Clinical Observation

    0 1 2 3 4 5 6 7 8

    SD 1 :hours after dosing

    Extended single dose study:

    SD2 and SD14 Histopath.

    Repeated Dose StudiesRepeated Dose Studies

    Depending on the duration of the studies, maybe referredas subacute, suchronic, or chronic.

    Specific duration should anticipate the length of the clinical trialthat will be conducted on the new drug

    Contents: Clinical observation (daily)Body weight (weekly)Food consumption (weekly)Ophthalmologic and EKG ExaminationGross necropsyClinical pathology (urine, whole blood, serum chemistry)Organ weightHistopathology

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