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    Dr. Charlene ChenDr. Charlene Chen

    [email protected]@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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    Subacute (week) 1 2 3 4 1 2 3 4

    Subchronic (week) 1 2 3 4 5 6 7 8 9 10 11 12 13 1 2 3 4

    Chronic (week) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 1 2 3 4

    Repeated Dose StudiesRepeated Dose Studies

    10+5R10+5R

    4+2R4+2R

    Dosing PeriodRecovery

    Period

    Body WeightClinical Pathology

    Gross Necropsy

    Histopathology

    Body Weight

    Clinical Pathology*

    Gross Necropsy

    Histopathology*

    C

    20+10R20+10R

    R

    Body WeightDosingClinical Observation

    Food Consumption

    YesNoYesYes

    Pre-study

    Body WeightClinical Observation

    Food ConsumptionOphthalmologic ExaminationECG & Clinical Pathology (CP)

    CP, Ophthalmology & ECG

    Ophthalmology & ECGOphthalmology & ECG

    1

    2

    3

    45

    1

    2

    3

    45

    3 Dose +1 Control

    Clinical ObservationsClinical Observations

    Respiratory Salivation

    Difficult or labored breathing

    Motor activities PiloerectionChanges in frequency and nature

    of movement

    Convulsion Analgesia

    reaction to induced pain

    Reflexes Muscle tone

    Hyptonia, Hypertonia

    Ocular signs GI signs

    Dropping, Emesis, Diuresis

    Cardiovascular signs Skin

    Vasoconstriction, Vasodilation, Edema, Erythema

    or heart rate

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    Animal WeighingAnimal Weighing

    Balance (g)mice 0.1

    rats 1

    rabbits 10

    dogs 100

    Quality Control of Balance- Check: twice daily

    - Calibration: once a year (CNLA)

    Historic Data- Establish historical data

    - Quality control reference

    pH Glucose

    Specific gravity Ketones

    Nitrites Urobilinogen

    Occult blood Bilirubin

    Protein Leukocytes

    UrinalysisUrinalysis (10 items)(10 items)

    (SOP: DCB-DV-TE00451)

    Bayer Clinitek 100 Urine Chemistry Analyzer(SOP: DCB-DV-EQ00066)

    Gravity will be examined by Clinical Specific Refractometer(SOP: DCB-DV-EQ00070)

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    Erythrocytes (Red blood cells) count

    Hemoglobin HematocritMean corpuscular volume (calculated)Mean corpuscular hemoglobin (calculated)Mean corpuscular hemoglobin concentration (calculated)Leukocytes (White blood cells) countLeukocyte differential count

    (Lymphocytes, Monocytes, Neutrophils, Eosinophils, Basophils, etc.)Reticulocytes Platelet count

    Prothrombin time Activated partial thromboplastin time

    Bayer ADVIA 120 Hematology Analyzer (SOP: DCB-DV-EQ00091)

    Sysmex CA-1000 Automated Coagulation Analyzer (SOP: DCB-DV-EQ00071)

    HematologyHematology (12 items)(12 items)

    (SOP: DCB-DV-TE00425, DCB-DV-TE00413 )

    Alkaline phosphatase Albumin/Globulin ratio (calculated)

    Alanine aminotransferase Sodium

    Aspartate aminotransferase Potassium

    -glutamyltransferase Chloride

    Glucose Calcium

    Total bilirubin Phosphorus

    Direct bilirubin Cholesterol

    Creatinine Triglycerides

    Blood urea nitrogen Lactate dehydrogenase

    Total protein Creatine phosphate kinase

    Albumin Uric acid

    Serum ChemistrySerum Chemistry (22 items)(22 items)

    Hitachi Model 7060 Automated Analyzer (SOP: DCB-DV-EQ00075)

    (SOP: DCB-DV-TE00442)

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    Histopathology ExaminationHistopathology Examination(37 items)(37 items)

    Adrenals Pancreas

    Aorta Penis (male only)

    Bone with bone marrow (femur &

    sternum)

    Pharynx/Larynx

    Pituitary gland

    Brain (medulla/pons, cerebellum,

    cerebrum)

    Prostate (male only)

    Salivary glands (submandibular & parotid

    Esophagus Sciatic nerve

    Eyes including optic nerve Skeletal muscle (thigh)

    Gall bladder Skin

    Gonads: Small intestine:

    Ovaries and oviducts (female only) Duodenum

    Testes with epididymis (male only) Ileum

    Heart Jejunum

    Kidneys Spinal cord (cervical, thoracic & lumbar)

    Large intestine: Spleen

    Cecum Stomach

    Colon Thymus

    Rectum Thyroid/Parathyroid

    Liver Tongue

    Lung (with main-stem bronchi) Tonsil

    Lymph nodes (submandibular &

    mesenteric)

    Trachea

    Urinary bladder

    Masses/Target organs Uterus (both horns) and cervix (female only

    Mammary glands (female only) Vagina (female only)

    Reproduction StudiesReproduction Studies

    Segment I :Provide the overview of reproductive toxicitywith treatment of both sexes throughoutgametogenesis

    (60 days for males and 15 days for females)

    Segment II:Teratology, screen the capability of an agent toelicit toxicity during the period of organogenesis

    Segment III: Assess agent-induced effects duringorganogenesis in neonatal life

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    Teratology StudiesTeratology Studies

    Purpose: Evaluate the effects of the test article on maternalpregnancy, embryo-fetal development and fetuses whileadministered orally to pregnant rats from gestation day6 to day 15.

    Contents: Clinical observation (daily)Body weight (at least twice weekly)Food consumption (weekly)Reproductive performanceGross necropsy (external, visceral and skeletal of fetus)

    Renal/Urinary system

    Gastrointestinal system

    Safety PharmacologySafety Pharmacology

    Core battery

    Cardiovascular system

    Central Nerve system

    Respiratory system

    Safety pharmacology core battery(GLP compliant ICH S7A)

    Motor activity

    Behavior changesCoordinationBody temperature

    Radiotelemetry(conscious animals)Blood pressureHeart rateECG/QT interval

    Respiratory rateTidal volumeRespiratory function

    Urine and blood parameter

    Creatinine clearance

    Functional measure

    Gastric emptying & GIpropulsion in rodents

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    Carcinogenesis study

    Historical data establishStudy conducting

    Animal condition:Routine monitoringAdditional monitorNecropsyHistopathology

    Related condition:Animal facilityDosing trainingAnimal allocation

    CarcinogenesisCarcinogenesisPurpose: Observe test animals for a major life span for the

    development of neoplastic lesions during or afterexposure to test article

    Duration: 18 months for mice, 24 months for rats

    Contents: Clinical observation (daily)Body weight (weekly for first 13 weeks, once every 4 weeks thereafter)

    Food consumption (weekly for first 13 weeks, approximately 3 monthsthereafter)

    Differential blood count (12, 18 months and prior to sacrifice)

    Gross necropsyHigh standard Histopathology

    ReferencesReferences

    ICH: www.ich.org -> Safety Topics

    USFDA: www.fda.gov/cder/PharmTox/guidance.html

    USFDA: Botanical drug products, 2004

    USFDA: www.cfsan.fda.gov/~redbook/red-toca.html

    OECD: www.sourceoecd.org

    EMEA: www.emea.eu.int

    OPPTS Harmonized Test Guidelines (US EPA)

    DOH: www.doh.gov.tw

    ISO10993

    USP