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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