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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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