CI-1

100100 年生技醫藥法規科學人才培訓課程 年生技醫藥法規科學人才培訓課程

抗癌新藥臨床前法規國際最新發展與起始劑量選擇

財團法人醫藥品查驗中心財團法人醫藥品查驗中心藥毒理小組長藥毒理小組長 // 審查員 汪徽五審查員 汪徽五

100100 年年 0808 月月 2525 日日

CI-2

本次演講內容純為個人意見，所說明的事項僅供與會人員參考，不必然與醫藥品查驗中心 (CDE) 或食品藥物管理局(TFDA) 的政策，及其案件的審查相關

說明

OutlineOutline Overview of Anticancer Drug Development ICH Topic S9 nonclinical Evaluation for Anticancer

Pharmaceuticals Components of Non-Clinical Drug Development What are Pharmacology Studies for Anti-Cancer Drugs? Non-Clinical Safety Studies Current Approach to Select Starting Doses of

Anticancer Drug Starting Doses for Biological Therapies US FDA Perspective 各階段抗癌藥物臨床試驗之臨床前試驗要求

Overview of Anticancer Drug Development ICH Topic S9 nonclinical Evaluation for Anticancer

Pharmaceuticals Components of Non-Clinical Drug Development What are Pharmacology Studies for Anti-Cancer Drugs? Non-Clinical Safety Studies Current Approach to Select Starting Doses of

Anticancer Drug Starting Doses for Biological Therapies US FDA Perspective 各階段抗癌藥物臨床試驗之臨床前試驗要求

CI-3

Overview of Anticancer Drug Development

Overview of Anticancer Drug Development

IND NDA

Chemical Synthesis and Formulation Development

Animal Models for Efficacy

Assay Development

Animal PK, PD and Safety

Dose Escalation and Initial PK

Proof of Concept and Dose Finding

Large Efficacy Trials with PK Screen

PHASE I PHASE II PHASE III

Pre-Clinical Development Clinical Development

PK/PD Studies in Special Populations

Chronic Nonclinical Safety

Goals of Non-Clinical Testing of DrugsGoals of Non-Clinical Testing of Drugs

To characterize potential adverse drug effects– Define end organ toxicities– Define reversibility of toxicity

To characterize pharmacokinetic profile To characterize beneficial pharmacodynamic effects

– Proof of principle

To guide safe use in human clinical studies– To determine a safe & reasonable starting dose– Provide monitoring guidelines for the clinical study

Provide sufficient data to conclude that patients are not exposed to unreasonable risks– Potential for benefit must also exist

To characterize potential adverse drug effects– Define end organ toxicities– Define reversibility of toxicity

To characterize pharmacokinetic profile To characterize beneficial pharmacodynamic effects

– Proof of principle

To guide safe use in human clinical studies– To determine a safe & reasonable starting dose– Provide monitoring guidelines for the clinical study

Provide sufficient data to conclude that patients are not exposed to unreasonable risks– Potential for benefit must also exist

ICH Topic S9 nonclinical Evaluation for Anticancer Pharmaceuticals

Current Step 4 version, dated 29 October 2009

ICH Topic S9 nonclinical Evaluation for Anticancer Pharmaceuticals

Current Step 4 version, dated 29 October 2009

1. INTRODUCTION 1.1 Objectives of the Guideline

1.2 Background

1.3 Scope

1.4 General Principles

2. STUDIES TO SUPPORT NONCLINICAL EVALUATION2.1 Pharmacology 2.2 Safety Pharmacology

2.3 Pharmacokinetics 2.4 General Toxicology

2.5 Reproduction Toxicology 2.6 Genotoxicity

2.7 Carcinogenicity 2.8 Immunotoxicity

2.9 Photosafety testing

1. INTRODUCTION 1.1 Objectives of the Guideline

1.2 Background

1.3 Scope

1.4 General Principles

2. STUDIES TO SUPPORT NONCLINICAL EVALUATION2.1 Pharmacology 2.2 Safety Pharmacology

2.3 Pharmacokinetics 2.4 General Toxicology

2.5 Reproduction Toxicology 2.6 Genotoxicity

2.7 Carcinogenicity 2.8 Immunotoxicity

2.9 Photosafety testing

CI-6

ICH Topic S9 nonclinical Evaluation for Anticancer Pharmaceuticals

Current Step 4 version, dated 29 October 2009

ICH Topic S9 nonclinical Evaluation for Anticancer Pharmaceuticals

Current Step 4 version, dated 29 October 2009

3. NONCLINICAL DATA TO SUPPORT CLINICAL TRIAL DESIGN AND MARKETING

3.1 Start Dose for First Administration in Humans 3.2 Dose Escalation and the Highest Dose in a Clinical Trial 3.3 Duration and Schedule of Toxicology Studies to Support Initial

Clinical Trials 3.4 Duration of Toxicology Studies to Support Continued Clinical

Development and Marketing 3.5 Combination of Pharmaceuticals 3.6 Nonclinical Studies to Support Trials in Pediatric Populations 4. OTHER CONSIDERATIONS 4.1 Conjugated Products 4.2 Liposomal Products 4.3 Evaluation of Drug Metabolites 4.4 Evaluation of Impurities 5. NOTES

3. NONCLINICAL DATA TO SUPPORT CLINICAL TRIAL DESIGN AND MARKETING

3.1 Start Dose for First Administration in Humans 3.2 Dose Escalation and the Highest Dose in a Clinical Trial 3.3 Duration and Schedule of Toxicology Studies to Support Initial

Clinical Trials 3.4 Duration of Toxicology Studies to Support Continued Clinical

Development and Marketing 3.5 Combination of Pharmaceuticals 3.6 Nonclinical Studies to Support Trials in Pediatric Populations 4. OTHER CONSIDERATIONS 4.1 Conjugated Products 4.2 Liposomal Products 4.3 Evaluation of Drug Metabolites 4.4 Evaluation of Impurities 5. NOTES

CI-7

Components of Non-Clinical Drug Development

Components of Non-Clinical Drug Development

1. In vitro studies: Cell lines, cell-free systems (drug screening)

2. Drug formulation

3. Chemistry, Manufacturing, and Controls: Drug supply & quality

4. In vivo efficacy studies: Animal models and proof of principle

5. Non-clinical safety studies

1. In vitro studies: Cell lines, cell-free systems (drug screening)

2. Drug formulation

3. Chemistry, Manufacturing, and Controls: Drug supply & quality

4. In vivo efficacy studies: Animal models and proof of principle

5. Non-clinical safety studies

Drug Supply and FormulationDrug Supply and Formulation

Drug supply: bulk chemical synthesis, natural product isolation, etc.

Good Manufacturing Practice (GMP) guidelines for pharmaceutical product manufacturing

Formulation for clinical delivery of drug: vehicles for intravenous or other routes of administration

Drug supply: bulk chemical synthesis, natural product isolation, etc.

Good Manufacturing Practice (GMP) guidelines for pharmaceutical product manufacturing

Formulation for clinical delivery of drug: vehicles for intravenous or other routes of administration

What are Pharmacology Studies for Anti-Cancer Drugs?

What are Pharmacology Studies for Anti-Cancer Drugs?

Evaluation of ability of a new agent to induce the desired therapeutic effect– in vitro studies of product binding, tumor cell

killing, and other effects– in vivo studies of anti-tumor activity

e.g., human tumor xenograft models Demonstration of pharmacologic and/or biologic

activity is the first step in the development of ANY new drug or biologic product

Evaluation of ability of a new agent to induce the desired therapeutic effect– in vitro studies of product binding, tumor cell

killing, and other effects– in vivo studies of anti-tumor activity

e.g., human tumor xenograft models Demonstration of pharmacologic and/or biologic

activity is the first step in the development of ANY new drug or biologic product

CI-10

In Vivo Study Goals: Animal ModelsIn Vivo Study Goals: Animal Models

Efficacy: Proof of therapeutic principle Toxicology: Toxicity profile Practical Issues:

– Animal pharmacokinetics and pharmacodynamics

– Starting dose and schedule for clinical trials

Efficacy: Proof of therapeutic principle Toxicology: Toxicity profile Practical Issues:

– Animal pharmacokinetics and pharmacodynamics

– Starting dose and schedule for clinical trials

Animal ModelsProof of Principle

Animal ModelsProof of Principle

Animal screening is too expensive for routine use

Efficacy in animal models of specific disease states occurs after in vitro studies

Evaluation of therapeutic index– Toxicity versus Efficacy

Animal screening is too expensive for routine use

Efficacy in animal models of specific disease states occurs after in vitro studies

Evaluation of therapeutic index– Toxicity versus Efficacy

Ideal Animal ModelIdeal Animal Model

ValiditySelectivityPredictabilityReproducibility

ValiditySelectivityPredictabilityReproducibility

“There is no perfect tumor model”

Animal Models in CancerAnimal Models in Cancer

Spontaneous tumors– Idiopathic– Carcinogen-induced– Transgenic/gene knockout animals: p53, RB, etc

Transplanted tumors– Animal tumors: Lewis lung, S180 sarcoma, etc– Human tumor xenografts: human tumor lines

implanted in immunodeficient mice (current NCI standard in vivo efficacy testing system)

– Human tumors growing in vivo in implantable hollow fibers

Spontaneous tumors– Idiopathic– Carcinogen-induced– Transgenic/gene knockout animals: p53, RB, etc

Transplanted tumors– Animal tumors: Lewis lung, S180 sarcoma, etc– Human tumor xenografts: human tumor lines

implanted in immunodeficient mice (current NCI standard in vivo efficacy testing system)

– Human tumors growing in vivo in implantable hollow fibers

Human Tumor XenograftsHuman Tumor Xenografts

Athymic “nude” mice developed in 1960’s Mutation in nu gene on chromosome 11 Phenotype: retarded growth, low fertility, no

fur, immunocompromized– Lack thymus gland, T-cell immunity

First human tumor xenograft of colon adenocarcinoma by Rygaard & Poulson, 1969

Athymic “nude” mice developed in 1960’s Mutation in nu gene on chromosome 11 Phenotype: retarded growth, low fertility, no

fur, immunocompromized– Lack thymus gland, T-cell immunity

First human tumor xenograft of colon adenocarcinoma by Rygaard & Poulson, 1969

Xenograft Study EndpointsXenograft Study Endpoints

Toxicity Endpoints:– Drug related death– Net animal weight loss

Efficacy Endpoints– Clonogenic assay– Tumor growth assay (corrected for tumor doubling

time)– Treated/control survival ratio– Tumor weight change

Toxicity Endpoints:– Drug related death– Net animal weight loss

Efficacy Endpoints– Clonogenic assay– Tumor growth assay (corrected for tumor doubling

time)– Treated/control survival ratio– Tumor weight change

Xenograft Tumor Weight ChangeXenograft Tumor Weight Change

Tumor weight change ratio (used by the NCI in xenograft evaluation)

Defined as: treated/control x 100% Tumor weight in mg = (a x b2)/2

– a = tumor length– b = tumor width

T/C < 40-50% is considered significant

Tumor weight change ratio (used by the NCI in xenograft evaluation)

Defined as: treated/control x 100% Tumor weight in mg = (a x b2)/2

– a = tumor length– b = tumor width

T/C < 40-50% is considered significant

Non-Clinical Efficacy TestingNon-Clinical Efficacy Testing

Pharmacological activity assessed by models of disease are generally of low relevance to safety (IND) and efficacy (NDA) decisions– Efficacy in vivo and in vitro from non-clinical studies may

not dependably predict clinical efficacy• Heterogeneity of disease• Interspecies differences in ADME• Role of immune system

Pharmacology studies are useful for:– Assessing an appropriate schedule (daily, weekly, q3wks)– Justification for a drug combination– Understanding effect at a molecular target

• Examine receptor specificity• Identifying and evaluating biomarkers

Pharmacological activity assessed by models of disease are generally of low relevance to safety (IND) and efficacy (NDA) decisions– Efficacy in vivo and in vitro from non-clinical studies may

not dependably predict clinical efficacy• Heterogeneity of disease• Interspecies differences in ADME• Role of immune system

Pharmacology studies are useful for:– Assessing an appropriate schedule (daily, weekly, q3wks)– Justification for a drug combination– Understanding effect at a molecular target

• Examine receptor specificity• Identifying and evaluating biomarkers

Components of Non-Clinical Drug Development

Components of Non-Clinical Drug Development

1. In vitro studies: Cell lines, cell-free systems (drug screening)

2. Drug formulation

3. Chemistry, Manufacturing, and Controls: Drug supply & quality

4. In vivo efficacy studies: Animal models and proof of principle

5. Non-clinical safety studies

1. In vitro studies: Cell lines, cell-free systems (drug screening)

2. Drug formulation

3. Chemistry, Manufacturing, and Controls: Drug supply & quality

4. In vivo efficacy studies: Animal models and proof of principle

5. Non-clinical safety studies

Non-Clinical Safety StudiesNon-Clinical Safety Studies

Safety pharmacology Toxicokinetics & pharmacokinetic studies Single dose toxicity studies Repeated dose toxicity studies

Safety pharmacology Toxicokinetics & pharmacokinetic studies Single dose toxicity studies Repeated dose toxicity studies

Pharmacokinetics/ToxicokineticsPharmacokinetics/Toxicokinetics

Analytic assay development and testing Preclinical PK/PD efficacy and toxicity

relationships Initial drug formulation testing Testing of different schedules and routes

of administration Animal ADME

Analytic assay development and testing Preclinical PK/PD efficacy and toxicity

relationships Initial drug formulation testing Testing of different schedules and routes

of administration Animal ADME

Non-Clinical Toxicology StudiesNon-Clinical Toxicology Studies

GLP Toxicology is expected Use the clinical schedule, route, and formulation Toxicity studies required in 2 mammalian species

prior to FIH studies– Classically rat and dog for small molecules

– Non-human primates for biological products

Repeat dose toxicology required for anticipated duration of clinical use for most non-oncology agents– 3 mo. toxicology for ≤3 mo. clinical study

Recommendations for agents used in the treatment of advanced cancer patients

GLP Toxicology is expected Use the clinical schedule, route, and formulation Toxicity studies required in 2 mammalian species

prior to FIH studies– Classically rat and dog for small molecules

– Non-human primates for biological products

Repeat dose toxicology required for anticipated duration of clinical use for most non-oncology agents– 3 mo. toxicology for ≤3 mo. clinical study

Recommendations for agents used in the treatment of advanced cancer patients

Expected Toxicology Testing for Phase I Oncology Drug Studies

Expected Toxicology Testing for Phase I Oncology Drug Studies

Clinical Schedule Preclinical study schedule *

Once every 3 weeks Single dose study

Daily for 5 days every 3 weeks Daily for 5 days

Weekly x 3, week off Once a week for 3 weeks

Continuous weekly Once a week for 4-5 doses

Continuous daily Daily for 28 days

* Study schedule does not include a recovery period-- 28 day toxicology is generally sufficient for DRUG trials

extending beyond 28 days

Non-Clinical Toxicology Studies For Oncology Drug Combinations

Non-Clinical Toxicology Studies For Oncology Drug Combinations

May not be necessary for testing in advanced cancer patients

May exclude if:– No PK, PD, or metabolic interactions

anticipated– Drugs are not packaged as a combination– All components well studied individually

May not be necessary for testing in advanced cancer patients

May exclude if:– No PK, PD, or metabolic interactions

anticipated– Drugs are not packaged as a combination– All components well studied individually

Single Dose Toxicity StudiesSingle Dose Toxicity Studies

Dose escalation study may be an alternative to a single dose design– Dose range should include maximally

tolerated dose (MTD) and no adverse effect level (NOAEL)

Standard design– Early sacrifice at 24 to 48 hr and after 14

days

Dose escalation study may be an alternative to a single dose design– Dose range should include maximally

tolerated dose (MTD) and no adverse effect level (NOAEL)

Standard design– Early sacrifice at 24 to 48 hr and after 14

days

Repeated Dose Toxicity StudiesRepeated Dose Toxicity Studies

Duration of repeated dose studies related to duration of anticipated clinical use– Use same schedule and duration– Typically 28 days– Should include recovery group

Use can support repeat dose clinical studies

Duration of repeated dose studies related to duration of anticipated clinical use– Use same schedule and duration– Typically 28 days– Should include recovery group

Use can support repeat dose clinical studies

Non-Clinical Toxicology Ongoing Endpoints

Non-Clinical Toxicology Ongoing Endpoints

Ongoing– Clinical signs, behavior– Body weights and food consumption– Clinical pathology (in larger species)

• Hematology• Chemistry panels

– Toxicokinetics End of Study

– Macroscopic changes at necropsy– Organ weights– Histopathology of all organs

Ongoing– Clinical signs, behavior– Body weights and food consumption– Clinical pathology (in larger species)

• Hematology• Chemistry panels

– Toxicokinetics End of Study

– Macroscopic changes at necropsy– Organ weights– Histopathology of all organs

Other Toxicology StudiesOther Toxicology Studies

Local tolerance studies– If warranted by route of administration

Genotoxicity studies Reproductive Toxicity studies Carcinogenicity studies

Local tolerance studies– If warranted by route of administration

Genotoxicity studies Reproductive Toxicity studies Carcinogenicity studies

Genotoxicity studiesGenotoxicity studies

General– Normally done prior to FIH studies, but not required prior to

phase I studies in oncology patients– Standard battery of genotoxicity tests required prior to

initiation of phase II Specific genotoxicity studies

– In vitro bacterial reverse mutation assays: Ames test, point mutation test

– In vitro chromosome damage tests in mammalian cells: metaphase cell analysis, murine lymphoma gene mutation assays

– In vivo chromosomal damage assays: rodent micronucleus tests

General– Normally done prior to FIH studies, but not required prior to

phase I studies in oncology patients– Standard battery of genotoxicity tests required prior to

initiation of phase II Specific genotoxicity studies

– In vitro bacterial reverse mutation assays: Ames test, point mutation test

– In vitro chromosome damage tests in mammalian cells: metaphase cell analysis, murine lymphoma gene mutation assays

– In vivo chromosomal damage assays: rodent micronucleus tests

Reproductive Toxicity StudiesReproductive Toxicity Studies Men

– May include in Phase I/II after relevant repeated dose toxicity studies

– Male fertility study should be completed prior to initiation of Phase III

Women not of childbearing potential– May include in clinical trials after relevant repeated dose

toxicity studies Women of childbearing potential

– May include in carefully monitored early studies with precautions

– Fertility and embryo-fetal toxicity studies should be completed prior to entry of women into phase III trials

Pregnant women– All reproductive toxicity and genotoxicity studies must be

completed prior to entry of these women in trials

Men– May include in Phase I/II after relevant repeated dose toxicity

studies– Male fertility study should be completed prior to initiation of

Phase III Women not of childbearing potential

– May include in clinical trials after relevant repeated dose toxicity studies

Women of childbearing potential– May include in carefully monitored early studies with

precautions– Fertility and embryo-fetal toxicity studies should be completed

prior to entry of women into phase III trials Pregnant women

– All reproductive toxicity and genotoxicity studies must be completed prior to entry of these women in trials

Carcinogenicity studiesCarcinogenicity studies

Usually not needed prior to clinical trial initiation

Not needed in advanced cancer indications

Usually not needed prior to clinical trial initiation

Not needed in advanced cancer indications

Preclinical Toxicology GoalsPreclinical Toxicology Goals

Determine the toxicity profile for acute and chronic administration

Estimate a “safe” starting dose for phase I studies

NCI guidelines recommend single dose and multidose toxicity in two species (one non-rodent)

Historical guidelines are 1/10 the LD10 in mice – Death, as an endpoint no longer required

Determine the toxicity profile for acute and chronic administration

Estimate a “safe” starting dose for phase I studies

NCI guidelines recommend single dose and multidose toxicity in two species (one non-rodent)

Historical guidelines are 1/10 the LD10 in mice – Death, as an endpoint no longer required

Current Approach to Select Starting Doses of Anticancer Drug

Current Approach to Select Starting Doses of Anticancer Drug

Starting dose of 1/10 the dose causing severe toxicity (or death) in 10% of rodents (STD10) on mg/m2 basis

Provided the same dose causes no severe irreversible toxicity in a non-rodent species (usually dogs)

If irreversible toxicities are seen, then 1/6 of the highest dose tested in non-rodents that does not cause severe, irreversible toxicity (HNSTD)– Occasionally, species specific difference may mandate

the use of alternative species for selection of starting dose

Starting dose of 1/10 the dose causing severe toxicity (or death) in 10% of rodents (STD10) on mg/m2 basis

Provided the same dose causes no severe irreversible toxicity in a non-rodent species (usually dogs)

If irreversible toxicities are seen, then 1/6 of the highest dose tested in non-rodents that does not cause severe, irreversible toxicity (HNSTD)– Occasionally, species specific difference may mandate

the use of alternative species for selection of starting dose

34

Determine dose severely toxic to 10% of rodents (STD10)

Convert from mg/kg to mg/m2

Mouse x 3; Rat x 6; Guinea-pig x 7.7Hamster x 4.1

Is 1/10rodent STD10 (mg/m2)

severely toxic tonon-rodents?

Determine non-rodent HighestNon-Severely Toxic Dose

(HNSTD)

YES

YES

Is non-rodent inappropriate?YES

Is rodent aninappropriate species?

(biochem, ADME, target, etc)

NO

NO

Start Dose =1/10Rodent STD10

Convert from mg/kg to mg/m2

Dog x 20; Monkey x 10Rabbit x 11.6

Start Dose =1/6Non-Rodent HNSTD

NO

Sample 1 for Starting Dose SlectionSample 1 for Starting Dose Slection Drug A is administered to patients with advanced solid tumors by

intravenous infusion over approximately 30 minutes, on days 1, 8, and 15 of a 28-day cycle.

34% inhibition of the hERG channel at 1 μM. Rat, IV, QDx5 for two cycles +10 day recovery between cycle1/2:

intestine, thymus, lymph nodes and bone marrow; STD: 10 mg/kg (60 mg/m2); HNSTD: 3 mg/kg (18 mg/m2); NOAEL: 1 mg/kg (6 mg/m2)

Dog, IV, QDx5 for two cycles +10 day recovery between cycle1/2: STD: 1 mg/kg (20 mg/m2); HNSTD: 0.3 mg/kg (6 mg/m2); NOAEL: 0.1 mg/kg (2 mg/m2)

For Drug A studies in human clinical trials, the algorithm suggests a starting dose of 1.8 mg/m2. Given the metabolic complexity of Drug A, a starting dose of 1.5 mg/m2 is recommended for Phase I.

Dose escalation in clinical trial: Standard (1-1/2-1/3)

Drug A is administered to patients with advanced solid tumors by intravenous infusion over approximately 30 minutes, on days 1, 8, and 15 of a 28-day cycle.

34% inhibition of the hERG channel at 1 μM. Rat, IV, QDx5 for two cycles +10 day recovery between cycle1/2:

intestine, thymus, lymph nodes and bone marrow; STD: 10 mg/kg (60 mg/m2); HNSTD: 3 mg/kg (18 mg/m2); NOAEL: 1 mg/kg (6 mg/m2)

Dog, IV, QDx5 for two cycles +10 day recovery between cycle1/2: STD: 1 mg/kg (20 mg/m2); HNSTD: 0.3 mg/kg (6 mg/m2); NOAEL: 0.1 mg/kg (2 mg/m2)

For Drug A studies in human clinical trials, the algorithm suggests a starting dose of 1.8 mg/m2. Given the metabolic complexity of Drug A, a starting dose of 1.5 mg/m2 is recommended for Phase I.

Dose escalation in clinical trial: Standard (1-1/2-1/3)

CI-35

Sample 2 for Starting Dose SlectionSample 2 for Starting Dose Slection

Drug B is administered to patients with advanced solid tumors by intravenous infusion over 3 hours every 21 days.

hERG assay, IC50 >10 M

Rat, IV, QDx5 +16 day recovery: LD10: 15~20 mg/kg (90~120 mg/m2); NOAEL: 1 mg/kg (6 mg/m2)

Dog, IV, QDx5 : LD: 1.5 mg/kg (30 mg/m2); NOAEL: 1 mg/kg (20 mg/m2)

The starting dose selection of Drug B in human clinical trials, the algorithm suggests a starting dose of 2 mg/m2.

Dose escalation in clinical trial: 2, 3, 4, 6.5, 10, 16, 24, 30, 36, 45, 64, 96, 120, 150, 190 and 240 mg/m2.)

Drug B is administered to patients with advanced solid tumors by intravenous infusion over 3 hours every 21 days.

hERG assay, IC50 >10 M

Rat, IV, QDx5 +16 day recovery: LD10: 15~20 mg/kg (90~120 mg/m2); NOAEL: 1 mg/kg (6 mg/m2)

Dog, IV, QDx5 : LD: 1.5 mg/kg (30 mg/m2); NOAEL: 1 mg/kg (20 mg/m2)

The starting dose selection of Drug B in human clinical trials, the algorithm suggests a starting dose of 2 mg/m2.

Dose escalation in clinical trial: 2, 3, 4, 6.5, 10, 16, 24, 30, 36, 45, 64, 96, 120, 150, 190 and 240 mg/m2.)

CI-36

A Safe Starting Dose in Man Should BeDriven by Pharmacology & ToxicologyA Safe Starting Dose in Man Should BeDriven by Pharmacology & Toxicology

Non-Clinical Toxicology for mAb TherapiesNon-Clinical Toxicology for mAb Therapies

mAb present major safety challenges Safety toxicology studies in primates

– Old world primates most common

– May exceed primate toxicology resources

– Chimpanzees in rare specialized cases Primate toxicology may still not predict human effects

– TGN1412 anti-CD28 super agonist causes non-specific broad T-cell activation in humans with catastrophic consequences

Transgenic rodents engineered to express human target may be selectively employed (knock out/knock in animals)

Surrogate mAb (mouse equivalent) toxicity and efficacy studies to support clinical studies

mAb present major safety challenges Safety toxicology studies in primates

– Old world primates most common

– May exceed primate toxicology resources

– Chimpanzees in rare specialized cases Primate toxicology may still not predict human effects

– TGN1412 anti-CD28 super agonist causes non-specific broad T-cell activation in humans with catastrophic consequences

Transgenic rodents engineered to express human target may be selectively employed (knock out/knock in animals)

Surrogate mAb (mouse equivalent) toxicity and efficacy studies to support clinical studies

Starting Doses for Biological TherapiesStarting Doses for Biological Therapies

Historically, some fraction of the no adverse event level (NOAEL)

If species specific differences preclude precise dose calculations, then…

Consider estimations of receptor occupancy, cellular dose response studies from best available models to estimate a Minimum Anticipated Biological Effect Level (MABEL)

Recommendations for biological therapies are in evolution

Historically, some fraction of the no adverse event level (NOAEL)

If species specific differences preclude precise dose calculations, then…

Consider estimations of receptor occupancy, cellular dose response studies from best available models to estimate a Minimum Anticipated Biological Effect Level (MABEL)

Recommendations for biological therapies are in evolution

TGN1412: MABEL dose calculationTGN1412: MABEL dose calculation

德國 TeGenero公司的 TGN1412超級抗體，能夠活化其他抗體無法活化的免疫細胞，以治療自體免疫疾病和白血病。然而在 2006 年 3 月 13日進行一項例行安全測試時，六名志願接受抗體的健康受試者，卻全都進入了加護病房。

Non-Clinical Drug Safety Testingfor Summary of the FDA Perspective

Non-Clinical Drug Safety Testingfor Summary of the FDA Perspective

Conduct 2 pivotal toxicology studies using the same schedule, formulation, and route as the proposed clinical trial– Conduct a rodent study that identifies life-threatening doses

– Conduct a non-rodent study that confirms non-life threatening doses have been identified

• Studies of 28 days should be provided for continuous administration

• Studies for one or several administrations, depending on the schedule for intermittent schedules

• Provide full histopathology in one of these studies

– Conduct other studies as needed

Conduct 2 pivotal toxicology studies using the same schedule, formulation, and route as the proposed clinical trial– Conduct a rodent study that identifies life-threatening doses

– Conduct a non-rodent study that confirms non-life threatening doses have been identified

• Studies of 28 days should be provided for continuous administration

• Studies for one or several administrations, depending on the schedule for intermittent schedules

• Provide full histopathology in one of these studies

– Conduct other studies as needed

Non-Clinical Drug Safety TestingSummary of the FDA PerspectiveNon-Clinical Drug Safety TestingSummary of the FDA Perspective

Multiple cycles/continuous treatment generally acceptable, assuming acceptable safety profile in the non-clinical setting

Pre-IND meeting with sponsors are encouraged to discuss problem areas and provide alternative pathways to initiation of the phase I trial

Most potential clinical holds resolved through discussion with sponsor

Guidelines for biologicals (monoclonal antibodies, etc) are in preparation but may differ from small molecule recommendations

Multiple cycles/continuous treatment generally acceptable, assuming acceptable safety profile in the non-clinical setting

Pre-IND meeting with sponsors are encouraged to discuss problem areas and provide alternative pathways to initiation of the phase I trial

Most potential clinical holds resolved through discussion with sponsor

Guidelines for biologicals (monoclonal antibodies, etc) are in preparation but may differ from small molecule recommendations

New Paradigms for Drug Development in the Post Genomic Era

New Paradigms for Drug Development in the Post Genomic Era

Expanding role for translational studies in Phase I clinical trials

Bridge the gap between preclinical pharmacologic studies and early clinical trials

New molecular and biochemical endpoints are essential for cancer prevention and antimetastatic agents

This is an exciting time to be developing new anticancer drugs!

Expanding role for translational studies in Phase I clinical trials

Bridge the gap between preclinical pharmacologic studies and early clinical trials

New molecular and biochemical endpoints are essential for cancer prevention and antimetastatic agents

This is an exciting time to be developing new anticancer drugs!

各階段抗癌藥物臨床試驗之臨床前試驗要求 各階段抗癌藥物臨床試驗之臨床前試驗要求 第一 / 二期 第三期 & 新藥查驗登記

主藥效學體外試驗 需提供作用機轉 鼓勵進一步研究活體內試驗 有效性試驗

與標準療法比較效果及安全性鼓勵進一步研究

毒性評估 需遵循 GLP 需遵循 GLP

安全性藥理 次級藥效學試驗，體外 hERG 分析CNS/ 呼吸道 / 心血管功能評估，不需在

獨立試驗實行，必要時需 follow-up

如左

單一劑量急毒性試驗 兩個物種，囓齒類與非囓齒類各一，需追加恢復期，可作為前導試驗

如左

重覆劑量毒性試驗 兩個物種，囓齒類與非囓齒類各一，2-4 週或是 1-2 給藥周期

若有嚴重毒性，需追加恢復期

兩個物種，囓齒類及非囓齒類各一，

需與臨床試驗期間等長，最長 3 個月

若有嚴重毒性，需追加恢復期基因毒性 得免除 基因毒性試驗系列

( 體外試驗陽性，免除微小核試驗 )

致癌性 得免除 得免除生殖毒性 可免除，但須全程避孕 可免除，但須全程避孕局部耐受性 給藥部位刺激性觀察，

併入一般毒性試驗設計給藥部位刺激性觀察

( 劑型改變時 )

藥動 / 毒動試驗 鼓勵提供 Cmax & AUC 需提供動物的 PK 係數 (ADME)

臨床試驗安全起始劑量 囓齒類 STD10 的 1/10 或非囓齒類 STD10 的 1/6

依臨床試驗之結果決定最佳臨床使用劑量

CI-45

參考資料參考資料 藥品查驗登記審查準則 行政院衛生署 編 中華民國九十四年九月十五日 藥品非臨床試驗安全性規範 第三版 行政院衛生署 編 中華民國八十九年六月 癌症治療藥品臨床試驗基準 行政院衛生署 編 中華民國八十八年十二月十五

日 ICH S9: NONCLINICAL EVALUATION FOR ANTICANCER

PHARMACEUTICALS Current Step 4 version, dated 29 October 2009. Non-Clinical Drug Development, Chris H. Takimoto, 2007 Regulatory considerations for preclinical development of anticancer

drugs, DeGeorge JJ et al., Cancer Chemotherapy Pharmacology (1998) 41:173-185.

Pharmaceutical Administration and Regulations in Japan http://www.jpma.or.jp/english/parj/0607.html

Toxicological testing of cytotoxic drugs. P. Colombo, et al. International Journal of Oncology (2001), 19: 1021-1028.

Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval (Second Edition). Beverly A. Teicher et al. Human Press, 2004.

藥品查驗登記審查準則 行政院衛生署 編 中華民國九十四年九月十五日 藥品非臨床試驗安全性規範 第三版 行政院衛生署 編 中華民國八十九年六月 癌症治療藥品臨床試驗基準 行政院衛生署 編 中華民國八十八年十二月十五

日 ICH S9: NONCLINICAL EVALUATION FOR ANTICANCER

PHARMACEUTICALS Current Step 4 version, dated 29 October 2009. Non-Clinical Drug Development, Chris H. Takimoto, 2007 Regulatory considerations for preclinical development of anticancer

drugs, DeGeorge JJ et al., Cancer Chemotherapy Pharmacology (1998) 41:173-185.

Pharmaceutical Administration and Regulations in Japan http://www.jpma.or.jp/english/parj/0607.html

Toxicological testing of cytotoxic drugs. P. Colombo, et al. International Journal of Oncology (2001), 19: 1021-1028.

Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval (Second Edition). Beverly A. Teicher et al. Human Press, 2004.