CI-1
100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
藥毒理小組長/審查員 汪徽五
100年08月25日
CI-2
說明
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
CI-3
Outline

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
NDA
IND
Chemical Synthesis and Formulation Development
Assay
Development
Animal Models
for Efficacy
Animal PK, PD
and Safety
Chronic Nonclinical Safety
Dose
Escalation
and Initial PK
Proof of
Concept and
Dose Finding
Large Efficacy
Trials
with PK Screen
PK/PD Studies in Special Populations
PHASE I
Pre-Clinical Development
PHASE II
PHASE III
Clinical Development
Goals 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
CI-6
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 EVALUATION
2.1 Pharmacology
2.3 Pharmacokinetics
2.5 Reproduction Toxicology
2.7 Carcinogenicity
2.9 Photosafety testing
2.2 Safety Pharmacology
2.4 General Toxicology
2.6 Genotoxicity
2.8 Immunotoxicity
CI-7
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
4.3 Evaluation of Drug Metabolites

5. NOTES
4.2 Liposomal Products
4.4 Evaluation of Impurities
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
Drug 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
CI-10
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
In 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
Animal Models
Proof 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
Ideal Animal Model
Validity
Selectivity
Predictability
Reproducibility
“There is no perfect tumor model”
Animal 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
Human 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
Xenograft 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
Xenograft 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
Non-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
Components of Non-Clinical
Drug Development
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.
Non-Clinical Safety Studies
 Safety
pharmacology
 Toxicokinetics & pharmacokinetic studies
 Single dose toxicity studies
 Repeated dose toxicity studies
Pharmacokinetics/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
Non-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
Expected Toxicology Testing for Phase I
Oncology Drug Studies
Clinical Schedule
Once every 3 weeks
Preclinical study schedule *
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
 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 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
Repeated 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
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
Other Toxicology Studies
 Local
tolerance studies
– If warranted by route of administration
 Genotoxicity studies
 Reproductive Toxicity studies
 Carcinogenicity studies
Genotoxicity 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
Reproductive 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
Carcinogenicity studies
 Usually
not needed prior to clinical trial
initiation
 Not needed in advanced cancer
indications
Preclinical 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
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
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 7.7
Hamster x 4.1
NO
Is 1/10
rodent STD10 (mg/m2)
severely toxic to
non-rodents?
Is rodent an
inappropriate species?
(biochem, ADME, target, etc) YES
YES
Determine non-rodent Highest
Non-Severely Toxic Dose
(HNSTD)
NO
YES
Is non-rodent inappropriate?
NO
Convert from mg/kg to mg/m2
Dog x 20; Monkey x 10
Rabbit x 11.6
Start Dose =1/10
Rodent STD10
Start Dose =1/6
Non-Rodent HNSTD
34
CI-35
Sample 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)
CI-36
Sample 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.)
A Safe Starting Dose in Man Should Be
Driven by Pharmacology & Toxicology
Non-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
Starting 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
TGN1412: 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 Testing
for 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
Non-Clinical Drug Safety Testing
Summary 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
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!
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
需提供作用機轉
鼓勵進一步研究
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
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
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
主藥效學
體外試驗
活體內試驗
毒性評估
重覆劑量毒性試驗
CI-45
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.