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

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

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

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

4. Overview of Anticancer Drug Development NDA IND Chemical Synthesis and Formulation Development Assay Development Animal Models for Efficacy Chronic Nonclinical Safety Large Efficacy Trials with PK Screen Dose Escalation and Initial PK Proof of Concept and Dose Finding Animal PK, PD and Safety PK/PD Studies in Special Populations PHASE I PHASE II PHASE III Pre-Clinical Development Clinical Development

5. 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

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 2.2 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

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 4.2 Liposomal Products 4.3 Evaluation of Drug Metabolites 4.4 Evaluation of Impurities • 5. NOTES

8. Components of Non-Clinical Drug Development • In vitro studies: Cell lines, cell-free systems (drug screening) • Drug formulation • Chemistry, Manufacturing, and Controls: Drug supply & quality • In vivo efficacy studies: Animal models and proof of principle 5. Non-clinical safety studies

9. 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

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

11. 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

12. 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

13. Ideal Animal Model • Validity • Selectivity • Predictability • Reproducibility “There is no perfect tumor model”

14. 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

15. 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

16. 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

17. 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

18. 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

19. Components of Non-Clinical Drug Development • In vitro studies: Cell lines, cell-free systems (drug screening) • Drug formulation • Chemistry, Manufacturing, and Controls: Drug supply & quality • In vivo efficacy studies: Animal models and proof of principle 5. Non-clinical safety studies

20. Non-Clinical Safety Studies • Safety pharmacology • Toxicokinetics & pharmacokinetic studies • Single dose toxicity studies • Repeated dose toxicity studies

21. 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

22. 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

23. Expected Toxicology Testing for Phase I Oncology Drug Studies * Study schedule does not include a recovery period -- 28 day toxicology is generally sufficient for DRUG trials extending beyond 28 days

24. 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

25. 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

26. 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

27. 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

28. Other Toxicology Studies • Local tolerance studies • If warranted by route of administration • Genotoxicity studies • Reproductive Toxicity studies • Carcinogenicity studies

29. 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

30. 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

31. Carcinogenicity studies • Usually not needed prior to clinical trial initiation • Not needed in advanced cancer indications

32. 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

33. 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

34. NO YES Is rodent an inappropriate species? (biochem, ADME, target, etc) Determine non-rodent Highest Non-Severely Toxic Dose (HNSTD) YES NO Is non-rodent inappropriate? YES 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 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 Is 1/10 rodent STD10 (mg/m2) severely toxic to non-rodents?

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)

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.)

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

38. 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

39. 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

40. 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。

41. 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

42. Non-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

43. 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!

44. 各階段抗癌藥物臨床試驗之臨床前試驗要求

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, DeGeorgeJJ et al., Cancer Chemotherapy Pharmacology (1998) 41:173-185. • Pharmaceutical Administration and Regulations in Japanhttp://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.