1.introduction(ci)

1、CI-1,,100年生技醫(yī)藥法規(guī)科學(xué)人才培訓(xùn)課程 抗癌新藥臨床前法規(guī)國(guó)際最新發(fā)展與起始劑量選擇財(cái)團(tuán)法人醫(yī)藥品查驗(yàn)中心藥毒理小組長(zhǎng)/審查員 汪徽五 100年08月25日,CI-2,本次演講內(nèi)容純?yōu)閭€(gè)人意見，所說明的事項(xiàng)僅供與會(huì)人員參考，不必然與醫(yī)藥品查驗(yàn)中心(CDE)或食品藥物管理局(TFDA)的政策，及其案件的審查相關(guān),說明,Outline,Overview of Anticancer Drug Developmen

2、tICH Topic S9 nonclinical Evaluation for Anticancer Pharmaceuticals Components of Non-Clinical Drug DevelopmentWhat are Pharmacology Studies for Anti-Cancer Drugs?Non-Clinical Safety StudiesCurrent Approach to Selec

3、t Starting Doses of Anticancer DrugStarting Doses for Biological TherapiesUS FDA Perspective各階段抗癌藥物臨床試驗(yàn)之臨床前試驗(yàn)要求,CI-3,Overview of Anticancer Drug Development,Chronic Nonclinical Safety,Goals of Non-Clinical Testing of

4、Drugs,To characterize potential adverse drug effectsDefine end organ toxicitiesDefine reversibility of toxicityTo characterize pharmacokinetic profileTo characterize beneficial pharmacodynamic effectsProof of princi

5、pleTo guide safe use in human clinical studiesTo determine a safe & reasonable starting doseProvide monitoring guidelines for the clinical studyProvide sufficient data to conclude that patients are not exposed to

6、 unreasonable risksPotential for benefit must also exist,ICH Topic S9 nonclinical Evaluation for Anticancer Pharmaceuticals Current Step 4 version, dated 29 October 2009,1. INTRODUCTION 1.1 Objectives of the Guide

7、line 1.2 Background 1.3 Scope 1.4 General Principles2. STUDIES TO SUPPORT NONCLINICAL EVALUATION2.1 Pharmacology 2.2 Safety Pharmacology 2.3 Pharmacokinetics 2.4 General Toxicology2.5 Reproduction

8、 Toxicology 2.6 Genotoxicity2.7 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,

9、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 Schedul

10、e 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 St

11、udies to Support Trials in Pediatric Populations4. OTHER CONSIDERATIONS 4.1 Conjugated Products 4.2 Liposomal Products 4.3 Evaluation of Drug Metabolites 4.4 Evaluation of Impurities5. NOTES,CI-7,Co

12、mponents of Non-Clinical Drug Development,In vitro studies: Cell lines, cell-free systems (drug screening)Drug formulation Chemistry, Manufacturing, and Controls: Drug supply & qualityIn vivo efficacy studies: Ani

13、mal models and proof of principle5.Non-clinical safety studies,Drug Supply and Formulation,Drug supply: bulk chemical synthesis, natural product isolation, etc.Good Manufacturing Practice (GMP) guidelines for pharmace

14、utical product manufacturingFormulation for clinical delivery of drug: vehicles for intravenous or other routes of administration,What are Pharmacology Studies for Anti-Cancer Drugs?,Evaluation of ability of a new agen

15、t to induce the desired therapeutic effectin vitro studies of product binding, tumor cell killing, and other effectsin vivo studies of anti-tumor activitye.g., human tumor xenograft modelsDemonstration of pharmacolog

16、ic 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 Models,Efficacy: Proof of therapeutic principleToxicology: Toxicity profilePractica

17、l Issues:Animal pharmacokinetics and pharmacodynamicsStarting dose and schedule for clinical trials,Animal ModelsProof of Principle,Animal screening is too expensive for routine useEfficacy in animal models of specif

18、ic disease states occurs after in vitro studiesEvaluation of therapeutic indexToxicity versus Efficacy,Ideal Animal Model,ValiditySelectivityPredictabilityReproducibility,“There is no perfect tumor model”,Animal Mod

19、els in Cancer,Spontaneous tumorsIdiopathicCarcinogen-inducedTransgenic/gene knockout animals: p53, RB, etcTransplanted tumorsAnimal tumors: Lewis lung, S180 sarcoma, etcHuman tumor xenografts: human tumor lines imp

20、lanted 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’sMutation in n

21、u gene on chromosome 11Phenotype: retarded growth, low fertility, no fur, immunocompromizedLack thymus gland, T-cell immunityFirst human tumor xenograft of colon adenocarcinoma by Rygaard & Poulson, 1969,Xenograft

22、 Study Endpoints,Toxicity Endpoints:Drug related deathNet animal weight lossEfficacy EndpointsClonogenic assayTumor growth assay (corrected for tumor doubling time)Treated/control survival ratioTumor weight chang

23、e,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)/2a = tumor lengthb = tumor widthT/C < 40-50% is c

24、onsidered significant,Non-Clinical Efficacy Testing,Pharmacological activity assessed by models of disease are generally of low relevance to safety (IND) and efficacy (NDA) decisionsEfficacy in vivo and in vitro from no

25、n-clinical studies may not dependably predict clinical efficacyHeterogeneity of diseaseInterspecies differences in ADMERole of immune systemPharmacology studies are useful for:Assessing an appropriate schedule (dail

26、y, weekly, q3wks)Justification for a drug combinationUnderstanding effect at a molecular targetExamine receptor specificityIdentifying and evaluating biomarkers,Components of Non-Clinical Drug Development,In vitro st

27、udies: Cell lines, cell-free systems (drug screening)Drug formulation Chemistry, Manufacturing, and Controls: Drug supply & qualityIn vivo efficacy studies: Animal models and proof of principle5.Non-clinical saf

28、ety studies,Non-Clinical Safety Studies,Pharmacokinetics/Toxicokinetics,Analytic assay development and testingPreclinical PK/PD efficacy and toxicity relationshipsInitial drug formulation testingTesting of different s

29、chedules and routes of administrationAnimal ADME,Non-Clinical Toxicology Studies,GLP Toxicology is expectedUse the clinical schedule, route, and formulationToxicity studies required in 2 mammalian species prior to FIH

30、 studiesClassically rat and dog for small moleculesNon-human primates for biological productsRepeat dose toxicology required for anticipated duration of clinical use for most non-oncology agents3 mo. toxicology for ≤

31、3 mo. clinical studyRecommendations for agents used in the treatment of advanced cancer patients,Expected Toxicology Testing for Phase I Oncology Drug Studies,,* Study schedule does not include a recovery period-- 28 d

32、ay 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 patientsMay exclude if:

33、No PK, PD, or metabolic interactions anticipatedDrugs are not packaged as a combinationAll components well studied individually,Single Dose Toxicity Studies,Dose escalation study may be an alternative to a single dose

34、 designDose range should include maximally tolerated dose (MTD) and no adverse effect level (NOAEL)Standard designEarly sacrifice at 24 to 48 hr and after 14 days,Repeated Dose Toxicity Studies,Duration of repeated do

35、se studies related to duration of anticipated clinical useUse same schedule and durationTypically 28 daysShould include recovery groupUse can support repeat dose clinical studies,Non-Clinical Toxicology Ongoing Endpo

36、ints,OngoingClinical signs, behaviorBody weights and food consumptionClinical pathology (in larger species)HematologyChemistry panelsToxicokineticsEnd of StudyMacroscopic changes at necropsyOrgan weightsHistopa

37、thology of all organs,Other Toxicology Studies,Local tolerance studiesIf warranted by route of administrationGenotoxicity studiesReproductive Toxicity studiesCarcinogenicity studies,Genotoxicity studies,GeneralNorma

38、lly done prior to FIH studies, but not required prior to phase I studies in oncology patientsStandard battery of genotoxicity tests required prior to initiation of phase IISpecific genotoxicity studiesIn vitro bacteri

39、al reverse mutation assays: Ames test, point mutation testIn vitro chromosome damage tests in mammalian cells: metaphase cell analysis, murine lymphoma gene mutation assaysIn vivo chromosomal damage assays: rodent micr

40、onucleus tests,Reproductive Toxicity Studies,MenMay include in Phase I/II after relevant repeated dose toxicity studiesMale fertility study should be completed prior to initiation of Phase IIIWomen not of childbearing

41、 potentialMay include in clinical trials after relevant repeated dose toxicity studiesWomen of childbearing potentialMay include in carefully monitored early studies with precautionsFertility and embryo-fetal toxicit

42、y studies should be completed prior to entry of women into phase III trialsPregnant womenAll reproductive toxicity and genotoxicity studies must be completed prior to entry of these women in trials,Carcinogenicity stud

43、ies,Usually not needed prior to clinical trial initiationNot needed in advanced cancer indications,Preclinical Toxicology Goals,Determine the toxicity profile for acute and chronic administrationEstimate a “safe” start

44、ing dose for phase I studiesNCI 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 A

45、pproach 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 basisProvided the same dose causes no severe irreversible toxicity

46、 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 dif

47、ference 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/m2Mouse x 3; Rat x 6; Guinea-pig x 7.7Hamster x 4.1

48、,Is 1/10rodent STD10 (mg/m2)severely toxic tonon-rodents?,,,Sample 1 for Starting Dose Slection,Drug A is administered to patients with advanced solid tumors by intravenous infusion over approximately 30 minutes, on d

49、ays 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);

50、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 hu

51、man 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 (

52、1-1/2-1/3),CI-35,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 ? MRat, IV, QDx5 +16 day rec

53、overy: 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

54、 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 & Toxic

55、ology,Non-Clinical Toxicology for mAb Therapies,mAb present major safety challengesSafety toxicology studies in primatesOld world primates most commonMay exceed primate toxicology resourcesChimpanzees in rare special

56、ized casesPrimate toxicology may still not predict human effectsTGN1412 anti-CD28 super agonist causes non-specific broad T-cell activation in humans with catastrophic consequencesTransgenic rodents engineered to exp

57、ress 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,

58、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

59、 models to estimate a Minimum Anticipated Biological Effect Level (MABEL)Recommendations for biological therapies are in evolution,TGN1412: MABEL dose calculation,德國(guó)TeGenero公司的TGN1412超級(jí)抗體，能夠活化其他抗體無法活化的免疫細(xì)胞，以治療自體免疫疾病和白血病

60、。然而在2006年3月13日進(jìn)行一項(xiàng)例行安全測(cè)試時(shí)，六名志願(yuàn)接受抗體的健康受試者，卻全都進(jìn)入了加護(hù)病房。,Non-Clinical Drug Safety Testingfor Summary of the FDA Perspective,Conduct 2 pivotal toxicology studies using the same schedule, formulation, and route as the propose

61、d clinical trialConduct a rodent study that identifies life-threatening dosesConduct a non-rodent study that confirms non-life threatening doses have been identifiedStudies of 28 days should be provided for continuous

62、 administrationStudies for one or several administrations, depending on the schedule for intermittent schedulesProvide full histopathology in one of these studiesConduct other studies as needed,Non-Clinical Drug Safet

63、y TestingSummary of the FDA Perspective,Multiple cycles/continuous treatment generally acceptable, assuming acceptable safety profile in the non-clinical settingPre-IND meeting with sponsors are encouraged to discuss p

64、roblem areas and provide alternative pathways to initiation of the phase I trialMost potential clinical holds resolved through discussion with sponsorGuidelines for biologicals (monoclonal antibodies, etc) are in prepa

65、ration 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

66、 pharmacologic studies and early clinical trialsNew molecular and biochemical endpoints are essential for cancer prevention and antimetastatic agentsThis is an exciting time to be developing new anticancer drugs!,各階段抗癌

67、藥物臨床試驗(yàn)之臨床前試驗(yàn)要求,CI-45,參考資料,藥品查驗(yàn)登記審查準(zhǔn)則 行政院衛(wèi)生署 編 中華民國(guó)九十四年九月十五日 藥品非臨床試驗(yàn)安全性規(guī)範(fàn) 第三版 行政院衛(wèi)生署 編 中華民國(guó)八十九年六月癌癥治療藥品臨床試驗(yàn)基準(zhǔn) 行政院衛(wèi)生署 編 中華民國(guó)八十八年十二月十五日 ICH S9: NONCLINICAL EVALUATION FOR ANTICANCER PHARMACEUTICALS Current Step 4 version

68、, dated 29 October 2009.Non-Clinical Drug Development, Chris H. Takimoto, 2007Regulatory considerations for preclinical development of anticancer drugs, DeGeorge JJ et al., Cancer Chemotherapy Pharmacology (1998) 41:17

69、3-185.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-