1、CI-1抗癌新藥臨床前法規國際最新發展抗癌新藥臨床前法規國際最新發展與起始劑量選與起始劑量選擇擇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
2、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-3Overview of Anticancer Drug Overview of Anticancer Drug DevelopmentDevelopmentINDNDAC
3、hemical Synthesis and Formulation DevelopmentAnimal Models for EfficacyAssay DevelopmentAnimal PK,PD and Safety Dose Escalation and Initial PK Proof of Concept and Dose FindingLarge Efficacy Trials with PK ScreenPHASE IPHASE IIPHASE IIIPre-Clinical DevelopmentClinical DevelopmentPK/PD Studies in Spe
4、cial PopulationsChronic Nonclinical Safety Goals of Non-Clinical Testing of Goals of Non-Clinical Testing of DrugsDrugs To characterize potential adverse drug effects Define end organ toxicities Define reversibility of toxicity To characterize pharmacokinetic profile To characterize beneficial pharm
5、acodynamic 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
6、existICH Topic S9 nonclinical Evaluation for ICH Topic S9 nonclinical Evaluation for Anticancer Pharmaceuticals 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
7、NONCLINICAL EVALUATION2.1 Pharmacology 2.2 Safety Pharmacology 2.3 Pharmacokinetics 2.4 General Toxicology2.5 Reproduction Toxicology 2.6 Genotoxicity2.7 Carcinogenicity 2.8 Immunotoxicity 2.9 Photosafety testingCI-6ICH Topic S9 nonclinical Evaluation for ICH Topic S9 nonclinical Evaluation for Anti
8、cancer Pharmaceuticals 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
9、 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 L
10、iposomal Products 4.3 Evaluation of Drug Metabolites 4.4 Evaluation of Impurities 5.NOTESCI-7Components of Non-Clinical Drug Components of Non-Clinical Drug DevelopmentDevelopment1.In vitro studies:Cell lines,cell-free systems(drug screening)2.Drug formulation 3.Chemistry,Manufacturing,and Controls:
11、Drug supply&quality4.In vivo efficacy studies:Animal models and proof of principle5.Non-clinical safety studiesDrug Supply and FormulationDrug Supply and Formulation Drug supply:bulk chemical synthesis,natural product isolation,etc.Good Manufacturing Practice(GMP)guidelines for pharmaceutical produc
12、t manufacturing Formulation for clinical delivery of drug:vehicles for intravenous or other routes of administrationWhat are Pharmacology Studies What are Pharmacology Studies for Anti-Cancer Drugs?for Anti-Cancer Drugs?Evaluation of ability of a new agent to induce the desired therapeutic effectin
13、vitro studies of product binding,tumor cell killing,and other effectsin 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 productCI-10In Vivo In Vivo Study Goa
14、ls:Animal Study Goals:Animal ModelsModels Efficacy:Proof of therapeutic principle Toxicology:Toxicity profile Practical Issues:Animal pharmacokinetics and pharmacodynamics Starting dose and schedule for clinical trialsAnimal ModelsAnimal ModelsProof of PrincipleProof of Principle Animal screening is
15、 too expensive for routine use Efficacy in animal models of specific disease states occurs after in vitro studies Evaluation of therapeutic index Toxicity versus EfficacyIdeal Animal ModelIdeal Animal Model Validity Selectivity Predictability Reproducibility“There is no perfect tumor model”Animal Mo
16、dels 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 eff
17、icacy testing system)Human tumors growing in vivo in implantable hollow fibersHuman Tumor Human Tumor XenograftsXenografts Athymic“nude”mice developed in 1960s Mutation in nu gene on chromosome 11 Phenotype:retarded growth,low fertility,no fur,immunocompromized Lack thymus gland,T-cell immunity Firs
18、t human tumor xenograft of colon adenocarcinoma by Rygaard&Poulson,1969XenograftXenograft Study Endpoints 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 rat
19、io Tumor weight changeXenograftXenograft Tumor Weight Change 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 10 MRat,IV,QDx5+16 day recovery:LD10:1520 mg/kg(90120 mg/
20、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-36A S
21、afe Starting Dose in Man Should BeA Safe Starting Dose in Man Should BeDriven by Pharmacology&ToxicologyDriven by Pharmacology&ToxicologyNon-Clinical Toxicology for Non-Clinical Toxicology for mAbmAb TherapiesTherapiesmAb present major safety challengesSafety toxicology studies in primates Old world
22、 primates most common May exceed primate toxicology resources Chimpanzees in rare specialized casesPrimate toxicology may still not predict human effects TGN1412 anti-CD28 super agonist causes non-specific broad T-cell activation in humans with catastrophic consequencesTransgenic rodents engineered
23、to express human target may be selectively employed(knock out/knock in animals)Surrogate mAb(mouse equivalent)toxicity and efficacy studies to support clinical studiesStarting Doses for Biological Starting Doses for Biological TherapiesTherapies Historically,some fraction of the no adverse event lev
24、el(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 evolut
25、ion 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 TestingNon-Clinical Drug Safety Testingfor Summary of the FDA Perspectivefor Summary of the FDA Perspec
26、tive 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 p
27、rovided 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 neededNon-Clinical Drug Safety TestingNon-Clinical Drug Safety TestingSummary of the FDA
28、PerspectiveSummary 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
29、 Most potential clinical holds resolved through discussion with sponsor Guidelines for biologicals(monoclonal antibodies,etc)are in preparation but may differ from small molecule recommendationsNew Paradigms for Drug Development in New Paradigms for Drug Development in the Post Genomic Erathe Post G
30、enomic 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 devel
31、oping 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45Thank you!Thank you!
