1、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,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,Outline,Overview of Anticancer Drug DevelopmentICH Topic S9 nonclinical Evaluation for Anticancer Pharmaceuticals Components of Non-Clini
2、cal Drug DevelopmentWhat are Pharmacology Studies for Anti-Cancer Drugs?Non-Clinical Safety StudiesCurrent Approach to Select Starting Doses of Anticancer DrugStarting Doses for Biological TherapiesUS 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,Chronic Nonclinical
3、 Safety,Goals of Non-Clinical Testing of Drugs,To characterize potential adverse drug effectsDefine end organ toxicitiesDefine reversibility of toxicityTo characterize pharmacokinetic profileTo characterize beneficial pharmacodynamic effectsProof of principleTo guide safe use in human clinical studi
4、esTo determine a safe & reasonable starting doseProvide monitoring guidelines for the clinical studyProvide sufficient data to conclude that patients are not exposed to unreasonable risksPotential for benefit must also exist,ICH Topic S9 nonclinical Evaluation for Anticancer Pharmaceuticals Current
5、Step 4 version, dated 29 October 2009,1. INTRODUCTION 1.1 Objectives of the Guideline 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 Toxicology 2.6 Genotox
6、icity2.7 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 2009,3. NONCLINICAL DATA TO SUPPORT CLINICAL TRIAL DESIGN AND MARKETING 3.1 Start Dose for First Administration in Huma
7、ns 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
8、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,Components of Non-Clinical Drug Development,In vitro studies: Cell lines, cell-free systems (drug screening)Drug
9、formulation Chemistry, Manufacturing, and Controls: Drug supply & qualityIn vivo efficacy studies: Animal 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) guid
10、elines for pharmaceutical 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 agent to induce the desired therapeutic effectin vitro studies of p
11、roduct binding, tumor cell killing, and other effectsin vivo studies of anti-tumor activitye.g., human tumor xenograft modelsDemonstration 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 Models,Effic
12、acy: Proof of therapeutic principleToxicology: Toxicity profilePractical 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 specific disease st
13、ates occurs after in vitro studiesEvaluation of therapeutic indexToxicity versus Efficacy,Ideal Animal Model,ValiditySelectivityPredictabilityReproducibility,“There is no perfect tumor model”,Animal Models in Cancer,Spontaneous tumorsIdiopathicCarcinogen-inducedTransgenic/gene knockout animals: p53,
14、 RB, etcTransplanted tumorsAnimal tumors: Lewis lung, S180 sarcoma, etcHuman 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” mic
15、e developed in 1960sMutation in nu 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 Study Endpoints,Toxicity Endpoints:Drug related death
16、Net animal weight lossEfficacy EndpointsClonogenic assayTumor growth assay (corrected for tumor doubling time)Treated/control survival ratioTumor weight change,Xenograft Tumor Weight Change,Tumor weight change ratio (used by the NCI in xenograft evaluation)Defined as: treated/control x 100%Tumor wei
17、ght in mg = (a x b2)/2a = tumor lengthb = tumor widthT/C 10 MRat, IV, QDx5 +16 day recovery: LD10: 1520 mg/kg (90120 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 sugges
18、ts 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 & Toxicology,Non-Clinical Toxicology for mAb Therapies,mAb present major safety challengesSa
19、fety toxicology studies in primatesOld world primates most commonMay exceed primate toxicology resourcesChimpanzees in rare specialized casesPrimate toxicology may still not predict human effectsTGN1412 anti-CD28 super agonist causes non-specific broad T-cell activation in humans with catastrophic c
20、onsequencesTransgenic 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 ev
21、ent level (NOAEL)If species specific differences preclude precise dose calculations, thenConsider 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
22、 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 Testingfor Summary of the FDA Perspective,Conduct 2 pivotal toxicology studies using the same schedule, formulation, and
23、 route as the proposed 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 administrationStudies for one or several administrations, dep
24、ending on the schedule for intermittent schedulesProvide full histopathology in one of these studiesConduct other studies as needed,Non-Clinical Drug Safety TestingSummary of the FDA Perspective,Multiple cycles/continuous treatment generally acceptable, assuming acceptable safety profile in the non-
25、clinical settingPre-IND meeting with sponsors are encouraged to discuss problem 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 preparation bu
26、t 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 trialsNew molecular and biochemical endpoints ar
27、e essential for cancer prevention and antimetastatic agentsThis 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,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 ANTI
28、CANCER PHARMACEUTICALS Current Step 4 version, 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) 41:173-185.Pharmaceutical Administration a
29、nd 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.,
