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1、CI-1,抗癌新藥臨床前法規國際最新發展與起始劑量選擇,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,Outline,Overview of Anticancer Drug DevelopmentICH Topic S9 nonclinical Evaluation for Anticancer Pharmaceuticals Components of Non-Clinical Drug DevelopmentWhat are Pharmacology Studies for A
2、nti-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 Safety,Goals of Non-Clinical Testing of Drugs,To chara
3、cterize 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 studiesTo determine a safe & reasonable starting doseProvide
4、 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 Step 4 version, dated 29 October 2009,1. INTRODUCTION 1
5、.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 Genotoxicity2.7 Carcinogenicity 2.8 Immunotoxicity 2.9 Photosa
6、fety 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 Humans 3.2 Dose Escalation and the Highest Dose in a Clinic
7、al 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 Populations4. OTHER CONSIDE
8、RATIONS 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 formulation Chemistry, Manufacturing, and Controls: Dru
9、g 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) guidelines for pharmaceutical product manufacturingFormulat
10、ion 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 product binding, tumor cell killing, and other effectsin
11、 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,Efficacy: Proof of therapeutic principleToxicology: Toxicity
12、 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 states occurs after in vitro studiesEvaluation of therape
13、utic indexToxicity versus Efficacy,Ideal Animal Model,ValiditySelectivityPredictabilityReproducibility,“There is no perfect tumor model”,Animal Models in Cancer,Spontaneous tumorsIdiopathicCarcinogen-inducedTransgenic/gene knockout animals: p53, RB, etcTransplanted tumorsAnimal tumors: Lewis lung, S
14、180 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” mice developed in 1960sMutation in nu gene on chromosome 1
15、1Phenotype: 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 deathNet animal weight lossEfficacy EndpointsClonogenic assa
16、yTumor 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 weight in mg = (a x b2)/2a = tumor lengthb = tumor widthT/
17、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) decisionsEfficacy in vivo and in vitro from non-clinical studies may not dependably predict clinical efficacyHeter
18、ogeneity of diseaseInterspecies differences in ADMERole of immune systemPharmacology studies are useful for:Assessing an appropriate schedule (daily, weekly, q3wks)Justification for a drug combinationUnderstanding effect at a molecular targetExamine receptor specificityIdentifying and evaluating bio
19、markers,Components 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: Animal models and proof of principle5.Non-clinical safety studies,Non-Clinical S
20、afety Studies,Safety pharmacologyToxicokinetics & pharmacokinetic studiesSingle dose toxicity studiesRepeated dose toxicity studies,Pharmacokinetics/Toxicokinetics,Analytic assay development and testingPreclinical PK/PD efficacy and toxicity relationshipsInitial drug formulation testingTesting of di
21、fferent schedules 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 studiesClassically rat and dog for small moleculesNon-human primates for
22、biological productsRepeat dose toxicology required for anticipated duration of clinical use for most non-oncology agents3 mo. toxicology for 3 mo. clinical studyRecommendations for agents used in the treatment of advanced cancer patients,Expected Toxicology Testing for Phase I Oncology Drug Studies,
23、* 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 patientsMay exclude if:No PK, PD, or metabolic in
24、teractions 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 designDose range should include maximally tolerated dose (MTD) and no adverse effect level (NOAEL)Standard d
25、esignEarly 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 useUse same schedule and durationTypically 28 daysShould include recovery groupUse can support repeat dose clinical studies,Non-Clinical
26、Toxicology Ongoing Endpoints,OngoingClinical signs, behaviorBody weights and food consumptionClinical pathology (in larger species)HematologyChemistry panelsToxicokineticsEnd of StudyMacroscopic changes at necropsyOrgan weightsHistopathology of all organs,Other Toxicology Studies,Local tolerance stu
27、diesIf warranted by route of administrationGenotoxicity studiesReproductive Toxicity studiesCarcinogenicity studies,Genotoxicity studies,GeneralNormally done prior to FIH studies, but not required prior to phase I studies in oncology patientsStandard battery of genotoxicity tests required prior to i
28、nitiation of phase IISpecific genotoxicity studiesIn vitro bacterial 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 micronucleus tests,R
29、eproductive 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 potentialMay include in clinical trials after relevant repeated dose toxicity studiesWomen of chil
30、dbearing potentialMay include in carefully monitored early studies with precautionsFertility and embryo-fetal toxicity 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 w
31、omen in trials,Carcinogenicity studies,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” starting dose for phase I studiesNCI guidelines reco
32、mmend 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 ro
33、dents (STD10) on mg/m2 basisProvided 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 speci
34、fic difference 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,Is 1/10rodent STD10 (mg/m2)severely toxic tonon-rodents?,Sample 1 for Start
35、ing 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 M. Rat, IV, QDx5 for two cycles +10 day recovery between cycle1/2: intestine, thymus,
36、 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 a
37、lgorithm 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-35,Sample 2 for Starting Dose Slection,Drug B is administered to patients with advanced solid
38、tumors by intravenous infusion over 3 hours every 21 days.hERG assay, IC50 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, th
39、e 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-36,A Safe Starting Dose in Man Should BeDriven by Pharmacology & Toxicology,Non-Clinical Toxicology for mAb Therapies,mAb present major s
40、afety challengesSafety 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 w
41、ith catastrophic consequencesTransgenic 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
42、 the no adverse event 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 biolog
43、ical 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 Testingfor Summary of the FDA Perspective,Conduct 2 pivotal toxicology studies using the same schedule
44、, formulation, and 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 ad
45、ministrations, depending 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 p
46、rofile in the non-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
47、 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 trialsNew molecular and biochemical endpoints are essential for cancer prevention and antimetastatic agentsThis is an exciting time to be developing new anticancer drugs!,各階段抗癌藥物臨床試驗之臨床前試驗要求,45,Thank you!,
