药事法施行细则第五条.ppt

1、Good IND Submission,Chia-Hsin Yeh, Ph.D. Reviewer, Division of Preclinical Sciences Center for Drug Evaluation,2020/10/10,IND-Preclinical Sciences,2,IND Evaluation in Preclinical Sciences,Assure that the drug used in the proposed trial is efficacious and safe Satisfactory information is essential Ba

2、sed on scientific and regulatory considerations Major concern for quality and safety,2020/10/10,IND-Preclinical Sciences,3,Regulatory Consideration,藥事法施行細則第五條 非販賣之研究、試製之藥品，應備有研究或試製紀錄，並以無商品化之包裝者為限 申請藥品臨床試驗計劃案應檢附資料 藥品特性資料(藥品物化性質、毒藥理作用、藥物動力學等非臨床及臨床試驗資料)或主持人手冊 製造管制標準書、批次製造紀錄、主成分及成品檢驗規格成績書及安定性試驗 (必要時得要求檢

3、送其他資料),2020/10/10,IND-Preclinical Sciences,4,Relevant Regulatory Guidance,DOH guidance -藥品非臨床試驗安全性規範 -藥品生體可用率及生體相等性試驗基準 -腎或肝功能不全病患的藥動學試驗基準 -藥品臨床試驗基準 ICH guidance: quality and safety issues,2020/10/10,IND-Preclinical Sciences,5,Scientific Consideration,Case by caseDepends on the development stage & c

4、omplexity of the case, preclinical requirements will be varied Consultation encouraged Save time and development effort,2020/10/10,IND-Preclinical Sciences,6,Submission for Preclinical Sciences,Requirement for: General information CMC information Pharm/Tox information Pharmacokinetic information,202

5、0/10/10,IND-Preclinical Sciences,7,CMC Requirements,In general Sufficient information to assure identification, quality, purity, and strength of tested drug Information needed will vary with the phase, proposed duration, dosage form, and others Discuss with the Agency regarding type of manufacturing

6、 data that should be submitted to support the safe use of the drug,2020/10/10,IND-Preclinical Sciences,8,Phase 1 Adequate information for evaluation of the safety of subjects Able to relate the drug product in clinical study to the one in the animal toxicology studies,CMC Requirements Cont,2020/10/1

7、0,IND-Preclinical Sciences,9,Phase 2 and 3 All updates or revisions of CMC information (e.g., manufacturing process, specifications, formulation),CMC Requirements Cont,2020/10/10,IND-Preclinical Sciences,10,CMC Requirements Cont,For cases of new chemical entities (NCE) In general, the draft of IND p

8、rocess will be followed For cases of non-NCE A brief summary of chemical and physical properties of study medication Drug substance information Drug product information,2020/10/10,IND-Preclinical Sciences,11,CMC Requirements Cont,Drug Substance Name and address of supplier if purchased from other ve

9、ndors and COA from supplier Synthetic scheme and COA if synthesized internally,2020/10/10,IND-Preclinical Sciences,12,CMC Requirements Cont,Drug Product Manufacturing process, in-process controls and batch records Product release COA Stability data and protocol (sufficient long enough to cover the d

10、uration of clinical trial) Labeling Placebo including composition,2020/10/10,IND-Preclinical Sciences,13,Phase 1 -Pharmacodynamics and safety pharmacology -Single dose toxicity -Repeated-dose toxicity studies -Genotoxicity in vitro,Pharm/Tox Requirements,2020/10/10,IND-Preclinical Sciences,14,Phase

11、2 -Repeated-dose toxicity of appropriate length -Complete genotoxicity assessment Phase 3 -Repeated-dose toxicity studies -Fertility and embryo-fetal developmental studies -Local tolerance,Pharm/Tox Requirements-Cont,2020/10/10,IND-Preclinical Sciences,15,Pharmacokinetic Requirements,Phase 1 -Suffic

12、ient animal PK information to support the study design of PK studies in healthy volunteers -Suitable bioanalytic method for biologic samples Phase 2 -Sufficient healthy volunteers PK information to support the study design of PK studies in patients,2020/10/10,IND-Preclinical Sciences,16,PK Requireme

13、nts-Cont,Phase 3 -Sufficient PK information of healthy volunteers and patients to support the study design of pop-PK or other PK studies,2020/10/10,IND-Preclinical Sciences,17,IND Cases with Submission Deficiencies,2020/10/10,IND-Preclinical Sciences,18,Deficiency Categories,2020/10/10,IND-Preclinic

14、al Sciences,19,General Issues,Lack of : Summary of preclinical information or an investigator brochure Rationale of developing formulation Relevant documentations in Chinese or English version,2020/10/10,IND-Preclinical Sciences,20,CMC Issues,Lack of : Component/composition of drug product and place

15、bo Specifications of drug substance and product (including impurities) Stability test protocol and result Complete analytic report or COA Description of manufacturing process, quality control, packaging and labeling Name and address of manufacturer for drug substance and drug product,2020/10/10,IND-

16、Preclinical Sciences,21,Pharm/Tox Issues,Lack of : Local tolerance for local use Pharmacodynamics to support proposed indication Safety pharmacology in specific cases Animal toxicity to support dose selection (e.g. NOAEL) and the duration of proposed clinical trial,2020/10/10,IND-Preclinical Science

17、s,22,Pharmacokinetic Issues,Lack of : Evidence for modified release dosage form (e.g. a comparative dissolution test or a BA study result) Information for drug-drug interaction PK characteristics (e.g., animal ADME, exposure data) BE study if formulation change,2020/10/10,IND-Preclinical Sciences,23

18、,Case Examples Those Had Not Been Approved By DOH Due to Preclinical Issues,2020/10/10,IND-Preclinical Sciences,24,Case Example,A domestic IND with a reference drug, new modified-release dosage form Sponsor submitted literarues and little of CMC information only Decision of DOH Review Board -Identif

19、y that drug substance could be modified-released -Sufficient CMC information for ensuring the quality and safety of tested drug,2020/10/10,IND-Preclinical Sciences,25,Case Example,A domestic IND without a reference drug, new combination dosage form for topical use Sponsor provided CMC information and a animal model to supp