TRENS IN MEDICINAL PLANT RESEARCH. 工研院生醫所 報告人 李連滋 中華民國九十六年十二月二十六日. Cost and Time per Drug to Market. Pre-Clinical. Clinical. Post-Marketing. Idea. Market. 10-15 Years. Drug Discovery & Development Process. Phase I. Phase II. Phase III. Demonstrate Safety and Efficacy in Patients
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Pre-Clinical Clinical Post-Marketing Idea Market 10-15 Years Drug Discovery & Development Process Phase I Phase II Phase III Demonstrate Safety and Efficacy in Patients Phase ll & lll Clinical Trial Exploratory Lead Optimization Development Candidate Pre-clinical & Phase I Development
From Drug Discovery to Market Discovery (HTS, Selectivity, Potency) Success Rate Preclinical Testing >10,000 Screened 200 enter preclinical test 3 - 5 enter clinical test 1 approved by FDA 60%* in late stage (Efficacy, Safety, DMPK, Tox) Phase I (20-80 volunteers for safety and dosage) 60% Phase II (100-300 patient for efficacy and side effects) 50% Phase III (1,000-5,000 patient for adverse reactions and efficacy) 80% NDA & Approval 90% Post- Marketing * survival rate (Additional testing for other indications and/or long-term safety monitoring) 10-15 Years (~$800 M)
Causes of New Drug Failure Pharmacokinetics 17% Toxicity 17% Miscellaneous 7% Adverse Effects 16% Efficacy 46% Commercial 7% PhRMA, 1998
NEW DRUG DISCOVERY & DEVELOPMENT PORCESS A LINEAR PROCESS Discovery Technologies / Development Services Target Identification Validation Lead Optimization Lead Prioritization Preclinical Development Clinical Development Post Approval Partnerships and Collaborations
處方藥之來源 B:生技藥物 N:天然物成分. ND天然物成分衍生物: S:純合成化合物. S*:由天然物成分發展之合成化合物. 資料來源：TRENDS IN MEDICINAL PLANT RESEARCH: SCREENING, BIOTECHNOLOGY AND RATIONAL PHYTOTHERAPY
中藥新藥開發新技術（開發現代化中藥之價值鏈）中藥新藥開發新技術（開發現代化中藥之價值鏈） In vitro test identified with gene pattern extraction Chronic response Acute response Acute response Acute response mRNA RAPD AFLP SSLP RFLP Enzyme activity signal transduction protein expression Supercritical extraction Two phase aquous extration Reversed micellar extraction affinity extraction cDNA variation Cell membrane voltage intra cell Ca 2+ change signal transduction PCR proliferate DNA DNA Arrays Survey Display gene biochemical assay cell-based physiological response assay Analysis gene pattern & compare with active components Materia medica extraction & separation biological activity Preclinical Clinical test • Bioreactor • suspension cultures • embryogenic cultures • HRC’s Affinity membrane artificial membrane ultrafiltration Transgene animal Animal model Bioavailability Pharmacokinetics Toxicology Phase I phase II phase III Pathology new resource Membrane separation In vivo test
Herbal Extraction Separation Purification Compound 1,2,…N Invitro screening Botanical library Crude extract 1,2,3,…n HTS screening Active extract Activity-guided separation Active compound Botanical library Crude extract 1,2,3,…n HPLC/FC prefractionation Fr 1,2,3,….n uHTS screening Active fraction Activity guided separation Active compound Active compound New approach Traditionally Recently
Botanical library collection • Plant materials source: endemic or native • Rich resources • Biodiversity uHTS screening • Over 20 screening models • 1 million compounds/day Fractionation –FC/HPLC
