1

Proof of concept

Pharmacology (mechanistic and animal models) Safety pharmacology (ICH S7A-S7B) Pharmacokinetics/Toxicokinetics (ICH S3A-S3B) General toxicology (ICH S4) Genetic toxicology (ICH S2) Reproductive toxicology (ICH S5A/5B) Carcinogenicity (ICH S1A-S1C) e.g., Immunotoxicity (ICH S8) ()Discovery and ScreeningSynthesis and PurificationPhase IPhase IIPhase IIIINDNDAAPPROVALPhase IVAdverse Reaction SurveillanceShort-term toxLong-term tox (3-6 month)Other toxPharmacologyRepro tox (Seg I/II/III)Immunotoxicity, Geno, Carc, Long-lerm toxReview time (Risk assessment): () first-in-human trials (dose limiting toxicities, DLT) (pregnancy) (carcinogenesis) (mutagenesis) (genotoxicity) (teratogenicity) (histopathological changes)

Guidelines 89 () http://regulation.cde.org.tw/

ICH M3 (R2): General guidance on non-clinical safety studies; type, duration and timing of studies.ICH S6: Preclinical safety evaluation of biotechnology-derived pharmaceuticalsOther ICH safety guidance: S1, 2, 3, 4, 5, 7, 8ICH S9: Nonclinical evaluation for anticancer pharmaceuticalshttp://www.ich.org/products/guidelines/safety/article/safety-guidelines.html

9

:: ()() ???Phase I/II vs Phase III Phase I/II

Phase I/II (: Ayurveda..)/(MedlineToxlineTOMESRTEC)1. 2. 3. 4. 5. Phase III to NDA (NDA)

Primary pharmacodynamic: (in vitro)/ (in vivo)- (dose-response relationship) (mechanism of action)CMC (bioassay) Secondary pharmacodynamic: Safety pharmacology: (core battery): (follow-up)(supplemental)

-() ()

/CMC(markers)

/ (segment I ) (segment II)/ (segment III)Ex, prostate hypertrophy, teratology studies usually are not required.

Fig. 1. Percentage of botanical IND submissions (20012008, FDA) that included genotoxicity information or studies (green bar: inclusion of GT Information refers to those that contain either studies performed or literature information, or both; shaded bar: inclusion of GT Studies refers to those that contain actual studies performed.) Regulatory Toxicology and Pharmacology 56 (2010)6 () (adjuvant therapy)

: (GLP)

Product E :Phase /II:Product E: 700 mg tid 1410 mg tid : 91. 120 2.1 300 2. 10-500 30-100 : 1. 2. 7/90 (non-GLP)

Product P85%:Phase II:Product P: 250, 500, 750 mg QD: : 1. 2. /30 (rat),

ICHend of Phase II: (2009)FDA: Guidance for Industry-Botanical Drug Products. (2004)Regulatory Toxicology Perspectives on the Development of Botanical Drug Products in the United States American Journal of Therapeutics. (2004)EMA: Guideline on Non-Clinical Documentation for Herbal Medicinal Products in Applications for Marketing Authorisation and in Applications for Simplified registration. (2006)THANK YOU