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Approval of Natural Chemopreventive Product

Approval of Natural Chemopreventive Product. Scope of The Study. Preclinical evaluation (In vivo) Toxicity testing Acute toxicity Subchronic toxicity Chronic toxicity Chemoprevention potency testing Clinical evaluation Phase I clinical trials Phase II clinical trials

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Approval of Natural Chemopreventive Product

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  1. Approval of Natural Chemopreventive Product

  2. Scope of The Study • Preclinical evaluation (In vivo) • Toxicity testing • Acute toxicity • Subchronic toxicity • Chronic toxicity • Chemoprevention potency testing • Clinical evaluation • Phase I clinical trials • Phase II clinical trials • Phase III clinical trials • Post-clinical evaluation • Phase IV marketing post-marketing surveillance

  3. Preclinical Evaluation • Crude extract from broccoli sprout. • Crude extract from curcumin. • The chemopreventive product (combination of curcumin and broccoli, lecithin use as a vehicle)

  4. Toxicity Testing • Route of administration : Oral • Test 1: Range finding for LD50 • 5 mice/Sex/Dose plus control group. • 5 doses • Test 2: The LD50 determination • 5 mice/Sex/Dose plus control group. • 5 doses base on Test 1.

  5. Toxicity Testing (Cont.) • Test 3: The LD50 determination (finely tuned) • 5 mice/Sex/Dose plus control group. • 5 doses base on Test 2. • Histopathological examination for dose-related lesions. • Test 4: Subchronic toxicity test • 5 mice/Sex plus control group. • Dose 10 times lower than LD50 (from Test 3) • Duration of treatment 90 days. • Observe animals for 360 days. • Histopathological examination for dose-related lesions.

  6. Toxicity Testing (Cont.) • Test 5: Chronic toxicity test • 10 mice/Sex plus control group. • Dose : Lowest no effect dose in Test 4. • Duration of treatment 1 year. • Observe animals life span. • Histophathology.

  7. Chemoprevention Potency Test • To evaluate the chemopreventive protency of the product. • 2 tests • Test I : No background of AFB1 exposed. • Test II : Exposed to AFB1 before the product administration. • HBV gene transgenic mice use in the studies to reduce number of mice. • Number of mice use • 10/sex/group

  8. 3 weeks of age Positive control (Oltipraz) Chemopreventive agent Control Developed tumor Non tumor Non tumor Chemoprevention Potency Test I Daily administration of the product 1 week Expose to dietary AFB1 52 weeks

  9. 3 weeks of age 1 weeks after AFB1 Positive control (Oltipraz) Chemopreventive agent Control Heavy tumor burden Reduce tumor burden Reduce tumor burden Chemoprevention Potency Test II AFB1 single dose (6 mg/kg by i.p.) 52 weeks

  10. Clinical Evaluation : Phase I • Objectives • To obtain pharmacokinetics of the product following single p.o. dose of the product. • To investigate the induction of GST in lymphocytes. • To evaluate toxicity associated with a single p.o. dose of the product. • Subjects • 60 healthy normal volunteers (30 males + 30 females).

  11. Clinical Evaluation : Phase I (cont.) • Treatment • 30 volunteers (15 males + 15 females) at dose X • 30 volunteers (15 males + 15 females) at dose Y • Pharmacokinetics study : Blood sample will be collect before administration and at 1, 2, 3, 4, 5, 6, 8, 16 and 24h after dosing to measure curcuminoid and sulforaphane levels. • Investigation of GST study : Blood sample will be collect before administration and at 6, 10 and 24h after dosing to measure GST levels. • Sample analysis • The samples will be measure by HPLC. • For toxicity grading, subjects will be evaluate for acute toxicity using standard U.S. National Cancer Institute toxicity criteria.

  12. Clinical Evaluation : Phase II • Objective • To preliminary assess the efficacy of the product by examining modulation in the levels of several biomarkers of aflatoxin in urine. • To characterize in more detail the rang of dose-limiting toxicities in a potential target population including individuals infected with HBV. • Study : placebo control, double blind study

  13. Clinical Evaluation : Phase II(cont.) • Subjects • Normal people (100 males + 100 females) • Product recipient (50 males + 50 females) • Placebo concurrent control (50 males + 50 females) • HBV carrier (50 males + 50 females) • Screening of subjects • Individual screening. • Determine base line level of aflatoxin–N-acetylcysteine in urine by HPLC.

  14. Clinical Evaluation : Phase II(cont.) • Treatment • Daily administration for 8 weeks. • Placebo • Define dose 1 • Define dose 2 • Urine samples collect once a week for 9 weeks after that once in 2 weeks till week 17.

  15. Clinical Evaluation : Phase III • Objective • The design of this phase is based on the finding in phase II to validate instruction for use and for imaging in the population. • Subjects • Normal people (200 males + 200 females) • Product recipient (100 males + 100 females) • Placebo concurrent control (100 males + 100 females) • HBV carrier (100 males + 100 females) • Liver resected (100 males + 100 females)

  16. Clinical Evaluation : Phase III(cont.) • Screening of subjects • Individual screening. • Determine base line level of aflatoxin–N-acetylcysteine in urine by HPLC. • Treatment • Administration dose base on phase II. • Daily administration for 24 months. • Urine samples collect once a month for 12 months after that once in 2 months till month 24.

  17. Post-clinical Evaluation : Phase IV • Objective • Designed to detect any rare or long-term adverse effects over a much larger population and timescale than was possible during the initial clinical trials. • Subjects • Same individual in phase III study. • Customers using the product. • Observation • Observe the side effects for 10 years after product on to the market.

  18. Conclusion • The product is safe for the population and high chemoprevention potency. • The product will on to the market as dietary supplement and above 10 years old children milk.

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