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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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Presentation Transcript
scope of the study
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
preclinical evaluation
Preclinical Evaluation
  • Crude extract from broccoli sprout.
  • Crude extract from curcumin.
  • The chemopreventive product (combination of curcumin and broccoli, lecithin use as a vehicle)
toxicity testing
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.
toxicity testing cont
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.
toxicity testing cont1
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.
chemoprevention potency test
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
chemoprevention potency test i

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

chemoprevention potency test ii

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

clinical evaluation phase i
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).
clinical evaluation phase i cont
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.
clinical evaluation phase ii
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
clinical evaluation phase ii cont
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.
clinical evaluation phase ii cont1
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.
clinical evaluation phase iii
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)
clinical evaluation phase iii cont
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.
post clinical evaluation phase iv
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.
conclusion
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.