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Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
Pharmacology/Toxicology information to submit an IND for an anticancer drug
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Pharmacology/Toxicology information to submit an IND for an anticancer drug

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  • 1. Pharmacology/Toxicology information to submit an IND for an anticancer drug
  • 2.
        • This presentation is not an official FDA guidance or policy statement. No official support or endorsement by the FDA is intended or should be inferred
  • 3. Disciplines involved in the review process of applications for oncology drug products
    • Project Manager (to coordinate meetings, respond to sponsors, provide regulatory insights)
    • Pharmacology/Toxicology
    • Chemistry
    • Medical
    • Clinical Pharmacology
    • Biostatistics (usually not at the initial IND stage)
  • 4. Pharmacology/ Toxicology Nonclinical Development
    • A compound is tested in cell cultures and whole animals in order to make educated guesses about how it should be used in people.
      • Pharmacology Studies (efficacy, mechanism)
      • Toxicology Studies (safety)
      • Pharmacokinetic studies (ADME)
  • 5. Pharmacology Studies
    • Used to evaluate desirable effects, but may give additional insight into toxicity
    • Exact mechanism of action may never be determined
  • 6. Toxicology: The search for the unexpected
  • 7. Toxicology Studies
    • Review the nonclinical (animal) studies to:
        • estimate the safe starting dose for clinical studies
        • assess toxic effects with respect to target organs; therefore, potential organ toxicities to be monitored in the clinical studies
        • assess potential reversibility
  • 8. Toxicology Studies (cont’d)
        • assess dose dependence
        • assess relationship to exposure
        • assess hazards that cannot be evaluated in clinical trials (e.g. carcinogenicity and teratogenicity)
    • To identify hazards and estimate the relatively safe starting dose
  • 9. Toxicology Studies (cont’d)
    • While risks for humans cannot be eliminated, they may be anticipated, ameliorated, and/or avoided
  • 10. Common Types of Toxicity Studies
    • General Toxicity (repeat dose), can have incorporated in it:
      • Safety Pharmacology
      • TK
    • Genotoxicity (later in the development unless disease-free subjects are entered)
    • Reproductive Toxicity (later in the development)
    • Carcinogenicity (for disease-free subjects; later in the development )
    • Immunotoxicity (occasionally required)
  • 11. Pharmacokinetic (ADME) Studies
    • Not required, but strongly encouraged
    • Assists the interspecies comparison of toxicity and extrapolation to humans
    • May suggest modifications in the intended dose, route or schedule for the clinical trial
    • Can contribute to optimal dose escalation in early clinical studies
  • 12. Nonclinical Information (Item 8 of the IND)
    • Line listed data
    • Interpretation of the data- The output is “information”, not report
  • 13. Interpretation of the data
    • Integration of intra-species findings
      • Clinical signs, clinical pathology, histopath...
      • Exaggerated pharmacologic effect? Intended or toxic effects?
    • Cross-species extrapolation
      • Allow educated guesses about the implications of nonclinical findings for human
      • Are findings consistent across species?
      • Correlate toxic doses with exposure
  • 14.
    • Estimation of the starting dose in cancer patients
    http://www.fda.gov/cder/cancer/docs/doseflow.pdf
  • 15. Good Laboratory Practices (GLP) 21CFR 58
    • The purpose of the GLPs is to assure the quality and integrity of the nonclinical safety data submitted to the regulatory agency
  • 16. Good Laboratory Practices (GLP) http://www.access.gpo.gov/nara/cfr/waisidx_00/21cfr58_00.html
  • 17. Plan in Advance Estimated Costs of Toxicology Studies Anticancer Drug Development Guide; BA Teicher and PA Andrews
  • 18. Example of Poor Planning! Acknowledge that planning is a dynamic process
  • 19. User Fee
    • No IND fee
    • NDA user fee is waived for Small Business (<500 employees) for the 1 st human drug application that a small business or its affiliate submits for review.
    • http://www.fda.gov/cder/about/smallbiz/Econonic.htm
    • http://www.fda.gov/cder/about/smallbiz/pdufa.htm
    • http://www.fda.gov/orphan/faq/index.htm
  • 20. Resources
    • Guidances and Guidelines:
    • ICH- http://www.fda.gov/cder/guidance/index.htm
      • S1 Carcinogenicity
      • S2 Genetic toxicity
      • S3 Toxicokinetics
      • S4 Duration of Chronic Toxicity Testing
      • S5 Reproductive toxicity
      • S6 Biotechnology
      • S7 Safety Pharmacology
      • M3 Nonclinical Safety Studies for the conduct of Human Clinical Trials
  • 21.  
  • 22. Resources (cont’d)
    • CFSAN Redbook: http://www.cfsan.fda.gov/~redbook/red-toca.html
  • 23.  
  • 24. Resources (cont’d)
    • Articles/Books (regulatory + technical )
    • DeGeorge et al .: “Regulatory considerations for preclinical development of anticancer drugs”. Cancer Chemother Pharmacol 1998, 41: 173-185
  • 25.  
  • 26. Resources (cont’d)
    • Diehl et al: “A good practice guide to the administration of substances and removal of blood, including routes and volumes”- Journal of Applied Toxicology 2001, 21: 15-23
  • 27.  

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