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

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

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