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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. dr shabeel pn. 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.

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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 dr shabeel pn

  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/ ToxicologyNonclinical Development • A compound is tested in cell cultures and whole animals in order to make educatedguesses 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 AdvanceEstimated 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 1st 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. Resources (cont’d) CFSAN Redbook: http://www.cfsan.fda.gov/~redbook/red-toca.html

  22. 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

  23. 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

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