Development of a New Cancer Drug

1. Development of a New Cancer Drug Martin J. Edelman, MD University of Maryland School of Medicine

2. Overview Scope of the problem Source of new agents Requirements for approval Preclinical development Phase I, II, III trials Post-marketing trials, extension of registration

4. Where do new drugs come from? Serendipity (cisplatin) Natural product screen (Vinca alkaloids) Derivatives of older agents (oxaliplatin, vinorelbine, many others) Rational design based upon putative targets (methotrexate, 5FU, estramustine, tamoxifen,Iressa, C225)

5. Cancer Drugs:How Do We Know We Have a Winner?

6. Six Essential Alterationsin Cell Physiology in Malignancy

7. SITES OF ACTION OF CYTOTOXIC AGENTS 6-MERCAPTOPURINE 6-THIOGUANINE METHOTREXATE 5-FLUOROURACIL HYDROXYUREA CYTARABINE

8. DRUG RESISTANCE EXTRACELLULAR INTRACELLULAR

9. �Rational� Drug Discovery

10. Requirements for FDA Approval Drug must be proven to be �safe and effective� Efficacy must be demonstrated in a �defined patient population� What is efficacy?

11. Definitions of Patient Benefit Survival Decreased requirement for supportive care e.g. transfusions, pain medication Improved quality of life ? Response

12. Cross Products

13. Phases of Drug Development Preclincal Phase I Phase II Phase III

14. Preclinical Development Identification of �lead compound� Able to be produced in adequate quantities Favorable properties for administration In vitro activity In vivo activity: animal models

15. Problems with animal models Mice are not men Transplanted human tumors behave very differently Uniformity of models: important for reproducibility, but inherently different from natural system

16. Investigational New Drug Application (INDA) Allows drug to be administered to humans Drug must be manufactured according to GMP

17. Clinical Trials Requires review by institutional review board (IRB) IRB must be constituted appropriately May require independent data safety monitoring (DSMB)

18. Phase I Development Dosage and schedule based upon animal data Not always correct e.g. UCN-01 Traditional Phase I designs New Phase I designs Phase I based upon target inhibition Very limited numbers of patients (e.g. 15)

19. Phase II Trials Typically several trials of the agent in diseases likely to be affected. Endpoint: �efficacy� Two-stage design

20. Problems with Phase II design May underestimate activity Unknown heterogeneity May overestimate activity Referral population Unknown heterogeneity

21. Phase III Study Definitive comparison with �standard of care� Superiority assumption Equivalence assumption

22. Approval of a New Drug New drug application (NDA) Patient benefit demonstrated Ability to manufacture the drug Oncology Drug Advisory Committee (ODAC)

23. Post-marketing testing Registration of an agent is only the beginning Many drugs may have much broader use than their registration No drug has ever been registered for use with radiation Adjuvant use

24. Summary Many sources for new anticancer drugs While in vitro and animal in vivo models are helpful for identifying active agents and beginning evaluation, they are insufficient for determining actual toxicity of efficacy. Several phases of development: agents may fail at any point Registration is only the beginning of a drugs life. Very expensive process