1. Accelerated Approval Update 2005 Ramzi Dagher, MD DDOP/OODP/CDER/FDA

2. Purpose review past accelerated approvals discuss current progress of associated phase 4 commitments solicit input for improving the process

3. Outline Regulatory History Summary Trial Design / Endpoints Confirmation of Benefit Conclusions Questions

4. Regulatory Basis (21CFR 314 and 601) For serious or life-threatening diseases Where the drug appears to provide benefit over available therapy Approval based on a surrogate reasonably likely to predict clinical benefit

5. 21CFR 314 and 601 (continued) Subject to the requirement that the applicant verify and describe benefit Post-marketing studies would usually be underway The applicant shall carry out such studies with due diligence

6. Available Therapy Guidance …should be interpreted as therapy that is specified in the approved labeling of regulated products, with only rare exceptions exceptional cases such as certain established oncologic treatments

7. Available Therapy Guidance approval of one therapy under the AA regulations should not preclude approval under the AA regulations of additional therapies

8. Status 2003 19 indications (16 drugs) 4 confirmation of benefit 8 presented at March 2003 ODAC –5 of which being presented again 2005

9. Status 2005 29 indications (25 different drugs) 13 no further confirmatory data expected –10 confirmation of benefit –2 restricted distribution –1 indication withdrawn 16 indications without confirmation of CB of 16, 6 prior to 2002

10. Trial Designs No concurrent comparator –19 indications Randomized trials –10 indications

11. Endpoints Utilized No concurrent comparator –objective response, complete remission, medical castration Randomized setting –cytologic response, number of polyps, objective response, time to progression, progression free survival, disease free survival, congestive heart failure

12. Uncertainty of Long-Term Outcome Amifostine (Ethyol) Dexrazoxane (Zinecard) Anastrozole (Arimidex) Imatinib mesylate (Gleevec) –first-line CML Letrozole (Femara)

13. Confirmation of Benefit docetaxel (Taxotere) –2nd line breast irinotecan (Camptosar) –2nd line colon dexrazoxane (Zinecard) –reduction of CHF capecitabine (Xeloda) –refractory breast liposomal doxorubicin (Doxil) –refractory ovarian

14. Confirmation of Benefit temozolomide (Temodar) –anaplastic astrocytoma imatinib mesylate (Gleevec) –CML BC, AP or CP after interferon oxaliplatin (Eloxatin) –2nd line colorectal anastrozole (Arimidex) –adjuvant ER+ breast cancer bortezomib (Velcade) –3rd line multiple myeloma

15. Abarelix: 21CFR parts 314 and 601 restricted distribution provisions GnRH antagonist approved 2003 for advanced symptomatic prostate cancer restricted indication and distribution due to risk of anaphylactic reaction and loss of castration effect patients in whom benefit > risk (with ureteral obstruction, impending neurologic loss, severe bone pain).

16. Gefitinib (Iressa) 2003: AA for 3rd line treatment of NSCLC No benefit in 4 randomized trials in NSCLC 2005: distribution limited to patients benefiting/have benefited from gefitinib

17. Approvals Prior to 2002 Without Confirmation of CB seven at the time of issuing invitations for this ODAC one indication has been withdrawn

18. Amifostine (Ethyol) 1996 AA to reduce cisplatin renal toxicity in NSCLC 2002 PMC study submitted –showed reduction in renal toxicity –results inconclusive regarding tumor protection –additional study required applicant feasibility assessment –high dose cisplatin regimen not often used –agents other than cisplatin also used 2005 indication for renal toxicity in NSCLC withdrawn

19. Status 2005 29 indications (25 different drugs) 13 no further confirmatory data expected –10 confirmation of benefit –2 restricted distribution –1 indication withdrawn 16 indications without confirmation of CB of 16, 6 prior to 2002

20. Applicant Presentations liposomal doxorubicin (Doxil) –Kaposi’s Sarcoma denileukin diftitox (ONTAK) liposomal cytarabine (DepoCyt) celecoxib (Celebrex) gemtuzumab ozogamicin (Mylotarg) alemtuzumab (Campath)

21. Conclusions 25 drugs made available for hematologic malignancies and solid tumors 3 drugs for pediatric indications approved under subpart H progress in confirmation of benefit

22. Conclusions Emphasize integration of AA strategy into drug development plan Includes early attention to design, conduct of confirmatory studies Continued public discussion

23. Questions for Individual Presentations For ongoing confirmatory studies –accrual satisfactory? –if not, any suggestions for improvement? For planned trials –any impedance to conduct? –any alternative trial designs?

24. Questions Regarding AA Process Trial Designs and Populations –AA in refractory patients and benefit in less refractory –AA based on interim analysis of randomized trial (surrogate endpoint) with confirmation of benefit in same study Any other suggestions for improving process