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

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

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Accelerated Approval Update 2005

Ramzi Dagher, MD

DDOP/OODP/CDER/FDA

Purpose

• review past accelerated approvals

• discuss current progress of associated phase 4 commitments

• solicit input for improving the process

Outline

• Regulatory History

• Summary

• Trial Design / Endpoints

• Confirmation of Benefit

• Conclusions

• Questions

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

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

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

Available Therapy Guidance

• approval of one therapy under the AA regulations should not preclude approval under the AA regulations of additional therapies

Status 2003

• 19 indications (16 drugs)

• 4 confirmation of benefit

• 8 presented at March 2003 ODAC – 5 of which being presented again 2005

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• 13 no further confirmatory data expected– 10 confirmation of benefit– 2 restricted distribution– 1 indication withdrawn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

Trial Designs

• No concurrent comparator– 19 indications

• Randomized trials– 10 indications

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

Uncertainty of Long-Term Outcome

• Amifostine (Ethyol)

• Dexrazoxane (Zinecard)

• Anastrozole (Arimidex)

• Imatinib mesylate (Gleevec)– first-line CML

• Letrozole (Femara)

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

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

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).

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

Approvals Prior to 2002 Without Confirmation of CB

• seven at the time of issuing invitations for this ODAC

• one indication has been withdrawn

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

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

Applicant Presentations

• liposomal doxorubicin (Doxil)– Kaposi’s Sarcoma

• denileukin diftitox (ONTAK)

• liposomal cytarabine (DepoCyt)

• celecoxib (Celebrex)

• gemtuzumab ozogamicin (Mylotarg)

• alemtuzumab (Campath)

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

Conclusions

• Emphasize integration of AA strategy into drug development plan

• Includes early attention to design, conduct of confirmatory studies

• Continued public discussion

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?

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