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• 13 no further confirmatory data expected– 10 confirmation of benefit– 2 restricted distribution– 1 indication withdrawn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