Accelerated Approval Update 2005

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Accelerated Approval Update 2005

• Ramzi Dagher, MD
• DDOP/OODP/CDER/FDA

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Purpose

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

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Outline

• Regulatory History
• Summary
• Trial Design / Endpoints
• Confirmation of Benefit
• Conclusions
• Questions

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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

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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

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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

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Available Therapy Guidance

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

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Status 2003

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

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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• 1 indication withdrawn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

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Trial Designs

• No concurrent comparator
• 19 indications
• Randomized trials
• 10 indications

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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

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Uncertainty of Long-Term Outcome

• Amifostine (Ethyol)
• Dexrazoxane (Zinecard)
• Anastrozole (Arimidex)
• Imatinib mesylate (Gleevec)
• first-line CML
• Letrozole (Femara)

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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

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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

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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 gt risk (with ureteral
  obstruction, impending neurologic loss, severe
  bone pain).

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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

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Approvals Prior to 2002 Without Confirmation of CB

• seven at the time of issuing invitations for this
  ODAC
• one indication has been withdrawn

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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

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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

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Applicant Presentations

• liposomal doxorubicin (Doxil)
• Kaposis Sarcoma
• denileukin diftitox (ONTAK)
• liposomal cytarabine (DepoCyt)
• celecoxib (Celebrex)
• gemtuzumab ozogamicin (Mylotarg)
• alemtuzumab (Campath)

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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

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Conclusions

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

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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?

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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