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Accelerated Approval Update 2005

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Title: Accelerated Approval Update 2005


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  • 1 indication withdrawn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 gt 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)
  • Kaposis 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
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