Safety in analgesia trials a rthritis advisory committee meeting july 29 30 2002
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Safety in Analgesia Trials. Arthritis Advisory Committee Meeting ... Efficacy in OA at 100 and 200 mg BID. Efficacy in RA at 200 and 400 mg BID. No efficacy ...

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Safety in Analgesia TrialsArthritis Advisory Committee Meeting July 29-30, 2002

M. Lourdes Villalba, M.D.

FDA/CDER/DAAODP


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Exposure Requirements

  • Chronic use - ICH Guidelines (E1A)

    • Minimum:

      • 300-600 patients for 6 months

      • 100 patients for one year

      • 1500 (total exposure)

    • Larger and/or longer term safety database may be needed

      • Specific safety concerns

      • Need to make risk/benefit decisions


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Exposure Requirements “Dose-creep” PhenomenonCelebrex® NDA

  • Randomized Controlled Trials

    • Efficacy in OA at 100 and 200 mg BID

    • Efficacy in RA at 200 and 400 mg BID

    • No efficacy advantage of the higher doses

  • Open label

    • Most patients (~70%) increased dose

    • Moved to a dose twice as high (200 mg BID for OA and 400 mg BID for RA)


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Exposure RequirementsChronic Use

  • Adequate assessment of chronic safety

  • Minimum ICH guidelines at the highest labeled dose

  • Specific safety concerns

  • Special populations


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Exposure Requirements

  • Acute or short-term use

    • As much as if it were intended for chronic use

      • Use beyond recommended duration

        • Vioxx® 50 mg (rofecoxib)

        • Duract® (bromfenac sodium)


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Acute or Short-Term UseVioxx® 50 mg Usage Data*

  • Number of total drug appearances (all dose strengths): 12,853,000

    50 mg strength (acute, 2X chronic): 652,000 (5 % of total)

     30 days 140,000 (21 %)

    * (IMS Health data, 5/99 to 9/00)


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Acute or Short Term UseDuract®(Bromfenac)

  • NSAID approved July 1997

  • Sponsor voluntary withdrawal June 1998 due to reports of hepatic failure

  • NDA originally proposed

    • Indications: acute pain, dysmenorrhea & OA

    • Dose: 25-50 mg q 6-8 hrs. up to 200 mg/day

  • At filing, insufficient exposure for OA indication

    • OA indication withdrawn

    • Chronic safety data submitted to NDA


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Patients Exposed to Bromfenac in NDA

  • Acute pain 1071

    Multiple dose (up to 1wk) 384

  • Dysmenorrhea 245

  • Chronic (OA & RA) 926

    Total 2242


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Chronic Exposure to Bromfenac in NDA

Dose (mg/d) >30* >90* >180* >360*

Any dose 799 578 474 193

200-225 164 124 105 24

150-199 102 81 68 50

76-149 453 349 283 108

75 or less 80 24 18 11

Safety update

Any dose 1195 926 734 247

* Days of exposure


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Bromfenac NDA-Chronic Studies

  • OA (N= 551) & RA (N= 316)

  • Fixed doses 50 to 200 mg/d

  • Placebo-controlled, 4-6 weeks

    Active-controlled, 4 weeks to 1 year (ASA, naproxen, ibuprofen, diclofenac)

  • Open label experience up to 4 years (some up to 225 mg/d)

N= patients randomized to bromfenac


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Bromfenac NDA

  • Acute pain studies: efficacy and safety at the 25 and 50 mg single dose

  • Safety data from short-term multiple dose

    • Absolutely no safety concerns

  • Chronic studies in OA and RA at 25 and 50 mg BID, TID and QID

    • “Flag” for hepatotoxicity


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Bromfenac NDA - Liver Signal

  • LFT elevation: mild 15% (< 3X ULN) and clinically significant 2.8% *( 3X ULN or higher)

  • Dose-related

  • Most reversible after drug discontinuation

  • Majority within 90 days

  • Earliest occurred around day 30

* NSAID template: LFT elevation in clinical trials mild ~ 15% & clinically significant~ 1%.


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Duract® Approved Label

WARNINGS

  • Risk of hepatic effects:

    • 2.8 % LFT elevation 3 x ULN & higher at some point (0.4% in short term trials)

    • 0.4% LFT elevations 8 x ULN & higher in in longer term trials

  • Short-term use for pain should be < 10 days

  • Because of risk of hepatic toxicity, if longer therapy is needed, LFT’s should be monitored after 4 weeks

    • Maximum daily dose limited to 150 mg/day

    • Removal of any references to treatment of OA, chronic pain and dysmenorrhea


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Duract®Post-marketing Reports

  • Liver toxicity including hepatic failure, need for liver transplantation and death

  • Most within labeled doses

  • Most exposed for longer than 10 days (2 to 8 months)


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Acute Pain - Safety Issues

  • Short-term safety is insufficient

  • Drug development should address potential safety concerns (dose-creep, use for longer than intended, potential for abuse)

  • Ideally, for short-term indication, unless contraindicated based on safety, formal efficacy studies needed in chronic setting


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Bromfenac NDA- Liver Signal

  • Notable LFT elevation in 23 / 830 patients (bromfenac 75 mg/d or more in chronic studies)

    • 19 ALT x 3-8 ULN

      2.8% *

    • 4 ALT x >8 ULN

  • 2 at 50 mg/d; 5 at 100 mg/d; 10 at 150 mg/d

  • Earliest occurred around day 30

* Similar to AST’s in Diclofenac NDA.

NSAID template: LFT elevation in clinical trials mild ~ 15% & notable ~ 1%


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Exposure RequirementsICH E1A

  • Larger or longer-term safety

    • Late AE or AE that increase in severity or frequency over time

    • Need to quantitate rate of expected specific low-frequency AE

    • To make risk/benefit decisions (small effect)

    • To detect prespecified increases over baseline morbidity or mortality


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