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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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  1. Safety in Analgesia TrialsArthritis Advisory Committee Meeting July 29-30, 2002 M. Lourdes Villalba, M.D. FDA/CDER/DAAODP

  2. 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

  3. 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)

  4. Exposure RequirementsChronic Use • Adequate assessment of chronic safety • Minimum ICH guidelines at the highest labeled dose • Specific safety concerns • Special populations

  5. 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)

  6. 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)

  7. 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 up to 200 mg/day • At filing, insufficient exposure for OA indication • OA indication withdrawn • Chronic safety data submitted to NDA

  8. Patients Exposed to Bromfenac in NDA • Acute pain 1071 Multiple dose (up to 1wk) 384 • Dysmenorrhea 245 • Chronic (OA & RA) 926 Total 2242

  9. 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

  10. 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

  11. 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

  12. 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%.

  13. 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

  14. 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)

  15. 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

  16. 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%

  17. 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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