Safety in Analgesia Trials Arthritis Advisory Committee Meeting July 2930, 2002

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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 Use Vioxx 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• OA indication withdrawn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) gt30 gt90 gt180
  gt360
• 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 (lt 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 lt 10 days
• Because of risk of hepatic toxicity, if longer
  therapy is needed, LFTs 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 gt8 ULN
• 2 at 50 mg/d 5 at 100 mg/d 10 at ?150 mg/d
• Earliest occurred around day 30

Similar to ASTs 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