P1254413694Pnjsa

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Presented by Kenneth M. Verburg, Ph.D. at
the Arthritis Advisory Committee meeting 07/29/02
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Development of New Guidelines for
Analgesics/Drugs Intended for the Treatment of
Pain

• General Comments
• Chronic Pain
• Acute Pain

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New Guidelines Considerations

• Mechanistic differences in
• Type of pain (nociceptive, neuropathic pain)
• Nociceptive pain- unclear differences between
  somatic and visceral pain
• Chronicity of pain (acute vs chronic)
• Pain severity (differences across models)
• Different classes of analgesics (monotherapy vs
  multi-modal) and sites of action

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New Guidelines Objectives

• Expedite development of therapies to meet the
  clear unmet medical need
• Efficient programs that provide the information
  needed for registration
• Consider conditions of clinical practice
• Pre-operative and/or post-operative
  administration
• Multi-modal analgesic regimens for certain
  conditions
• Differences in treatment of acute vs chronic pain

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Development of New Guidelines for
Analgesics/Drugs Intended for the Treatment of
Pain

• General Comments
• Chronic Pain
• Acute Pain

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Experience with Chronic Pain Models

• Osteoarthritis/rheumatoid arthritis
• Low back pain
• Ankylosing spondylitis
• Neuropathic pain (post-herpetic neuralgia,
  painful diabetic neuropathy)
• Cancer pain

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Chronic Pain Points for Consideration

• Approach to the determination of efficacy
• Pain intensity assessment
• Global assessment
• Function/disability assessment
• Limited number of models suitable for study
  of 3 months duration
• Extended placebo treatment
• Models chronic intermittent pain endpoints/
  duration of treatment and/or number of
  cycles
• Define safety requirements

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Chronic Pain Points for Consideration

• Due to the heterogenous nature of chronic pain
  conditions, consider a tiered approach with
• A separate indication for each condition with
  replicate studies
• An indication of chronic musculoskeletal pain
  with a single study in 3 chronic musculoskeletal
  models
• A general chronic pain indication with a single
  study in 2 chronic musculoskeletal models and a
  single study in 2 neuropathic models

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Development of New Guidelines for
Analgesics/Drugs Intended for the Treatment of
Pain

• General Comments
• Chronic Pain
• Acute Pain

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Experience With Acute Pain Models
Model Advantages Limitations
Dental Pain Low placebo response lends itself to single dose assessments Limited multiple dose utility due to finite duration of moderate to severe pain
Post-surgical (abdominal or orthopedic) pain Duration of pain suitable for multiple dose assessment Experience with COX-2s and opioids suggest good model for combination therapy High placebo response limits determination of analgesia onset
Musculoskeletal Pain (OA flare, acute tendinitis) Duration of pain suitable for multiple dose efficacy monotherapy assessment Despite severity of disease, demonstrating single dose efficacy with traditional measures is difficult
Primary Dysmenorrhea Multiple-dose intermittent model suitable for onset and duration Pain self-limiting therefore limitations for multiple dose assessment
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Demonstrating Single Dose Efficacy in
Acute Pain

• Current guidelines provide adequate criteria to
  evaluate single dose analgesic efficacy
• Replicate studies in dental pain and
  post-surgical pain
• Well-defined efficacy measures assessing onset,
  extent, and duration of analgesia
• Time to onset of analgesia should be lt1 hour
• Time to rescue medication is used to support dose
  regimen on Day 1 and subsequent days

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Demonstrating Multiple Dose Efficacy in
Acute Pain

• Criteria to demonstrate multiple dose efficacy
  (an effective regimen) are less well
  defined in current guidelines
• Study Design/Conduct Considerations
• Self-limiting nature of pain in some models
• Severity of initial pain in some models may not
  be controlled by monotherapy

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Worst Pain in Past 24 Hours
Laparoscopic Cholecystectomy
100
Placebo
Active
75
of Patients Mod to Severe Pain
50


25
0
Day 2
Day 3
Day 4
Day 5
Day 6
Days Post-surgery
Significantly lower than placebo (plt0.05)
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Multi-modal Analgesia

• Obtain additional clinical benefit by controlling
  pain with agents from two or more classes
• Operating through different mechanisms or
  different sites
• Efficacy measures vs monotherapy
• Reduced medication requirements
• Improved analgesia
• Reduce adverse effects
• Improved patient global assessment

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Pain Intensity Difference
Total Knee Arthroplasty
Active 1x vs Pbo
plt0.05
1.00
Active 0.5x vs Pbo
H
H
0.75
H
J
J
0.50
H
J
H
Mean Score
H
0.25
B
J
J
H
0
B
J
H
J
H
B
B
B
B
B
-0.25
J
J
B
B
-0.50
Hours
Categorical Scale PI Scale 0 (none) - 3
(severe)
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Acute Pain Points for Consideration

• One acute pain model does not fill all criteria
  for determination of single dose and multiple
  dose efficacy
• Specify which models are best to define onset,
  peak effect and duration
• Specify compartmental approaches for pain
  studies e.g. single-dose, multi-dose on
  day 1 and subsequent days
• Propose models best for monotherapy vs
  combination therapy

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Acute Pain Points for Consideration

• Specify what acute pain models are needed
  to obtain broad acute pain indication by
  severity and/or etiology
• Specify how many models and whether
  replication is needed in each. If models are
  of similar etiology only one model
  should need replication
• Define safety requirements for acute pain (alone
  or in combination with chronic pain)