Analgesic Drug Development for Neuropathic Pain Methodologic Issues

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Analgesic Drug Development for Neuropathic
Pain Methodologic Issues

• Najib Babul, PharmD
• TheraQuest Biosciences
• nbabul_at_theraquestinc.com

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Analgesic Drug Development Regulatory Framework

• FDA
• Guideline for the Evaluation of Analgesic Drugs
  (December, 1992)
• EMEA
• Guidance on Clinical Investigation of Medicinal
  Products for Treatment of Pain (CPMP Draft,
  November 2001)

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Supportive Guidelines

• Clinical development programs for drugs, devices
  and biological products intended for the
  treatment of osteoarthritis (FDA Guidance, July
  1999)
• Clinical investigation of medicinal products used
  in the treatment of osteoarthritis (CPMP PTC,
  July 1998)
• Clinical investigation of slow-acting
  anti-rheumatic medicinal products used in the
  treatment of rheumatoid arthritis (CPMP PTC, Dec
  1998)

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Neuropathic PainWhat is the regulatory
framework for drug approval?

• Should a sponsor be able to obtain a broad
  indication for neuropathic pain or is it
  necessary to provide replicate evidence of
  efficacy for each neuropathic pain state?

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Broad Indication vs. Multiple Sub-indicationsPro
s and Con

• Broad Indication
• Response is often generalizable
• Pivotal studies in a several pain states should
  be adequate for broad claim
• Need for replicate evidence in every pain state
  will push developers to a minimalist approach
  (off label use)
• Consequently, many painful neuropathies may
  remain orphaned

• Sub-indications
• Etiology, presentation natural course is
  different
• Mechanisms of pain are frequently different
• Replication is essential to avoid erroneous
  conclusions from chance findings
• Failure to require studies in each painful
  neuropathy may also result in orphaning

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Making a Case for a Broad Neuropathic Pain
Claims Structure
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Taxonomy

• Peripheral neuropathies
• Phantom pain/post-amputation pain
• CRPS I (RSD), CRPS II (Causalgia)
• Nerve root disorders arachnoiditis
• Central pain
• Spinal cord injury pain

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Peripheral Neuropathic Pain

• Traumatic Mononeuropathies
• - Entrapment neuropathies
• - Transection
• - Causalgia
• - Post-thoracotomy
• - Stump pain
• Mononeuropathies/Multiple
• - Diabetic
• - Postherpetic
• - Trigeminal
• - Glossopharyngeal
• - Radiation plexopathy
• - Malignant nerve/plexus invasion

• Polyneuropathies
• - Nutritional/metabolic Diabetic,
• Alcoholic, Amyloid, Pellagra, Beriberi
• - Drugs INH, Platinum, Vinca
• - Hereditary Fabrys
• - Malignant myeloma, carcinomatous
• - Other Guillain-Barre, idiopathic

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Will we (ever) get drugs approved for
neuropathic pain if there is a requirement for
replicate evidence in each painful neuropathy?
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RCTs in Cancer Pain Pain Characteristics
Babul and Hagen, American Society for Clinical
Pharmacology Therapeutics, March 2002
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Is there a Wide Divergence in the Efficacy
Responseto Various Pharmacologic Agents in
Painful Neuropathies?

• If YES, a Broad Claim may not be possible
• If NO, a Broad Claim may be possible
• What is the evidence for a comparable response
  across painful neuropathies?

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Recent Retrospective Evaluation

• Randomized, Double-blind, Placebo-controlled
• Orally administered drug
• Treatment duration 4 weeks
• Postherpetic neuralgia (PHN) or
• Diabetic peripheral neuropathy (DPN)
• Pre-treatment (baseline) primary endpoint score
• Final primary endpoint score
• Response ? Drug/Baseline Drug ?
  Placebo/Baseline Placebo x 100
• Babul and Watson, American Pain Society,
  Baltimore, March 2002  

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What to Measure in Neuropathic Pain Studies?
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Pain Descriptors

• Brief Pain (87)
• -Sharp
• -Jabbing
• -Shooting
• -Electric
• Evoked Pain (87)
• -Mechanical
• -Thermal

• Steady Pain (97)
• -Burning
• -Aching
• -Stinging
• -Throbbing
• -Itching
• -Numbing
• -Pins Needles
• -Pulling

Watson and Babul. Neurology 1998501837-41
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Pain Characteristics

• Steady (ongoing) pain
• Paroxysmal pains
• Allodynia
• Sensory impairment

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Pharmacologic Response in PHN
P 0.0001
P 0.0001
P 0.0004
Watson and Babul. Neurology 1998501837-41
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What else to measure?

• Depends on claim characteristics sought
• Durability of efficacy response
• Quality of life
• Function
• Quantitative sensory testing?
• Neuropyschological/cognitive effects?

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Core Development Program 505 (b) (1)for
Neuropathic Pain (Broad Indication)

• Dose (and dosing frequency) finding studies in at
  least two painful neuropathies (may be
  incoporated into pivotal studies) plus
• Replicate evidence of 12-week efficacy in PHN
  plus
• Replicate evidence of 12-week efficacy in DPN or
• Robust evidence of 12 week efficacy in 2 painful
  peripheral neuropathies plus 1 or 2 other models
  (CP, SCP, CRPS, nerve root pain, etc)
• Cognitive impairment evaluation with acute and
  chronic dosing (for centrally acting drugs)
• Long-term safety data
• Clinical pharmacology of label should reflect
  efficacy data

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Analgesic Drug Development for Neuropathic
Pain Key Methodologic Issues

• Najib Babul, PharmD
• TheraQuest Biosciences
• nbabul_at_theraquestinc.com