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Analgesic Drug Development for Neuropathic Pain
Methodologic Issues
Najib Babul, PharmDTheraQuest Biosciences
Najib Babul, PharmD
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)
Najib Babul, PharmD
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)
Neuropathic Pain
What 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?
Najib Babul, PharmD
Broad Indication vs. Multiple Sub-indications:
Pros and ConBroad 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”
Najib Babul, PharmD
Making a Case for a Broad Neuropathic Pain Claims
Structure
Najib Babul, PharmD
Taxonomy
• Peripheral neuropathies
• Phantom pain/post-amputation pain
• CRPS I (RSD), CRPS II (Causalgia)
• Nerve root disorders & arachnoiditis
• Central pain
• Spinal cord injury pain
Najib Babul, PharmD
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: Fabry’s
- Malignant: myeloma, carcinomatous
- Other: Guillain-Barre, idiopathic
Najib Babul, PharmD
Will we (ever) get drugs approved for neuropathic pain if
there is a requirement for replicate evidence in each painful
neuropathy?
Najib Babul, PharmD
RCT’s in Cancer Pain Pain Characteristics
Study # 1 Study # 2 Study # 3 Study #4 Bone/Soft Tissue
32%`
64%
45%
61%
Visceral
49%
18%
16%
23%
Neuropathic Plus
14%
9%
34%
45%
Neuropathic Only
5%
9%
2%
12%
Babul and Hagen, American Society for Clinical Pharmacology & Therapeutics,Babul and Hagen, American Society for Clinical Pharmacology & Therapeutics, March 2002 March 2002
Is there a Wide Divergence in the Efficacy Response
to 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?
Najib Babul, PharmD
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 = [Δ Drug/Baseline Drug] – [Δ Placebo/Baseline
Placebo] x 100%
Babul and Watson, American Pain Society, Baltimore, March 2002Babul and Watson, American Pain Society, Baltimore, March 2002
Najib Babul, PharmD
Diabetic Neuropathy
05
1015202530354045
Eff
ect
Siz
e (%
)
Amitriptyline Desipramine Gabapentin Pregabalin Lamotrigine Mexiletine Dextromethorphan Tramadol Oxycodone
Najib Babul, PharmD
Postherpetic Neuralgia
0
5
10
15
20
25
30
35
Eff
ec
t S
ize
(%
)
Oxycodone Amitriptyline Desipramine Gabapentin Pregabalin
What to Measure in Neuropathic Pain Studies?
Najib Babul, PharmD
Pain DescriptorsSteady Pain (97%)-Burning -Aching-Stinging-Throbbing-Itching-Numbing-Pins & Needles-Pulling
Brief Pain (87%)
-Sharp
-Jabbing
-Shooting
-Electric
Evoked Pain (87%)
-Mechanical
-Thermal
Watson and Babul. Neurology 1998;50:1837-41
Najib Babul, PharmD
Pain Characteristics
• Steady (ongoing) pain
• Paroxysmal pains
• Allodynia
• Sensory impairment
Pharmacologic Response in PHN
10
20
30
40
50
60
Steady Pain Paroxysmal Pain AllodyniaWee
kly
VA
S P
ain
Sco
re (
0-10
0 m
m)
Placebo OxyContin
Watson and Babul. Neurology 1998;50:1837-41
P = 0.0001 P = 0.0001 P = 0.0004
Najib Babul, PharmD
What else to measure?
Depends on claim characteristics sought
• Durability of efficacy response
• Quality of life
• Function
• Quantitative sensory testing?
• Neuropyschological/cognitive effects?
Najib Babul, PharmD
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
Analgesic Drug Development for Neuropathic Pain
Key Methodologic Issues
Najib Babul, PharmDTheraQuest Biosciences