1. Analgesic Drug Development for Neuropathic Pain Methodologic Issues Najib Babul, PharmD TheraQuest Biosciences nbabul@theraquestinc.com

2. 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)

3. 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)

4. 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?

5. Najib Babul, PharmD Broad Indication vs. Multiple Sub-indications: Pros 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”

6. Najib Babul, PharmD Making a Case for a Broad Neuropathic Pain Claims Structure

7. 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

8. 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

9. Najib Babul, PharmD Will we (ever) get drugs approved for neuropathic pain if there is a requirement for replicate evidence in each painful neuropathy?

10. RCT’s in Cancer Pain Pain Characteristics Babul and Hagen, American Society for Clinical Pharmacology & Therapeutics, March 2002

11. 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?

12. 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 2002 Babul and Watson, American Pain Society, Baltimore, March 2002

13. Najib Babul, PharmD

15. What to Measure in Neuropathic Pain Studies?

16. Pain Descriptors Steady 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

17. Najib Babul, PharmD Pain Characteristics Steady (ongoing) pain Paroxysmal pains Allodynia Sensory impairment

18. Pharmacologic Response in PHN Watson and Babul. Neurology 1998;50:1837-41 P = 0.0001 P = 0.0004

19. 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?

20. 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

21. Analgesic Drug Development for Neuropathic Pain Key Methodologic Issues Najib Babul, PharmD TheraQuest Biosciences nbabul@theraquestinc.com