Analgesic Drug Development for Neuropathic Pain Methodologic Issues

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

2. 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

3. 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) Najib Babul, PharmD

4. 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?

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

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

7. 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

8. 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 Peripheral Neuropathic Pain Najib Babul, PharmD

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

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

11. 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?

12. 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 Najib Babul, PharmD

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15. What to Measure in Neuropathic Pain Studies?

16. Steady Pain (97%) -Burning -Aching -Stinging -Throbbing -Itching -Numbing -Pins & Needles -Pulling Brief Pain (87%) -Sharp -Jabbing -Shooting -Electric Evoked Pain (87%) -Mechanical -Thermal Pain Descriptors Watson and Babul. Neurology 1998;50:1837-41

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

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

19. 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

20. 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 Najib Babul, PharmD

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