# Presentation: 904021

##  Analgesic Drug Development for Neuropathic Pain Methodologic Issues

- Najib Babul, PharmD
- TheraQuest Biosciences
- nbabul@theraquestinc.com

## 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)

- Najib Babul, PharmD

## 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?

## 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”

- 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

- Babul and Hagen, American Society for Clinical Pharmacology & Therapeutics, March 2002

- Najib Babul, PharmD

## 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?*

## 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

## Slide 13

- Najib Babul, PharmD

## Slide 14

- Najib Babul, PharmD

## What to Measure in Neuropathic Pain Studies?

## 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

- Najib Babul, PharmD

## Pain Characteristics

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

- Najib Babul, PharmD

## Pharmacologic Response in PHN

- 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

- Najib Babul, PharmD

##  Analgesic Drug Development for Neuropathic Pain Key Methodologic Issues

- Najib Babul, PharmD
- TheraQuest Biosciences
- nbabul@theraquestinc.com