1. Specific Clinical/Regulatory Issues in Development of Drugs for Peripheral Neuropathy and Neuropathic Pain Gerald J. Dal Pan, MD, MHS Medical Officer Division of Anesthetics, Critical Care and Addiction Drug Products, FDA

2. Basic Challenge FFDCA: –“...substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof...” Challenge: –To operationalize the substantial evidence requirement into clinical trial design and clinical development planning for drugs to treat peripheral neuropathy and neuropathic pain.

3. Example A Company’s proposed claimed effect: –To slow or reverse the progression of diabetic polyneuropathy Trials design issues: –Appropriate outcome measure(s) No regulatory precedent/Few large-scale trials Composite versus single measure Magnitude of effect is important –Slowing progression versus arresting disease versus reversing disease –Role of electrophysiologic testing –Symptoms versus change in course of disease

4. Example B Company’s proposed claimed effect: –The treatment of chronic neuropathic pain due to diabetes mellitus Clinical trial design issues: –Appropriate outcome measure(s) Pain, function, quality of life Symptom characteristics Magnitude of effect is important –Role of potential confounders Severity of nerve dysfunction Level of diabetic control –Durability of effect

5. Example C Sponsor’s proposed claimed effect: –Treatment of chronic painful diabetic neuropathy and post-herpetic neuralgia Clinical development plan: –Degree to which data from one etiology of neuropathic pain can support data for another etiology of neuropathic pain –Generalizability of results to types of neuropathic pain not studied