You have heard described:

1. Risk Management of Modified-Release Opiate Analgesics: PalladoneSharon Hertz, M.D.Medical Team Leader, AnalgesicsDivision of Anesthetic, Critical Care, and Addiction Drug Products Center for Drug Evaluation and Research

2. You have heard described: • Roles of the FDA and DEA in risk management • Benefits of clinical use of opioids and data reflecting that use • Risks of misuse and abuse of opioids and data reflecting this abuse • Concerns about prescription opiate diversion

3. You have also heard: • General principles of risk management programs • Examples from existing non-opioid and opioid programs • Abuse liability of hydromorphone • Specific features of the Palladone RMP

4. Task at Hand Based on the discussion yesterday and today, does the Palladone risk management plan define a program that will likely result in safe use limit the potential for abuse and misuse without limiting access for appropriate patients?

5. Challenges for Risk Management Palladone • Avoidance of accidental/unintended exposure • Proper Patient Selection • Prevention of Misuse and Abuse

6. Approaches for Risk Management Palladone • Education/risk communication • Surveillance • Intervention

7. Education/Risk Communication • Healthcare providers • PI • CME programs • Brochures • Appropriate sales force training • Patients and Caregivers • PPI

8. Surveillance • Exposure data • National Prescription Audit (IMS Health) • National Disease and Therapeutic Index (IMS Health) • Patient Tracking Analysis Report (NDC Health)

9. Surveillance • Abuse data • DAWN • National Household Survey on Drug Abuse • TESS • RADARS • Adverse Events • Post-marketing AE surveillance

10. Surveillance: Limitations of Data Sources DAWN • Has been used as numerator • Reflects events resulting in emergency room visits or Medical Examiners cases • Distinguish between products for any given opioid? • Anticipated changes may limit evaluation of trends

11. Surveillance RADARS datasources: • Key Informant Network • Law Enforcement Drug Diversion Network • Drug Evaluation Network System • Poison Control Center Study • Focused studies

12. Surveillance: Limitations of Data Sources RADARS Key Informant Network • Uneven geographical distribution of informants • Only about half respond/survey • Different participants each survey • Sites with high rates - catchment areas likely greater than 3-digit zip code area • Denominator?

13. Surveillance: Limitations of Data Sources RADARS Law Enforcement Drug Diversion Study • Small number of participants • High turnover among participants • Data collection inconsistent

14. Surveillance: Limitations of Data Sources RADARS Drug Evaluation Network System • Limited sampling – mostly urban areas • Only adult treatment programs • High staff turnover at treatment programs

15. Surveillance: Limitations of Data Sources RADARS Poison Control Center Study • Limited sampling • only poison control calls

16. Risk Assessment • Numerator • Case definition- will this be abuse, addiction, misuse, diversion, dealers, problem prescribers? • Denominators • Patient exposure • Number of prescriptions dispensed • Kg sold • Population

17. Risk Assessment • Sensitivity of detection • A signal detection level: >5 cases/100,000 population in a 3-digit zip code

18. Risk Assessment • Interpretation • What are appropriate comparators? • Baseline • Level of signal that defines “problem” • Resolution of discrepancies • Ambiguous reporting responsibilities

19. Interventions • When • What • Who

20. Task at Hand Based on the information that has been presented at this meeting, and taking into account your earlier discussion and deliberation about risk management plans for modified-release opioids, does the Palladone risk management plan (including its proposed labeling and indications) define a program that will likely result in safe use of the product and limit the potential for abuse and misuse of the product while assuring that appropriate patients are able to receive the medication ?