Lessons Learned from Opioid Addiction Trials

1. Lessons Learned from Opioid Addiction Trials Rachel Skeete, MD, MHS Medical Officer Division of Anesthesia, Analgesia, and Addiction Products (DAAAP) Center for Drug Evaluation and Research Food and Drug Administration MOST Meeting March 25, 2015

2. Key Lessons Learned:Probuphine Case Study

3. Background: Probuphine (buprenorphine; ethylene vinyl acetate) • Product/Class:Implantable formulation of buprenorphine (BPN) • Sustained release of buprenorphine (BPN) for up to 6 months • Dosage/Administration: Sublingual (SL) BPN induction  implantation  removal • Induction: SL BPN 12–16 mg/day ≥ 3 consecutive days prior to implantation • Implantation: 4 rods inserted into inner side of upper arm 12–24 h post induction • 5th rod > 2wks later based on supplemental SL BPN needs • Rod Removal: 6 months after implantation • Continuation: Implant in opposite arm same day • re-induction otherwise

4. Probuphine Efficacy and Safety Trials:PRO-805 and PRO-806

5. Probuphine Efficacy and Safety Trials:PRO-805 and PRO-806

6. Cumulative Distribution Function (CDF) Adapted from Sponsor Presentation at March 21, 2013, Advisory Committee Meeting

7. CDF % (-) urines, PRO-805 Primary Efficacy Results, Weeks 1 – 24 CDF % (-) urines, PRO-806 Adapted from March 21, 2013, Advisory Committee Meeting Presentation

8. Lesson Learned: Treatment Response/Failure DefinitionsSubject-level results of urine samples – PRO-805 Placebo (n=55) Probuphine (n=108) Week Presented at Advisory Committee Meeting, March 21, 2013

9. Lesson Learned: Treatment Response/Failure DefinitionsSubject-level results of urine samples – PRO-806 Placebo (n=54) Probuphine (n=114) Week Presented at Advisory Committee Meeting, March 21, 2013

10. Lesson Learned: Placebo Failure/Placebo DropoutSubject-level use of SL BPN – PRO-805 Probuphine (n=108) Placebo (n=55) Study Day Presented at Advisory Committee Meeting, March 21, 2013

11. Lesson Learned: Placebo Failure/Placebo DropoutSubject-level use of SL BPN – PRO-806 Probuphine (n=114) Placebo (n=54) Study Day Presented at Advisory Committee Meeting, March 21, 2013

12. Lesson Learned: Treatment Retention ≠ Accrued Clinical BenefitSubject Disposition – PRO-805 & PRO-806 Treatment Retention • Early withdrawal based on supplemental buprenorphine use, but not urine toxicology • Clinic visits for daily treatment vs. implant Adapted from March 21, 2013, Advisory Committee Meeting Presentation

13. Lesson Learned: Treatment Retention ≠ Accrued Clinical BenefitAllowing a Grace Period – PRO-805 Weeks 17-24 Weeks 1-24 Presented at Advisory Committee Meeting, March 21, 2013

14. Lesson Learned: Treatment Retention ≠ Accrued Clinical BenefitAllowing a Grace Period – PRO-806 Weeks 17-24 Weeks 1-24 Presented at Advisory Committee Meeting, March 21, 2013

15. Lesson Learned: Response Profile InterpretationCDF – PRO-805 & PRO-806 PRO-805 PRO-806 Presented at Advisory Committee Meeting, March 21, 2013

16. Lesson Learned: Response Profile Interpretation – Graphical Display MattersCDF -PRO-805 Presented at Advisory Committee Meeting, March 21, 2013

17. Key Lessons LearnedSummary

18. Questions