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
Treatment failure criteria based on rescue medication use
Treatment response definitions based on drug use behavior
Treatment Failure/Treatment Response Definitions
Patients on placebo anticipated to have higher rescue needs
Treatment failures discontinued from the trial
Missing urines are considered opioid-positive
Study Design Elements Can Impel Placebo Failure/Bias toward Positive Result
Patients with longer time on-study are not always improving
Grace period presumed beneficial
Not guaranteed that patients will improve over time
Treatment Retention ≠ Change in Drug-Use Behavior
Relationship between use patterns and clinical benefit must still be understood and established
Graphical presentation can influence perception of results
Response Profile Approach

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
Study Design
24-week, P3, R, DB, PC trials in opioid-dependent adults
Treatments
(1) Initial Treatment: Target dose of SL BPN 12–16 mg/day
(2) Probuphine/Placebo Rods: 4 rods for 24 wks
Dose increase (+1) rod if supplemental SL BPN needs criteria met
Supplemental Buprenorphine
Criteria:
COWS > 12
Opioid Craving VAS > 20 mm
Patient request for dose increase
Obtained at clinic or pharmacy
Dose increase (+1 rod)
Supplemental needs
≥ 3 dys/wk in 2 wks or
≥ 8 dys in 4 wks

5. Probuphine Efficacy and Safety Trials: PRO-805 and PRO-806
Assessments
Urine toxicology – thrice weekly collection
Results blinded
Self-report every 2 weeks
Early Withdrawal
Criteria
Treatment Failure
Supplemental buprenorphine needs
Noncompliance
9 missed consecutive urine visits
6 consecutive counseling sessions missed
Endpoints
Cumulative Distribution Function (CDF):
CDF % opioid (-) urines, Weeks 1–24
Urine toxicology & self-report
Missed samples considered (+)

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

7. Primary Efficacy Results, Weeks 1 – 24
CDF % (-) urines, PRO-805
% (-) urines Weeks 1 – 24
Study
% (-) urines
% of subjects
Probuphine
Placebo
PRO-805
≥ 30 45 27
≥ 50 32 16
≥ 75 15 7
≥ 80 10 5
≥ 85 6 2
≥ 90 -
≥ 95 1
100
PRO-806 42 13 4 12 9
CDF % (-) urines, PRO-806
Adapted from March 21, 2013, Advisory Committee Meeting Presentation

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

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

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

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

12. Lesson Learned: Treatment Retention ≠ Accrued Clinical Benefit Subject Disposition – PRO-805 & PRO-806
Disposition – n [%]
PRO-805
Probuphine
N=108
Placebo
N=55
N=114
N=54
Early Withdrawal
37 [34]
38 [69]
41 [36]
40 [74]
Common Reasons
Non-Compliance
12 [11]
7 [13]
10 [9]
9 [17]
Treatment Failure
17 [31]
6 [5]
Subject Request
8 [7]
9 [16]
5 [4]
Lost to Follow-Up
4 [7]
9 [9]
3 [6]
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 Benefit Allowing 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 Benefit Allowing a Grace Period – PRO-806
Weeks 17-24
Weeks 1-24
Presented at Advisory Committee Meeting, March 21, 2013 14

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

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

17. Key Lessons Learned Summary
Challenges in Interpreting Results of Analyses
Treatment Failure / Treatment Responder Definitions
Findings inconsistent if all components not considered
Placebo Failure
Bias toward positive result when study design fosters placebo failure, and dropouts adjudicated as non-responders
Treatment Retention
Does not always equate to improvement, as patients may continue in study despite having minimal change or no change in drug use behavior
Response Profile / Graphical Representation
Statistical difference ≠ Clinically-meaningful difference universally
Choice of display impacts representation of results

18. Questions