Lessons Learned from Opioid Addiction Trials

Rachel Skeete, MD, MHSMedical Officer

Division of Anesthesia, Analgesia, and Addiction Products (DAAAP)

Center for Drug Evaluation and Research

Food and Drug Administration

MOST MeetingMarch 25, 2015

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Key Lessons Learned:Probuphine Case Study

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Background: Probuphine (buprenorphine; ethylene vinyl acetate)

• Product/ClassProduct/Class: Implantable formulation of buprenorphine (BPN)• Sustained release of buprenorphine (BPN) for up to 6 months

• Dosage/AdministrationDosage/Administration:

Sublingual (SL) BPN induction implantation removal– INDUCTIONINDUCTION: SL BPN 12–16 mg/day ≥ 3 consecutive days prior to

implantation– IMPLANTATIONIMPLANTATION: 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 REMOVALROD REMOVAL: 6 months after implantation– CONTINUATIONCONTINUATION: Implant in opposite arm same day

• re-induction otherwise

Probuphine Efficacy and Safety Trials:PRO-8055 and PRO-8066

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

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

Assessments• Urine toxicology – thrice weekly collection

Results blinded• Self-report every 2 weeks

Early WithdrawalCriteria

•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 (+)

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Cumulative Distribution Function (CDF)

6Adapted from Sponsor Presentation at March 21, 2013, Advisory Committee Meeting

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Primary Efficacy Results, Weeks 1 – 24

% (-) 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 2 -

≥ 95 1 -

100 - -

PRO-806 ≥ 30 42 7

≥ 50 27 6

≥ 75 13 4

≥ 80 12 2

≥ 85 9 2

≥ 90 4 2

≥ 95 1 -

100 - -

CDF % (-) urines, PRO-805

CDF % (-) urines, PRO-806

Adapted from March 21, 2013, Advisory Committee Meeting Presentation

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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

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Probuphine (n=114)Placebo (n=54)

Lesson Learned: Treatment Response/Failure DefinitionsSubject-level results of urine samples – PRO-806

Week

Presented at Advisory Committee Meeting, March 21, 2013

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Lesson Learned: Placebo Failure/Placebo DropoutSubject-level use of SL BPN – PRO-805

Placebo (n=55) Probuphine (n=108)

Study Day

Presented at Advisory Committee Meeting, March 21, 2013

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Lesson Learned: Placebo Failure/Placebo DropoutSubject-level use of SL BPN – PRO-806

Placebo (n=54) Probuphine (n=114)

Study Day

Presented at Advisory Committee Meeting, March 21, 2013

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Lesson Learned: Treatment Retention ≠ Accrued Clinical BenefitSubject Disposition – PRO-805 & PRO-806

Disposition – n [%]

PRO-805Probuphine

N=108

PRO-805Placebo

N=55

PRO-805Probuphine

N=114

PRO-805Placebo

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 0 17 [31] 6 [5] 9 [17]

Subject Request 8 [7] 9 [16] 5 [4] 9 [17]

Lost to Follow-Up 10 [9] 4 [7] 9 [9] 3 [6]

Treatment Retention1.Early withdrawal based on supplemental buprenorphine use, but not urine toxicology

2.Clinic visits for daily treatment vs. implant

Adapted from March 21, 2013, Advisory Committee Meeting Presentation

Lesson Learned: Treatment Retention ≠ Accrued Clinical BenefitAllowing a Grace Period – PRO-805

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Weeks 17-24

Weeks 1-24

Presented at Advisory Committee Meeting, March 21, 2013

Lesson Learned: Treatment Retention ≠ Accrued Clinical BenefitAllowing a Grace Period – PRO-806

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Weeks 17-24

Weeks 1-24

Presented at Advisory Committee Meeting, March 21, 2013

Lesson Learned: Response Profile InterpretationCDF – PRO-805 & PRO-806

PRO-805 PRO-806

15Presented at Advisory Committee Meeting, March 21, 2013

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Lesson Learned: Response Profile Interpretation – Graphical Display Matters CDF -PRO-805

Presented at Advisory Committee Meeting, March 21, 2013

Key Lessons LearnedSummary

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Questions

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