The Unimpressive FDA Clinical Labeling for Sublingual Buprenorphine

Update: For a later blog that adds depot injection and adds the context of Medicare OTP rulemaking, here.
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It is a truism today that medication-assisted management is best for opioid disorders.  One common form is sublingual, once-a-day buprenorphine (Subutex).  What does the FDA labeling say regarding clinical trials? See the current, online FDA labeling -  Here.

The initial US approval is stated as 2002, labeling updated in 2017 and 2018.   SUBUTEX buprenorphine sublingual tablets is "indicated for the treatment of opioid dependence."   Also, use "should be part of a complete treatment plan that includes counseling and psychosocial support."

I'm used to seeing fairly complete clinical trial descriptions on drug labeling (or device labeling) including graphs, outcomes, etc.  Not here.   Three studies are briefly and incompletely described.
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It looks like in total, across three studies, 575 patients got Suboxone (buprenorphine/naloxone), and 2450 got Subotex (sublingual buprenorphine).  All trials used comprehensive therapy with psychosocial counseling.

In a double blind placebo and active-control study, 326 heroin addicts got Subotex or placebo or Suboxone.  Clinic dosing was provided M-F and home dosing on weekends.  Both drugs had "statistically higher" negative urine tests than placebo.   The degree of difference and the time course don't appear to be stated.

A second study provides time course information.  162 patients were randomized to (a) ethanolic sublingual buprenorphine, or (b) low dose active control, with a 16 week maintenance phase and a 7 week detox (withdrawal) phase.   Doses were tapered 20-30% per week during the taper phase.  " buprenorphine was  more effective than the low dose of the control, in keeping heroin addicts in treatment and in reducing their use  of opioids while in  treatment."  The degree of difference isn't stated.

A third study also provides time course information.  731 subjects were randomized to one of four doses of "ethanolic buprenorphine solution," at 1, 4, 8, 16 mg.  Maintenance for 16 weeks.   Based on "retention in treatment and percentage of negative urine samples," they found that "the three highest tested doses were superior to the 1 mg dose."   No degree of difference is stated.   Doses used here should be crosswalked to slightly higher sublingual-tablet dosing (e.g. 16 mg ethanolic = 24 mg sublingual tablet).

Analysis

The on-label FDA data, usually considered a gold standard for drug approvals, is very weak.

• In some studies, patients had daily attendance at a clinic, something that wouldn't happen with real-world buprenorphine scrips.   
• All patients were in controlled clinical counseling environments that were funded and tracked as part of the drug study. 
• None of the labeled clinical studies reported the scale of outcome at all. 
• (Were there 50% more clean urine samples ... or 5% pr 1%?)  
• The largest of the three studies involved 16 week therapy and then a 7 week taper down to zero; nearly all popular press I read emphasizes long-term use of buprenorphine.   

There may be other data on the effectiveness of long term buprenorphine, and on modern real-world outcomes in clinical use, but it's completely absent from the FDA labeling.  The lack of any meaningful outcome data, including scale-of-impact, in the drug labeling was surprising.