FDA Panel Gives Cautious Thumbs Up to Opioid Delivery System

Pauline Anderson

January 13, 2016

As the United States deals with a growing opioid crisis, an implantable formulation of buprenorphine has moved a step closer to being available for the maintenance treatment of opioid addiction.

The US Food and Drug Administration's (FDA's) Psychopharmacologic Drug Advisory Committee voted in favor of approving a new drug application (NDA) for probuphine (buprenorphine hydrochloride and ethylene vinyl acetate) subdermal implant, which promises to be less subject to diversion, abuse, and misuse than other formulations.

"Clearly, there was no evidence of significant risk using this agent, and there is evidence of significant benefit, and hopefully great promise once it's actually out there," said Thomas Grieger, MD, staff psychiatrist, Maryland Department of Health and Mental Hygiene, Thomas B. Finan Center, Cumberland, who echoed the sentiments of many on the panel.

Although the committee determined that the efficacy, safety, and risk/benefit profile of the medication support the application's approval, many committee members voiced concerns about elements of the noninferiority analysis used in the assessment and about potential labeling being clear as to the population being treated.

Sustained Delivery

Probuphine was developed as a treatment for opioid dependence that is a potentially safer alternative to methadone. It provides sustained delivery of buprenorphine, a partial agonist at the μ- opiate receptor, for up to 6 months by way of rods that are inserted subdermally into the upper arm.

Unlike sublingual buprenorphine (SLBPN), probuphine is difficult to divert or abuse or be accidentally ingested by small children. It also offers the possibility of improved adherence to treatment and patient convenience.

However, because it must be surgically inserted and removed, its administration requires special training.

The original NDA was submitted for approval in October 2012. It included two phase 3 placebo-controlled trials that demonstrated superiority over placebo in treating new entrants to treatment with buprenorphine.

The FDA deemed the dose in this initial submission to be too low to be effective for a broad population of patients. That application was not approved, but the FDA encouraged the company to study a higher dose of probuphine.

At this latest advisory committee meeting, the company (Braeburn Pharmaceuticals, Inc, on behalf of Titan Pharmaceuticals) presented data from a new study (PRO-814).

The multisite, double-blind, double-dummy study included 177 adults, the majority of whom were white, who were clinically stable while receiving a maintenance dose of 8 mg/day or less of SL BPN. Many of these patients had been under treatment for long periods prior to entering the study.

In addition to enrolling clinically stable patients, the study had other novel features, such as the objective of demonstrating the noninferiority of probuphine over an active control (SLBPN) and infrequent verification of abstinence from illicit drug use (because stable patients receiving established treatment would not ordinarily be seen regularly, this was seen as a barrier to participation).

The FDA has historically been reluctant to agree to noninferiority trials of drugs for opioid dependence, but some flexibility was deemed appropriate because of the potential public health benefits of an implantable formulation.

During the study, 10 urine toxicology samples were taken (six scheduled and four random). However, a significant percentage of patients missed in providing urine samples.

For the primary outcome of noninferiority to SLBPN, the company selected a 20-point noninferiority margin based on an estimated treatment effect of at least 75% for the active comparator and a maximum treatment effect of 25% in the absence of treatment.

FDA Reanalysis

The study showed that the percentage of patients who responded to treatment was 96.4% for probuphine compared with 87.6% for SLBPN. This met the statistical criterion for noninferiority (0.088; 95% confidence interval, 0.009 - 0.167). The proportion of responders also suggested that probuphine is superior to SLBPN.

Noninferiority was demonstrated in all secondary endpoints: analyses of illicit opioid use by month; of craving; of withdrawal symptoms; and of supplemental use.

The sponsor excluded from the intention-to-treat analysis three patients who had received the implants (two were lost to follow-up, and one was incarcerated).

In addition, a number of patients needed supplemental SLBPN (15 in the probuphine group and 13 in the SLBPN group).

An FDA reanalysis of the data addressed a number of issues, including missing data and rescue use. This analysis nevertheless found evidence of noninferiority (although not superiority) for the study medication.

A number of committee members applauded the FDA for its rigorous and thorough reanalysis of the data.

The company presented safety data from 309 patients who were treated with probuphine. The overall safety was found to be consistent with the known safety profile of buprenorphine. Rates of mild to moderate implant-related adverse events decreased with improved equipment, procedures, and training.

However, the implant involves surgical insertion and removal. Prescribers generally lack surgical training and may not practice in environments that would allow them to perform the insertion or removal procedures or to manage complications.

To address this, the company has developed a training program that includes practice of insertion and removal of the rods using a pork tenderloin model and that includes a certification examination. The company has several master trainers available at various sites across the country.

In addition, the company has designed a risk evaluation and mitigation strategy intended to establish a closed distribution system that ensures that probuphine is only distributed directly to certified healthcare providers and that implants are inserted and removed only by certified providers.

The company expects that general practitioners and psychiatrists will be the largest group of prescribers for this medication, according to Behshad Sheldon, president and chief executive officer of Braeburn Pharmaceuticals.


Not all committee members felt that the training program is adequate. "Practicing on pork loin doesn't do it for me; it needs to be something more," said Dr Grieger.

Laura McNicholas, MD, PhD, clinical associate professor of psychiatry, Perelman School of Medicine, University of Pennsylvania, asked how many psychiatrists have done any suturing in the past 10 years. She also wondered whether the distribution system would mean a "paperwork nightmare" for offices.

David Pickar, MD, adjunct professor of psychiatry, Johns Hopkins Medical School, Baltimore, Maryland, noted that a bigger issue is getting the product to enough patients ― whether it is from general practitioners, psychiatrists, or others.

During an open public hearing, committee members heard from experts and patients about the epidemic of opioid abuse. They learned that 4.3 million Americans abuse opioids each year, and that 26,000 Americans died from opioid-related overdoses in 2014.

They also heard about the need for better treatments of opioid addiction and about barriers to treatment, which include long waits, logistical problems, such as long distance from treatment facilities, and medication diversion.

Opioid addicts have to deal with societal stigma and loss. Some told tearful stories of lives dramatically affected and families torn apart emotionally and financially by addiction.

Speakers stressed that addiction is a brain disease that does not discriminate on the basis of age, geography, or socioeconomic circumstance. One former addict who has been "clean" for 4 years ― a firefighter and a grandfather ― said, "I'm the poster person for 'it can happen to anybody.' "

The committee also heard that opioid addicts are a difficult population to treat. Challenges include psychosocial problems, comorbid psychiatric and medical disorders, and problems with the justice system.

The new implanted medication "will save some folks' lives. You heard from the public how intense and awful these experiences are for everybody involved," said Dr Pickar.

Dawn Ionescu, MD, Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, in Boston, noted the novelty of the new product. "It's an example of psychiatry breaking through the status quo that we currently have, thinking outside the box," she said.

In their discussions, many committee members stressed the need for clear labeling about the appropriate patient population for the implants and how to manage breakthrough withdrawal, relapse, and polysubstance abuse.

"I think there needs to be something in the labeling about how to manage supplemental doses and what the implications of supplemental doses are," said Dr McNicholas.

Mixed Feelings, Multiple Caveats

Although she voted in favor of approving the applications, Kathleen Carroll, PhD, Albert E. Kent Professor of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, who joined the discussion by telephone and email, said she did so with "mixed feelings and multiple caveats." One of her concerns was having a clearer definition of what constitutes a "stable" patient.

Adam Gordon, MD, professor of medicine and clinical and translational sciences, University of Pittsburgh and VA Pittsburgh Healthcare System, was also concerned about stability being well defined. "I worry post marketing whether we're going to have a lot of aberrant behaviors, aberrant use of this medication in a very vulnerable population.... In general, I think we will have a lot of people on supplementary doses."

Not everyone thought the evidence was compelling enough to warrant approval of the application (the vote was 12 in favor and 5 against). One of those who voted against approval was Acting Committee Chairperson Judith Kramer, MD, professor emeritus of medicine, Duke University School of Medicine, Durham, North Carolina.

Dr Kramer said she was "dismayed" by what she considered a less than very rigorous approach on the part of the sponsor "in terms of things like deciding to leave out three patients and then claiming that it's really superior" to sublingual buprenorphine.

"I'm very concerned about the precedent this sets," said Dr Kramer. Her other concerns were about training, lack of "strategy," and confusion about what the goal is for treating opioid addiction.

"What are we actually doing? It doesn't appear we're trying to withdraw people, because the specialists say that at this level, if these patients come off, 75% to 80% will be using, so we're talking about long-term treatment, maintenance treatment, but we haven't studied that."

Margaret Kotz, DO, professor of psychiatry and anesthesiology, Case Western Reserve University School of Medicine, and director, Addiction Recovery Services, University Hospitals Cleveland, who also did not support approval, expressed concern about long-term treatment as well. "What do you do after 2 years is a huge question for me."

The implanted rods can be replaced every 6 months, but only four sites for implantation have been evaluated. The company did say it will be investigating other sites, such as the abdomen and lower back.

The biggest "elephant in the room" is the problem of access, said Dr Kramer. "People aren't getting treatments that are available because of a law that limits the number of patients a practitioner, who is willing to treat more, could treat."

Asked what additional developments the sponsor should take, several committee members mentioned studying a more diverse population and different doses and exploring how the product could be extended beyond 2 years.

Source: Webcast of FDA Center for Drug Evaluation and Research (CDER) Psychopharmacologic Drugs Advisory Committee meeting, January 12, 2016.


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