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Background Analysis: US FDA Advisory Committees to Review Buprenorphine Sublingual Spray by INSYS – MAY 22, 2018 (AADPAC/DSRM)


The US FDA has scheduled a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) and the Drug Safety and Risk Management (DSRM) Advisory Committee for Tuesday, May 22, 2018.

The Committees will discuss a new drug application (NDA) for buprenorphine sublingual spray, submitted by INSYS Development Company, Inc. (INSYS), for the treatment of moderate-to-severe acute pain where the use of an opioid analgesic is appropriate. The Committees will also be asked to discuss whether this product should be approved. 

Indication Background

Description of Indication

Acute pain occurs as a sensation to alert us to possible bodily injury. The pain is typically sudden and sharp in nature and can be caused by many types of bodily injury (e.g., joint sprains, broken bones, dental problems, burns or cuts, childbirth). Acute pain usually disappears when the underlying cause of pain has been treated or has healed.

Chronic pain is pain that lasts more than 12 weeks. It can originate from an initial injury, such as a back sprain, or there may be an ongoing cause, such as illness. Sometimes the cause is unclear.

Product Background

Mechanism of Action

Opioid agonists are a class of drugs that reduce the perception of pain through binding to opioid receptors that are found in the brain, spinal cord, gastrointestinal tract, and other organs in the body.

Buprenorphine is a partial opioid agonist at the mu-opioid receptor and antagonist at the kappa-opioid receptor.

Due to its partial agonist properties, the effects of buprenorphine are understood to reach a “ceiling” at moderate doses, beyond which increasing doses of the drug do not produce the same increase in euphoric effects that would result from similarly increasing the dose of a full opioid agonist. Buprenorphine also has a long duration of action; this is believed to provide a more level drug effect compared to shorter-acting opioids, which cause highs and lows. These properties are thought to limit its attractiveness as a drug of abuse. INSYS also believes the aforementioned “ceiling” effect may lead to reduced risk for respiratory depression, which is a concerning side effect of opioids.

Due to its antagonist properties, at sufficiently high doses, buprenorphine blocks full opioid agonists from achieving their full effects, deterring abuse.

Approved Drug Products

Buprenorphine is an active ingredient of several FDA-approved products for the treatment of chronic pain that cannot be managed with a non-opioid analgesic, as well as several products for the treatment of opioid use disorder. US trade names for products containing buprenorphine include the following: Belbuca, Buprenex, Butrans, Bunavail, Probuphine, Suboxone, Subutex, and Zubsolv.

Buprenorphine has not been approved for the treatment of acute pain.

Description of Investigational Drug Product

INSYS buprenorphine sublingual spray is formulated using a proprietary technology intended to enhance absorption through the sublingual mucosa. INSYS believes it addresses an unmet need for physicians and patients who would like an alternative to the traditional opioids used to treat their moderate-to-severe acute pain.

Clinical Trials of Proposed Indication

Because the proposed product is a reformulation of a previously approved product, it is likely that NDA uses the 505(b)(2) regulatory pathway, which means that it relies in part on the demonstration of safety and efficacy from a previously approved buprenorphine application.

The NDA submission is supplemented with results from a phase 3 trial conducted by INSYS (ClinicalTrials.gov ID: NCT02634788). This trial was a multicenter, randomized, double-blind, multiple-dose, placebo-controlled study evaluating the efficacy and safety of three dosing regimens of buprenorphine sublingual spray (0.5 mg three times daily (“tid”), 0.25 mg tid, or 0.125 mg tid), and/or matching placebo in subjects with moderate to severe postoperative pain after bunionectomy.  322 subjects were randomized. The primary efficacy endpoint was the Summed Pain Intensity Difference relative to baseline over a period of 48 hours (SPID-48). The patient assessment of pain intensity utilized a numeric pain scale (11-point scale, with 0 = no pain to 10 = worst possible pain).

INSYS has reported the following results.

•           The primary efficacy endpoint was statistically significant at all doses studied.

•           Buprenorphine sublingual spray 0.5 mg tid demonstrated the largest reduction in SPID-48 and was statistically significant to placebo (p<0.0001).

•           The 0.25 mg tid and 0.125 mg tid doses also demonstrated statistically significant reductions in SPID-48 (p = 0.0108 and p = 0.0120, respectively). 

•           All treatments were generally well-tolerated.

Additional study results are posted at ClinicalTrials.gov.

Furthermore, INSYS has stated that data submitted to the FDA in the 120-day Safety Update to the NDA demonstrated that the product can be administered for 7 days without untoward effects.

A detailed review of the full NDA submission, including in-depth analyses by INSYS and the FDA, will be provided in briefing materials that will post ahead of the meeting. These materials will be summarized on the day they are posted in our subsequent report, named the Briefing Summary.

Regulatory Background

US Regulatory Considerations for Opioid Analgesics

The US is facing an epidemic of overprescribing, misuse and abuse of opioid drugs. The US Centers for Disease Control and Prevention (CDC) has reported that, in 2015, drug overdoses accounted for 52,404 US deaths, including 33,091 (63%) that involved an opioid.

In response to the epidemic, the FDA initiated an Opioid Action Plan (February 2016) and formed an Opioid Policy Steering Committee (May 2017). Among the actions the Agency is taking, the actions that are, or that may be, relevant to this meeting are as follows:

·      Requiring that all NDAs for an opioid product that does not have abuse-deterrent properties must be reviewed by an FDA advisory committee;

·      Requiring Risk Evaluation and Mitigation Strategies for immediate-release opioid products intended for use in the outpatient setting (Note: In FDA meeting materials for the November 1, 2017 joint meeting of the Psychopharmacologic Drugs Advisory Committee (PDAC) and the DSRM, the FDA noted that buprenorphine sublingual products have been increasingly identified in the illicit drug market, and it is known that they are diverted, abused, and misused.);

·      Exploring ways to change packaging in order to tailor how much drug physicians prescribe based on clinical need; and

·      Reassessing the risk-benefit approval framework for opioid-containing drug products.

US Regulatory Background for the Proposed Product

July 28, 2018 – PDUFA date

September 29, 2017 – NDA submission date. (NDA 209588).

Ex-US Regulatory Background for the Proposed Product

Tarius has not found information regarding ex-US development of sublingual buprenorphine spray by INSYS.

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: INSYS Development Company, Inc. Drug Name: buprenorphine Drug Class: partial opioid agonist Indication: pain

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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.