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Background Analysis: US FDA Advisory Committee to Review Proposed Abuse-Deterrent, Immediate-Release Oxycodone by SpecGx – NOV 14, 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 Wednesday, November 14, 2018. The committees will discuss a 505(b)(2) new drug application (NDA) for an immediate-release oral tablet formulation of oxycodone, named MNK-812, which is formulated with the intent to resist common methods of physical or chemical manipulation and to deter intravenous and intranasal abuse. 505(b)(2) NDAs are a type of abbreviated NDA that contain reports of investigations of safety and effectiveness where at least some of the information required for approval comes from studies not conducted by or for the Applicant and for which the Applicant has not obtained a right of reference or use. The MNK-812 NDA was submitted by SpecGx LLC (SpecGx), a wholly owned subsidiary of Mallinckrodt Pharmaceuticals. The Applicant proposes that MNK-812 be approved for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate, and they propose labeling that claims abuse-deterrent properties (ADP). The committees will also be asked to determine whether the Applicant adequately demonstrated that the ADP of the proposed product are sufficient to include this information in the product label, and whether the product should be approved.


Description of Indication

Acute pain is pain that occurs as a sensation to alerts us to possible injury. Acute pain is distinct from chronic pain, which 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; however, sometimes the cause is unclear.

Description of the Opioid Drug Class

Opioids are a class of small molecule drugs that are prescribed to treat moderate to severe pain. Opioids work by reducing the perception of pain through binding to opioid receptors found in the brain, spinal cord, gastrointestinal tract, and other organs in the body. The FDA has approved several opioid-containing products, which include the following active ingredients: fentanyl, oxymorphone, hydromorphone, morphine, hydrocodone, and oxycodone.

FDA Considerations for the Drug Class

The US is currently experiencing an epidemic of overprescribing, misuse and abuse of opioid drugs. Because opioids affect regions of the brain that are involved in reward mechanisms, many people experience a euphoric response. Abusers may take higher or more frequent opioid doses than prescribed or tamper with opioid products in order to administer them in ways that were not intended (e.g., manipulating an oral opioid for injection or to snort it) in an attempt to increase the euphoric affect, which is referred to as dose-dumping. Such misuse and abuse can lead to fatal respiratory depression. 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 (63.1%) that involved an opioid. Several US agencies have been undergoing efforts to evaluate and attempt to curb the opioid epidemic.

In February 2016, the FDA announced its Opioid Action Plan. Among the key components, the Agency said it will encourage the development of opioids with abuse-deterrent properties (ADP). Formulations with ADP target the known or expected routes of abuse, such as dissolving for injection or crushing for snorting, with the aim of making these routes of abuse more difficult. Since the science of abuse deterrence is relatively new, the formulation technologies and the analytical, clinical, and statistical methods for evaluating those technologies are rapidly evolving. In light of the increased pace of scientific development of ADP technology and related drugs, the FDA has frequently sought the joint input of the AADPAC-DSRM in related regulatory decisions.

In May 2017, the FDA established an Opioid Policy Steering Committee (OPSC) to explore and develop additional approaches or strategies the FDA can use to combat the opioid crisis. The Committee is comprised of senior FDA leaders as designated by the Commissioner and resides in the Office of Medical Products and Tobacco (OMPT). Since its establishment, the Opioid Policy Steering Committee meetings have included Scott Gottlieb, Peter Marks, Janet Woodcock, Jeffrey Shuren, Amanda Edmonds, John Martin, Melinda Plaisier, Rachel Sherman, and Theresa Toigo. Additional FDA staff participate in meetings, as needed, to provide additional information or expertise on particular topics.

In June 2017, the FDA requested removal of an oxymorphone product named Opana ER, based on a review of all available postmarketing data that demonstrated a significant shift in the route of abuse of Opana ER from nasal to injection following the product’s proposed ADP reformulation. Injection abuse of reformulated Opana ER was associated with a serious outbreak of HIV and hepatitis C, as well as cases of a serious blood disorder (thrombotic microangiopathy). This decision followed a March 2017 AADPAC-DSRM meeting, in which the committees voted 18-8 that the benefits of reformulated Opana ER no longer outweighed its risks.

In July 2017, the FDA held a public workshop to engage in a scientific discussion with expert panel members and interested stakeholders about the challenges in using the currently available data and methods for assessing the impact of opioid formulations with abuse-deterrent properties on opioid misuse, abuse, addiction, overdose, and death in the postmarket setting. The goal of the meeting was to discuss ways to improve the analysis and interpretation of existing data, as well as to discuss opportunities and challenges for collecting and/or linking additional data to improve national surveillance and research capabilities in this area.

In December 2017, the FDA held a public workshop to engage in a scientific discussion with expert panel members and interested stakeholders regarding the role of packaging, storage, and disposal options within the larger landscape of activities aimed at addressing abuse, misuse, or inappropriate access of prescription opioid drug products (opioids); guiding principles and considerations for the design of packaging, storage, and disposal options for opioids; integrating packaging, storage, and disposal options into existing health care and pharmacy systems, including both open and closed healthcare systems (e.g., a closed system such as the US Department of Veterans Affairs); data needs and how to address challenges in assessing the impact of packaging, storage, and disposal options in both the premarket and postmarket settings; and ways in which FDA could encourage the development and assessment of packaging, storage, and disposal options for opioids that have the potential to enhance opioid safety. For example, blister packaging can limit the number of pills dispensed and make it easier to track the number of doses that have been taken. Other options could improve upon storage and encourage prompt disposal to reduce the available supply and reduce the risk for third-party access, such as a child accidentally ingesting pills they found in a medicine cabinet. There are also technologies that could allow healthcare providers, pharmacists, or family members to monitor patient use of prescription opioids.

In January 2018, the FDA announced its 2018 Strategic Policy Roadmap, which defined new actions and refined ongoing actions within the Agency’s 2016 Opioid Action Plan. Among the announcements, the FDA said they will further support the development of opioids with ADP by exploring new methods for analyzing and evaluating ADP; evaluating the nomenclature used to describe ADP; facilitating development of science for generic development of these drugs; and, taking new steps to encourage the conversion of the market to effective opioids with ADP.

In July 2018, the FDA issued a large batch of product-specific guidances related to the development of generic drug products, including three revised product-specific guidances for opioid products with ADP. These guidances recommend specific in vivo studies and in vitro study considerations for abuse deterrence evaluations. The guidances are in addition to prior guidances that were issued in the fall of 2017 to guide development of generic opioids with ADP.

In August 2018, the FDA announced that they awarded a contract to the National Academies of Sciences, Engineering, and Medicine (NASEM) to help advance the development of evidence-based guidelines for appropriate opioid analgesic prescribing for acute pain resulting from specific conditions or procedures. The primary scope of this work will be to understand what evidence is needed to ensure that all current and future clinical practice guidelines for opioid analgesic prescribing are sufficient, and what research is needed to generate that evidence in a practical and feasible manner. In their announcement, the Agency referred to analyses suggesting that the first prescription for many common, acute indications could typically be for many fewer pills – maybe just a day or two of medication rather than a 30-day supply, which is typically prescribed.

In September 2018, the FDA finalized Risk Evaluation and Mitigation Strategies (REMS) for opioid products that expanded the existing REMS for extended-release and long-acting (ER/LA), which began in 2012, from ER/LA to immediate-release (IR) opioid analgesics intended for use in an outpatient setting.

Product Background

Description of Product

The investigational product MNK-812 is a reformulation of Roxicodone, an immediate-release oral tablet containing oxycodone hydrochloride. The reformulation is intended to resist common methods of physical or chemical manipulation and to deter intravenous and intranasal abuse.

Roxicodone was first approved in the US in August 2000. Its current indication is for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Products by Other Sponsors

The FDA-approved opioid-containing products with abuse-deterrent language in labeling are as follows: Egalet’s Arymo ER (morphine), Teva’s Vantrela ER (hydrocodone), Purdue’s Oxycontin (oxycodone), Targiniq ER (oxycodone/naloxone) and Hysingla ER (hydrocodone), Pfizer’s Embeda (morphine/naltrexone) and Troxyca ER (oxycodone), Collegium’s Xtampza ER (oxycodone), and Inspirion’s MorphaBond ER (morphine) and RoxyBond (immediate-release oxycodone).

Regulatory Background

US Regulatory Background

November 16, 2018 – PDUFA date

unknown – NDA 209774 submission date

Relevant Guidance

“Guidance for Industry: Abuse-Deterrent Opioids – Evaluation and Labeling” (final guidance) explains the FDA’s current thinking about the studies that should be conducted to demonstrate that a given formulation has abuse-deterrent properties. It also makes recommendations about how those studies should be performed and evaluated, and discusses what labeling claims may be approved based on the results of those studies.

Ex-US Regulatory Background

Tarius has not found any publicly-available information regarding ex-US development of MNK-812.

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: SpecGx Drug Name: oxycodone Drug Class: opioid 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.