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Background Analysis: US FDA Advisory Committee to Review Proposed Abuse-Deterrent, Extended-Release Oxycodone by Pain Therapeutics – JUN 26, 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, June 26, 2018. The committees will discuss new drug application (NDA) 022324, oxycodone extended-release capsules, submitted by Pain Therapeutics, with the proposed indication of the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. The product is intended to have abuse-deterrent properties based on its physicochemical properties. The proposed trade name for this product is Remoxy ER. The committees will be asked to discuss whether the data submitted by the Applicant are sufficient to support labeling of the product with the properties expected to deter abuse.

A portion of this meeting, from 8 am to 9:30 am (US ET), will be closed to permit discussion and review of trade secret and/or confidential commercial information (5 U.S.C. 552b(c)(4)). During this session, the committees will discuss the drug development program of an investigational opioid formulation with properties designed to deter abuse.


Description of Indication

Acute pain is pain that occurs as a sensation to alerts us to possible injury.

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.

Chronic pain can limit a person’s movements, reducing flexibility and strength. The pain associated with doing important and enjoyable activities for a person with chronic pain can cause emotional despair. Chronic pain also contributes to other health problems, such as fatigue, sleep disturbance, decreased appetite, and mood changes.

Description of Drug Class

Opioids are a class of small molecule drugs that are commonly 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 crisis.

In response to the 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 January 2018, the FDA announced its 2018 Strategic Policy Roadmap, which detailed several proposed actions within the Agency’s Opioid Action Plan, including:

• Re-examine and modernize the FDA’s framework for evaluating the pre- and post-market safety of opioid products based on risk and benefit considerations; including an evaluation of a product’s potential risks for illicit use or its potential for abuse.

• Address inappropriate prescribing of prescription opioids with new modifications to Risk Evaluation and Mitigation Strategies (REMS) programs that require, for example: training on non-opioid pain alternatives; training for prescribing related to immediate-release (IR) formulations of opioid drugs in addition to extended-release (ER) formulations (which had REMS prior to IR opioids); and, broader training that covers more health care providers who help manage patients with pain.

• Support development of opioids with ADP by exploring new methods for analyzing and evaluating abuse-deterrent features; evaluating the nomenclature used to describe these abuse-deterrent features; 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.

• Finalize policies to enable the OTC availability of naloxone.

• Generate further opportunities for stakeholder input with public hearings and workshops on opioid issues while the FDA explores new steps through innovations in regulation, packaging, and prescribing to reduce overall exposure to opioid drugs and address misuse and abuse. This could result in a new, comprehensive approach – using education, packaging, labeling and other tools – to encourage more appropriate prescribing and dispensing of opioid drugs.

• Advance policies to enable more product innovation in the development of non-addictive pain remedies; as well as the development of improved medication-assisted treatment (MAT).

• Implementing a new and more robust approach to the oversight of illicit controlled substances and foreign unapproved drugs imported into the US through international mail facilities (IMFs). Among other things, the FDA will pursue new resources in these facilities and will expand its efforts through the formation of a new Enforcement Task Force.

• Launch a public campaign to drive more widespread, appropriate adoption of medication-assisted treatment and take new steps to address the stigma and other obstacles to more widespread availability and appropriate prescribing of MAT.

Product Background

Description of Product

In company press releases, Pain Therapeutics says it developed Remoxy ER as an abuse-deterrent, ER, capsule formulation of oxycodone prescription drug for severe pain. Remoxy ER is designed to make oxycodone difficult to abuse, yet provide 12 hours of steady pain relief when used appropriately by patients with pain. Remoxy ER has a thick, sticky, high-viscosity capsule formulation designed to deter unapproved routes of drug administration, such as injection, snorting or smoking. The drug is designed to leave patients with a bad taste in their mouths if chewed rather than swallowed. Remoxy ER uses the Oradur gel matrix technology developed by Durect Corporation. This technology provides several unique properties aimed at deterring opioid abuse through snorting, injecting, smoking, chewing, and dissolving in drinks.

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

August 7, 2018 – PDUFA date

March 1, 2018 – NDA 022324 acceptance date

There is a long regulatory history of submissions to the FDA for Remoxy ER. In its early stages, Pain Therapeutics partnered with King Pharmaceuticals in the drug’s development. Pain Therapeutics first submitted an NDA for Remoxy ER to the FDA in June 2008. In December 2008, the company announced that they had received a Complete Response Letter (CRL) from the FDA. They reported that the FDA indicated additional non-clinical data would be required to support the approval of Remoxy ER, but that additional clinical efficacy studies had not been requested or recommended prior to approval.

In December 2010, Pain Therapeutics resubmitted the NDA for Remoxy ER. In June 2011, the company, at the time partnered with Pfizer, after Pfizer’s acquisition of King Pharmaceuticals, announced that the FDA again had issued a CRL for the NDA submission. Pain Therapeutics reported that the June 2011 CRL raised concerns related to the Chemistry, Manufacturing, and Controls (CMC) section of the NDA, as well as other issues. They said that certain drug lots showed inconsistent release performance during in vitro testing, and it was not whether the performance issues were due to artifacts of the testing method or manufacturing deficiencies. Following these developments, Pfizer discontinued their agreement with Pain Therapeutics regarding Remoxy ER in 2014.

In March 2016, Pain Therapeutics again resubmitted an NDA to the FDA for Remoxy ER. Later, in September 2016, Pain Therapeutics said that it had received a CRL from the FDA. The company said that this CRL focused on the ADP of Remoxy ER, as well as proposed drug labeling. Pain Therapeutics provided the following details of the FDA’s requests for additional information to support abuse-deterrent properties for Remoxy ER:

·       To support a potential drug label claim against abuse by injection: the FDA advised the company to repeat an injectability/syringeability study using thin films of drug, smaller volumes of solvents, additional mixed solvents and alternative extraction methods and syringe filter.

·       To support a potential drug label claim against abuse by inhalation, the FDA advised the company to repeat a volatilization study using the same thickness for each drug to increase surface area.

·       To support a potential drug label claim against abuse by snorting, the FDA advised the company to conduct an intranasal abuse potential study in human volunteers (i.e., not the animal data that had been submitted) with drug applied directly inside the human nasal cavity.

Related to the CRL, on September 8, 2016, the Office of Prescription Drug Promotion (OPDP) within the Center for Drug Evaluation and Research (CDER) sent an Untitled Letter warning Pain Therapeutics and Durect about the promotion of Remoxy ER on both drugmakers' websites. The Untitled Letter said that the companies’ presentation of the drug included statements that were “phrased as established facts” rather than acknowledging the experimental status of the drug.

Relevant Draft Guidance

General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products (March 2016)

Ex-US Regulatory Background

Tarius has not found any publicly-available information regarding ex-US development of Remoxy ER.

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: Pain Therapeutics Drug Name: oxycodone extended-release 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.