Background Analysis: US FDA Advisory Committee to Review Two New Opioid-Containing Drug Products– JAN 15, 2020 (AADPAC-DSRM)

Announcement

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 meeting for Wednesday, January 15, 2020. During the morning session, the committees will discuss a new drug application (NDA) for E-58425, by Esteve Pharmaceuticals, S.A. (Esteve), proposed for the management of acute pain in adults that is severe enough to require an opioid analgesic and for which alternative treatments are inadequate. During the afternoon session, the committees will discuss an NDA for an extended-release oral tablet formulation of oxycodone (proposed US trade name: Aximris XR), submitted by Intellipharmaceutics Corp. (Intellipharmaceutics), proposed for the management of moderate-to-severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.

Background – Morning Session

Description of Product

E-58425 is a fixed-dose combination product containing an opioid (tramadol, 44 mg) and a non-steroid anti-inflammatory drug (celecoxib, 56 mg). Esteve co-crystallizes these active ingredients with the intent of conferring unique properties (e.g., pharmacokinetics) that that translate to clinical advantages over traditional (non-co-crystallized) combination products.

Products by Other Sponsors

Tramadol is a component of a traditional fixed-dose combination product with acetaminophen that is marketed by Janssen Pharmaceuticals using the US trade name Ultracet. Each tablet combines 37.5 mg tramadol with 325 mg acetaminophen.

Clinical Trials

Regarding fixed-dose combination products, 21 CFR 300.50 (a.k.a.., “The Combination Rule”) states that: (1) each component must make a contribution to the claimed effects; and (2) the dosage of each component (amount, frequency, duration) must be such that the combination is safe and effective for the intended patient population. Thus, the NDA for Aximris is primarily based on the outcomes of a Phase 3, randomized, double-blind, controlled, parallel-group, clinical trial of E-58425 compared to tramadol, to celecoxib, and to placebo (ClinicalTrials.gov Identifier: NCT03108482). The primary objective of the trial was to establish the analgesic efficacy of E-58425 by demonstrating a superior effect compared to tramadol and to celecoxib for the management of moderate to severe acute post-operative pain for 48 hours after bunionectomy.

A summary of the data package in the NDA will be made available two days prior to the AADPAC-DSRM meeting, in briefing materials posted online by the FDA. These materials will be summarized on the day they are posted, in our subsequent report, the Briefing Summary.

Regulatory History – Morning Session

US Regulatory History

unknown – Prescription Drug User Fee Action (PDUFA) goal date

July 2019 – Esteve announced the FDA’s acceptance of the NDA (NDA 213426).

Notable Guidance

Opioid Analgesic Drugs: Considerations for Benefit Risk Assessment Framework (draft guidance)

Ex-US Regulatory History

Tarius did not find any reports in the public domain pertaining to ex-US development.

Background – Afternoon Session

Description of Product

The active ingredient in Aximris XR is oxycodone (dose strengths: 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg and 80 mg). The drug product has been formulated with properties intended to deter abuse. It was previously referred to using the proposed US trade name Rexista.

Products by Other Sponsors

Opioid-containing drug products that are FDA-approved with abuse-deterrent language in labeling include the following: 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), Inspirion’s MorphaBond ER (morphine) and RoxyBond (immediate-release oxycodone).

Clinical Trials

The NDA resubmission presumably addresses information requested by the FDA in their September 2017 complete response letter, in particular: 1) results of pharmacokinetic and pharmacodynamic abuse-deterrence studies (a.k.a., Category 2 studies); 2) results of human abuse liability studies (a.k.a., Category 2 studies); and 3) information about a blue dye component of the drug product, which that is released when the product is manipulated and intended to deter abuse. The initial NDA submission included only the results of in vitro abuse deterrence studies (a.k.a., Category 1 studies), as well as data demonstrating bioequivalence to OxyContin (oxycodone).

Regulatory Perspective – Afternoon Session

At past AADPAC-DSRM meetings for proposed abuse-deterrent opioids, the joint committee has noted that despite required post-market epidemiologic assessment of the actual abuse rates for drugs with abuse-deterrent properties, evidence to support an impact has been made are lacking. In general, when the joint committee has nonetheless voted in favor of approval of an abuse-deterrent opioid, they have cited the sponsor’s adherence to the FDA’s guidance on abuse-deterrence studies and oft-stated support of “incremental advances” in abuse-deterrent opioids, as one component of the FDA’s Action Plan to combat the current crisis of misuse, abuse and addiction of opioids.

Regulatory History – Afternoon Session

US Regulatory History

August 28, 2019 – PDUFA goal date

The PDUFA goal date for the FDA to decide on whether to approve Aximris XR was August 28, 2019. Due to the FDA’s temporary postponement of product-specific advisory committee meetings for opioid analgesics during 2019, the PDUFA goal date was not met.

February 28, 2019 – Acceptance date of the current NDA resubmission

September 25, 2017 – Date of a complete response letter (CRL) that was issued by the FDA in response to the initial NDA

July 26, 2019 – AADPAC-DSRM met to review the initial NDA. A majority of the joint committee, 22 of 23 members, voted to recommend against approval. Overall, the joint committee recommended a complete assessment of abuse-deterrence, which included the aforementioned additional categories of data described in FDA guidance. The joint committee also noted there was no assessment of the benefit or harm of the blue dye when taken orally or when abused nasally or intravenously, and that there was no evidence of a proven deterrent effect of the blue dye.

February 2, 2017 – Acceptance date of the initial NDA (NDA 209653) for review by the FDA. The proposed US trade name at that time was Rexista.

Notable 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.

·       Opioid Analgesic Drugs: Considerations for Benefit Risk Assessment Framework (draft guidance)

Ex-US Regulatory History

Tarius did not find any reports in the public domain pertaining to ex-US development.

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 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: Esteve Pharmaceuticals, Intellipharmaceutics Corp. Drug Name: tramadol and celecoxib, oxycodone Drug Class: opioid, non-steroid anti-inflammatory drug 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.