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Background Analysis: US FDA Advisory Committee to Discuss Opioid Sparing Claims in Acute Pain Trials – NOV 15, 2018 (AADPAC-DSRM)


The US FDA has scheduled an Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) meeting for Thursday, November 15, 2018. The committee will discuss the assessment of opioid analgesic sparing outcomes in clinical trials of acute pain. The committee will be asked to comment on the trial design and endpoints of these studies and how to determine the clinical relevance of the results.


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.

FDA Considerations for 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.

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.

Opioid Sparing Outcomes

Among many efforts by the FDA to curb the opioid epidemic is their development of guidance to assist drug sponsors with the development of drugs that can spare the use of opioids. On August 29, 2018, the FDA Commissioner, Scott Gottlieb, announced that the Agency plans to issue guidance for opioid-sparing drugs for the treatment of acute pain by 2019. The upcoming guidance will set forth the FDA’s current thinking on how sponsors can demonstrate a clinically meaningful reduction in the use of opioid pain medications when used for acute pain.

The concept of incorporating “opioid sparing” endpoints in analgesic clinical trials was discussed earlier this year at a joint meeting of the AADPAC and the Drug Safety and Risk Management (DSRM) Advisory Committee, on February 14-15, 2018. The Committees reviewed a supplemental new drug application for Pacira Pharmaceuticals, Inc.’s EXPAREL (bupivacaine liposomal injectable suspension). The concept of “opioid sparing” arose during the committees’ discussion about the adequacy of safety data to evaluate the risks of EXPAREL. On this topic, the official FDA meeting minutes state, “Most committee members agreed that “opioid sparing” is not a valuable safety endpoint. One committee member added that data is needed to compare dose in relation to either pain intensity or functional outcome to determine the relationship between the two to provide context.” The Tarius Results Wire report for this meeting also summarized the discussion about opioid sparing, in which we noted, “The Committee briefly discussed the general concept of opioid-sparing as a drug benefit. Since Pacira was not seeking an opioid-sparing efficacy claim, the Committee mainly focused on the data to support the proposed new indication. But during the discussion of opioid-sparing, the Committee agreed it would be a desirable benefit for an analgesic because it might help to curb the current epidemic of opioid abuse. However, they felt that more work needs to be done in order to well-define what opioid-sparing means in the context of a clinical development program that could support a related claim. They commented that it would be important to show a reduction in opioid use that is related to levels of pain improvements or other functional outcomes, rather than a stand-alone reduction in opioid use.”

Other Pending Opioid-Related FDA Guidance

Along with the aforementioned guidance, the FDA has announced plans to issue the following additional opioid-related guidance in 2019:

1) Guidance to assist sponsors with the development of new non-opioid pain medications for chronic pain that can provide therapeutic alternatives to the use of opioids.

2) Guidance to outline a path for developing extended-release local anesthetics, which can serve as an alternative to the systemic use of oral opioid drugs. This guidance will address the clinical pharmacology, the proper evaluation of safety and efficacy, and the types of studies that may support approval of these products.

3) Guidance to recommend specific populations to pursue limited indications for the treatment of specific kinds of pain. Existing guidance typically requires a large number of studies for a general chronic pain indication, which can be difficult to implement because it is so broad.

4) Guidance to outline the information that the FDA will ask drug sponsors to provide to help assess the benefits and risks when new opioid pain drugs are put into development. This will include an updated framework for evaluating the risks associated with intentional or illicit misuse or abuse of drugs.

The FDA also intends to withdraw its existing analgesic guidance (“Guidance for Industry Analgesic Indications: Developing Drug and Biological Products”) in concert with the issuance of these guidances.

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: none Drug Name: none 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.