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FDA Rejects Request for Meeting on Pain-Drug Device

Product received regulatory ‘thumbs down’ last July

The FDA’s Division of Anesthesia, Analgesia, and Addiction Products (DAAAP) has turned down a request for a special meeting to discuss safety issues regarding the Zalviso patient-controlled analgesia (PCA) system (AcelRx Pharmaceuticals), a noninvasive device designed for patients to self-administer sublingual tablets of the opioid analgesic sufentanil without the need for traditional intravenous (IV) systems.

The Zalviso PCA device has been at the heart of a nearly year-long dispute between AcelRx and federal regulators. In July 2014, the FDA rejected the new drug application (NDA) for Zalviso, citing concerns over optical system errors, as well as the shelf life of the sufentanil tabs that the device uses. In March 2015, the FDA told AcelRx that a human clinical study of the device was required to evaluate the risk of accidental dispensing and the overall risk of dispensing problems. Last week, the agency again maintained that AcelRx should conduct additional clinical trials to ensure proper safety standards.

A spokesman for AcelRx said that the company will be considering “all options to determine a pathway forward for Zalviso,” including the possibility of seeking dispute resolution through one of the FDA-prescribed pathways as well as conducting additional clinical studies.

According to AcelRx, Zalviso met the primary endpoints in two double-blind, placebo-controlled, phase III registration studies conducted in patients who had undergone major open-abdominal surgery or orthopedic surgery that involved knee- or hip-replacement procedures. In each of these trials, patients treated with Zalviso to manage their postsurgical pain reported a greater sum of the pain-intensity difference to baseline over 48 hours (SPID-48) compared with placebo-treated patients (P = 0.001 and P < 0.001, respectively). Adverse events considered possibly or probably related to treatment were generally mild to moderate in nature and were similar between Zalviso- and placebo-treated patients, with the exception of itching, which was significantly greater (P < 0.05) in the Zalviso group.

In addition, an open-label, phase III trial comparing Zalviso with IV PCA with morphine demonstrated that:

  • Zalviso was noninferior (P < 0.001) to IV PCA with morphine based on the primary endpoint of the patient global assessment (PGA) of pain control over the 48-hour trial period (PGA48), as determined by the combined percentage of patients with PGA ratings of “good” or “excellent.”
  • A secondary comparison of the primary endpoint demonstrated that Zalviso was statistically superior to IV PCA with morphine for the PGA48 endpoint (P = 0.007). Statistically superior and noninferior PGA comparisons for Zalviso versus IV PCA with morphine were also seen at 24 and 72 hours.
  • Secondary endpoints of summed pain intensity, summed pain relief, and dropouts due to inadequate analgesia over the 48-hour study period were similar between the two treatment groups.

Zalviso provided a significantly faster reduction in pain intensity compared with IV PCA with morphine during the first 4 hours of treatment. In addition, both nurses and patients rated Zalviso significantly higher for overall satisfaction and ease of care compared with IV PCA with morphine.

AcelRx is developing another noninvasive pain-treatment system, ARX-04, which has applications for use in military personnel as well as in civilians. The company reported dosing the first patient in a phase III trial to evaluate the efficacy and safety of ARX-04. The system is a single-use, 30-mcg sufentanil sublingual tablet in a disposable, prefilled, single-dose applicator.

Sources: BioSpace; May 5, 2015; and Zalviso; 2013.

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