FDA Rejects Sublingual Sufentanil for Pain Relief
Delivery device questioned
The FDA has rejected the new drug application (NDA) for Zalviso (sufentanil sublingual tablet system).
The agency’s complete response letter (CRL) contained requests for additional information on the Zalviso System — a hand-held, patient-controlled analgesia (PCA) device — to ensure its proper use. The requests included the provision of bench data demonstrating a reduction in the incidence of optical system errors, which may cause a premature change of the drug cartridge; changes to the instructions for use for the device; and additional data to support the shelf life of the product.
According to the product’s developer (AcelRx Pharmaceuticals), additional bench testing will be required and human-factors testing may be required to address certain items in the CRL. The FDA did not request additional human clinical studies.
Zalviso is designed to improve the management of moderate-to-severe acute pain in hospitalized adult patients by delivering a high-therapeutic-index opioid through a non-invasive route via a hand-held, pre-programmed PCA device.
Positive results were reported from three completed phase III clinical trials. 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 either knee- or hip-replacement procedures. In each of these trials, patients treated with Zalviso to manage their post-surgical pain reported a greater sum of the pain intensity difference versus baseline over 48 hours (SPID-48) compared with placebo-treated patients (P = 0.001 and P < 0.001, respectively).
A third phase III study — an open-label, active-comparator trial — compared Zalviso with intravenous (IV) PCA with morphine. This study demonstrated that:
- Zalviso was non-inferior (P < 0.001) to IV PCA morphine based on the primary endpoint of the patient’s global assessment of the method of pain control comparison 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 morphine for the PGA48 endpoint (P = 0.007). Statistically superior and non-inferior PGA comparisons for Zalviso compared with IV PCA morphine were also seen at the 24-hour and 72-hour time points.
- Secondary endpoints of the summed pain intensity, summed pain relief, and dropouts due to inadequate analgesia over the 48-hour study period were similar between treatment groups.
AcelRx said it would resubmit its marketing application for Zalviso by the end of the year, pending further discussions with the FDA.