FDA Panel Split on Approval of Non-Opioid for Surgical Pain

A US Food and Drug Administration (FDA) advisory panel was split on recommending approval of bupivacaine to control post-surgical pain.

During the daylong deliberations, many of the members of the Anesthetic and Analgesic Drug Products Advisory Committee said the data presented were too complex, making them difficult to interpret.

"This was a tough decision; I felt conflicted and confused from the beginning of the meeting," said meeting chair Ronald Litman, DO, professor of anesthesiology and pediatrics, Perelman School of Medicine, Philadelphia, who voted against the drug's approval.

Several of his colleagues thought the evidence was more compelling.

"We all know this is not a magic bullet, but it's certainly better than placebo and probably better than standard bupivacaine, at least in some procedures," said Basavana Goudra, MD, clinical associate professor of anesthesiology and critical care medicine, also of the Perelman School of Medicine, who was in favor of approval.

Over 50 million surgical procedures take place in the United States every year. Up to 70% of patients experience moderate to severe pain after surgery, with pain being most severe during the first 72 hours. Poorly controlled pain can have negative outcomes and delay recovery.

Up to 90% of surgical patients receive opioids for pain management, but these can have significant adverse events, including nausea, vomiting, constipation, sedation, and respiratory depression.

Fraught History

The new drug has been in the regulatory works for some time. A new drug application for Posimir was originally submitted in April 2013 but did not receive the go-ahead at that time because of a number of concerns.

The FDA issued a Complete Response Letter (CRL). The applicant then filed an appeal, which was denied.

The company submitted a Complete Response to the CRL that addressed issues pertaining to safety and inconsistent efficacy findings across surgical models and included information from a new trial. The advisory committee met to discuss this resubmission.

Posimir is an investigational extended-release formulation of bupivacaine, which is directly administered into a surgical site. Bupivacaine, an amide-type local anesthetic widely used in surgical practice, is the active ingredient, but the product also contains sucrose acetate isobutyrate and benzyl alcohol.

The new product is typically administered as a single dose through a needleless syringe into the surgical incision. Following administration, it releases bupivacaine at a stable rate, ranging from 10-20 mg/hour over the first 2 days and declining to 5 mg/hour or less by the end of the third day.

The company completed six efficacy studies in a range of surgical models that met FDA criteria for adequacy. All studies were randomized, double-blind, and multicenter, with a parallel-group design.

According to presentations by company representatives, two of the studies demonstrated significant evidence of analgesic effectiveness. The first was a soft tissue model (patients undergoing inguinal hernia repair); the second was an orthopedic model (patients undergoing arthroscopic shoulder surgery).

The primary efficacy endpoints of these trials were analgesic effectiveness (pain on movement over 72 hours assessed using a self-report 0-10 numerical scale) and systemic opioid use.

The soft tissue study included two dose groups: 2.5 mL (330 mg) and 5 mL (660 mg). The latter dose was used in the other studies and is the one proposed for commercial use.

This first efficacy study assessed 122 patients, mostly male and white, with a mean age of 49.3 years. Pain intensity was significantly lower for the 5-mL treatment group compared with the placebo group (mean difference, –1.14; 95% CI, –1.84 to –0.44; P = .003), which signaled a clinically meaningful benefit, according to the company.

The lower dose produced about half the analgesic effect relative to placebo, with a nonsignificant P value. This suggests a linear dose response and supports the choice to recommend the higher dose, said the company.

Less Opioid Use

The first study uncovered a trend for a reduced need for opioid rescue medication with the higher dose compared with placebo (–51% vs 70% over 72 hours postoperatively; P = .0664). At 15 days, almost half of treated patients needed an opioid compared to the placebo group (28% vs 47%; P = .09), the company reported.

The second study, which included 78 orthopedic patients in the comparison with placebo, also had positive efficacy outcomes. The mean difference in pain intensity in the active versus placebo arms was –1.27 (95% CI, –2.25 to –2.28; P = .012).

This study showed a significant reduction in postoperative opioid use with treatment compared to placebo. As well, the median time to first use of opioid rescue medication was significantly prolonged in those who received the active drug.

The company maintains that the opioid-use findings support the primary analgesic outcomes of the two studies. Less opioid use is hypothesized to result from reduced pain, and so provides confirmation of the clinical meaningfulness of the pain relief.

Four of the six efficacy studies in patients undergoing abdominal hysterectomy, laparoscopically assisted colectomy, laparoscopic cholecystectomy, and subacromial decompression, did not show significant differences in pain reduction compared with placebo.

However, because the point estimates for these comparisons favored the investigational drug in each study, the company believes this adds weight to the evidence supporting efficacy.

The company also provided safety data showing a stable bupivacaine release rate, safe bupivacaine systemic exposure, and no effect on wound healing. Durect reported that the adverse event profile was unremarkable, with the exception of an increased rate of bruise-like discoloration around the incision site, most often with larger incisions, in treated patients. The discoloration was not painful or tender and faded over 2-4 weeks, and the company considers it clinically inconsequential.

Durect's goal was not to establish evidence of superiority over immediate-release bupivacaine HCI (hydrochloride).

FDA officials presented somewhat different interpretations of some of the data.

"Not Clinically Meaningful"

According to Renee Petit-Scott, MD, a medical officer at the FDA Center for Drug Evaluation and Research, the statistically significant difference between treatment groups "is not clinically meaningful."

For example, she said the 1.1 to 1.3 difference above placebo treatment on an 11-point pain scale "does not offer any benefit to the patient."

She also outlined some safety concerns. Depending on the study, these included an increased incidence of surgical site bleeding, surgical site infection, somnolence, headache, pruritus, dysgeusia, and dizziness, as well as the bruising. Some adverse events may be because of the benzyl alcohol, she said.

Katherine Meaker, MS, an FDA statistical reviewer, noted that the majority of the treatment effect was observed in the first 24 hours after treatment.

Some committee members were concerned about accidental injection of the drug into a vein, and whether, in the case of such a scenario, the drug's effects are reversible.

Many who voted against approving the new product cited limited demonstration of efficacy.

"It's probably very slightly better than placebo, but the concern is that very slightly better than placebo, coupled with some potentially relatively minor safety concerns, makes the benefit-to-risk calculation really challenging," said Abigail Shoben, PhD, associate professor, Division of Biostatistics, College of Public Health, Ohio State University, Columbus.

Maura McAuliffe, PhD, professor, College of Nursing, and director, Nurse Anesthesia Program, East Carolina University, Greenville, North Carolina, was concerned about lack of demonstrated efficacy in the more invasive surgeries, especially orthopedic surgeries.

There were some questions about the drug's use in cases when local anesthesia is used during surgery, as all but one study involved patients receiving general anesthesia.

Litman said he "would love to see this drug work" as anything that extends post-op analgesia beyond 6 or 7 hours "would be a huge improvement." However, in the end, he determined that the drug's risks outweigh the benefits.

Some who voted to approve the drug, including Sherif Zaafran, MD, noted the promise of opioid-sparing. Minimizing the use of opioids in the post-op period, and even beyond, is an important goal, said Zaafran, who is vice-chair, Clinical Governance Board, US Anesthesia Partners Gulf Coast Memorial Healthcare System Acute and Chronic Pain Committee, and president of the Texas Medical Board.

"Pain scores are relatively useless and I worry that we're spending so much time focusing on that from the standpoint of efficacy. When you look at the decision by the patient to ask for their first dose of opioid medication, it's clearly different with this medication compared to others; that to me is a stronger point of efficacy," he said.

The final vote was six for, and six against, recommending approval of the product.

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