FDA Panel Delivers Mixed Reviews for Two New Opioids

Pauline Anderson

October 15, 2018

A US Food and Drug Administration (FDA) advisory committee met twice late last week to discuss two opioid pain medications — one an intravenous preparation, the other a sublingual tablet — with very different outcomes.

The Anesthetic and Analgesic Drug Products Advisory Committee narrowly voted against approving the oliceridine opioid injection (Trevena Inc).

However, committee members voted 10-3 in favor of approving the 30-μg sufentanil tablet (proposed name, Dsuvia;AcelRx Pharmaceuticals, Inc).

"We are pleased with the Advisory Committee's recommendation to approve Dsuvia as a treatment in medically supervised settings for adults experiencing moderate-to-severe acute pain," Pamela Palmer, MD, PhD, chief medical officer and cofounder of AcelRx, said in a press release.

"We believe Dsuvia represents an important non-invasive acute pain management option with potential to significantly improve the current standard of care."

Potentially Lethal?

The advisory committee chair — Raeford E. Brown Jr, MD, professor of anesthesiology and pediatrics, University of Kentucky, Lexington, and chair, Section on Anesthesiology and Pain Medicine, American Academy of Pediatrics, who was unable to attend the meeting, feels very differently.

In an interview with Medscape Medical News, Brown expressed his concern about allowing an opioid as potent and potentially lethal as this one onto the market. He's also worried about the lack of appropriate postmarketing education for prescribers.

"The FDA's inability to enforce controls, the potency of the drug, and the ease with which it will be diverted are some of the reasons why I would never consider this product for marketing in the US," said Brown.

Sufentanil is a synthetic opioid analgesic that is five to 10 times more potent than its analogue, fentanyl (multiple brands). It's currently marketed for IV and epidural anesthesia and analgesia.

The new sufentanil sublingual preparation was designed for rapid pain relief. Its onset of action is as little as 15 minutes, and it provides about 3 hours of analgesia.

The single-dose, prefilled disposable packaging should mitigate the possibility of dosing errors, misuse, and diversion, according to background materials from AcelRx.

The company believes there's a need for noninvasive opioid analgesics that don't require swallowing, because some patients have difficulty taking oral medication and may not have access to IV opioids.

If approved, this product would be the first sufentanil analgesic for sublingual use.

During the advisory committee meeting, committee members, FDA staff, and company representatives discussed efficacy and safety data.

One phase 3 placebo-controlled trial presented by the company included 161 adult patients who experienced acute pain following abdominal surgery. Patients reported pain on a 11-point numerical rating scale.

That study showed a statistically significant difference in pain intensity at 12 hours between treatment groups (mean difference with placebo, 12.7; 95% confidence interval, 7.2 - 18.2; P < .001).

Safety Concerns

Efficacy was supported by results of secondary outcomes, including time to first use of rescue medication and amount of rescue medication used during the first 12 hours.

Another study in patients who underwent bunionectomy also showed the intervention significantly reduced pain compared to placebo.

Adverse events (AEs) were generally consistent with those associated with opioids in the postsurgical setting. The most common were nausea, headache, and vomiting, with nausea and vomiting occurring more frequently in the group taking sufentanil compared to the group taking placebo.

The company reported that AEs leading to discontinuation occurred at the same frequency in the treatment group as in the placebo group. Respiratory events were rare, the most common being decreased oxygen saturation.

The FDA had earlier flagged two safety concerns. These include possible AEs in patients who require the maximal proposed dosing, and the risk for misplaced pills (they're small in size), which could contribute to abuse and accidental exposure. The company had resubmitted a new drug application for consideration.

To address the first concern, the company reduced the maximum daily dose from 24 to 12 tablets per day and provided new pooled safety data. To address the second, the company modified directions for use and carried out a further human factors validation study.

The new results showed that although the rate of opioid-related gastrointestinal AEs were generally higher in patients who took the maximal daily dose, the occurrence of respiratory AEs, severe AEs, and AEs leading to discontinuation were comparable between higher- and lower-dose groups.

The company emphasized that the product is not intended for home use. Availability would be limited to certified healthcare facilities; the drug would not be distributed through retail pharmacies.

"The availability of a single-dose, non-invasive opioid, like Dsuvia, could significantly improve my ability to effectively, efficiently and safely alleviate acute pain experienced by my patients," David Leiman, MD, clinical assistant professor of surgery, University of Texas at Houston, and director, HD Research Corp, was quoted as saying in the company press release.

Diversion, Abuse, Death

In Brown's view, though, sufentanil poses substantial risks for respiratory depression, diversion, abuse, and death.

Currently, the drug is restricted to IV use by professionals such as anesthesiologists who have some understanding of its lethality, said Brown. "It's really a drug used in the operating room where there are airway management experts available," he said.

Outside that environment, however, clinicians across the United States have little experience with this drug, said Brown.

Sufentanil is "extremely divertible," he said. "We have learned a hard lesson in the US that if you put a drug on the market, it will be diverted, and if it's diverted, people will die."

The drug is so potent that people "will become rapidly addicted to it" and may be in danger of overdosing or "rapidly transitioning" to heroine if it's not available, said Brown.

For the drug to be restricted to closely controlled settings, prescriber education needs to be guaranteed, something that Brown said is not currently the case. All too often, he has seen the same scenario "pan out" with other opioids over the years.

"There's the suggestion that a drug will be fine because it will be closely monitored, and then it's not. The FDA realistically does not have the statutory authority, or the will, to go after people who are using these drugs inappropriately," he said.

Brown has let his views be known to the FDA. He said he "begged" the agency not to hold the advisory committee meeting while anesthesiologist members like himself were unavailable (they were attending the American Society of Anesthesiologists in San Francisco), but the meeting went ahead anyway.

He's convinced that had he attended, the discussion would have been different, as would the vote.

He sees himself as the "voice of reason" concerning public health and does not feel it's his role to "protect the profit margin" of the pharmaceutical industry.

Experts weighing approval of opioids should be "very circumspect" about their decisions, said Brown. "This is very different from an oncologic drug or an asthma drug or a biologic drug; these are drugs that kill and addict, and we have to worry about public health."

Brown wasn't the only one with concerns. Meena Aladdin, PhD, a health researcher with Public Citizen's Health Research Group, was scheduled to testify against approving sufentanil sublingual before the FDA panel.

The drug "does not offer any unique advantages over the numerous available FDA-approved opioid products for treating acute pain, and thus does not fill any unmet medical need," said Aladdin in a press release issued by Public Citizen. "However, it does pose unique risks of serious harm if it's misused or abused or if accidental exposure occurs."

Olicerine Decision

At another meeting, the advisory committee considered a new drug application for oliceridine 1 mg/mL injection for the management of moderate to severe acute pain in adults for whom an IV opioid is warranted. As with sufentanil, this product would be used within a hospital or other controlled clinical setting.

Oliceridine is the first of a new class of μ-opioid receptor ligands that selectively activates the G-protein pathway, which is associated with analgesia, and reduces activation of the β-arrestin pathway, so should avoid respiratory depression and gastrointestinal dysfunction.

The drug was designed to provide analgesia as effectively as morphine, with faster onset of action, less respiratory depression, less slowing of gastrointestinal motility, and less sedation compared with morphine. Its onset of action is within 5 minutes, and effects lasting 1 to 3 hours.

It comes in three doses — 0.1 mg, 0.35 mg, and 0.5 mg. The company is seeking approval for the 0.1-mg and 0.35-mg doses.

The drug's clinical development program included three phase 3 studies in patients after abdominal or bunion surgery, as well as other medical and surgical patients. The drug was compared with placebo and IV morphine, a drug frequently used in the postoperative setting.

According to the FDA's analysis, all three doses of oliceridine in one study demonstrated a statistically greater reduction in pain intensity than placebo. However, so too did morphine.

In the second study, the 0.35- and 0.5-mg doses of oliceridine led to a statistically significant reduction in pain intensity compared to placebo, but the 0.1-mg dose did not. The third study showed that morphine provided greater reduction in pain intensity than the 0.1-mg and 0.35-mg doses of oliceridine that was statistically significant.

According to the company's background materials, morphine has active metabolites that accumulate over time, with delayed onset of metabolic effects, so it's possible that patients receive more analgesia than is necessary.

The study results, said the company, suggest that although the effect on pain was numerically greater with the morphine regimen, a similar proportion of patients were able to achieve a level of analgesia they found to be sufficient with the oliceridine 0.35-mg and 0.5-mg regimens.

Respiratory Safety

A secondary objective of the studies was to show superiority of oliceridine to morphine in terms of respiratory safety. According to the FDA, none of the oliceridine treatment arms showed a significant reduction in the expected cumulative duration of respiratory safety events compared to morphine.

Although there were trends toward decreased respiratory events with oliceridine than with morphine for some safety parameters, this was not consistent across all parameters, said the FDA.

Brown called oliceridine "a disappointment."

"The problem with this drug is that it's not a substantial improvement over what we have now," he said.

"This drug was touted as having similar analgesic properties to morphine without some of the problematic behavior, like addiction and respiratory depression. What they found was that there was not equal analgesic and there were suggestions that some of the activities of the drug that were expected not to be problematic in fact continued to be problematic," he said.

Brown noted that addiction, nausea, vomiting, and respiratory depression remain problems associated with other opioids that have been approved in the recent past.

He said he was "surprised" that the advisory committee vote on oliceridine was so narrow (8-7 against approval.)

Again, he believes that if he had been able to attend that advisory committee meeting, the outcome may have been different. "I don't think the vote would have been that close," he said.

The panel is reported to have sought more data on proposed doses and safety and studies on potential public health risk from the treatment.

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