BETHESDA, Md. -- A joint committee of FDA advisors voted 3-14 against recommending approval of a new extended-release oxycodone dubbed Remoxy ER, with members citing broad concerns over the potential public health consequences of bringing another opioid to market and more specific concerns related to the company's failure to effectively demonstrate certain abuse-deterrence properties.
Remoxy ER would come as capsules with 5-40 mg of oxycodone formulated as a thick gel intended to make it difficult to liquefy for injection or pulverize or vaporize for inhalation.
Pain Therapeutics, based in Austin, Texas, is seeking an indication for severe pain requiring long-term opioid treatment, with language indicating abuse deterrence for injection, snorting or smoking the product. The developer did not request a claim of deterrence for oral abuse.
Tuesday's meeting brought together members of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee.
Do We Even Need This?
While the questions asked of committee members related to the specific data for one specific opioid product claiming abuse-deterrent properties, a question many were asking was a different one: Does the country need another oxycodone product?
Opioids were responsible for more than 42,000 overdose deaths in 2016, nearly half of which were tied to prescription opioids, according to
"Putting another abuse deterrent formulation on the market has the potential effect of making the statement that the agency does not believe that there's a problem," said committee chair Raeford Brown Jr., MD, of the University of Kentucky in Lexington.
Cutting straight to the point, Brown asked FDA staff whether there was "a warrant" for a new abuse-deterrent opioid.
Sharon Hertz, MD, director of the Division of Anesthesia, Analgesia, and Addiction Products for the Office of Drug Evaluation II, stressed that the number of versions of any product that are appropriate to be on the market is "as many as meet adequate criteria for marketing."
The FDA doesn't limit the given number of drugs in a category but instead creates standards, Hertz said. But the agency does look for differences in efficacy and safety and considers their impact on public health.
Throughout the meeting she emphasized that, despite growing public concern, approving another opioid product for market would not necessarily mean a concurrent increase in prescriptions -- and by extension an increase in abuse and misuse -- citing a 2017 study published in .
Over time, despite the increasing number of opioid approvals, the number opioid prescriptions has fallen. "They have opposite slopes," Hertz said.
Brown ultimately voted against recommending approval.
"We don't improve the lives of patients by offering bad solutions, in this and other circumstances like it. That is what I fear we are doing," he said.
In contrast, Thomas Prisinzano, PhD, of the University of Kansas in Lawrence, voted to recommend approval, saying the sponsor met the criteria for abuse deterrence, in particular for intranasal administration.
Oral abuse is "always going to be a problem," he said, and "we're in desperate need of things for chronic pain."
Nothing Abuse-Proof
Steven Meisel, PharmD, the system director of medication safety at Fairview Health Services/Healtheast Care System in Minneapolis, who initially saw some measure of abuse deterrence for Remoxy, "reluctantly" voted against recommending approval.
"Maybe the whole concept of abuse-deterrence is something that's inherently flawed and we should move on to something else," he pondered aloud during discussions.
In casting his vote, he urged the FDA to "rethink the entire pathway of abuse-deterrence" including its guidance to industry.
Nothing any drugmaker does to an oxycodone product can deter abuse, he said.
"If somebody is intent to abuse it, they'll find a way."
Hertz agreed there is no such thing as an "abuse-proof" opioid and conceded a "downside" to abuse-deterrent products: the potential for a "false sense of safety."
"At this point in time, based on the information available to us ... it's reasonable to conclude that the utility of abuse deterrent opioid analgesics has yet to be determined in the real world," Hertz said.
In its research, Pain Therapeutics studied four routes of abuse: oral, injection, nasal, and smoking. The company argued that the product's high viscosity -- four times more viscous than Vaseline -- and stickiness, make it difficult to snort, smoke, or inject. The company also noted that "irritants" are released when attempts are made to vaporize the product.
As for Remoxy's oral abuse potential, one trial found that the peak serum concentration of volunteers in a fasted state who chewed Remoxy before swallowing was about twice that in participants swallowing the capsules intact.
"I can't think of any easier way of misusing or abusing [an opioid]" said Sidney Wolfe, MD, co-founder of Public Citizen's Health Research Group, arguing that chewing the product turns Remoxy ER into an immediate-release product. (Wolfe is not a committee member but spoke during the meeting's public testimony portion.)
The FDA's technical staff also noted that oral abuse is more common than other methods.
Conflicting data about intravenous abuse from the FDA and Pain Therapeutics created some confusion among committee members.
FDA researchers said they could extract over 80% of the oxycodone into an injectable form, and one process yielded as much as 29 mg of oxycodone that was "syringible" -- far more than the sponsor said was possible.
For Daniel Ciccarone, MD, MPH, of the University of California San Francisco, this "high yield" might encourage "sharing situations" that could increase the risk of HIV, soft tissue infections, and vein loss (a reaction to acids used to dissolve pills) as well as potential renal problems. Ciccarone voted against recommending approval.
Ciccarone and several other members worried that Remoxy might create a situation similar to one that led to Opana ER's removal from the market. It became clear that abuse of that extended-release oxymorphone product had shifted from snorting the drug to injecting it, which was linked to an outbreak of HIV and hepatitis C in rural Indiana.
If approved with abuse deterrence claims, Remoxy ER's developer will be required to complete postmarket epidemiological studies to look for any "meaningful reduction in abuse, misuse and related adverse clinical outcomes" including "addiction, overdose and death."
The FDA is not required to follow the advice of its advisory committees, but it usually does.