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During an opioid-addiction epidemic, can any new opioid pain drug meet prevailing safety demands to gain regulatory approval?
On Jan. 14 and 15, a Food and Drug Administration advisory committee voted virtually unanimously against two new opioid formulations and evenly split for and against a third; the 2 days of data and discussion showed how high a bar new opioids face these days for getting onto the U.S. market.
The bar’s height is very understandable given how many Americans have become addicted to opioids over the past decade, more often than not by accident while using pain medications as they believed they had been directed, said experts during the sessions held on the FDA’s campus in White Oak, Md.
Among the many upshots of the opioid crisis, the meetings held to discuss these three contender opioids highlighted the bitter irony confronting attempts to bring new, safer opioids to the U.S. market: While less abusable pain-relief medications that still harness the potent analgesic power of mu opioid receptor agonists are desperately desired, new agents in this space now receive withering scrutiny over their safeguards against misuse and abuse, and over whether they add anything meaningfully new to what’s already available. While these demands seem reasonable, perhaps even essential, it’s unclear whether any new opioid-based pain drugs will ever fully meet the safety that researchers, clinicians, and the public now seek.
A special FDA advisory committee that combined the Anesthetic and Analgesic Drug Products Advisory Committee with members of the Drug Safety and Risk Management Advisory Committee considered the application for three different opioid drugs from three separate companies. None received a clear endorsement. Oxycodegol, a new type of orally delivered opioid molecule engineered to slow brain entry and thereby delay an abuser’s high, got voted down without any votes in favor and 27 votes against agency approval. Aximris XR, an extended-release oxycodone formulation that successfully deterred intravenous abuse but had no deterrence efficacy for intranasal or oral abuse failed by a 2-24 vote against. The third agent, CTC, a novel formulation of the schedule IV opioid tramadol with the NSAID celecoxib designed to be analgesic but with limited opioid-abuse appeal, came the closest to meaningful support with a tied 13-13 vote from advisory committee members for and against agency approval. FDA staff takes advisory committee opinions and votes into account when making their final decisions about drug marketing approvals.
In each case, the committee members, mostly the same roster assembled for each of the three agents, identified specific concerns with the data purported to show each drug’s safety and efficacy. But the gathered experts and consumer representatives also consistently cited holistic challenges to approving new opioids and the stiffer criteria these agents face amid a continuing wave of opioid misuse and abuse.
“In the context of the public health issues, we don’t want to be perceived in any way of taking shortcuts,” said Linda S. Tyler, PharmD,, an advisory committee member and professor of pharmacy and chief pharmacy officer at the University of Utah in Salt Lake City. “There is no question that for a new product to come to market in this space it needs to add to what’s on the market, meet a high bar, and provide advantages compared with what’s already on the market,” she said.
Tramadol plus celecoxib gains some support
The proposed combined formulation of tramadol and celecoxib came closest to meeting that bar, as far as the advisory committee was concerned, coming away with 13 votes favoring approval to match 13 votes against. The premise behind this agent, know as CTC (cocrystal of tramadol and celecoxib), was that it combined a modest dose (44 mg) of the schedule IV opioid tramadol with a 56-mg dose of celecoxib in a twice-daily pill. Eugene R. Viscusi, MD, professor of anesthesiology and director of acute pain management at Thomas Jefferson University in Philadelphia and a speaker at the session on behalf of the applicant company, spelled out the rationale behind CTC: “We are caught in a dilemma. We need to reduce opioid use, but we also need to treat pain. We have an urgent need to have pain treatment options that are effective but have low potential for abuse and dependence. We are looking at multimodal analgesia, that uses combination of agents, recognizing that postoperative pain is a mixed pain syndrome. Multimodal pain treatments are now considered standard care. We want to minimize opioids to the lowest dose possible to produce safe analgesia. Tramadol is the least-preferred opioid for abuse,” and is rated as schedule IV, the U.S. designation for drugs considered to have a low level of potential for causing abuse or dependence. “Opioids used as stand-alone agents have contributed to the current opioid crisis,” Dr. Viscusi told the committee.
In contrast to tramadol’s schedule IV status, the mainstays of recent opioid pain therapy have been hydrocodone and oxycodone, schedule II opioids rated as having a “high potential for abuse.”
Several advisory committee members agreed that CTC minimized patient exposure to an opioid. “This drug isn’t even tramadol; it’s tramadol light. It has about as low a dose [of an opioid] as you can have and still have a drug,” said member Lee A. Hoffer, PhD, a medical anthropologist at Case Western Reserve University, Cleveland, who studies substance use disorders. “All opioids are dangerous, even at a low dose, but there is a linear relationship based on potency, so if we want to have an opioid for acute pain, I’d like it to have the lowest morphine milligram equivalent possible. The ideal is no opioids, but that is not what happens,” he said. The CTC formulation delivers 17.6 morphine milligram equivalents (MME) per pill, the manufacturer’s representatives said. The Centers for Disease Control and Prevention defines a “relatively low” daily opioid dose as 20-50 MME.
Some committee members hailed the CTC formulation as a meaningful step toward cutting opioid consumption.
“We may be very nervous about abuse of scheduled opioids, but a schedule IV opioid in an opioid-sparing formulation is as good as it gets in 2020,” said committee member Kevin L. Zacharoff, MD, a pain medicine specialist at the State University of New York at Stony Brook. “Any opioid has potential for abuse, but this is a safer alternative to the schedule II drugs. There is less public health risk with this,” said committee member Sherif Zaafran, MD, a Houston anesthesiologist. “This represents an incremental but important approach to addressing the opioid crisis, especially if used to replace schedule II opioids,” said Brandon D.L. Marshall, PhD, an epidemiologist and substance abuse researcher at Brown University in Providence, R.I.
But despite agreement that CTC represented a new low in the MME of an opioid given to patients, several committee members still saw the formulation as problematic by introducing any opioid, no matter how small the dose.
“The landscape of tramadol use and prescribing is evolving. There’s been an exponential upturn in tramadol prescribing. It’s perceived [as] safer, but it’s not completely safe. Will this change tramadol abuse and open the door to abuse of other opioids? This is what got us into trouble with opioids in the first place. Patients start with a prescription opioid that they perceive is safe. Patients don’t start with oxycodone or heroin. They start with drugs that are believed to be safe. I feel this combination has less risk for abuse, but I’m worried that it would produce a false sense of security for tolerability and safety,” said committee member Maryann E. Amirshahi, MD, a medical toxicologist at Georgetown University and MedStar Health in Washington.
Several other committee members returned to this point throughout the 2 days of discussions: The majority of Americans who have become hooked on opioids reached that point by taking an opioid pain medication for a legitimate medical reason and using the drug the way they had understood they should.
“I’m most concerned about unintentional misuse leading to addiction and abuse. Most people with an opioid addiction got it inadvertently, misusing it by mistake,” said committee member Suzanne B. Robotti, a consumer representative and executive director of DES Action USA. “I’m concerned about approving an opioid, even an opioid with a low abuse history, without a clearer picture of the human abuse potential data and what would happen if this drug were abused,” she added, referring to the proposed CTC formulation.
“All the patients I work with started [their opioid addiction] as pain patients,” Dr. Hoffer said.
“The most common use and abuse of opioids is orally. We need to avoid having patients who use the drug as prescribed and still end up addicted,” said committee member Friedhelm Sandbrink, MD, a neurologist and director of pain management at the Veterans Affairs (VA) Medical Center in Washington.
What this means, said several panelists, is functionally clamping down a class-wide lid on new opioids. “The way to reduce deaths from abuse is to reduce addiction, and to have an impact you need to reduce opioid exposure.” said committee member Sonia Hernandez-Diaz, MD, professor of epidemiology at the Harvard School of Public Health in Boston.
“In this opioid crisis, we ask for data that we wouldn’t ordinarily ask for. I feel there are unanswered questions about the abuse potential [of CTC]. We have seen a recent reduction in oxycodone use, which is great, but also an increase in tramadol use. We should not be fooled. Tramadol is an opioid, even if it’s schedule IV,” Dr. Tyler said.
Two other opioids faced greater opposition
The other two agents that the committee considered received much less support and sharper skepticism. The application for Aximris XR, an extended release form of oxycodone with a purported abuse-deterrent formulation (ADF) that relies on being difficult to extract for intravenous use as well as possibly having effective deterrence mechanisms for other forms of abuse. But FDA staffers reported that the only effective deterrence they could document was against manipulation for intravenous use, making Aximris XR the first opioid seeking ADF labeling based on deterrence to a single delivery route. This led several committee members, as well as the FDA, to comment on the clinical meaningfulness of ADF for one route. So far, the FDA approved ADF labeling for seven opioids, most notably OxyContin, an extended-release oxycodone with the biggest share of the U.S. market for opioids with ADF labeling.
“For ADF, we label based on what we expect from the premarket data. We don’t really know how that translates into what happens once the drug is on the market. Every company with an ADF in their label is required to do postmarketing studies on the abuse routes that are supposed to be deterred. We see shifts to other routes. Assessment of ADF is incredibly challenging, both scientifically and logistically, because there has not been a lot of uptake of these products, for a variety of reasons,” said Judy Staffa, PhD, associate director for Public Health Initiatives in the Office of Surveillance & Epidemiology in the FDA’s Center for Drug Evaluation and Research. The company that markets OxyContin has been the first to submit to the FDA all of its required postmarketing data on ADF efficacy, and the agency is now reviewing this filing, Dr. Staffa said.
The data presented for Aximris XR appeared to generally fail to convince committee members that it provided a meaningful addition to the range of opioids with ADF designations already available, which meant that their decision mostly came down to whether they felt it made sense to bring a me-too opioid to the U.S. market. Their answer was mostly no.
“In the end, it’s another opioid, and I’m not sure we need another opioid,” said committee member Lonnie K. Zeltzer, MD, professor of pediatrics, anesthesiology, psychiatry, and biobehavioral sciences and director of pediatric pain at the University of California, Los Angeles “There are so many options for patients and for people who abuse these drug. I don’t see this formulation as having a profound impact, but I’m very concerned about adding more prescription opioids,” said Martin Garcia-Bunuel, MD, deputy chief of staff for the VA Maryland Health Care System in Baltimore. Another concern of some committee members was that ADF remains a designation with an uncertain meaning, pending the FDA’s analysis of the OxyContin data.
“At the end of the day, we don’t know whether any of the [ADF] stuff makes a difference,” noted Steve B. Meisel, PharmD, system director of medication safety for M Health Fairview in Minneapolis and a committee member,
The third agent, oxycodegol, a molecule designed to pass more slowly across the blood-brain barrier because of an attached polyethylene glycol chain that’s supposed to prevent a rapid high after ingestion and hence cut abuse potential. It received unanimous committee rejection, primarily because its safety and efficacy evidence had so many holes, but the shadow of opioid abuse permeated the committee’s discussion.
“One dogma in the abuse world is that slowing entry into the brain reduces abuse potential, but the opioid crisis showed that this is not the only factor. Some people have become addicted to slow-acting drugs. The abuse potential of this drug, oxycodegol, needs to be considered given where we’ve been with the opioid crisis,” said Jane B. Acri, PhD, chief of the Medications Discovery and Toxicology Branch of the National Institute on Drug Abuse.
“During the opioid epidemic, do we want to approve more opioids? If the [pain] efficacy is about the same as oxycodone, is better safety or abuse potential a reason to approve it? We need guidance [from the FDA] about what is ‘better enough.’ No opioid will ever be perfect; there will always be abuse and misuse. But what is good enough to justify bringing another opioid onto the market? What is a good enough improvement? I don’t have an answer,” Dr. Hernandez-Diaz said.
Adviser comments showed that the continued threat of widespread opioid addiction has cooled prospects for new opioid approvals by making FDA advisers skittish over how to properly score the incremental value of a new opioid.
“Do we need to go back to the drawing board on how we make decisions on exposing the American public to these kinds of agents?” Dr. Garcia-Bunuel asked. “I don’t think we have the tools to make these decisions.”
During an opioid-addiction epidemic, can any new opioid pain drug meet prevailing safety demands to gain regulatory approval?
On Jan. 14 and 15, a Food and Drug Administration advisory committee voted virtually unanimously against two new opioid formulations and evenly split for and against a third; the 2 days of data and discussion showed how high a bar new opioids face these days for getting onto the U.S. market.
The bar’s height is very understandable given how many Americans have become addicted to opioids over the past decade, more often than not by accident while using pain medications as they believed they had been directed, said experts during the sessions held on the FDA’s campus in White Oak, Md.
Among the many upshots of the opioid crisis, the meetings held to discuss these three contender opioids highlighted the bitter irony confronting attempts to bring new, safer opioids to the U.S. market: While less abusable pain-relief medications that still harness the potent analgesic power of mu opioid receptor agonists are desperately desired, new agents in this space now receive withering scrutiny over their safeguards against misuse and abuse, and over whether they add anything meaningfully new to what’s already available. While these demands seem reasonable, perhaps even essential, it’s unclear whether any new opioid-based pain drugs will ever fully meet the safety that researchers, clinicians, and the public now seek.
A special FDA advisory committee that combined the Anesthetic and Analgesic Drug Products Advisory Committee with members of the Drug Safety and Risk Management Advisory Committee considered the application for three different opioid drugs from three separate companies. None received a clear endorsement. Oxycodegol, a new type of orally delivered opioid molecule engineered to slow brain entry and thereby delay an abuser’s high, got voted down without any votes in favor and 27 votes against agency approval. Aximris XR, an extended-release oxycodone formulation that successfully deterred intravenous abuse but had no deterrence efficacy for intranasal or oral abuse failed by a 2-24 vote against. The third agent, CTC, a novel formulation of the schedule IV opioid tramadol with the NSAID celecoxib designed to be analgesic but with limited opioid-abuse appeal, came the closest to meaningful support with a tied 13-13 vote from advisory committee members for and against agency approval. FDA staff takes advisory committee opinions and votes into account when making their final decisions about drug marketing approvals.
In each case, the committee members, mostly the same roster assembled for each of the three agents, identified specific concerns with the data purported to show each drug’s safety and efficacy. But the gathered experts and consumer representatives also consistently cited holistic challenges to approving new opioids and the stiffer criteria these agents face amid a continuing wave of opioid misuse and abuse.
“In the context of the public health issues, we don’t want to be perceived in any way of taking shortcuts,” said Linda S. Tyler, PharmD,, an advisory committee member and professor of pharmacy and chief pharmacy officer at the University of Utah in Salt Lake City. “There is no question that for a new product to come to market in this space it needs to add to what’s on the market, meet a high bar, and provide advantages compared with what’s already on the market,” she said.
Tramadol plus celecoxib gains some support
The proposed combined formulation of tramadol and celecoxib came closest to meeting that bar, as far as the advisory committee was concerned, coming away with 13 votes favoring approval to match 13 votes against. The premise behind this agent, know as CTC (cocrystal of tramadol and celecoxib), was that it combined a modest dose (44 mg) of the schedule IV opioid tramadol with a 56-mg dose of celecoxib in a twice-daily pill. Eugene R. Viscusi, MD, professor of anesthesiology and director of acute pain management at Thomas Jefferson University in Philadelphia and a speaker at the session on behalf of the applicant company, spelled out the rationale behind CTC: “We are caught in a dilemma. We need to reduce opioid use, but we also need to treat pain. We have an urgent need to have pain treatment options that are effective but have low potential for abuse and dependence. We are looking at multimodal analgesia, that uses combination of agents, recognizing that postoperative pain is a mixed pain syndrome. Multimodal pain treatments are now considered standard care. We want to minimize opioids to the lowest dose possible to produce safe analgesia. Tramadol is the least-preferred opioid for abuse,” and is rated as schedule IV, the U.S. designation for drugs considered to have a low level of potential for causing abuse or dependence. “Opioids used as stand-alone agents have contributed to the current opioid crisis,” Dr. Viscusi told the committee.
In contrast to tramadol’s schedule IV status, the mainstays of recent opioid pain therapy have been hydrocodone and oxycodone, schedule II opioids rated as having a “high potential for abuse.”
Several advisory committee members agreed that CTC minimized patient exposure to an opioid. “This drug isn’t even tramadol; it’s tramadol light. It has about as low a dose [of an opioid] as you can have and still have a drug,” said member Lee A. Hoffer, PhD, a medical anthropologist at Case Western Reserve University, Cleveland, who studies substance use disorders. “All opioids are dangerous, even at a low dose, but there is a linear relationship based on potency, so if we want to have an opioid for acute pain, I’d like it to have the lowest morphine milligram equivalent possible. The ideal is no opioids, but that is not what happens,” he said. The CTC formulation delivers 17.6 morphine milligram equivalents (MME) per pill, the manufacturer’s representatives said. The Centers for Disease Control and Prevention defines a “relatively low” daily opioid dose as 20-50 MME.
Some committee members hailed the CTC formulation as a meaningful step toward cutting opioid consumption.
“We may be very nervous about abuse of scheduled opioids, but a schedule IV opioid in an opioid-sparing formulation is as good as it gets in 2020,” said committee member Kevin L. Zacharoff, MD, a pain medicine specialist at the State University of New York at Stony Brook. “Any opioid has potential for abuse, but this is a safer alternative to the schedule II drugs. There is less public health risk with this,” said committee member Sherif Zaafran, MD, a Houston anesthesiologist. “This represents an incremental but important approach to addressing the opioid crisis, especially if used to replace schedule II opioids,” said Brandon D.L. Marshall, PhD, an epidemiologist and substance abuse researcher at Brown University in Providence, R.I.
But despite agreement that CTC represented a new low in the MME of an opioid given to patients, several committee members still saw the formulation as problematic by introducing any opioid, no matter how small the dose.
“The landscape of tramadol use and prescribing is evolving. There’s been an exponential upturn in tramadol prescribing. It’s perceived [as] safer, but it’s not completely safe. Will this change tramadol abuse and open the door to abuse of other opioids? This is what got us into trouble with opioids in the first place. Patients start with a prescription opioid that they perceive is safe. Patients don’t start with oxycodone or heroin. They start with drugs that are believed to be safe. I feel this combination has less risk for abuse, but I’m worried that it would produce a false sense of security for tolerability and safety,” said committee member Maryann E. Amirshahi, MD, a medical toxicologist at Georgetown University and MedStar Health in Washington.
Several other committee members returned to this point throughout the 2 days of discussions: The majority of Americans who have become hooked on opioids reached that point by taking an opioid pain medication for a legitimate medical reason and using the drug the way they had understood they should.
“I’m most concerned about unintentional misuse leading to addiction and abuse. Most people with an opioid addiction got it inadvertently, misusing it by mistake,” said committee member Suzanne B. Robotti, a consumer representative and executive director of DES Action USA. “I’m concerned about approving an opioid, even an opioid with a low abuse history, without a clearer picture of the human abuse potential data and what would happen if this drug were abused,” she added, referring to the proposed CTC formulation.
“All the patients I work with started [their opioid addiction] as pain patients,” Dr. Hoffer said.
“The most common use and abuse of opioids is orally. We need to avoid having patients who use the drug as prescribed and still end up addicted,” said committee member Friedhelm Sandbrink, MD, a neurologist and director of pain management at the Veterans Affairs (VA) Medical Center in Washington.
What this means, said several panelists, is functionally clamping down a class-wide lid on new opioids. “The way to reduce deaths from abuse is to reduce addiction, and to have an impact you need to reduce opioid exposure.” said committee member Sonia Hernandez-Diaz, MD, professor of epidemiology at the Harvard School of Public Health in Boston.
“In this opioid crisis, we ask for data that we wouldn’t ordinarily ask for. I feel there are unanswered questions about the abuse potential [of CTC]. We have seen a recent reduction in oxycodone use, which is great, but also an increase in tramadol use. We should not be fooled. Tramadol is an opioid, even if it’s schedule IV,” Dr. Tyler said.
Two other opioids faced greater opposition
The other two agents that the committee considered received much less support and sharper skepticism. The application for Aximris XR, an extended release form of oxycodone with a purported abuse-deterrent formulation (ADF) that relies on being difficult to extract for intravenous use as well as possibly having effective deterrence mechanisms for other forms of abuse. But FDA staffers reported that the only effective deterrence they could document was against manipulation for intravenous use, making Aximris XR the first opioid seeking ADF labeling based on deterrence to a single delivery route. This led several committee members, as well as the FDA, to comment on the clinical meaningfulness of ADF for one route. So far, the FDA approved ADF labeling for seven opioids, most notably OxyContin, an extended-release oxycodone with the biggest share of the U.S. market for opioids with ADF labeling.
“For ADF, we label based on what we expect from the premarket data. We don’t really know how that translates into what happens once the drug is on the market. Every company with an ADF in their label is required to do postmarketing studies on the abuse routes that are supposed to be deterred. We see shifts to other routes. Assessment of ADF is incredibly challenging, both scientifically and logistically, because there has not been a lot of uptake of these products, for a variety of reasons,” said Judy Staffa, PhD, associate director for Public Health Initiatives in the Office of Surveillance & Epidemiology in the FDA’s Center for Drug Evaluation and Research. The company that markets OxyContin has been the first to submit to the FDA all of its required postmarketing data on ADF efficacy, and the agency is now reviewing this filing, Dr. Staffa said.
The data presented for Aximris XR appeared to generally fail to convince committee members that it provided a meaningful addition to the range of opioids with ADF designations already available, which meant that their decision mostly came down to whether they felt it made sense to bring a me-too opioid to the U.S. market. Their answer was mostly no.
“In the end, it’s another opioid, and I’m not sure we need another opioid,” said committee member Lonnie K. Zeltzer, MD, professor of pediatrics, anesthesiology, psychiatry, and biobehavioral sciences and director of pediatric pain at the University of California, Los Angeles “There are so many options for patients and for people who abuse these drug. I don’t see this formulation as having a profound impact, but I’m very concerned about adding more prescription opioids,” said Martin Garcia-Bunuel, MD, deputy chief of staff for the VA Maryland Health Care System in Baltimore. Another concern of some committee members was that ADF remains a designation with an uncertain meaning, pending the FDA’s analysis of the OxyContin data.
“At the end of the day, we don’t know whether any of the [ADF] stuff makes a difference,” noted Steve B. Meisel, PharmD, system director of medication safety for M Health Fairview in Minneapolis and a committee member,
The third agent, oxycodegol, a molecule designed to pass more slowly across the blood-brain barrier because of an attached polyethylene glycol chain that’s supposed to prevent a rapid high after ingestion and hence cut abuse potential. It received unanimous committee rejection, primarily because its safety and efficacy evidence had so many holes, but the shadow of opioid abuse permeated the committee’s discussion.
“One dogma in the abuse world is that slowing entry into the brain reduces abuse potential, but the opioid crisis showed that this is not the only factor. Some people have become addicted to slow-acting drugs. The abuse potential of this drug, oxycodegol, needs to be considered given where we’ve been with the opioid crisis,” said Jane B. Acri, PhD, chief of the Medications Discovery and Toxicology Branch of the National Institute on Drug Abuse.
“During the opioid epidemic, do we want to approve more opioids? If the [pain] efficacy is about the same as oxycodone, is better safety or abuse potential a reason to approve it? We need guidance [from the FDA] about what is ‘better enough.’ No opioid will ever be perfect; there will always be abuse and misuse. But what is good enough to justify bringing another opioid onto the market? What is a good enough improvement? I don’t have an answer,” Dr. Hernandez-Diaz said.
Adviser comments showed that the continued threat of widespread opioid addiction has cooled prospects for new opioid approvals by making FDA advisers skittish over how to properly score the incremental value of a new opioid.
“Do we need to go back to the drawing board on how we make decisions on exposing the American public to these kinds of agents?” Dr. Garcia-Bunuel asked. “I don’t think we have the tools to make these decisions.”
During an opioid-addiction epidemic, can any new opioid pain drug meet prevailing safety demands to gain regulatory approval?
On Jan. 14 and 15, a Food and Drug Administration advisory committee voted virtually unanimously against two new opioid formulations and evenly split for and against a third; the 2 days of data and discussion showed how high a bar new opioids face these days for getting onto the U.S. market.
The bar’s height is very understandable given how many Americans have become addicted to opioids over the past decade, more often than not by accident while using pain medications as they believed they had been directed, said experts during the sessions held on the FDA’s campus in White Oak, Md.
Among the many upshots of the opioid crisis, the meetings held to discuss these three contender opioids highlighted the bitter irony confronting attempts to bring new, safer opioids to the U.S. market: While less abusable pain-relief medications that still harness the potent analgesic power of mu opioid receptor agonists are desperately desired, new agents in this space now receive withering scrutiny over their safeguards against misuse and abuse, and over whether they add anything meaningfully new to what’s already available. While these demands seem reasonable, perhaps even essential, it’s unclear whether any new opioid-based pain drugs will ever fully meet the safety that researchers, clinicians, and the public now seek.
A special FDA advisory committee that combined the Anesthetic and Analgesic Drug Products Advisory Committee with members of the Drug Safety and Risk Management Advisory Committee considered the application for three different opioid drugs from three separate companies. None received a clear endorsement. Oxycodegol, a new type of orally delivered opioid molecule engineered to slow brain entry and thereby delay an abuser’s high, got voted down without any votes in favor and 27 votes against agency approval. Aximris XR, an extended-release oxycodone formulation that successfully deterred intravenous abuse but had no deterrence efficacy for intranasal or oral abuse failed by a 2-24 vote against. The third agent, CTC, a novel formulation of the schedule IV opioid tramadol with the NSAID celecoxib designed to be analgesic but with limited opioid-abuse appeal, came the closest to meaningful support with a tied 13-13 vote from advisory committee members for and against agency approval. FDA staff takes advisory committee opinions and votes into account when making their final decisions about drug marketing approvals.
In each case, the committee members, mostly the same roster assembled for each of the three agents, identified specific concerns with the data purported to show each drug’s safety and efficacy. But the gathered experts and consumer representatives also consistently cited holistic challenges to approving new opioids and the stiffer criteria these agents face amid a continuing wave of opioid misuse and abuse.
“In the context of the public health issues, we don’t want to be perceived in any way of taking shortcuts,” said Linda S. Tyler, PharmD,, an advisory committee member and professor of pharmacy and chief pharmacy officer at the University of Utah in Salt Lake City. “There is no question that for a new product to come to market in this space it needs to add to what’s on the market, meet a high bar, and provide advantages compared with what’s already on the market,” she said.
Tramadol plus celecoxib gains some support
The proposed combined formulation of tramadol and celecoxib came closest to meeting that bar, as far as the advisory committee was concerned, coming away with 13 votes favoring approval to match 13 votes against. The premise behind this agent, know as CTC (cocrystal of tramadol and celecoxib), was that it combined a modest dose (44 mg) of the schedule IV opioid tramadol with a 56-mg dose of celecoxib in a twice-daily pill. Eugene R. Viscusi, MD, professor of anesthesiology and director of acute pain management at Thomas Jefferson University in Philadelphia and a speaker at the session on behalf of the applicant company, spelled out the rationale behind CTC: “We are caught in a dilemma. We need to reduce opioid use, but we also need to treat pain. We have an urgent need to have pain treatment options that are effective but have low potential for abuse and dependence. We are looking at multimodal analgesia, that uses combination of agents, recognizing that postoperative pain is a mixed pain syndrome. Multimodal pain treatments are now considered standard care. We want to minimize opioids to the lowest dose possible to produce safe analgesia. Tramadol is the least-preferred opioid for abuse,” and is rated as schedule IV, the U.S. designation for drugs considered to have a low level of potential for causing abuse or dependence. “Opioids used as stand-alone agents have contributed to the current opioid crisis,” Dr. Viscusi told the committee.
In contrast to tramadol’s schedule IV status, the mainstays of recent opioid pain therapy have been hydrocodone and oxycodone, schedule II opioids rated as having a “high potential for abuse.”
Several advisory committee members agreed that CTC minimized patient exposure to an opioid. “This drug isn’t even tramadol; it’s tramadol light. It has about as low a dose [of an opioid] as you can have and still have a drug,” said member Lee A. Hoffer, PhD, a medical anthropologist at Case Western Reserve University, Cleveland, who studies substance use disorders. “All opioids are dangerous, even at a low dose, but there is a linear relationship based on potency, so if we want to have an opioid for acute pain, I’d like it to have the lowest morphine milligram equivalent possible. The ideal is no opioids, but that is not what happens,” he said. The CTC formulation delivers 17.6 morphine milligram equivalents (MME) per pill, the manufacturer’s representatives said. The Centers for Disease Control and Prevention defines a “relatively low” daily opioid dose as 20-50 MME.
Some committee members hailed the CTC formulation as a meaningful step toward cutting opioid consumption.
“We may be very nervous about abuse of scheduled opioids, but a schedule IV opioid in an opioid-sparing formulation is as good as it gets in 2020,” said committee member Kevin L. Zacharoff, MD, a pain medicine specialist at the State University of New York at Stony Brook. “Any opioid has potential for abuse, but this is a safer alternative to the schedule II drugs. There is less public health risk with this,” said committee member Sherif Zaafran, MD, a Houston anesthesiologist. “This represents an incremental but important approach to addressing the opioid crisis, especially if used to replace schedule II opioids,” said Brandon D.L. Marshall, PhD, an epidemiologist and substance abuse researcher at Brown University in Providence, R.I.
But despite agreement that CTC represented a new low in the MME of an opioid given to patients, several committee members still saw the formulation as problematic by introducing any opioid, no matter how small the dose.
“The landscape of tramadol use and prescribing is evolving. There’s been an exponential upturn in tramadol prescribing. It’s perceived [as] safer, but it’s not completely safe. Will this change tramadol abuse and open the door to abuse of other opioids? This is what got us into trouble with opioids in the first place. Patients start with a prescription opioid that they perceive is safe. Patients don’t start with oxycodone or heroin. They start with drugs that are believed to be safe. I feel this combination has less risk for abuse, but I’m worried that it would produce a false sense of security for tolerability and safety,” said committee member Maryann E. Amirshahi, MD, a medical toxicologist at Georgetown University and MedStar Health in Washington.
Several other committee members returned to this point throughout the 2 days of discussions: The majority of Americans who have become hooked on opioids reached that point by taking an opioid pain medication for a legitimate medical reason and using the drug the way they had understood they should.
“I’m most concerned about unintentional misuse leading to addiction and abuse. Most people with an opioid addiction got it inadvertently, misusing it by mistake,” said committee member Suzanne B. Robotti, a consumer representative and executive director of DES Action USA. “I’m concerned about approving an opioid, even an opioid with a low abuse history, without a clearer picture of the human abuse potential data and what would happen if this drug were abused,” she added, referring to the proposed CTC formulation.
“All the patients I work with started [their opioid addiction] as pain patients,” Dr. Hoffer said.
“The most common use and abuse of opioids is orally. We need to avoid having patients who use the drug as prescribed and still end up addicted,” said committee member Friedhelm Sandbrink, MD, a neurologist and director of pain management at the Veterans Affairs (VA) Medical Center in Washington.
What this means, said several panelists, is functionally clamping down a class-wide lid on new opioids. “The way to reduce deaths from abuse is to reduce addiction, and to have an impact you need to reduce opioid exposure.” said committee member Sonia Hernandez-Diaz, MD, professor of epidemiology at the Harvard School of Public Health in Boston.
“In this opioid crisis, we ask for data that we wouldn’t ordinarily ask for. I feel there are unanswered questions about the abuse potential [of CTC]. We have seen a recent reduction in oxycodone use, which is great, but also an increase in tramadol use. We should not be fooled. Tramadol is an opioid, even if it’s schedule IV,” Dr. Tyler said.
Two other opioids faced greater opposition
The other two agents that the committee considered received much less support and sharper skepticism. The application for Aximris XR, an extended release form of oxycodone with a purported abuse-deterrent formulation (ADF) that relies on being difficult to extract for intravenous use as well as possibly having effective deterrence mechanisms for other forms of abuse. But FDA staffers reported that the only effective deterrence they could document was against manipulation for intravenous use, making Aximris XR the first opioid seeking ADF labeling based on deterrence to a single delivery route. This led several committee members, as well as the FDA, to comment on the clinical meaningfulness of ADF for one route. So far, the FDA approved ADF labeling for seven opioids, most notably OxyContin, an extended-release oxycodone with the biggest share of the U.S. market for opioids with ADF labeling.
“For ADF, we label based on what we expect from the premarket data. We don’t really know how that translates into what happens once the drug is on the market. Every company with an ADF in their label is required to do postmarketing studies on the abuse routes that are supposed to be deterred. We see shifts to other routes. Assessment of ADF is incredibly challenging, both scientifically and logistically, because there has not been a lot of uptake of these products, for a variety of reasons,” said Judy Staffa, PhD, associate director for Public Health Initiatives in the Office of Surveillance & Epidemiology in the FDA’s Center for Drug Evaluation and Research. The company that markets OxyContin has been the first to submit to the FDA all of its required postmarketing data on ADF efficacy, and the agency is now reviewing this filing, Dr. Staffa said.
The data presented for Aximris XR appeared to generally fail to convince committee members that it provided a meaningful addition to the range of opioids with ADF designations already available, which meant that their decision mostly came down to whether they felt it made sense to bring a me-too opioid to the U.S. market. Their answer was mostly no.
“In the end, it’s another opioid, and I’m not sure we need another opioid,” said committee member Lonnie K. Zeltzer, MD, professor of pediatrics, anesthesiology, psychiatry, and biobehavioral sciences and director of pediatric pain at the University of California, Los Angeles “There are so many options for patients and for people who abuse these drug. I don’t see this formulation as having a profound impact, but I’m very concerned about adding more prescription opioids,” said Martin Garcia-Bunuel, MD, deputy chief of staff for the VA Maryland Health Care System in Baltimore. Another concern of some committee members was that ADF remains a designation with an uncertain meaning, pending the FDA’s analysis of the OxyContin data.
“At the end of the day, we don’t know whether any of the [ADF] stuff makes a difference,” noted Steve B. Meisel, PharmD, system director of medication safety for M Health Fairview in Minneapolis and a committee member,
The third agent, oxycodegol, a molecule designed to pass more slowly across the blood-brain barrier because of an attached polyethylene glycol chain that’s supposed to prevent a rapid high after ingestion and hence cut abuse potential. It received unanimous committee rejection, primarily because its safety and efficacy evidence had so many holes, but the shadow of opioid abuse permeated the committee’s discussion.
“One dogma in the abuse world is that slowing entry into the brain reduces abuse potential, but the opioid crisis showed that this is not the only factor. Some people have become addicted to slow-acting drugs. The abuse potential of this drug, oxycodegol, needs to be considered given where we’ve been with the opioid crisis,” said Jane B. Acri, PhD, chief of the Medications Discovery and Toxicology Branch of the National Institute on Drug Abuse.
“During the opioid epidemic, do we want to approve more opioids? If the [pain] efficacy is about the same as oxycodone, is better safety or abuse potential a reason to approve it? We need guidance [from the FDA] about what is ‘better enough.’ No opioid will ever be perfect; there will always be abuse and misuse. But what is good enough to justify bringing another opioid onto the market? What is a good enough improvement? I don’t have an answer,” Dr. Hernandez-Diaz said.
Adviser comments showed that the continued threat of widespread opioid addiction has cooled prospects for new opioid approvals by making FDA advisers skittish over how to properly score the incremental value of a new opioid.
“Do we need to go back to the drawing board on how we make decisions on exposing the American public to these kinds of agents?” Dr. Garcia-Bunuel asked. “I don’t think we have the tools to make these decisions.”