By Ronald S. Litman
In January 2020, the Anesthetic and Analgesic Drug Products Advisory Committee of the FDA (AADPAC) met jointly with the Drug Safety and Risk Management Advisory Committee (DSaRM) to consider approval of three opioid-related new drug applications (NDAs).
The first was oxycodegol (also referred to as NKTR-181), a highly-anticipated novel opioid produced by Nektar Therapeutics (San Francisco, CA).
Oxycodegol is a pure mu receptor agonist with opioid properties that was formulated with a polyethylene glycol (PEG) side chain. The PEG side chain slows the drug’s transport across the blood-brain-barrier, thus delaying and mitigating the euphoria that accompanies opioid-related pain relief. In theory, this delay would discourage recreational users from its use, because it would result in a suboptimal “high.”
In its NDA, Nektar sought labeling for oxycodegol for the “management of chronic low back pain in adult patients with pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.”
Nektar scientists presented a host of data demonstrating that when compared with ingestion of equianalgesic doses of oxycodone in animals, oxycodegol resulted in a lower rate of centrally mediated adverse effects and addictive behaviors. In human volunteers, it resulted in a slower onset of action and lower “drug liking,” both of which could lead to less propensity for addiction.
On the basis of these preclinical studies, oxycodegol appeared to be an ideal opioid formulation: effective analgesia with less euphoria, abuse, and addiction.
Yet, criticism of oxycodegol was widespread by the members of both AdComs. Committee members were concerned that opioid use for chronic back pain was an outdated and ultimately harmful practice.
Furthermore, the FDA typically requires two successful phase 3 studies for ultimate approval, but Nektar presented data from only one 12-week phase 3 trial, along with a 52-week unblinded cohort study that demonstrated longer-term safety. Some members expressed the sentiment that approval based on only one prospective efficacy trial would set an ill-advised precedent for future drug approvals.
More importantly, AdCom members were skeptical of the phase 3 study’s “enriched enrollment” design, which first tests the drug on all eligible patients and then uses only the positive responders for the subsequent placebo-controlled efficacy trial, a strategy called “predictive enrichment.”
Predictive enrichment with an open trial prior to randomization is mainly useful for proof-of-concept studies, or for teasing out certain subpopulations that are more likely to benefit from the drug, or when the investigators want to understand longer term risks in responders who will maintain therapy after an initial trial period. It should not be used to predict overall clinical efficacy in the general population of patients with chronic back pain because it will falsely increase the drug’s efficacy.
The AdComs recommended against approval by a vote of 27-0. That evening, Nektar issued a press release stating that it would withdraw the NDA and shut down further investment in oxycodegol.
ADPAC and DSARM met next to consider an NDA for an immediate-release, co-crystal form of a fixed-dose tramadol 44 mg + celecoxib 56 mg combination tablet (CTC; Esteve Pharmaceuticals, Barcelona, Spain) given every 12 hours “for the management of acute pain in adults with pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.”
Currently, there are no other approved products containing the combination of these two drugs. According to Esteve, the combination drug “modifies and improves the pharmacology of both active pharmaceutical ingredients (APIs),” providing greater efficacy and tolerability, while maintaining the overall safety profile of tramadol alone, and carrying low potential for abuse and dependence.
In addition to patient convenience and increased compliance, combination drug products, in theory, take advantage of each individual drug’s efficacy and potential synergism while minimizing side effects related to larger doses of each. Disadvantages, however, include the inability to titrate each medication separately, the inability to distinguish the cause of unwanted side effects, and increased cost, as a combination medication that receives new patent protection may be more expensive than the sum of the individual products.
The AdComs evaluated results from a phase 3 double-blind, randomized, factorial study that compared CTC (200 mg BID) with celecoxib (100 mg BID) alone, tramadol (50 mg QID) alone, and placebo, for relief of postoperative bunionectomy pain. Rescue medications included IV acetaminophen and/or oral oxycodone. After a total of 637 patients completed the study, analysis demonstrated that use of CTC resulted in slightly better pain scores and less need for rescue medications than the single-dose arms or placebo, at the expense of typical opioid side effects such as nausea, vomiting, dizziness, and somnolence.
After considerable debate, the AdComs’ vote to approve was split 13-13. Those who favored approval felt the overall benefits outweighed the risks because of patient convenience as well as the lower overall dose of tramadol. AdCom members against approval worried that because it was only slightly better than the individual products, patients would need some type of rescue pain medication, thus increasing the potential risks of adding on another, stronger opioid. Some AdCom members voiced the concern that if CTC is perceived to be relatively safer than standalone opioids, it may lead to over-prescribing, and subsequent abuse.
The final NDA to be evaluated was for Aximris XR, an extended-release oral tablet formulation of oxycodone, submitted by Intellipharmaceutics Corporation (Toronto, CA). The sponsor sought labeling for the “management of moderate-to-severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.” Aximris XR was formulated with a proprietary outer coating that resists physical or chemical manipulation; thus, Intellipharmaceutics was requesting abuse-deterrent labeling as well.
This was the second time that our committees evaluated this NDA. In July 2017, we met to discuss the same oxycodone product but with a different method of abuse deterrence: each tablet contained within its coating a blue dye that was expelled when users attempted to crush the tablet, resulting in the blue dye splattering over their mouth or nose.
At the July 2017 meeting, the committees voted 22-1 against approval, primarily on the basis that the sponsor submitted data demonstrating deterrent properties for only intravenous injection, and because the blue dye excipient had no proven efficacy or safety, and was considered by many of the panel members to be unethically stigmatizing to patients with a legitimate medical disease, opioid use disorder (OUD).
Abuse deterrent opioid formulations (ADFs) are one of the many possible harm reduction strategies for prevention of addiction and overdose resulting from abuse of the long-acting oral tablet forms of prescription opioids. Addiction and overdose are facilitated and accelerated when people with opioid use disorder chew the tablets or crush them to facilitate smoking, nasal insufflation, or IV injection. ADFs are designed to prevent these altered routes of abuse, while retaining efficacy with oral administration for legitimate pain relief. It is currently unclear if the ADF strategy has decreased addiction and overdose, because their sales represent only a small proportion of all prescribed opioids. Furthermore, evidence indicates that impeding access to oral prescription opioids has caused individuals with OUD to select a different non-ADF opioid, or illegal street drugs. And notably, the ADF technology does not prevent individuals from ingesting multiple pills, a common method of abuse.
For this NDA resubmission, Intellipharmaceutics reformulated the extended-release oxycodone to retain the crush-proof outer coating, but removed the blue dye excipient. However, they again submitted data supporting only the prevention of IV administration; chewing and nasal insufflation were still possible, and resulted in significant drug liking by research subjects. Therefore, the committee members were largely in agreement that the data was insufficient to grant ADF labeling for a product that was deterrent for only one route, and the vote was 24-2 against approval.
All materials related to these AdCom meetings are freely available on the FDA website. At the time of this writing, the official transcripts of these meetings have not yet been posted, nor has the FDA made final determinations of approval for CTC or Aximris.
Dr. Litman is the current Chair of the Anesthetic and Analgesic Drug Products Advisory Committee of the FDA, Professor of Anesthesiology & Critical Care, Children’s Hospital of Philadelphia, and the Perelman School of Medicine at the University of Pennsylvania, and Medical Director of the Institute for Safe Medication Practices, Horsham, PA. The views and opinions expressed in this article belong solely to the author, and do not represent those of his employers, the U.S. Food and Drug Administration, or the Institute for Safe Medication Practices. Dr. Litman is on Twitter @DrRonLitman; his email is Litmanr@email.chop.edu.