The Food and Drug Administration is the government agency with the most substantial influence on the clinical care of patients by anesthesiologists. All physiologic monitoring, all software, all drugs, are cleared within the building complex at White Oak, just off of the beltway around Washington, D.C. Drug shortages, the opioid crisis, the use of artificial intelligence in the diagnosis and treatment of patients are each studied by groups of experts within the Agency. The purity of the coffee that we drink and the safety of the artificial sweeteners that we use daily are their responsibility. This Agency has 15,000 employees and a budget of nearly 5 billion dollars. Twenty-five percent of the gross domestic product, about 5 trillion dollars, is within their jurisdiction.
In 2018, the Agency examined many drugs, monitoring devices, and even techniques pertinent to the practice of anesthesiology. In this piece, I will touch on many of the topics that have been presented to the FDA Advisory Committee on Anesthetic and Analgesic Drug Products, the committee that I currently chair (heretofore referred to as the Committee). Please note that the Agency solicits experts from outside of the Agency to review the available data concerning new drug formulations, but is not required to agree with these experts, or to base its decisions on the results of the committee’s comments or votes. In many cases more than one committee reviews many of the same issues.
The Committee considered input and advice on strategies to increase the availability of naloxone products intended for use in the community. The Committee, along with others, were asked to consider various options for improving access to naloxone, weighing logistical, economic, and harm reduction aspects, and whether naloxone should be co-prescribed with all or some opioid prescriptions to reduce the risk of overdose death. Because of the potential significant costs and burdens that may be associated with naloxone co-prescribing (e.g., economic costs to consumers and health systems, manufacturing volume growth, drug shortages), the committees will also be asked to consider the potential burdens that may be associated with naloxone co-prescribing for all or some prescription opioid patients.
The Committee discussed the assessment of opioid analgesic sparing outcomes in clinical trials of acute pain. The Committee commented on the trial design and endpoints of these studies, and how to determine the clinical relevance of the results. Guidance was provided to the Agency concerning the design and the analysis of these studies.
The Committee discussed new drug application (NDA) 209774, for an immediate-release oral tablet formulation of oxycodone. This new formulation is intended to resist common methods of physical or chemical manipulation and to deter intravenous and intranasal abuse, submitted by SpecGx Inc., “for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate”. The Committee along with others, were asked to determine whether the Applicant adequately demonstrated that the abuse-deterrent properties of the proposed product are sufficient to include this information in the product label and whether the product should be approved. The Committee voted to approve this opioid.
The Committee was asked to discuss new drug application (NDA) 209128, sufentanil sublingual tablets, submitted by AcelRx Pharmaceuticals, Inc., “for the management of moderate-to-severe acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate, in adult patients, in a medically supervised setting.” The Committee was asked to discuss risk-benefit considerations and whether this product should be approved. In the absence of the Chair and many anesthesiologists, who were attending the ASA in San Francisco, the committee approved this formulation notwithstanding serious questions associated with its safety and efficacy. The Chair of the Committee recorded his objections. The Agency approved the drug ten days later.
The Committee was asked to discuss new drug application (NDA) 210730, for oliceridine 1 milligram/milliliter injection, submitted by Trevena, Inc. for the management of moderate-to-severe pain, and was asked to discuss the efficacy and safety data and benefit-risk considerations. The Committee did not approve this formulation. Oliceridine is a novel drug that has different effects on the mu receptor than opioids, and is thought to have a lower incidence of nausea, vomiting, respiratory depression and addiction potential. The Committee asked for additional data.
The Committee discussed results from assessments of the transmucosal immediate-release fentanyl (TIRF) medicines' risk evaluation and mitigation strategy (REMS), approved in December 2011. These medicines were approved specifically for break through cancer pain. The TIRF REMS requires that healthcare providers who prescribe TIRF medicines for outpatient use are specially certified, that pharmacies that dispense TIRF medicines for inpatient and outpatient use are specially certified, and that completion of the prescriber-patient agreement form occurs before dispensing TIRF medicines for outpatient use. The Agency sought the committees’ assessment as to whether this REMS with elements to assure safe use (ETASU) actually assures safe use, is not unduly burdensome to patients, and to the extent practicable, minimizes the burden to the healthcare delivery system. The Agency sought the committees’ input on any possible modifications to the TIRF REMS goals and requirements, as well as input on the adequacy of the evaluations conducted in the REMS assessments to determine whether the TIRF REMS goals are being met. The Committee commented that the REMS for transmucosal fentanyl products had failed, that the medications were being used outside the parameters described above, and that further approvals of opioid formulations should not be based on the efficacy of this program.
Several committees discussed new drug application 022324, oxycodone extended-release capsules, submitted by Pain Therapeutics, with the proposed indication of the “management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate”. The product was intended to have abuse-deterrent properties based on its physicochemical structure. The Committees were asked to discuss whether the data submitted by the Applicant were sufficient to support the labeling of the product with the features expected to deter abuse. The committees did not support the safety of this formulation.
Several committees were asked to discuss new drug application (NDA) 209588, for buprenorphine sublingual spray, submitted by INSYS Development Company, Inc., “for the treatment of moderate-to-severe acute pain where the use of an opioid analgesic is appropriate”. The committees were asked to discuss whether this product should be approved. The evidence for its analgesic efficacy was lacking and the committees did not support the approval of this formulation.
The Committee discussed supplemental new drug application (s NDA) 022496/S-009, for EXPAREL (bupivacaine liposomal injectable suspension), submitted by Pacira Pharmaceuticals, Inc., to produce local analgesia and as a nerve block to produce regional analgesia. Though the Committee noted the risks associated with apposition of concentrated bupivacaine within a closed space, the Agency approved this drug specifically for an interscalene blockade.
Several committees were asked to discuss new drug application (NDA) 209257, proposed tradename, HYDEXOR, a fixed-dose combination oral tablet, submitted by Charleston Laboratories, Inc., that contains hydrocodone, acetaminophen, and promethazine, for the “short-term management of acute pain severe enough to require an opioid analgesic”, while preventing and reducing opioid-induced nausea and vomiting. The committees noted the risks associated with the approval of fixed drug compounds containing potent opioids, and promethazine. The Committees voted not to approve this formulation.
The decisions that the Agency makes should be transparent and based on the best available science and expert opinion. Unfortunately, most decisions are made by the Agency in extreme isolation, and the results may only be obliquely related to known data, causing the public to question the Agency’s ability to protect the general health. In the past twenty years, the balance of providing for the safety of the public has seemingly been lost in a rush to approve an increasing number of drugs, technologies, and biologics. This is a problem.