FDA Briefing Document Meeting of Psychopharmacologic Drugs Advisory Committee March 27, 2018 DISCLAIMER STATEMENT The attached package contains background information prepared by the Food and Drug Administration (FDA) for the panel members of the Advisory Committee. The FDA background package often contains assessments and/or conclusions and recommendations written by individual FDA reviewers. Such conclusions and recommendations do not necessarily represent the final position of the individual reviewers, nor do they necessarily represent the final position of the Review Division or Office. We have brought NDA 209229, Lucemyra (lofexidine hydrochloride) tablets, 0.18 mg by US World Meds, LLC, to this Advisory Committee in order to gain the Committee’s insights and opinions, and the background package may not include all issues relevant to the final regulatory recommendation and instead is intended to focus on issues identified by the Agency for discussion by the advisory committee. The FDA will not issue a final determination on the issues at hand until input from the advisory committee process has been considered and all reviews have been finalized. The final determination may be affected by issues not discussed at the advisory committee meeting. 2 FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and Research Meeting of the Psychopharmacologic Drugs Advisory Committee March 27, 2018 Table of Contents Background Materials Page 1. Division of Anesthesia, Analgesia, and Addiction Products (DAAAP) Director Memorandum (Dr. Hertz) ...............................................................................4 2. Discussion and Points for Consideration ......................................................................6 3. Summary of Efficacy and Safety ..................................................................................7 4. Drug Utilization Review ...............................................................................................77 3 Food and Drug Administration CENTER FOR DRUG EVALUATION AND RESEARCH Division of Anesthesia, Analgesia, and Addiction Products MEMORANDUM DATE: February 15, 2018 FROM: Sharon Hertz, M.D., Division Director Division of Anesthesia, Analgesia, and Addiction Products TO: Chair, Members, and Invited Guests, Psychopharmacologic Drugs Advisory Committee (PDAC) RE: Overview of the March 27, 2018 PDAC Meeting on NDA 209229 for Lucemyra (lofexidine hydrochloride) tablets for the symptomatic treatment of opioid withdrawal At this meeting of the Psychopharmacologic Drugs Advisory Committee, we will be discussing a new drug application (NDA) 209229 for Lucemyra (lofexidine hydrochloride) tablets submitted by US World Meds, Inc., for the symptomatic treatment of opioid withdrawal. During this meeting, representatives from the Agency and the Applicant will present data from the clinical trials performed to assess the safety and efficacy of lofexidine in the treatment of opioid withdrawal symptoms during abrupt discontinuation of opioids. Lofexidine is a new molecular entity, not previously approved for marketing in the United States. The efficacy data derive primarily from two brief inpatient studies of patients with opioid use disorder (OUD) abruptly discontinuing illicit use of short-acting opioids. Following these presentations, you will be asked to assess these findings and to discuss the adequacy of the data to support approval of lofexidine for marketing. Two claims are proposed to be supported by these studies 1. That lofexidine reduces the symptoms of opioid withdrawal (in the context of abrupt discontinuation) and 4 2. That lofexidine thereby increases the likelihood that the course of withdrawal treatment will be completed, and the patient will reach a state of no longer being physically dependent. First, it should be noted that these effects have been demonstrated only in patients discontinuing opioids abruptly. Many patients discontinuing opioids do so gradually, and the symptoms of withdrawal can often be mitigated by slowing the taper. However, there are clinical circumstances in which opioids are discontinued abruptly. In patients who are physically dependent on opioids, an uncomfortable constellation of symptoms predictably ensues. While self-limiting, opioid withdrawal is difficult to tolerate through completion, and in patients with opioid use disorders (OUD), relapse to illicit opioid use is a common response to opioid withdrawal. For this reason, treatment of this self-limiting and generally non-life-threatening syndrome has important implications in the treatment of OUD. When patients with opioid dependence experience withdrawal symptoms, they are uncomfortable, and making people more comfortable is important. But how can we interpret the information on symptomatic relief to determine whether the effect is not just statistically significant, but clinically significant? How do we know if the drug has made enough difference to be clinically meaningful? If the patient is comfortable enough to tolerate the withdrawal, and to remain opioid-free until withdrawal is complete, the clinical meaningfulness is clear. If the patient has some relief of symptoms, but is still too uncomfortable to complete the withdrawal process, can we conclude that the amount of relief was not clinically relevant? We will ask you to discuss the relationship between the two concepts, mitigation of symptoms of opioid withdrawal, and facilitation of completion of detoxification, and whether the data support both claims. We will ask you to discuss whether it is possible to make a claim of symptomatic relief without evidence that the effect translates to improvement in completion of detoxification. The clinical data submitted in support of this application provide very limited exposures beyond five days of dosing. Moreover, the studied dose in the efficacy studies, 3.2 mg/day, was approximately twice the dose that has been reported to be effective in literature. Only one study provides efficacy data to support a dose lower than 3.2 mg/day. The data indicate dose-limiting adverse events include hypotension, bradycardia, and syncope. We will ask for your thoughts on what dose regimen should be recommended. There is a lack of any evidence of benefit of lofexidine when used in the extremely common scenario of gradual opioid taper. We will ask you how this information gap would be best addressed. The Division and the Agency are grateful to the members of the committee and our invited guests for taking time from your busy schedules to participate in this important meeting. Thank you in advance for your advice, which will aid us in making the most informed and appropriate decision possible. 5 Summary of Efficacy and Safety 1. Executive Summary ............................................................................................................ 12 2. Therapeutic Context .......................................................................................................... 12 Analysis of Condition .................................................................................................... 12 Analysis of Current Treatment Options ...................................................................... 13 3. History and Background .................................................................................................... 15 4. Nonclinical Pharmacology/Toxicology ............................................................................ 18 5. Clinical Pharmacology ....................................................................................................... 18 6. Review of Efficacy .................................................................................................................. 21 USWM-LX1-3002 ............................................................................................................ 21 Study Design ........................................................................................................... 21 Study Results ........................................................................................................... 29 USWM-LX1-3003-1 ......................................................................................................... 34 Study Design ........................................................................................................... 34 Study Results ........................................................................................................... 36 7. Review of Safety .................................................................................................................... 43 Review of the Safety Database ...................................................................................... 43 Overall Exposure ..................................................................................................... 43 Relevant characteristics of the safety population: ................................................. 45 Adequacy of the safety database: .......................................................................... 47 Adequacy of Applicant’s Clinical Safety Assessments .................................................... 47 Categorization of Adverse Events ........................................................................... 47 Routine Clinical Tests .............................................................................................. 47 Safety Results ................................................................................................................