Braeburn Inc.BRIXADI (buprenorphine) extended-release injection for subcutaneous use

NDA 210136 COMPLETE RESPONSE

Braeburn Inc. 450 Plymouth Road, Suite 400 Plymouth Meeting, PA 19462-1644

Attention: | Susan Franks, MS Senior Vice President, Head of Regulatory Affairs

Dear Ms. Franks:

Please refer to your new drug application (NDA) dated July 19, 2017, received July 19, 2017, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA) for BRIXADI (buprenorphine) extended-release injection for subcutaneous use.

We acknowledge receipt of your amendment dated June 1, 2020, which constituted a response to our December 21, 2018, action letter.

We have completed our review of this application, as amended, and have determined hat we cannot approve this application in its present form. We have described our reasons for this action below and, where possible, our recommendations to address hese issues.

FACILITY INSPECTIONS

During a recent inspection for this application of the Pharmaceutics International |" FEI 3006503102) manufacturing and testing facility located in Cockeysville, MD and he Pharmaceutics International © (FEI 1000513101) warehouse and testing acility located in Hunt Valley, MD, our field investigator conveyed deficiencies to the representatives of each facility. Satisfactory resolution of these deficiencies is required before this application may be approved.

PRESCRIBING INFORMATION

Your proposed Prescribing Information (Pl) must conform to the content and format regulations found at 21 CFR 201.56(a) and (d) and 201.57. As you develop your proposed PI, we encourage you to review the labeling review resources on the PLR Requirements for Prescribing Information’ and Pregnancy and Lactation Labeling Final

" http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/LawsActsandRules/ucm08415 9.htm

Reference ID: 4709890

NDA 210136 Page 2

Rule? websites, which include:

e The Final Rule (Physician Labeling Rule) on the content and format of the PI for human drug and biological products

e The Final Rule (Pregnancy and Lactation Labeling Rule) on the content and format of information in the PI on pregnancy, lactation, and females and males of reproductive potential

e Regulations and related guidance documents e Asample tool illustrating the format for Highlights and Contents, and

e The Selected Requirements for Prescribing Information (SRPI) - a checklist of important format items from labeling regulations and guidances.

e FDA's established pharmacologic class (EPC) text phrases for inclusion in the Highlights Indications and Usage heading.

Submit draft labeling that addresses our proposed revisions in the attached labeling.

Prior to resubmitting the labeling, use the SRPI checklist to correct any formatting errors to ensure conformance with the format items in regulations and guidances. In addition, submit updated content of labeling [21 CFR 314.50(I)(1)(i) in structured product labeling (SPL) format as described at FDA.gov.?

To facilitate review of your submission, provide a highlighted or marked-up copy that shows all changes, as well as a clean Word version. The marked-up copy should include annotations that support any proposed changes.

PROPRIETARY NAME

Please refer to correspondence dated, August 16, 2018, which addresses the proposed proprietary name, BRIXADI. This name was found acceptable pending approval of the application in the current review cycle. Please resubmit the proposed proprietary name when you respond to the application deficiencies.

RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS

We acknowledge the submission of your proposed modified REMS on June 1, 2020, which contains a Medication Guide, elements to assure safe use, an implementation system and a timetable for submission of assessments of the REMS. We will continue

? http://www. fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm09330 Zhtm

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

Reference ID: 4709890

NDA 210136 Page 3

discussion of your proposed modified REMS after your complete response to this action letter has been submitted.

SAFETY UPDATE

When you respond to the above deficiencies, include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and clinical studies/trials of the drug under consideration regardless of indication, dosage form, or dose level.

(1) Describe in detail any significant changes or findings in the safety profile.

(2) When assembling the sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, incorporate new safety data as follows:

e Present new safety data from the studies/clinical trials for the proposed indication using the same format as in the original submission.

e Present tabulations of the new safety data combined with the original application data.

e Include tables that compare frequencies of adverse events in the original application with the retabulated frequencies described in the bullet above.

e For indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in clinical trials.

(3) Present a retabulation of the reasons for premature trial discontinuation by incorporating the drop-outs from the newly completed trials. Describe any new trends or patterns identified.

(4) Provide case report forms and narrative summaries for each patient who died during a clinical trial or who did not complete a trial because of an adverse event. In addition, provide narrative summaries for serious adverse events.

(5) Describe any information that suggests a substantial change in the incidence of common, but less serious, adverse events between the new data and the original application data.

(6) Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).

(7) Provide a summary of worldwide experience on the safety of this drug. Include an updated estimate of use for drug marketed in other countries.

(8) Provide English translations of current approved foreign labeling not previously submitted.

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

Reference ID: 4709890

NDA 210136 Page 4

POSTMARKETING REQUIREMENTS UNDER 505(0)(3)

As described in our letter dated December 21, 2018, we have determined that, if this application is approved, you will be required to conduct postmarketing studies of BRIXADI to assess a known serious risk of precipitated withdrawal in patients whose initial injection of BRIXADI at a dose providing effective blockade of exogenous opioids (24 mg to 32 mg weekly; 64 mg to 96 mg monthly); and the unexpected risk of serious systemic histopathological changes, reproductive and developmental effects or cancer due to elemental impurities or leachables from the container closure into the drug product.

Specifically, we have determined that, if NDA 210136 is approved, you will be required, pursuant to section 505(0)(3) of the FDCA, to conduct the following:

1. Postmarketing clinical trial exploring how BRIXADI can be safely initiated at doses of 24 mg to 32 mg BRIXADI (weekly) without titration. The goals of the trial are to determine an accelerated dose-initiation regimen using BRIXADI (weekly) and assess the associated risks of precipitated withdrawal or inadequate dosing. Prespecify case definitions of precipitated withdrawal/lack of tolerability and dose inadequacy for the purposes of quantifying the risks of a more rapid initiation of BRIXADI (weekly).

2. Postmarketing clinical trial exploring how BRIXADI can be safely initiated at doses of 64 mg to 96 mg BRIXADI (monthly) without transferring from a period of treatment with another buprenorphine product. The goals of the trial are to determine an accelerated dose-initiation regimen using BRIXADI (monthly) and assess the associated risks of precipitated withdrawal or inadequate dosing. Prespecify case definitions of precipitated withdrawal/lack of tolerability and dose inadequacy for the purposes of quantifying the risks of a more rapid initiation of BRIXADI (monthly).

3. Evaluate elemental impurity levels in at least three batches of drug product on stability at 12 and 24 months or provide adequate extraction data to characterize the elemental impurities that could be leached from the container closure system using suitable solvents (e.g., nitric acid for elementals from glass).

4. Conduct a study to confirm, using validated methods, the identity of the

unspecified ©® the unidentified compound with relative retention time (RRT) of 7 minutes, the unknown compound containing with RRT of ® min, and the unknown compound with © with RRT of

min that were detected in your leachable studies above the safety concern threshold of 5 mcg/day and the levels of the identified leachables

©® Evaluate at least three batches of your to-be-marketed drug product at multiple timepoints over the

() 4)

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

Reference ID: 4709890

NDA 210136 Page 5

course of your stability studies to identify trends in leachable levels over time. Base the final safety assessment on the maximum predicted levels of leachables identified in individual batches to determine the safe level of exposure via the label-specified route of administration. Do not combine samples from different batches. Once chemical identification is confirmed for the unknown compounds, provide a toxicological risk assessment for each of these compounds and any other compounds detected at 25 mcg/day.

Any additional specific details of this required postmarketing study, including a timetable and annual reporting requirements, will be described more fully in the approval letter for this application, if it is approved.

If you complete this study prior to re-submitting your application, you may include the final report and relevant data sets in your Complete Response submission to facilitate review of the information.

ADDITIONAL COMMENTS

We have the following comments/recommendations that are not approvability issues:

Your assessment to establish a mode of action (MOA) for the NMP-induced ‘tumorigenesis observed in the 18-month study in B6C3F1 mice did not include adequate information to clearly demonstrate that the findings are not human- relevant. The information submitted was inadequate to conclude that the NMP- induced effects are potentially attributed entirely to a Peroxisome Proliferator- Activated Receptor (PPAR) alpha-mediated mechanism as proposed. However, because a no-observed effect level (NOEL) was established in the mouse study hat provided an 8-fold safety margin, we acknowledge that the risk to humans may not be significant. Therefore, no additional data are required, but the findings must be included in labeling. If you want to remove the language from labeling, you must submit a revised MOA assessment with additional data to bolster the weight of evidence that the tumorigenesis is driven by a PPAR alpha- mediated pathway. Refer to Klaunig et al., PPAR alpha Agonist-Induced Rodent Tumors: Modes of Action and Human Relevance. Critical Reviews In toxicology 33(6): 655-780. 2003.

OTHER

Within one year after the date of this letter, you are required to resubmit or take other actions available under 21 CFR 314.110. If you do not take one of these actions, we may consider your lack of response a request to withdraw the application under

21 CFR 314.65. You may also request an extension of time in which to resubmit the application.

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

Reference ID: 4709890

NDA 210136 Page 6

A resubmission must fully address all the deficiencies listed in this letter and should be clearly marked with "RESUBMISSION' in large font, bolded type at the beginning of the cover letter of the submission. The cover letter should clearly state that you consider his resubmission a complete response to the deficiencies outlined in this letter. A partial response to this letter will not be processed as a resubmission and will not start a new review cycle.

You may request a meeting or teleconference with us to discuss what steps you need to ake before the application may be approved. If you wish to have such a meeting, submit your meeting request as described in the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products.

The drug product may not be legally marketed until you have been notified in writing hat this application is approved.

If you have any questions, call Matthew Sullivan, Chief, Project Management Staff, at 301) 796-1245, or via email at matthew.sullivan@fda.gov.

Sincerely, {See appended electronic signature page}

Celia Winchell, MD

Associate Director for Addiction Medicine

Division of Anesthesiology, Addiction Medicine, and Pain Medicine

Office of Neuroscience

Center for Drug Evaluation and Research

ENCLOSURE: e Labeling

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov 51 Pages have been Withheld in Full as B4 (CCI/TS) immediately following this Reference ID: 4709890 page

Signature Page 1 of 1

This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.

CELIA J WINCHELL 12/01/2020 04:15:54 PM

Reference ID: 4709890