`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`202788Orig1s000
`
`
`Subsys
`
`Fentanyl sublingual spray
`
`Insys Therapeutics, Inc.
`
`January 2, 2012
`
`Trade Name:
`
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
` For the management of breakthrough pain in adult
`cancer patients who are already receiving and who are
`tolerant to around-the-clock opioid therapy for their
`underlying persistent cancer pain
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`
`
`CONTENTS
`
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
`
`X
`X
`X
`X
`
`X
`X
`X
`
`X
`X
`X
`X
`X
`X
`X
`X
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`202788Orig1s000
`
`
`APPROVAL LETTER
`
`
`
`
`
`

`

`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`NDA 202788
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`NDA APPROVAL
`
`
`
`Insys Therapeutics, Inc.
`(c/o) The Weinberg Group, Inc.
`1129 Twentieth Street, NW
`Suite 600
`Washington, DC 20036
`
`Attention: Lauren H. Wind, MPH
`
`
`Senior Consultant
`
`
`The Weinberg Group, Inc.
`
`Dear Ms. Wind:
`
`Please refer to your New Drug Application (NDA) dated and received March 4, 2011, submitted
`pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA), for Subsys
`(fentanyl sublingual spray).
`
`We acknowledge receipt of your amendments dated March 14, April 5, 15, 21, and 29, May 18,
`20, and 27, June 29, July 7 and 11, August 5 and 25, September 21, 26 (2), and 29, October 3
`and 21, November 18, 23, and 28, and December 6, 19, 21, 22, and 28, 2011.
`
`This new drug application provides for the use of Subsys (fentanyl sublingual spray) for the
`management of breakthrough pain in adult cancer patients who are already receiving and who are
`tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain.
`
`We have completed our review of this application, as amended, and it is approved, effective on
`the date of this letter, for use as recommended in the enclosed agreed-upon labeling text.
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert, Medication
`Guide). Information on submitting SPL files using eLIST may be found in the guidance for
`industry titled “SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`Reference ID: 3066874
`
`

`

`NDA 202788
`Page 2
`
`
`
`The SPL will be accessible via publicly available labeling repositories.
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`Submit final printed carton and container labels that are identical to the enclosed carton and
`immediate container labels as soon as they are available, but no more than 30 days after they are
`printed. Please submit these labels electronically according to the guidance for industry titled
`“Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Product
`Applications and Related Submissions Using the eCTD Specifications (June 2008).”
`Alternatively, you may submit 12 paper copies, with 6 of the copies individually mounted on
`heavy-weight paper or similar material. For administrative purposes, designate this submission
`“Final Printed Carton and Container Labels for approved NDA 202788.” Approval of this
`submission by FDA is not required before the labeling is used.
`
`Marketing the product(s) with FPL that is not identical to the approved labeling text may render
`the product misbranded and an unapproved new drug.
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`We are waiving the pediatric study requirement for this application because necessary studies are
`impossible or highly impracticable. There are too few children who would be appropriate for this
`product for studies to be feasible.
`
`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`Section 505-1 of the FDCA authorizes FDA to require the submission of a risk evaluation and
`mitigation strategy (REMS), if FDA determines that such a strategy is necessary to ensure that
`the benefits of the drug outweigh the risks [section 505-1(a)].
`
`In accordance with section 505-1 of FDCA, we have determined that a REMS is necessary for
`Subsys (fentanyl sublingual spray) to ensure the benefits of the drug outweigh the risks of
`misuse, abuse, addiction, overdose, and serious complications due to medication errors.
`
`In accordance with section 505-1 of FDCA, as one element of a REMS, FDA may require the
`development of a Medication Guide as provided for under 21 CFR 208. Pursuant to
`21 CFR 208, FDA has determined that Subsys (fentanyl sublingual spray) poses a serious and
`significant public health concern requiring the distribution of a Medication Guide. The
`Medication Guide is necessary for patients’ safe and effective use of Subsys (fentanyl sublingual
`spray). FDA has determined that Subsys (fentanyl sublingual spray) is a product for which
`
`Reference ID: 3066874
`
`

`

`NDA 202788
`Page 3
`
`
`patient labeling could help prevent serious adverse effects and that has serious risks (relative to
`benefits) of which patients should be made aware because information concerning the risks could
`affect patients’ decisions to use, or continue to use Subsys (fentanyl sublingual spray). Under
`21 CFR 208, you are responsible for ensuring that the Medication Guide is available for
`distribution to patients who are dispensed Subsys (fentanyl sublingual spray).
`
`Pursuant to 505-1(f)(1), we have also determined that Subsys (fentanyl sublingual spray) can be
`approved only if elements necessary to assure safe use are required as part of a REMS to
`mitigate the risks of misuse, abuse, addiction, overdose, and serious complications due to
`medication errors that are listed in the labeling. The elements to assure safe use will help assure
`proper patient selection and dispensing of Subsys (fentanyl sublingual spray).
`
`We remind you that section 505-1(f)(8) of FDCA prohibits holders of an approved covered
`application with elements to assure safe use from using any element to block or delay approval
`of an application under section 505(b)(2) or (j). A violation of this provision in 505-1(f) could
`result in enforcement action.
`
`Your proposed REMS, submitted on December 28, 2011, and appended to this letter, is
`approved. The REMS consists of a Medication Guide, elements to assure safe use,
`implementation system, and a timetable for submission of assessments of the REMS.
`
`This REMS will use a single shared system for the elements to assure safe use and
`implementation system in the approved REMS. The individual sponsors who are part of the
`single shared system are collectively referred to as TIRF sponsors. This single shared system,
`the TIRF REMS Access program, includes the following products:
`
`NDA 020747
`NDA 021947
`NDA 022266
`NDA 022510
`NDA 022569
`NDA 202788
`ANDA 077312
`
`Actiq (fentanyl citrate) oral transmucosl lozenge
`Fentora (fentanyl buccal tablets)
`Onsolis (fentanyl buccal soluble film)
`Abstral (fentanyl) sublingual tablets
`Lazanda (fentanyl) nasal spray
`Subsys (fentanyl sublingual spray)
`Fentanyl Citrate Oral Transmucosal Lozenge
`
`
`
`
`
`Other products may be added in the future if additional NDAs or ANDAs are approved.
`
`Your REMS must be fully operational before you introduce Subsys (fentanyl sublingual spray)
`into interstate commerce.
`
`The REMS assessment plan should include, but is not limited to, the following:
`
`
`1. The TIRF REMS Access Program Outreach
`The following metrics will be tabulated for every reporting period to assess program
`outreach efforts:
`
`Reference ID: 3066874
`
`

`

`NDA 202788
`Page 4
`
`
`
`a. Number of Dear HCP letters mailed to prescribers (by date)
`b. Number of returned mailings of Dear HCP letters to prescribers
`c. Number of Pharmacist letters mailed to pharmacies (by date)
`d. Number of returned mailings of Pharmacist letters to pharmacies
`
`
`
`2. The TIRF REMS Access Program Utilization Statistics
`For the assessment of enrollment, utilization, and discontinuation statistics for
`prescribers, pharmacies, patients, and distributors, the following data will be tabulated for
`each reporting period and cumulatively:
`a. Number of new patients enrolled by state
`b. Number of patients inactivated
`c. Number of new prescribers enrolled by state. Include the method of enrollment and
`number of incomplete forms and, to extent possible, a brief description of the reason
`for incomplete data fields
`d. Number of attempts needed for prescribers to successfully complete Knowledge
`Assessments, along with the method of completion utilized
`e. Number of prescribers who are inactivated
`f. Number of new pharmacies enrolled by type (inpatient or outpatient), by state.
`Include the method of enrollment and number of incomplete forms and, to extent
`possible, a brief description of the reason for incomplete data fields
`g. Number of attempts needed for pharmacies to successfully complete Knowledge
`Assessments
`h. Number of pharmacies that are inactivated by type (inpatient or outpatient)
`i. Dispensing activity for enrolled outpatient pharmacies. Including,
`(1) Total number of prescriptions authorized
`(2) Total number of prescriptions denied and reasons for denial
`i. Number of prescriptions rejected for safety issues (include description
`of safety issues and any interventions or corrective actions taken)
`ii. Number of prescriptions rejected for other reasons (include description
`of other reasons, e.g., prescriber not being enrolled)
`j. Summary of cases identified where a patient received prescriptions for a TIRF
`medicine from multiple prescribers within an overlapping time frame (description of
`any investigations and the outcome)
`k. Number of new distributors enrolled. Include the method of enrollment and number
`of incomplete forms and, to extent possible, a brief description of the reason for
`incomplete data fields
`
`Reference ID: 3066874
`
`

`

`NDA 202788
`Page 5
`
`
`
`l. Number of distributors inactivated, total
`m. A histogram of the number of days between passive enrollment and receipt of a
`Patient-Prescriber Agreement Form stratified by the method of PPAF submission
`n. A histogram of the number of prescriptions dispensed per patient during the first 10
`days after patient passive enrollment stratified by whether there is a PPAF in place.
`
`
`
`3. Program Infrastructure and Performance
`The following metrics on program infrastructure performance will be tabulated for each
`reporting period and cumulatively:
`a. Assessment of process for pharmacies to upgrade their pharmacy management
`systems (mean, maximum, and minimum time needed, number of pharmacies that
`attempted and failed to upgrade their systems)
`b. Number of times a backup system was used to validate a prescription, with reason for
`each instance (pharmacy level problem, switch problem, or REMS database problem)
`c. Call center report with
`(1) Summary of frequently asked questions
`(2) Problems reported
`d. Description of corrective actions taken to address program/system problems.
`e. Number of reports of lack of enrolled prescribers in a patient’s area
`f. Number of reports of lack of enrolled pharmacies in a patient’s area
`g. Delays after original prescriptions are denied by pharmacy and brief summary to
`include characterization of delays
`The following reports for unintended system interruptions will be provided for each
`reporting period:
`h. Reports identified of inadvertent enrollment deactivations
`i. Reports of false positives (e.g., all entities not enrolled but system generated a
`prescription authorization code)
`j. Reports of failure of re-enrollment notifications to reach stakeholders
`k. Reports of false negatives (e.g., all entities enrolled but the system generated a
`prescription rejection notice), including brief summary of reason for rejection.
`
`
`4. Safety Surveillance
`a. TIRF Sponsors will process adverse event reports related to their specific products
`and report to the FDA according to current regulations outlined in 21 CFR 314.80 and
`the sponsor’s respective Standard Operating Procedures.
`b. Surveillance data from the following sources will be included in the REMS
`Assessment Reports:
`
`Reference ID: 3066874
`
`

`

`NDA 202788
`Page 6
`
`
`
`(1) FDA AERS database using signal detection methods for TIRF medicines with
`outcomes of death, overdose, misuse, abuse, addiction, inappropriate
`prescribing, medication errors, and accidental exposures/ingestion
`(2) Other external databases.
`
`
`
`5. Periodic Surveys of Patients, Healthcare Providers, and Pharmacies
`Prescribers’, pharmacists’, and patients’ understanding regarding the appropriate use of
`TIRF medicines and TIRF REMS Access program requirements will be evaluated
`through knowledge, attitude, and behavior (KAB) surveys. The surveys will be
`administered to randomly selected prescribers, pharmacies, and patients. Survey results
`will be reported at 12 months and 24 months after the TIRF REMS Access program
`approval. The TIRF REMS Industry Working Group (TRIG) will discuss with the FDA
`if additional surveys are needed after 24 months. The results from the surveys will be
`analyzed together with other REMS assessment data, and a report on any corrective
`actions taken and the outcome of those actions will be provided.
`
`
`
`
`
`
`
`6. TIRF REMS Access Non-Compliance Plan
`The TIRF Sponsors will implement a process for addressing stakeholder non-compliance
`in the program. The TRIG should provide the following in the first assessment:
`a. A description of personnel that constitute the Non-Compliance Review Team
`b. Describe how non-compliance information is collected and tracked to determine
`when the plan should be modified
`If changes occur in any of the above information, it should be provided in subsequent
`assessments.
`The TIRF sponsors should provide the following data regarding non-compliance in each
`assessment report:
`a. Identify the number of non-compliant events.
`b. Describe the non-compliant event and the corrective action measure taken.
`c. Provide the outcome of the corrective action.
`
`7. The requirements for assessments of an approved REMS under section 505-1(g)(3)
`include, in section 505-1(g)(3)(A), an assessment of the extent to which the elements to
`assure safe use are meeting the goal or goals to mitigate a specific serious risk listed in
`the labeling of the drug, or whether the goal or goals or such elements should be
`modified.
`
`8. Information on the status of any postapproval study or clinical trial required under section
`505(o) or otherwise undertaken to investigate a safety issue. With respect to any such
`postapproval study, you must include the status of such study, including whether any
`difficulties completing the study have been encountered. With respect to any such
`
`Reference ID: 3066874
`
`

`

`NDA 202788
`Page 7
`
`
`
`postapproval clinical trial, you must include the status of such clinical trial, including
`whether enrollment has begun, the number of participants enrolled, the expected
`completion date, whether any difficulties completing the clinical trial have been
`encountered, and registration information with respect to requirements under subsections
`(i) and (j) of section 402 of the Public Health Service Act. You can satisfy these
`requirements in your REMS assessments by referring to relevant information included in
`the most recent annual report required under section 506B and 21 CFR 314.81(b)(2)(vii)
`and including any material or significant updates to the status information since the
`annual report was prepared. Failure to comply with the REMS assessments provisions in
`section 505-1(g) could result in enforcement action.
`
`
`Under section 505-1(g)(2)(C) and (D), FDA may require the submission of a REMS assessment
`if FDA determines that new safety or effectiveness information indicates that a REMS element
`should be modified or included in the strategy.
`
`We remind you that in addition to the assessments submitted according to the timetable included
`in the approved REMS, you must submit a REMS assessment and may propose a modification to
`the approved REMS when you submit a supplemental application for a new indication for use as
`described in section 505-1(g)(2)(A) of the FDCA.
`
`If the assessment instruments and methodology for your REMS assessments are not included in
`the REMS supporting document, or if you propose changes to the submitted assessment
`instruments or methodology, you should update the REMS supporting document to include
`specific assessment instrument and methodology information at least 90 days before the
`assessments will be conducted. Updates to the REMS supporting document may be included in a
`new document that references previous REMS supporting document submission(s) for
`unchanged portions. Alternatively, updates may be made by modifying the complete previous
`REMS supporting document, with all changes marked and highlighted. Prominently identify the
`submission containing the assessment instruments and methodology with the following wording
`in bold capital letters at the top of the first page of the submission:
`
`
`NDA 202788 REMS CORRESPONDENCE
`(insert concise description of content in bold capital letters, e.g.,
`UPDATE TO REMS SUPPORTING DOCUMENT - ASSESSMENT
`METHODOLOGY)
`
`
`An authorized generic drug under this NDA must have an approved REMS prior to marketing.
`Should you decide to market, sell, or distribute an authorized generic drug under this NDA,
`contact us to discuss what will be required in the authorized generic drug REMS submission..
`
`Prominently identify the submission containing the REMS assessments or proposed
`modifications with the following wording in bold capital letters at the top of the first page of the
`submission:
`
`
`
`
`Reference ID: 3066874
`
`

`

`NDA 202788
`Page 8
`
`
`
`NDA 202788 REMS ASSESSMENT
`
`NEW SUPPLEMENT FOR NDA 202788
`PROPOSED REMS MODIFICATION
`REMS ASSESSMENT
`
`NEW SUPPLEMENT (NEW INDICATION FOR USE)
`FOR NDA 202788
`REMS ASSESSMENT
`PROPOSED REMS MODIFICATION (if included)
`
`
`If you do not submit electronically, please send 5 copies of REMS-related submissions.
`
`
`EXPIRY DATING PERIOD
`
` A
`
` 36-month expiration dating period is granted for the drug product when stored at 20-25°C
`(68 to 77°F) with excursions permitted from 15° to 30°C (59° to 86°F).
`
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
`proposed materials in draft or mock-up form with annotated references, and the package insert
`to:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
`package insert, at the time of initial dissemination or publication, accompanied by a Form FDA
`2253. For instruction on completing the Form FDA 2253, see page 2 of the Form. For more
`information about submission of promotional materials to the Office of Prescription Drug
`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`
`
`
`Reference ID: 3066874
`
`

`

`NDA 202788
`Page 9
`
`
`
`
`If you have any questions, call Matthew Sullivan, Senior Regulatory Project Manager, at (301)
`796-1245.
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Bob A. Rappaport, M.D.
`Director
`Division of Anesthesia, Analgesia,
` and Addiction Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`
`
`ENCLOSURE(S):
`Content of Labeling
`Carton and Container Labeling
`REMS
`
`Reference ID: 3066874
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`BOB A RAPPAPORT
`01/04/2012
`
`Reference ID: 3066874
`
`