CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`
`APPLICATION NUMBER:
`202788Orig1s000
`
`
`
`OTHER REVIEW(S)
`
`
`
`
`
`

`

`505(b)(2) ASSESSMENT
`
`NDA # 202788
`
`NDA Supplement #: 8-
`
`Efficacy Supplement Type SE-
`
`malignancies
`
`Proprietary Name: Subsys
`Established/Proper Name: fentanyl
`Dosage Form: sublingual spray
`Stren Is: 100, 200, 400. 600, 800 mc
`
`Applicant: Insys Therapeutics
`
`Date of Receipt: March 4. 2011
`
`PDUFA Goal Date: January 4, 2012
`
`Action Goal Date (if different):
`Possibl mid-December
`
`Proposed Indication(s): Management of breakthrough cancer pain in opioid tolerant patients with
`
`GENERAL INFORMATION
`
`1)
`
`Is this application for a recombinant or biologically-derived product and/or protein or peptide
`product OR is the applicant relying on a recombinant or biologically-derived product and/or
`protein or peptide product to support approval of the proposed product?
`
`YEsEl
`
`N0|Z|
`
`If “YES “contact the (b)(2) review staflin the Immediate Oflice, Ofiice ofNew Drugs.
`
`Reference ID: 3066691
`
`Page 1
`Version: March 2009
`
`

`

`
`
`INFORMATION PROVIDED VIA RELIANCE
`(LISTED DRUG OR LITERATURE)
`
`
`2) List the information essential to the approval of the proposed drug that is provided by reliance
`on our previous finding of safety and efficacy for a listed drug or by reliance on published
`literature. (If not clearly identified by the applicant, this information can usually be derived
`from annotated labeling.)
`
`
`Source of information* (e.g.,
`published literature, name of
`referenced product)
`Actiq (NDA 020747)
`
`Information provided (e.g.,
`pharmacokinetic data, or specific
`sections of labeling)
`Nonclinical labeling
`
`
`
`
`
`
`
`
`
` *each source of information should be listed on separate rows
`
`
`3) Reliance on information regarding another product (whether a previously approved product
`or from published literature) must be scientifically appropriate. An applicant needs to
`provide a scientific “bridge” to demonstrate the relationship of the referenced and proposed
`products. Describe how the applicant bridged the proposed product to the referenced
`product(s). (Example: BA/BE studies)
`
`BA/BE studies
`
`
`
`RELIANCE ON PUBLISHED LITERATURE
`
`
`4) (a) Regardless of whether the applicant has explicitly stated a reliance on published literature
`to support their application, is reliance on published literature necessary to support the
`approval of the proposed drug product (i.e., the application cannot be approved without the
`published literature)?
` YES
` NO
`
`If “NO,” proceed to question #5.
`
`
`
`(b) Does any of the published literature necessary to support approval identify a specific (e.g.,
`brand name) listed drug product?
` YES
` NO
`
`If “NO”, proceed to question #5.
`If “YES”, list the listed drug(s) identified by name and answer question #4(c).
`
`
`
`(c) Are the drug product(s) listed in (b) identified by the applicant as the listed drug(s)?
` YES
`
` NO
`
`
`
`
`
`
`
`
`
`Page 2
`Version: March 2009
`
`Reference ID: 3066691
`
`

`

`
`
`
`
`RELIANCE ON LISTED DRUG(S)
`
`Reliance on published literature which identifies a specific approved (listed) drug constitutes
`reliance on that listed drug. Please answer questions #5-9 accordingly.
`
`
`5) Regardless of whether the applicant has explicitly referenced the listed drug(s), does the
`application rely on the finding of safety and effectiveness for one or more listed drugs
`(approved drugs) to support the approval of the proposed drug product (i.e., the application
`cannot be approved without this reliance)?
`
` NO
` YES
`If “NO,” proceed to question #10.
`
`
`6) Name of listed drug(s) relied upon, and the NDA/ANDA #(s). Please indicate if the applicant
`explicitly identified the product as being relied upon (see note below):
`
`
`Name of Drug
`
`NDA/ANDA #
`
`020747
`
`
`
`Did applicant
`specify reliance on
`the product? (Y/N)
`Y
`
`
`
`Actiq
`
`
`
`
`
`Applicants should specify reliance on the 356h, in the cover letter, and/or with their patent
`certification/statement. If you believe there is reliance on a listed product that has not been
`explicitly identified as such by the applicant, please contact the (b)(2) review staff in the
`Immediate Office, Office of New Drugs.
`
`
`7) If this is a (b)(2) supplement to an original (b)(2) application, does the supplement rely upon
`the same listed drug(s) as the original (b)(2) application?
` N/A
` NO
`
` YES
`If this application is a (b)(2) supplement to an original (b)(1) application or not a supplemental
`application, answer “N/A”.
`If “NO”, please contact the (b)(2) review staff in the Immediate Office, Office of New Drugs.
`
`
`8) Were any of the listed drug(s) relied upon for this application:
`a) Approved in a 505(b)(2) application?
` YES
` NO
`
`If “YES”, please list which drug(s).
`Name of drug(s) approved in a 505(b)(2) application:
`
`
`b) Approved by the DESI process?
` YES
` NO
`
`If “YES”, please list which drug(s).
`Name of drug(s) approved via the DESI process:
`
`c) Described in a monograph?
` YES
` NO
`
`If “YES”, please list which drug(s).
`
`
`
`
`
`
`Page 3
`Version: March 2009
`
`Reference ID: 3066691
`
`

`

`
`
`
`
`Name of drug(s) described in a monograph:
`
`d) Discontinued from marketing?
` YES
` NO
`
`If “YES”, please list which drug(s) and answer question d) i. below.
`If “NO”, proceed to question #9.
`Name of drug(s) discontinued from marketing:
`
`i) Were the products discontinued for reasons related to safety or effectiveness?
` YES
`
` NO
`(Information regarding whether a drug has been discontinued from marketing for
`reasons of safety or effectiveness may be available in the Orange Book. Refer to
`section 1.11 for an explanation, and section 6.1 for the list of discontinued drugs. If
`a determination of the reason for discontinuation has not been published in the
`Federal Register (and noted in the Orange Book), you will need to research the
`archive file and/or consult with the review team. Do not rely solely on any
`statements made by the sponsor.)
`
`9) Describe the change from the listed drug(s) relied upon to support this (b)(2) application (for
`example, “This application provides for a new indication, otitis media” or “This application
`provides for a change in dosage form, from capsule to solution”).
`
`This application provides for a new dosage form.
`
`
`
`The purpose of the following two questions is to determine if there is an approved drug product
`that is equivalent or very similar to the product proposed for approval that should be referenced
`as a listed drug in the pending application.
`
`The assessment of pharmaceutical equivalence for a recombinant or biologically-derived product
`and/or protein or peptide product is complex. If you answered YES to question #1, proceed to
`question #12; if you answered NO to question #1, proceed to question #10 below.
`
`10) (a) Is there a pharmaceutical equivalent(s) to the product proposed in the 505(b)(2)
`application that is already approved (via an NDA or ANDA)?
`
`
`
`
`
`
`
`
`(Pharmaceutical equivalents are drug products in identical dosage forms that: (1) contain
`identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the
`same therapeutic moiety, or, in the case of modified release dosage forms that require a
`reservoir or overage or such forms as prefilled syringes where residual volume may vary,
`that deliver identical amounts of the active drug ingredient over the identical dosing period;
`(2) do not necessarily contain the same inactive ingredients; and (3) meet the identical
`compendial or other applicable standard of identity, strength, quality, and purity, including
`potency and, where applicable, content uniformity, disintegration times, and/or dissolution
`rates. (21 CFR 320.1(c)).
`
`Note that for proposed combinations of one or more previously approved drugs, a pharmaceutical
`equivalent must also be a combination of the same drugs.
`
` YES
`
`
`
`
`
`
`Page 4
`Version: March 2009
`
`Reference ID: 3066691
`
` If “NO” to (a) proceed to question #11.
`
`
`
` NO
`
`

`

`
`
`(b) Is the pharmaceutical equivalent approved for the same indication for which the
`505(b)(2) application is seeking approval?
` YES
`
`
`If “YES” to (a), answer (b) and (c) then proceed to question #12.
`
`
` NO
`
`(c) Is the listed drug(s) referenced by the application a pharmaceutical equivalent?
` YES
` NO
`
`
`
`If “YES” to (c) and there are no additional pharmaceutical equivalents listed, proceed to
`question #12.
`If “NO” or if there are additional pharmaceutical equivalents that are not referenced by the
`application, list the NDA pharmaceutical equivalent(s); you do not have to individually list all
`of the products approved as ANDAs, but please note below if approved approved generics are
`listed in the Orange Book. Please also contact the (b)(2) review staff in the Immediate Office,
`Office of New Drugs.
`
`Pharmaceutical equivalent(s):
`
`
`11) (a) Is there a pharmaceutical alternative(s) already approved (via an NDA or ANDA)?
`
`(Pharmaceutical alternatives are drug products that contain the identical therapeutic moiety, or its
`precursor, but not necessarily in the same amount or dosage form or as the same salt or ester. Each
`such drug product individually meets either the identical or its own respective compendial or other
`applicable standard of identity, strength, quality, and purity, including potency and, where applicable,
`content uniformity, disintegration times and/or dissolution rates. (21 CFR 320.1(d)) Different dosage
`forms and strengths within a product line by a single manufacturer are thus pharmaceutical
`alternatives, as are extended-release products when compared with immediate- or standard-release
`formulations of the same active ingredient.)
`
`Note that for proposed combinations of one or more previously approved drugs, a pharmaceutical
`alternative must also be a combination of the same drugs.
`
` NO
`
` YES
`If “NO”, proceed to question #12.
`
`
`
`(b) Is the pharmaceutical alternative approved for the same indication for which the
`505(b)(2) application is seeking approval?
` YES
`
`(c) Is the approved pharmaceutical alternative(s) referenced as the listed drug(s)?
` YES
`
` NO
`
`If “YES” and there are no additional pharmaceutical alternatives listed, proceed to question
`#12.
`If “NO” or if there are additional pharmaceutical alternatives that are not referenced by the
`application, list the NDA pharmaceutical alternative(s); you do not have to individually list all
`of the products approved as ANDAs, but please note below if approved generics are listed in
`the Orange Book. Please also contact the (b)(2) review staff in the Immediate Office, Office of
`New Drugs.
`
` NO
`
`
`
`
`
`
`
`
`
`Page 5
`Version: March 2009
`
`Reference ID: 3066691
`
`

`

`Pharmaceutical alternative(s):
`
`NDA#
`
`Duragesic
`
`
`
`019813
`
`020747
`
`NDA#
`
`NDA#
`
`022266
`
`NDA#
`
`022510
`
`NDA#
`
`021947
`
`NDA#
`
`016619
`
`Sublimaze
`
`Actiq
`
`Onsolis
`
`Abstral
`
`Fentora
`
`Ionsys
`
`Lazanda
`
`fentanyl
`
`NDA#
`
`021338
`
`NDA #
`
`022569
`
`various
`ANDAs
`
`
`
`
`
`refer to Orange book for
`complete list
`
`PATENT CERTIFICATION/STATEMENTS
`
` proceed to question #14
`
`
`12) List the patent numbers of all unexpired patents listed in the Orange Book for the listed
`drug(s) for which our finding of safety and effectiveness is relied upon to support approval of
`the (b)(2) product.
`
`Listed drug/Patent number(s):
`
` No patents listed
`
`
`
`13) Did the applicant address (with an appropriate certification or statement) all of the unexpired
`patents listed in the Orange Book for the listed drug(s) relied upon to support approval of the
`(b)(2) product?
` YES
` NO
`
`If “NO”, list which patents (and which listed drugs) were not addressed by the applicant.
`
`Listed drug/Patent number(s):
`
`
`14) Which of the following patent certifications does the application contain? (Check all that
`apply and identify the patents to which each type of certification was made, as appropriate.)
`
`
`
`
` No patent certifications are required (e.g., because application is based solely on
`published literature that does not cite a specific innovator product)
`
`
`
`
`
`Page 6
`Version: March 2009
`
`Reference ID: 3066691
`
`

`

`
`
` 21 CFR 314.50(i)(1)(i)(A)(1): The patent information has not been submitted to
`FDA. (Paragraph I certification)
`
`
`X
`
`
`21 CFR 314.50(i)(1)(i)(A)(2): The patent has expired. (Paragraph II certification)
`
`Patent number(s):
`
`
`
`
`
`
`
` 21 CFR 314.50(i)(1)(i)(A)(3): The date on which the patent will expire. (Paragraph
`III certification)
`
`Patent number(s):
`
`Expiry date(s):
`
`
`
` 21 CFR 314.50(i)(1)(i)(A)(4): The patent is invalid, unenforceable, or will not be
`infringed by the manufacture, use, or sale of the drug product for which the
`application is submitted. (Paragraph IV certification). If Paragraph IV certification
`was submitted, proceed to question #15.
`
` 21 CFR 314.50(i)(3): Statement that applicant has a licensing agreement with the
`NDA holder/patent owner (must also submit certification under 21 CFR
`314.50(i)(1)(i)(A)(4) above). If the applicant has a licensing agreement with the
`NDA holder/patent owner, proceed to question #15.
`
`21 CFR 314.50(i)(1)(ii): No relevant patents.
`
`
` 21 CFR 314.50(i)(1)(iii): The patent on the listed drug is a method of use patent
`and the labeling for the drug product for which the applicant is seeking approval
`does not include any indications that are covered by the use patent as described in
`the corresponding use code in the Orange Book. Applicant must provide a
`statement that the method of use patent does not claim any of the proposed
`indications. (Section viii statement)
`
`Patent number(s):
`Method(s) of Use/Code(s):
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`15) Complete the following checklist ONLY for applications containing Paragraph IV
`certification and/or applications in which the applicant and patent holder have a licensing
`agreement:
`
`(a) Patent number(s):
`(b) Did the applicant submit a signed certification stating that the NDA holder and patent
`owner(s) were notified that this b(2) application was filed [21 CFR 314.52(b)]?
` YES
`
` NO
`If “NO”, please contact the applicant and request the signed certification.
`
`
`(c) Did the applicant submit documentation showing that the NDA holder and patent
`owner(s) received the notification [21 CFR 314.52(e)]? This is generally provided in the
`form of a registered mail receipt.
`
`
`
`
`
`Page 7
`Version: March 2009
`
`Reference ID: 3066691
`
`

`

`
`
`
`
` NO
`
` YES
`If “NO”, please contact the applicant and request the documentation.
`
`
`(d) What is/are the date(s) on the registered mail receipt(s) (i.e., the date(s) the NDA holder
`and patent owner(s) received notification):
`
`Date(s):
`
`(e) Has the applicant been sued for patent infringement within 45-days of receipt of the
`notification listed above?
`
`
`
`Note that you may need to call the applicant (after 45 days of receipt of the notification)
`to verify this information UNLESS the applicant provided a written statement from the
`notified patent owner(s) that it consents to an immediate effective date of approval.
`
`
` Patent owner(s) consent(s) to an immediate effective date of
`approval
`
`YES
`
`NO
`
`
`
`
`
`Cleared on 1/3/11
`S. Stradley
`
`
`
`
`
`Page 8
`Version: March 2009
`
`Reference ID: 3066691
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SARA E STRADLEY
`01/04/2012
`
`Reference ID: 3066691
`
`

`

`5'
`1%.
`
`“rm
`
`.
`-
`v
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`'
`
`M E M O R A N D U M
`
`Food and Drug Administration
`Center for Devices and
`Radiological Health
`Office of Device Evaluation
`White Oak Building 66
`.
`10903 New Hampshire Avenue
`Silver Spring, MD 20993
`
`Date:
`
`From:
`
`To:
`
`September. 7 2011
`
`LCDR Alan Stevens, Infusion Pump Team Leader W066. RM 2561
`General Hospital Devices Branch, DAGID, ODE. CDRH
`
`Kathleen Davies. Project Manager. W022 RM3189
`CDERION DIODEIIIDAAAP
`
`Subject:
`
`CDRH Consult. GEN 1 100679, NDA 202788, sublingual spray unit dose system to
`deliver Fentanyl
`
`1. issue
`
`The Center for Drug Evaluation and Research (CDER)] has requested a consult from the 7
`Center for Devices and Radiological Health (CDRH. regarding NDA 202788. The device
`constituent of this combination product consists of a sublingual spray unit dose system.
`
`2. Devlgg‘ Descrlfllon .
`
`
`
`Reference ID: 3064767
`
`Page 1 of 3
`
`

`

`NDA 202788, GEN1100679
`
`
`Insys Therapeutics, Incorporated
`
`
`Sublingual Spray Unit Dose System for delivery of Fentanyl
`
`
`
`
`
`
`
`
`no further mitigations are required. However, no design controls are identified. Instead,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the dFMEA has identified manufacturing controls. Please'modify the dFMEA to identify
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`design controls and provide evidence that implementation of the design controls are
`effective.
`
`
`
`
`
`
`
`
`
`
`
`
`If you have any questions, please contact LCDR Alan Stevens at 301-796-6294.
`
`Sincerely,
`
`‘
`
`LCDR Alan Stevens
`
`
`
`Mechanical Engineer
`
`
`
`C n urred 8W
`
`
`
`aqu me Ryan
`bin tion Products Team Leader
`
`
`
`
`
`Reference ID: 3064767
`Reference ID: 3064767
`
`Page 3 of 3
`
`
`
`

`

`NDA 202788, GEN1100679
`Insys Therapeutics. Incorporated
`Sublingual Spray Unit Dose System for delivery of Fentanyl
`
`The Fentanyl Sublingual Spray unit dose system consists of an actuator, insert, spray pin,
`needle, stopper, glass vial and vial holder.
`(”i“)
`
`(b) (4)
`
`3. Documents Reviewed
`
`NDA 202788, Sequence 0000, Section 3.2.P.7 (Container Closure System)
`NDA 202778, Sequence 0000, Section 3.2.P.2 (Design Failure Modes and Effects Analysis)
`Drug Master File
`“(4) —
`(him
`
`4. CDRH Review and Comments
`
`CDRH’s Review of the device constituent for this Combination Product ‘consisted of an
`
`assessment of the Failure Modes and Effects Analysis.
`
`«
`
`Design Failure Modes and Effects Analysis
`The dFMEA analyzed failure modes associated with each component of the device
`constituent, including:
`
`Container (glass vial)
`Plunger (stopper)
`Cannula (needle)
`insert (nozzle)
`Container holder (vial holder)
`Actuator
`
`Spray Pin
`
`For each component, the sponsor identifies potential failure modes and associated causes.
`
`The sponsor claims to have identified design controls for each failure mode and, based on
`their analysis, concludes that no further mitigations are required. However, no design controls
`are identified. instead, the sponsor has identified manufacturing controls.
`
`The sponsor should identify design controls for each failure mode, and provide data verifying
`the effectiveness of each control measure.
`
`"’"4’ contained only biocompatibility test reports for materials of construction, which
`DMF
`were not reviewed at this time.
`-
`
`5. CDRH Recommendation
`
`Based on our review, the following deficiencies should be conveyed to the Sponsor:
`
`1. You have provided a design failure modes and effects analysis. For each component,
`you have identified potential failure modes and associated causes. You claim to have
`identified design controls for each failure mode and, based on the analysis. conclude that
`
`Reference ID: 3064767
`
`Page 2 of 3
`
`

`

`
`
`ADDENDUM:
`
`
`December 28, 2011
`
`
`
`
`
`
`
`
`
`
`
`
`
`It appears comprehensive. The
`l have reviewed the dFMEA provided by the sponsor.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`device is quite simple, and all of the risk priority numbers fell within an acceptable range.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The most common failures result in under dosing or no doses. All of the failures have a
`
`
`
`
`
`
`
`
`
`
`
`
`
`severity rating of 3 or less, which is entirely acceptable.
`I regard this device issue as
`resolved.
`
`
` (
`
`
`
`Richard Chapman
`
`
`Branch Chief, GHDB
`
`Reference ID: 3064767
`Reference ID: 3064767
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SARA E STRADLEY
`12/28/2011
`Dec 28, 2011 amended consult review from CDRH.
`
`Reference ID: 3064767
`
`

`

`
`
`
`M E M O R A N D U M
`Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`
`
`
`Date:
`
`To:
`
`
`Through:
`
`
`From:
`
`
`Subject:
`
`December 21, 2011
`
`Bob Rappaport, M.D., Director
`Division of Anesthesia, Analgesia, and Addiction Products
`
`Michael Klein, Ph.D., Director
`Silvia Calderon, Ph.D., Team Leader
`Controlled Substance Staff
`
`Chad J. Reissig, Ph.D., Pharmacologist
`Controlled Substance Staff
`
`NDA 202788 Fentanyl Sublingual Spray
`Indication: Breakthrough cancer pain
`Dosages: 100, 200, 400, 600 or 800 µg of fentanyl per
`Sponsor: Insys Therapeutics
`
`
`Materials reviewed: Previous NDA review by Chad J. Reissig, Ph.D.
`Chemistry Review by Julia C. Pinto, Ph.D.
`Previous IND review (72,411) by Jovita Randall-Thompson, Ph.D.
`
` spray
`
`
`
`The Division of Anesthesia, Analgesia, and Addiction Products (DAAAP) requested
`clarification from the Controlled Substance Staff (CSS) regarding the following
`recommendation provided in the CSS review, dated November 30, 2011:
`
`Improve the FSS device to avoid accidental disassembly by caregivers, children,
`and pets (e.g. chewing or crushing), and to prevent misuse.
`
`
`Initial concerns of this reviewer were based on personal observation of how easily the
`FSS sample device provided by the Sponsor could be disassembled, thus presenting a
`potential accidental exposure risk to children and pets. However, based upon the
`conclusions stated in the final Chemistry review (DARRTS, NDA 202-788, Julia C.
`Pinto, November 21, 2011), that the product attributes are adequate and the device meets
`CMC requirements, I retract my prior recommendation. Thus, the Sponsor does not need
`to improve the construction of the FSS device.
`
`
`
`Reference ID: 3062286
`
`
`
`1 of 1
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CHAD REISSIG
`12/21/2011
`
`SILVIA N CALDERON
`12/21/2011
`
`MICHAEL KLEIN
`12/21/2011
`
`Reference ID: 3062286
`
`

`

`.‘ “man
`$4)
`
`”I.
`
`ifa
`
`75
`”m...
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`M E M 0 R A N D U M
`
`
`-
`
`Food and Drug Administration
`Center for Devices and
`
`Radiological Health
`Office of Device Evaluation
`
`White Oak Building 66
`10903 New Hampshire Avenue
`Silver Spring, MD 20993
`
`Date:
`
`September 14, 2011
`
`From:
`
`To:
`
`LCDR Alan Stevens. Infusion Pump Team Leader W066. RM 2561
`General Hospital Devices Blanch. DAGID. ODE, CDRH
`
`Kathleen Davies. Preject Manager, W022 RM3189
`CDER/OND/ODEIIIDAAAP
`
`Subject:
`
`CDRH Consult, GEN 1100679, NDA 202788. sublingual spray unit dose system to
`deliver Fentanyl
`
`1 .
`
`Issue
`
`The Center for Drug Evaluation and Research (CDER)] has requested a consult from the
`Center for Devices and Radiological Health (CDRH, regarding NDA 202788. The device
`constituent of this combination product consists of a sublingual spray unit dose system.
`
`2. Device Description
`
`
`
`Reference ID: 3058849
`
`Page1of3
`
`

`

`NDA 202788, GEN1 100679
`Insys Therapeutics, Incorporated
`Sublingual Spray Unit Dose System for delivery of Fentanyl
`
`The Fentanyl Sublingual Spray unit dose system consists of an actuator, insert. spray pin,
`needle, stopper, glass vial and vial holder.
`(mm
`
`(b) (4)
`
`3. Documents Reviewed
`
`NDA 202788, Sequence 0000, Section 3.2.P.7 (Container Closure System)
`NDA 202778, Sequence 0000, Section 3.2.P.2 (Design Failure Modes and Effects Analysis)
`Drug Master File
`(mm
`
`4. CDRH Review and Comments
`
`CDRH’s Review of the device constituent for this Combination Product consisted of an
`assessment of the Failure Modes and Effects Analysis.
`
`Design Failure Modes and Effects Analysis
`The dFMEA analyzed failure modes associated with each component of the device
`constituent, including:
`
`Container (glass vial)
`Plunger (stopper)
`Cannula (needle)
`Insert (nozzle)
`Container holder (vial holder)
`Actuator
`
`Spray Pin
`
`For each component, the sponsor identifies potential failure modes and associated causes.
`
`The sponsor claims to have identified design controls for each failure mode and, based on
`their analysis. concludes that no further mitigations are required. However, no design controls
`are identified. Instead, the sponsor has identified manufacturing controls.
`
`The sponsor should identify design controls for each failure mode, and provide data verifying
`the effectiveness of each control measure.
`
`0”“) contained only biocompatibility test reports for materials of construction, which
`DMF
`were not reviewed at this time.
`
`5. CDRH Recommendation
`
`Based on our review, the following deficiencies should be conveyed to the Sponsor:
`
`1. You have provided a design failure modes and effects analysis. For each component,
`you have identified potential failure modes and associated causes. You claim to have
`identified design controls for each failure mode and, based on the analysis. conclude that
`
`Reference ID: 3058849
`
`Page 2 of 3
`
`

`

`NDA 202788, GEN1 100679
`
`
`Insys Therapeutics, Incorporated
`
`
`Sublingual Spray Unit Dose System for delivery of Fentanyl
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`no further mitigations are required. However, no design controls are identified. Instead,
`
`
`
`
`
`
`
`
`
`
`
`the dFMEA has identified manufacturing controls. Please modify the dFMEA to identify
`
`
`
`
`
`
`
`
`
`
`
`design controls and provide evidence that implementation of the design controls are
`effective.
`
`
`
`
`
`
`
`
`
`
`
`
`If you have any questions, please contact LCDR Alan Stevens at 301—796—6294.
`
`Sincerely,
`
`
`LCDR Alan Stevens
`
`Mechanical Engineer
`
`curred By: I
`
`
`
`ine Ryan
`mbination Products Team Leader
`
`
`Reference ID: 3058849
`Reference ID: 3058849
`
`Page 3 of 3
`
`
`
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SARA E STRADLEY
`12/15/2011
`Submitting this review to DARRTS for CDRH.
`
`Reference ID: 3058849
`
`

`

`FOOD AND DRUG ADMINISTRATION
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`Division of Direct-to-Consumer Promotion
`
`****Pre-decisional Agency Information****
`
`
`
`
`
`Memorandum
`
`Date:
`December 8, 2011
`
`
`To:
`
`
`
`
`
`
`From:
`
`
`
`
`
`CC:
`
`
`
`
`Kathleen Davies, Regulatory Project Manager
`Division of Anesthesia, Analgesia, and Addiction Products
`(DAAAP)
`
`L. Shenee’ Toombs, Regulatory Review Officer
`Division of Direct-to-Consumer Promotion (DDTCP)
`Office of Prescription Drug Promotion (OPDP)
`
`Shefali Doshi, Group Leader, DDTCP, OPDP
`Mathilda Fienkeng, Regulatory Review Officer, Division of
`Professional Promotion (DPP)
`Olga Salis, Senior Regulatory Health Project Manager
`Michael Wade, Regulatory Health Project Manager
`(OPDP)
`
`
`
`
`
`
`
`
`
`
`
`
`Subject:
`
`
`NDA 202788
`DDTCP labeling comments for SUBSYS (fentanyl) Sublingual
`Spray, CII Medication Guide
`
`
`
`
`
`
`DDDTCP has reviewed the Medication Guide (Med Guide) for SUBSYS
`(fentanyl) Sublingual Spray - CII (Subsys) which was submitted for consult on
`March 30, 2011. DDMAC used DMPP's tracked changes version of the Med
`Guide as the base document for review. DMPP's review of the Med Guide is
`being provided to the Reviewing Division under separate cover. We conferred
`with DMPP to the extent possible for consistency in our comments.
`
`Thank you for the opportunity to comment on these proposed materials.
`
`If you have any questions, please contact Shenee’ Toombs at (301) 796-4174 or
`latoya.toombs@fda.hhs.gov.
`
`
`
`Reference ID: 3056070
`
`1
`
`16 Page(s) of Draft Labeling has been Withheld in Full as B4 (CCI/TS)
`immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LATOYA S TOOMBS
`12/08/2011
`
`Reference ID: 3056070
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Medical Policy Initiatives
`Division of Medical Policy Programs
`
`PATIENT LABELING REVIEW
`
`December 8, 2011
`
`Bob A. Rappaport, MD, Director
`Division of Anesthesia, Analgesia, and Addiction
`Products (DAAAP)
`
`LaShawn Griffiths, MSHS-PH, BSN, RN
`Team Leader, Patient Labeling Team
`Division of Medical Policy Programs (DMPP)
`Barbara Fuller, RN, MSN, CWOCN
`Team Leader, Patient Labeling Team
`Division of Medical Policy Programs
`
`Sharon R. Mills, BSN, RN, CCRP
`Senior Patient Labeling Reviewer
`Division of Medical Policy Programs
`
`Date:
`
`To:
`
`Through:
`
`From:
`
`Subject:
`
`DMPP Review of Patient Labeling (Medication Guide)
`
`Drug Name (established
`name):
`
`SUBSYS (fentanyl) CII
`
`Dosage Form and Route: sublingual spray
`
`NDA 202-788
`
`Insys Therapeutics, Inc
`
`2011-1030
`
`Application
`Type/Number:
`
`Applicant:
`
`OSE RCM #:
`
`
`
`
`
`
`
`
`
`Reference ID: 3055948
`
`1
`
`

`

`1
`
`INTRODUCTION
`This review is written in response to a request by the Division of An