CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-350
`
`‘
`
`ADMINISTRATIVE and CORRESPONDENCE
`
`DOCUMENTS
`
`’
`
`

`

`Fm“ APPWVE": 0MB ”0- 09100513
`Department of Health and Human Services
`Expiration Date: 04/30/10
`.
`.
`.
`See OMB Statement on Page 3.
`Food and Drug Administration
`PATENT INFORMATION SUBMITTED WITH THE WNWNUMBER
`'
`FILING OF AN NDA, AMENDMENT, OR SUPPLEMENT
`22.350
`
`
`For Each Patent That Claims a Drug Substance
`NAME OF APPUCANT/ NDA HOLDER
`(Active Ingredient), Drug Product (Formulation and
`Brlsml'MYerS Squ‘bb COumy
`
`Composition) and/or Method of Use
`
`
`_
`
`The following is provided in accordance with Section 505(b) and (c) of the Federal Food, Drug, and Cosmetic Act.
`TRADE NAME (OR PROPOSED TRADE NAME)
`N/A
`'
`
`ACTIVE INGREDIENT(S)
`Saxagiiptin
`
`'
`
`STRENGTH(S)
`2.5 mg/ 5.0 mg
`
`DOSAGE FORM
`Tablet
`
`
`
`This patent declaration form is required to be submitted to the Food and Drug Administration (FDA)'with an NDA application.
`amendment, or supplement as required by 21 CFR 314.53 at the address provided in 21 CFR 314.53(d)(4).
`Within thirty (30) days after approval of an NDA or supplement. or within thirty (30) days of issuance of a new. patent, a new patent
`declaration must be submitted pursuant
`to 21 CFR 314.53(c)(2)(il) with all of the required information based on the approved NDA
`or supplement. The Information submitted in the declaration form submitted upon or after approval will be the only information relied
`upon by FDA for listing a patent in the Orange Book.
`
`For handwritten or typewriter versions (only) of this report: if additional space is required for any narrative answer (i.e., one
`that does not require a "Yes" or "No" response), please attach an additional page referencing the question number.
`
`
`
`
`
`FDA will not list patent information If you file an Incomplete patent declaration or the patent declaration indicates the
`
`pa tent is not eligible for listing. .M.,
`
`
`For each patent submitted for the pending NDA, amendment, or supplement referenced above, you must submit all the
`information described below. If you are not submitting any patents for this pending NDA, amendment, or supplement,
`
`co_
`lete above secton a sections 5a"°l,5-_.
`..
`
`
`
`
`“muse-J“ . >“"~
`.Mmfifiz‘d , c:
`
`
`b.
`issue Date of Patent
`‘
`
`6,395,767
`May 28, 2002
`
`
`d. Name of Patent Owner
`Address (of Patent Owner)
`
`
`
`PO. Box 4000
`Bristol-Myers Squibb Company
`
`
`
`
`
`
`City/State
`Princeton, New Jersey
`
`
`
`ZIP Code
`08543-4000
`
`FAX Number (if available)
`~
`
`Telephone Number
`(609)-252-4000
`
`E»Mail Address (if available)
`patents@bms.com
`
`
`
`
`Telephone Number
`
`E-Mail Address (If available)
`
`i.
`
`is the patent referenced above a patent that has been submitted previously for the
`approved NDA or supplement referenced above?
`. if the patent referenced above has been submitted previously for listing, is the expiration
`date a new expiration date?
`
`' D Yes '
`
`No
`
`-
`
`El Yes
`
`E] No
`
`FORM FDA 3542a (7/07)
`
`‘
`
`Page 1
`PSCGmme (30D4434090 EF '
`
`Approved v2.0
`
`930028719 1.0
`
`e. Name. of agent or representative who resides or maintains Address (of agent or representative named in 1.9.)
`a place of business within the United States authorized to
`
`receive notice of patent certification under section
`505(b)(3) and (l)(2)(B) of the Federal Food, Drug, and
`Cosmetic Act and 21 CFR 314.52 and 314.95 (if patent
`owner or NDA applicant/holder does not reside or have a
`place of business within the United States)
`c?
`
`
`
`City/State
`
`
`
`
`B'U Qoa.to
`
`FAX Number (if available)
`
`
`
`
`
`
`

`

`For the patent referenced above, provide the following Information on the drug substance, drug product and/or method of
`use that is the subject of the pending NDA, am
`
`
`
`
`
`
`described in the pending NDA, amendment. or supplement?
`2.2 Does the patent claim a drug substance that is a different polymorph of the active
`ingredient described in the pending NDA, amendment, or supplement?
`2.3 it the answer to question 2.2 is ”Yes." do you certify that, as of the date of this declaration, you have test data
`demonstrating that a drug product containing the polymorph will perform the same as the drug product
`described in the NBA? The type of test data required is described at 21 CFR 314.53(b).
`2.4 Specify the polymorphic form(s) claimed by the patent for which you have the test results described in 2.3.
`
`*1 Yes
`
`D No
`
`D Yes
`
`No
`
`2.5 Does the patent claim only a metabolite of the active ingredient pending in the NDA or supplement?
`(Complete the information in section 4 below if the patent claims a pending method of using the pending
`drug product to administer the metabolite.)
`
`2.6 Does the patent claim only an intermediate?
`
`2.7 it the patent referenced in 2.1 is a product-by—process patent, is the product claimed in the
`
`
`
`“Ema-‘ “
`
`'=
`7mm”.
`'
`mesa. - . -.
`~
`.-
`-
`in he pen 3.1 Does the patent claim the drug product. as defined in 21 CFR 314.3.
`
`
`
`amendment. or supplement?
`
`
`
`
`
`5'
`"
`‘~
`v.
`...
`
`*'
`-
`we
`
`
`4.1 Does the patent claim one or more methods of use for which approval is being sought in
`the pending NDA, amendment, or supplement?
`4.2 Patent Claim Number(s) (as listed in the patent)
`23, 24
`
`[I No
`K4 Yes
`
`Does (Do) the patent clalm(s) referenced in 4.2 claim a
`
`
`
`pending method of use for which approval is being sought
`
`D No
`Yes
`In the pending NDA, amendment, or supplement?
`
`4.2a if the answer to 4.2 is
`
`
`Use: (Submit Indication or method of use infonnation as identified specifically in the approved labeling.)
`
`“Yes," identify with speci-
`
`
`Saxagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
`ficity the use with refer-
`
`ence to the proposed
`
`
`labeling for the drug
`
`product.
`
`
`
`drug product (formulation or composition) or method(s) of use, for which the applicant is seeking approval and with respect to
`which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in
`the manufacture, use, or sale of the drug product.
`
`D Yes
`
`FORM FDA 3542a (7/07)
`
`Page 2
`
`Approved v2.0
`
`930028719 1.0
`
`

`

`
`
`amendment, or supplement pending under section 505 of the Federal Food, Drug, and Cosmetic Act. This time-
`sensitive patent information is submitted pursuant to 21 CFR 314.53. lattes! that I am familiar with 21 CFR 314.53 and
`this submission complies with the requirements of the regulation. l verify under penalty ofperjury that the foregoing
`is true and correct.
`.
`
`Warning: A willfully and knowingly false statement is a criminal offense under 18 U.S.C. 1001.
`
`
`
`Authorized Signature of NBA Applicant/Holder or Patent Owner (Attorney, Agent, Representative or
`other Authorized Official) (Provide information below)
`
`
`Date Signed
`
`May 28, 2008
`
`
`
`MWJ), DMZ/W:
`
`
`NOTE: Only an NBA applicant/holder may submit this declaration directly to the FDA. A patent owner who is not the NDA applicant!
`holder is authorized to sign the declaration but may not submit it directly to FDA. 21 CFR 314.53(c)(4) and (d)(4).
`
`D NDA Applicant/Holder
`
`Check applicable box and provide information below.
`
`
`NDA Applicant‘s/Holder’s Aitomey. Agent (Representative) or other
`Authorized Official
`
`[1 Patent Owner
`Patent Owner‘s Attorney, Agent (Representative) or Other Authorized
`Official
`‘
`
`Name
`Maureen P. O'Brien
`
`Address
` To the attention ofVice President and Deputy General Counsel, 1?
`
`Route 206 & Province Line Road
`P.O. Box 4000
`
`ZIP Code
`085434000
`
`FAX Number (if available)
`(609)252-4526
`
`4
`
`
`
`
`City/State
`Princeton, New Jersey
`
`Telephone Number
`(609)252-5286
`
`E-Mail Address (if available}
`patents@bms.com
`
`
`
`The public reporting burden for this collection of information has been estimated to average 20 hours per response, including the time for reviewing instructions,
`searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this
`burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to:
`Food and Drug Administration
`CDER (HFD—007)
`5600 Fishers Lane
`Rockvillc, MD 20857
`
`An agency may not conduct orsponsor, and a person I: not required to respond to, a collection of
`information unless it displays a currently Valid OMB control number.
`
`FORM FDA 35423 (7/07)
`
`Page 3
`
`Approved v2.0
`
`930028719 1.0
`
`

`

`Administrative Reviews
`
`

`

`NDA/BLA REGULATORY FILING REVIEW
`
`(Including Memo of Filing Meeting)
`
`
`A # 22-350
`
`
`BLA# n/a
`
`
`
`Proprietary Name: Onglyza
`
`
`saxagliptin
`Established/Proper Name:
`
`
`Dosage Form:
`tablet
`'
`-
`
`Stren hs: 2.5m, 5m
`
`
`
`Applicant: Bristol—Myers Squibb
`
`
`
`A-ent for A» nlicant if a licable): n/a
`
`
`Date of Application: 30Jun08
`
`Date of Receipt: 30Jun08
`Date clock started afier UN: n/a
`
`PDUFA Goal Date: 30Apr09
`
`
`
`
`
`Filing Date: 29Aug08
`Date of Filin; Meetin_: 26Au- 08
`1
`Chemical Classification: 1,2,3etc. oriinalNDAs onl
`Proposed Indication(s): treatment. of type 2 diabetes mellitus .
`
`Action Goal Date (if different):
`
`.
`
`
`
`)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`[XI 505(b)(1)
`E] 505(b)(2)
`I: 505(b)(1)
`El 505(b)(2)
`
`'
`
`_
`
`E] Fast Track
`D Rolling Review
`[:I Orphan Designation
`
`'
`
`Type of Original NDA:
`AND (if applicable)
`
`Type of NDA Supplement: n/a
`
`
`
`Refer to AppendixA forfurther information.
`
`
`
`
`Review Classification:
` Standard
`
`E] Priority
`
`
`Iftheapplication includes a complete response to pediatric WR,
`
`review classification is Priority.
`
`
`[:l Tropical disease Priority
`
`
`
`Ifa tropical disease Priority review voucher was submitted, review
`review voucher submitted
`classification defaults to Priority.
`
`
`
` Resubmission after withdrawal? El
`Resubmission after refuse to file? [I
`
`
`Part 3 Combination Product? El
`[:I Drug/Biologic
`
`E] Drug/Device
`[:1 Bioloic/Device
`
`I:] PMC response
`
`
`E] PMR response:
`
`
`I: FDAAA [505(0)]
`
`
`[:I PREA deferred pediatric studies [21 CFR
`[I Rx—to—OTC switch, Full
`314.55(b)/21 CFR 601.27(b)]
`
`
`El Rx-to-OTC switch, Partial
`E] Accelerated approval confirmatory studies (21
`El Direct-to-OTC
`CFR 314.510/21CFR 601.41)
`
`
`
`E] Animal rule postmarketing studies to verify
`
`
` Other:
`clinical benefit and safety (21 CFR 314.610/21 CFR
`
`601.42)
`
`
`Version 6/9/08
`
`'
`
`1
`
`

`

`Collaborative Review Division (ifOTC product): n/a
`
`-
`
`List referenced IND Number(s): 63,634C
`
`J
`
`These are the dates used or calculatin ins: ection dates.
`
`Are the proprietary, established/proper, and applicant names
`correct in tracking system?
`
`pediatric data) entered into tracking system?
`
`
`
`
`
`
`'
`PDUFA and Action Goal dates correct in tracking system?
`
`
` Ifnot, ask the document room staffto correct them immediately.
`
`
` Ifnot, ask the document room staflto make the corrections. Also,
`
`ask the document room staff to add the established name to the
`
`supporting IND(s) ifnot already entered into tracking system.
`
`
` Are all classification codes/flags (e.g. orphan, OTC drug,
` Ifnot, ask the document room staffto make the appropriate
`entries.
`51'
`7339'"
`
`
`
`s the application affected by the Application Integrity Policy
` (AIP)? Check the AIP list at:
`http://www.[(111.0aov/ora/complian cc ret/aiglist. html
`
`If yes, explain:
`
`If yes, has OC/DMPQ been notified of the submission?
`
`’
`
`Comments:
`
`
`User Fee Status
`
`E] Exempt (orphan, government)
`
`[3 Waived (e.g., small business,
`public health)
`
`[:I Not re uired
`-
`
`
`Note: 505(b) (2) applications are no longer exemptfrom userfees pursuant to the passage ofFDAAA. It is
`
`expected that all 505([2) applications, whether 505(b)(1) or 505(b) (2), will require userfees unless
`otherwise waived or exempted (e.g., business waiver, orphan exemption).
` ‘Does another product have orphan exclusivity for the same
`
`
`Form 3397 (User Fee Cover Sheet) submitted
`
`" '
`
`‘ “ 3*
`
` Comments:
`
`i?‘
`
`
`
`
`
`indication? Check the Electronic Orange Book at:
`
`
`http://ivww. (do. gov/ctIer/ob/detault. htm
`
`
`
`
`If yes, is the product considered to be the same product
`according to the orphan drug definition of sameness [21 CFR
`316.3(b)(13)]?
`
`
`Version 6/9/08
`
`~
`
`'
`
`2
`
`

`

`Has the applicant requested 5—year or 3-year Waxman-Hatch
`exclusivity? (NDAsflVDA efficacy supplements only)
`
`YES
`
`If the proposed product is a single enantiomer of a racemic
`drug previously approved for a different therapeutic use
`(NDAs only):
`
`
`
`
`OGD/DLPS/LRB.
`
`
` Ifyes, consult the Director, Division ofRegulatory Policy 11,
`
`Office ofRegulatory Policy (HFD-007)
`
`Comments:
`
`
`
`
`
`
`# years requested: 5yrs
`
`
`
`
`
`[:INO
`
`
`Note: An applicant can receive exclusivity without requesting it;
`
`’
`therefore, requesting exclusivity is not required.
`
`Comments: '
`
`Ki Not applicable
`
`
`
`
`EYES
`
`
`Did the applicant (a) elect to have the single enantiomer
`1:] NO
`
`
`(contained as an active ingredient) not be considered the
`
`same active ingredient as that contained in an already
`
`approved racemic drug, and/or (b) request exclusivity
`pursuant to section 505(u) of the Act (per FDAAA Section
`1113)?
`
` Ifyes, contact Mary Ann Holovac, Director ofDrug Information,
`
` Not applicable
`
`Is the application fer a duplicate of a listed drug and
`eligible for approval under section 5050) as an ANDA?
`
` Is the application for a duplicate of a listed drug whose
`
`only difference is that the extent to which the active
`ingredient(s) is absorbed or otherwise made available to
`
`the site of action less than that of the reference listed
`drug (RLD)? (see 21 CFR 314.54(b)(1)).
`
` Is the application for a duplicate of a listed drug whose
`
`only difference is that the rate at which the proposed
`
`
`product’s active ingredient(s) is absorbed or made
`available to the site of action is unintentionally less than
`that of the listed drug (see 21 CFR 314.54(b)(2))?
`
`
`
`
`
`
`
`
` Note: ifyou answeredyes to any ofthe above questions, the
`application may be refusedforfiling under 21 CFR 314.1 01(d)(9).
`
`
`Version 6/9/08
`
`3
`
`

`

`
` Is there unexpired exclusivity on the active moiety (e.g.,
`
`
`5-year, 3—year, orphan or pediatric exclusivity)? Check
`the Electronic Orange Book at:
`httQ://www. (do. gov/cder/ob/detoult. htm
`
`El YES
`[:l NO
`
`If yes, please list below:
`
`
`
`Exclusivi Code
`
`
`
`Exclusivity Ex-iration
`
`
`
`
`
`
`
`
`
`Ifthere is unexpired, 5-year exclusivity remaining on the active moietyfor the proposed drug
`
`product, a 505(b) (2) application cannot be submitted until the period ofexclusivity expires
`(unless the applicant provides paragraph IVpatent certification; then an application can be
`
`submittedfour years after the date ofapproval.) Pediatric exclusivity will extend both ofthe
`timefi'ames in this provision by 6 months. 21 CFR 108(b)(2). Unexpired, 3-year exclusivity will
`only block the a roval, not the submission 0 a 505(b 2 a :lication.
`
`
`
`[:1 Mixed (paper/electronic)
`Do not check mixed submission ifthe only electronic component
`is the content oflabeling (COL).
`CTD
`
`
` Comments:
`
`
`
` ‘ If mixed (paper/electronic) submission, which parts of the A
`application are submitted in electronic format?
`
`
`
`If electronic submission:
`mpg forms and certifications signed (non—CTD) or
`
`
`electronic forms and certifications signed (scanned or digital
`
`signature)(CTD)?
` Forms include: 356k, patent information (3542a), financial
`
`D All paper (except for COL)
`All electronic
`
`E] Non-CTD
`I] Mixed (CTD/non—CTD)
`
`disclosure (3454/3455), userfize cover sheet (3542a), and clinical
`
`trials (3674); Certifications include: debarment certification,
`
`patent certzfication(s), field copy certification, andpediatric
`
`certification.
`Comments:
`
`
`
` If electronic submission, does it follow the eCTD guidance?
`://M-’ww. do. ov/ca'er/ uidance/7087rev.
`(Ir/ft
`
`
` If not, exlain (e. .
`
`Version 6/9/08
`
`4
`
`

`

`Form 356h: Is a signed form '356h included?
`
`Ifforeign applicant, both the applicant and the U.S. agent must
`sign theform.
`
`Are all establishments and their registration numbers listed
`on the form?
`
`Comments:
`
`Index: Does the submission contain an accurate
`
`comprehensive index?
`
`Comments:
`
`Is the submission complete as required under 21 CFR 314.50
`(NDAs/NDA efiicacy supplements) or under 21 CFR 601.2
`(BLAs/BLA efficacy supplements) including:
`
`legible
`English (or translated into English)
`-
`pagination
`El navigable hyperlinks (electronic submissions only)
`
`If no, explain:
`
`
`
`Controlled substance/Product with abuse potential:
`
`Not Applicable
`
`Abuse Liability Assessment, including a proposal for
`scheduling, submitted?
`
`Consult sent to the Controlled Substance Staff?
`
`Comments:
`
`'
`
`BLAs/BLA efficacy supplements only:
`
`Companion application received if a shared or divided
`manufacturing arrangement?
`
`.43;
`
`Correctly worded Debarment Certlficatlon with authorized
`signature?
`
`I orein a: licant, both the ar licant and the U.S. Aent must
`
`Version 6/9/08
`
`5
`
`

`

`NO
`
`submission or no CMC technical
`
`section)
`
`Not Applicable
`YES
`NO
`
`YES
`
`sign the certification.
`
`Note: Debarment Certification should use wording in FD&C Act
`section 306(k)(l) i. e., ”[Name ofapplicant] hereby certifies that it
`did not and will not use in any capacity the services ofany person
`debarred under section 306 ofthe Federal Food, Drug, and
`Cosmetic Act in connection with this application. " Applicant may
`not use wording such as, "To the best ofmy knowledge... ”
`
`Cmm
`
`
`
`I Fleld Copy Certification: that 1t 15 a true copy ofthe CMC
`technical section (applies to paper submissions only)
`
`Ifmaroon field copy jacketsfromforeign applicants are received,
`return them to CDR or delive
`to the a: roriate zeld 0 ice.
`
`Financial Disclosure forms included with authorized
`signature?
`
`Forms 3454 and/or 3455 must be included and must be signed by
`theAPPLICANT, not an Agent.
`
`Note: Financial disclosure is requiredfor bioequivalence studies
`that are the basisfor approval.
`
`Comments:
`
`PREA
`
`Note: NDAs/BLAs/eflicacy supplementsfor new active ingredients,
`new indications, new dosageforms, new dosing regimens, or new
`routes ofadministration trigger PREA. All waiver & deferral
`requests, pediatric plans, andpediatric assessment studies must be
`reviewed by PeRC prior to approval ofthe application/supplement.
`
`Are the required pediatric assessment studies or a full waiver
`of pediatric studies included?
`
`If no, is a request for full waiver of pediatric studies OR a
`request for partial waiver/deferral and a pediatric plan
`included?
`
`If no, request in 74-day letter.
`
`If yes, does the application contain the
`certification(s) required under 21 CFR 314.55(b)(1),
`(0X2), (C)(3)/21 CFR 601270))(1), (0X2), (0X3)
`
`Comments:
`
`Version 6/9/08
`
`

`

`BPCA (NDAs/NDA efficacy supplements only):
`
`Is this submission a complete response to a pediatric Written
`Request?
`
`Ifyes, contact PMHS (pediatric exclusivity determination by the
`Pediatric Exclusivity Board is needed).
`
`Comments:
`
`'
`
`Check all types of labeling submitted.
`
`El Not applicable
`Package Insert (PI)
`Patient Package Insert (PPI)
`Instructions for Use
`MedGuide
`Carton labels
`
`
`
`Comments:
`
`Is electronic Content of Labeling submitted in SPL format?
`
`If no, request in 74-day letter.
`
`Comments:
`
`Package insert (PI) submitted in PLR format?
`
`If no, was a waiver or deferral requested before the
`application was received or in the submission?
`If before, what is the status of the request?
`
`Ifno, request in 74-day letter.
`
`Comments:
`
`All labeling (Pl, PPI, MedGuide, carton and immediate
`container labels) consulted to DDMAC?
`
`Comments: Will be consulted after label is closer to the
`final version.
`
`MedGuide or PPI (plus PI) consulted to OSE/DRISK? (send
`WORD version ifavailable)
`
`Comments: RCM # 2008-] 199
`
`REMS consulted to OSE/DRISK?
`
`Comments: RMP consulted — RCM # 2008—1199
`Carton and immediate container labels, PI, PPI, and
`proprietary name (if any) sent to OSE/DMEDP?
`
`Comments: RCM #2008-1199
`
`.
`
`I:] Not Applicable
`D YES
`[:1 NO
`E] Not Applicable
`IX YES
`1:] NO
`
`Version 6/9/08
`
`7
`
`

`

`M Not Applicable
`‘
`E] Outer carton label
`I:I Immediate container label
`E] Blister card
`[I Blister backing label
`D Consumer Information Leaflet
`(GIL)
`I:I Physician sample
`I:I Consumer sample
`El Other 5 eci
`
`Check all types of labeling submitted.
`
`Comments:
`
`Is electronic content of labeling submitted?
`
`Ifno, request in 74-day letter.
`
`Comments:
`
`.
`
`Are annotated specifications submitted for all stock keeping
`units (SKUs)?
`
`Ifno, request in 74-day letter.
`
`Comments:
`
`If representative labeling is submitted, are all represented
`SKUs defined?
`
`Ifno, request in 74-day letter.
`
`Comments:
`
`Proprietary name, all labeling/packaging, and current
`approved Rx PI (if switch) sent to OSE/DMEDP?
`
`Comments
`
`1:] NO
`
`End-of Phase 2 meeting(s)?
`Ifyes, distribute minutes beforefiling meeting.
`
`Comments:
`
`Date(s): July 28, 2005
`[:1 NO
`
`Pre-NDA/Pre-BLA/Pre-Supplement meeting(s)?
`Ifyes, distribute minutes beforefiling meeting.
`
`YES
`
`Date(s): November 14, 2007
`
`Comments: pre-NDA
`
`Any Special Protocol Assessment (SPA) agreements?
`Ifyes, distribute letter and/0r relevant minutes beforefiling
`meeting.
`-
`
`Comments:
`
`Version 6/9/08
`
`

`

`ATTACHMENT
`
`MEMO OF FILING MEETING
`
`DATE: August 26, 2008
`
`NDA/BLA #: 22-350
`
`PROPRIETARY/ESTABLISHED NAMES: Onglyza (saxagliptin) Tablets, 2.5mg, 5mg
`
`APPLICANT: Bristol-Myers Squibb
`
`BACKGROUND: NDA 22-350 for Onglyza (saxagliptin) tablets was submitted for review on
`June 30, 2008. Saxagliptin is a dipeptidyl-peptidase IV (DPP-IV) inhibitor. The proposed
`indication is for the treatment of type 2 diabetes mellitus in adults as an adjunct to diet and
`exercise to improve glycemic control.
`
`Onglyza is part of CMC’s Quality by Design '(QbD) pilot program. The trade name, Onglyza, is
`currently under review. Saxagliptin was studied under IND 63,634 submitted on November 1,
`2001.
`
`On January 11, 2007, Bristol—Myers Squibb and AstraZeneca announced an alliance to develop
`saxagliptin. Bristol-Myers Squibb will continue to hold the IND and will file the NDA on behalf
`of the alliance.
`
`REVIEW TEAM:
`
`»' A
`
`L.
`
` Y
`
`
`
`CPMS/TL: Lina Aljuburi
`
`Cross-Discipline Team Leader (CDTL) Hylton Joffe
`
`-
`
`Social Scientist Review (for OTC
`products)
`
`Labeling Review (for OTC products)
`v
`
`OSE
`
`TL:
`
`- Hylton Joffe
`
`Reviewer:
`
`TL:
`—
`
`
`
`
`
`
`
`
`
`
`
`
`
`TL:
`' _
`
`Clinical Microbiology (for antimicrobial
`
`
`
`products)
`
`
`
`
`
`
`Version 6/9/08
`
`‘
`
`I
`
`,
`
`I
`
`9
`
`

`

`
`
`Clinical Pharmacology
`
`
`Biostatistics
`
`
`
`Nonclinical
`
`
`(Pharmacology/Toxicology)
`
`
`
`'
`
`
`Statistics, carcinogenicity
`
`
`Product Quality (CMC)
`
` Facility (for BLAs/BLA supplements)
`
`
`
`
` Microbiology, sterility (for NDAs/NDA
`efficacy supplements)
`
` Bioresearch Monitoring (DSI)
`
`
`Other reviewers
`
`
`
`
`
`Jayabharathi Vaidyanathan
`
` Y
`
`
`
`Sally Choc
`
`Joy Mele
`
`Todd Sahlroot
`
`Fred Alavi
`
`Todd Bourcier
`
`Blair Fraser
`
`Reviewer:
`
`Susan Leibenhaut
`
`TL:
`
`
`
`
`
`
`OTHER ATTENDEES:
`
`Mary Parks, Director, Division of Metabolism and Endocrinology Products (DMEP)
`Ilan Irony, Clinical Reviewer, DMEP
`Julie Marchick, Safety RPM, DMEP
`Lee Ripper, ADRA, Office of Drug Evaluation 11
`Immo Zdrojewski, Clinical Pharmacology Reviewer
`Ritesh Jain, Clinical Pharmacology Reviewer
`
`505(b)(2) filing issues?
`
`If yes, list issues:
`
`translation? If no, ex-lain:
`
`Per reviewers, are all parts in English or English
`
`Version 6/9/08
`
`10
`
`

`

`Electronic Submission comments
`
`[I Not Applicable
`
`List comments: NO comments
`
`CLINICAL
`
`-
`
`I: Not Applicable
`IX] FILE
`D REFUSE TO FILE
`
`Comments:
`
`-
`
`Review issues for 74-day letter
`
`6 Clinical study site(s) inspections(s) needed?
`
`If no, explain:
`
`
`. Advisory Committee Meeting needed?
`
`Comments:
`
`Date if known:
`
`D NO
`To be determined
`
`Ifno, for an originalNME or BLA application, include the Reason:
`reason. For example:
`0
`this drug/biologic is not the first in its class
`0
`the clinical study design was acceptable
`0
`the application didnot raise significant safety
`or efficacy issues
`the application did not raise significantpublic
`health questions on the role ofthe
`drug/biologic in the diagnosis, cure,
`mitigation, treatment orprevention ofa
`disease
`
`0
`
`If the application is affected by the AIP, has the
`division made a recommendation regarding whether
`or not an exception to the AIP should be granted to
`permit review based on medical necessity or public
`health significance?
`
`Not Applicable
`CI YES
`[3 NO
`
`Comments:
`
`CLINICAL MICROBIOLOGY
`
`>24 Not Applicable
`[I FILE
`1:] REFUSE TO FILE
`
`
`
`Comments:
`
`I:] Review issues for 74-day letter
`
`CLINICAL PHARMACOLOGY
`
`D Not Applicable
`FILE
`
`El REFUSE TO FILE
`
`Version 6/9/08
`
`ll
`
`

`

`
`Comments;
`Review issues for 74—day letter
`
`
`0 Clinical pharmacology study site(s) inspections(s)
`El YES
`needed?
`NO
`
`‘
`
`
`
`
`
`BIOSTATISTICS
`
`[:1 Not Applicable
`IXI FILE
`'
`
`D REFUSE TO FEE
`
`
`Review issues for 74—day letter Comments:
`
`
`
`
`NONCLINICAL
`[I Not Applicable
`
`
`(PHARMACOLOGY/TOXICOLOGY)
`IX] FILE
`
`[:1 REFUSE TO FILE
`
`
`
`E] Review issues for 74-day1etter
`Comments:
`
`
`
`
`
`I:] Not Applicable
` PRODUCT QUALITY (CMC)
`El FILE
`
`El REFUSE TO FILE
`
`
`X Review issues for 74-day letter Comments:
`
`
`
`
`o Categorical exclusion for environmental assessment
`El Not Applicable
`
`
`YES
`(EA) requested?
`'
`
`
`
`
`El N0
`
` If no, was a complete EA submitted?
`If EA submitted, consulted to EA officer (OPS)?
`
` El Not Applicable
`
`Comments:
`
`Establishment(s) ready for inspection?
`
`YES
`
`
`BNO
`
`
`[I Not Applicable
`[XI YES
`
`EINO
`
`
`Comments:
`
`Establishment Evaluation Request (EER/TBP—EER)
`submitted to DMPQ?
`
`
`
`
`
`
`Sterile product?
`
`
`Version 6/9/08
`
`12
`
`

`

`
` If yes, was Microbiology Team consulted for
`validation of sterilization? (NDAs/NDA
`
`
`su lements on]
`
` [:1 Not Applicable
`FACILITY (BLAs only)
`
`
`[:1 FILE
`
`El REFUSETO FILE
`
`[I Review issues for 74-day letter
`
`
`
`
`Comments:
`
`Signatory Authority: Curtis Rosebraugh, Director, Officeo
`
`Comments:
`
`The application is unsuitable for filing. Exp ain why.
`
`GRMP Timeline Milestones: n/a
`
`
`
`I H V
`
` The application, on its face, appears to be suitable for filing.
`
`
`E] No review issues have been identified for the 74—day letter.
` IX Review issues have been identified for the 74-day letter. List (optional):
` Clinical
`
`
`
`
`
`Submit a revised Table 1.2.3A (page 51 of the summary of clinical safety)
`that outlines exposure to study drug overall and by doses according to the
`following groups: 224 weeks, 252 weeks.
`
`
`
`
`Provide narratives for all Dermatologic adverse'events (AEs), including
`more specific information about the appearance and location (generalized
`vs. localized) of each AE.
`
`
`
`
`
`As discussed in the preNDA meeting, provide narratives for all serious
`adverse events, not just those you consider treatment—related. As an
`example, in the Study Report for CV181011 (page 174), it appears that
`you have only provided subject narratives describing Serious Adverse
`Events (SAEs) that were reported as related to study drug and SAEs of
`special interest.
`
`
`
`
`
`
`
`Explain the criteria used in coding preferred terms used for your
`cardiovascular adverse events analyses (page 181 of the summary of
`
`
`clinical safety).
`'
`
`
`
`Version 6/9/08
`
`13
`
`

`

`8. I Submit a summary table ofall planned and ongoing studies (including
`expected completion dates) if this is not included in the NDA already. If
`the information is in the NDA, please indicate where it is located.
`
`
`
`
`. Provide narratives for all subjects with potential cardiac preferred terms
`
`that may have been classified under other System-Organ Classes (SOCs),
`
`
`such as “chest pain” and preferred terms related to abnormal
`
`
`electrocardiograms.
`
` . List cardiovascular events by type (e.g., “ischemia—related”, “heart
`
`rate/rhythm-related”, “heart failure-related”, and “other”) for your
`
`
`controlled Phase 2/3 database using standardized MedDRA queries
`. (SMQs) for ischemic heart disease. Include a detailed description of the
`
`methodology used (e.g., which preferred terms were included).
`
`
`. For a composite variable MACE (cardiovascular-death, non-fatal
`
`myocardial infarction, and non-fatal stroke) using the controlled Phase 2/3
`
`database, show the number of people with at least one MACE event and
`
`
`
`provide both the total number of randomized patients and the patient-year
`exposure for the various treatment groups. Please show these numbers
`
`
`both by individual study and pooled.
`
`
`
`
`9. Submit a table of exposures broken down by clinical development Phase
`(1, 2, and 3) with the following variables: total subjects exposed to any
`
`
`dose of saxagliptin, dosage range of saxagliptin, range of days on
`saxagliptin, and mean number of days on saxagliptin.
`
` Clinical Pharmacolog
`
`
`
`
`
`
`
`
`11. Provide Kaplan-Meier curves by treatment group for time to
`discontinuation for Studies CV181011, CV181013, CV181014,
`
`CV181038, CV181039, and CV181040.
`
`
`
`12. Provide disposition datasets (xpt files) for Studies CV181011, CV181013,
`CV181014, CV181038,CV181039, and CV181040 which contain a single
`
`record per patient and provide disposition information for the double blind
`
`
`portion of each of these trials. Only patients who were randomized and
`
`
`entered the double-blind se;
`ent should be included in the dataset. This
`
`10. Saxagliptin is a chiral molecule with four chiral centers and is an S-
`isomer. There is no information whether chiral conversion occurs in the
`body. We recommend you address the chiral conversion using a stereo-
`specific assay for detection of saxagliptin and its isomer.
`
`Biostatistics
`
`Version 6/9/08
`
`'
`
`14
`
`

`

`dataset should include both a coded numeric variable (like NNCPRNN on
`the raw dataset STAT) and a character variable showing the reason for
`discontinuation. A variable for time on study and a variable for completer
`status should also be included (these variables should allow FDA to
`reproduce the Kaplan—Meier curves requested above). Variables for
`region, country and site should be included along with the usual
`demographic variables.
`
`Chemistfl, Manufacturing, and Controls
`
`13. Confirm that the manufacturing and testing facilities listed in Form FDA
`356h are all the facilities involved in the manufacture and testing of the
`commercial drug substance and drug product.
`
`l4. Clarify whether the 2.5 mg tablets will be packaged in blisters because this
`packaging is not in the proposed labeling even though this packaging is
`listed for this dosage strength in the Container Closure System and
`Stability sections of the NDA.
`
`15. Provide references to the 21 CFR food additive regulations for the drug-
`contact components of the container closure systems used to package the
`drug substance and drug product.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 16. Provide the following or their location in the NDA:
`
`
`a) Physical dimensions of the finished tablets.
`
`
`b) Stability information on the potential C
`
`c) Characterization information on saxagliptin hydrochloride, which
`
`
`is the active ingredient form in the final drug product. The
`
`
`information should include structural and physicochemical
`
`
`characterization, details on manufacturing conditions that C )
`C,,
`>
`
`
`
`
`
`
`
`W“
`
`W“
`
`“W
`
`it
`A
`V
`C
`d) Stability information on the chirality of the molecule during the
`drug product manufacture and storage to support L
`C,
`_
`b
`
`J
`
`e) The characterization report, including data and analysis, on the
`comparability between metformin and saxagliptin. The information
`should include, at minimum, structural and physicochemical
`
`
`characterization of the active ingredients, their comparative
`
`
`stability profiles, polymorph/crystal forms, and degradation
`
`pathways and products.
`
`Version 6/9/08
`
`' 15
`
`

`

`
`
`D Data to support your statement that the saxagliptin hydrochloride
`
`
`
`{1(4)
`
`17. Regarding the pharmaceutical development information:
`
`
`
`
`
`a) All data, figures, graphs, and tables provided in section 3.2.P.2
`must be identified in their captions as being generated using
`
`saxagliptin or metformin.
`b) Was the predictive coating model developed using a design space
`generated for metformin or saxagliptin?
`
` c) How much of the process model, used to extend the design space,
`
`is based on metformin data?
`
`
`
`
`
`
`
`
`
` d)
`on data generated using metformin.
` 12 Standard Review
` E] Priority Review
`
`eAI-‘
`
`nent
`
`
`
`
`f RTF action, notify everybody who already received a consult request, OSE PM., and
`Product Quality PM. Cancel EER/TBP-EER.
`
` If filed and the application is under AIP, prepare a letter either granting (for signature by
`
`
`Center Director) or denying (for signature by ODE Director) an exception for review.
`
`
`
`Indicate which aspects/parameters of the control strategy are based
`
`If BLA or priority review NDA, send 60-day letter.
`
`Send review issues/no rev1ew Issues by day 74
`
`