CENTER FOR DRUG EVALUATION AND
`
`'
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-995
`
`' ADMINISTRATIVE and CORRESPONDENCE
`
`DOCUMENTS
`
`

`

`Department of Health and Human Sta oes
`Food and Drug Administration
`
`Form Approv‘ed: 0MB No)0910om
`5’9"“ °" 03'6' 07 31/05
`
`.
`
`PATENT INFORMATION SUBMITTED WITH THE FlLlNG
`OF AN NDA, AMENDMENT, on SUPPLEMENT
`
`NDA NUMBER
`21-995
`
`For Each Patent That Claims 3 Drug Substance
`(Active ingredient), Drug Product (Formulation and
`Composition) and/or Method of Use
`
`NAME OF APPLICANT/ NDA HOLDER
`MERCK & 00, NO,
`
`The [allowing is provided in accordance with Section 505(1)) and (c) at the Federal Food, Drug, and Cosmetic Act.
`
`TRADE NAME (OR PROPOSED TFlADE NAME)
`JANUVIATM
`
`ACTlVE lNGREDlENTlS)
`Sitagliptin phosphate
`
`DOSAGE FORM
`Tablets
`
`I
`
`STRENGTH(S)
`25, 50, and 100mg
`
`This patent declaration form is required to be submitted to the Food and Drug Administration (FDA) with an NBA 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
`alter approval of an NBA or supplement, or within thirty (30) daysIol issuance of a new patent, a new patent declaration must be
`submitted pursuant to 21 CFR 314. 53(c)(2)(ii) with all of the required information based on the approved NDA or supplement The
`information submittedIn the declaration form submitted upon or after approval wlil be the only Information relied upon by the FDA
`for '-stln a n'tentIn the Oran-e Book.
`'
`For hand-written or typewriter versions (only) at .,
`' ‘port:
`if additional space is required for any narrative answer (i.e.. one
`that does not require a “Yes" or “No" response), pie
`‘achIan additional page referencing the question number.
`
`FDA will not list patent information ifyou submit an incomplete patent declaration or the patent declaration indicates the
`patent is not eligible for listing
`
`For each patent submitted for the pending NDA, amendment, or supplement reierenced above, you must submit all the
`information described below. If you are not submitting any patents for this pending NDA, amendment or supplement,
`I complete above section and sections 5 and 6.
`1. GENERAL
`
`a. United States Patent Number
`6,303,661
`
`b. Issue Date of Patent ‘
`October 16, 2001
`
`i
`
`c. Expiration Date of Patent
`April 24. 2017
`
`d. Name of Patent Owner
`
`A
`
`PHOSIDfON LIMITED
`
`Address (of Patent Owner)
`WellingtonRoad
`City/State
`
`Oxford, United Kingdom
`
`ZIP Code
`0X4 6LT
`
`Telephone Number
`44-1865-782600
`
`.
`
`FAX Number (if available)
`44-1865-782601
`
`E-Mail Address (it available)
`
`Address (of agent or representative namedIn 1. e )
`58.3 ujh Service Fioad Suite 1 10
`,
`_
`_
`
`_
`
`a. Name of agent or representative who .
`resides or maintains a place of business
`within the United States authorized to
`receive notice of patent certification under
`section 505(b)(3)and 0)(2)(B) ot the
`Federal Food, Drug. and Cosmetic Act
`and 21 CFR 314.52 and 314.95 (it patent
`owner or MBA applicant/holder does not
`reside or have a place of business within
`the United States)
`
`03. PHARMACEUTICALS, lNC.
`
`ZIP Code
`
`1 1747
`
`Telephone Number
`631 —962-2000
`
`FAX Number (if available)
`
`631-752-3880
`
`E-Mail Address (llavailable)
`
`D Yes
`
`NO
`
`
`
`t.
`
`is the patent referenced above a patentthat has been submitted previously for the
`approved NDA or supplement referenced above?
`
`g It the patent referenced above has been submitted previously for listing, is the
`expiration date a new expiration date?
`.
`
`’ MHM FDA 3542a (7/03)
`
`-
`
`Page 1
`'
`-
`Computer generated form ‘Pntenl Submission with NDA' (Miscellaneous folder) Merck a Co.. the 10/26/2005
`
`

`

`
` 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 NBA, amendment or supplement.
`
`2. Drug Substance (Active ingredient)
`,
`
`
`
`2.1 Does the patent claim the drug substance that is.
`ctive ingredient in the drug product
`
`described in the pending NDA. amendment, or supplement?
`'3 Yes
`No
` 2.2 Does the patent claim a dmg substance that is a different polymorph of the actlv
`
`ingredient described in the NDA. amendment, or supplement?
`‘
`
`2.3 If the answer to question 2.2 is “Yes." do you ceniiy that. as of the date of this declaration,
`
`
`
`you have test data demonstrating that a drug product containing the polymorph will
`>
`[3 Yes
`periorrn the same as the drug product described in the NBA? The type of test data
`C] No
`required is described at 21 CFR 314.53(b).
`
`2.4 Specify the polymorphic torm(s) claimed by the patent for which you have the test results described in 2.3.
`
`
`
`
`2.7 It the patent referenced in 2.1 is a productrby-process patent. is the product claimed in the
`patent novel? (An answer is required only it the patent is a product-by-process patent.)
`
`4. Method of Use
`
`D Yes
`
`D No
`
`
`
`
`
`2.5 Does the patent claim only a metabolite oi the active Ingredient pending in the NDA or supplement?
`
`(Complete the information In section 4 below it the patent claims a pending method of using the
`
`D Yes
`.No
`pending drug product to administer the metabolite)
`‘
`
`
`
`
` 2.6 Does the patent claim only an intermediate? V
`
`
`[:JYes DNo‘
`3. Drug Product (Composition/F0rmulation)
`
`
`"
`‘I'
`3.1 Does the patent claim the drug product. asdel‘
`amendment, or su- dement?
`
`
`
`3.2 Does the patent claim only an intermediate?
`
`
`3.3 it the patent relerenced in 3.1 I is a product-by-process patent. is the product claimed in the
`patent novel? (An answer is required only it the patent is a product-by-process patent.)
`
`
`Sponsors must submit the information in section 4 separately for each patent claim claiming a method 0! using the pending
`drug product for which approval is being sought. For each method of use claim referenced, pro vide the (allowing information:
`
`
`4.1 Does the patent claim one or more methods of use forWhich approval is being sought
`[2‘ Yes D No
`in the endin- NDA. amendment. or su lement?
`
`
`4.2 Claim Number (as listed in the pateno
`Does the patent claim referenced in 4.2 claim a 4
`
`
`1
`andan method of use for which approval is being
`sought in the pending NDA, amendment.
`
`
`
`or supplement?
`‘
`4.2a it the answer to 4.2 is
`Use: (Submit indication or method at use information as identified specifically In the proposed labeling.)
`
`
`"Yes," identity with
`JANUVlA is indicated as an adjunct to diet and exercise to improve glycemic control in patients
`
`specificity the use
`with type 2 diabetes mellitus
`JANUVlA is also indicated to improve glycemic control in
`with reterence to
`
`
`
`combination with metiormin or a PPAFt-Gamma agonist when diet and exercise plus the single
`the proposed labeling
`
`agent do not provide adequate glycemic control
`
`
`for the drug product
`
`,
`
`Yes D No
`
`
`
` FORM FDA 3542a (7/03)
`
`
`Computer generated tom-I 'Fatent Submission with NDA‘ (Miscellaneous (older) Merck 5 Co. Inc 1012612005
`
`

`

`4. Method of Use (continued)
`
`Sponsors must submit the informationIn section ” _"separately for each patent claim claiming a method of using the pending
`drug product for which approval is being sought; 'For each method of use claim referenced, provide the following information:
`4.1 Does the patent claim one or more methods of use for which approval is being sought
`In the uendin- NDA. amendment. or so - niement?
`4.2 Claim Number (as listed in the pateno
`.
`
`3
`
`Yes
`
`Does the patent claim referenced in 4.2 claim a
`pending method of use ior which approval is being
`sought"In the pending NDA amendment.
`or supplement?
`423 [f the answer to 42 is Use. (Submit indication or method of use information as identified specifically'In the proposed labeling)
`"YES; 3519"th With
`JANUVIA is indicated as an adjunct to diet and exercise to improve giycemic control in patients
`SPeCihCW the use
`with type 2 diabetes meiiitus. JANUViA'Is also indicated toImprove giycemlc control'In
`“nth reference ‘0
`combination with metlormin or a PPAR-Gamma agonist when diet and exercise plus the single
`"19 PYOPOSBd [3'39""9
`agent do not provide adequate giycemic control
`ior the drug product,
`
`4. Method of Use (continued)
`Sponsors must submit the information in section 43’separateiy for each patent claim claiming a method of using the pending
`drug product for which approval is being sought. For each method of use claim referenced, provide the following information:
`4.1 Does the patent claim one or more methods of use tor which approval is being sought
`in the nendin - NDA. amendment; or su . olement?
`
`4.2 Claim Number (as listed in the patent)
`5
`
`'
`
`Does the patent claim referenced in 4.2 claim a
`pending method of use for which approval is being
`sought in the pending NDA. amendment,
`or supplement?
`
`Yes D NO
`
`4.23 It the answer to 4.2 is
`"Yes," identify 'Wiih
`specificity the use
`With relerence ‘0
`the proposed labeling
`for the drug product
`
`Use: (Submit indication or method of use infonnatlon as identified specifically in the proposed labeling.)
`JANUViA'Is indicated as an adjunct to diet and exercise to improve giycemic control'In patients
`with type 2 diabetes meiilius. JANUViA is also indicated to improve giycemic controlIn
`combination with" 'éiiormin era PPAFl—Gamma agonist when diet and exercise plus the single
`agent do not prdiiidé'adequate glycemic control
`
`4. Method of Use (continued)
`Sponsors must submit the information in section 4 separately for each patent claim claiming a method of using the pending
`dru roduct for which a - rovai is beln . sou ht. For each method of use claim referenced -rovfde the followin - information:
`4.1 Does the patent claim one or more methods oi use for which approval'is being sought
`in the pending NDA. amendment, or supplement?
`
`torthe drug product.
`
`4.2 Claim Number (as listed in the patent)
`6
`
`'
`
`:
`
`'
`
`_
`
`.
`
`4.23 It the answer to 42 is
`"Yes:"_icientity Wilh
`599‘“me "‘9 “59
`with reference i°
`the P'OPOSEd labeling
`tor the drug product.
`
`Dora:. the pit“; cifim refer??? in 4.2 cilaiimbaI
`_ pen Ing me 0 0 use OI’W to approve is eng
`- sought in the pending NDA. amendment.
`r-
`or supplement?
`h or method of use information as identified specificallyIn the proposed labeling.)
`7.
`
`L d asan adjunct to diet and exercise to improve giycemic control in patients
`'
`~
`with type 2 diab'e'té meliitus JANUVtA Is also indicated to improve glycemic control in
`combination with 'metiormln or a PPAR-Gamma agonist when diet and exercise plus the single -
`(agent do not provide adequate glycemic control
`
`Y Das
`
`No
`
`4. Method of Use (continued)
`Sponsors must submit the information in section 4 separately for each patent claim claiming a method of using the pending
`drug product for which ap roval is being sought. For each method of use claim referenced, - rovlde the following lnlormatlon:
`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? .
`
`42 Claim Number (as listed in the patent)
`7
`
`'
`
`'I Does the patent claim referenced in 4.2 claim a
`i- pending method of use tor-which approval is being
`sought in the pending NDA. amendment.
`or supplement?
`
`I
`
`<
`
`Yes D No
`
`423 If the answer to 42 Is
`"Yes,“ identity with
`specificity the use
`with relerence to
`the proposed labeling
`
`Use: (Submit indication. or method of use information as identified specifically in the proposed labeling.)
`JANUVIA is indicated as an adjunct to diet and exercise to improve giycemic control in patients
`with type 2 diabetes meiliius. JANUViA is also indicated to improve giycemic control in
`conflication with metionnin or a PPAH-Gamma agonist when diet and exercise plus the single
`agent do not provide adequate glycemic control
`
`I «swam FDA 3542a (7/03)
`
`,
`
`
`
`Page 3
`_
`Grammar generated loan 'Patenl Submission with NDA' (Miscellaneous loldar) Merck a Go. inc 1026/2005
`
`

`

`
`
`5. No Relevant Patents
`
`
`
`Representative or olherAuthon‘zed Official) (Provide inionnation below)
`
`
`
`
`For this pending NDA, amendment or supplement, there are no relevant patents that claim the approved drug substance
`(active ingredient). drug product (iormulation or composition) or melhods(s) of use, for which the applicant is seeking D Yes
`
`
`approval and with respect to which a claim at 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.
`6. Declaration Certification
`
`6.1 The undersigned declares that this is an accurate and complete submission ofpatent Information for the NDA,
`
`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 CPR 314.53. [attest that lam familiar with 21 CFR 314.53
`
`
`and this submission complies with the requirements of the regulation. I verify under penalty of perjury that the
`foregoing is true and correct.
`
`
`
`Warning: A willfully and knowingly false statement is a criminal offense under 18 05.0. 1001.
`Date Signed
` 6.2 Authorized Signature of NDA Applicant/Holder or Patent Owner (Altomey, Agent,
`
`
`
`December 5. 2005
`
`NOTE: Only an NDA applicant/holder may sub
`applicant/holder is authorized to sign the declaraji
`Check applicable box and provide information below:
`
`we?
`
`eclaration directly to the FDA. A patent owner who is not the NDA
`
`
`ut may not submit it directly to FDA. 21 CFR 314.53(c)(4) and (d)(4).
`
`
`
`
`
`
`'
`
`Name
`
`NDA A i‘c
`
`t/H id
`
`NDA Applicant's/Holder's Attorney. Agent (Representative)
`
`
`
`'
`
`Patent Owner's Attorney. Agent (Representative) or Other
`
`Merck & 00.. inc.
`
`
`
`
` Address ' City/State
`
`
`
`
`
`PO. Box 2000, FiYGO-SO
`Rahway, NJ
`ZIP Code
`
`
`
`Telephone Number
`
`07065-0907
`
`
`(732) 594-4568
`
` FAX Number (if available)
`
`E-Maii Address (if available)
`
` (732) 594-4720 phil_durette@merck.com
`
`
`FORM FDA 3542a (7/03)
`
`Page 4
`
`in.»
`
`
`
`Computer generated term 'Pntent Submission with NDA' (Miscellaneous lotder) Merck a. 00.. Inc 10/20/2005
`
`

`

`(Complete for all filed original applications and efficacy supplements)
`
`PEDIATRIC PAGE
`
`EDA #: 21-995
`
`Supplement Type (e.g. SE5): M Supplement Number: M
`
`Stamp Date: December 16, 2006
`
`PDUFA Goal Date: October 16, 2006
`
`HFD-SIO
`
`Trade and generic names/dosage form: Januvia jsitag‘liptin phosphate) Tablets
`
`7 Applicant: Merck & Co. , lnc.
`
`Therapeutic Class: antidiabetic agent
`
`I
`
`Does this application. provide for new active ingredient(s), new indication(s), new dosage form, new dosing regimen, or new
`route of administration? *
`
`X
`Cl
`
`Yes. Please proceed to the next section.
`No. PREA does not apply. Skip to signature block.
`
`* SE5, SE6, and SE7 submissions may also trigger PREA. If there are questions, please contact the Rosemary Addy or Grace Carmouze.
`
`[ndication(s) previously approved (please complete this section for supplements only): N/A
`
`Each indication covered by current application under review must have pediatric studies: Completed, Deferred, and/or Waived.
`
`Number ofindications for this application(s):i
`
`Indication #1: Monotherapy
`
`Indication #2: Combination therapy with metformin when diet and exercise plus the single agent do not provide adeguate
`glycemic control
`
`.lndication #3: Combination thera witha eroxisome roliferator-activated rece tor amma PPAR a onist e.
`
`
`‘aiazolidinediones when diet and exercise [us the sin le 3 ent do not
`rovide ade uate l cemic control
`
`I
`.
`
`.
`
`
`Responses belo/w apply to all three indications.
`
`Is this an orphan indication?
`
`Cl Yes. PREA does not apply. Skip to signature block.
`
`X No. Please proceed to the next question.
`
`Is there a full waiver for this indication (check one)?
`
`Cl- Yes: Please proceed to Section A.
`
`X No: Please check all that apply: _LPartial Waiver _X____Deferred __Completed
`
`NOTE: More than one may apply
`
`Please proceed to Section B, Section C, and/or Section D and Complete as necessary.
`
`Section A: Fully Waived Studies
`
`Reason(s) for full waiver:
`
`El Products in this class for this indication have been studied/labeled for pediatric population
`El Disease/condition does not exist in children
`
`;
`
`Cl Too few children with disease to study
`C] There are safety concerns
`,
`[3 Other:
`
`

`

`NDA 21—995
`
`Page 2
`
`fstudies arefully waived, then pediatric information is completefor this indication. Ifthere is another indication, please see
`Attachment A. Otherwise, this Pediatric Page is complete and should be entered into DFS.
`Section B: Partially Waived Studies
`
`'
`
`Age/weight range being partially waived (fill in applicable criteria below):
`
`yr.
`0
`
`yr.
`10
`
`
`
`kg
`Min
`kg
`Max
`Reason(s) for partial waiver:
`
`mo.
`mo.
`
`
`Tanner Stage
`
`Tanner Stage
`
`D Products in this class for this indication have been studied/labeled for pediatric population
`C] Disease/condition does not exist in children
`X Too few children with disease to study
`C] There are safety concerns
`Cl Adult studies ready for approval
`Cl Formulation needed
`El Other:
`
`Ifstudies are deferred, proceed to Section C. Ifstudies are completed, proceed to Section D. Otherwise, this Pediatric Page is
`complete and should be entered into DFS.
`
`SectionC: Deferred Studies
`
`.
`
`Age/weight range being deferred (fill in applicable criteria below):
`
`_—
`
`mo.
`m0.
`
`yr.
`yr.
`
`11
`16
`
`Min
`Max
`
`kg
`kg
`
`
`Tanner Stage
`
`Tanner Stage
`
`Reason(s) for deferral:
`
`D Products in this class for this indication have been studied/labeled for pediatric population
`D Disease/condition does not exist in children
`1:! Too few children with disease to study
`C] There are safety concerns
`.
`X Adult studies ready for approval
`0 Formulation needed
`Other:
`
`. Date studies are due (mm/dd/yy): December 31, 2010
`[fstudies are completed, proceedto Section D. Otherwise, this Pediatric Page is complete andshould be entered into DFS.
`Section D: Completed Studies
`.
`'
`,
`
`Age/weight range of completed studies (fill in applicable criteria below):
`
`
`
`Min
`Max
`
`kg
`kg
`
`mo.
`mo.
`
`yr.
`yr.
`
`
`Tanner Stage
`
`Tanner Stage
`
`Comments:
`
`.
`
`i
`
`Ifthere are additional indications, please proceedto Attachment A. Otherwise, this Pediatric Page is complete andshouldbe entered
`
`

`

`NDA 21—995
`
`Page 3
`
`yo DFS.
`
`This page was completed by:
`
`{See appended electronic signature page}
`
`Lina AlJuburi, Pharm.D., M.S.
`Regulatory Project Manager
`
`CC:
`
`NDA 21-995
`
`'HFD-960/ Rosemary Addy or Grace Carmouze
`
`FOR QUESTIONS ON COMPLETING THIS FORM CONTACT THE DIVISION OF PEDIATRIC DRUG
`DEVELOPMENT, HFD—960, 301—594—7337.
`(revised 6-23-2005)
`
`-
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Lina Aljuburi
`10/17/2006 04:28:11 PM
`
`

`

`MK-0431 Tablets
`Debarment Certification
`
`1
`
`As required by §306(k)(1) of 21 U.S.C. 335a(k)(1), we hereby certify that, in connection
`with this application, Merck & Co., Inc did not and will not use in any capacity the
`services of any person debarred under subsections 306(3) or (b) of the Act.
`
` Date
`
`Director
`
`Regulatory Affairs
`
`.\
`
`3 6-
`
`-‘-
`
`,
`
`MK-0431 Debarment Certification
`
`Restricted 6 Confidential — Limited Access
`
`24-Oct-2005
`
`

`

`
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`Food and Drug Administration
`Rockviile, MD 20857
`
`NBA 21-995
`
`Merck & Co.
`
`Attention: Patricia Tway
`BLA—20 PO. Box 4
`
`West Point, PA 19486
`
`Dear Dr. Tway:
`
`Please refer to your New Drug Application (NDA) submitted under section 505(b) of the Federal
`Food, Drug, and Cosmetic Act for sitagliptin phosphate tablets.
`
`' We refer to the meeting between representatives of your firm and the FDA on June 29, 2006.
`The purpose of the meeting was to discuss the questions and cements provided in the IR letter
`dated May 18, 2006.
`
`The official minutes ofthe above meeting are enclosed. You are responsible for notifying us of
`any significant differences in understanding regarding the meeting outcomes.
`
`If you have any questions, call me; at (301) 7964647." '
`
`Sincerely,
`
`{Sec appendéd L'Iec'frrm'lic sigm'n‘ure {.m‘i’ze,‘
`
`Amy Bertha
`Regulatory Health Project Manager
`Ofiice of New Drug Quality Assessment .
`Center for Drug Evaluation. and Research >
`
`- Enclosure
`
`

`

`ADRA Rev #1 of Action Package for NDA 21-995
`
`Reviewer: Lee Ripper, HFD—102
`Date received: 9/25/06
`
`Date of review: 9/26/06;-10/16/06
`
`Date original NDA received: 12/16/05
`UF goal date: 10/16/06
`
`Proposed Indication: As an adjunct to diet and exercise to improve glycemic control in patients
`with type 2 diabetes.
`Action pipe: AP
`
`RPM: Lina AlJuburi
`
`Drug Classification: 1S
`505(b)(1) application
`
`Patent Info on form FDA 3542a: AC
`
`Debarment Certification: SAC
`Financial Disclosure. Addressed in MOR #1, p. 28.
`Safefl Update: Dated 5/4/06, MOR #1, p 181
`Risk Management Plan: PPI and pregnancy registry; OSE rev 9/14/06
`Clinical Inspection Summagy: 9/5/06, data appear AC
`DMETS Review of Proprietary Name: UN 11/3 0/05 and 8/2/06. No review of carton and
`container labels. 9?27: RPM reports DMETS has the labels UR. Rev 10/5/06. DD memofinds
`proprietary name AC.
`DSRCS Review of PPI: 8/25/06
`DDMAC Review: 9/ 13/06
`
`SEALD Review: 8/23/06; 10/1 [/06
`'
`'
`fl: Merck requested a categorical exemption
`E_E_R: One inspection pending - finished dosage manufacturer/release tester, MSD in Pavia
`Italy. RPM was told on 9/25 that the inspection has been completed; probably AC, but decision
`not official yet. EER AC 10/12/06
`PSC/WU Mtg: 9/26/06
`
`1'
`
`<
`
`CMC section to Chi-Wan Chen, CMC review is pending; when completed will check to see if
`CWC needs a separate review package. CMC rev 10/16/06
`P/T section to Ken Hastings, 9/27/06; rev 10/16/06
`
`1. No DMETS review of carton and container labels; most recent version of labels are not in
`pkg.
`I have asked the RPM to provide a copy of most recent version if final version or, if
`not final version, final version when available.
`2. Final labeling receivedfrom Merck on 10/16/06
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Leah Ripper
`10/16/2006 06:15:56 PM
`CSO
`
`W“
`
`

`

`Al'luburi, Lina
`
`"om:
`ant:
`To:
`Subject:
`
`’
`
`Aljuburi, Lina
`Wednesday, October 1 1. 2006 9:34 AM
`'Aurecchia, Steven A.'
`' NDA 21-995 Januvia dissolution method
`
`Attachments:
`
`Picture (Metafile)
`
`, Steve,
`
`Your request for disintegration in lieu of dissolution for sitagliptin phosphate is unacceptable.
`Disintegration does not necessarily correlate with solubilization of the drug substance.
`Dissolution testing, on the other hand, incorporates both disintegration and the solubilization of the drug
`substance into the media in its specification. ICH 6A guidance (decision tree #7) stipulates that when a
`relationship has not been determined between dissolution and disintegration, disintegration is not acceptable
`instead of dissolution. For your product, there was no relationship between dissolution and disintegration.
`Therefore, the dissolution test is requested.
`
`Please refer to the following dissolution method and acceptance criterion:
`
`
`
`
`In vitro dissomtion medium
`V01mm of dissolution meditm
`"fledium temperamre
`
`E
`
`
`
`
`
`
`
`Acceptance criterion
`
`We request that you submit an amendment to NDA 21—995 to reflect this information.
`
`«s7
`
`Feel free to contact me if you have questions.
`
`Thanks,
`Lina
`
`Lina AIJuburi, Pharm.D., M. 8.
`Regulatory Project Manager
`Division of Metabolism and Endocrinology Products
`Center for Drug Evaluation and Research
`Food and Drug Administration
`301-796-1168 (phone)
`301-796-9712 (fax)
`-
`
`

`

`This'Is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Lina Aljuburi
`10/11/2006 09:43:26 AM
`CSO
`
`m‘7'
`
`an;-
`
`

`

`
`
`MEMORANDUM
`'
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`DATE:
`
`September 14, 2006
`
`TO:
`
`I Mary Parks, M.D., Director
`Division of Metabolic and Endocrine Products
`
`FROM:
`
`Office of Surveillance and Epidemiology (OSE) Risk Management Team
`
`DRUG:
`
`Januvia (sitagliptin phosphate) Tablets
`
`NDA#:
`
`21-995
`
`SPONSOR: Merck & co.
`
`SUBJECT: Review of Proposed Risk Management Plan (RMP) submitted
`December 16, 2005
`
`PID #:
`
`D060096
`
`INTRODUCTION/BACKGROUND
`
`This consult follows a request by the Division of Metabolic and Endocrine Products
`(DMEP), for the Office of Surveillance and Epidemiology (OSE) to review and comment
`on the Sponsor’s proposed Risk Management Plan (RMP) for Januvia (sitagliptin
`phosphate) Tablets.
`g
`-
`
`“
`
`Sitagliptin is a new molecular entity that belongs to a new class of therapeutic agents
`recognized as dipeptidyl peptidase IV (DPP4) inhibitors. The DPP4 inhibitors exert
`glycemic control in patients with type 2 diabetes by preventingthe rapid degradation of
`incretin hormones. Incretin hormones, including glucagon—like peptide-1 (GLP—1) and
`glucose-dependent insulinotropic peptide (GIP),' are released by the intestine throughout
`the day, and levels are increased in response to a meal. The proposed indication for
`' Januvia at 100 mg once daily is as monotherapy as an adjunct to diet and exercise to
`improve glycemic control in patients with type 2 diabetes mellitus and as combination
`therapy in patients with type 2 diabetes mellitus to improve glycemic control in
`combination with metformin or a PPARy agonist (e.g., thiazolidinedione) when diet and
`exercise, plus the single agent do not provide adequate glycemic control.
`
`

`

`The Sponsor’s summary of safety data in the Risk Management Plan submission did not
`identify any safety signals in any of the studies or potential risks that would normal
`warrant risk management measures beyond routine labeling and pharmacovigilance. They
`did mention that there is one important potential risk identified by the FDA, necrotic skin
`lesions in the monkey and there is misSing information in children, i.e., patients <18
`years of age and in pregnant women.
`
`_
`Ilan Irony, M.D., the medical officer assigned to the clinical reView of this NDA,
`indicated in his review1 that common adverse events (at least 3% of subjects in the group)
`and present with higher incidence in sitagliptin-treated subjects than in control subjects
`include diarrhea, nasopharyngitis, upper respiratory tract infection, urinary tract infection,
`arthralgia and headache. The frequency of hypoglycemic symptoms or events was similar
`in sitagliptin-treated subjects as in control-treated subjects and much lower than those
`treated with glipizide. He also noted laboratory findings of interest include a dose-related
`decrease in serum levels of alkaline phosphatase, small and transient mean increases in
`serum uric acid and creatinine, white blood cell counts and absolute neutrophil counts,
`and small decreases in hemoglobin. He agrees with the risk management plan proposed
`by the Sponsor.
`'
`
`REVIEW OF SPONSOR’S RIVIP
`
`The Sponsor does not believe that a Risk Minimization Action Plan (RiskMAP) is
`warranted for this product. They are proposing the following Pharmacovigilance/
`Surveillance and Post-marketing Activities:
`
`0 Labeling — professional labeling and the patient package insert will be utilized to
`convey to prescribers, other healthcare professionals, and patients about the risks
`associated with Januvia. A separate Patient Package Insert (PPI) consult was
`performed by the OSE Division of Surveillance, Research and Communication
`Support (DSRCS)?
`o Routine Pharrnacovigilance Practices - reporting of adverse event information
`(including AE’s of special interest to the Sponsor, hypoglycemia, selected
`gastrointestinal and laboratory events) will be accomplished in accordance with the
`relevant legal requirements and appropriate international declarations and protocols.
`o Necrotic skin lesions in monkeys — based on the Agency’s concern regarding animal
`data indicating that the administration of DPP-IV inhibitors to monkeys results in
`dose-dependent and duratiOn-dependent increases in necrotic skin lesions, the
`Sponsor is undertaking an oral toxicity study in monkeys over a range of doses for up
`to 3 months duration, the design of which has been reviewed and agreed upon by the
`US. FDA.
`_
`0 Pregnancy Registry - In order to develop a better assessment of the safety profile of
`Januvia in pregnant women, the Sponsor proposes the establishment of a pregnancy
`
`
`1 llan Irony, MD, Medical Officer. Clinical Review of Januvia (sitagliptin phosphate), NDA 21-995; in
`DFS, dated AugUSt 31, 2006.
`2 Sharon Mills, Patient Product Information Specialist, DSRCS Review of Patient Labeling for Januvia, in
`DFS, dated August 25, 2006.
`
`

`

`registry for more intensified follow-up of pregnancy exposures. The pregnancy
`registry will be an enhanced surveillance program of women exposed to Januvia at .
`any time from the date of the last menstrual period through the duration of the
`pregnancy.
`
`CONCLUSION
`
`The Sponsor’s proposed RMP does not appear to differ substantially from routine risk
`management measures, such as FDA—approved professional labeling and routine post-
`marketing surveillance. The Sponsor has proposed other measures including a plan to
`undertake an oral toxicity study in monkeys to assess the risk of necrotic skin lesions
`over a range of doses and a pregnancy registry to determine if there is any risk to the
`pregnant woman.
`
`The Division of Surveillance, Research and Communication Support (DSRCS)
`completed a separate Patient Package Insert (PPI) consult and the Division of Medication
`Error3and Technical SUpport (DMETS) conducted a separate review 'ofthe proprietary
`name .
`
`OSE concludes (after consulting with the MO in DMEP) that the Sponsor’s proposal for
`routine risk management measures and planned pharmacovigilance activities is sufficient
`at this time. If the sponsor or the review division identifies a safety concern in the future
`and determines that a RiskMAP is warranted or should the review division wish OSE to
`review any proposed Phase IV protocols or epidemiological post-marketing studies,
`please provide a consult request.
`'
`
`3 Linda Wisniewiski, R.N., DMETS Proprietary Name Review of Januvia, August 2, 2006.
`
`

`

`OSE Risk Management Team
`Mary Dempsey, Project Management Officer
`Claudia Karwoski, PharmD, Scientific Coordinator for Risk Management (Lead author)
`Joyce Weaver, PharmD, Senior Risk Management Analyst
`Mary Willy, PhD, Senior Risk Management Epidemiologist
`
`-
`
`

`

`This is a representation of an electronic record that was signed electronically and
`‘ this page is the manifestation of the electronic signature.
`
`Mary Dempsey
`9/14/2006 08:38:52 AM
`DRUG SAFETY OFFICE REVIEWER
`
`Claudia Karwoski
`9/14/2006 08:42:24 AM
`DRUG SAFETY OFFICE REVIEWER
`
`

`

`Steven A Aurecchia M D
`Director
`Worldwide Regulatory Affairs
`
`_
`
`August 24 , 2006
`
`Mary H. Parks, M.D., Director
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Metabolism & Endocrinology Products
`5901-8 Ammendale Road
`BeltSville, MD 20705—1266
`
`_
`
`'
`
`Merck & Co , inc
`.
`P 0 Box 1000. 116200-48
`North Wales PA 194544099
`Tel 267 305 6569
`Fax 267 305 6405
`steven_aurecchia@memk com
`
`
`
`'
`
`MERCK
`Hesemh Laboratories
`
`Dear Dr. Parks:
`
`NDA 21-995: JANUVIAIM (Sitagliptin Phosphate) Tablets
`
`Response to FDA Request for Information
`
`Reference is made to the New Drug Application cited above, submitted by Merck Research
`Laboratories (MRL), a Division of Merck & Co., Inc, on December 16, 2005. Reference is also
`made to the telephone conversation between Dr. Todd Bourcier (FDA) and Dr. Steven Aurecchia
`(MRL) on August 14, 2006, in which Dr. Bourcier requested MRL's pre-clinical study reports for
`the MK—O43l/metformin combination toxicity studies in the dog. Further reference is made to
`the e—mail communications on August 14, 2006 and August 18. 2006, from Dr. Aurecchia to
`Dr. Bourcier, that contained .pdf'copies of these reports.
`
`With this response, MRL is providing the official submission of‘ the pre—clinical reports e-mailed
`on August 14, 2006 and August 18, 2006 entitled, MK-0431 and Metforrnin: Exploratory Single
`Dose Oral Toxicokinetic Study in Dogs [Refi 4.2.3.2: TTOSIlSO], Metfonnin: Exploratory
`5- Week Oral Tolerability Study in Female Dogs [Ref42.32. TT066018], MK-0431 +
`Metforrnin. Fourteen Week Oral Toxicity Studyin Dogs [Ref.4.2.3.2_; TT066000] and MK—0431
`‘+ Metfor‘rnr'n: Sixteen-Week Oral Toxicity Studytn Female Dogs [Ref.4.2.3.2: TT066017], to the
`pending New Drug Application for JANUVIATM '
`
`Information in [Sec...,266]
`’ ,4 pre--clinical dog reports
`
`[Secm267] and [Sec.24] has been updated to include these
`-
`
`This submission is formatted as required in Title 21 paragraph 314.50 of the Code of Federal
`Regulations and is being submitted in accordance with the current FDA Guidance Documents for
`the electronic common technical document
`including, but not
`limited to the following:
`Comprehensive Table of Con