CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`201281Orig1s000
`
`ADMINISTRATIVE and CORRESPONDENCE
`DOCUMENTS
`
`
`
`
`
`
`

`

`EXCLUSIVITY SUMMARY
`
`NDA # 201281
`
`
`
`
`
`SUPPL #
`
`
`
`
`
`HFD # 510
`
`Trade Name Jentadueto
`
`Generic Name Linagliptin and Metformin Hydrochloride Fixed-Dose Combination tablets
`
`Applicant Name Boehringer Ingelheim Pharmaceuticals, Inc.
`
`Approval Date, If Known January 30, 2012
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`PART I
`
`IS AN EXCLUSIVITY DETERMINATION NEEDED?
`
`1. An exclusivity determination will be made for all original applications, and all efficacy
`supplements. Complete PARTS II and III of this Exclusivity Summary only if you answer "yes" to
`one or more of the following questions about the submission.
`
`a) Is it a 505(b)(1), 505(b)(2) or efficacy supplement?
`
`
`
`
`
` YES
`
`
`
`
`
`NO
`
`If yes, what type? Specify 505(b)(1), 505(b)(2), SE1, SE2, SE3,SE4, SE5, SE6, SE7, SE8
`
`
`
`505(b)(2)
`
`c) Did it require the review of clinical data other than to support a safety claim or change in
`labeling related to safety? (If it required review only of bioavailability or bioequivalence
`data, answer "no.")
`
`
`
`
`
` YES
`
`
`
`NO
`
`If your answer is "no" because you believe the study is a bioavailability study and, therefore,
`not eligible for exclusivity, EXPLAIN why it is a bioavailability study, including your
`reasons for disagreeing with any arguments made by the applicant that the study was not
`simply a bioavailability study.
`
`
`N/A
`
`If it is a supplement requiring the review of clinical data but it is not an effectiveness
`supplement, describe the change or claim that is supported by the clinical data:
`
`N/A
`
`d) Did the applicant request exclusivity?
`
`
`Reference ID: 3079330
`
`
`Page 1
`
`

`

`If the answer to (d) is "yes," how many years of exclusivity did the applicant request?
`
`
`
`
`
` YES
`
`
`
`NO
`
`3 years
`
`e) Has pediatric exclusivity been granted for this Active Moiety?
`
`
` YES
`
`
`
`NO
`
` If the answer to the above question in YES, is this approval a result of the studies submitted in
`response to the Pediatric Written Request?
`
`
`
`N/A
`
`IF YOU HAVE ANSWERED "NO" TO ALL OF THE ABOVE QUESTIONS, GO DIRECTLY TO
`THE SIGNATURE BLOCKS AT THE END OF THIS DOCUMENT.
`
`2. Is this drug product or indication a DESI upgrade?
`
`
`
`
`
` YES
`
`
`
`NO
`
`IF THE ANSWER TO QUESTION 2 IS "YES," GO DIRECTLY TO THE SIGNATURE BLOCKS
`ON PAGE 8 (even if a study was required for the upgrade).
`
`FIVE-YEAR EXCLUSIVITY FOR NEW CHEMICAL ENTITIES
`PART II
`(Answer either #1 or #2 as appropriate)
`
`1. Single active ingredient product.
`
`Has FDA previously approved under section 505 of the Act any drug product containing the same
`active moiety as the drug under consideration? Answer "yes" if the active moiety (including other
`esterified forms, salts, complexes, chelates or clathrates) has been previously approved, but this
`particular form of the active moiety, e.g., this particular ester or salt (including salts with hydrogen
`or coordination bonding) or other non-covalent derivative (such as a complex, chelate, or clathrate)
`has not been approved. Answer "no" if the compound requires metabolic conversion (other than
`deesterification of an esterified form of the drug) to produce an already approved active moiety.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` YES
`
`
`
`NO
`
`If "yes," identify the approved drug product(s) containing the active moiety, and, if known, the NDA
`#(s).
`
`NDA# N/A
`
`
`
`
`Reference ID: 3079330
`
`
`Page 2
`
`

`

`2. Combination product.
`
`If the product contains more than one active moiety(as defined in Part II, #1), has FDA previously
`approved an application under section 505 containing any one of the active moieties in the drug
`product? If, for example, the combination contains one never-before-approved active moiety and
`one previously approved active moiety, answer "yes." (An active moiety that is marketed under an
`OTC monograph, but that was never approved under an NDA, is considered not previously
`approved.)
`
`
`
`
`
`YES
`
`
`
`NO
`
`If "yes," identify the approved drug product(s) containing the active moiety, and, if known, the NDA
`#(s).
`
`NDA# 201280
`NDA# 020357
`
`Tradjenta (linagliptin) tablets
`Glucophage (metformin hydrochloride) tablets
`
`IF THE ANSWER TO QUESTION 1 OR 2 UNDER PART II IS "NO," GO DIRECTLY TO THE
`SIGNATURE BLOCKS ON PAGE 8. (Caution: The questions in part II of the summary should
`only be answered “NO” for original approvals of new molecular entities.)
`IF “YES,” GO TO PART III.
`
`PART III
`
`THREE-YEAR EXCLUSIVITY FOR NDAs AND SUPPLEMENTS
`
`To qualify for three years of exclusivity, an application or supplement must contain "reports of new
`clinical investigations (other than bioavailability studies) essential to the approval of the application
`and conducted or sponsored by the applicant." This section should be completed only if the answer
`to PART II, Question 1 or 2 was "yes."
`
`1. Does the application contain reports of clinical investigations? (The Agency interprets "clinical
`investigations" to mean investigations conducted on humans other than bioavailability studies.) If
`the application contains clinical investigations only by virtue of a right of reference to clinical
`investigations in another application, answer "yes," then skip to question 3(a). If the answer to 3(a)
`is "yes" for any investigation referred to in another application, do not complete remainder of
`summary for that investigation.
`
`
`
`
`
`YES
`
`
`
`NO
`
`IF "NO," GO DIRECTLY TO THE SIGNATURE BLOCKS ON PAGE 8.
`
`2. A clinical investigation is "essential to the approval" if the Agency could not have approved the
`application or supplement without relying on that investigation. Thus, the investigation is not
`essential to the approval if 1) no clinical investigation is necessary to support the supplement or
`application in light of previously approved applications (i.e., information other than clinical trials,
`
`
`Reference ID: 3079330
`
`
`Page 3
`
`

`

`such as bioavailability data, would be sufficient to provide a basis for approval as an ANDA or
`505(b)(2) application because of what is already known about a previously approved product), or 2)
`there are published reports of studies (other than those conducted or sponsored by the applicant) or
`other publicly available data that independently would have been sufficient to support approval of
`the application, without reference to the clinical investigation submitted in the application.
`
`(a) In light of previously approved applications, is a clinical investigation (either conducted
`by the applicant or available from some other source, including the published literature)
`necessary to support approval of the application or supplement?
`
`
` YES
`
`NO
`
`
`
`If "no," state the basis for your conclusion that a clinical trial is not necessary for approval
`AND GO DIRECTLY TO SIGNATURE BLOCK ON PAGE 8:
`
`N/A
`
`(b) Did the applicant submit a list of published studies relevant to the safety and
`effectiveness of this drug product and a statement that the publicly available data would not
`independently support approval of the application?
`
`
`
`
`NO
`
`
`
` YES
`
`(1) If the answer to 2(b) is "yes," do you personally know of any reason to disagree
`with the applicant's conclusion? If not applicable, answer NO.
`
`
`
`
`
`
`
` YES
`
`
`
`NO
`
` If yes, explain:
`
`
`
`N/A
`
`(2) If the answer to 2(b) is "no," are you aware of published studies not conducted or
`sponsored by the applicant or other publicly available data that could independently
`demonstrate the safety and effectiveness of this drug product?
`
` If yes, explain:
`
`
`
`
`
` YES
`
`
`
`NO
`
`N/A
`
`(c)
`
`If the answers to (b)(1) and (b)(2) were both "no," identify the clinical
`investigations submitted in the application that are essential to the approval:
`
`Study 1218.46: A Phase III randomised, double-blind, placebo-controlled
`parallel group study to compare the efficacy and safety of twice daily administration
`
`
`Reference ID: 3079330
`
`
`Page 4
`
`

`

`of the free combination of linagliptin 2.5 mg +metformin 500 mg or of linagliptin 2.5
`mg + metformin 1000 mg, with the individual components of metformin (500 mg or
`1000 mg, twice daily) and linagliptin (5 mg, once daily) over 24 weeks in drug naïve
`or previously treated (4 weeks washout and 2 weeks placebo run-in) type 2 diabetic
`patients with insufficient glycaemic control
`
`Studies comparing two products with the same ingredient(s) are considered to be bioavailability
`studies for the purpose of this section.
`
`3. In addition to being essential, investigations must be "new" to support exclusivity. The agency
`interprets "new clinical investigation" to mean an investigation that 1) has not been relied on by the
`agency to demonstrate the effectiveness of a previously approved drug for any indication and 2) does
`not duplicate the results of another investigation that was relied on by the agency to demonstrate the
`effectiveness of a previously approved drug product, i.e., does not redemonstrate something the
`agency considers to have been demonstrated in an already approved application.
`
`a) For each investigation identified as "essential to the approval," has the investigation been
`relied on by the agency to demonstrate the effectiveness of a previously approved drug
`product? (If the investigation was relied on only to support the safety of a previously
`approved drug, answer "no.")
`
`Investigation #1
`
`
`
`
`
`
`
`
`
`
`
`YES
`
`
`
`NO
`
`If you have answered "yes" for one or more investigations, identify each such investigation
`and the NDA in which each was relied upon:
`
`N/A
`
`b) For each investigation identified as "essential to the approval", does the investigation
`duplicate the results of another investigation that was relied on by the agency to support the
`effectiveness of a previously approved drug product?
`
`Investigation #1
`
`
`
`
`
`
`
`
`
`
`
`YES
`
`
`
`NO
`
`If you have answered "yes" for one or more investigation, identify the NDA in which a
`similar investigation was relied on:
`
`N/A
`
`c) If the answers to 3(a) and 3(b) are no, identify each "new" investigation in the application
`
`
`Reference ID: 3079330
`
`
`Page 5
`
`

`

`or supplement that is essential to the approval (i.e., the investigations listed in #2(c), less any
`that are not "new"):
`
`
`
`Study 1218.46
`
`4. To be eligible for exclusivity, a new investigation that is essential to approval must also have
`been conducted or sponsored by the applicant. An investigation was "conducted or sponsored by"
`the applicant if, before or during the conduct of the investigation, 1) the applicant was the sponsor of
`the IND named in the form FDA 1571 filed with the Agency, or 2) the applicant (or its predecessor
`in interest) provided substantial support for the study. Ordinarily, substantial support will mean
`providing 50 percent or more of the cost of the study.
`
`a) For each investigation identified in response to question 3(c): if the investigation was
`carried out under an IND, was the applicant identified on the FDA 1571 as the sponsor?
`
`Investigation #1
`
`
`
`IND # N/A
`
`
`
`
`
`
`
`
`
`
`YES
`
`
`
`
`
`
`
`
`
`!
`!
`
`
`! NO
`
`! Explain:
`Study 1218.46 was not conducted under an IND.
`
`
`
`
`
`
`
`
`
`
`(b) For each investigation not carried out under an IND or for which the applicant was not
`identified as the sponsor, did the applicant certify that it or the applicant's predecessor in
`interest provided substantial support for the study?
`
`Investigation #1
`
`
`
`
`
`YES
`
`
`
`
`
`
`
`Explain:
`Applicant provided substantial
`support for Study 1218.46
`
`!
`!
`! NO
`! Explain:
`
`
`
`(c) Notwithstanding an answer of "yes" to (a) or (b), are there other reasons to believe that
`the applicant should not be credited with having "conducted or sponsored" the study?
`(Purchased studies may not be used as the basis for exclusivity. However, if all rights to the
`drug are purchased (not just studies on the drug), the applicant may be considered to have
`sponsored or conducted the studies sponsored or conducted by its predecessor in interest.)
`
`If yes, explain:
`N/A
`
`
`
`
`
`YES
`
`
`
`NO
`
`=================================================================
`
`
`Reference ID: 3079330
`
`
`Page 6
`
`

`

`Name of person completing form: Mehreen Hai, Ph.D.
`Title: Regulatory Project Manager
`Date: January 30, 2012
`
`Name of Office/Division Director signing form: Jean-Marc Guettier, M.D.
`Title: Acting Clinical Team Leader
`
`Form OGD-011347; Revised 05/10/2004; formatted 2/15/05
`
`
`Reference ID: 3079330
`
`
`Page 7
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`MEHREEN HAI
`01/30/2012
`
`JEAN-MARC P GUETTIER
`01/30/2012
`
`Reference ID: 3079330
`
`

`

`Hai, Mehreen
`
`From:
`nt:
`J:
`Cc:
`Subject:
`
`Greeley, George
`Thursday, October 13, 2011 8:16 AM
`Hai, Mehreen
`Mathis, Lisa; Addy, Rosemary; Suggs, Courtney; Lee, Catherine 8.; Parks, Mary H
`NDA 201-281 Linagiiptin+Metformin
`
`Importance:
`
`High
`
`Attachments:
`
`1_Pediatric_Record.pdf
`
`Hi Mehreen,
`
`This email serves as confirmation of the review for Linagliptin+Metformin conducted by the PeRC
`PREA Subcommittee on October 12, 2011.
`
`The Division presented a partial waiver in pediatric patients ages birth to nine years because the
`disease / condition does not exist in children and a deferral for patients ten through sixteen years
`because the product is ready for approval in adults for the indication of treatment of type 2
`diabetes mellitus.
`
`The PeRC agreed with the Division to grant a partial waiver and deferral for the fixed—dose
`combination product.
`
`The pediatric record is attached for Linagliptin+Metformin.
`
`”Q
`
`i_Pediatric_Record
`.pdf (66 KB),..
`
`Thank you.
`
`George Greeley
`Regulatory Health Project Manager
`Pediatric and Maternal Health Staff
`
`FDA/CDER/ 0ND
`10903 New Hampshire Avenue
`Bldg. 22, Room 6467
`Silver Spring, MD 20993-0002
`Phone: 301.796.4025
`
`Email: george.greeley@fda.hhs.gov
`(9 Please consider the environment before printing this e-mail.
`
`Reference ID: 30831 09
`
`2pages has beenwithheldin full as B(4) CCI/TS
`immediately following this page
`
`

`

`Boehringer Ingelheim Pharmaceuticals, Inc.
`NBA 201281
`
`Linagliptin I Metformin Tablets
`
`DEBARTMENT CERTIFICATION
`
`Page 1 of 1
`
`Certification Requirement Section 306(k)(l) of the Act 21 U.S.C. 3553(k)
`
`Boehringer Ingelheim Pharmaceuticals, Inc. hereby certifies that it did not and will not use in
`any capacity the services of any person debarred under Section 306 of the Federal Food,
`Drug and Cosmetic Act in connection with this application.
`
`Signature:
`
`WW
`
`Name of Applicant:
`
`Joanne Palmisano, M.D., F.A.C.P.
`Vice President, Drug Regulatory Affairs
`Boehringer Ingelheim Pharmaceuticals, Inc.
`
`Date:
`
`Mailing Address:
`
`7 JM% 30/ i
`
`Boehringer Ingelheim Pharmaceuticals Inc.
`900 Ridgebury Road
`P.O. Box 368
`
`Ridgefield, CT 06877-0368
`
`

`

`From:
`To:
`Subject:
`Date:
`
`Hai, Mehreen
`"dawn.collette@boehringer-ingelheim.com"
`RE: NDA 201281 resubmission (linagliptin-metformin FDC)
`Monday, January 30, 2012 11:33:00 AM
`
`Hi Dawn,
`I received the package insert and the patient information for the linagliptin-metformin NDA that you
`emailed to me on Friday, January 27, 2012. We accept your revisions included in this labeling.
`
`Thank you,
`
`Mehreen Hai, Ph.D.
`Regulatory Project Manager
`Division of Metabolism & Endocrinology Products
`Center for Drug Evaluation and Research
`Food and Drug Administration
`mehreen.hai@fda.hhs.gov
`Ph: 301-796-5073
`Fax: 301-796-9712
`
`From: dawn.collette@boehringer-ingelheim.com [mailto:dawn.collette@boehringer-ingelheim.com]
`Sent: Friday, January 27, 2012 9:42 AM
`To: Hai, Mehreen
`Cc: dawn.collette@boehringer-ingelheim.com
`Subject: RE: NDA 201281 resubmission
`
`Dear Mehreen,
`Find attached a word document of the updated, proposed draft linagliptin-metformin package
`insert and patient information. BI has agreed to all the recent FDA edits.
`
`Changes in the attached version include:
`•
`Revised copyright to trademark symbol in JENTADUETO tradename
`•
` replaced with www.jentadueto.com in the patient information section
`• Minor formatting, typographical and grammatical changes
`
`
`
`Thank You,
`Dawn
`
`Drug Regulatory Affairs
`Boehringer Ingelheim
`Phone:203 798 4268
`Mobile:
`Fax: 203 837 4268
`
`From: Hai, Mehreen [mailto:Mehreen.Hai@fda.hhs.gov]
`Sent: Wednesday, January 25, 2012 11:30 AM
`
`Reference ID: 3079226
`
`(b) (4)
`
`(b) (6)
`
`

`

`To: Collette,Dawn (DRA) BIP-US-R
`Subject: RE: NDA 201281 resubmission
`
`Hello Dawn,
`Please find attached our edits/comments on the package insert and patient information that
`you emailed me yesterday for the linagliptin-metformin NDA. If you agree with the edits we have
`made, and have no further edits of your own, please clean up the document and email it back to me.
`Otherwise, if you have further edits, please let me know when you will be able to send us those edits.
`
`Thanks!
`
`Mehreen Hai, Ph.D.
`Regulatory Project Manager
`Division of Metabolism & Endocrinology Products
`Center for Drug Evaluation and Research
`Food and Drug Administration
`mehreen.hai@fda.hhs.gov
`Ph: 301-796-5073
`Fax: 301-796-9712
`
`From: dawn.collette@boehringer-ingelheim.com [mailto:dawn.collette@boehringer-ingelheim.com]
`Sent: Tuesday, January 24, 2012 1:44 PM
`To: Hai, Mehreen
`Cc: dawn.collette@boehringer-ingelheim.com
`Subject: RE: NDA 201281 resubmission
`
`Dear Mehreen,
`Find attached a word document of the updated, proposed draft linagliptin-metformin package
`insert and patient information. All FDA edits that BI has agreed to have been accepted and are no
`longer visible in the document. The remaining edits and comments reflect BI responses related to
`FDA prior comments. Additional BI editorial changes are also included in this version.
`
`Please do not hesitate to contact me if you have any questions or comments concerning this
`submission.
`
`Thank You,
`Dawn
`
`Drug Regulatory Affairs
`Boehringer Ingelheim
`Phone:203 798 4268
`Mobile:
`Fax: 203 837 4268
`
`From: Hai, Mehreen [mailto:Mehreen.Hai@fda.hhs.gov]
`Sent: Wednesday, January 18, 2012 4:15 PM
`To: Collette,Dawn (DRA) BIP-US-R
`Subject: RE: NDA 201281 resubmission
`
`Reference ID: 3079226
`
`(b) (6)
`
`

`

`Hi Dawn,
`Please find attached our edits/comments on the package insert and patient information that you
`submitted in the November 30, 2011 resubmission of the linagliptin-metformin NDA. We have no
`further comments on the carton and container labels.
`
`Please let me know when you expect to respond to these comments.
`THanks!
`
`Mehreen Hai, Ph.D.
`Regulatory Project Manager
`Division of Metabolism & Endocrinology Products
`Center for Drug Evaluation and Research
`Food and Drug Administration
`mehreen.hai@fda.hhs.gov
`Ph: 301-796-5073
`Fax: 301-796-9712
`
`Reference ID: 3079226
`
`21 pages of draft labeling has been withheld in full as
`B(4) 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/
`----------------------------------------------------
`MEHREEN HAI
`01/30/2012
`
`Reference ID: 3079226
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`NDA 201281
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`PROPRIETARY NAME REQUEST
`CONDITIONALLY ACCEPTABLE
`
`Boehringer Ingelheim Pharmaceuticals, Inc.
`900 Ridgebury Road/P.O. Box 368
`Ridgefield, CT 06877-0368
`
`Attention:
`
`
`
`Dawn Collette
`Associate Director, Drug Regulatory Affairs
`
`Dear Ms. Collette:
`Please refer to your New Drug Application (NDA) dated January 19, 2011, received January 19, 2011,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Linagliptin and
`Metformin Hydrochloride Tablets, 2.5 mg/500 mg, 2.5 mg/850 mg and
`2.5 mg/1000 mg.
`Please also refer to your complete Class 2 resubmission to this NDA, dated and received November 30,
`2011. We also refer to:
`• Your initial proprietary name submission, dated November 1, 2011, for the proposed
`proprietary name Jentadueto;
`• Our initial correspondence dated November 9, 2011, finding this proposed proprietary name
`conditionally acceptable;
`• Your January 17, 2012, correspondence, received January 17, 2012, requesting re-review of
`your proposed proprietary name, Jentadueto.
`We have completed our re-review of the proposed proprietary name, Jentadueto, and have concluded
`that it is acceptable
`The proposed proprietary name, Jentadueto, will be re-reviewed 90 days prior to the approval of the
`NDA. If we find the name unacceptable following the re-review, we will notify you.
`If any of the proposed product characteristics as stated in your January 17, 2012, submission are altered
`prior to approval of the marketing application, the proprietary name should be resubmitted for review.
`
`Reference ID: 3077356
`
`

`

`NDA 201281
`Page 2
`
`If you have any questions regarding the contents of this letter or any other aspects of the proprietary
`name review process, contact Margarita Tossa, Safety Regulatory Project Manager in the Office of
`Surveillance and Epidemiology, at (301) 796-4053. For any other information regarding this
`application contact the Office of New Drugs (OND) Regulatory Project Manager Mehreen Hai at (301)
`796-5073.
`
`Sincerely,
`{See appended electronic signature page}
`
`Carol Holquist, RPh
`Director
`Division of Medication Error Prevention and Analysis
`Office of Medication Error Prevention and Risk Management
`Office of Surveillance and Epidemiology
`Center for Drug Evaluation and Research
`
`Reference ID: 3077356
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`CAROL A HOLQUIST
`01/26/2012
`
`Reference ID: 3077356
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`ACKNOWLEDGE --
` CLASS 1 COMPLETE RESPONSE
`
`NDA 201281
`
`Boehringer Ingelheim Pharmaceuticals, Inc.
`Attention: Dawn Collette
`Associate Director, Drug Regulatory Affairs
`900 Ridgebury Rd/ P.O. Box 368
`Ridgefield, CT 06877-0368
`
`Dear Ms. Collette:
`
`We acknowledge receipt on November 30, 2011, of your November 30, 2011 resubmission of
`your new drug application submitted pursuant to section 505(b)(2) of the Federal Food, Drug,
`and Cosmetic Act for linagliptin and metformin hydrochloride tablets (2.5 mg/500 mg,
`2.5 mg/850 mg, and 2.5 mg/1000 mg).
`
`We consider this a complete, class 1 response to our action letter dated November 16, 2011.
`Therefore, the user fee goal date is January 30, 2012.
`
`If you have any questions, please call me at (301) 796-5073.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Mehreen Hai, Ph.D.
`Regulatory Project Manager
`Division of Metabolism & Endocrinology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`Reference ID: 3065321
`
`

`

`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`
`MEHREEN HAI
`
`12/22/2011
`
`Reference ID: 3063240
`
`Reference ID: 3083109
`Reference ID: 3083109
`
`

`

`From:
`To:
`Subject:
`Date:
`Attachments:
`
`Hai, Mehreen
`"dawn.collette@boehringer-ingelheim.com";
`PI for NDA 201281
`Tuesday, November 22, 2011 11:37:25 AM
`Lina-Met proposed label-FDA edits-21Nov2011.doc
`
`Hi Dawn,
`Please find attached our edits/comments on the package insert (PI) that you
`submitted on November 3, 2011 for the linagliptin-metformin NDA. We
`recommend that you submit the PI with your further revisions/comments when
`you re-submit this NDA. We also recommend that you include the revised PPI
`(patient information) that you emailed me on November 10, 2011 in the NDA re-
`submission. We will re-start labeling negotiations once the NDA re-submission
`has been received.
`
`Hope that's clear. If not, please let me know.
`
`Mehreen Hai, Ph.D.
`Regulatory Project Manager
`Division of Metabolism & Endocrinology Products
`Center for Drug Evaluation and Research
`Food and Drug Administration
`mehreen.hai@fda.hhs.gov
`Ph: 301-796-5073
`Fax: 301-796-9712
`
`Reference ID: 3048512
`
`17 pages of draft labeling has been withheld in full as
`B(4) 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.
`
`
`
`MEHREEN HAI
`
`11/22/2011
`
`Reference ID: 3048512
`
`Reference ID: 3083109
`Reference ID: 3083109
`
`

`

`From:
`
`To:
`
`Subject:
`Date:
`
`Hi Dawn,
`
`Hai Mehreen
`
`"dawn.col|ette@boehringer-ingelheim.
`
`com";
`
`RE: Action letter for NDA 201281
`Tuesday, November 22, 2011 9:13:01 AM
`
`Please see our response below (in blue) to your query.
`Let me know if you have any further questions.
`
`Mehreen Hai, Ph.D.
`
`Regulatory Project Manager
`
`Division of Metabolism & Endocrinology Products
`
`Center for Drug Evaluation and Research
`
`Food and Drug Administration
`
`mehreen.hai@fda.hhs.gov
`
`Ph: 301-796-5073
`
`Fax: 301-796-9712
`
`From: dawn.col|ette@boehringer—ingelheim.com [mailto:dawn.
`collette@boehringer-ingelheim.com]
`Sent: Thursday, November 17, 2011 4:25 PM
`To: Hai, Mehreen
`Cc: dawn.collette@boehringer—ingelheim.com
`Subject: RE: Action letter for NDA 201281
`
`Dear Mehreen,
`
`We’d appreciate guidance from the Agency as we plan for resubmission of
`
`the linagliptin/metformin NDA.
`
`am as a testing facility,
`1) We are planning to remove
`and replace it with other facilities already included in the application.
`
`Does FDA agree that this change fully addresses the deficiencies
`
`listed in the Complete Response letter?
`
`(5X4)
`
`FDA Response: Yes, the proposed deletion of
`
`from the NDA would address the deficiency listed in the Complete
`
`Reference ID: 3048400
`
`

`

`Response letter. However, our action on your resubmission will be
`based on the GMP-compliance status of all manufacturing and
`testing sites listed in the resubmission at the time of the action.
`
`2) Since the 4-month safety update (4MSU), there is limited new
`safety information for linagliptin/metformin fixed dose combination
`tablets. Outlined below is the current status of the only studies that
`were ongoing as of the 4MSU. No other studies for linagliptin/
`metformin are ongoing at this time.
`
`-- 1218.20, 104-week active controlled study linagliptin vs
`glimepiride, with metformin background therapy. 4MSU data cut-off
`was June 30, 2010, and last patient out (LPO) was Dec 21, 2010. The
`final report is planned to be submitted as a supplement to NDA
`201280 for TRADJENTA (linagliptin) tablets in the next weeks.
`-- 1218.40, 78-week uncontrolled open-label extension for linagliptin
`tablets, some patients treated with metformin background therapy.
`4MSU data cut-off was Oct 15, 2010, LPO was Dec 29, 2010
`-- 1218.52, 54-week double-blind, metformin-controlled extension
`study of 1218.46 (pivotal factorial design study). 4MSU data cut-off
`was Oct 15, 2010, LPO was June 16, 2011.
`
`With these new data, no significant changes or findings relevant to the
`safety profile of linagliptin/metformin fixed dose combination tablets
`have been identified. Please also note that linagliptin/metformin fixed
`dose combination tablets are not yet marketed in any country, so no
`foreign labeling or post-marketing safety information are available.
`
`BIPI is therefore requesting to waive the requirement for a safety
`update in the resubmission. Does the Division concur?
` FDA Response: We cannot waive this requirement and would
`ask that at time of your resubmission you provide us with an
`update of new safety information as you have done so in this
`correspondence. If the status for postmarketing safety data of
`linagliptin remains unchanged or limited, the Division can
`determine at that point to what extent a review is necessary.
`
`Reference ID: 3048400
`
`

`

`3) Does the Division agree that the Complete Response, with
`information outlined above, could be considered a Class 1
`resubmission?
` FDA Response: In general, a resubmission without new clinical data
`will be a Class 1 resubmission. However, you are proposing other
`facilities to replace
` If inspection of these facilities are
`required, this will be a Class 2 resubmission. A final determination of
`the type of resubmission will be made upon receipt of your application.
`
`
`4) With respect to the facilities inspection of the
`testing facility, we would appreciate clarification of the following
`points:
`
`●
`
`●
`
`FDA’s Complete Response Letter states that FDA
`conducted an inspection at this site for our application.
`We are aware that FDA performed a general inspection of
` but not an inspection for our
`application, i.e., a Preapproval Inspection (PAI).
`
` is listed in FDA’s Inspectional
`Classification Database with a classification
`“VAI” (Voluntary Action Indicated) Per FDA’s PAC-
`ATLS Guidance, a VAI classification is considered a
`“Satisfactory Current Good Manufacturing Practice
`
`(cGMP) Inspection”. We agree to remove
`from the application (as stated above), but would like to
`understand how to interpret the VAI classification in
`FDA’s database in the context of FDA’s Complete
`Response Letter.
`FDA Response: FDA's inspectional database does not show the
`most current GMP status of a specific site. You should
`communicate with your contract facilities for their current GMP
`status.
`
`Please do not hesitate to contact me if you have any questions.
`
`Reference ID: 3048400
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Thank You,
`Dawn
`
`Drug Regulatory Affairs
`Boehringer Ingelheim
`Phone:203 798 4268
`Mobile:
`Fax: 203 837 4268
`
`
`
`From: Hai, Mehreen [mailto:Mehreen.Hai@fda.hhs.gov]
`Sent: Wednesday, November 16, 2011 1:06 PM
`To: Collette,Dawn (DRA) BIP-US-R
`Subject: Action letter for NDA 201281
`
`Hi Dawn,
`We took action a couple of days early for the linagliptin-metformin NDA 201281- it is
`a complete response based on deficiencies in the facilities inspections. Please
`confirm receipt of the attached letter, and let me know if you have any questions.
`The paper copy should come to you in the mail in a few days.
`
`Thanks!
`
`Mehreen Hai, Ph.D.
`Regulatory Project Manager
`Division of Metabolism & Endocrinology Products
`Center for Drug Evaluation and Research
`Food and Drug Administration
`mehreen.hai@fda.hhs.gov
`Ph: 301-796-5073
`Fax: 301-796-9712
`
`Reference ID: 3048400
`
`(b) (6)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`MEHREEN HAI
`11/22/2011
`
`Reference ID: 3048400
`
`

`

`Hai, Mehreen
`
`. ”rom:
`nt:
`no:
`Cc:
`Subject:
`
`Wood-Cummings, Terri
`Thursday, November 10, 2011 2:59 PM
`Hai, Mehreen
`Mena-Grillasca, Carlos; Oleszczuk, Zachary; Tossa, Margarita
`FW: Revised CC labels for NDA 201281 in DARRTS
`
`Subject: RE: NDA 201281 linagliptin—metformin: Response to Container Label Revisions
`
`Hi Mehreen,
`
`DMEPA has reviewed the revised container labels submitted by the Applicant on November 8,
`2011. All of DMEPA's recommendations from our October 28, 2011 review (RCM# 2011—353)
`have been addressed, and the labels
`are found acceptable.
`
`Please let me know if I can be of further assistance.
`
`Thank you,
`
`Terri Wood-Cummings, MD.
`Medical Officer/Medication Safety Evaluator
`Division of Medication Error Prevention and Analysis
`Office of Mediation Error Prevention and Risk Management (OMEPRM)
`FDA/CDERIOSE
`W0 Bldg. 22, Room 4421
`Mail Stop. Bldg. 22, Room 4447
`10903 New Hampshire Avenue
`Silver Spring, MD 20993
`terri.wood-cummings@fda.hhs.gov
`301.796.2887 (p)
`
`From:
`Sent:
`To:
`Subj