`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`201280Orig1s000
`
`ADMINISTRATIVE and CORRESPONDENCE
`DOCUMENTS
`
`
`
`
`
`
`

`

`Form APPfOVWZ OMB NO- 0910'0513
`EXp'rat'O” Date: 7/31/10
`See OMB Statement on Page 3.
`PATENT INFORMATION SUBMITTED WITH THE FILING NDA NUMBER
`
`Department of Health and Human Services
`Food and Drug Administration
`
`OF AN NDA, AMENDMENT, on SUPPLEMENT
`
`For Each Patent That Claims a Drug Substance
`(Active Ingredient), Drug Product (Formulation and Composition)
`and/or Method of Use
`
`NAME OF APPLICANT/NDA HOLDER
`Boehringer Ingelhe‘m Pharmaceuncals Inc
`
`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)
`ONDERO
`
`ACTIVE |NGRED|ENT(S)
`
`Linagliptin
`
`STRENGTH(S)
`
`5 mg
`
`I O ‘
`
`O ' V
`
`Tablet (oral)
`
`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)(ii) 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 hand-written 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 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 referenced above, you must submit all the
`information described below. If you are not submitting any patents for this pending NDA, amendment, or supplement,
`complete above section and sections 5 and 6.
`
`1. GENERAL
`
`a. United States Patent Number
`
`b. issue Date of Patent
`
`0. Expiration Date of Patent
`
`d. Name of Patent Owner
`
`Boehringer Ingelheim Pharma GmbH & Co., KG.
`
`e. ‘ame 0 agent or representative w 0 rest-es or maintains
`a p ace of Busmess Within the United States authorized to
`receive notice of patent certification under section 505(b)(3)
`and (j)(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)
`
`Boehringer lngelheim Pharmaceuticals, Inc.
`
`Gemtany
`
`Telephone Number
`
`I
`
`
`
`
`
`Address (of Patent Owner)
`Binger Strasse 173
`City/State
`
`lngelheim
`ZIP Code
`
`FAX Number (ifavailable)
`
`
`E-Maii Address (IfavaI/able)
`
`‘ I ress 0 agent or representatlve name
`~
`900 Rldgebury Road
`
`,
`Gill/State
`Rldgefield/CT
`ZIP Code
`06877-0368
`
`FAX Number (ifavailable)
`203-798—4408
`
`Telephone Number
`
`E-Mail Address (if available)
`
`.
`
`Is the patent re erenced above a patent that has oeen submitted previously or the
`approved NDA or supplement referenced above?
`
`g.
`
`the patent re erenced above has been submitted previously or listing, is the expiration
`|
`date a new expiration date?
`
`FORM FDA 3542a (12/08)
`
`
`
`
`
`
`
`Yes
`
`Yes
`
`
`
`No
`
`
`
`3 No
`
`Page 1
`PSC Graphics (301) 4434090
`EF
`
`

`

`2. Drug Substance (Active Ingredient)
`2.1 Does the patent claim the drug substance that‘Is the active ingredientIn the drug product
`describedIn the pending NDA, amendment, or supplement?
`
`2.2 Does the patent claim a drug substance thatIs a different polymorph of the active
`ingredient describedIn the pending NDA, amendment, or supplement?
`
`
`
`
`
`
`2.3 If 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
`
`
`:] No
`described in the NDA? The type of test data required is described at 21 CFR 314.53(b).
`[:1 Yes
`
`
`2.4 Specify the polymorphic form(s) claimed by the patent for which you have the test results described in 2.3.
`
`
`
`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.)
`
`IAN0
`
`Yes
`
` 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, amendment, or supplement.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2.6 Does the patent claim only an intermediate?
`
`2.7 if the patent referencedIn 2.1 is a product-by- process patent, is the product claimedIn the
`patent novel? (An answer is required only if the patentIs a product-by—process patent.)
`
`3. Drug Product (Composition/Formulation)
`
`IAND
`
`E] No
`
`3.1 Does the patent claim the drug product, as defined'In 21 CFR 314.3, in the pending NDA, amendment,
`
`
`[3 No
`or supplement?
`KY
`
`
`3.2 Does the patent claim only an intermediate?
`
`
`1 Yes
`No
`
`
`
`3.3 it the patent referenced in 3.1 is a product-by-process patent, is the product claimed in the
`
`
`
`patent novel? (An answer is required only if the patent is a product-by-process patent.)
`
`
`
`
`4. Method of Use
`Sponsors must submit the information in section 4 for each method of using the pending drug product for which approval is being
`sought that is claimed by the patent. For each pending method of use claimed by the patent, provide the following information:
`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)
`Does (Do) the patent claim(s) referenced in 4.2 claim a
`
`pending method of use for which approval is being sought
`
`
`
`in the pending NDA, amendment, or supplement?
`l: Yes
`X] No
`4.2a if the answerto 4.2 is
`Use: (Submit indication or method of use information as identified specifically in the proposed labeling.)
`
`
`
`"Yes," identify with speci—
`
`
`ficity the use with refer-
`
`ence to the proposed
`
`labeling for the drug
`product.
`
`
`
`
`5. No Relevant Patents
`
`For this pending NDA, amendment, or supplement, there are no relevant patents that claim the drug substance (active ingredient),
`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 assened if a person not licensed by the owner of the patent engaged in the
`manufacture, use, or sale of the drug product.
`
`FORM FDA 3542a (12/08)
`
`Page 2
`
`

`

`6. Declaration Certification
`
`6.1 The undersigned declares that this is an accurate and complete submission of patent 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 CFR 314.53. lattest that I am 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 U.S.C. 1001.
`
`6.2 Authorized Signature of NDA Applicant/Holder or Patent Owner (Attorney, Agent, Representative or
`otherA orlzed Official) (Provide
`formation below}
`
`/
`
`Date Signed
`
`05/24/2010
`
`NOTE: Only an NDA 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).
`
`Check applicable box and provide information below.
`
`
`NDA Applicant/Holder
`
`K] NDA Applicant’s/Holder‘s Attorney, Agent (Representative) or other
`Authorized Official
`
`
`
`
`
`Patent Owner’s Attorney, Agent (Representative) or Other Authorized
`Official
`
`Patent Owner
`
`Name
`
`ii/jbrmation unless it displays a currently valid OMB control number.
`
`
`
`
`
`
`
`
`
`
`David L. Kershner
`
`Address
`
`
`City/State
`
`900 Ridgebury Road
`
`
`Ridgefield/CT
`
`Telephone Number
`ZIP Code
`203-798-9988
`06877-0368
`
`FAX Number (ifavailable)
`E-Mail Address (lfavallab/e)
`
`203-798-5469
`
`david.kershner@boehringer-ingelheim.com
`
`The public reporting burden for this collection ofinfomtation 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 ofinfonnation. Send
`comments regarding this burden estimate or any other aspect ofthis collection ofinformation, including suggestions for reducing this burden to:
`
`Department of Health and Human Services
`Food and Drug Administration
`Office of Chief Information Officer (HFA-710)
`5600 Fishers Lane
`Rockville, MD 20857
`
`A n age/My may not conduct or sponsor, and a person is no! required to respond to, a collection of
`
`FORM FDA 3542a (12/08)
`
`Page 3
`
`

`

`a) Is it a 505(b)(1), 505(b)(2) or efficacy supplement?
`
`
`
`
`
` YES
`
`
`
`NO
`
`
`
`EXCLUSIVITY SUMMARY
`
`
`NDA # 201280
`
`
`
`
`
`SUPPL # N/A
`
`
`
`HFD # 510
`
`Trade Name Tradjenta Tablets
`
`Generic Name linagliptin
`
`
`
`
`
`Applicant Name Boehringer Ingelheim Pharmaceuticals, Inc.
`
`Approval Date, If Known
`
`PART I
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`IS AN EXCLUSIVITY DETERMINATION NEEDED?
`
`
`
`If yes, what type? Specify 505(b)(1), 505(b)(2), SE1, SE2, SE3,SE4, SE5, SE6, SE7, SE8
`
`
`
`505(b)(1)
`
`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.
`
`
`
`
`
`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:
`
`
`
`
`
`d) Did the applicant request exclusivity?
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 2940172
`
`Page 1
`
`

`

`
`If the answer to (d) is "yes," how many years of exclusivity did the applicant request?
`
`
`
`
`
`
` YES
`
`
`
`NO
`
`
`
`5 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?
`
`
`
`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#
`
`
`
`
`
`
`
`
`
`Reference ID: 2940172
`
`Page 2
`
`

`

`NDA#
`
`
`
`NDA#
`
`
`
`
`
`
`
`
`
`
`
`
`If "yes," identify the approved drug product(s) containing the active moiety, and, if known, the NDA
`#(s).
`
`NDA#
`NDA#
`NDA#
`
`
`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
`
`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.
`
`
`
`
`
`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
`
`
`
`
`
`
`
`
`
`
`
`THREE-YEAR EXCLUSIVITY FOR NDAs AND SUPPLEMENTS
`
`
`
`
`
`YES
`
`
`
`NO
`
`
`
`
`
`Reference ID: 2940172
`
`Page 3
`
`

`

`(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
`
`
`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:
`
`
`
`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,
`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.
`
`
`
`
`
`
`
`
`(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?
`
`
` YES
`
`
`
`NO
`
`
`
`
`
`
`(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:
`
`
`
`
`
`(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
`
`
`
`
`
`Reference ID: 2940172
`
`Page 4
`
`

`

`
`
`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.
`
`
`(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:
`
`
`
`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
`
`Investigation #2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`YES
`
`YES
`
`
`
`
`
`NO
`
`NO
`
`
`
`
`
`If you have answered "yes" for one or more investigations, identify each such investigation
`and the NDA in which each was relied upon:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Investigation #1
`
`Investigation #2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`YES
`
`YES
`
`
`
`
`
`NO
`
`NO
`
`
`
`
`
`
`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?
`
`
`
`
`
`
`
`
`If you have answered "yes" for one or more investigation, identify the NDA in which a
`similar investigation was relied on:
`
`
`
`Reference ID: 2940172
`
`Page 5
`
`

`

`
`
`
`
`
`
`c) If the answers to 3(a) and 3(b) are no, identify each "new" investigation in the application
`or supplement that is essential to the approval (i.e., the investigations listed in #2(c), less any
`that are not "new"):
`
`
`
`
`
`
`
`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.
`
`
`Investigation #1
`
`
`
`IND #
`
`
`
`
`
`
`
`
`
`YES
`
`
`Investigation #2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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?
`
`!
`!
`
`! NO
`! Explain:
`
`
`
`!
`!
`
`! NO
`! Explain:
`
`
`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?
`
`
`YES
`
`
`
`
`
`
`
`
`
`
`Investigation #1
`
`
`YES
`Explain:
`
`
`
`
`
`
`
`
`
`Reference ID: 2940172
`
`
`
`
`
`
`
`
`
`
`
`!
`!
`
`! NO
`! Explain:
`
`
`
`Page 6
`
`

`

`
`
`Investigation #2
`
`
`YES
`Explain:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`!
`!
`
`! 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.)
`
`
`
`
`
`
`YES
`
`
`
`NO
`
`
`
`If yes, explain:
`
`
`
`
`
`
`
`
`=================================================================
`
`Name of person completing form: Raymond Chiang
`Title: Consumer Safety Officer
`Date: 3.22.11
`
`
`Name of Office/Division Director signing form: Mary Parks, M.D.
`Title: Director, Division of Metabolism and Endocrinology Products
`
`
`
`Form OGD-011347; Revised 05/10/2004; formatted 2/15/05
`
`
`
`
`Reference ID: 2940172
`
`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/
`----------------------------------------------------
`
`RAYMOND S CHIANG
`04/29/2011
`
`ILAN IRONY
`04/29/2011
`I concur.
`
`Reference ID: 2940172
`
`

`

`Boehringer Ingelheim Pharmaceuticals, Inc.
`NDA 201280
`
`Linagliptin Tablet
`
`Page 1 0f 1
`
`DEBARMENT CERTIFICATION
`
`Certification Requirement Section 306(k)(1) of thexAct 21 U.S.C. 355a(k)
`
`Boehringer lngelheim 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: W [O M
`
`
`
`Name of Applicant:
`
`Christopher Corsico, M.D.
`Vice President, Drug Regulatory Affairs
`Bochringer Ingelheim Pharmaceuticals, Inc.
`
`Date:
`
`
`q 37mg?» to
`
`Mailing Address:
`
`Boehringer Ingelheim Pharmaceuticals Inc.
`900 Ridgebury Road
`PO. Box 368
`
`Ridgefield, CT 06877-0368
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`Food and Drug Administration
`
`Form Approved: OMB No. 0910-0396
`Expiration Date: August 31, 2012
`
`ARRANGEMENTS OF CLINICAL INVESTIGATORS
`
`CERTIFICATION: FINANCIAL INTERESTS AND
`
`TO BE COMPLETED BYAPPLICANT
`
`With respect to all covered clinical studies (or specific clinical studies listed below (if appropriate» submitted in
`support of this application,
`I certify to one of the statements below as appropriate.
`I understand that this
`certification is made in compliance with 21 CFR part 54 and that for the purposes of this statement, a clinical
`investigator includes the spouse and each dependent child of the investigator as defined in 21 CFR 54.2(d).
`
`
`Please mark the applicable checkbox.
`
`l
`
`(1) As the sponsor of the submitted studies, I certify that l have not entered into any financial arrangement
`with the listed clinical investigators (enter names of clinical investigators below or attach list of names to
`this form) whereby the value of compensation to the investigator could be affected by the outcome of the
`study as defined in 21 CFR 54.2(a). I also certify that each listed clinical investigator required to disclose
`to the sponsor whether the investigator had a proprietary interest in this product or a significant equity in
`the sponsor as defined in 21 CFR 54.2(b) did not disclose any such interests.
`I further certify that no
`listed investigator was the recipient of significant payments of other sorts as defined in 21 CFR 54.2(f).
`
`
`
`Please see attached list of sites for study numbers:
`
`
`
`
`ClinicalInvestigators
`
`1218.5,1218.6,1218.15, l218.16,1218.17,1218.18
`
`1218.20,1218.23,1218.35, 1218.50
`
`[:l (2) As the applicant who is submitting a study or studies sponsored by a firm or party other than the
`applicant,
`I certify that based on information obtained from the sponsor or from participating clinical
`investigators, the listed clinical investigators (attach list of names to this form) did not participate in any
`financial arrangement with the sponsor of a covered study whereby the value of compensation to the
`investigator for conducting the study could be affected by the outcome of the study (as defined in 21
`CFR 542(8)); had no proprietary interest in this product or significant equity interest in the sponsor of
`the covered study (as defined in 21 CFR 54.2(b)); and was not the recipient of significant payments of
`other sorts (as defined in 21 CFR 54.2(f)).
`
`[:1 (3) As the applicant who is submitting a study or studies sponsored by a firm or party other than the
`applicant,
`I certify that l have acted with due diligence to obtain from the listed clinical investigators
`(attach list of names) or from the sponsor the information required under 54.4 and it was not possible to
`do so. The reason why this information could not be obtained is attached.
`
`NAME
`TITLE
`
`US. Regional Medical Director
`Christopher Corsico, MD, MPH
`
`FIRM/ORGANIZATION
`
`Boehringcr Ingelheim Pharmaceuticals, Inc.
`
`DATE (mm/dd/yyyy)
`SIGNATUR /
`
`
`
`171 June 2&[0
`
`Paperwork Reduction Act Statement
`An agency may not conduct or sponsor, and a person is not required to respond to, a collection of
`information unless it displays a currently valid OMB control number. Public reporting burden for this
`collection of information is estimated to average 1 hour per response,
`including time for reviewing
`instructions, searching existing data sources, gathering and maintaining the necessary data, and
`completing and reviewing the collection of information. Send comments regarding this burden estimate
`or any other aspect 01‘ this collection ofinformation to the address to the right:
`
`Department of Health and Human Services
`Food and Drug Administration
`Office of Chieflnformation Officer
`1350 Piccard Drive, 420A
`Rockvillc. MD 20850
`
`FORM FDA 3454 (10/09)
`
`I‘scompiucsismrw moo
`
`15F
`
`

`

`MEMORANDUM OF TELECON
`
`April 19, 2011
`9:00 am EST
`NDA 201280
`Tradjenta (linagliptin)
`
`
`
`MEETING DATE:
`TIME:
`
`
`APPLICATION:
`
`DRUG NAME:
`
`
`MEETING RECORDER: Raymond Chiang, M.S.
`
`FDA ATTENDEES: (Title and Office/Division)
`
`
`
`Mary Parks, M.D.
`Curt Rosebraugh, M.D., M.P.H.
`Ilan Irony, M.D.
`
`Somya Verma, M.D.
`
`Raymond Chiang, M.S.
`
`Amy Egan, M.D., M.P.H.
`
`Xiao Ding, Ph.D.
`
`Matt Soukup, Ph.D.
`
`Todd Sahlroot, Ph.D.
`
`
`Division Director, DMEP
`Office Director, ODEII
`Diabetes Clinical Team Leader, DMEP
`Clinical Reviewer, DMEP
`Regulatory Project Manager, DMEP
`Deputy Director of Safety
`Biometrics Reviewer
`Biometrics Team Leader
`Deputy Director, Division of Biometrics II (DBII)
`
`
`EXTERNAL CONSTITUENT ATTENDEES:
`
`
`Klaus Dugi, M.D.
`Sabine Luik, M.D.
`
`
`
`
`
`Corporate Senior Vice President Medicine
`Corporate Senior Vice President QM, Regulatory
`Affairs, Pharmacovigilance, Epidemiology
`US Regional Medical Director
`Vice President Therapeutic Area Metabolism
`Senior Vice President Clinical Development and
`Medical Affairs
`Vice President, Drug Regulatory Affairs-US
`Team Member Medicine Linagliptin
`International Project Management
`International Project Management
`Project Statistician Linagliptin
`Team Member RA Linagliptin, Global Regulatory
`Affairs
`Sr Associate Director DRA Product Group-US
`Global Regulatory Affairs-US (Eli Lilly)
`Executive Director DRA Product Group-US
`
`
`Christopher Corsico, M.D.
`Hans-Juergen Woerle, M.D.
`John Smith, M.D.
`
`Joanne Palmisano, M.D.
`Sanjay Patel, M.D.
`
`Mathias Senger, Ph.D.
`Thomas Rauch, M.D.
`Dietmar Neubacher, Ph.D.
`Paul Bispham, Ph.D.
`
`
`
`
`
`
`Maureen Oakes, PharmD
`Beth Weinberg, RPh
`Heidi Reidies, M.S.
`
`
`
`
`
`
`
`
`
`SUBJECT: Discussion of CAROLINA trial and PMR for a cardiovascular safety trial for
`linagliptin (NDA 201280)
`
`TELECONFERENCE:
`
`Reference ID: 2936739
`
`Page 1
`
`

`

`
`BI questioned why FDA was now requesting a placebo-controlled cardiovascular outcomes trial
`given FDA’s agreement in August 2010 for BI to conduct an active-controlled cardiovascular
`outcomes trial using glimepiride as comparator to satisfy the PMR.
`
`FDA stated that the cardiovascular safety of sulfonylureas is unknown, and showing non-
`inferiority, or even superiority, to a drug (glimepiride) that may have adverse cardiovascular
`risks would not establish that linagliptin does not cause cardiovascular events. Dr. Rosebraugh
`reviewed for BI the rationale behind the requirement for all new anti-diabetic therapies to
`establish that there is not a cardiovascular risk that is intrinsic to the agent itself and noted that all
`trials currently underway for anti-diabetic drugs as PMR commitments are placebo-controlled.
`Dr. Rosebraugh added that the CAROLINA trial would be of interest to the FDA and to
`clinicians as the cardiovascular safety of sulfonylurea agents has long been question. However,
`CAROLINA, would not answer the question that is the basis for the requirement of CV
`assessment which is does linagliptin itself carry a risk of cardiovascular harm, not whether it is
`comparable to another agent, particularly one with an unknown cardiovascular safety profile.
`
`BI argued that standard of care is frequently sulfonylureas. BI would not be able to incorporate a
`third placebo arm because the CAROLINA trial is already recruiting well, and because all
`patients are already on metformin therapy.
`
`FDA stated that BI will need to perform as a PMR a cardiovascular trial that will allow for a
`primary comparison of linagliptin cardiovascular safety to placebo in some form, either as an
`additional arm to CAROLINA or in an additional stand alone placebo-controlled trial.
`
`BI asked whether future meta-analysis of other ongoing and future trials, trying to combine those
`trials with placebo arms, would satisfy the CV-safety PMR, if it rules out the 1.3 risk threshold.
`Dr. Rosebraugh stated that he did not think this approach would answer the primary question
`outlined above.
`
`FDA stated that if the sponsor decided that incorporating a placebo arm into CAROLINA was
`not feasible at this time, that only a stand alone trial against placebo would satisfy the CV-safety
`PMR. FDA stated that they were still interested in the CAROLINA results, but again, even if
`linagliptin would show a non-inferior or superior CV-risk profile over glimepiride, there would
`still be doubts as to the cardiovascular safety of linagliptin compared to placebo.
`
`BI understood and committed to conducting a trial against placebo to satisfy the CV-safety PMR.
`BI provided the following tentative dates for the CV-safety PMR:
`
`
`
`
`
`Final Protocol Submission:
`Study Completion:
`
`Final Report Submission
`
`June 2012
`October 2018
`May 2019
`
`Reference ID: 2936739
`
`Page 2
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RAYMOND S CHIANG
`04/21/20