CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`201280Orig1s000
`
`OTHER REVIEW(S)
`
`
`
`
`

`

`
`
`Attachment B: Sample PMR/PMC Development Template
`
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`
`PMR/PMC Description: An epidemiologic study to compare the risk of severe hypersensitivity and
`severe cutaneous reactions in type 2 diabetics exposed to linagliptin to the risk
`in type 2 diabetics exposed to other antidiabetic medications.
`
` 05/30/2012
` 11/30/2018
` 6/30/2019
`
`
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Study/Ttrial Completion:
`
`Final Report Submission:
`
`Other: NA
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
`
`
`Linagluptin is a dipeptidyl peptidase (DPP)-4 inhibitor. Severe hypersensitivity reactions have been
`reported in the postmarketing setting for sitagliptin and saxaglitpin, which are the only FDA-
`approved DPP-4 inhibitors. Some hypersensitivity reactions occurred in the linagliptin clinical
`development program. There were two cases of angioedema in patients on linagliptin; one of these
`was considered a serious adverse event. There were three cases of skin exfoliation that were
`considered possibly associated with linagliptin therapy; none was serious. Overall, the incidence of
`severe hypersensitivity reactions with linagliptin (if such an association exists) appears to be rare,
`but this study will help characterize this potential risk.
`
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is
`a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new
`safety information.”
`
`See response under Question 1. The goal of the epidemiological study is to compare the risk of
`severe hypersensitivity reactions and severe cutaneous reactions among type 2 diabetics exposed to
`linagliptin to those exposed to other antidiabetic medications.
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 5/1/2011
`
`Page 1 of 3
`
`Reference ID: 2940496
`
`

`

`
`3. If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`- Which regulation?
` Accelerated Approval (subpart H/E)
` Animal Efficacy Rule
` Pediatric Research Equity Act
` FDAAA required safety study/clinical trial
`
`
`
`- If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
` Assess a known serious risk related to the use of the drug?
` Assess signals of serious risk related to the use of the drug?
` Identify an unexpected serious risk when available data indicate the potential for a serious
`risk?
`
`
`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
` Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to
`assess or identify a serious risk
`
`
`
` Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the
`FDA is required to establish under section 505(k)(3) has not yet been established and is thus
`not sufficient to assess this known serious risk, or has been established but is nevertheless not
`sufficient to assess or identify a serious risk
`
` Study: all other investigations, such as investigations in humans that are not clinical trials as
`defined below (e.g., observational epidemiologic studies), animal studies, and laboratory
`experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a
`serious risk
`
`
`
`
`
` Clinical trial: any prospective investigation in which the sponsor or investigator determines
`the method of assigning investigational product or other interventions to one or more human
`subjects?
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the
`study or trial will be performed in a subpopulation, list here.
` Risk of severe hypersensitivity reactions and severe cutaneous reactions.
`
`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
` Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 5/1/2011
`
`Page 2 of 3
`
`Reference ID: 2940496
`
`

`

`
`
`
`
`Continuation of Question 4
`
`
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
` Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation)
`
`
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition,
`different disease severity, or subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify)
`
` Other
`
`
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
` Does the study/clinical trial meet criteria for PMRs or PMCs?
` Are the objectives clear from the description of the PMR/PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process?
`
`
`PMR/PMC Development Coordinator:
` This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine
`the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug
`quality.
`
`
`_______________________________________
`(signature line for BLAs)
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 5/1/2011
`
`Page 3 of 3
`
`Reference ID: 2940496
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`AMY G EGAN
`05/01/2011
`
`Reference ID: 2940496
`
`

`

`FOOD AND DRUG ADMINISTRATION
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`
`****Pre-decisional Agency Information****
`
`
`
`
`
`Memorandum
`
`Date:
`
`April 26, 2011
`
`
`To:
`
`
`
`
`From:
`
`Raymond Chiang, Regulatory Project Manager
`Division of Metabolism and Endocrinology Products (DMEP)
`
`Samuel Skariah, Regulatory Review Officer
`Division of Drug Marketing, Advertising, and Communications (DDMAC)
`
`NDA 201280 TRADENAME (linagliptin) Tablets
`
`DDMAC’s review of the carton container labeling for TRADENAME (linagliptin)
`
`
`
`DDMAC has reviewed the proposed carton and container labeling for TRADENAME (linagliptin)
`submitted on March 17, 2011 and the blister labels submitted on March 25, 2011. DDMAC does
`not have any comments at this time.
`
`Thank you for the opportunity to comment on these proposed materials. If you have any
`questions please contact Samuel Skariah at 301. 796. 2774 or Sam.Skariah@fda.hhs.gov.
`
`
`
`
`
`Subject:
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 2938383
`
`1
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SAMUEL M SKARIAH
`04/26/2011
`
`Reference ID: 2938383
`
`

`

`PMR/PMC Development Template
`
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`
`PMR/PMC Description: A clinical pharmacology study in pediatric patients with type 2 diabetes to
`determine doses for the subsequent phase 3b study that will be conducted
`under Pediatric Research Equity Act (PREA) to evaluate the efficacy and
`safety of linagliptin for the treatment of type 2 diabetes mellitus in pediatric
`patients ages 10 to 16 years (inclusive)
`
` 11/30/2011
` 02/28/2014
` 08/31/2014
`
`
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Study/Trial Completion:
`
`Final Report Submission:
`
`Other: N/A
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
`
`
`Linagliptin is ready for approval for use in adults. However, the pediatric studies have not been
`completed.
`
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is
`a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new
`safety information.”
`
`Deferred pediatric study required under PREA in pediatric patients ages 10 to 16 years (inclusive)
`with type 2 diabetes.
`
`PMR/PMC Development Template
`
`Last Updated 4/25/2011
`
`Page 1 of 3
`
`Reference ID: 2938032
`
`

`

`
`
`3. If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`- Which regulation?
` Accelerated Approval (subpart H/E)
` Animal Efficacy Rule
` Pediatric Research Equity Act
` FDAAA required safety study/clinical trial
`- If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
` Assess a known serious risk related to the use of the drug?
` Assess signals of serious risk related to the use of the drug?
` Identify an unexpected serious risk when available data indicate the potential for a serious
`risk?
`
`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
` Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to
`assess or identify a serious risk
`
`
`
` Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the
`FDA is required to establish under section 505(k)(3) has not yet been established and is thus
`not sufficient to assess this known serious risk, or has been established but is nevertheless not
`sufficient to assess or identify a serious risk
`
` Study: all other investigations, such as investigations in humans that are not clinical trials as
`defined below (e.g., observational epidemiologic studies), animal studies, and laboratory
`experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a
`serious risk
`
`
`
`
`
` Clinical trial: any prospective investigation in which the sponsor or investigator determines
`the method of assigning investigational product or other interventions to one or more human
`subjects?
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the
`study or trial will be performed in a subpopulation, list here.
`A phase 1 pharmacokinetic dose finding study of linagliptin in pediatric patients ages 10 to 16
`years (inclusive).
`
`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
` Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
`
`PMR/PMC Development Template
`
`Last Updated 4/25/2011
`
`Page 2 of 3
`
`Reference ID: 2938032
`
`

`

`Continuation of Question 4
`
`
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
` Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation)
`Subpopulation: Pediatric patients ages 10-16 years (inclusive) with type 2 diabetes mellitus
`
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition,
`different disease severity, or subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify)
`
` Other
`
`
`
`
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
` Does the study/clinical trial meet criteria for PMRs or PMCs?
` Are the objectives clear from the description of the PMR/PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process?
`
`
`PMR/PMC Development Coordinator:
` This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine
`the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug
`quality.
`
`
`_______________________________________
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 4/25/2011
`
`Page 3 of 3
`
`Reference ID: 2938032
`
`

`

`PMR/PMC Development Template
`
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`
`PMR/PMC Description: Deferred randomized and controlled pediatric study under Pediatric Research
`Equity Act (PREA) to evaluate the efficacy and safety of linagliptin for the
`treatment of type 2 diabetes mellitus in pediatric patients ages 10 to 16 years
`(inclusive).
`
` 06/30/2014
` 03/31/2017
` 09/30/2017
`
`
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Study/Trial Completion:
`
`Final Report Submission:
`
`Other: N/A
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
`
`
`Linagliptin is ready for approval for use in adults. However, the pediatric studies have not been
`completed.
`
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is
`a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new
`safety information.”
`
`Deferred pediatric study required under PREA in pediatric patients ages 10 to 16 years (inclusive)
`with type 2 diabetes. The goal of the trial is to establish the safety and efficacy of linagliptin in this
`subpopulation.
`
`PMR/PMC Development Template
`
`Last Updated 4/25/2011
`
`Page 1 of 3
`
`Reference ID: 2938032
`
`

`

`
`
`3. If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`- Which regulation?
` Accelerated Approval (subpart H/E)
` Animal Efficacy Rule
` Pediatric Research Equity Act
` FDAAA required safety study/clinical trial
`- If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
` Assess a known serious risk related to the use of the drug?
` Assess signals of serious risk related to the use of the drug?
` Identify an unexpected serious risk when available data indicate the potential for a serious
`risk?
`
`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
` Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to
`assess or identify a serious risk
`
`
`
` Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the
`FDA is required to establish under section 505(k)(3) has not yet been established and is thus
`not sufficient to assess this known serious risk, or has been established but is nevertheless not
`sufficient to assess or identify a serious risk
`
` Study: all other investigations, such as investigations in humans that are not clinical trials as
`defined below (e.g., observational epidemiologic studies), animal studies, and laboratory
`experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a
`serious risk
`
`
`
`
`
` Clinical trial: any prospective investigation in which the sponsor or investigator determines
`the method of assigning investigational product or other interventions to one or more human
`subjects?
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the
`study or trial will be performed in a subpopulation, list here.
`A randomized, double-blind, placebo-controlled and active-controlled clinical trial evaluating the
`efficacy, safety and pharmacokinetics of linagliptin in pediatric patients ages 10 to 16 years
`(inclusive). Treatment-naïve patients will be randomized to treatment with linagliptin, metformin
`and placebo in a 2:1:1 ratio (monotherapy setting). Patients inadequately controlled with metformin
`will be randomized to linagliptin or placebo (add-on to metformin setting). In the monotherapy
`setting, after an initial 12-week treatment period, patients treated with placebo will be randomized
`to treatment with linagliptin or metformin in a 2:1 ratio for 40 weeks. In the add-on to metformin
`setting, patients will be studied for 52 weeks, with the primary efficacy endpoint assessed at week
`12.
`
`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
`
`PMR/PMC Development Template
`
`Last Updated 4/25/2011
`
`Page 2 of 3
`
`Reference ID: 2938032
`
`

`

` Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
`Continuation of Question 4
`
`
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
` Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation)
`Subpopulation: Pediatric patients ages 10-16 years (inclusive) with type 2 diabetes mellitus
`
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition,
`different disease severity, or subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify)
`
` Other
`
`
`
`
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
` Does the study/clinical trial meet criteria for PMRs or PMCs?
` Are the objectives clear from the description of the PMR/PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process?
`
`
`PMR/PMC Development Coordinator:
` This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine
`the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug
`quality.
`
`
`_______________________________________
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 4/25/2011
`
`Page 3 of 3
`
`Reference ID: 2938032
`
`

`

`PMR/PMC Development Template
`
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`
`PMR/PMC Description: A randomized, double-blind, placebo-controlled trial evaluating the
`effect of linagliptin on the incidence of major adverse cardiovascular
`events in patients with type 2 diabetes mellitus. Secondary objectives
`must include an assessment of the long-term effects of linagliptin on
`immunological reactions, hypersensitivity reactions, neoplasms, serious
`hypoglycemia, pancreatitis, and renal safety.
`
` 06/30/2012
` 10/31/2018
` 05/31/2019
`
`
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Study/Trial Completion:
`
`Final Report Submission:
`
`Other: N/A
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
`
`
`Meta-analysis of the combined Phase 2 and Phase 3 premarketing clinical trials of linagliptin did not
`demonstrate an overall increased risk of major adverse cardiovascular events (MACE). However,
`the population studied had low baseline cardiovascular risk; few MACE occurred; the events were
`predominantly from the active control study; and the duration of blinded controlled study was not
`sufficient to address the risk definitively.
`
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is
`a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new
`safety information.”
`
`PMR/PMC Development Template
`
`Last Updated 4/21/11
`
`Page 1 of 4
`
`Reference ID: 2938032
`
`

`

`To support approvability and continued marketing, sponsors of unapproved drugs and biologics
`developed for the treatment of type 2 diabetes mellitus should provide evidence that these therapies
`do not result in an unacceptable increase in cardiovascular risk as recommended in the 2008
`Guidance to Industry entitled "Diabetes Mellitus - Evaluating Cardiovascular Risk in New
`Antidiabetic Therapies to Treat Type 2 Diabetes." This trial is intended to demonstrate that
`linagliptin does not increase the risk of major adverse cardiovascular events (myocardial infarction,
`stroke or cardiovascular death).
`
`The sponsor has already provided sufficient evidence that linagliptin does not unacceptably increase
`cardiovascular risk to support marketing, but has not definitively excluded unacceptable
`cardiovascular risk to a magnitude needed for approved antidiabetic products. Therefore, consistent
`with the above guidance, the primary objective of the required postmarketing trial is to establish that
`the upper bound of the 2-sided 95% confidence interval for the estimated risk ratio comparing the
`incidence of major adverse cardiovascular events observed with linagliptin to that observed in the
`control group is less than 1.3.
`
`Secondary objectives and adverse events of interest will include an assessment of the long-term
`effects of linagliptin on pancreatitis, renal safety, serious hypoglycemia, immunological reactions,
`and neoplasms. These are adverse events of interest based on data from clinical trials with
`linagliptin or other pharmacologically related products.
`
`
`
`3. If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`- Which regulation?
` Accelerated Approval (subpart H/E)
` Animal Efficacy Rule
` Pediatric Research Equity Act
` FDAAA required safety study/clinical trial
`- If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
` Assess a known serious risk related to the use of the drug?
` Assess signals of serious risk related to the use of the drug?
` Identify an unexpected serious risk when available data indicate the potential for a serious
`risk?
`
`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
` Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to
`assess or identify a serious risk
`
`
`
`
`
` Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the
`FDA is required to establish under section 505(k)(3) has not yet been established and is thus
`not sufficient to assess this known serious risk, or has been established but is nevertheless not
`sufficient to assess or identify a serious risk
`
`PMR/PMC Development Template
`
`Last Updated 4/21/11
`
`Page 2 of 4
`
`Reference ID: 2938032
`
`

`

` Study: all other investigations, such as investigations in humans that are not clinical trials as
`defined below (e.g., observational epidemiologic studies), animal studies, and laboratory
`experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a
`serious risk
`
`
`
` Clinical trial: any prospective investigation in which the sponsor or investigator determines
`the method of assigning investigational product or other interventions to one or more human
`subjects?
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the
`study or trial will be performed in a subpopulation, list here.
`A randomized, double-blinded, placebo-controlled cardiovascular outcomes trial to be conducted in
`patients with type 2 diabetes and increased cardiovascular risk. The primary endpoint will be the
`first occurrence of cardiovascular death, nonfatal myocardial infarction or stroke. Hospitalization
`for unstable angina will also be accepted as part of the endpoint. The trial will be event-driven,
`continuing until a sufficient number of events from the primary endpoint composite have occurred,
`in order for the trial to have adequate power to rule out an increase in risk of 30% for the primary
`endpoint. The trial will also have a minimum duration of follow-up of 400 weeks after
`randomization for each patient.
`
`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
` Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
`Continuation of Question 4
`
`
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
` Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation)
`
`
`
`
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition,
`different disease severity, or subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify)
`
`
`PMR/PMC Development Template
`
`Last Updated 4/21/11
`
`Page 3 of 4
`
`Reference ID: 2938032
`
`

`

` Other
`
`
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
` Does the study/clinical trial meet criteria for PMRs or PMCs?
` Are the objectives clear from the description of the PMR/PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process?
`
`
`PMR/PMC Development Coordinator:
` This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine
`the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug
`quality.
`
`
`_______________________________________
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 4/21/11
`
`Page 4 of 4
`
`Reference ID: 2938032
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`AMY G EGAN
`04/25/2011
`
`Reference ID: 2938032
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`
`
`Date:
`
`To:
`
`Through:
`
`April 4, 2011
`
`Mary Parks, MD, Director
`Division of Metabolism and Endocrinology
`
`Zachary Oleszczuk, Pharm.D., Team Leader
`Carol Holquist, RPh, Director
`Division of Medication Error Prevention and Analysis (DMEPA)
`
`Manizheh Siahpoushan, Pharm.D., Safety Evaluator
`Division of Medication Error Prevention and Analysis (DMEPA)
`
`Addendum to February 14, 2011 Label and Labeling Review
`
`Linagliptin Tablets, 5 mg
`
`Application Type/Number: NDA 201280
`
`Boehringer Ingelheim Pharmaceuticals, Inc.
`
`2010-2474-1
`
`
`From:
`
`Subject:
`
`Drug Name(s):
`
`Applicant:
`
`OSE RCM #:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 2927430
`
`

`

`1
`INTRODUCTION
`This review summarizes DMEPA’s evaluation of the revised blister labels submitted on
`March 25, 2011. The revisions were made in response to recommendations from DMEPA via
`email on March 17, 2011 (see Appendix A).
`
`2 METHODS AND MATERIALS
`DMEPA evaluated the revised sample blister labels (see Appendix B) for Linagliptin Tablets, 5
`mg using Failure Mode and Effects Analysis (FMEA), principles of human factors, and lessons
`learned from the post marketing experience to identify areas that can contribute to medication
`errors. Additionally, we evaluated the blisters to ensure DMEPA’s recommendations have been
`implemented.
`
`3 CONCLUSION
`DMEPA finds the new sample blister labels acceptable and we have no additional comments. If
`you have any further questions or need clarifications on this review, please contact the OSE
`Project Manager Margarita Tossa at 301-796-4053.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 2927430
`
`2
`
`

`

`Appendix A: Email Communications
`RE: C