CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`205103Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`M E M O R A N D U M
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`DATE:
`
`TO:
`
`
`
`
`
`FROM:
`
`
`
`
`
`THROUGH:
`
`
`SUBJECT:
`
`August 19, 2016
`Donna Griebel, M.D
`Director
`Division of Gastroenterology and Inborn Errors
`Products, Office of Drug Evaluation III,
`Office of New Drugs
`Hasan A. Irier, Ph.D.
`Division of Generic Drug Bioequivalence Evaluation
`Office of Study Integrity and Surveillance
`Office of Translational Sciences
`
`Young Moon Choi, Ph.D.
`Deputy Director (Acting)
`Division of Generic Drug Bioequivalence Evaluation
`Office of Study Integrity and Surveillance
`Office of Translational Sciences
`
`for NDA 205103
`
`Summary:
`The Office of Study Integrity and Surveillance (OSIS) conducted an
`inspection of the bioanalytical portions of the PA8140-104 and
`PA32540-119 studies(under NDA 205103)
` Based on the inspection
`findings, OSIS recommends accepting the analytical data from the
`PA8140-104 and PA32540-119 studies for further Agency review.
`
`Studies Audited during this Inspection:
`
`Study number: PA8140-104 (NDA 205103)
`Study title: “A Single-Dose Randomized Crossover Study to Assess
`
`
`
`the Intrasubject Variability of Acetylsalicylic
`
`
`
`Acid from Administration of Three Tablets (Dosed
`
`
`
`Concurrently) of PA8140 and to Evaluate the
`
`
`
`Relative Bioavailability of Three Tablets (Dosed
`
`
`
`Concurrently) of Two Formulations of PA8140 with
`
`
`
`the Partial Reference-Replicated 3-Way Design and
`
`
`
`the Reference-Scaled Average Bioequivalence
`
`Reference ID: 3973507
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Page 2. Review of EIR
`
`
`
`
`Approach.”
`
`Sample Analysis: Analysis of human plasma samples began on 07
`
`
`
` January 2016 and was completed on 17 January
` 2016.
`
`Study number: PA32540-119 (NDA 205103)
`Study title: “A Single-Dose Randomized Crossover Study to Assess
`
`
`
`the Intrasubject Variability of Acetylsalicylic
`
`
`
`Acid from Administration of PA32540 and to Evaluate
`
`
`
`the Relative Bioavailability of Two Formulations of
`
`
`
`PA32540 with the Partial Reference-Replicated 3-Way
`
`
`
`Design and the Reference-Scaled Average
`
`
`
`
`Bioequivalence Approach.”
`
`Sample Analysis: Analysis of human plasma samples began on 22
`
`
`
` February 2016 and was completed on 07 March 2016
`
`
`OSIS scientist Hasan Irier, Ph.D. conducted an inspection of the
`bioanalytical portions of the studies specified above
` The audit covered the bioanalytical method validation
`and the PA8140-104 and PA32540-119 sample analyses for
`acetylsalicylic acid. The audit also included a thorough review
`of facilities, equipment, study records and correspondences, and
`interviews and discussions with
`management and staff. At the
`conclusion of the inspection, no Form FDA 483 observations were
`issued.
`
`
`Conclusion:
`
`
`Based on the inspectional fi
`bioanalytical study conduct
` this OSIS reviewer concluded that the data from the
`PA8140-104 and PA32540-119 studies are reliable. Therefore, OSIS
`recommends accepting the analytical portions of the PA8140-104 and
`PA32540-119 studies for further (FDA) Agency review.
`
`
`Hasan A. Irier, Ph.D.
`OSIS, DGDBE
`
`Final Site Classification:
`
`NAI –
`FEI:
`
`
`
`
`
`Reference ID: 3973507
`
`2
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Page 3. Review of EIR
`
`DARRTS CC:
`OTS/OSIS/Kassim/Taylor/Haidar/Turner-Rinehardt/Nkah/Fenty-Stewart
`OTS/OSIS/DGDBE/Cho/Skelly/Choi/Au/Irier
`OTS/OSIS/DNDBE/Bonapace/Dasgupta/Ayala/Biswas
`
`Draft: HAI 08/15/16,
`Edits: SA 08/15/16, YMC 08/17/16, HAI 8/19/16
`
`ECMS: Cabinets/CDER_OC/OSI/Division of Bioequivalence & Good
`Labora
`gram/ANALYTICAL
`SITES/
`
`
`OSI fil
`FACTS:
`
`
`38
`
`
`
`
`
`
`Reference ID: 3973507
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`HASAN A IRIER
`08/19/2016
`
`YOUNG M CHOI
`08/19/2016
`
`Reference ID: 3973507
`
`

`

`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.
`
`
`NDA/BLA #
`Product Name:
`
`PMR/PMC Description:
`
`205103
`Yosprala (aspirin/omeprazole)
`
`#3111-1 Conduct an in vitro study to characterize and quantify the
`degradants of immediate release omeprazole of Yosprala at various pHs (i.e.,
`pH 1, 1.5, 2, 2.5, 3, 3.5, 4) following a minimum of 1 hour of exposure at
`37°C, and evaluate the differences in the profiles across pHs. Submit the
`chromatograms and a summary of quantitative data generated during the
`study.
`
`
` 01/2017
` 04/2017
` 06/2017
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Study/Trial Completion:
`
`Final Report Submission:
`
`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
`
`
`
`
`The drug’s safety profile has been adequately assessed in the pre-approval program.
`
`However, because this product contains non-enteric coated omeprazole which may be unstable in acidic
`pH, there is residual uncertainty regarding potential omeprazole degradants in the acidic pH of the
`stomach. To address this residual uncertainty an in vitro study will be conducted to characterize and
`quantify the degradants of immediate release omeprazole of Yosprala at various pH ranges (i.e., pH 1, 1.5,
`2, 2.5, 3, 3.5, 4) following a minimum of 1 hour of exposure at 37°C and to evaluate the differences in the
`profiles across the pH range; the applicant should submit the chromatograms and summary of quantitative
`data generated in the study.
`
`
`
`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 9/14/2016
`
`Page 1 of 4
`
`Reference ID: 3985436
`
`

`

`See Response to 1 above.
`
`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.
`See response to 1 above.
`
`
`
`PMR/PMC Development Template
`
`Last Updated 9/14/2016
`
`Page 2 of 4
`
`Reference ID: 3985436
`
`

`

`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)
` 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
`Continuation of Question 4
`
`
` 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
`in vitro study to evaluate degradants that could be formed in vivo in gastric acid.
`
`
`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?
`
`
`
`
`
`
`
`
`
` Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial
`
`If so, does the clinical trial meet the following criteria?
`
` There is a significant question about the public health risks of an approved drug
` There is not enough existing information to assess these risks
` Information cannot be gained through a different kind of investigation
` The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and
` The trial will emphasize risk minimization for participants as the protocol is developed
`
`PMR/PMC Development Template
`
`Last Updated 9/14/2016
`
`Page 3 of 4
`
`Reference ID: 3985436
`
`

`

`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 9/14/2016
`
`Page 4 of 4
`
`Reference ID: 3985436
`
`

`

`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.
`
`
`NDA/BLA #
`Product Name:
`
`PMR/PMC Description:
`
`205103
`Yosprala (aspirin/omeprazole)
`
`#3111-2 Conduct a clinical PK study evaluating the systemic exposures of
`the omeprazole degradants that are shown to be present at a higher level at pH
`<3.0 compared to higher pHs in the in vitro studies (PMC #3111-1). This
` include both Yosprala and the reference product for the
`omeprazole component of Yosprala. Compare the individual omeprazole
`degradant exposures between the two products.
`
`
`
` 11/2017
` 03/2018
` 06/2018
`
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Study/Trial Completion:
`
`Final Report Submission:
`
`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
`
`
`
`
` The drug’s safety profile has been adequately assessed in the pre-approval program. However, because
`this product contains non-enteric coated omeprazole, which may be unstable in acidic pH, there is residual
`uncertainty regarding potential omeprazole degradants in the acidic pH of the stomach. To address this
`residual uncertainty, a clinical PK study will be conducted to evaluate the systemic exposures of
`degradants of non-enteric coated omeprazole of Yosprala and degradants of a reference enteric-coated
`omeprazole product that are shown to be present at higher level at pH <3.0 compared to pHs that exceed
`3.0 in the in vitro studies of Yosprala (see PMC #1 template for a discussion of the in vitro studies); the
`exposures associated with these specific omeprazole degradants will be compared between the two
`products.
`
`
`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 9/14/2016
`
`Page 1 of 4
`
`Reference ID: 3985436
`
`(b) (4)
`
`

`

`
`See Response to 1 above.
`
`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.
`See Response to 1 above.
`
`
`
`PMR/PMC Development Template
`
`Last Updated 9/14/2016
`
`Page 2 of 4
`
`Reference ID: 3985436
`
`

`

`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)
` 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
`Continuation of Question 4
`
`
` 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
`a clinical PK study
`
`
`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?
`
`
`
`
`
`
`
`
`
` Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial
`
`If so, does the clinical trial meet the following criteria?
`
` There is a significant question about the public health risks of an approved drug
` There is not enough existing information to assess these risks
` Information cannot be gained through a different kind of investigation
` The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and
` The trial will emphasize risk minimization for participants as the protocol is developed
`
`PMR/PMC Development Template
`
`Last Updated 9/14/2016
`
`Page 3 of 4
`
`Reference ID: 3985436
`
`

`

`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 9/14/2016
`
`Page 4 of 4
`
`Reference ID: 3985436
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MIMI T PHAN
`09/14/2016
`
`ANIL K RAJPAL
`09/14/2016
`
`Reference ID: 3985436
`
`

`

`505(b)(2) ASSESSMENT
`
`‘
`
`. lication Information
`
`NDA # 205103
`
`NDA Supplement #2 8-
`
`Efficacy Supplement Type SE-
`
`Proprietary Name: Yosprala
`Established/Proper Name: aspirin/omeprazole
`Dosage Form:
`tablets
`Stren hs: a irin 81 m-
`
`gastric ulcers.
`
`Date of Receipt: March 25. 2013; CR issued April 25, 2014; Resubmission Received June 30,
`2014: CR issued December 16. 2014; Resubmission Received on March 14. 2016.
`
`PDUFA Goal Date: September 14. 2016
`
`Action Goal Date (if different):
`
`Proposed Indication(s):
`Secondary prevention of cardiovascular and cerebrovascular events in patients at risk of
`developing aspirin associated gastric ulcers.
`Decreasing the risk of developing aspirin associated gastric ulcers in patients at risk for
`developing aspirin-associated gastric ulcers due to age (2 55) or documented history of
`
`GENERAL INFORMATION
`
`1)
`
`Is this application for a recombinant or biologically-derived product and/or protein or peptide
`product OR is the applicant relying on a recombinant or biologically-derived product and/or
`protein or peptide product to support approval of the proposed product?
`
`YES|:]
`
`NO®
`
`If “YES "contact the (b) (2) review staflin the Immediate Ofiice, Ofl‘ice ofNew Drugs.
`
`Reference ID: 3984971
`
`Page 1
`Version: Janumy 2015
`
`

`

`INFORMATION PROVIDED VIA RELIANCE
`(LISTED DRUG OR LITERATURE)
`
`Information relied-upon (e.g., specific
`sections of the application or labeling)
`
`
`2) List the information essential to the approval of the proposed drug that is provided by reliance
`on our previous finding of safety and efficacy for a listed drug by reliance on published
`literature, or by reliance on a final OTC monograph. (If not clearly identified by the
`applicant, this information can usually be derived from annotated labeling.)
`
`
`Source of information* (e.g.,
`published literature, name of listed
`drug(s), OTC final drug
`monograph)
`
`OTC Monograph for Aspirin (21 CFR
`343.80)
`
`
`NDA 019810 Prilosec (omeprazole)
`Capsules
`
`Nonclinical section 13
`Clinical Pharmacology sections 4, 7, 8, 12
`Clinical sections 5, 6, 8, 14
`
`
`
`Nonclinical section
`Clinical Pharmacology sections 7, 8, 12
`Clinical sections 5, 6, 8
`
`
` *each source of information should be listed on separate rows, however individual
`literature articles should not be listed separately
`
`
`3) The bridge in a 505(b)(2) application is information to demonstrate sufficient similarity
`between the proposed product and the listed drug(s) or to justify reliance on information
`described in published literature for approval of the 505(b)(2) product. Describe in detail how
`the applicant bridged the proposed product to the listed drug(s) and/or published literature1.
`See also Guidance for Industry Providing Clinical Evidence of Effectiveness for Human Drug
`and Biological Products.
`The bridging was established through bioequivalent (BE) study for aspirin component
`and relative bioavailability (BA) study for omeprazole component.
`
`
`
`
`RELIANCE ON PUBLISHED LITERATURE
`
`
`4) (a) Regardless of whether the applicant has explicitly stated a reliance on published literature
`to support their application, is reliance on published literature necessary to support the
`approval of the proposed drug product (i.e., the application cannot be approved as labeled
`without the published literature)?
`
` NO
`
` YES
`If “NO,” proceed to question #5.
`
`
`
`(b) Does any of the published literature necessary to support approval identify a specific (e.g.,
`brand name) listed drug product?
`
` NO
`
` YES
`If “NO”, proceed to question #5.
`If “YES”, list the listed drug(s) identified by name and answer question #4(c).
`
`
`1For 505(b)(2) applications that rely on a listed drug(s), bridging studies are often BA/BE studies comparing the proposed product to the listed drug(s) Other examples include: comparative
`physicochemical tests and bioassay; preclinical data (which may include bridging toxicology studies); pharmacokinetic/pharmacodynamic (PK/PD) data; and clinical data (which may
`include immunogenicity studies) A bridge may also be a scientific rationale that there is an adequate basis for reliance upon FDA’s finding of safety and effectiveness of the listed drug(s)
`For 505(b)(2) applications that rely upon literature, the bridge is an explanation of how the literature is scientifically sound and relevant to the approval of the proposed 505(b)(2) product
`
`Page 2
`
`Reference ID: 3984971
`
`Version: January 2015
`
`

`

`(c) Are the drug product(s) listed in (b) identified by the applicant as the listed drug(s)?
` YES
`
` NO
`
`
`
`1For 505(b)(2) applications that rely on a listed drug(s), bridging studies are often BA/BE studies comparing the proposed product to the listed drug(s) Other examples include: comparative
`physicochemical tests and bioassay; preclinical data (which may include bridging toxicology studies); pharmacokinetic/pharmacodynamic (PK/PD) data; and clinical data (which may
`include immunogenicity studies) A bridge may also be a scientific rationale that there is an adequate basis for reliance upon FDA’s finding of safety and effectiveness of the listed drug(s)
`For 505(b)(2) applications that rely upon literature, the bridge is an explanation of how the literature is scientifically sound and relevant to the approval of the proposed 505(b)(2) product
`
`Page 3
`
`Reference ID: 3984971
`
`Version: January 2015
`
`

`

`
`
`RELIANCE ON LISTED DRUG(S)
`
`Reliance on published literature which identifies a specific approved (listed) drug constitutes
`reliance on that listed drug. Please answer questions #5-9 accordingly.
`
`
`5) Regardless of whether the applicant has explicitly cited reliance on listed drug(s), does the
`application rely on the finding of safety and effectiveness for one or more listed drugs
`(approved drugs) to support the approval of the proposed drug product (i.e., the application
`cannot be approved without this reliance)?
` YES
`
` NO
`
`If “NO,” proceed to question #10.
`
`
`6) Name of listed drug(s) relied upon, and the NDA #(s). Please indicate if the applicant
`explicitly identified the product as being relied upon (see note below):
`
`
`Name of Listed Drug
`
`NDA #
`
`Did applicant
`specify reliance on
`the product? (Y/N)
`Y
`
`
`
`Prilosec (omeprazole)
`
`
`
`
`
`NDA 19810
`
`
`
`Applicants should specify reliance on the 356h, in the cover letter, and/or with their patent
`certification/statement. If you believe there is reliance on a listed product that has not been
`explicitly identified as such by the applicant, please contact the (b)(2) review staff in the
`Immediate Office, Office of New Drugs.
`
`
`7) If this is a (b)(2) supplement to an original (b)(2) application, does the supplement rely upon
`the same listed drug(s) as the original (b)(2) application?
`
` NO
`
` YES
` N/A
`If this application is a (b)(2) supplement to an original (b)(1) application or not a supplemental
`application, answer “N/A”.
`If “NO”, please contact the (b)(2) review staff in the Immediate Office, Office of New Drugs.
`
`
`8) Were any of the listed drug(s) relied upon for this application:
`a) Approved in a 505(b)(2) application?
`
` NO
`
` YES
`If “YES”, please list which drug(s).
`Name of drug(s) approved in a 505(b)(2) application:
`
`
`b) Approved by the DESI process?
`
` NO
`
` YES
`If “YES”, please list which drug(s).
`Name of drug(s) approved via the DESI process:
`
`c) Described in a final OTC drug monograph?
`
` NO
`
` YES
`If “YES”, please list which drug(s).
`
`
`
`
`
`
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`Version: January 2015
`
`Reference ID: 3984971
`
`

`

`Name of drug(s) described in a final OTC drug monograph: Ecotrin (aspirin)
`
`
`
`
`
`d) Discontinued from marketing?
`
` NO
`
` YES
`If “YES”, please list which drug(s) and answer question d) i. below.
`If “NO”, proceed to question #9.
`Name of drug(s) discontinued from marketing: Prilosec NDA 19810
`
`i) Were the products discontinued for reasons related to safety or effectiveness?
` YES
`
` NO
`(Information regarding whether a drug has been discontinued from marketing for
`reasons of safety or effectiveness may be available in the Orange Book. Refer to
`section 1.11 for an explanation, and section 6.1 for the list of discontinued drugs. If
`a determination of the reason for discontinuation has not been published in the
`Federal Register (and noted in the Orange Book), you will need to research the
`archive file and/or consult with the review team. Do not rely solely on any
`statements made by the sponsor.)
`
`9) Describe the change from the listed drug(s) relied upon to support this (b)(2) application (for
`example, “This application provides for a new indication, otitis media” or “This application
`provides for a change in dosage form, from capsule to solution”).
`
`This application provides for a new fixed-combination and indication, to decrease the risk of
`developing gastric ulcers in patients at risk for developing aspirin-associated gastric ulcers.
`
`
`
`The purpose of the following two questions is to determine if there is an approved drug product
`that is equivalent or very similar to the product proposed for approval that should be referenced
`as a listed drug in the pending application.
`
`The assessment of pharmaceutical equivalence for a recombinant or biologically-derived product
`and/or protein or peptide product is complex. If you answered YES to question #1, proceed to
`question #12; if you answered NO to question #1, proceed to question #10 below.
`
`10) (a) Is there a pharmaceutical equivalent(s) to the product proposed in the 505(b)(2)
`application that is already approved (via an NDA or ANDA)?
`
`
`
`
`
`
`
`
`(Pharmaceutical equivalents are drug products in identical dosage forms intended for the
`same route of administration that: (1) contain identical amounts of the identical active drug
`ingredient, i.e., the same salt or ester of the same therapeutic moiety, or, in the case of
`modified release dosage forms that require a reservoir or overage or such forms as prefilled
`syringes where residual volume may vary, that deliver identical amounts of the active drug
`ingredient over the identical dosing period; (2) do not necessarily contain the same inactive
`ingredients; and (3) meet the identical compendial or other applicable standard of identity,
`strength, quality, and purity, including potency and, where applicable, content uniformity,
`disintegration times, and/or dissolution rates. (21 CFR 320.1(c), FDA’s “Approved Drug
`Products with Therapeutic Equivalence Evaluations” (the Orange Book)).
`
`Note that for proposed combinations of one or more previously approved drugs, a pharmaceutical
`equivalent must also be a combination of the same drugs.
`
` YES
`
`
`
` NO
`
`
`
`
`
`
`
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`
`Reference ID: 3984971
`
`

`

`
`
` If “NO” to (a) proceed to question #11.
`If “YES” to (a), answer (b) and (c) then proceed to question #12.
`
`
`(b) Is the pharmaceutical equivalent approved for the same indication for which the
`505(b)(2) application is seeking approval?
` YES
`
`
` NO
`
`
`
`
`
`(c) Is the listed drug(s) referenced by the application a pharmaceutical equivalent?
` N/A
` YES
`
` NO
`
`If this application relies only on non product-specific published literature, answer “N/A”
`If “YES” to (c) and there are no additional pharmaceutical equivalents listed, proceed to
`question #12.
`If “NO” or if there are additional pharmaceutical equivalents that are not referenced by the
`application, list the NDA pharmaceutical equivalent(s);